text stringlengths 12 4.76M | timestamp stringlengths 26 26 | url stringlengths 32 32 |
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A typical fluorescent tube lamp socket (commonly referred to in the art as a tombstone socket or simply a tombstone) is adapted to receive the one or more pins traditionally located on the end caps of a fluorescent lamp. The tombstone provides electricity to the lamp as well as mechanical support for the lamp. A tombstone is sometimes a removable part of a larger system (e.g., fluorescent lamp fixture, display case, refrigeration case, etc.) and is sometimes integral with the larger system. | 2024-04-14T01:26:51.906118 | https://example.com/article/6599 |
GOSSIP: Charlie Sheen’s Lawyer finally reveals when we will return to Two And A Half Men
The actor’s attorney, Yale Galanter, finally revealed that the actor will be returning to the set of Two and a Half Men before the end of the month.
“We are thinking Charlie will be going back to work two weeks from today,” he said.
Galanter refused to comment on Sheen’s current rehab whereabouts, but he did say, “Charlie is fine healthwise and doing really well. Things are looking good. Everybody’s intentions are to get him back in the swing of things as soon as possible.
And despite recent troubles, Sheen’s family is sticking by him.
“They are a very close-knit family,” Galanter tells E! News. “Charlie has seen all of his kids since he was in the hospital. He is even spending time with the boys today.”
Last week, after sending a text to us denouncing stories about his party habits as “all crap,” Sheen sent a more restrained message via his publicist, Stan Rosenfield.
“I have a lot of work to do to be able to return the support I have received from so many people. I want to say ‘thank you’ to my fellow cast members, the crew of Two and a Half Men, and everyone at CBS and Warner Bros…And to my fans, your good wishes have touched me very much. Like Errol Flynn, who had to put down his sword on occasion, I just want to say, ‘thank-you.’ ” | 2023-12-06T01:26:51.906118 | https://example.com/article/4208 |
1 The One Condition
2 Back Of A Taxi
3 Business French Kiss
4 How To Deconstruct
5 Unusable Signal
6 Pollution Of Nonsense
7 Columnist
8 You Are Being Videotaped
9 Census
10 Excommunication List
11 The Comfort System
12 Easy Assault | 2024-05-18T01:26:51.906118 | https://example.com/article/1727 |
Orthodox Church in America Archdiocese of Canada
The Archdiocese of Canada is a diocese of the Orthodox Church in America (OCA). Its territory includes parishes, monasteries, and missions located in nine provinces and territories in Canada—Alberta, British Columbia, Manitoba, Newfoundland, Nova Scotia, Ontario, Quebec, Saskatchewan, and Yukon. The diocesan center is located in Rawdon, Quebec.
The Archdiocese of Canada is the descendant in Canada of the Orthodox mission of the Russian Empire in North America. The diocese was founded and incorporated by Saint Tikhon, Patriarch of Moscow and all Rus, in 1903.
Seraphim (Storheim) was consecrated auxiliary bishop of Edmonton in 1987, and became ruling bishop of the archdiocese of Canada in 1990. He was elevated to Archbishop during the Spring Holy Synod meeting in March 2007.
On April 2, 2009, the Holy Synod of the Orthodox Church in America, elevated Higoumène Irénée (Rochon) to the rank of Archimandrite, and elected him to be Auxiliary Bishop for Archbishop Seraphim of Ottawa and Canada, with the title of Bishop of Québec City. On October 21, 2014, the Holy Synod of Bishops of the Orthodox Church in America elected Bishop Irénée as Bishop of Ottawa and the Archdiocese of Canada. On March 20, 2015, during the Spring Session of the Holy Synod of Bishops of the Orthodox Church in America, Bishop Irénée was elevated to the rank of Archbishop of Ottawa and the Archdiocese of Canada.
Deaneries
The diocese is grouped geographically into five deaneries, each consisting of a number of parishes. Each deanery is headed by a parish priest, known as a dean. The deans coordinate activities in their area's parishes, and report to the diocesan bishop. the deaneries of the Archdiocese of Canada were:
Alberta and Northwest Territories Deanery
British Columbia and Yukon Deanery
Manitoba, Saskatchewan and Nunavut Deanery
Ontario Deanery
Quebec & Atlantic Provinces Deanery
External links
Canada
Category:Eastern Orthodox dioceses in Canada | 2024-01-19T01:26:51.906118 | https://example.com/article/6477 |
Q:
Setting up a grid to carousel?
Alright everyone, I'm sure this is a relatively simple thing, but I'm on the verge of tearing my hair out.
What I'm trying to accomplish is setting up images to appear in a grid, that when clicked pulls up a gallery/carousel, allowing you to scroll through the images there as well.
I've downloaded the slick modules, and correct dependencies. I also have bootstrap correctly set up as well. Honestly if you have an alternative your prefer more, please let me know.
https://www.drupal.org/project/slick
-https://github.com/kenwheeler/slick/
-https://github.com/gdsmith/jquery.easing
https://www.drupal.org/project/slick_media
https://www.drupal.org/project/media_entity_image
https://www.drupal.org/project/video_embed_field
https://www.drupal.org/project/blazy
Drupal 8
A:
I prefer the Lightgallery module which is available for Drupal 7 and Drupal 8 also. It integrates the lightGallery jquery plugin into Drupal. This is compatible with Views and it also provides an image field formatter.
You can see demos for the lightGallery jquery plugin here.
| 2024-05-31T01:26:51.906118 | https://example.com/article/3101 |
The Venezuelan government launched the pre-sale of the world’s first national, oil-backed cryptocurrency Petro (PTR), Financial Times reports Tuesday, Feb. 20.
82.4 million Petros are already available for purchase for fiat currencies and top cryptocurrencies, although not for Venezuelan Bolivars.
The government intends to attract foreign investors from countries like Poland, Denmark and Norway, as well as skirt the US and EU sanctions, according to Venezuela’s Minister of Foreign Trade and International Investment José Vielma Mora.
Previously, President Nicolas Maduro had ordered the issue of 100 million Petros with the value of a single barrel of oil each. The president hopes to raise a total of just over $6 billion via the sale of PTR.
To buy and trade in Petro, investors need to download a digital Petro wallet, developed by the Venezuelan government. Once acquired it will generate an address you can provide to anybody who wants to transfer PTR to you.
The catastrophic drop in the value of the Bolivar made the country’s government search for alternative ways to save the economy from a meltdown. In the last 12 months, the inflation in Venezuela totaled 4,115 percent and the Bolivar lost up to 96 percent of its value, which sent the country's economy into a downward spiral.
What do you think? Will Venezuela be able to outperform the entire ICO market of 2017 by securing $6 bln during the sale of Petro?
#CT_questions ? Venezuela has officially launched the pre-sale of its #Petro cryptocurrency, first such issuance done by a government. The value of all tokens is equal to $6 bln, more than all 2017 #ICOs combined.
Will Venezuela manage to collect such a massive sum? — Cointelegraph — Bitcoin and Cryptocurrency News (@Cointelegraph) February 20, 2018
Ana Heide | 2024-04-20T01:26:51.906118 | https://example.com/article/9033 |
include $(IMAGINE_PATH)/make/config.mk
include $(buildSysPath)/macOSX-gcc.mk
ARCH := x86
CPPFLAGS += -arch i386
LDFLAGS_SYSTEM += -arch i386
PKG_CONFIG_PATH := $(PKG_CONFIG_PATH):$(macportsPkgconfigPath)
| 2024-03-10T01:26:51.906118 | https://example.com/article/5514 |
Bob – Santa Cruz Patient of Dr. Robert Matiasevich
I’ve been coming here since probably about 1973.
I’ve been coming here since probably about 1973 and I essentially transferred from Bob Senior to Bob Junior without any blip at all and was pleased to find out that Bob Junior was at least as good as his dad, if not better as a dentist. He had the advantage actually of bringing with him I think the latest work in dentistry because he was new out of school. The office kept its same demeanor and professionalism that it always had so rather than worrying that, “Oh my God, I’ve got the junior,” I turned out to be very pleased and it was fortunate that he was here.
My experience here is that I’ve never had any reason to be fearful so why would you have when you come in, and secondly I think it’s probably just the way the office is even set up, so if you go to some dentists they have these big orgasmic chairs with all the tubes and everything. When you come here, you’re on a chaise lounge and you see none of the equipment. I don’t know if Dr. Matiasevich does it on purpose or it just works out, but he keeps all the equipment behind you so it’s not one of these things where you’re sitting there for ten minutes staring at this gigantic needle that they’re going to put in you, which would cause you to have anxiety. He just comes in from behind and it’s done.
I must say I think the other thing is that I never know with Bob Junior how many other people he’s working on. There may be somebody else, I never know, but you never have the feeling like when I originally came here and went to a dentist and I knew there were other people and he had me sitting there with my mouth open while he rushed over somewhere else and drilled somebody else and then came back to me. If that happens here I’m totally unaware of it. I see myself while I’m sitting in there as his main focus.
The teeth cleaning, she’s very thorough and she also pays attention to my general gum health and the health of my teeth so it’s a rather positive atmosphere as they give me suggestions as to how I ought to do things better. At one level they’re particularly good and that is occasionally the insurance company is hesitant about paying their share, and the way it works here they follow up.
Meet Dr. Matiasevich, DDS
As a second-generation dentist, Dr. Matiasevich was raised in Santa Cruz. Dr. Matiasevich completed his undergraduate work in economics at the University of California Irvine and then attended the University of Southern California for his dental degree. | 2023-09-16T01:26:51.906118 | https://example.com/article/1064 |
This image shows exactly what most of the universe will look like — on a 1:1 scale, or many other scales — as soon as the long Black Hole Era has begun, so this is the view, sometime after 1040 years have passed since the Big Bang. This is such a long time that it means essentially the same thing as “1040 years from now,” the mere ~1010 years between the beginning of time, and now, fading into insignificance by comparison, not even close to a visible slice of a city-wide pie chart.
This isn’t just after the last star has stopped burning, but also after the last stellar remnant (such as white dwarfs and neutron stars), other than black holes, is gone, which takes many orders of magnitude more time. What is left, in the dark, by this point? A few photons (mostly radio waves), as well as some electrons and positrons — and lots — lots — of neutrinos and antineutrinos. There are also absurd numbers of black holes; their mass dominates the mass of the universe during this time, but slowly diminishes via Hawking radiation, with this decay happening glacially for large black holes, and rapidly for small ones, culminating in a micro-black-hole’s final explosion. Will there be any baryonic matter at all? The unanswered question of the long-term stability of the proton creates uncertainty here, but there will, at minimum, be at least be some protons and neutrons generated, each time a micro-black-hole explodes itself away.
Things stay like this until the last black hole in the cosmos finally evaporates away, perhaps a googol years from now. That isn’t the end of time, but it does make things less interesting, subtracting black holes, and their Hawking radiation, from the mix. It’s still dark, but now even the last of the flashes from a tiny, evaporating black hole has stopped interrupting the darkness, so then, after that . . . nothing does. The universe continues to expand, forever, but the bigger it becomes, the less likely anything complex, and therefore interesting, could possibly have survived the eons intact.
—
For more on the late stages of the universe, please visit this Wikipedea article, upon which some of the above draws, and the sources cited there.
If inflation moves point A so far from point B right after the Big Bang that you can’t get to A from B now, then could the matter and energy in all the parts of the universe that we can’t access (because they’re too far away) provide the missing 90+% of the universe that we can’t account for? | 2024-04-26T01:26:51.906118 | https://example.com/article/8313 |
LEGEND TUFF™. Designed for those who demand comfort & durability. Our Unisex LEGENDARY Compression Hike/Outdoor Socks provide the ideal blend of comfort and performance for the avid outdoor adventurer. Cushion on the sole and shin along with our seamless toe construction make these socks extremely comfortable in any hiking shoe. With graduated compression technology, these unique mid-calf compression hiking socks provide improved blood flow and circulation that will combat tired and achy feet. Our soft merino wool fabric is moisture wicking, odor resistant and temperature regulating providing you the perfect sock to explore the great outdoors. Proudly Made in the USA | 2023-08-11T01:26:51.906118 | https://example.com/article/3155 |
OUAGADOUGOU/TORONTO (Reuters) - A Canadian kidnapped this week in a restive region of Burkina Faso has been found dead, a spokesman for the security ministry said on Thursday, drawing condemnation from the foreign ministers of Canada and Burkina Faso.
Kirk Woodman was abducted on Tuesday night by a dozen gunmen on a mining site owned by Vancouver-based Progress Minerals in the northeast near the border with Niger, an area that the government says is under growing threat from armed jihadists. Woodman was an employee of the company.
“It’s the Canadian that was found last night in the province of Oudalan,” spokesman Jean Paul Badoum said.
“Canada condemns those responsible for this terrible crime,” Canadian Foreign Minister Chrystia Freeland said in a statement. “We are working with the government of Burkina Faso and other international partners to pursue those responsible and bring them to justice.”
Progress Minerals said in a Thursday statement the company is “heartbroken” by Woodman’s death.
“Kirk was an incredibly accomplished and highly respected geologist with a career spanning over 30 years, with 20 years spent in West Africa. More importantly, Kirk was a kind person, a dedicated father and husband and considered a friend by all who knew him,” reads a quote attributed to Progress CEO Adam Spencer.
Burkina Faso Foreign Minister Alpha Barry offered his condolences, condemned the killing and said there will be an investigation to find and punish those responsible.
Barry said in a statement Woodman’s body was found on Wednesday afternoon in the district of Gorom Gorom and was subsequently identified by colleagues.
The death will fan concerns that the influence of violent groups with links to al Qaeda and Islamic State has spread uncontested into Burkina from neighboring Mali and Niger.
Attacks by Islamist militants have surged in the West African country in recent months. A state of emergency in several northern provinces has been in effect since Dec. 31.
“Kirk was a loving and hardworking husband, father, son and brother.” his son Matt Woodman said in a statement to Reuters. “Not a day will go by that he won’t be missed,” the statement added.
Earlier this month a Canadian woman and an Italian man went missing in Burkina Faso, the security minister said. There has been no word since then on their fate.
Security has deteriorated over the last few years across the remote and arid Sahel region just south of the Sahara Desert. In response, the United States, France and other European powers have sent troops and equipment to help stamp out the threat.
Tuesday’s kidnapping occurred on the third anniversary of an attack at a hotel in the center of the capital, Ouagadougou, that killed dozens, shocking a country that until then had largely been spared the violence that plagued its neighbors.
That attack was claimed by Al Qaeda in the Islamic Maghreb. | 2024-06-01T01:26:51.906118 | https://example.com/article/9086 |
Effect of high dosage of methylprednisolone on rat retinal ganglion cell apoptosis after optic nerve crush.
To investigate the effect of high dose methylprednisolone (MP) on retinal ganglion cells (RGC) apoptosis. One hundred and twenty six Wistar rats were divided into normal control, crush control and MP treatment groups. High dose MP and 0.9% sodium chloride were injected intravenously at 1 h after injury in the treatment group and crush control group, respectively. Apoptotic cells, Bcl-2 and Bax positive cells were located and calculated by terminal-deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL), immunohistochemical method and retinal whole-mount combined with section technique at day 4, 7, 14 after crush, respectively. The TUNEL-labeling cells, Bcl-2 and Bax positive cells were detected in the ganglion cell layer of retina. Few apoptotic cells, a few of Bcl-2 and Bax positive cells were observed in normal control groups. The numbers of positive cells increased gradually after crush. The number of apoptotic cells and Bax positive tells in treatment groups was less than that in crush group significantly (P < 0.05), while the number of Bcl-2 positive cells in treatment group was more than that in crush group at day 4, 7 and 14 after crush significantly (P < 0.05). These results suggest that high dose MP can inhibit the apoptosis of RGC after optic nerve crush probably through up-regulation of Bcl-2 expression and down-regulation of Bax expression. | 2023-12-15T01:26:51.906118 | https://example.com/article/3422 |
BROOKLYN, N.Y. — It was telling that Anthony Beauvillier wasn’t talking about the beauty of his three goals, his first NHL hat trick that included two nicely placed tips from in front of Henrik Lundqvist and one breakaway goal on Thursday night here.
He instead talked about what made his four-point night happen after going the first 17 games of the season with a single point. “I got to play with Leo and Fil,” Beauvillier said of Leo Komarov and Valtteri Filppula, the two throwback 30-something forwards. “We got some grit in our game, we were hard to play against.”
That is Barry Trotz’s anti-modernist mantra with this Islanders team that now sits an eyebrow-raising 10-6-2 after Thursday’s sloppy win over the Rangers. The work is the thing for the Islanders, not the skill; that’s how Beauvillier ended up with a hat trick and Mathew Barzal ended up on the bench for the final 6:47 after his cross-checking penalty gave... | 2024-01-03T01:26:51.906118 | https://example.com/article/2219 |
Bacunayagua
Bacunayagya is a Cuban village and consejo popular ("people's council", i.e. voting district) of the municipality of Santa Cruz del Norte, in Mayabeque Province. In 2011 it had a population of 3,371.
Geography
The small northern Cuban settlement was established on the side of the important Vía Blanca (road), where a deep canyon cuts the coastal hills between the Yumuri Valley and the Straits of Florida coast. It marks the boundary between the Mayabeque Province and Matanzas Province.
Transport
Bacunayagua Bridge
The Bridge of Bacunayagua, inaugurated in September 1959, crosses the canyon, and at above the valley floor is the highest bridge in Cuba. Cubans consider it one of the seven wonders of Cuban civil engineering. It was built under the leadership of Civil Engineer Manuel (Manolo) Arvesu. A restaurant with an observation deck is built on the Havana side, while the coastal cove on the Matanzas side includes a campground.
The bridge used to divide the provinces of La Habana and Matanzas, but after the reorganization of 2010, it now divides Matanzas Province from the new Mayabeque Province (the island's smallest, except for the city of Havana itself).
See also
Vía Blanca
Arcos de Canasí
Jibacoa
Boca de Jaruco
Camilo Cienfuegos (Hershey)
References
External links
Category:Populated places in Matanzas Province
Category:Geography of Mayabeque Province | 2024-02-27T01:26:51.906118 | https://example.com/article/1916 |
Q:
On do statement
In the C specification 6.8.5.2 the do iteration statement is written alone, not
as do/while.
Why, maybe because are they, in that context, two separate statements?
Is this also explain the ; character put at the end of the while?
do
{
statement; // first statement
}
while(expr); // null statement???
A:
In the C specification the do iteration statement is written alone, not as do/while.
This is not correct. C11 6.8.5 Iteration statements:
iteration-statement:
while ( expression ) statement
do statement while ( expression ) ;
...
Why, maybe because are they, in that context, two separate statements?
No, do-while is one statement as specified by the syntax cited above. It is sometimes referred to as the do statement (as it is in 6.8.5.2), but the while on the end is mandatory, as it is part of the same statement.
Is this also explain the ; character put at the end of the while?
No, the ; is there because it is required by the syntax cited above.
| 2023-12-09T01:26:51.906118 | https://example.com/article/8484 |
Static Analyzer:
libtoolize --force --copy
aclocal -I m4
autoconf
autoheader
automake --add-missing
scan-build -k -v -V ./configure --prefix=/usr --enable-extfs --disable-reiserfs --enable-fat \
--enable-hfsp --enable-btrfs --enable-ncursesw --enable-ntfs \
--enable-exfat --enable-f2fs --enable-minix --disable-nilfs2 --enable-xfs \
--sbindir=/usr/bin
make clean
scan-build -k -v -V make -j4
Sanitizer:
export CC=clang
export CFLAGS="$CFLAGS -Wall -fsanitize=address -fsanitize=undefined -fno-omit-frame-pointer -g"
export LDFLAGS="$LDFLAGS -fsanitize=address -fsanitize=undefined"
libtoolize --force --copy
aclocal -I m4
autoconf
autoheader
automake --add-missing
./configure --prefix=/usr --enable-extfs --disable-reiserfs --enable-fat \
--enable-hfsp --enable-btrfs --enable-ncursesw --enable-ntfs \
--enable-exfat --enable-f2fs --enable-minix --disable-nilfs2 --enable-xfs \
--sbindir=/usr/bin
make clean
make -j4
| 2023-08-13T01:26:51.906118 | https://example.com/article/2149 |
Billy_KinettaPaladin of the Lost HourGold Supporting MemberSupporting Member
Violent imagery has reached a level of vileness not seen in the past. From blood and brain splatter to secret codes in popular games to open rape scenarios.
Add that many have lost the separation of fantasy vs. reality as they soak every waking minute into social media sites that damage young minds before learning proper social interaction.
The creators openly admitted it.
Now a host of school lockdowns nationwide as threats are made against schools on social media by sociopath users.
Who the hell would have even entertained a threat decades ago?
My opinion is it is a contributing factor of many.
Click to expand...
The same violent games and movies we have here, they have in every other country around the world. Yet we are the only country with mass shooting epidemics. So what makes us different from France or Israel or the UK, who gets the same movies, tv shows, and video games we get?
Click to expand...
It is not the fault of the Constitution that you people screw up everything you touch.
Nothing could be more irrelevant to me than what happens in other countries. I live in this one.
Click to expand...
Actually it's completely relevant to what we're discussing because video games are the constant; meaning they get the same video games in Japan and Canada that we get in the US. So since the games are the same, yet mass shootings occur in just the US, it's not the games that are causing the mass shootings, otherwise there'd be mass shootings in Japan and Canada.
Actually it's completely relevant to what we're discussing because video games are the constant; meaning they get the same video games in Japan and Canada that we get in the US. So since the games are the same, yet mass shootings occur in just the US, it's not the games that are causing the mass shootings, otherwise there'd be mass shootings in Japan and Canada.
Very interesting! I read the whole thing. I was not surprised --- but many will be --- at how MUCH of America's entertainment budget is soaked up by video games. 54% with the other candidates in the pie being movies, DVDs, and music. (Sports was not included, nor TV, however.) How the growth line is a 45% slant up. How many people are employed -- and how much they make.
I was surprised at the relatively high age of the game buyers -- 37 -- and don't believe it correctly reflects the players. I expect a lot of those are parents buying for their teenage kids.
So then it isn't the video games. So what about American culture is different than English culture? They play Call of Duty in England. They watch Game of Thrones and Walking Dead in England. They watch violent movies in England. Yet they don't have mass shootings in England. Why?
Bloomberg right now is dealing with the gaming and Trump's conference going on now. They are saying that Nikolas Cruz was known to be a very intensely active gamer with the most violent shooter game (the speaker seemed to hint it was Call of Duty but there are others). Of course, what else did the kid have to do, being expelled and unemployed.
Still, that perhaps explains the president's interest: he would know that about Cruz.
Bloomberg right now is dealing with the gaming and Trump's conference going on now. They are saying that Nikolas Cruz was known to be a very intensely active gamer with the most violent shooter game (the speaker seemed to hint it was Call of Duty but there are others). Of course, what else did the kid have to do, being expelled and unemployed.
Still, that perhaps explains the president's interest: he would know that about Cruz.
Click to expand...
Call of Duty is sold worldwide.
They play Call of Duty in Japan, Korea, Israel, France, the UK, and the US.
But only the US has mass shootings.
So video games aren't the cause; something else is. What is different in the US than in any of those other places? The guns.
Useful Searches
About USMessageBoard.com
USMessageBoard.com was founded in 2003 with the intent of allowing all voices to be heard. With a wildly diverse community from all sides of the political spectrum, USMessageBoard.com continues to build on that tradition. We welcome everyone despite political and/or religious beliefs, and we continue to encourage the right to free speech.
Come on in and join the discussion. Thank you for stopping by USMessageBoard.com! | 2024-03-23T01:26:51.906118 | https://example.com/article/1681 |
In Texas, there are two types of assault cases, namely assault and aggravated assault. Both of these are criminal activities punishable by law. For a case to qualify as only an assault, one has to do any of the following activities:
Intentionally causing bodily harm to the victim
Intentionally threatening to harm another person physically
A case qualifies to be an aggravated assault if one:
Injures the victim badly
Uses a deadly weapon to cause harm to the victim
Aggravated assaults carry more and hefty penalties as compared to simple assaults such as threats.
The Tom Gregory Case
In December 2006, Gregory was charged with physically assaulting his girlfriend Natasha. It started with an intense argument and after sometime, it went to exchange of abusive words. According to Gregory, he unwillingly slapped his girlfriend severally and banged her head on the door. Though she was not badly injured, Natasha sued Gregory for an aggravated assault.
During his trial, Gregory hired a criminal defense lawyer who could help him shake off the charges. In his defense, Gregory’s lawyer claimed that Natasha provoked his client’s feelings and both of them were in the wrong. It was therefore uncouth for the court to charge his client with aggravated assault while the victim was not badly injured.
In the ruling, the judge decided that the case was a simple assault. Gregory was sentenced to one year of community service and had a restraining order against physically contacting Natasha again. Gregory had to attend anger management classes too.
Conclusion
Assault cases are rampant in Texas. However, how bad the assaults are will determine the penalty you will face. Assaults can be verbal too, though most go unreported because they are hard to prove. On the other hand, hiring a qualified and professional lawyer for your defense would be a wise decision in case you are convicted | 2023-09-11T01:26:51.906118 | https://example.com/article/8611 |
This invention provides novel compositions of matter.
Particularly this invention provides novel lactones of some of the known prostaglandins or prostaglandin analogs.
The known prostaglandins include the PGE compounds, e.g. prostaglandin E.sub.1 (PGE.sub.1), prostaglandin E.sub.2 (PGE.sub.2), prostaglandin E.sub.3 (PGE.sub.3), and dihydroprostaglandin E.sub.1 (dihydro-PGE.sub.1).
The known prostaglandins include PGF.sub..alpha. compounds, e.g. prostaglandin F.sub.1.alpha. (PGF.sub.1.alpha.), prostaglandin F.sub.2.alpha. (PGF.sub.2.alpha.), prostaglandin F.sub.3.alpha. (PGF.sub.3.alpha.), and dihydroprostaglandin F.sub.1.alpha. (dihydro-PGF.sub.1.alpha.).
The known prostaglandins include PGF.sub..beta. compounds, e.g. prostaglandin F.sub.1.beta. (PGF.sub.1.beta.), prostaglandin F.sub.2.beta. (PGF.sub.2.beta.), prostaglandin F.sub.3.beta. (PGF.sub.3.beta.), and dihydroprostaglandin F.sub.1.beta. (dihydro-PGF.sub.1.beta.).
The known prostaglandins include PGA compounds, e.g. prostaglandin A.sub.1 (PGA.sub.1), prostaglandin A.sub.2 (PGA.sub.2), prostaglandin A.sub.3 (PGA.sub.3), and dihydroprostaglandin A.sub.1 (dihydro-PGA.sub.1).
The known prostaglandins include PGB compounds, e.g. prostaglandin B.sub.1 (PGB.sub.1), prostaglandin B.sub.2 (PGB.sub.2), prostaglandin B.sub.3 (PGB.sub.3), and dihydroprostaglandin B.sub.1 (dihydro-PGB.sub.1).
Each of the above mentioned known prostaglandins (PG's) is a derivative of prostanoic acid which has the following structure and carbon atom numbering ##STR1## See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. A systematic name for prostanoic acid is 7-[(2.beta.-octyl)-cyclopent-1.alpha.-yl]-heptanoic acid.
PGE.sub.1 has the following structure: ##STR2##
PGE.sub.2 has the following structure: ##STR3##
PGE.sub.3 has the following structure: ##STR4##
Dihydro-PGE.sub.1 has the following structure: ##STR5##
PGF.sub.1.alpha. has the following structure: ##STR6##
PGF.sub.2.alpha. has the following structure: ##STR7##
PGF.sub.3.alpha. has the following structure: ##STR8##
Dihydro-PGF.sub.1.alpha. has the following structure: ##STR9##
PGF.sub.1.beta. has the following structure: ##STR10##
PGF.sub.2.beta. has the following structure: ##STR11##
PGF.sub.3.beta. has the following structure: ##STR12##
Dihydro-PGF.sub.1.beta. has the following structure: ##STR13##
PGA.sub.1 has the following structure: ##STR14##
PGA.sub.2 has the following structure: ##STR15##
PGA.sub.3 has the following structure: ##STR16##
Dihydro-PGA.sub.1 has the following structure: ##STR17##
PGB.sub.1 has the following structure: ##STR18##
PGB.sub.2 has the following structure: ##STR19##
PGB.sub.3 has the following structure: ##STR20##
Dihydro-PGB.sub.1 has the following structure: ##STR21##
In the above formulas, as well as in the formulas hereinafter given, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring. The use of wavy lines (.about.) herein will represent attachment of substituents in either the alpha or beta configuration or attachment in a mixture of alpha and beta configurations.
The side-chain hydroxy at C-15 in the above formulas is in S configuration. See, Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins. Expressions such as C-9, C-11, C-15, and the like, refer to the carbon atom in the prostaglandin analog which is in the position corresponding to the position of the same number in prostanoic acid.
Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e. the dextrorotatory and levorotatory forms. As drawn, the above formulas each represent the particular optically active form of the prostaglandin as is obtained from mammalian tissues, for example, sheep vesicular glands, swine lung, or human seminal plasma, from carbonyl and/or double bond reduction of the prostaglandin so obtained. See, for example, Bergstrom et al., cited above. The mirror image of each of these formulas represents the other enantiomer of that prostaglandin. The racemic form of a prostaglandin contains equal numbers of both enantiomeric molecules, and one of the above formulas and the mirror image of that formula is needed to represent correctly the corresponding racemic prostaglandin.
For convenience hereinafter, use of the term, prostaglandin or "PG" will mean the optically active form of that prostaglandin thereby referred to with the same absolute configuration as PGE.sub.1 obtained from mammalian tissues. When reference to the racemic form of one of those prostaglandins is intended, the word "racemic" or "dl" will precede the prostaglandin name.
The term "prostaglandin-type" (PG-type) compound, as used herein, refers to any cyclopentane derivative herein which is useful for at least one of the same pharmacological purposes as the prostaglandins, as indicated herein.
The term prostaglandin-type intermediate, as used herein, refers to any cyclopentane derivative useful in preparing a prostaglandin-type compound.
The formulas, as drawn herein, which depict a prostaglandin-type compound or an intermediate useful in preparing a prostaglandin-type compound, each represent the particular stereoisomer of the prostaglandin-type compound which is of the same relative stereochemical configuration as a corresponding prostaglandin obtained from mammalian tissues, or the particular stereoisomer of the intermediate which is useful in preparing the above stereoisomer of the prostaglandin-type compounds.
The term "prostaglandin analog", as used herein, represents that stereoisomer of a prostaglandin-type compound which is of the same relative stereochemical configuration as a corresponding prostaglandin obtained from mammalian tissues, a mixture comprising that stereoisomer and the enantiomer thereof, or the enantiomer thereof. In particular, where a formula is used to depict a prostaglandin-type compound herein, the term prostaglandin analog refers to the compound of that formula, or a mixture comprising that compound and the enantiomer thereof.
The term "prostaglandin-type lactone" as used herein refers to a 1,9-; 1,11-; or 1,15-lactone of a prostaglandin or prostaglandin analog, but only to the extent that the C-9, C-11, or C-15 position, respectively, is hydroxylated and thus capable of lactone formation with the PG carboxyl. For example, as applied to a PGE-type compound (e.g. PGE.sub.2) the term "prostaglandin-type lactone" refers only to a 1,11- or 1,15-lactone. Further, where a formula is used to depict a prostaglandin-type lactone herein, or a prostaglandin analog from which the prostaglandin-type lactone is prepared, the term "prostaglandin-type lactone" refers to the compound of that formula (or the lactone prepared therefrom) or a mixture comprising that compound (or the lactone prepared therefrom) and the enantiomer thereof.
The various PG's named above, their esters, acylates and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and references cited therein.
For the PGE compounds these biological responses include:
a. stimulating smooth muscle (as shown by tests, for example, on guinea pig ileum, rabbit duodenum, or gerbil colon);
b. affecting lipolytic activity (as shown by antagonism of epinephrine induced release of glycerol from isolated rat fat pads);
c. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systematic administration of prostaglandin synthetase inhibitors;
d. controlling spasm and facilitating breathing in asthmatic conditions;
e. decongesting nasal passages;
f. decreasing blood platelet adhesion (as shown by platelet to glass adhesiveness) and inhibiting blood platelet aggregation and thrombus formation induced by various physical stimuli (e.g., arterial injury) or chemical stimuli (e.g., ATP, ADP, serotinin, thrombin, and collagen);
g. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstrual cycle; and
h. accelerating growth of epidermal cells and keratin in animals.
For the PGF.sub..alpha. compound these biological responses include:
a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon);
b. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systemic administration of prostaglandin synthetase inhibitors;
c. decongesting nasal passages;
d. decreasing blood platelet adhesion (as shown by platelet to glass adhesiveness) and inhibiting blood platelet aggregation and thrombus formation induced by various physical stimuli (e.g., arterial injury) or chemical stimuli (e.g., ADP, ATP, serotinin, thrombin, and collagen); and
e. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstral cycle.
For the PGF.sub..beta. compounds these biological response include:
a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon);
b. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systematic administration of prostaglandin synthetase inhibitors;
c. controlling spasm and facilitating breathing in asthmatic conditions;
d. decongesting nasal passages;
e. decreasing blood platelet adhesion (as shown by platelet to glass adhesiveness) and inhibiting blood platelet aggregation and thrombis formation induced by various physical stimuli (e.g., arterial injury) or chemical stimuli (e.g., ADP, ATP, serotinin, thrombin, and collagen); and
f. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstrual cycle.
For the PGA compounds these biological responses include:
a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon);
b. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systematic administration of prostaglandin synthetase inhibitors;
c. controlling spasm and facilitating breathing in asthmatic conditions;
d. decongesting nasal passages; and
e. increasing kidney blood flow.
For the PGB compounds these biological responses include:
a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon); and
b. accelerating growth of epidermal cells and keratin in animals.
Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.
The compounds so cited above as extremely potent in causing stimulation of smooth muscle are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore, these compounds for example, are useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the prostaglandin is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50.mu.g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.
As mentioned above, the PGE compounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.
The prostaglandins so cited above as useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reduce or avoid gastrointestinal ulcer formation, and accelerate the healing of such ulcers already present in the gastrointestinal tract. For this purpose, these compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 .mu.g. to about 500 .mu.g. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
These compounds are also useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration of the prostaglandin and the anti-inflammatory prostaglandin synthetase inhibitor. See Partridge et al., U.S. Pat. No. 3,781,429, for a disclosure that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins of the E and A series, including PGE.sub.1, PGE.sub.2, PGE.sub.3, 13,14-dihydro-PGE.sub.1, and the corresponding 11-deoxy-PGE and PGA compounds. Prostaglandins are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned in Partridge et al. as non-steroidal, anti-inflammatory agents. These are also known to be prostaglandin synthetase inhibitors.
The anti-inflammatory synthetase inhibitor, for example, indomethacin, aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflammatory condition, for example, in any dosage regimen and by any of the known routes of systemic administration.
The prostaglandin is administered along with the anti-inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by a different route. For example, if the anti-inflammatory substance is being administered orally, the prostaglandin is also administered orally or, alternatively, is administered rectally in the form of a suppository or, in the case of women, vaginally in the form of a suppository or a vaginal device for slow release, for example as described in U.S. Pat. No. 3,545,439. Alternatively, if the anti-inflammatory substance is being administered rectally, the prostaglandin is also administered rectally, or, alternatively, orally or, in the case of women, vaginally. It is especially convenient when the administration route is to be the same for both anti-inflammatory substance and prostaglandin, to combine both into a single dosage form.
The dosage regimen for the prostaglandin in accord with this treatment will depend upon a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, the sensitivity of the particular individual mammal to the particular synthetase inhibitor with regard to gastrointestinal effects, and the particular prostaglandin to be administered. For example, not every human in need of an anti-inflammatory substance experienced the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree. But it is within the skill of the attending physician or veterinarian to determine that administration of the anti-inflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject and to prescribe an effective amount of the prostaglandin to reduce and then substantially to eliminate those undesirable effects.
The prostaglandins so cited above as useful in the treatment of asthma, are useful, for example, as bronchodilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia, and emphysema. For these purposes, the compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally; subcutaneously; or intramuscularly; with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of about 0.01 to 5 mg. per kg. of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration. For the above use these prostaglandins can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, epinephrine, etc.); xanthine derivatives (theophylline and aminophylline); and corticosteroids (ACTH and prednisolone). Regarding use of these compounds see M. E. Rosenthale, et al., U.S. Pat. No. 3,644,638.
The prostaglandins so cited above as useful in mammals, including man, as nasal decongestants are used for this purpose, in a dose range of about 10 .mu.g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.
The prostaglandins so cited above as useful whenever it is desired to inhibit platelet aggregation, reduce the adhesive character of platelets, and remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
These compounds are further useful as additives to blood, blood products, blood substitutes, or other fluids which are used in artificial extracorporeal circulation or perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001 to 10 mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.
The prostaglandins so cited above as useful in place of oxytocin to induce labor are used in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 .mu.g. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. An alternative route of administration is oral.
These compounds are further useful for controlling the reproductive cycle in menstruating female mammals, including humans. By the term menstruating female mammals is meant animals which are mature enough to menstruate, but not so old that regular menstruation has ceased. For that purpose the prostaglandin is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Intravaginal and intrauterine routes are alternate methods of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first or second trimester of the normal mammalian gestation period.
These compounds are further useful in causing cervical dilation in pregnant and nonpregnant female mammals for purposes of gynecology and obstetrics. In labor induction and in clinical abortion produced by these compounds, cervical dilation is also observed. In cases of infertility, cervical dilation produced by these compounds is useful in assisting sperm movement to the uterus. Cervical dilation by prostaglandins is also useful in operative gynecology such as D and C (Cervical Dilation and Uterine Curettage) where mechanical dilation may cause perforation of the uterus, cervical tears, or infections. It is also useful in diagnostic procedures where dilation is necessary for tissue examination. For these purposes, the prostaglandin is administered locally or systemically.
The prostaglandin, for example, is administered orally or vaginally at doses of about 5 to 50 mg. per treatment of an adult female human, with from one to five treatments per 24 hour period. Alternatively the prostaglandin is administered intramuscularly or subcutaneously at doses of about one to 25 mg. per treatment. The exact dosages for these purposes depend on the age, weight, and condition of the patient or animal.
These compounds are further useful in domestic animals as an abortifacient (especially for feedlot heifers), as an aid to estrus detection, and for regulation or synchronization of estrus. Domestic animals include horses, cattle, sheep, and swine. The regulation or synchronization of estrus allows for more efficient management of both conception and labor by enabling the herdsman to breed all his females in short pre-defined intervals. This synchronization results in a higher percentage of live births than the percentage achieved by natural control. The prostaglandin is injected or applied in a feed at doses of 0.1-100 mg. per animal and may be combined with other agents such as steroids. Dosing schedules will depend on the species treated. For example, mares are given the prostaglandin 5 to 8 days after ovulation and return to estrus. Cattle, are treated at regular intervals over a 3 week period to advantageously bring all into estrus at the same time.
The PGA compounds and derivatives and salts thereof increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. For that reason, PGA compounds are useful in managing cases of renal dysfunction, especially those involving blockage of the renal vascular bed. Illustratively, the PGA compounds are useful to alleviate and correct cases of edema resulting, for example, from massive surface burns, and in the management of shock. For these purposes, the PGA compounds are preferably first administered by intravenous injection at a dose in the range 10 to 1000 .mu.per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 .mu.g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.
The compounds so cited above as promoters and acceleraters of growth of epidermal cells and keratin are useful in animals, including humans, useful domestic animals, pets, zoological specimens, and laboratory animals for this purpose. For this reason, these compounds are useful to promote and accelerate healing of skin which has been damaged, for example, by burns, wounds, and abrasions, and after surgery. These compounds are also useful to promote and accelerate adherence and growth of skin autografts, especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homografts.
For the above purposes, these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically acceptable diluents. In some instances, for example, when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration is advantageous, for example, by intravenous injection or infusion, separate or in combination with the usual infusions of blood, plasma, or substitutes thereof. Alternative routes of administration are subcutaneous or intramuscular near the site, oral, sublingual, buccal, rectal, or vaginal. The exact dose depends on such factors as the route of administration, and the age, weight, and condition of the subject. To illustrate, a wet dressing for topical application to second and/or third degree burns of skin area 5 to 25 square centimeters would advantageously involve use of an isotonic aqueous solution containing 1 to 500 .mu.g. per ml. of the prostaglandin pound. Especially for topical use, these prostaglandins are useful in combination with antibiotics, for example, gentamycin, neomycin, polymixin, bacitracin, spectinomycin, and oxytetracycline, with other antibacterials, for example, mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoid steroids, for example, hydrocortisone, prednisolone, methylprednisolone, and fluprednisolone, each of those being used in the combination at the usual concentration suitable for its use alone.
In addition to the discovery of the prostaglandins cited above, various prostaglandin analogs have likewise been discovered. In particular, there are known prostaglandin analogs of the formula ##STR22##
wherein D is ##STR23## wherein R.sub.8 is hydrogen or hydroxy;
wherein L.sub.1 is ##STR24## or a mixture of ##STR25## and ##STR26## wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro, only when the other is hydrogen or fluoro;
wherein M.sub.1 is ##STR27## or ##STR28## wherein R.sub.5 is hydrogen or methyl;
wherein R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3, wherein m is one to 5, inclusive, cis--CH.dbd.CH--CH.sub.2 --CH.sub.3, or ##STR29## wherein T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, the various T's being the same or different, s is zero, one, 2, or 3, and Z.sub.3 is oxa or methylene, with the proviso that not more than two T's are other than alkyl, and the further proviso that Z.sub.3 is oxa only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different;
wherein Y.sub.1 is trans--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, cis--CH.dbd.CH--, or --C.tbd.C--; and
wherein Z.sub.1 is
(1) cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --, PA1 (2) cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 --, PA1 (3) cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --, PA1 (4) --(ch.sub.2).sub.3 --(ch.sub.2).sub.g --CH.sub.2 --, PA1 (5) --(ch.sub.2).sub.3 --(ch.sub.2).sub.g --CF.sub.2 --, PA1 (6) --ch.sub.2 --o--ch.sub.2 --(ch.sub.2).sub.g --CH.sub.2 --, ##STR30## wherein g is one, 2, or 3.
While the use and preparation of many of the prostaglandin analogs described above is widely known in the art, the Appendix, hereto provides a discussion of the preparation of each of the various compounds depicted by formula I above.
For the prostaglandin analogs described in formula I above, a convenient classification system according to cyclopentane ring structure is effected by referencing:
a. PGF.sub..alpha. -type compounds when D is ##STR31##
b. 11-deoxy-PGF.sub..alpha. -type compounds when D is ##STR32##
c. PGE-type compounds when D is ##STR33##
d. 11-deoxy-PGE-type compounds when D is ##STR34##
e. PGF.sub..beta. -type compounds when D is ##STR35##
f. PGD-type or 9.beta.-PGD-type compounds when D is ##STR36## and
g. 9-deoxy-PGD-type compounds when D is ##STR37##
h. 9-deoxy-9,10-didehydro-PGD-type compounds when D is ##STR38## and
i. PGA-type compounds when D is ##STR39##
j. PGB-type compounds when D is ##STR40##
k. 8.beta.,12.alpha.-PGF.sub..alpha. -type compounds when D is ##STR41##
l. 8.beta.,12.alpha.-11-deoxy-PGF.sub..alpha. -type compounds when D is ##STR42##
m. 8.beta.,12.alpha.-PGE-type compounds when D is ##STR43##
n. 8.beta.,12.alpha.-11-deoxy-PGE-type compounds when D is ##STR44##
o. 8.beta.,12.alpha.-PGF.sub..beta. -type compounds when D is ##STR45##
p. 8.beta.,12.alpha.-PGD-type or 8.beta.,9.beta.,12.alpha.-PGD-type compounds when D is ##STR46##
q. 8.beta.,12.alpha.-9-deoxy-PGD-type compounds when D is ##STR47## and
s. 8.beta.,12.alpha.-PGA-type compounds when D is ##STR48##
Those prostaglandin analogs wherein Z.sub.1 is cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 -- or cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 -- are named as "PG.sub.2 " compounds. The latter compounds are further characterized as "2,2-difluoro" PG.sub.2 -type compounds. When g is 2 or 3, the prostaglandin analogs so described are "2a-homo" or "2a,2b-dihomo" compounds, since in this event the carboxy terminated side chain contains 8 or 9 carbon atoms, respectively, in place of the 7 carbon atoms contained in PGE.sub.1. These additional carbon atoms are considered as though they were inserted between the C-2 and C-3 positions. Accordingly, these additional carbon atoms are referred to as C-2a and C-2b, counting from the C-2 to the C-3 position.
Further when Z.sub.1 is --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CH.sub.2 -- or --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CF.sub.2, wherein g is as defined above, the PG analogs so described are "PG.sub.1 " compounds. When g is 2 or 3, the "2a-homo" and "2a,2b-dihomo" compounds are described as is discussed in the preceding paragraph.
When Z.sub.1 is --CH.sub.2 --O--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 -- the PG analogs so described are named as "5-oxa-PG.sub.1 " compounds. When g is 2 or 3, the compounds so described are "2a-homo" or "2a,2b-dihomo" compounds, respectively, as discussed above.
When Z.sub.1 is cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --, wherein g is as defined above, the PG analogs so described are named "cis-4,5-didehydro-PG.sub.1 " compounds. When g is 2 or 3, the compounds so described are further characterized as "2a-homo" or "2a,2b-dihomo" compounds, respectively, as discussed above.
For the PG analogs wherein Z.sub.1 is ##STR49## there are described, respectively, 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor or 3,7-inter-m-phenylene-4,5,6-trinor-PG-type compounds, when g is 1. When g is 2 or 3, the above compounds are additionally described as "2a-homo" or "2a,2b-dihomo" PG-type compounds, respectively.
The prostaglandin analogs described herein which contain a cis--CH.dbd.CH-- moiety at the C-13 to C-14, the compounds so described are "13-cis" compounds.
Further when the C-13 to C-14 moiety is --C.tbd.C-- or --CH.sub.2 CH.sub.2 -- the compounds so described are named as "13,14-didehydro" or "13,14-dihydro" compounds, respectively.
When R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3, wherein m is as defined above, the PG analogs so described are named as "19,20-dinor", "20-nor", "20-methyl", or "20-ethyl" compounds when m is one, 2, 4, or 5, respectively. When R.sub.7 is ##STR50## wherein T and s are as defined above, the PG analogs so described are named as "17-phenyl-18,19,20-trinor" compounds, when s is 0. When s is 1, 2, or 3, the corresponding compounds are named as "17-(substituted phenyl)-18,19,20-trinor" compounds.
When R.sub.7 is ##STR51## wherein T and s are as defined above, and neither R.sub.3 nor R.sub.4 is methyl, the PG analogs so described are named as "16-phenoxy-17,18,19,20-tetranor" compounds, when s is 0. When s is 1, 2, or 3, the corresponding compounds are named as "16-(substituted phenoxy)-17,18,19,20-tetranor" compounds. When one and only one of R.sub.3 and R.sub.4 is methyl or both R.sub.3 and R.sub.4 are methyl, then the corresponding compounds wherein R.sub.7 is as defined in this paragraph are named as "16-phenoxy or 16- (substituted phenoxy)-18,19,20-trinor" compounds or "16-methyl-16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor" compounds, respectively.
When R.sub.7 is cis--CH.dbd.CH--CH.sub.2 --CH.sub.3, the compounds so described are "PG.sub.3 " or "cis-17,18-didehydro" compounds depending on whether Z.sub.1 is cis--CH.dbd.CH--(CH.sub.2).sub.g --C(R.sub.2).sub.2, wherein R.sub.2 is hydrogen or fluoro, or another moiety, respectively.
When at least one of R.sub.3 and R.sub.4 is not hydrogen then (except for the 16-phenoxy compounds discussed above) there are described the "16-methyl" (one and only one of R.sub.3 and R.sub.4 is methyl), "16,16-dimethyl" (R.sub.3 and R.sub.4 are both methyl), "16-fluoro" (one and only one of R.sub.3 and R.sub.4 is fluoro), "16,16-difluoro" (R.sub.3 and R.sub.4 are both fluoro) compounds. For those compounds wherein R.sub.3 and R.sub.4 are different, the prostaglandin analogs so represented contain an asymmetric carbon atom at C-16. Accordingly, two epimeric configurations are possible: "(16S)" and "(16R)". Further, there is described by this invention the C-16 epimeric mixture: "(16RS)."
When R.sub.5 is methyl, the compounds so described are named as "15-methyl" compounds.
Some formulas of 13-cis-cyclopentane derivatives described hereinafter contain a moiety of the formula: ##STR52## wherein the cyclopentane ring is variously substituted, wherein M is variously defined according to the subscripts provided herein; wherein L.sub.1 and R.sub.7 are as defined above; and wherein Y.sub.4 is cis--CH.dbd.CH--. Optionally the above formula is depicted with one or both of L.sub.1 and M above the carbon atom to which it is attached, e.g., as follows: ##STR53## When either of the above representations is employed, it is hereby defined to indicate the following convention with respect
to the representation of the cis-13 double bond: ##STR54## Further in employing this convention when M is, for example, ##STR55## or ##STR56## then the corresponding representations: ##STR57## or ##STR58## are intended, respectively. Accordingly all the formulas herein which represent 13-cis cyclopentane derivatives are depicted by the same convention as that for the cis-13-PGE.sub.1 when drawn as follows: ##STR59## Thus, by this convention the (15S)-hydroxy of cis-13-PGE.sub.1 is in the beta configuration.
cis-13-PG-type compounds as drawn herein which have an hydroxy or methoxy at C-15 in the alpha configuration are of the opposite relative stereochemical configuration at C-15 as that of cis-13-PGE.sub.1, and are therefore named as "15-epi" compounds. When the beta hydroxy or methoxy configuration is present, no special designation of this stereochemistry is provided.
Accordingly, 15-epi-16,16-difluoro-cis-13-PGD.sub.2 is depicted herein as follows: ##STR60##
Alternate representations of cis-13-PGE.sub.1 affect the depiction of C-15 as an alpha or beta hydroxy. Thus, by a representation contrary to the instant convention, cis-13-PGE.sub.1 appears as follows: ##STR61##
Accordingly, care must be taken to consistently draw the formulas of cis-13-PG-type compounds herein such that the C-15 carbon atoms is properly represented, i.e., all cis-13-15-epi-PG' s are of the 15.alpha.-hydroxy configuration.
13,14-trans-13,14-dihydro, or 13,14-didehydro cyclopentane derivatives which contain the moiety ##STR62## wherein the cyclopentane ring is variously substituted, wherein M is variously defined according to the subscripts provided herein; wherein L.sub.1 and R.sub.7 are as defined above; and wherein Y.sub.3 is trans--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, or --C.tbd.C-- respectively. When this representation is employed, it is hereby defined to indicate the following convention with respect to the representation of the C-13 to C-14 moiety: ##STR63## or ##STR64## respectively. Likewise in employing this convention when M is, for example ##STR65## or ##STR66## then the corresponding representation for the trans-13 compounds: ##STR67## or ##STR68## the 13,14-dihydro compounds: ##STR69## or ##STR70## and the 13,14-didehydro compounds: ##STR71## or ##STR72## are intended, respectively. Accordingly all the formulas herein which represent trans-13, 13,14-dihydro, or 13,14-di-dehydro-cyclopentane derivatives are depicted by the same convention as that for PGE.sub.1 when drawn as above, i.e., ##STR73##
Thus, for all trans-13, 13,14-dihydro, or 13,14-didehydro-PG-type compounds, as drawn herein the 15.alpha.-hydroxy configuration corresponds to the relative C-15 stereochemical configuration of PGE.sub.1 as obtained from mammalian tissues. No special designation of the C-15 stereochemistry is provided in naming these compounds. For compounds of the opposite stereochemical configuration at C-15 (i.e., 15.beta.-hydroxy), the description "15 -epi" will be employed.
The prostaglandin analogs of formula I are known to correspond to the prostaglandins described above, in that these prostaglandin analogs exhibit prostaglandin-like activity.
Specifically the PGE-, 8.beta.,12.alpha.-PGE-, 8.beta.,12.alpha.-11-deoxy-PGE-, and 11-deoxy-PGE-type compounds correspond to the PGE compounds described above, in that these PGE-, 8.beta.,12.alpha.-PGE-, 8.beta.,12.alpha.-11-deoxy-PGE-, and 11-deoxy-PGE-type compounds are useful for each of the above-described purposes for which the PGE compounds are used, and are used in the same manner as the PGE compounds, as described above.
The PGF.sub..alpha. -, 8.beta.,12.alpha.-PGF.sub..alpha. -, 8.beta.,12.alpha.-11-deoxy-PGF.sub..alpha. -, and 11-deoxy-PGF.sub..alpha. -type compounds correspond to the PGF.sub..alpha. compounds described above, in that these PGF.sub..alpha. -, 8.beta.,12.alpha.-PGF.sub..alpha. -, 8.beta.,12.alpha.-11-deoxy-PGF.sub..alpha. -, and 11-deoxy-PGF.sub..alpha. -type compounds are useful for each of the above-described purposes for which the PGF.sub..alpha. compounds are used, and are used in the same manner as the PGF compounds, as described above.
The PGD-, 9.beta.-PGD-, 8.beta.,12.alpha.-PGD-, 8.beta.,9.beta.,12.alpha.-PGD-, 9-deoxy-PGD-, 8.beta.,12.alpha.-9-deoxy-PGD-, 8.beta.,12.alpha.-9,10-didehydro-9-deoxy-PGD-, and 9,10-didehydro-9-deoxy-PGD-type compounds of formula I correspond to the PGE or PGF.sub..alpha. compounds described above, in that these PGD-, 8.beta.,12.alpha.-PGD-, 9-deoxy-PGD-, 8.beta.,12.alpha.-9-deoxy-PGD-, 8.beta.,12.alpha.-9-deoxy-9,10-didehydro-PGD-, or 9-deoxy-9,10-didehydro-PGD-type compounds are useful for each of the above-described purposes for which either the PGE or PGF.sub..alpha. compounds are used, and are used in the same manner as the PGE or PGF.sub..alpha. compounds, as described above.
The PGA- or 8.beta.,12.alpha.-PGA-type compounds of formula I correspond to the PGA compounds described above, in that these PGA- or 8.beta.,12.alpha.-PGA-type compounds are useful for each of the above described purposes for which the PGA compounds are used, and are used in the same manner as the PGA compounds, as described above. The PGB-type compounds of formula I correspond to the PGB compounds described above in that the PGB compounds are useful for each of the above described purposes for which PGB compounds are used, and are used in the same manner as the PGB compounds described above.
The prostaglandins described above, are all known to be potent in causing multiple biological responses even at low doses. Moreover, for many applications, these prostaglandins are known to exhibit a relatively short duration of biological activity. Significantly, the prostaglandin analogs of formula I are known to be substantially more selective with regard to potency in causing prostaglandin-like biological responses, and have a somewhat longer duration of biological activity. Thus, each of these prostaglandin analogs is known to be equally or even more useful than one of the corresponding prostaglandins described above for at least one of the pharmacological purposes indicated above for the latter.
Another property of the prostaglandin analogs of formula I, compared with the corresponding prostaglandins, is that these PG analogs are known to be capable of effective administration orally, sublingually, intravaginally, buccally, or rectally in many cases where the corresponding prostaglandin is known to be effective only by the intravenous, intramuscular, or subcutaneous injection or infusion methods of administration indicated above as uses of these prostaglandins. When alternate routes of administration are employed, they are known to facilitate maintaining unilevels of these compounds in the body with fewer, shorter, or smaller doses, and to make possible self-administration by the patient.
Accordingly, the prostaglandin analogs of formula I are known to be capable of administration in various ways for various purposes: e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically, and in the form of sterile implants for prolonged action. For intravenous injection or infusion, sterile aqueous isotonic solutions are known to be preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, the use of sterile tablets or silicone rubber capsules or other objects containing or impregnated with the substance is known.
Methods for the preparation of large ringed lactones are known in the art. See, for example, E. J. Corey, et al., Journal of the American Chemical Society 96: 5614 (1974). Further, certain 1,9 lactones of cyclopentane containing carboxylic acids are known in the art. See Sourth African Application No. 737,357, Derwent Farmdoc CPI No. 28414V, which discloses 1,9-lactones of .omega.-heterocyclic prostaglandin analogs, Japanese Application No. 50-0037-793, Derwent Farmdoc CPI No. 61147W, which discloses 15-deoxy-15-methyl-PGF.sub. 2.alpha., 1,9-lactone; and E. J. Corey, et al., Journal of the American Chemical Society 97: 653 (1975), which discloses PGF.sub.2.alpha. 1,9-lactone. Further, the latter reference additionally discloses PGF.sub.2.alpha., 1,15-lactone.
Finally, see Japanese Patent Application No. 50013-385, Derwent Farmdoc CPI No. 56267W, which discloses 1,9-lactones of PGF.sub.2.alpha. and (15RS)-15-methyl-PGF.sub.2.alpha.. | 2023-10-17T01:26:51.906118 | https://example.com/article/3849 |
1. Introduction {#sec1-molecules-20-19433}
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Microscopic damage to the structure of bone is repaired by bone metabolism. This begins in the fetus and continues throughout life. It is essential in order to maintain the structure and mechanical strength of bone \[[@B1-molecules-20-19433]\]. In bone metabolism, the destructive process of bone resorption is followed by the productive process of bone formation \[[@B2-molecules-20-19433]\]. Osteoclasts are unique amongst somatic cells in that they can resorb bone matrices, and are the principal mediator of bone resorption \[[@B3-molecules-20-19433]\]. Along with macrophages, they are derived from hematopoietic stem cells \[[@B4-molecules-20-19433]\]. In contrast, osteoblasts and their precursors are, as with chondrocytes and adipocytes, of mesenchymal stem cell origin \[[@B5-molecules-20-19433]\]. The interaction between osteoclasts and osteoblasts contributes to coupling of bone resorption and formation. Under normal circumstances, bone formation and resorption are in balance, as a consequence of precisely regulated processes \[[@B6-molecules-20-19433]\]. The coordinated formation of osteoclasts and osteoblasts is critical for maintaining physiological bone metabolism \[[@B7-molecules-20-19433]\], which is always determined by the differentiation of osteoclast and osteoblast precursors to form mature cells \[[@B8-molecules-20-19433]\]. Abnormal bone metabolism, caused by enhanced osteoclast differentiation or decreased osteoblast differentiation, leads to a number of pathological bone destruction diseases \[[@B9-molecules-20-19433]\], including rheumatoid arthritis (RA) and osteoporosis \[[@B10-molecules-20-19433]\]. Such disorders are associated with a significant decrease in the patient's quality of life \[[@B11-molecules-20-19433]\] as well as a financial huge cost to healthcare systems \[[@B12-molecules-20-19433]\].
To address these issues, a number of studies have focused on the differentiation of osteoclasts and osteoblasts to identify new therapeutic strategies for bone metabolism disorders. Specific factors expressed sequentially, and acting as an intracellular cascade, control the differentiation of hematopoietic progenitor cells into fully functioning osteoclasts \[[@B13-molecules-20-19433],[@B14-molecules-20-19433]\]. These include macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL) \[[@B15-molecules-20-19433]\]. These activate various intracellular signaling pathways and, in so doing, regulate the transcription and expression of osteoclast-specific genes \[[@B3-molecules-20-19433]\]. Members of the fibroblast growth factor (FGFs) \[[@B16-molecules-20-19433]\] and transforming growth factor beta (TGFβ) families are known to be essential for osteoblast differentiation \[[@B17-molecules-20-19433]\]*.* The functions of these factors are regulated by microRNAs (miRNAs), a class of conserved RNAs \[[@B18-molecules-20-19433]\], which function as post-transcriptional factors \[[@B19-molecules-20-19433]\] in osteoclast and osteoblasts differentiation \[[@B20-molecules-20-19433]\].
MiRNAs are small endogenous non-coding RNAs, made up of 22 nucleotides. They are well-studied and are known to affect the stability and expression of messenger RNA (mRNA) \[[@B21-molecules-20-19433]\]. MiRNA genes are transcribed by RNA polymerase II to form primary miRNA (pri-miRNA) \[[@B22-molecules-20-19433]\]. Nuclear pri-miRNA is processed to precursor miRNA (pre-miRNA), comprising 70 nucleotides, through the action of the RNase III enzyme, Drosha, and is exported from the nucleus \[[@B23-molecules-20-19433]\]. Within the cytoplasm, the enzyme known as Dicer converts pre-miRNA into miRNA \[[@B24-molecules-20-19433]\], which is loaded into the RNA-induced silencing complex (RISC) \[[@B25-molecules-20-19433]\]. The miRNA is responsible for ushering RISC to the 3ʹ-untranslated region (3′-UTR) of the target mRNA. Nucleotides 2--8 are crucial for this process and are called the seed region \[[@B26-molecules-20-19433]\]. The binding complementarity of the miRNAs to their seed region is usually imperfect \[[@B26-molecules-20-19433]\]. Mechanisms known to be involved in the silencing of expression by the association of miRNAs with their target mRNA including the inhibition of the initiation, continuation of translation and the destabilization of target mRNA \[[@B21-molecules-20-19433]\]. The latest miRBase release (v21, June 2014) contained 28645 miRNA loci that can produce 35828 mature miRNA products in 223 species \[[@B27-molecules-20-19433]\]. One of these miRNAs, miR-223, which was first identified in the haematopoietic cells \[[@B28-molecules-20-19433]\], is known to be highly conserved \[[@B29-molecules-20-19433]\], and has been found in 10 species (miRBase release21, June 2014). It is reported that miR-223 is also expressed in bone, adipose tissue \[[@B30-molecules-20-19433]\] and cardiac muscle tissue \[[@B31-molecules-20-19433]\] and its effect on cell differentiation, inflammation and cancer is well studied \[[@B32-molecules-20-19433]\].
Recent reports have demonstrated regulatory roles for miR-223 in bone metabolism \[[@B33-molecules-20-19433],[@B34-molecules-20-19433],[@B35-molecules-20-19433]\], mainly in mediating repression of the critical proteins required for osteoclast and osteoblast differentiation. To provide a better understanding of the mechanisms by which miR-223 regulates bone metabolism, we highlight the roles of miR-223 in the repression of key factors during the processes of osteoclast and osteoblast differentiation, as well as the potential clinical applications of miR-223 in bone metabolism disorders.
2. Targets of miR-223 Involved in Bone Metabolism {#sec2-molecules-20-19433}
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The latest release of TargetScan (v7.0, Whitehead Institute for Biomedical Research, Cambridge, MA, USA August 2015, <http://www.targetscan.org/vert_70/>) \[[@B36-molecules-20-19433]\] predicts 412 transcripts with conserved sites as biological targets of miR-223 in human and 284 transcripts in mouse (v6.2, Whitehead Institute for Biomedical Research, Cambridge, MA, USA, June 2012, <http://www.targetscan.org/mmu_61/>). Context++ scores of the sites are used to determine the predicted efficacy of targeting. They are measured using the contribution of 14 features, such as site-type, supplementary pairing and minimum distance \[[@B37-molecules-20-19433]\]. The predictions are then ranked. According to these predictions, more than 20 miR-223 targets have been validated in studies conducted in humans or mice. Such targets include CCAAT/enhancer-binding protein-β (C/EBPβ), inhibitor of nuclear factor κB kinase subunit-α (IKKα), nuclear factor 1 A-type (NFIA) and fibroblast growth factor receptor 2 (FGFR2) \[[@B32-molecules-20-19433]\].
FGFR2 and NFIA have been identified as miR-223 targets that participate in the osteoblasts differentiation and osteoclastogenesis \[[@B38-molecules-20-19433]\], a process which includes osteoclast differentiation \[[@B35-molecules-20-19433]\]. IKKα, a critical regulator of the NF-κB pathway, has been reported as a miR-223 target, with binding resulting in suppression of monocyte and macrophage differentiation \[[@B39-molecules-20-19433]\]. Given that osteoclasts are monocyte-and macrophage-derived cells \[[@B40-molecules-20-19433]\], IKKα is implicated in the mechanism by which miR-223 regulates osteoclast differentiation.
3. Regulation of miR-223 in Osteoclast Differentiation {#sec3-molecules-20-19433}
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3.1. MIR-223 Regulates Osteoclast Differentiation by Inhibiting NFIA Expression {#sec3dot1-molecules-20-19433}
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NFIA is a CCAAT-box binding transcription factor, belonging to a dimeric DNA-binding nuclear factor I (NFI) protein family \[[@B41-molecules-20-19433]\]. Zardo *et al*. demonstrated that miR-223 binds to specific sites within the promoter of its target gene NFIA and represses transcription by influencing epigenetic events \[[@B42-molecules-20-19433]\]. Based on these reports, researchers investigated the potential of miR-223 to regulate osteoclast differentiation by inhibiting NFIA expression. Li *et al*. showed that miR-223 expression was down- regulated in the synovium of mice following intraperitoneal injection of a lentiviral vectors expressing the miR-223 target sequence (LVmiR-223T), with a concomitant increase in NFIA expression. Staining with the osteoclast-specific marker, tartrate-resistant acid phosphatase (TRAP), showed that osteoclast numbers were greatly reduced in LVmiR-223T-transduced bone marrow macrophages (BMMs), and increased NFIA expression was also detected. Similar results were also obtained using RAW 264.7 cells \[[@B33-molecules-20-19433]\]. Hruska *et al*. found that in cells which expressed DGCR8, Dicer 1 or Ago and in Dicer-null osteoclast precursors (BMMs), NFIA was upregulated. However there was no detectable expression of NFIA in scrambled cells which expressed siRNA or in miR-223 expressing Dicer^wt/wt^ osteoclasts \[[@B43-molecules-20-19433]\]. Subsequently, osteoclast formation assays using antisense miR-223 oligonucleotides showed that 92% inhibition of miR-223 induced down-regulation of TRAP-positive osteoclast formation in RAW264.7 cells compared with controls, while NFIA levels were upregulated. Previously, the same authors had found that in pre-miR-223 siRNA-expressing RAW264.7 cells in which the miR-223 was decreased by 66%, TRAP-positive osteoclast formation was unaffected \[[@B44-molecules-20-19433]\], with no alterations of NFIA expression associated with this level of miR-223 inhibition. The authors speculated that the direct suppression of mature miRNAs by antisense oligonucleotides may be more effective than that of pre-miR-223 mediated by siRNA containing the stem-loop structure target sequence \[[@B43-molecules-20-19433]\].
In turn, miR-223 expression is regulated by the competition between NFIA and CCAAT/enhancer-binding protein-α (C/EBPα) \[[@B45-molecules-20-19433]\], which is known to function as an activator of target genes through binding directly to the consensus DNA sequence \[[@B46-molecules-20-19433]\]. In undifferentiated NB4 cells, an acute promyelocytic leukemia cell line, NFIA binds the miR-223 promoter, maintaining miR-223 expression levels and consequently, low levels of miR-223-mediated translational repression. The process of differentiation involves NFIA being replaced by C/EBP α on the miR-223 promoter. This increases the expression of miR-223 \[[@B38-molecules-20-19433]\], causing increased miR-223-dependant repression of NFIA mRNA and decreased NFIA protein expression \[[@B32-molecules-20-19433]\]. In this way, NFIA limits miR-223 expression under undifferentiated conditions, while miR-223 limits NFIA expression during the differentiation process. In terms of miRNAs that inhibit mRNA translation \[[@B47-molecules-20-19433]\], Shibuya *et al*. examined the NFIA expression in peripheral blood mononuclear cells at both the mRNA and protein levels 3 days after transfection with double-stranded-miR-223 and a double-stranded negative control \[[@B34-molecules-20-19433]\]. It was found that miR-223 overexpression resulted in downregulated NFIA expression at the protein level but not at the mRNA level during osteoclast differentiation. In this way, NFIA will be upregulated when miR-223 expression is extremely low, thus, blocking osteoclast differentiation.
Moreover, Hruska *et al*. revealed a positive feedback loop between PU.1, macrophage colony-stimulating factor receptor (M-CSFR), NFIA and miR-223, which was involved in osteoclast differentiation \[[@B43-molecules-20-19433]\]. In osteoclast precursors, PU.1, known as a transcription factor encoded by the SPI1 gene \[[@B48-molecules-20-19433]\], is induced by M-CSF stimulated production of pri-miR-223. Pre-miR223 is processed by RNase III enzymes including Dicer, into mature miR-223. The result of this is downregulation of NFIA levels necessary for upregulation of M-CSFR levels in cells. Consequently, there is an increase in the expression of PU.1, MITF, and other transcription factors induced by M-CSF. As a consequence, cells differentiate into activated osteoclasts with upregulated expression of osteoclast-specific markers \[[@B43-molecules-20-19433]\]. Furthermore, NFIA overexpression was shown to decrease osteoclast differentiation with downregulation of M-CSFR levels, while forced M-CSFR expression rescued osteoclast differentiation with upregulation of PU.1 levels in MCSF-dependent BMMs prepared from miR-223 Dicer-deficient mice. In accordance with this theory, M'Baya-Moutoula *et al*. confirmed that anti-miR-223 treatment inhibited osteoclastogenesis and overexpression miR-223 triggered differentiation in both RAW 264.7 cells and peripheral blood mononuclear cells (PBMCs) \[[@B49-molecules-20-19433]\]. Although NFIA expression was found to be inversely associated with M-CSFR \[[@B33-molecules-20-19433]\] and two putative NFIA-binding sites on the M-CSFR promoter, the precise identity of the cells expressing NFIA and the M-CSFR and the mechanism by which NFIA exerts negative effects on M-CSFR expression were not identified \[[@B43-molecules-20-19433]\].
In conflict with the PU.1/miR-223/NFIA positive feedback theory, miR-223 overexpression was reported to block osteoclast differentiation in RAW264.7 cells \[[@B44-molecules-20-19433]\] and PBMCs \[[@B34-molecules-20-19433]\]. The mechanisms underlying these dual effects of miR-223 on osteoclast differentiation are not well-defined \[[@B50-molecules-20-19433]\] and the precise interaction between NFIA and M-CSFR is likely to be critical for fully understanding this discrepancy. Given that the regulatory effect of NFIA on M-CSFR does not sufficiently explain why either overexpression or knockdown of miR-223 inhibits osteoclastogenesis, it can be speculated that there are other intracellular pathways which interact independently with NFIA in the regulation of miR-223 in osteoclast differentiation.
3.2. IKKα Could be Involved in the Regulation of miR-223 for Osteoclast Differentiation via Non-Canonical NF-κB Pathway {#sec3dot2-molecules-20-19433}
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Shibuya *et al*. investigated the effect of over-expression miR-223 in osteoclastogenesis induced in vitro by RANKL. The results show that numbers of TRAP-positive osteoclasts were significantly reduced, suggesting that signaling pathways downstream of RANKL are the targets of miR-223 \[[@B34-molecules-20-19433]\]. RANKL is expressed in osteoclast precursors and mature osteoclast \[[@B51-molecules-20-19433]\]. The binding of RANKL and RANK is known to be pivotal in the regulation of mature osteoclast differentiation by activating intracellular signals, such as NF-κB \[[@B52-molecules-20-19433]\]. IKKα, one of critical factors in the NF-κB pathway, is considered to be a target of miR-223 for inhibiting differentiation of osteoclasts \[[@B40-molecules-20-19433]\], therefore, we focus here, on the possible roles of IKKα in the regulation of miR-223 for osteoclast differentiation via NF-κB pathway \[[@B53-molecules-20-19433]\].
IKKα mRNA was predicted as target sequence of miR-223 by the Memorial Sloan Kettering Cancer Center miRNA database \[[@B54-molecules-20-19433]\], and further identified in a series of experiments \[[@B39-molecules-20-19433]\]. IKK is a part of the complex responsible for the induction of phosphorylation and the degradation of IκB-α in the conventional NF-κB pathway \[[@B55-molecules-20-19433]\]. Therefore, IKKα also participates in the non-canonical NF-κB pathway \[[@B56-molecules-20-19433]\]. MiR-223 target sites have been shown to contribute to the suppression of expression IKKα but did not affect the expression of IKKβ or IKKγ in monocytes or macrophages, suggesting that miR-223 specifically regulates the non-canonical NF-κB pathway but not the canonical NF-κB pathway \[[@B39-molecules-20-19433]\].
NF-κB p100 is a non-canonical inhibitory κB protein. In unstimulated cells, it binds to RelB, preventing its translocation to the nucleus \[[@B57-molecules-20-19433]\]. The ubiquitination and lysosomal degradation of TRAF3 is induced by RANKL by the action of TRAF2/cellular inhibitor of apoptosis 1/2 (cIAP1/2). This releases NF-κB-inducing kinase (NIK), enabling it to phosphorylate IKK-α. The effect of this is conversion of p100 to p52 by proteasomes \[[@B58-molecules-20-19433]\]. Thus, miR-223 overexpression would downregulate p52, and miR-223 knockdown would upregulate p52 expression. Li *et al*. suggested two probable roles for p52 during the miR-223 regulated differentiation process \[[@B39-molecules-20-19433]\]. The first is the prevention of the hyperactivation of new macrophages. The second is activation of gene transcription. The first role may be mediated, at least partially, by the upregulation of p52 in the absence of Re1B expression, leading to reduced gene transcription. The second role is likely to be a consequence of p52 binding to newly synthesized Re1B protein \[[@B59-molecules-20-19433]\]. RelB has been implicated as a key factor in the activation of non-canonical NF-κB dimers that is detected at low levels in unstimulated macrophages \[[@B60-molecules-20-19433]\]. RelB/p52 heterodimers can translocate to the nucleus to induce nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) \[[@B61-molecules-20-19433]\], which is necessary for osteoclast differentiation \[[@B62-molecules-20-19433]\]. Thus, it can be speculated that miR-223 knockdown leading to increased IKKα expression can inhibit osteoclast differentiation via excess p52 in the absence of RelB. The decrease in IKKα expression which is downregulated by miR-223 overexpression will also inhibit osteoclast differentiation with the reduction of RelB/p52 heterodimers.
Therefore, the non-canonical NF-κB pathway induced by binding of RANKL is probably involved in the regulation of miR-223 which down-regulates the expression of IKKα in osteoclasts differentiation. Although the precise mechanism remains to be confirmed in further experiments, this could be one explanation for the dual role of miR-223 in regulation of osteoclast differentiation.
4. The Regulation of miR-223 in Osteoblast Differentiation {#sec4-molecules-20-19433}
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The reciprocal regulation of the differentiation of adipocytes and osteoclasts involves miR-223. Guan *et al*. found that, following osteogenic treatment, miR-223 was reduced in preosteoblast MC3T3-E1. If miR-223 levels are supplemented by synthetic mimics, the growth of C3H10T1/2 and ST2 cells is slowed, whilst the differentiation of progenitor cells into adipocytes is induced, as is C/EBPα. Another illustration of the role of miR-223 on the formation of adipocytes from ST2 cells is provided by the overexpression of miR-223 caused by the lentivirus. The differentiation of ST2 cells into osteoblasts is prevented by miR-223 supplementation.
Dual luciferase reporter assay revealed that fibroblast growth factor receptor 2 (FGFR2) is a direct target of miR-223 \[[@B63-molecules-20-19433]\]. FGFR2 is a critical regulator of osteoblasts. FGFR2 knockdown in C3H10T1/2 cells downregulated ERK phosphorylation, upregulated C/EBPα expression and dramatically enhanced the differentiation of the cells into adipocytes \[[@B35-molecules-20-19433]\]. Other studies showed that activation of FGFR2 signaling enhanced osteoblast differentiation \[[@B17-molecules-20-19433]\] by increasing runt-related transcription factor 2 (RUNX2) phosphorylation \[[@B64-molecules-20-19433]\] mediated by extracellular signal regulated kinase (ERK) involved in MAPK pathway \[[@B65-molecules-20-19433]\]. ERK also reduces C/EBPα activity by phosphorylation \[[@B66-molecules-20-19433]\] and since C/EBPα induces miR-223 expression through binding to the miR-223 promoter sites \[[@B67-molecules-20-19433]\], it is proposed that miR-223 down-regulates osteoblast differentiation through a C/EBPα/miR-223/FGFR2 regulatory feedback loop \[[@B35-molecules-20-19433]\].
5. The Mediating Role of PU.1 in Regulation of miR-223 During Osteoblast and Osteoclast Differentiation {#sec5-molecules-20-19433}
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PU.1 is a member of the Ets family of transcription factors. It is important in the development of hematopoietic cell lines. This is particularly so for monocyte/dendritic cells \[[@B68-molecules-20-19433]\]. It also has a role in osteoclast-specific gene expression with NFATc1 \[[@B69-molecules-20-19433]\]. The regulation of specific genes in response to M-CSF and RANKL signaling during osteoclast differentiation is controlled by the transcription factors NFATc1, PU.1 and by microphthalmia-associated transcription factor (MITF), acting together \[[@B70-molecules-20-19433]\].
As shown in previous studies, miR-223 overexpression induced by excess PU.1 would indirectly down-regulate the differentiation of osteoclasts and osteoblasts in aberrant bone metabolism. In these processes, the promoter of PU.1 is activated by C/EBPα \[[@B71-molecules-20-19433]\], which cooperates with PU.1 and induces the expression of miR-223 \[[@B72-molecules-20-19433]\]. In cells of the hematopoietic myeloid-osteoclast lineage, M-CSF induces PU.1 expression through M-CSFR \[[@B73-molecules-20-19433],[@B74-molecules-20-19433]\]. Therefore, PU.1 acts as a mediating factor in the regulation of miR-223 in osteoclast and osteoblast differentiation.
In light of these findings, it can be concluded that regulatory networks involving miR-223 play multiple roles in regulating bone metabolism ([Figure 1](#molecules-20-19433-f001){ref-type="fig"}).
{#molecules-20-19433-f001}
6. MiR-223 in Diseases with Bone Disorders {#sec6-molecules-20-19433}
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It has been found that miR-223 expression in synovium of patients with RA (21.0 ± 14.4-fold) is significantly higher than in the synovium of patients with osteoarthritis (OA) and healthy individuals \[[@B34-molecules-20-19433]\]. Furthermore, the synovial tissue expressing high miR-223 exhibited poorly controlled bone destruction and severe acute synovitis. Increased levels of miR-223 expression detected in the ankle joints of mice during the collagen-induced arthritis (CIA) are accompanied by reduced NFIA levels and elevated M-CSFR levels. In this model, the level of miR-223 expression increased 29-fold on day 21 after collagen immunization (onset of arthritis), but had decreased to nearly basal level on day 42 (arthritic stage) \[[@B33-molecules-20-19433]\]. Mild osteopetrosis in mice is known to be associated with high levels of miR-223 in osteoclasts \[[@B43-molecules-20-19433]\].
Zhang *et al.* reported significantly lower miR-223 levels in osteosarcoma tissues compared with those in non-cancerous bone tissues, which is consistent with the previous studies conducted by Li *et al.* \[[@B75-molecules-20-19433]\] and Xu *et al*. \[[@B76-molecules-20-19433]\]. More significantly, they found that aggressive features, such as high tumor grade, metastases and recurrence were associated with the deregulation of the miR-223/ECT2 axis. Moreover, it also predicted a poor response to chemotherapy and decreased survival of patients with osteosarcomas \[[@B77-molecules-20-19433]\]. The oncogenic heat shock protein 90B1 (HSP90B1) is a target of miRNA-223 in human osteosarcoma \[[@B75-molecules-20-19433]\]. Furthermore, recent data show that miR-223 is abundantly expressed in multiple myeloma, its expression being the 15th highest among 722 miRNAs \[[@B78-molecules-20-19433]\]. Extramedullary plasmacytomas can be distinguished from multiple myeloma on the basis of a lack of miR-223 \[[@B79-molecules-20-19433]\].
Vascular calcification is found to be an actively process, which shares all features with bone metabolism \[[@B80-molecules-20-19433],[@B81-molecules-20-19433]\]. Massy *et al*. found miR-223 upregulated in vascular smooth muscle cells (VSMCs) under inorganic phosphate conditions and promoting VSMC proliferation and migration by suppressing the expression of MEF2C and RHOB \[[@B31-molecules-20-19433],[@B82-molecules-20-19433]\]. Studies showed that miR-223 was also increased in calcified aortas isolated from murine models of chronic kidney disease, which is implicated in vascular calcification \[[@B83-molecules-20-19433],[@B84-molecules-20-19433]\]. M\'Baya-Moutoula *et al*. identified that miR-223 induced osteoclastogenesis by affecting the expression of NFIA and RHOB and they demonstrated an approach that overexpresses miR-223 to selectively increase osteoclast-like activity in calcified vessels of chronic kidney disease-mineral and bone disorder (CKD-MBD) to alleviate vascular calcification \[[@B49-molecules-20-19433]\].
All these findings demonstrated that miR-223 is an important regulator in diseases with bone disorders, with changes in its expression associated with the development stages and control of clinical signs ([Table 1](#molecules-20-19433-t001){ref-type="table"}).
molecules-20-19433-t001_Table 1
######
MiR-223 in diseases with bone disorders.
Disease MiR-223 Expression Target Gene Species MiR-223 Effect Reference
------------------------------------------------------------ --------------------------------------------------- -------------- --------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------
Rheumatoid arthritis (RA) ↑ (21.0 ± 14.4-fold) NFIA Human Accompany by acutely severe synovitis and poorly controlled bone destruction \[[@B33-molecules-20-19433],[@B34-molecules-20-19433],[@B43-molecules-20-19433]\]
Osteoarthritis (OA) ↑ (4.1 ± 3.1-fold) NFIA Human Not mentioned \[[@B33-molecules-20-19433],[@B34-molecules-20-19433],[@B43-molecules-20-19433]\]
Collagen-induced arthritis (CIA) ↑ (29-fold) on day 21 after collagen immunization NFIA Mouse Accompany with reduction of NFIA and elevation of M-CSFR \[[@B33-molecules-20-19433],[@B43-molecules-20-19433]\]
Osteopetrosis ↓ NFIA Mouse Down-regulation of osteoclast differentiation \[[@B43-molecules-20-19433]\]
Osteosarcoma ↓ ECT2 HSP90B1 Human Correlated with high tumor grade, the presence of tumor metastasis and recurrence, and the poor response to chemotherapy and also predicted a decreased survival prediction of patients \[[@B75-molecules-20-19433],[@B76-molecules-20-19433],[@B77-molecules-20-19433],[@B85-molecules-20-19433]\]
Multiple myeloma ↑ Human Not mentioned \[[@B78-molecules-20-19433],[@B79-molecules-20-19433]\]
Vascular calcification ↑ RHOB, MEF2C Human Promotion of VSMC proliferation and migration \[[@B81-molecules-20-19433],[@B86-molecules-20-19433]\]
Chronic kidney disease-mineral and bone disorder (CKD-MBD) ↓ NFIA RHOB Human Obliterate the inhibitory effects of inorganic phosphate on osteoclastogenesis \[[@B49-molecules-20-19433]\]
7. Discussion and Perspectives {#sec7-molecules-20-19433}
==============================
Here, a new aspect regarding the multiple roles of miR-223 in regulating bone metabolism has been revealed. There are at least two different pathways involved in the regulation of miR-223 in osteoclast differentiation, which exert antagonistic or synergistic functions at different expression levels. When miR-223 is elevated during abnormal bone metabolism, the expression of IKKα and NFIA are both downregulated, resulting in the reduction of osteoclast differentiation or increased osteoclast differentiation. When miR-223 expression is extremely low due to the effects of anti-miR-223 oligonucleotides or siRNA, the elevation of IKKα and NFIA expression causes a concomitant downregulation in osteoclast differentiation. This indicates the existence of a switch point in the expression levels of miR-223 that controls the inhibitory and stimulatory effects on osteoclast differentiation. Therefore, identification of this switch point is a prerequisite for the clinical use of miR-223 in treating pathological bone destruction diseases.
It has been found that miRNAs are useful diagnostically and therapeutically in several malignancies \[[@B85-molecules-20-19433]\]. They can be detected, and their concentrations measured, in small peripheral blood samples. In serum, they are stable at room temperature and can withstand freeze-thaw conditions \[[@B87-molecules-20-19433]\]. Therefore, miR-223 represents a promising diagnostic and/or prognostic tool for the treatment of bone diseases that are related to aberrant bone metabolism, such as RA, OA and osteoporosis. Similarly, miR-223 is implicated as a biomarker that can be used to monitor the effectiveness of therapies.
The improved stability and long-lasting effects of synthetic anti-miRNAs make complementarity-based inhibition when given intravenously or locally to specific sites within the cardiovascular compartment, which is an exciting potential treatment modality of the future \[[@B88-molecules-20-19433]\]. Miravirsen, an anti-miRNA of miR-122, can be considered as a representative of this new class of therapeutic agents. It has undergone phase II testing in patients infected with the hepatitis C virus \[[@B89-molecules-20-19433]\]. Down-regulating the expression of miR-223 to extremely low level can either decrease osteoclastogenesis or enhance osteoblast differentiation, an approach that represents a therapeutic strategy for the treatment of bone metabolism disorders which increase bone resorption or decrease bone formation.
There is a number of methods to deliver miR-223 in pathological tissues, for example, augmenting miRNA levels can be used to deliver miRNA through viral-based vectors such as adenoviruses, adeno-associated viruses, and lentiviruses. Also, systemic delivery of siRNAs have been developed and tested by lipid- and polymer-based nanoparticles \[[@B90-molecules-20-19433]\]. Furthermore, microvesicles and apoptotic bodies, which contain circulating miRNAs, can be considered as a therapeutic transport system \[[@B91-molecules-20-19433]\]. However, overexpressing miR-223 is not suitable for treatment of pathological bone destruction diseases, on account of its dual effect in stimulating osteoclast differentiation and inhibiting osteoblast differentiation. Replacing downregulated miRNA or increasing miRNA expression is problematic for a number of reasons, which include their short half-lives and short durations of action \[[@B92-molecules-20-19433],[@B93-molecules-20-19433]\]. The solution is likely to be miRNA mimics designed for specific sites and delivered using novel systems \[[@B88-molecules-20-19433]\].
Given that individual miRNA modulate over 100 target genes, their modulation might reasonably be expected to result in both positive (therapeutic) and negative (pathological) effects. This may also be the case with antisense RNA oligonucleotides (ASOs) against miRNA. Multiple genes acting together in a common pathway can be the target of a single miRNA. An equally important consideration is to determine the appropriate doses to use of ASOs and miRNA mimics. This will require careful evaluation of the pharmacokinetics of differentially modified short oligonucleotides \[[@B87-molecules-20-19433]\]. Therefore, further studies are needed to fully elucidate the modulatory roles of miR-223 targets in bone metabolism, and the association between these targets and miR-223 expression level.
Y.X., P.T. and L.Z. are supported by the National Natural Science Foundation of China (31370947). Y.G. and W.G. is supported by the National Natural Science Foundation of China (81373150).
Each author has participated in the work to take public responsibility for the article content. W.G. and P.T. made substantial contributions to conception and design this review; Y.X., L.Z. and Y.G. participated in drafting the article and prepared it in the model of the journal; All authors gave final contributions and approved the final version to be submitted.
The authors declare no conflict of interest.
Abbreviations
Full Term
ASO
antisense RNA oligonucleotides
BMMs
bone marrow macrophages
C/EBPα
CCAAT/enhancer binding protein-α
CIA
collagen-induced arthritis
CKD-MBD
chronic kidney disease-mineral and bone disorder
ECT2
epithelial cell-transforming sequence 2
ERKs
extracellular signal regulated kinases
FGFs
fibroblast growth factors
FGFR2
fibroblast growth factor receptor 2
HSP90B1
heat shock protein 90B1
IKKα
inhibitor of nuclear factor κB kinase subunit-α
LVmiR-223T
lentiviral vectors expressing the miR-223 target sequence
MAPK
mitogen-activated protein kinase
M-CSF
macrophage colony-stimulating factor
M-CSFR
macrophage colony-stimulating factor receptor
MEF2C
myocyte-specific enhancer factor 2C
MiRNA
microRNA
MiR-223
microRNA-223
MITF
microphthalmia-associated transcription factor
NFκB
nuclear factor κB
NFIA
nuclear factor 1 A-type
NIK
NF-κB-inducing kinase
NEMO
NF-κB essential modulator
NFATc1
nuclear factor of activated T-cells, cytoplasmic 1
OA
osteoarthritis
PBMCs
peripheral blood mononuclear cells
RA
rheumatoid arthritis
RANK
receptor activator of nuclear factor κB
RANKL
receptor activator of nuclear factor κB ligand
RHOB
rho-related GTP-binding protein RhoB
RUNX2
runt-related transcription factor 2
TRAP
tartrate-resistant acid phosphatase
TRAF2/3
TNF receptor-associated factor 2/3
TGFβ
transforming growth factor beta
VSMCs
vascular smooth muscle cells
3ʹ-UTR
3ʹ-untranslated region
[^1]: These authors contributed equally to this work.
| 2023-12-18T01:26:51.906118 | https://example.com/article/5534 |
Looks We Loved From Lollapalooza 2012
Another year, another Lollapalooza has come and gone. Even though the festival is all about music, booze, and parties, it turned out to also be about fashion as some artists were sporting great florals, prints, and leather. Check out our favorite looks from the weekend! | 2024-03-06T01:26:51.906118 | https://example.com/article/2381 |
Our Guidance Department is staffed with dedicated professionals. The services offered by guidance are many and diverse. Our primary function is to help students understand themselves in order to make better decisions about their lives. We help students identify their strengths and talents with the intention of providing appropriate and informed academic, college and career choices. Throughout the school year students will meet with their counselor individually, and/or in groups, and as needed. Students are encouraged to schedule appointments when the need arises. Counselors are also receptive to students in need of personal counseling. | 2024-04-07T01:26:51.906118 | https://example.com/article/1019 |
<@lib.dto
title = "DeploymentResourceDto"
desc = "A JSON object corresponding to the `Resource` interface in the engine.
Its properties are as follows:" >
<@lib.property
name = "id"
type = "string"
desc = "The id of the deployment resource." />
<@lib.property
name = "name"
type = "string"
desc = "The name of the deployment resource" />
<@lib.property
name = "deploymentId"
type = "string"
last = true
desc = "The id of the deployment." />
</@lib.dto>
| 2023-09-19T01:26:51.906118 | https://example.com/article/3148 |
Popular Cities
Projects With A Purpose
How GMA Construction Group impacts its community, one project at a time
GMA Construction Group hires people like Carl Nesbitt, Assistant Superintendent (pictured on the left) from within the housing communities it renovates. Also shown are Deon King, Superintendent (middle) and Cornelius Griggs, President.
Rendering of one of GMA Construction Group’s projects, Gads Hill Center in Brighton Park, shows the conversion of an existing commercial space into a full-service early childhood learning facility.
Chicago is the third-largest city in the United States, with nearly three million people living in 77 communities that contain more than 100 neighborhoods. With so many people and the vast variety of communities that exist within the metropolitan area, it would seem an impossible dream for someone to improve the landscape and the lives of the residents across the city’s diverse cultural and economic spectrum—not only in the most desirable areas of the city, but also in those places where things seem the darkest.
But for Chicago native Cornelius Griggs, President and co-founder of Griggs Mitchell & Alma of IL (doing business as GMA Construction Group) in Chicago, the dream is becoming a reality with each project his company completes. GMA Construction Group, founded in 2015, is a veteran-owned, fully integrated general contracting, construction management and design-build firm. Its projects span a variety of types and sites, including the Chicago Public Library, the historic Hotel Florence in Chicago, ACCESS Des Plaines Valley Health Center, Forest Preserves of Cook County campgrounds, J.T. Manning Elementary School and several multi-unit residences.
For Cornelius, construction is a method for improving the Chicagoland area through the skills and experience he has developed over the years. And because of his background, those people seemingly living under a cloud of economic depression are in the areas where he sees an opportunity to make the biggest impact.
Preparation for the Future
Growing up on the West Side of Chicago, Cornelius could not have predicted that his life experiences would be foundational elements on his road to a career in construction and would fuel his passion to help others. “I grew up in some of the toughest parts of the city. I was a ward of the state from the time I was nine until I was 23 years old,” says Cornelius. He further explains, “Bouncing around through the system, living in multiple housing projects, having that experience with that part of my life and being able, now, to be in a position where I could have never dreamed of being is all very humbling and inspiring.”
One of the housing projects Griggs lived in was Cabrini-Green, a low-income public housing complex characterized by buildings in disrepair, unmaintained landscaping, high crime rates and gang activity.
How did he excel beyond circumstances that would have made others crumble or choose a path of destruction? Cornelius explains, “I often think about that. When I do, I tend to fall back on the fact that there was a higher power guiding me. I had an internal instinct that was placed in me by a higher power to say, ‘Hey this probably isn’t the right thing to do. Let them go that way, you go this way.’ ”
It was that internal instinct, along with his perseverance, work ethic and educational accomplishments that enabled him to transition out of what some may have described as a hopeless situation. He would go on to use those skills in the U.S. Army Reserve—serving 10 years with tours in Afghanistan and Uzbekistan—and in every other area of his life.
Seizing Opportunity and Industry Experience
Although a career in construction was not on his radar when he first started college, during his junior year he landed an internship with Clark Construction that changed the trajectory of his life. After graduating, Cornelius immersed himself in the industry, working full time at Clark Construction in the corporate risk management department and then out in the field, where he discovered his calling. “I found that I had a passion for the field of construction and construction management,” Cornelius explains. Although he considered law school, when Clark Construction offered to pay for his master’s degree, he took full advantage of the opportunity. He earned a degree in industrial technology and operations with a concentration in construction management while continuing to work for Clark Construction.
It was with this company that he first gained experience working on a range of projects, including the McCormick Place West Building expansion. “On that project, I oversaw a ton of trade contractors. Roughly $40 million to $50 million worth of trade contractors were under my watch,” says Cornelius.
If Cornelius wanted to leave the Windy City, he could have moved to the West Coast when Clark Construction gave him the option after the recession caused a reduction of projects in Chicago. Instead, he landed a job at Walsh Construction and stayed in Chicago. For the next decade, this is where he continued to hone his skills and build his personal portfolio, which included projects that ranged from a $152 million downtown high-rise, Metra stations and Chicago Housing Authority projects, to several Chicago Public School (CPS) buildings. Many of the CPS projects took him back to the same streets he grew up on, reminding him of how far he had come—going from a student walking the halls to being responsible for overseeing the restoration of the very same structures.
“We deliver a high-quality product to residents who would not get that type of quality living in those communities.”
Cornelius Griggs,
President and Co-Founder,
GMA Construction Group
Associating Education with Industrial Change
Working on site at those projects, where he saw faces like his—people with the same ethnic background and economic beginnings—was quite different than working at the management level where he witnessed a lack of minority representation. “When I was first introduced to the field of construction management back in 2002, I noticed that there was a kind of a drought of minority managers. I participated in various organizations and meetings; there was hardly ever, at any point, anyone who looked like me, resembled me, in these meetings,” he says.
Instead of just observing the need for diversity, Cornelius became a change agent and established a platform through which minorities could learn about construction management. In 2008, he worked with Robert Kelly, Dean of Dawson Technical Institute, to establish an associate science degree in construction management at the City Colleges of Chicago. “This program is geared towards minorities and disadvantaged students from throughout the city of Chicago, who are interested in the field of construction management,” says Cornelius. During the first two years of the program, Cornelius taught all 10 of the classes. Now there are five instructors teaching the 30-hour construction management coursework.
Passion for Improving Property and Equipping People
Cornelius’ commitment to diversifying the industry didn’t end there. After 13 years of working for other construction companies, he recognized that owning his own business would put him in the best position to help students transition into the industry by creating jobs. About 85 percent of his workforce is made up of former students. “I’ve been able to extract students from that program and give them an opportunity that they would not have been able to get in our industry with their lack of experience,” he says. GMA Construction Group employs 17 individuals on the management level and between 30-45 people in the field, with each person playing an integral role in the organization’s success.
Owning his own firm also allowed him to pursue bids in the disadvantaged neighborhoods he once called home. “When I started my own firm, I geared my business around projects within those low-income areas,” Cornelius shares. He further emphasizes, “We deliver a high-quality product to residents who would not get that type of quality living in those communities.”
The East Park Apartments project in Chicago, a $14-million renovation effort, is a prime example of how GMA Construction Group is not only bringing new life to a neighborhood complex, but also to its inhabitants. Restoration of the 153-unit building includes gutting existing units and updating them with new drywall, paint, floors, cabinets, appliances, countertops and lighting, as well as new corridor lighting fixtures and flooring and other improvements.
The work on the building, however, is not what Cornelius is most proud of. Instead, it’s the team of people he works with—including John Adams, Project Executive; Nnamdi Ogbuagu, Assistant Project Manager; and Deon King, Superintendent. He’s also proud of the three community-hire positions he created to provide East Park residents with the opportunity to get hands-on experience in the construction industry. These jobs—assistant superintendent, general laborer, and site security—establish another avenue for minorities to enter the trade without the need for previous industry experience.
“I feel like my duty or goal in life is to use construction to put people in places that they wouldn’t normally be able to be in. If I can impact the lives of those who live in the communities through the projects that we do, then that’s really what I think I’ve been put here to do,” says Cornelius. “That’s what drives me, every day.”
Cornelius has come full circle—and his company is prospering. In just two years’ time his business revenue has increased by nearly 300 percent each year. GMA Construction Group was recently selected to work in the neighborhood he once called home, on the Cabrini-Green Site 1 Redevelopment Project, a 6.9-acre site that will include more than 482 units of mixed-income housing. Cornelius also continues to pursue new endeavors, such as the new Obama Presidential Center planned for Jackson Park. One look at his life’s journey, and it’s clear he is passionately pursuing his purpose.
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Contributors
Tracy Torma of Torma Communications is a former newspaper reporter and now corporate journalist who specializes in writing, editing and publication production. She’s been telling people’s stories for more than 40 years.
Marge O’Connor, owner of TMC Resources, has been providing marketing and editorial services for the AEC community for more than 25 years. She especially enjoys interviewing people, learning about their experiences, and crafting stories about them for Who’s Who. | 2024-05-06T01:26:51.906118 | https://example.com/article/7271 |
Home > Sewage legislation passed in Harrisburg; Current standard to remain in place
Sewage legislation passed in Harrisburg; Current standard to remain in place
By David Hulse and Fritz Mayer
July 2, 2013 —
HARRISBURG, PA — Legislation passed in the Pennsylvania General Assembly last week prevents new policy from being implemented that could have greatly increased the cost of installing new septic systems in areas with high quality (HQ) and exceptional value (EV) watersheds in Pennsylvania. The legislation was supported by Senator Lisa Baker, and representatives Sandra Major, Rosemary Brown and Mike Peifer.
The bill allows the Department of Environmental Protection (DEP) to approve septic systems using the current standards.
“We are pleased to have this legislation garner such strong support in both the House and Senate and look forward to House Bill 1325 being signed into law by the governor in the coming days,” announced the lawmakers. “We also appreciate the work of our local elected officials, conservation districts, planning boards and sewage enforcement officers, who take great strides to maintain and protect our waterways. Their hard work and successful track record is what helped this legislation ultimately pass.”
The new policy that was to be adopted by the DEP was bitterly opposed by local officials.
At the Pike County Commissioners’ meeting on June 18, Commissioner Matt Osterberg said it was important that the bill pass. He said, “I don’t have to tell you how important this is to Pike County residents with the economy the way it is.”
As he has said in past, Chairman Rich Caridi insisted, “There is no nitrate problem in Pike County. Apparently the legislature agrees with us.”
The DEP proposed the new rules after losing a court challenge to its approval of a Lycoming County sewage plan. Since that decision (Pine Creek Valley Watershed Assoc. v. DEP), the DEP proposed new guidance for on-lot systems within HQ and EV watersheds. Uncommon in most of the state, these streams drain much of Wayne and most of Pike counties.
That guidance reportedly would have prohibited septic systems closer than 150 feet from a body of water or 30 feet from a stream, and require underground septic systems to be surrounded by a barrier to prevent the effluent from traveling underground.
Sponsors of the house legislation said it had become clear through public input that the proposed DEP guidance would be impractical, leaving the DEP with no approach upon which to rely when approving development projects using on-lot systems in HQ and EV watersheds.
Caridi said that Baker had met with environmental groups supporting the new rules. “Once our concerns were explained to them, they took a neutral position and did not lobby against the legislation.” | 2023-08-05T01:26:51.906118 | https://example.com/article/8035 |
The BASP1 family of myristoylated proteins abundant in axonal termini. Primary structure analysis and physico-chemical properties.
Proteins BASP1 and GAP-43/B-50, which are abundant in nerve endings, show a number of similar physico-chemical properties. Nevertheless, they belong to different protein families. In this work, complete amino acid sequences of bovine BASP1 and human BASP1 were established. They proved to be very similar to the sequences of rat brain protein NAP-22 and chicken brain protein CAP-23. Relatively to human BASP1 its bovine, rat and chicken analogues show 80%, 70% and 45% sequence identity respectively, confirming their membership of a definite protein family (BASP1 family). All members of BASP1 family contain several 'good' PEST sequences characteristic for short-living proteins. Conservation of PEST sequences in BASP1 of different species points to their significance for BASP1 functions. In contrast to GAP-43/B-50 showing high immunological cross-reactivity between the proteins belonging to different species of mammals, immunological properties of BASP1 are species specific. BASP1 shows both high hydrophilicity and some properties characteristic for hydrophobic proteins. These properties are caused by N-terminal myristoylation of BASP1 molecules. Unlike GAP-43/B-50, BASP1 is present in high amounts also in some non-nervous tissues: testis, kidney and lymphoid organs (spleen, thymus). So far examined characteristics, including myristoylation, peptide maps and detected by isoelectrofocusing microheterogeneity, proved to be the same for BASP1 samples isolated from both brain and non-nervous tissues. Therefore, in spite of different physiological consequences, biochemical functions of BASP1 must also be similar in different tissues. | 2024-07-27T01:26:51.906118 | https://example.com/article/8161 |
/*
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package java.lang;
import java.io.PrintStream;
import java.util.Arrays;
import java.util.List;
import java.util.Map;
import java.util.Optional;
class VersionProps {
private static final String launcher_name =
"@@LAUNCHER_NAME@@";
private static final String java_version =
"@@VERSION_SHORT@@";
private static final String java_version_date =
"@@VERSION_DATE@@";
// This field is read by HotSpot
private static final String java_runtime_name =
"@@RUNTIME_NAME@@";
// This field is read by HotSpot
private static final String java_runtime_version =
"@@VERSION_STRING@@";
private static final String VERSION_NUMBER =
"@@VERSION_NUMBER@@";
private static final String VERSION_SPECIFICATION =
"@@VERSION_SPECIFICATION@@";
private static final String VERSION_BUILD =
"@@VERSION_BUILD@@";
private static final String VERSION_PRE =
"@@VERSION_PRE@@";
private static final String VERSION_OPT =
"@@VERSION_OPT@@";
private static final boolean isLTS =
"@@VERSION_OPT@@".startsWith("LTS");
private static final String CLASSFILE_MAJOR_MINOR =
"@@VERSION_CLASSFILE_MAJOR@@.@@VERSION_CLASSFILE_MINOR@@";
private static final String VENDOR =
"@@VENDOR@@";
private static final String VENDOR_URL =
"@@VENDOR_URL@@";
// The remaining VENDOR_* fields must not be final,
// so that they can be redefined by jlink plugins
// This field is read by HotSpot
private static String VENDOR_VERSION =
"@@VENDOR_VERSION_STRING@@";
private static String VENDOR_URL_BUG =
"@@VENDOR_URL_BUG@@";
// This field is read by HotSpot
@SuppressWarnings("unused")
private static String VENDOR_URL_VM_BUG =
"@@VENDOR_URL_VM_BUG@@";
/**
* Initialize system properties using build provided values.
*
* @param props Map instance in which to insert the properties
*/
public static void init(Map<String, String> props) {
props.put("java.version", java_version);
props.put("java.version.date", java_version_date);
props.put("java.runtime.version", java_runtime_version);
props.put("java.runtime.name", java_runtime_name);
if (!VENDOR_VERSION.isEmpty())
props.put("java.vendor.version", VENDOR_VERSION);
props.put("java.class.version", CLASSFILE_MAJOR_MINOR);
props.put("java.specification.version", VERSION_SPECIFICATION);
props.put("java.specification.name", "Java Platform API Specification");
props.put("java.specification.vendor", "Oracle Corporation");
props.put("java.vendor", VENDOR);
props.put("java.vendor.url", VENDOR_URL);
props.put("java.vendor.url.bug", VENDOR_URL_BUG);
}
private static int parseVersionNumber(String version, int prevIndex, int index) {
if (index - prevIndex > 1 &&
Character.digit(version.charAt(prevIndex), 10) <= 0)
throw new IllegalArgumentException("Leading zeros not supported (" +
version.substring(prevIndex, index) + ")");
return Integer.parseInt(version, prevIndex, index, 10);
}
// This method is reflectively used by regression tests.
static List<Integer> parseVersionNumbers(String version) {
// Let's find the size of an array required to hold $VNUM components
int size = 0;
int prevIndex = 0;
do {
prevIndex = version.indexOf('.', prevIndex) + 1;
size++;
} while (prevIndex > 0);
Integer[] verNumbers = new Integer[size];
// Fill in the array with $VNUM components
int n = 0;
prevIndex = 0;
int index = version.indexOf('.');
while (index > -1) {
verNumbers[n] = parseVersionNumber(version, prevIndex, index);
prevIndex = index + 1; // Skip the period
index = version.indexOf('.', prevIndex);
n++;
}
verNumbers[n] = parseVersionNumber(version, prevIndex, version.length());
if (verNumbers[0] == 0 || verNumbers[n] == 0)
throw new IllegalArgumentException("Leading/trailing zeros not allowed (" +
Arrays.toString(verNumbers) + ")");
return List.of(verNumbers);
}
static List<Integer> versionNumbers() {
return parseVersionNumbers(VERSION_NUMBER);
}
static Optional<String> pre() {
return optionalOf(VERSION_PRE);
}
static Optional<Integer> build() {
return VERSION_BUILD.isEmpty() ?
Optional.empty() :
Optional.of(Integer.parseInt(VERSION_BUILD));
}
static Optional<String> optional() {
return optionalOf(VERSION_OPT);
}
// Treat empty strings as value not being present
private static Optional<String> optionalOf(String value) {
if (!value.isEmpty()) {
return Optional.of(value);
} else {
return Optional.empty();
}
}
/**
* In case you were wondering this method is called by java -version.
*/
public static void print(boolean err) {
print(err, false);
}
/**
* This is the same as print except that it adds an extra line-feed
* at the end, typically used by the -showversion in the launcher
*/
public static void println(boolean err) {
print(err, true);
}
/**
* Print version info.
*/
private static void print(boolean err, boolean newln) {
PrintStream ps = err ? System.err : System.out;
/* First line: platform version. */
if (err) {
ps.println(launcher_name + " version \"" + java_version + "\""
+ " " + java_version_date
+ (isLTS ? " LTS" : ""));
} else {
/* Use a format more in line with GNU conventions */
ps.println(launcher_name + " " + java_version
+ " " + java_version_date
+ (isLTS ? " LTS" : ""));
}
/* Second line: runtime version (ie, libraries). */
String jdk_debug_level = System.getProperty("jdk.debug", "release");
if ("release".equals(jdk_debug_level)) {
/* Do not show debug level "release" builds */
jdk_debug_level = "";
} else {
jdk_debug_level = jdk_debug_level + " ";
}
String vendor_version = (VENDOR_VERSION.isEmpty()
? "" : " " + VENDOR_VERSION);
ps.println(java_runtime_name + vendor_version
+ " (" + jdk_debug_level + "build " + java_runtime_version + ")");
/* Third line: JVM information. */
String java_vm_name = System.getProperty("java.vm.name");
String java_vm_version = System.getProperty("java.vm.version");
String java_vm_info = System.getProperty("java.vm.info");
ps.println(java_vm_name + vendor_version
+ " (" + jdk_debug_level + "build " + java_vm_version + ", "
+ java_vm_info + ")");
}
}
| 2023-09-24T01:26:51.906118 | https://example.com/article/2757 |
-----Original Message-----
From: Jones, Tana
Sent: Monday, January 28, 2002 2:59 PM
To: Aronowitz, Alan
Cc: Bailey, Susan
Subject: pre-petition mutual terminations
As you requested, I am attaching my list of pre-petition mutual terminations (as well as 3 post-petition mutual terminations). This list is located in excel in my misc. directory. As per your direction, I will also deliver my binder of mutual terminations to Susan Bailey. | 2024-07-22T01:26:51.906118 | https://example.com/article/4581 |
Top Ten Signs You Know It’s Time to Buy a Server
Server refers to software, hardware, or both. Server software can be the whole package, such as Mac OS X Server, or one of its features, such as the e-mail server. The Mac that Mac OS X Server runs on is also referred to as a server.
Client can refer to the Mac or PC on a user’s desk, or to a piece of user software, like an e-mail client, that talks to server software.
You’ve probably discovered that you can have a small network without a server. Macs and PCs can talk to each other. They can share files and printers, and you may be able to use a router to share an Internet connection.
But a server enables users to collaborate in ways that aren’t possible without it. A server gives you control; it centralizes data, making it easier to manage. A server provides fast access to information and collaborative tools and provides network security.
At some point, you’ll need to add a server. Here are the top ten signs you know it’s time to buy a server:
You have too many computers to go around futzing with them all.
With centralized management of client computers, you can set users’ passwords and settings for network access and install software on the client computers from the server. A server doesn’t eliminate messing with individual clients but can cut it down quite a bit.
Users keep running out of hard drive space.
Instead of replacing or adding hard drives on multiple users’ computers, put one or more hulking, huge hard drives in a server that everyone can use.
Users need special software that everyone can access.
Database software, accounting software, or software specific to your line of business needs a central location.
You have critical data that would cause big problems if you lost it.
Storing mission-critical files in one central location makes them easier to back up than when the files sit on user machines.
Your Mac slows when other users are trying to get files off it.
Your Mac or PC should work for you, not for other users. A server frees up your computer for your work. Servers can also handle multiple users faster than a client computer.
People keep changing settings on Macs, messing things up.
With a server, school computer labs and even user machines can be managed to keep or restore needed settings.
People in your group need to connect to your network from home or while traveling.
Your server can provide secure, encrypted access to your organization’s network, even while the user sits across the ocean sipping a cappuccino in a Wi-Fi cafe in Piazza Navona.
You want to host your own websites.
Whether you or your users want to temporarily post something for your own viewing or permanently for the public, having your own web server gives you the most flexibility to host one or more sites.
Your e-mail inbox fills up with messages about finding times for meetings.
A shared server-based scheduling server enables everyone to share one or more calendars. Multiple people can change details of an event or adds new ones.
The number one reason that you know it’s time to get a server:
You want to do all these things and maybe more.
Dummies Insider
Sign up for insider news on books, authors, discounts and more content created just for you. | 2023-08-17T01:26:51.906118 | https://example.com/article/6223 |
Induction method of tyrosine kinase A-mediated cell death in rat pheochromocytoma.
Nerve Growth Factor (NGF) is a neurotrophic factor that prevents apoptosis in neuronal progenitor cells. In rat pheochromocytoma (PC12) cells, tyrosine kinase A receptor (TrkA) mediates neurotrophic or protective effects, while p75 neurotrophin receptor (p75NTR) functions as a death receptor. We have determined whether TrkA mediates any cytotoxic effect. Following serum deprivation, TrkA expression increased 2.2-fold and apoptosis began with expression of Bax proapoptotic protein. Application of NGF halved cell viability but this was reversed by K252a, the TrkA inhibitor. These results confirmed the paradoxical cytotoxic effect of neurotrophic NGF via TrkA in PC12 cells following serum deprivation. | 2024-04-07T01:26:51.906118 | https://example.com/article/4166 |
1. Introduction {#sec1}
===============
1.1. Ebola virus disease {#sec1.1}
------------------------
Caused by the virus from which it is named, Ebola virus disease (EVD) is deadly and infectious. In past outbreaks, the death rates have varied from 45% to 90% (50% on average) \[[@bib1]\]. The West Africa Ebola outbreak that began in March 2014 mainly affected Liberia, Sierra Leone, Guinea, and Nigeria \[[@bib2]\]. By December 17, 2014, the total number of confirmed, possible, and suspected EVD cases was 18,603 worldwide, 6,915 of which were fatal \[[@bib3]\]. From an epidemiological perspective, infected humans and primates were the major sources of infection. Humans were infected from contact through broken skin or mucous membranes with blood, secretions, excretions, organs, and other bodily fluids of infected animals. Soiled surfaces and materials (such as bedding items and clothes) can likewise cause infection \[[@bib4]\]. The virus then spread through human-to-human transmission with an incubation period of 2--21 days (average: 8--10 days). Schieffelin et al. \[[@bib5]\] observed an incubation period of 6--16 days. Most patients died of hemorrhage and multi-organ dysfunction within two weeks of infection. Laboratory tests found that patients developed a variable degree of multi-organ dysfunction, including liver and kidney damage \[[@bib5], [@bib6], [@bib7]\]. As of December 2014, specific EVD treatment protocols have not been established \[[@bib8], [@bib9], [@bib10]\]. As of the time of this study, Ebola virus vaccines have been the focus of research and development; however, none of them have been licensed.
1.2. Stress and risks {#sec1.2}
---------------------
Severe infection among medical staff characterized the March 2014 outbreak. Medical personnel were easily infected if they did not strictly follow the preventive protocol for infection control, and then came into close contact with suspected or confirmed EVD patients during diagnosis and treatment \[[@bib5]\]. According to the World Health Organization, 605 medical personnel were infected in Guinea, Liberia, and Sierra Leone. Among these, 339 died, resulting in a mortality rate of 56% \[[@bib11]\]. Koh et al. \[[@bib12]\] found that Singaporean Chinese nurses felt themselves at high risk when handling cases of severe acute respiratory syndrome (SARS) and influenza A H1N1. The nurses even believed that infections were unavoidable; however, they remained loyal to their duties. Bonnie and Barry retrospectively studied first-line central African nurses during the EVD outbreaks in 1995, 2000--2001, and 2003. The nurses' stress was found to be mainly due to the lack of protective gear and basic equipment, especially during the early phases of the outbreaks. The nurses were likewise stigmatized by their community, coworkers, and family \[[@bib13]\]. A qualitative research reported that nurses caring for patients with Middle East respiratory syndrome coronavirus (MERS-CoV) were considered to be "going into a dangerous field," or as "strong pressure because of MERS-CoV" \[[@bib14]\]. Another study found that a significant percentage of workers encountered stressors due to isolation, alterations in home life, and discrimination. Physicians and nurses exhibited stressors that were primarily related to patient care \[[@bib15]\].
1.3. Anti-Ebola medical team on a Sierra Leone aid mission {#sec1.3}
----------------------------------------------------------
On September 16, 2014, a Military Infectious Disease Hospital dispatched the first anti-Ebola medical team to Sierra Leone. Composed of physicians, nurses, staff on infection control, and staff providing general services, this team was the first Chinese delegation to West Africa and the mission lasted two months in Freetown. In the early stage (September 17--30), they completed material preparations and remodeled the originally comprehensive China-SL Friendship Hospital into an admission and observation center for severe infectious disease. The staff from SL underwent training, while workflows and protocols were created. In the middle stage (October 1--31), the team practiced and optimized the workflows and protocols, then admitted and treated patients with diagnosed or suspected EVD. In the final stage (November 1--15), patient admission and observation continued while the team prepared for homecoming and work turnover to the next Chinese team. On November 16, the first team returned to China and underwent 21 days of quarantine. This first team achieved the goal of zero infection among the medical staff from both China and Sierra Leone. Moreover, the admitted patients did not develop hospital-acquired infections, which established a satisfactory administrative and organizational basis for subsequent medical teams. However, the anti-Ebola medical nurses suffered deeply from stress. The present study aimed to understand the main stress sources, symptoms, and relievers for nurses of the first anti-Ebola medical team during their mission in Sierra Leone and their quarantine period back home. The findings can provide basis for future stress relief and counseling programs for the anti-Ebola medical team. Similarly, the study can provide basis for the organization, administration, and training of medical agencies.
2. Methods {#sec2}
==========
2.1. Design {#sec2.1}
-----------
This study is a part of a large research project that investigated the stress, emotion, education, and organization of nurses during the mission. Colaizzi\'s seven-step method \[[@bib16]\] was used in this study, as qualitative research aims to explore complex phenomena experienced by clinicians, healthcare providers, policymakers and consumers in the healthcare system \[[@bib17]\]. In qualitative nursing research, phenomenology is a useful methodological approach as it enables researchers to set aside their perceptions of a phenomenon and give meaning to a participant\'s experiences.
2.2. Participants {#sec2.2}
-----------------
A total of 15 nurses were included in the first military anti-Ebola medical team. A purposive sampling method was used and the inclusion criteria were as follows: a registered nurse; working as a nurse in Sierra Leone and directly involved in the care of EVD patients; directly involved in hospital restructuring and Sierra Leone medical staff training. A few nurses did not directly care for patients, as four nurses worked on infection control and one nurse was responsible for rear services. A total of 10 nurses were selected as the study participants, all of whom were females and nurses-in-charge. [Table 1](#tbl1){ref-type="table"} summarizes the general information about the interviewed participants. The qualitative sample size was determined by data saturation; that is, a participant was excluded when data redundancy occurred during the subject interview and nothing new was added during data analysis \[[@bib18]\]. The brief interview with the other 5 nurses provided no new information, and thus, data saturation occurred after 10 study participants.Table 1General information of study subjects.Table 1IDAgeEducationExperience (years)PositionA32Bachelor14NurseB30Bachelor10NurseC38Bachelor16NurseD32Bachelor13NurseE32Master12Chief nurseF35Bachelor16NurseG34Bachelor16Chief nurseH30Bachelor11NurseI44Bachelor23NurseJ36Bachelor16Nurse
2.3. Data collection {#sec2.3}
--------------------
To ensure that participants' memories about their experiences were still clear, data were collected via phone and semi-structured interviews on the day before the quarantine ended. The interviews were scheduled ahead of time and conducted in a private room without interruption. Before the interview, the study objectives and processes were explained to the nurses, who all signed a letter of content. All the interviews were voluntary, confidential, and approved by the ethical committee of the hospital. Each semi-structured interview used a guideline that contained open questions, such as:●Did you feel stressed during this mission? What were the major symptoms?●At which stage did you feel the most stress? What were the major causes?●Did you feel stressed during the quarantine? What were the major symptoms?●What were the major causes for stress during the quarantine?●When did you feel that the stress has disappeared? What were the major symptoms?
During the phone interview, the phone was in hands-free mode and the responses were taped by recording-pen. To ensure the coherence, the first author was the interviewer and recorder. The original language of the interviewer and interviewees was Chinese. Each interview lasted for approximately 30--40 min and was terminated when no new information was added. Participants were encouraged to fully express their feelings. The interviewer carefully listened to the responses without interruptions, induction, comments, or summaries, although specific words and tones were written down.
2.4. Data analysis {#sec2.4}
------------------
Within 24 h, the recorded interviews were transcribed word-per-word and sentence-by-sentence, then compared with notes. Two investigators worked together on the coding process. The first author and another investigator independently reviewed the transcriptions to conduct open coding and compared them to agree on the codes. The recorded materials were then converted into text documents. As personal relationships and trust were built with the nurses, Janice\'s strategy \[[@bib19]\] was used to ensure confidence and trustworthiness, as it does not apply measuring tools. Colaizzi\'s seven-step method was used in the data analysis, which involved carefully reviewing materials, extracting and summarizing major statements from the specific and scattered data, describing significant statements, and encoding recurring statements. Colaizzi\'s qualitative method is a rigorous and robust descriptive phenomenological approach, and therefore ensures the credibility and reliability of its results \[[@bib20]\]. The coded statements were then integrated to generate detailed and complete descriptions. Similar statements were identified to establish the fundamental structure of the observations. Finally, the nurses reviewed and confirmed the documented interviews to ensure their authenticity.
2.5. Truthfulness {#sec2.5}
-----------------
Rigor is the process of application of appropriate techniques and research methods to achieve consistent and reliable data \[[@bib21]\]. The following measures were taken to ensure rigor in this study: Full explanation of all stages including data collection, data analysis, and development of the investigated concepts to the participants; Verification of codes with the participants and engagement with the study phenomenon; Comparison of the text with the initial codes to ensure the homogeneity of extracted ideas \[[@bib22]\]; Peer checking of codes and categories by two qualitative experts to confirm the coding process and analysis.
2.6. Ethical approval {#sec2.6}
---------------------
This study obtained approval from the research committee and ethical committee of the Fifth Medical Center of PLA General Hospital. The study objective was clarified for participants and all of their questions were answered. All participants were allowed to use the tape recorder and were assured that their names and addresses were to remain confidential.
3. Results {#sec3}
==========
3.1. Causes of stress during different periods {#sec3.1}
----------------------------------------------
All 10 nurses revealed that they experienced stress during this mission. Among the participants, seven nurses indicated that the stress level was highest at the early stage of the mission, then decreased in the middle stage and was lowest during the final stage. The other three nurses stated that stress was higher at the middle stage compared with the early stage but also lowest at the final stage. During these different stages, the causes of stress mainly related to safety, responsibility, and unfamiliarity.
### 3.1.1. Unsafety {#sec3.1.1}
Among the participants, seven nurses indicated that the highest level of stress occurred at the early stage due to feelings of panic about the disease and uncertainties about personal safety. The situation in West Africa was complex with many uncertainties. In addition, hot weather and poor hygiene caused the widespread of various diseases, which was one of the factors that caused stress among the nurses."*"The stress was highest before formally meeting patients as the training processes did not provide direct appreciation of the effects of Ebola. We were not sure whether or not the prevention and control measures were proper and effective. We were also concerned about other infectious diseases such as malaria and typhoid."* (Nurse B)""*"During the middle stage, we focused on proper protection to avoid infection. The first couple of days were used to adjust and we were all cautious. Later on, we found that we worked well with the nurses from Sierra Leone and protection measures were properly carried out. Additionally, many of us had experience in handling SARS and flu, and we trusted our team members. Therefore, stress was not significant after we started work."* (Nurse C)""*"During the later stage, the stress was not significant. It was close to the end and we were very excited. However, we were still nervous about possible problems, such as inadequate protection or omission."* (Nurse I)"
### 3.1.2. Responsibility {#sec3.1.2}
Responsibility comes from the duties of military personnel. In Chinese traditional culture, responsibility means the call of the mission, the embodiment of ability, and the execution of institution. Compared with other cultures, responsibility is unique and helpful for the mission. As the first anti-Ebola medical team, the nurses were responsible for preparing supplies and creating protocols for hospital remodeling plans, training programs, and communication. Without previous guidelines, they needed to learn on site and become directly involved in these processes."*"The stress was highest at the early stage. We started to unload supplies, perform on-site surveys, define working zones, and remodel the hospital. We had few clues about the work. Everything was subject to discussion and re-discussion, and the progress was slow. In addition, we couldn\'t properly understand what the SL personnel said, which made communication rather difficult."* (Nurse A)""*"The beginning stage was the most stressful. As the nurse group leader, my stress mainly came from arranging jobs and training personnel from Sierra Leone. Workload and the organization of teams needed to be reasonable. Processes and measures needed to be fully thought out in detail. As the personnel from Sierra Leone had rather poor knowledge and skills, and were unfamiliar with some protective clothing, we needed to train them about protection and processes to ensure work safety for everyone and the smooth implementation of each plan. Such responsibility was significant."* (Nurse G)"
### 3.1.3. Unfamiliarity {#sec3.1.3}
Unfamiliarity was ascribable to environments, language, EVD, and the nursing materials. This EVD outbreak was not the first and nurses from Asia had some previous knowledge; however, they commonly faced unanticipated difficulties. Learning how to handle such an outbreak of a sudden and lethal disease was challenging."*"We were away from familiar living and working environments and family. We had an 18-hour flight of over 10,000 km and arrived in Freetown. Everything was unfamiliar to me, which made me feel upset."* (Nurse B)""*"Everything was unfamiliar and uncertain, including the diseases, language, environment, and working partners. The information about EVD was unfamiliar, inconsistent, incomplete, and could not be evaluated. It is hard to believe that I survived."* (Nurse D)""*"It might be a race issue; that is, Sierra Leone people all looked very similar, and it was hard to distinguish them in my eyes. They tended to get together without following rules. They often slept on the floor. It was rather difficult to identify the patient and confirm the information."* (Nurse E)"
3.2. Symptoms of stress {#sec3.2}
-----------------------
### 3.2.1. Sleep and physiological disturbances {#sec3.2.1}
Sleep disturbances were common among the participants. Seven nurses indicated that during the early stage of the mission, they experienced difficulties in falling asleep, waking early, or light sleep almost every night. During the middle and final stages, the situation slightly improved. However, sleeplessness often occurred the night before work. In addition to the low quality of sleep, the participants tended to feel tired with poor appetites, disrupted menstrual cycles, and acne breakouts."*"I was stressed out during the SL aid mission, which mainly manifested as low quality of sleep. I often fell asleep only after midnight. This situation occurred 5 or 6 days each week." (Nurse E)*""*"I did not sleep well. It might have been related to the jet lag during the early period. I would wake up often from sleep. During the middle and final period, I could not sleep well, mainly on the night before work or on a 24-h shift. If this happened, I had to use a sleep aid."* (Nurse F)""*"During the mission, my period came a week to 10 days earlier each time. I felt very tired."* (Nurse C)""*"I lost my appetite, had a bloated stomach, and had frequent constipation."* (Nurse I)"
### 3.2.2. Emotional and cognitive symptoms {#sec3.2.2}
Major symptoms included anxiety, mood swings, attention deficits, and poor memory."*"I always felt slow and had difficulty finding or expressing the proper words when talking. Sometimes I could not focus on what I was doing, while at other times I became too engrossed."* (Nurse B)""*"I was always anxious, with many worries. I easily forgot what I had already done."* (Nurse C)""*"I was very moody at the early stage. Sometimes I lost control in front of my partner for trivial issues. Now I feel that was inappropriate."* (Nurse G)"
### 3.2.3. Behavioral symptoms {#sec3.2.3}
Major symptoms included negative thoughts and self-doubt."*"I felt that during that period, I was a troublemaker with endless talk and sluggish behavior. Sometimes I needed to make sure of what I had done again and again. I might not go to the restroom the whole day during work but then might stay in the restroom all the time while taking a break."* (Nurse B)""*"I did not know why I cried a lot during the aid mission. I cried out of sight of others after I called my family. I also cried if I could not fall asleep or had misunderstandings with my colleagues. I did not behave like that before."* (Nurse F)"
3.3. Stress relief {#sec3.3}
------------------
During the quarantine period back in China, the stress among the nurses decreased substantially. Their physiological, emotional, cognitive, and behavioral symptoms significantly improved. Among the participants, six nurses indicated that their stress disappeared once they came back, while four nurses still felt a certain amount of stress. Moreover, seven nurses started to have normal appetites, sleep, and moods, while three nurses still experienced sleep disturbances but to a lesser degree. After 10 days of quarantine, all participants felt that their stress had disappeared and they had normal sleep and relaxed moods."*"When the flight smoothly arrived back at the Capital Airport, everyone\'s eyes simultaneously welled up with tears. It was an unforgettable experience."* (Nurse G)""*"I still did not sleep well at the beginning after coming back. However, the situation was much better than that in Sierra Leone. At least I could fall asleep without a sleep aid, although I stayed up late. I had no problems with food, exactly like before."* (Nurse F)""*"We did not worry much about the infection, possibly because we had experience of handling SARS and the protection was adequate. We were pretty relaxed during the quarantine period. It is not clear if such sudden relaxation explains why we were not as excited as expected at the beginning. We were low all the time, with no interest in doing anything. Complete recovery occurred only after resting at home for several days."* (Nurse C)""*"I was completely relaxed at about day 10 after coming back, with my normal life back. I started to exercise and have social gatherings. I also started to experience good sleep and appetite."* (Nurse I)"
4. Discussion {#sec4}
=============
All of the nurses in this Sierra Leone aid mission had over 10 years of job experience and were in active military service. Most of them had been involved in urgent, difficult, and dangerous tasks, such as the fight against SARS, prevention and control of influenza A H1N1, aid to the earthquakes in Wenchuan and Haiti, and medical services during the Olympic Games. They had rich experience in treating, preventing, and isolating infectious diseases. However, working in an unfamiliar environment under unfamiliar working conditions was somewhat stressful. After arrival at the China-Sierra Leone Friendship Hospital, this medical team spent a short period completing the adjustment training in all of the procedures. They also worked to obtain recognition and community support and to be responsive in relieving stress among team members.
4.1. Correct prediction and prevention of risks can help the anti-Ebola nurses effectively cope with stress {#sec4.1}
-----------------------------------------------------------------------------------------------------------
Faced with an unfamiliar living environment, complex public safety issues, tough natural conditions, and severe disease outbreak situations in Sierra Leone, this first medical team experienced many different stressors. Unsafety and unfamiliarity were the most significant sources of stress. Mishel suggested that feeling unsafe may occur during events or with diseases that cannot be precisely explained and categorized, but with predictable and undesirable outcomes \[[@bib23]\]. During this anti-Ebola medical mission, an unsafe feeling may occur during diagnosis, treatment, prediction of transmission routes, and deciphering the disease infectivity. Under such circumstances, reliable and timely scientific evidence can help the medical staff to lower their feelings of unsafety, face the risks, and relieve unnecessary stress. This study suggests that full cooperation between the medical team and local hospital in both the front- and rear lines, safety training, and close communication with the worldwide disease control centers are necessary. The medical team members can obtain updates about the disease and ensure smooth information flow so that all involved can properly understand the risks.
4.2. Proper responses and strategies could reduce discomfort resulting from stress {#sec4.2}
----------------------------------------------------------------------------------
The nurses' symptoms during this mission mainly included insomnia, poor appetite, fatigue, and attention deficit. Before the team was dispatched, the hospital arranged counseling, sleep guidance, social etiquette training, and verbal English training for the nurses to reduce possible sources of stress. The hospital also provided sleep aids and improved food to help the nurses relieve stress symptoms. Reasonable shift arrangements were adopted to avoid fatigue at work. This medical team had a psychological counselor and the nurses were encouraged to confide and seek timely, positive help. However, examining the difficulties and demands of healthcare providers is imperative in establishing a safe healthcare system that can respond effectively during national disasters. In addition, developing strategies to protect healthcare providers from severe physical and psychological stress is likewise necessary.
4.3. Good community support helped relieve stress {#sec4.3}
-------------------------------------------------
Before the medical team was dispatched, the General Logistics department provided substantial support. All the medical supplies and protective clothing were fully prepared. Subsequent supplies were also efficiently arranged through coordination among relevant agencies to avoid shortage of supplies or protective clothing. The team members represented China and therefore were admired by their community, family, friends, and colleagues, who all provided significant moral support. The hospital also provided moral support to the team members, such as organizing a team birthday party, arranging a video talk between the team members and their families, and organizing trips and group vacations for team members' families. Therefore, the team members did not have to worry about their families. In the interview, most of the participants stated that the support from family and the hospital helped them feel relaxed.
At present, the epidemic of EVD has been controlled. As of July 2018, the hospital has dispatched over 200 medical staff in six batches to help set up hospitals in Sierra Leone and prevent and control tropical infectious diseases. The teams remained under constant pressure. The present study shows that the nurses experience stress during the mission, possibly due to concerns about unsafety and responsibility, as well as the unfamiliarity of the surroundings. Targeted measures, proper responses, and good community support can effectively lower stress to ensure the nurses' physical and mental health, and enable them to play better roles during international aid missions.
Conflicts of Interest {#sec5}
=====================
None.
Appendix A. Supplementary data {#appsec1}
==============================
The following is the Supplementary data to this article:Multimedia component 1Multimedia component 1
Peer review under responsibility of Chinese Nursing Association.
Supplementary data to this article can be found online at <https://doi.org/10.1016/j.ijnss.2019.03.007>.
| 2024-04-19T01:26:51.906118 | https://example.com/article/7185 |
8th Jan 2018
Ground-breaking Black-led theatre company Eclipse kickstart a pioneering writing scheme this February with an innovative show by rapper and beatboxer Testament. Delving into 2000 years of Black British history, Black Men Walking will spearhead Eclipse’s Revolution Mix – the largest ever national delivery of Black British shows produced and performed in regional theatres.
Photo Credit: Tristram Kenton
Following its Manchester premiere, the show comes directly to Coventry’s Belgrade Theatre as part of a 2018 tour coinciding with the 70th anniversary of the Windrush – a milestone often celebrated as the beginning of modern multicultural Britain. Both Black Men Walking and Revolution Mix look to challenge this idea, unearthing untold stories that have shaped British culture over hundreds of years.
Blending dramatic storytelling with original music, the play is inspired by the real-life Peak District-based Black Men’s Walking Group, and tells the story of Thomas (Tyrone Huggins), Matthew (Trevor Laird) and Richard (Tonderai Munyevu), three middle-aged men who meet up for a planned hike only to discover that the rest of their group has cancelled. As they set off on their walk alone, they find themselves forced to walk backwards through 2000 years of Black history, encountering supernatural elements and the spirits of their ancestors along the way.
Director Dawn Walton said: “This powerful story perfectly encompasses everything the Rev Mix movement stands for; turning the spotlight onto Britain’s missing Black history with a piece inspired by real people and real events. It is so important that these stories are told, especially when you look at the recent online backlash faced by Mary Beard who was accused of ‘re-writing history’ by pointing out the ethnic diversity of Roman Britain. This reaction is evidence of a real lack of understanding about our true British heritage.
Black Men Walking runs at the Belgrade Theatre from Wednesday 7 until Saturday 10 February. | 2024-03-22T01:26:51.906118 | https://example.com/article/2906 |
Archive: August, 2013
Virginia A. Smith, Inquirer Staff Writer
POSTED: Thursday, August 15, 2013, 4:51 PM
Chanticleer any day is a treat, but it was especially so today. The morning was sunny, clear, cool. I wore a fleece, for heaven's sake. The gate had just been opened, and within minutes, the parking lots were pretty full. Not everyone is at the Shore, although I like it when everyone goes away. I can get a dinner reservation pretty much when and where I want, traffic's (almost) manageable, the neighborhood is blessedly quiet.
So I was a little surprised to see so many people at Chanticleer - lots of young mothers with children, some grandparents, some couples and a few strays like me. It was a perfect day.
Interesting to see the serpentine planted with two types of kale, a darker, moodier serpentine than I've seen before. Lots of people didn't know what the kale was. So much for kale being the "it" vegetable. Kale was also scattered about in some of the other gardens; quite a surprise when you come upon it.
Virginia A. Smith, Inquirer Staff Writer
POSTED: Wednesday, August 14, 2013, 1:10 PM
Good grief, has anyone had a decent crop of tomatoes this summer? Heard from a friend this morning who is the most skillful grower I know of tomatoes and all else. She's a master gardener and canner and even she's had a bad time of it.
I bought four grafted heirloom tomatoes, touted as the biggest, the tastiest, the toughest. They started out well and then the rains came. Then record-busting heat. I actually lost one of those grafteds. Another one doesn't even have blossoms on it. A third has green fruit but shows no signs of ripening. And the fourth plant, the only producer in the lot, has given me exactly three tomatoes.
Were it not for a hybrid called 'Fourth of July,' which puts out about one smallish, not great-tasting, tomato every other day, I'd pratically have a shut-out.
Ginny Smith, a Philadelphia native, joined the Inquirer at 1985. After stints as both reporter and editor in the city and suburbs, she’s been happily writing – and learning - about gardening full time since 2006. She’s won two silver medals of achievement from the national Garden Writers Association and in 2011, Bartram’s Garden honored her with its Green Exemplar award for her stories about “the region’s deeply rooted horticultural history, cultural attractions and bountiful gardens.” She plays in her own – mostly - bountiful garden in East Falls.
Reach Virginia A. at vsmith@phillynews.com . | 2023-10-08T01:26:51.906118 | https://example.com/article/8729 |
Basic telecommunications access method
Basic Telecommunications Access Method (BTAM) is a low-level programming interface specified by IBM for use on the IBM System/360 for start-stop and binary synchronous telecommunications terminals. Later, IBM specified higher-level interfaces QTAM and TCAM.
BTAM was superseded by VTAM for Systems Network Architecture (SNA) devices. BTAM continued to be supported in later iterations of the system architecture, and IBM finally withdrew support in 2000.
BTAM requires the application program or transaction processing system to handle almost every detail of the protocol. This is harder than using a higher-layer protocol, but it permits interfacing to non-standard devices in non-standard ways.
An access method for terminals
BTAM is an access method for interactively communicating with remote terminals, usually connected through a front end processor such as a 270x communications controller, although support for local channel-attached 3270 terminals is included. BTAM dynamically builds Channel command words (CCWs) for reading, writing and "polling" terminals and deals with specific responses from those terminals, according to the success or failure of the communication channel.
Key role in transaction processing systems
BTAM was a key component in IBM's early transaction processing systems such as MTCS, CICS and IMS and underpinned the rise of online transaction processing for many large commercial banks and insurance companies. It was not unusual for BTAM and later developed access methods (such as VTAM) to co-exist, supporting different devices simultaneously under the same transaction processing system.
Programming
Material in this section taken from IBM System/360 Operating System Basic Telecommunications Access Method; GC30-2004-6.
BTAM programming requires detailed knowledge of the characteristics of the specific terminals to be used.
THE DCB macro is used to define a communications line group:
dcbname DCB DSORG=CX...
DEVD=BS can be coded to specify a Binary Synchronous (Bisync) line. Many other operands specify unique characteristics of the attached terminals.
A terminal list, specified by the DFTRMLST macro, identifies the terminals attached to the line. This macro specifies the line characteristics—start-stop, bisync, point-to-point, multipoint, leased line or dial — and the type of polling required— wrap around or open. The polling characters or telephone number used to identify each specific remote device on the line are coded. The CHGNTRY macro can be used to modify information for a specific device in the list during execution. A wrap-around polling list will cause each device in the list to be polled sequentially by the channel until a response was received, This reduces the load on the CPU for continuous polling.
The programmer can specify a buffer pool, a data structure used to hold messages transmitted to or from the terminals. BTAM can construct the pool automatically or the programmer can construct the pool in various ways. The BUILD macro will format the pool in static or dynamic storage previously acquired, or the GETPOOL macro will acquire and format storage automatically. For read operations BTAM will automatically obtain one or more buffers from the pool and store the received message. For a write operation the programmer needs to code REQBUF to obtain the number of buffers necessary to build the output message. In either case the RELBUF is used to free the buffers on completion of the read or write.
Tha ASMTRTAB and TRNSLATE include translation tables and translate to and from non EBCDIC character codes.
The standard OS/360 OPEN and CLOSE macros are used to initiate and terminate processing of a BTAM line. The LOPEN macro can reinitialize a line that, for whatever reason, failed to open successfully.
BTAM provides a large number of options for the READ and WRITE macros, depending on the line and terminal types and the current status. These are such operations as "read initial with reset", "read conversational", "read repeat", "write initial", "write break", and "write continue transparent". These are specified by codes, such as READ decbaddr,TI,... for a "read initial." The read or write operation is executed asynchronously by the channel. Following a read or write, a WAIT or TWAIT macro is required to wait for completion and retrieve ending status.
The RESETPL macro cancels an outstanding read and/or stops polling on a line.
Supported devices
Amongst many other devices supported, BTAM handles:
IBM 1050 terminals
IBM 2740 terminals
IBM 2741 terminals
Teletype terminals
IBM 2260 visual display unit terminals
IBM 3270 visual display unit terminals
IBM 2780 terminals used for remote job entry
References
VTAM | 2024-07-30T01:26:51.906118 | https://example.com/article/1201 |
Food Bank (Wikipedia)
Food bank
From Wikipedia, the free encyclopedia
A food bank is a non-profit organization which distributes non-perishable goods and perishable food items to non-profit agencies involved in local emergency food programs. Emergency food programs provide immediate hunger relief to individuals and families who are unable to afford food and receive inadequate government financial assistance from programs such as the Food Stamp Program. Food stamps is the government program whereby households below certain income thresholds are provided monthly food spending credits which can be redeemed at local food stores.
The agencies receiving food from food banks are typically non-profit organizations operated as part of a church, government or community group, and commonly called a "food pantry". A food bank is like the wholesale arm of the food distribution system for those living in poverty, while food pantries are the retail arm that serve people directly with the emergency food. Some food pantries serve only a few families each month, but there are many that provide emergency food support to hundreds of families each month. The need for food bank and food pantry services has been growing in recent years as income has not kept up with rising costs and federal program funding is not tied to inflation.
Food banks receive their food from companies or supermarkets with unsaleable stock, and also from donations from the general public, especially around holidays such as Thanksgiving and Christmas. In addition, the U.S. government and state governments often contract with food banks to distribute USDA surplus commodities and FEMA food. In addition, food banks who are members of America's Second Harvest, the nation's food bank network organization, are able to take advantage of relationships with major manufacturers. Food banks distribute goods such as canned and boxed dry groceries, fresh produce, frozen foods, bakery products, and some personal hygiene or household cleaning products.
The first food bank was St. Mary's Food Bank, started in 1967 in Phoenix, Arizona. America's Second Harvest represents a network of over 200 food banks across the U.S. While some food banks operate in Canada and Europe, food banks are much more predominant and important in the U.S. in providing efficient resources to support emergency food relief efforts.
Many food banks around the country have employed the use of Virtual Food Drives, originally developed by The North Texas Food Bank and The Aidmatrix Foundation, to make it easy for the public to help their local communities contribute to the hunger relief efforts in their area. many schools are now opening food pantries. | 2023-11-23T01:26:51.906118 | https://example.com/article/6248 |
Error analysis of the de-crosstalk algorithm for the multianode-PMT-based quadrant tracking sensor.
For the multianode-PMT-based quadrant tracking sensor, one of the tracking error sources is the crosstalk. The crosstalk can be reduced by de-crosstalk algorithm, so the tracking error of the de-crosstalk algorithm for the multianode-PMT-based quadrant tracking sensor are analyzed in theory and verified by experiments. Both the theoretical analysis and the experimental results showed that the spot displacement sensitivity could be improved by the de-crosstalk algorithm, but the spot centroid detecting error increased at the same time. So the de-crosstalk algorithm could not improve the tracking accuracy effectively. | 2023-09-29T01:26:51.906118 | https://example.com/article/2821 |
Techren Solar Project
The Techren Solar Project is a 300 megawatt (MWAC) solar photovoltaic power plant near Boulder City, Nevada was originally founded and developed by SECP (Sustainable Energy Capital Partners) and is currently being developed by 174 Power Global, the US subsidiary of the South Korean company, Hanwha Group. Two phases of the project are currently under construction: the 100 MW Techren 1 began in 2017 and the 200 MW Techren 2 began in 2018.
Project details
The project is located on 2,300 acres near the existing 64 MW Nevada Solar One, 150 MW Boulder Solar, and 552 MW Copper Mountain Solar Facilities in the Eldorado Valley. NV Energy intends to purchase the electricity from both facilities, which are eligible for further customer participation under the NV GreenEnergy Rider opportunity. As with the Fort Churchill Solar Array and Boulder Solar, Apple Inc. has helped to motivate the project through its participation of its northern Nevada data centers in the program.
Both units are being built to a 1.5 kVdc maximum system voltage standard. This increase from the previous 1.0 kVdc standard enables the inverter to operate at higher efficiency and reliability, and is expected to reduce overall balance of system costs over the lifetime of the facility. Swinerton Renewable Energy is the EPC contractor, and Clenera is providing asset management services. Expected completion is by September 2019.
An additional 100 MW is also in planning for development: the 25 MW Techren 3, the 25 MW Techren 4, and the 50 MW Techren 5.
See also
List of photovoltaic power stations
List of power stations in Nevada
Solar power plants in the Mojave Desert
Solar power in Nevada
Solar power in the United States
References
Category:Solar power in the Mojave Desert
Category:Buildings and structures in Boulder City, Nevada
Category:Solar power stations in Nevada
Category:Photovoltaic power stations in the United States | 2024-04-18T01:26:51.906118 | https://example.com/article/8141 |
Save Article
The Morning Ledger: Bernanke Won’t Budge on Bond Buying
By
David Hall
Feb 27, 2013 6:55 am ET
Ben Bernanke isn’t budging in his support for continued bond buying. “Keeping long-term interest rates low has helped spark a recovery in the housing market and has led to increased sales and production of automobiles and other durable goods,” he said in his semiannual report to Congress yesterday. Mr. Bernanke faced some hostile questioning from the Senate Banking Committee – particularly from Sen. Bob Corker (R., Tenn.), who told the Fed chief that his easy-money policies were sparking a global currency war and creating “faux” stock-market wealth. He also accused Mr. Bernanke of “throwing seniors under the bus” by pushing down interest rates and reducing their returns on savings. Mr. Bernanke was pretty perturbed by those comments, the WSJ’s Jon Hilsenrath notes. He shot back by pointing out that his record of keeping inflation low and stable is better than that of any Fed chairman since World War II.
Content from our sponsorDeloitteCFO insight and analysis written and compiled by Deloitte
Finance, organizational strategy, public policy and other fields have traditionally been shaped by the assumption that people’s behavior is characterized by unbounded rationality, self-interest, and self-control. Richard Thaler, who earlier this month won the Nobel Prize for economics, believed that the actual world, run as it is by humans, is replete with market and business process inefficiencies, and that smart companies must take human psychology into account. In this 2016 interview with James Guszcza, U.S. chief data scientist, Deloitte Consulting LLP, Mr. Thaler discusses why and how behavioral economics can be used to help people make decisions more consistent with their long-term goals.
Please note: The Wall Street Journal News Department was not involved in the creation of the content above.More from Deloitte → | 2023-08-28T01:26:51.906118 | https://example.com/article/1882 |
Androgen regulation of transferase II activity in the mouse kidney.
Castration of adult male mice reduced the ability of the transferase factors of the kidney to stimulate amino acid incorporation by polysomes in vitro. The administration of testosterone propionate (TP) to the mice for 11 days greatly increased the activity of the transferase fraction. The changes occurred only in transferase II. The induction of the increase in transferase activity was evident 24 h after the injection of TP and required a lag period of at least 12 h. The concentration of pH 5 enzymes (protein) was slightly decreased by castration and was restored by TP administration. The radioactivity in the hot perchloric acid extract of the protein after amino acid incorporation was increased but the activity of the pH 5 enzyme fraction on amino incorporation was not significantly changed by androgen administration. | 2024-04-21T01:26:51.906118 | https://example.com/article/1999 |
Q:
split string for firstname and lastname in vb.net
i have a string that comes in say "Joesph Van Andrews".
I want to split it in such a way that firstname is "Joseph" and lastname is "Van Andrews"
how can i do that in vb.net?
A:
Dim firstName As String = name.Substring(0,name.IndexOf(" "))
Dim lastName As String = name.Substring(name.IndexOf(" ")+1)
Assumptions: first name and last name are separated by a space, and if multiple spaces are present, the first space is used as the separator.
| 2023-08-02T01:26:51.906118 | https://example.com/article/3785 |
Digital Distribution This Winter Ahead of Remastered DVD Release
Sentai Filmworks proudly announces the company’s acquisition of distribution rights for the critically acclaimed animation masterpiece Grave of the Fireflies, Studio Ghibli co-founder Isao Takahata's adaptation of Nosaka Akiyuki's semi-autobiographical story of life in the wake of the the World War II firebombing of Japan. Digital distribution of the movie will begin through many outlets this winter, and a DVD of the digitally restored master will be in stores next year.
Sentai Filmwork describes the movie:
Grave of the Fireflies has been universally hailed as both an artistic and emotional tour de force, with famed critic Roger Ebert calling the feature “An emotional experience so powerful that it forces a rethinking of animation” and stating that “it belongs on any list of the greatest war films ever made.” Sentai Filmworks is extraordinarily honored to have been given the privilege of handling the digitally restored version of one of the art of animation’s true crowning achievements.
As the Empire of the Sun crumbles upon itself and a rain of firebombs falls upon Japan, the final death march of a nation is echoed in millions of smaller tragedies. This is the story of Seita and his younger sister Setsuko, two children born at the wrong time, in the wrong place, and now cast adrift in a world that lacks not the care to shelter them, but simply the resources. Forced to fend for themselves in the aftermath of fires that swept entire cities from the face of the earth, their doomed struggle is both a tribute to the human spirit and the stuff of nightmares. Beautiful, yet at times brutal and horrifying, it is a film that perhaps only the animated medium could render without completely overloading human senses, transforming the fog of war and the screams of the dying into what Ebert calls “visual poetry.” | 2023-10-20T01:26:51.906118 | https://example.com/article/8516 |
No.41 Living our Internationalism: The first 30 years of the IIRE
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Price including shipment to:
This summer marks IIRE’s thirtieth anniversary. In commemoration of the occasion, the latest issue of IIRE Notebooks for Study and Research is dedicated to covering the origins, activities and highlights of the Institute’s three decades of existence.
In this unique volume, the International Institute for Research and Education’s current and previous co-directors explain its origins, activity and challenges. On 11 June 1981, the Institut international de recherches et de formation pour promouvoir le socialisme scientifi que et democratique (later shortened to the more versatile Institut International de Recherche et de Formation) was founded by a Belgian royal charter. It fulfilled a plan by Jacob Moneta, the editor-in-chief of the important big German trade union journal Metall, the Belgian Marxist economist Ernest Mandel, the Swiss economist Charles-André Udry and the philologist Jan Philipp Reemtsma. The following summer, the IIRE opened in Amsterdam as a centre for education and research in the service of progressive activists, linked closely to the Marxist and workers’ movements worldwide.
After three decades, hundreds of successful seminars, schools and lectures have taken part at the IIRE, with many dozens of participants from every continent coming to the IIRE.
The IIRE continues to serves progressive forces internationally through its educational programmes and by hosting scholar-activists. In Amsterdam, as in the new IIREs in Manila and Islamabad, its meeting rooms and bedrooms are used by a wide range of progressive activists and organisations. The IIRE is also the home for projects like the Notebooks for Study and Research, the Ernest Mandel Study Centre and the Institute for Critical Research. | 2024-03-16T01:26:51.906118 | https://example.com/article/7923 |
Q:
'in()' works as expected, but 'not in()' does not
I have a two column table (n and p), where half the n values exist in p and the other half do not. The following code returns 'NULL' instead of returning the half of the n values which are not in p.
select n
from bst
where n
not in
(
select p from bst
)
order by n
;
But when the keyword 'not' is removed, everything works as expected. Why is this code returning no values?
A:
I strongly recommend using not exists instead of not in with a subquery:
select bst.n
from bst
where not exists select p from bst bst2 where bst2.p = bst.n)
order by bst.n
Why? Because the two are not equivalent. If any value of p is NULL, then NOT IN returns no rows at all. NOT EXISTS has more expected behavior.
Of course, you could fix this problem by filtering in the subquery:
select bst.n
from bst
where bst.n not in (select bst2.p from bst bst2)
order by bst.n;
But I think it is easier just to remember to use not exists rather than not in.
| 2023-11-13T01:26:51.906118 | https://example.com/article/8792 |
Dietemann v. Time, Inc.
No. 23096
UNITED STATES COURT OF APPEALS FOR THE NINTH CIRCUIT
449 F.2d 245
August 23, 1971
HUFSTEDLER, Circuit Judge:
This is an appeal from a judgment for plaintiff in an action for invasion of privacy. Jurisdiction was grounded in diversity. The parties agreed that California law governed. After a court trial plaintiff was awarded $1000 general damages. On appeal we are asked to consider significant questions involving the relationship between personal privacy and the freedom of the press.
The district court's decision is reported in Dietemann v. Time, Inc., 284 F. Supp. 925 (1968). The facts, as narrated by the district court, are these:
"Plaintiff, a disabled veteran with little education, was engaged in the practice of healing with clay, minerals, and herbs--as practiced, simple quackery.
"Defendant, Time, Incorporated, a New York corporation, publishes Life Magazine. Its November 1, 1963 edition carried an article entitled 'Crackdown on Quackery.' The article depicted plaintiff as a quack and included two pictures of him. One picture was taken at plaintiff's home on September 20, 1963, [246] previous to his arrest on a charge of practicing medicine without a license, and the other taken at the time of his arrest.
"Life Magazine entered into an arrangement with the District Attorney's Office of Los Angeles County whereby Life's employees would visit plaintiff and obtain facts and pictures concerning his activities. Two employees of Life, Mrs. Jackie Metcalf and Mr. William Ray, went to plaintiff's home on September 20, 1963. When they arrived at a locked gate, they rang a bell and plaintiff came out of his house and was told by Mrs. Metcalf and Ray that they had been sent there by a friend, a Mr. Johnson. The use of Johnson's name was a ruse to gain entrance. Plaintiff admitted them and all three went into the house and into plaintiff's den.
"The plaintiff had some equipment which could at best be described as gadgets, not equipment which had anything to do with the practice of medicine. Plaintiff, while examining Mrs. Metcalf, was photographed by Ray with a hidden camera without the consent of plaintiff. One of the pictures taken by him appeared in Life Magazine showing plaintiff with his hand on the upper portion of Mrs. Metcalf's breast while he was looking at some gadgets and holding what appeared to be a wand in his right hand. Mrs. Metcalf had told plaintiff that she had a lump in her breast. Plaintiff concluded that she had eaten some rancid butter 11 years, 9 months, and 7 days prior to that time. Other persons were seated in the room during this time.
"The conversation between Mrs. Metcalf and plaintiff was transmitted by radio transmitter hidden in Mrs. Metcalf's purse to a tape recorder in a parked automobile occupied by Joseph Bride, Life employee, John Miner of the District Attorney's Office, and Grant Leake, an investigator of the State Department of Public Health. While the recorded conversation was not quoted in the article in Life, it was mentioned that Life correspondent Bride was making notes of what was being received via the radio transmitter, and such information was at least referred to in the article.
"The foregoing events were photographed and recorded by an arrangement among Miner of the District Attorney's Office, Leake of the State Department of Public Health, and Bride, a representative of Life. It had been agreed that Life would obtain pictures and information for use as evidence, and later could be used by Life for publication.
"Prior to the occurrences of September 20, 1963, on two occasions the officials had obtained recordings of conversations in plaintiff's home; however, no pictures had been secured. Life employees had not participated in obtaining the recordings on these occasions.
"On October 15, 1963, plaintiff was arrested at his home on a charge of practicing medicine without a license in violation of Section 26280, California Health and Safety Code. At the time of his arrest, many pictures were made by Life of plaintiff at his home. Plaintiff testified that he did not agree to pose for the pictures but allowed pictures because he thought the officers could require it. Also present were newspaper men who had also been invited by the officials to be present at the time of arrest.
"Defendant contends that plaintiff posed for pictures at the time of his arrest and thus permission was given to take those pictures. As hereinafter pointed out, it is unnecessary to decide whether or not permission was given to take pictures at the time of his arrest.
"Plaintiff, although a journeyman plumber, claims to be a scientist. Plaintiff had no listings and his home had no sign of any kind. He did not advertise, nor did he have a telephone. He made no charges when he attempted to diagnose or to prescribe herbs and minerals. He did accept contributions. [247]
"Life's article concerning plaintiff was not published until after plaintiff was arrested but before his plea on June 1, 1964 of nolo contendere for violations of Section 2141 of the California Business and Professions Code and Section 26280 of the California Health and Safety Code (misdemeanors).
"* * *
"Defendant's claim that the plaintiff's house was open to the public is not sustained by the evidence. The plaintiff was administering his so-called treatments to people who visited him. He was not a medical man of any type. He did not advertise. He did not have a phone. He did have a lock on his gate. To obtain entrance it was necessary to ring a bell. He conducted his activities in a building which was his home. The employees of defendant gained entrance by a subterfuge."
The district court concluded: "The publication in Life Magazine on November 1, 1963 of plaintiff's picture taken without his consent in his home on September 20, 1963 was an invasion of his privacy under California law for which he is entitled to damages. The acts of defendant also constituted an invasion of plaintiff's right of privacy guaranteed by the Constitution of the United States which would entitle him to relief under Section 1983, Title 42, United States Code." The court awarded $1,000 general damages "for injury to [Dietemann's] feelings and peace of mind. Time appeals from that decision.
The appeal presents three ultimate issues: (1) Under California law, is a cause of action for invasion of privacy established upon proof that defendant's employees, by subterfuge, gained entrance to the office portion of plaintiff's home wherein they photographed him and electronically recorded and transmitted to third persons his conversation without his consent as a result of which he suffered emotional distress? (2) Does the First Amendment insulate defendant from liability for invasion of privacy because defendant's employees did those acts for the purpose of gathering material for a magazine story and a story was thereafter published utilizing some of the material thus gathered? (3) Were the defendant's employees acting as special agents of the police and, if so, did their acts violate the First, Fourth, and Fourteenth Amendments of the Federal Constitution, thereby subjecting defendant to liability under the Civil Rights Act (42 U.S.C. § 1983)? [note 1] Because we hold that plaintiff proved a cause of action under California law and that the First Amendment does not insulate the defendant from liability, we do not reach the third issue.
Were it necessary to reach the Civil Rights Act questions, we would be obliged to explore the relationship between the defendant's employees and the police for the purpose of ascertaining the existence of the "color of law" element of the Act. Because we do not reach the issue, we can and do accept the defendant's disclaimer that its employees were acting for or on behalf of the police.
In jurisdictions other than California in which a common law tort for invasion of privacy is recognized, it has been consistently held that surreptitious electronic recording of a plaintiff's conversation causing him emotional distress is actionable. Despite some variations in the description and the labels applied to the tort, there is agreement that publication is not a necessary element of the tort, that the existence of a technical trespass is immaterial, and that proof of special damages is not required. (E.g., Nader v. General Motors Corp. (1970) 25 N.Y.2d 560, 307 N.Y.S.2d 647, 255 N.E.2d 765 (applying District of Columbia law); Hamberger v. Eastman [248] (1964) 106 N.H. 107, 206 A.2d 239; Roach v. Harper (1958) 143 W.Va. 869, 105 S.E.2d 564; McDaniel v. Atlanta Coca-Cola Bottling Co., (1939) 60 Ga.App. 92, 2 S.E.2d 810; cf. Pearson v. Dodd, 133 U.S.App.D.C. 279; 410 F.2d 701, cert denied (1969) 395 U.S. 947).
Although the issue has not been squarely decided in California, we have little difficulty in concluding that clandestine photography of the plaintiff in his den and the recordation and transmission of his conversation without his consent resulting in his emotional distress warrants recovery for invasion of privacy in California. [note 1a] California began developing a common law privacy tort in 1931 with the decision of Melvin v. Reid, 112 Cal.App. 285, 297 P. 91. Since then, the California Supreme Court has decided a number of privacy cases in some of which there are indications that California would recognize the plaintiff's claim.
The most recent expression is found in Briscoe v. Reader's Digest Ass'n,supra, 4 Cal.3d at , 93 Cal.Rptr. at 869, 483 P.2d at 37, a privacy action based upon the publication of an article disclosing plaintiff's conviction of a felony 11 years earlier. The court equated the growing acceptance of the right of privacy with
"the increasing capability of * * * electronic devices with their capacity to destroy an individual's anonymity, intrude upon his most intimate activities, and expose his most personal characteristics to public gaze. * * *
"Men fear exposure not only to those closest to them; much of the outrage underlying the asserted right to privacy is a reaction to exposure to persons known only through business or other secondary relationships. The claim is not so much one of total secrecy as it is of the right to define one's circle of intimacy--to choose who shall see beneath the quotidian mask. Loss of control over which 'face' one puts on may result in literal loss of self-identity (Westin, supra, at p. 1023 [Westin, Science, Privacy, and Freedom: Issues and Proposals for the 1970's (1966) 66 Colum.L.Rv. 1003]; cf. Fried, Privacy (1968) 77 Yale L.J. 475), and is humiliating beneath the gaze of those whose curiosity treats a human being as an object."
In Gill v. Hearst Publishing Co. (1953) 40 Cal.2d 224, 230, 253 P.2d 44 1, 444, which denied recovery for invasion of privacy to plaintiffs whose picture was taken in a public market and later published without their consent, the court stressed that the picture had not been "surreptitiously snapped on private grounds, but rather was taken of plaintiffs in a pose voluntarily assumed in a public market place."
Although these cases are not direct authority [249] in the privacy area, they are indicative of the trend of California law to protect interests analogous to those asserted by plaintiff in this case.
We are convinced that California will "approve the extension of the tort of invasion of privacy to instances of intrusion, whether by physical trespass or not, into spheres from which an ordinary man in plaintiff's position could reasonably expect that the particular defendant should be excluded." (Pearson v. Dodd,supra, 410 F.2d at 704.)
Plaintiff's den was a sphere from which he could reasonably expect to exclude eavesdropping newsmen. He invited two of defendant's employees to the den. One who invites another to his home or office takes a risk that the visitor may not be what he seems, and that the visitor may repeat all he hears and observes when he leaves. But he does not and should not be required to take the risk that what is heard and seen will be transmitted by photograph or recording, or in our modern world, in full living color and hi-fi to the public at large or to any segment of it that the visitor may select. A different rule could have a most pernicious effect upon the dignity of man and it would surely lead to guarded conversations and conduct where candor is most valued, e.g., in the case of doctors and lawyers.
The defendant claims that the First Amendment immunizes it from liability for invading plaintiff's den with a hidden camera and its concealed electronic instruments because its employees were gathering news and its instrumentalities "are indispensable tools of investigative reporting." We agree that newsgathering is an integral part of news dissemination. We strongly disagree, however, that the hidden mechanical contrivances are "indispensable tools" of newsgathering. Investigative reporting is an ancient art; its successful practice long antecedes the invention of miniature cameras and electronic devices. The First Amendment has never been construed to accord newsmen immunity from torts or crimes committed during the course of newsgathering. The First Amendment is not a license to trespass, to steal, or to intrude by electronic means into the precincts of another's home or office.[note 2] It does not become such a license simply because the person subjected to the intrusion is reasonably suspected of committing a crime.[note 3]
Defendant relies upon the line of cases commencing with New York Times Co. v. Sullivan (1964) 376 U.S. 254, and extending through Rosenbloom v. Metromedia, Inc. (1971) 403 U.S. 29 [note 4] (1971) to sustain its contentions that (1) publication of news, however tortuously gathered, insulates defendant from liability for the antecedent tort, and (2) even of it is not thus shielded from liability, those cases prevent consideration of publication as an element in computing damages.
As we previously observed, publication is not an essential element of plaintiff's cause of action. Moreover, it is not the foundation for the invocation of a privilege. Privilege concepts developed in defamation cases and to some extent in privacy actions in which publication is [250] an essential component are not relevant in determining liability for intrusive conduct antedating publication. (Cf. Nimmer, "The Right to Speak From Time to Time: First Amendment Theory Applied to Libel and Misapplied to Privacy" (1968) 56 Calif.L.Rev. 935, 957.) Nothing in New York Times or its progeny suggests anything to the contrary. Indeed, the Court strongly indicates that there is no First Amendment interest in protecting news media from calculated misdeeds. (E.g., Time, Inc. v. Hill,supra, 385 U.S. at 389-390 and 384 n. 9.)
No interest protected by the First Amendment is adversely affected by permitting damages for intrusion to be enhanced by the fact of later publication of the information that the publisher improperly acquired. Assessing damages for the additional emotional distress suffered by a plaintiff when the wrongfully acquired data are purveyed to the multitude chills intrusive acts. It does not chill freedom of expression guaranteed by the First Amendment. A rule forbidding the use of publication as an ingredient of damages would deny to the injured plaintiff recovery for real harm done to him without any counter-vailing benefit to the legitimate interest of the public in being informed. The same rule would encourage conduct by news media that grossly offends ordinary men.
The judgment is affirmed.
JAMES M. CARTER, Circuit Judge (concurring and dissenting).
I concur in all of the majority opinion except that portion refusing to meet the issue of the liability of defendants' agents, acting as agents of the police. The opinion states:
"(3) Were the defendant's employees acting as special agents of the police and, if so, did their acts violate the First, Fourth, and Fourteenth Amendments of the Federal Constitution, thereby subjecting defendant to liability under the Civil Rights Act (42 U.S.C. § 1983)? Because we hold that plaintiff proved a cause of action under California law and that the First Amendment does not insulate the defendant from liability, we do not reach the third issue."
The complaint stated a cause of action under claim of diversity jurisdiction. 28 U.S.C. § 1332. No contention was made that a cause of action was stated under the Civil Rights Act, 42 U.S.C. § 1983. I agree we should not reach any issue under the Civil Rights Act, but think we should reach and decide the issue as to Time's liability for the acts of its employees, as agents of the police, in view of Time's reliance on Fourth Amendment cases.
The district court found that an agreement had been entered into between Life magazine, owned by Time, Inc., and the District Attorney's office in Los Angeles, for Life's agents to acquire information which would be used against Dietemann in a criminal prosecution and published by Life. Dietemann v. Time, Inc., 284 F. Supp. 925, 927. It thus appears that the agreement constituted Life and its employees agents of the police. Time in its appellate briefs, disclaimed any contention that its employees were acting for or on behalf of the police and for this reason the majority refused to reach the issue of the liability of Time for the acts of its employees, as agents for the police.
This issue was briefed extensively below, and but for the disclaimer, is still in the case. Time cited the criminal cases involving the Fourth Amendment, referred to infra.
These were cases arising in the United States courts, involving the surreptitious monitoring or recording of conversations and activities of defendants by police and police agents, in which the Supreme Court considered contentions that the conduct violated the Fourth Amendment. On Lee v. United States, 343 U.S. 747 (1952); Lopez v. United States, 373 U.S. 427 [251] (1963); Lewis v. United States, 385 U.S. 206 (1966); Hoffa v. United States, 385 U.S. 293 (1966); Osborn v. United States, 385 U.S. 323 (1966); Katz v. United States, 389 U.S. 347 (1967) and United States v. White, 401 U.S. 745 (1971). The Supreme Court held that in the situations involved in the cases, there was no violation of the Fourth Amendment, except in Katz. White sustained the continuing validity of On Lee,Lopez,Lewis and Hoffa. It did not cite Osborn and distinguished Katz.
The above cases all concerned restrictions on federal action under the Fourth Amendment, but Mapp v. Ohio, 367 U.S. 643 (1961) held in substance that all evidence obtained by searches and seizures in violation of the United States Constitution is inadmissible in a criminal trial in the State Court, and thus incorporated the scope of the Fourth Amendment within the Fourteenth.
It does not follow that, if the intrusion in the case at bar by police agents, did not violate the Fourth Amendment, as incorporated into the Fourteenth, that there can be no civil liability for the intrusion.
A State constitutionally has power to provide protection for the right to privacy. In Katz v. United States, 389 U.S. 347 (1967) the Court stated, "But the protection of a person's general right to privacy--his right to be let alone by other people--is, like the protection of his property and of his very life, left largely to the law of the individual States." [pp. 350-351, 88 S. Ct. p. 510] [Emphasis in text].
Justice Harlan in a concurring and dissenting opinion in Time, Inc. v. Hill, 385 U.S. 374 stated, "The power of a State to control and remedy such intrusion ['upon * * * solitude or private affairs in order to obtain information for publication'] for news gathering purposes cannot be denied, cf. Mapp v. Ohio, 367 U.S. 643, 81 S. Ct. 1684, * * *".[p. 404. 87 S. Ct. p. 550]
Justice Fortas, dissenting in Time, Inc. v. Hill,supra, stated, "Privacy, then, is a basic right. The States may, by appropriate legislation and within proper bounds, enact laws to vindicate that right. Cf. Kovacs v. Cooper, 336 U.S. 77 (1949), sustaining a local ordinance regulating the use of sound trucks; and Breard v. Alexandria, 341 U.S. 622 (1951), sustaining a state law restricting solicitation in private homes of magazine subscriptions." [p. 415, 87 S. Ct. p. 556].
Justice Brennan, writing for the Court in Time, Inc. v. Hill,supra, took care to state in footnote 9, p. 385, 87 S. Ct., p. 541, "Nor do we intimate any view whether the Constitution limits state power to sanction publication of matter obtained by an intrusion into a protected area, for example, through use of electronic listening devices."
A State is free to reassess the interests involved and reach results that restrict the activities of state police to a greater extent than do the decisions of the Supreme Court. The Fourth Amendment, incorporated into the Fourteenth Amendment by Mapp, says only that the police cannot engage in certain activities. It does not dictate that the police be given the privilege to engage in activities it does not prohibit.
A state must enforce the federal exclusionary rules in a criminal prosecution because of Mapp v. Ohio,supra. But a State court can also enforce the additional restrictions it would impose on the police, by recognizing a private right of action for intrusion by the victim of police activity even if the activity does not violate the Fourth Amendment. In fact, a State might recognize a civil action for intrusion when it would not exclude evidence in a criminal prosecution [252] because of the intrusion. The rationale would be that an unsuccessful prosecution is too high a social price to pay to deter the police.
Various conflicting interests would be weighed by a State court in arriving at a decision as to whether it would allow the cause of action involved in this case. Certain interests that cut toward restricting police activities, include the interest of citizens in privacy, the interests of preventing the police from violating the societal norms of what constitutes fair play and the interest in preventing behavior by the police which could cumulate in tyranny. The primary interest that cuts the other way, is that of society in discovering and successfully prosecuting criminal activities.
There is a basis however for believing that in spite of Life's agreement with law enforcement officers, law enforcement interest was not furthered by the intrusion. Time admits [appellant's reply brief p. 16] that the intrusion was conducted primarily for its benefit. The law enforcement officers had already on two occasions obtained recordings which should have been sufficient for a prosecution. When allied with the police in making intrusions, the press can serve its private purpose without the public prosecution interest being served.
There is a risk that an intrusion from such an alliance between press and police would not further the public prosecution interest, if the press were allowed to decide when the alliances were formed and when the intrusion should take place.
Here Time, through its publication Life, realizing it could not unilaterally invade Dietemann's house and privacy, sought the protection of cooperation with state officials. The officials, recognizing their duty not to publicly expose the results of police investigations, accepted the services of Life. Each thereby achieved jointly which neither could have achieved separately.
No California case has expressly considered the existence of a cause of action for an invasion of privacy by an intrusion by either private persons or police agents. We are therefore required to place ourselves in the position of the highest California court considering the matter initially. United States v. Hayes (9 Cir.1966) 369 F.2d 671; Edwards v. American Home Assurance Company (9 Cir.1966) 361 F.2d 622; See Gates v. P. F. Collier, Inc. (9 Cir.1967) 378 F.2d 888, cert. denied 389 U.S. 1038 (1968); 1 Barron & Holtzoff, Fed. Practice and Procedure, § 8, p. 40 (1960).
California Supreme Court cases in the general privacy realm have suggested a sensitivity to protecting "the right to be let alone." Gill v. Curtis Publishing Co., 38 Cal.2d 273, 275, 239 P.2d 630, 632 (1952). In denying recovery for the publication of a photo taken in the Los Angeles Farmer's Market, the court noted that a different result might have occurred if the picture had been "surreptitiously snapped on private grounds." Gill v. Hearst Publishing Company, 40 Cal.2d 224, 230, 253 P.2d 441 (1953).
Based on the above considerations, and the California cases cited by the majority, we believe that California would recognize a cause of action for intrusion against Time for the activities of Life's employees as agents of the police.
This case presents a proper vehicle for that determination. The issue has been extensively briefed and argued below. The issue should be here decided and not avoided.
Footnotes to the Majority Opinion
1. Although the complaint did not initially cite the Civil Rights Act as a foundation of liability, the district court concluded that a claim for relief had been proved under the Act. On appeal plaintiff pressed liability under the Act as an alternative basis for supporting the judgment.
1a. It is unnecessary for us to decide whether California will adopt Dean Prosser's analysis of privacy, including his classification of intrusion as a separate tort (Prosser, "Privacy" (1960) 48 Calif.L.Rev. 383; W. Prosser, Torts 832-33 (3d ed. 1964)), or Prosser Bloustein's more expansive concept of the right of privacy (Bloustein, "Privacy as an Aspect of Human Dignity: An Answer to Dean Prosser" (1964) 39 N.Y.U.L.Rev. 962; Bloustein, "Privacy, Tort Law, and the Constitution: Is Warren and Brandeis' Tort Petty and Unconstitutional as Well?" (1968) 36 Tex.L.Rev. 611), because the facts of this case would expose the defendant to liability under either view. (See also Briscoe v. Reader's Digest Ass'n, Inc. (1971) 4 Cal.3d 529, n. 4, 93 Cal.Rptr. 866, 869 n. 4, 483 P.2d 34, 37 n. 4.)
2. In this respect the facts of this case are different from those in Pearson v. Dodd,supra, 410 F.2d 701. In Pearson, the defendant received documents knowing that they had been removed by the donor without the plaintiff's consent. But the donor was not the defendant's agent, and the defendant did not participate in purloining the documents.
3. Because we have accepted defendant's disclaimer that it was acting for or on behalf of the police, we have no occasion to consider the impact of the Fourth and Fourteenth Amendments on the relationship between the exclusionary rules in criminal cases and substantive law in a private tort action. | 2024-04-06T01:26:51.906118 | https://example.com/article/9770 |
Mike D’Antoni: Phil Jackson Will Hang Over Lakers For Next 10 To 15 years
No matter who the coach of the Lakers is for the forseeable future, he will always be compared to Phil Jackson and the Zen Master’s accomplishment’s.
D’Antoni during a moment of reflection, told The Los Angeles Times that “Jackson will hang over the Lakers for the next 10-15 years.’
No, the specter of Phil Jackson never quite left the Lakers.
“I think anybody that comes in here the next 10, 15 years, it’s going to be that way,” D’Antoni said. “I don’t think there is any doubt that he was so good and so large and he’s still sitting out there.
“Had that bothered me, I shouldn’t have taken the job because you know it’s going to be there. I wasn’t stupid enough to think that, ‘Oh, they won’t remember him.’ Sure they will. It doesn’t really affect what we do day-to-day and how we approach the game.” | 2023-12-22T01:26:51.906118 | https://example.com/article/8622 |
Little Women
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This collection is exclusive to Little Women and you won't find them anywhere else. They have been designed specifically in small cup sizes with matching briefs and thongs and they are produced in small quantities on a seasonal basis - once they’re gone, they’re gone!
We work hard to ensure that our embroideries, laces and fabrics reflect mainstream fashions, including prints, pastels, vibrant colours and flat laces that are versatile enough to be worn under sheer tops - we sell beautiful lingerie for every occasion; smooth seamless bras perfect for wearing under t-shirts, sexy and sophisticated lingerie for the most glamorous situations, even strapless bras for evening wear. | 2023-09-22T01:26:51.906118 | https://example.com/article/2800 |
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Interested in our roofing services? Call us today for more information. | 2024-03-05T01:26:51.906118 | https://example.com/article/7241 |
BoJack Horseman is riding off into the L.A. sunset.
Netflix has announced that the forthcoming sixth season of the adult animated comedy will be its last. The streamer also revealed the concluding season will air in two parts, the first launching Oct. 25, 2019, and the second on Jan. 31, 2020.
“BoJack Horseman” features the voice of Arnett as the titular former ’90s sitcom star who is also a horse, as well as the voices of Amy Sedaris, Alison Brie, Paul F. Tomkins and Aaron Paul. Created by Raphael Bob-Waksberg, the series is executive produced by Bob-Waksberg, Steven A. Cohen, and Noel Bright. Arnett and Paul also exec-produce.
Fans will still be able to catch reruns of “BoJack” on Comedy Central, after the cabler acquired the rights in Oct. 2018 from Lionsgate-owned Debmar-Mercury and producer the Tornante Company. At the time, the deal was believed to be the first such U.S. linear syndication agreement for a Netflix original series.
Netflix has released a trailer for the final season which sees BoJack writing a letter to his friend Diane (Brie) from rehab, in which he re-evaluates how he wants to live his life from now on.
“Every time someone leaves rehab, makes you think about your own progress. I bought into this idea that I was the thing that couldn’t be changed, but the main thing I think about is how stupid I am that I didn’t do this sooner. I wasted so many years being miserable because I assumed that was the only way to be, and I don’t want to be that anymore,” BoJack writes.
Watch the final season trailer below: | 2023-10-18T01:26:51.906118 | https://example.com/article/3109 |
Q:
Connect to LDAP via ColdFusion
I am trying to get the following connection to our LDAP working via ColdFusion, however, I can never get it to return any values (i.e. results.recordcount always equals 0). I assume my problem is with the "start" portion of the query so I did some research and have tried numerous values but nothing seems to work.
<cfldap
server = "adserver"
action = "query"
username = "DOMAIN\username"
password = "apassword"
name = "results"
scope="subtree"
start = "dc=domain.local"
attributes = "givenname,surname,uid,userid,groupMembership,mail,dn,roles,memberof,cn,samaccountName">
<cfoutput>
#results.recordcount#
</cfoutput>
The structure of the AD that I'm trying to access is as follows. I'm trying to get to the "Users" section at the bottom of the tree shown.
Active Directory Users and Computers
- Saved queries
- domain.local
- option1
- option2
- NAME1
- option1
- option2
- NAME2
- Computers
- Disabled Users
- Groups
- Users
If I right-click on "User" and view the properties it tells me the canonical name for it is domain.local/NAME1/NAME2/Users, which I assume is relevant to my problem.
Any ideas what I should be using for the "start" portion of cfldap?
Thanks in advance.
A:
I highly recommend browsing your AD with a program like Softerra's LDAP Browser (http://www.ldapbrowser.com/) and then locating the distinguished name of the hierarchy where you want to start searching. Using this, I was able to find the exact DN of the LDAP structure to target.
| 2024-02-14T01:26:51.906118 | https://example.com/article/6837 |
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<?xml version="1.0" encoding="utf-8"?>
<!-- Automatically generated file. Do not edit. -->
<html xmlns="http://www.w3.org/1999/xhtml">
<head>
<title>2 punkty i długość</title>
<link rel="stylesheet" type="text/css" href="../../../../../style.css" />
<meta http-equiv="content-type" content="text/html; charset=UTF-8" /></head>
<body style="font-family:Arial, Helvetica, sans-serif">
<p style="text-align:right;"><a href="/doc/qcad/latest/reference/pl/index.php?page=scripts/Draw/Arc/Arc2PL/doc/Arc2PL">      </a></p>
<p style="font-style: italic;">Jest to tłumaczenie automatyczne.</p>
<div class="nobreak">
<h2>2 punkty i długość</h2>
<p class="toolinfo">
<b>Pasek narzędziowy / ikona:</b>
<br /><img src="../../doc/Arc.png" width="40" height="40" />
   
<img src="../doc/Arc2PL.png" width="40" height="40" />
   
<br/>
<b>Menu:</b> <font face="courier new">Rysowanie > Łuk > 2 punkty i długość</font>
<br /><b>Skrót:</b> <font face="courier new">A, L</font>
<br /><b>Polecenia:</b> <font face="courier new">arclength | al</font>
</p>
</div>
<h3>Opis</h3>
<p>Rysuje łuk przy użyciu punktu początkowego, punktu końcowego i długości
łuku.</p>
<h3>Usage</h3>
<ol>
<li>Wpisz długość łuku na pasku narzędzi opcji i wybierz kierunek łuku
（zgodnie z ruchem wskazówek zegara lub przeciwnie do ruchu wskazówek
zegara).</li>
<li>Określ punkt początkowy łuku.</li>
<li>Określ punkt końcowy łuku. Jeżeli punkt końcowy jest zbyt odległy od
punktu początkowego rozwiązania, nic nie jest narysowane.</li>
</ol>
</body>
</html>
| 2024-03-10T01:26:51.906118 | https://example.com/article/7053 |
. What is y(p)?
11
Suppose 4*p - 12*p + 24 = 0. Let f(s) = 5*s**2 - s - 5 - s**p - 3 + 9. What is f(5)?
-4
Let f(t) = -t**3 - 2*t**2. Let h(c) = -7*c**3 - 26*c**2 + 17*c + 32. Let j(i) = 6*f(i) - h(i). Give j(-15).
-2
Let p(o) = -3*o + 5. Let c be (-9)/(-1) + -13 + 12. Suppose 4*g - f - 6 = c, 10 = g + 3*f. Give p(g).
-7
Let r(y) = y**2 - 2*y - 18. Let l be r(8). Suppose 11*g = 16*g - l. Let b(i) be the first derivative of -i**2 + 6*i - 1. Calculate b(g).
-6
Let p(n) = -n**2 + 6*n - 7. Let w be (-18)/(3*(-4)/8). Suppose -4*q + w = -3*q. Suppose 0*i + q = 2*i. What is p(i)?
-7
Let n be 88/56 + (-9)/(-21). Suppose -o + 3*b + n*b - 23 = 0, -2*o = 4*b - 10. Let i(a) = a + 4. What is i(o)?
1
Suppose 0 = k - s, 2*k - 2*s = -2*k. Suppose 6*l - l + i + 75 = k, 0 = -4*i. Let r be (2/3)/((-2)/l). Let c(d) = d**2 - 5*d + 7. Calculate c(r).
7
Suppose 81 + 7 = 44*f. Let h(i) = 2*i**2 - i**3 + i - 5 + 3 + i. What is h(f)?
2
Let z(o) be the first derivative of o**2 + o - 6. Let y(v) be the first derivative of 5*v**2/2 + 3*v + 1. Let r(l) = -3*y(l) + 7*z(l). Determine r(2).
-4
Let o(l) = 17*l**2 + 2*l - 1. Let n be o(1). Let p = 12 - n. Let r(t) be the first derivative of -t**3/3 - 5*t**2/2 + 4*t - 2. Determine r(p).
-2
Let x(l) be the first derivative of -l**4/12 - 7*l**3/6 - l**2 - 14*l - 30. Let y(p) be the first derivative of x(p). Determine y(-5).
8
Let g be ((-2)/(-3))/((-30)/315). Let x(k) = -4*k - 9. Determine x(g).
19
Let o(s) = -4*s - 4. Suppose -111 = -5*a + 119. Let k = a + -43. Determine o(k).
-16
Let k(a) = 2*a - 12. Let f(z) = -1. Let v(s) = -28*f(s) + 2*k(s). Suppose 4*j - 3*u + 32 = 0, 0 = -3*j - 0*j - 2*u - 7. Calculate v(j).
-16
Let c(n) = -n - 4. Let z(q) = q**2 + 4*q - 11. Let b be z(-5). Let g be c(b). Let a(d) = -4*d - 8*d + 1 + 8*d. Determine a(g).
-7
Let l(x) be the second derivative of -x**5/20 + x**4/2 + 5*x**3/3 - x**2 - 2*x. Let j be 1/((-4)/(-28))*2/2. What is l(j)?
19
Let q(m) = 2*m + 3. Let p(w) = -1 + 2*w + w**2 - w**2 - 2*w**2 + w**2. Let n be p(1). Suppose -l + n = -3. What is q(l)?
9
Let u be (56/70)/(1/(-10)). Let x(k) = -k - 12. What is x(u)?
-4
Let l = -24 + 26. Suppose -16 + 4 = l*q. Let z(y) = -y**2 - 5*y + 2. Calculate z(q).
-4
Let x(t) = -61*t**3 - t**2 - 6*t**2 + 5*t + 62*t**3 + 2*t**2. Let r = 100 - 96. Determine x(r).
4
Let i(w) = 6*w - 3*w + 11*w - 14 + 3*w. Let b(c) = 6*c - 5. Let r(m) = -11*b(m) + 4*i(m). What is r(4)?
7
Let a(b) be the third derivative of -b**6/120 + 3*b**5/10 + 8*b**3/3 - b**2 - 5*b. What is a(18)?
16
Let u(v) = -v - 6. Let h be u(-8). Let c(j) = 5*j + 0 - 1 - 11*j + 11*j. What is c(h)?
9
Let b(p) be the second derivative of 5/2*p**2 - 1/20*p**5 + 0 - 3/2*p**3 + 5*p + 2/3*p**4. Determine b(7).
-9
Let o(p) = p - 3. Suppose n - 3*n = -2. Suppose 0 = -2*a + a - n. Let x be -1*a/(-3)*-6. What is o(x)?
-1
Let s(l) = 3*l + 10 - l + 0 - 3 - l**2 - 3. Let j be 19/7 + 2/7. Give s(j).
1
Let z(a) = 306*a**3 - a**2 + 302*a**3 - 607*a**3 + 12. Give z(0).
12
Suppose -8*p = 4*g - 10*p - 16, -4*p - 4 = -g. Let l(o) be the first derivative of o**2/2 - o + 2. Calculate l(g).
3
Let j(a) = -a**3 + 21*a**2 - 31*a + 15. Let u(k) = -k**3 + 21*k**2 - 33*k + 15. Let t(m) = -6*j(m) + 5*u(m). What is t(20)?
5
Let l(f) = -f**2 - 2*f + 5. Let o be ((-24)/20)/(((-21)/(-20))/(-7)). Let a be 1/(-3)*0 + 16. Suppose -4*b + b = v + a, -4*v - o = -2*b. Determine l(v).
-3
Let v(n) = n**3 - 2*n**2 - 2*n - 3. Let c be v(3). Let d(f) = 4 + c*f - f - 8 - 3. Determine d(-6).
-1
Let z(l) be the second derivative of l**3/6 - l**2/2 - l. Let g be z(3). Let m(n) = 91 - 93 + 2*n + 6*n**3 - 5*n**2 - 5*n**3. Determine m(g).
-10
Let j(r) = 2*r - 11. Let a be j(7). Let h(f) = -f**3 + 6*f**2 - 5*f + 3. Let w be h(5). Let c(i) = 6 + 2*i - i**2 - w + 2*i. Calculate c(a).
6
Let u(m) = -m**3 - 3*m**2 + 4*m + 1. Suppose 4*t + 105 - 5 = 0. Suppose -p = -12*r + 7*r - 27, 2*p = 2*r + 46. Let s = t + p. Give u(s).
-11
Let f(j) = -j**3 - 4*j**2 - 3*j + 2. Let b(c) = -2*c + 39. Let r be b(-8). Let p be r/(-11) + 2/2. Give f(p).
14
Let l(k) be the third derivative of -k**5/20 - 7*k**4/24 - 3*k**3/2 + 563*k**2. Determine l(-3).
-15
Let b(h) = -h - 4. Suppose -4 = 22*d - 18*d. Let o be 3/(-6)*(23 + 5/d). Determine b(o).
5
Suppose -f - i = -5*i, -3*i - 11 = 2*f. Let t(n) = -n - 3. Let l(j) = 3*j + 8. Suppose 3*c - 23 + 56 = 0. Let g(z) = c*t(z) - 4*l(z). Calculate g(f).
5
Let v(h) be the third derivative of h**4/8 - 3*h**3/2 - 2*h**2 - 26. What is v(10)?
21
Let l(u) = -2*u + 3 + 0*u - 6 - 2 - u. What is l(-3)?
4
Suppose 2*b - b = 2*q - 10, -2*b - 2*q - 44 = 0. Let g = 23 + b. Let s(x) = -x**2 + 6*x - 7. Give s(g).
-2
Let y(c) = 35*c - 10 - 6 - 36*c. Calculate y(-13).
-3
Let u(f) = -11*f. Let k = -3 + 10. Suppose -2*o - 5 - k = 2*z, 3*z - 4*o = 17. Calculate u(z).
11
Let n(u) = -u**2 - 4*u. Let s be 5 - (1 + (-1 - 0)). Let a(d) = -11*d - 3. Let c(v) = 16*v + 5. Let r(z) = 3*a(z) + 2*c(z). Let p be r(s). Give n(p).
0
Let n(f) = -f**3 + 10*f**2 - 9*f + 6. Suppose 4*g + 2*s - 14 = 0, 3*s = -4*g - 0*s + 13. Suppose -36 + 72 = g*a. Give n(a).
6
Let j(r) = 2*r**2 - 8*r - 10 - 3*r + 2 + 9. What is j(6)?
7
Let y(q) = -2*q + 4. Suppose -z + 75 = 14*z. Determine y(z).
-6
Let s(f) be the first derivative of -f**4/4 + 4*f**3/3 + f**2/2 - 4*f - 11. Let z be ((-6)/(-9))/((-2)/(-12)). Give s(z).
0
Let p(b) be the third derivative of -b**5/60 - 5*b**4/24 + b**3 - 68*b**2. Calculate p(-8).
-18
Let o = 431 - 10343/24. Let k(w) be the third derivative of 0 + 0*w - 7*w**2 - 2/3*w**3 - o*w**4. Calculate k(-4).
0
Let y(n) = n**2 - 3*n - 3. Suppose 2*t = 2*o + 8, -4*t + 3*o = -0*o - 18. What is y(t)?
15
Let y(d) = d - 7. Let a be y(10). Let t(k) = 1 - 4*k**2 + 23*k - 2*k**a + k**3 - 25*k. Calculate t(-3).
-2
Suppose 26 + 4 = 10*b. Let k(t) = -t**2 + 3*t + 1. Determine k(b).
1
Suppose 2*k - 22 = -7*w + 4*w, -3*w + 5*k = 13. Suppose 5*j - 34 = -w. Let c(y) = -j - 7 + 13 - y. Calculate c(5).
-5
Let y(z) be the third derivative of -z**6/120 - z**5/60 - 11*z**3 + 458*z**2. What is y(0)?
-66
Let y be 13 - ((-4 - -8) + -6). Suppose 3*m + 8 - 3 = -i, y = -5*m. Let r(n) = -n**3 + 5*n**2 - n + 1. Give r(i).
13
Let d = 611 + -606. Let c(u) = -u**2 + 5*u + 4. Give c(d).
4
Let w(d) be the third derivative of -1/60*d**5 - 1/120*d**6 + d**2 + 0*d + 0 - 1/6*d**3 + 0*d**4. Let t be (-3)/2*8/6. What is w(t)?
3
Suppose 4*n - 21 = -3*n. Let o(c) = c**n - 5 - c**2 - 5*c + 2 + 5. Calculate o(3).
5
Let o(k) be the first derivative of 3*k**2/2 - 10*k + 42. What is o(3)?
-1
Suppose 30*n - 14*n = -112. Let k(t) = t**3 + 8*t**2 + 7*t - 4. Determine k(n).
-4
Let r = 644 - 638. Let m(k) = -k**3 + 6*k**2 - 4*k + 5. What is m(r)?
-19
Let u(t) be the second derivative of t**4/12 + 4*t**3/3 - 75*t. What is u(-6)?
-12
Suppose 7 = 4*r - 5. Let i(s) be the first derivative of 5 + 4 - 4 - 1 - r*s - s**2. Determine i(-3).
3
Let p(w) = w**3 + 10*w**2 + 8*w - 13. Let h be (-4)/6 - (2200/24)/11. Calculate p(h).
-4
Let w(p) = -3*p**2 + 15*p + 39. Let t be w(-2). Let r(a) = -a**3 + a. Give r(t).
24
Let l(g) be the second derivative of 24*g - g**3 + 0 - 3/2*g**2. Calculate l(4).
-27
Let c(u) = 4*u**2 + 50*u - 28*u + 2*u**3 - u**3 + 1 - 21*u. Give c(-3).
7
Let u(z) = -20 - 13 - 4*z - 11 + 47. Let s = 2 - 0. Suppose 0 = 3*w - s*h + 2, -2*w + h - 2*h + 8 = 0. Determine u(w).
-5
Let k(y) = -7*y - 4. Let n(t) = t - 3 + 0*t - 3*t - 5*t. Let l(j) = 4*k(j) - 5*n(j). Determine l(-1).
-8
Suppose -59*l + 75*l = -48. Let w(v) = -1 - 4 - v**2 - v + 5. Give w(l).
-6
Let y be 0/(2 + 2 + -5). Let w(h) = -h - 4. What is w(y)?
-4
Let w(x) = -x**3 + 17*x**2 - 14*x - 18. Let c be w(16). Let g = -6 + c. Let a = g + -15. Let r(u) = -u**3 - 6*u**2 + 8*u + 3. Give r(a).
-4
Let a(v) = 3*v - 4. Let x(w) = 2*w - 3. Suppose -3*p + z - 7 = -z, 0 = -5*z - 5. Let j(u) = p*a(u) + 4*x(u). Give j(5).
-5
Let z(l) = -14*l**2 - 2*l + 13. Let y(j) = -30*j**2 - 4*j + 24. Let m(x) = -6*y(x) + 11*z(x). Calculate m(1).
27
Let i(o) be the second derivative of -o**5/20 + o**4/4 + o**3/3 - 2*o**2 + 306*o. Calculate i(3).
2
Let c(x) be the third derivative of -x**5/60 + x**4/24 - x**3/3 + 66*x**2. Determine c(3).
-8
Let b(g) = -2*g**3 + 3*g**2 + 6*g - 1. Let t be b(-2). Let i = t + -12. Let l(n) = -n**2 + 7*n - 4. Calculate l(i).
8
Let u(y) = -6*y**2 + 0*y - 6*y - | 2023-08-18T01:26:51.906118 | https://example.com/article/3555 |
Epidemiological, clinical, and pathomorphological characteristics of epidemic poliomyelitis-like disease caused by enterovirus 71.
In May-September, 1975, an outbreak of epidemic disease clinically and pathomorphologically simulating nearly all known forms of poliomyelitis occurred predominantly among young infants in Bulgaria. Most cases presented benign aseptic meningitis, sometimes with a short period of general cerebra- symptoms. Paralytic forms, such as bulbar polioencephalitis, anterior poliomyelitis, isolated pareses of the facial nerve, occasional cases of encephalomyocarditis, etc., were observed in about 21% of all cases. Over one-fourth of the paralytic cases with bulbar symptoms ended fatally. In March, 1976 another sporadic fatal case of this disease was examined. No new cases occurred in 1977. Histopathological examinations in all fatal cases regularly revealed lesions in the grey matter of the medulla and spinal cord typical of acute anterior poliomyelitis and bulbar polioencephalitis, with some peculiar features of localization and depth of the involvement of the brain stem. The similarity to poliomyelitis and precariously rapid increase in the incidence led to the decision to urgently vaccinate the entire human population with Sabin's live poliovirus vaccine simultaneously in the whole country in order to produce interference with the circulating agent. This aim appeared to have been achieved partially because soon the number of new cases of the disease began to decrease; however, no sharp and complete break in the curve of the incidence occurred. By the time of mass vaccination, the results of virological examinations started before were not yet available. Later, comprehensive complete evidence was obtained that over 25 fatal and many other typical cases of the disease were associated with an enterovirus proved to be antigenically related to enterovirus 71. The diseases in Bulgaria, 1975, differ considerably in the frequency of paralytic forms and in severity from the epidemics caused by enterovirus 71 in Sweden, 1973, Australia, 1972--1973, USA, 1969--1972, and Japan, 1972--1973. | 2023-09-28T01:26:51.906118 | https://example.com/article/6391 |
Behind the Brand: Made In
Words by Elliot Jay Stocks | Published 11.15.18
They say never work with your friends. But a genuine friendship between co-founders can be a far stronger company foundation than many business-centric goals. After all, you’re going to be spending a lot of time with this person; you’re going to make some tough decisions with this person; you should probably, well, like this person.
And yet, mixing business and pleasure is not without its challenges. The stakes can be high — especially when that friendship is one that dates back to pre-school. “Jake [Kalick] and I have known each other since we were five,” recalls Made In’s co-founder Chip Malt. “And we went all the way through high school together.” But the company’s roots date back further still, when Jake’s grandfather set up a kitchen supply company in Boston in 1929. Prior to Made In’s founding, Jake was running that company while Chip was running an ecommerce business in New York.
The pivotal point came, Chip says, when he was 28 and was investing in nicer items for his home. “The Caspers of the world were out there, so I was upgrading my bed, upgrading my sheets, upgrading everything else — but there was just no-one doing it in the kitchen industry. As something that I used on a daily basis, I knew it could directly affect my life.” This spurred him to reach out to Jake and ask if he was interested in starting a direct-to-consumer cookware company. Jake loved the idea and recognised that most people he knew had no idea what was in their kitchen — that most pots and pans were either a hand-me-down, or something bought from Ikea for that first move out to college. So the two lifelong friends decided to create a brand that people cared about, and educate them about why it’s important to invest in good cookware.
Chip points out that “there’s never been an easier time to not cook at home, but people are cooking more and more at home — because it’s actually an enjoyable experience.
“It’s important to establish ourselves as not being an amorphous group of internet people up in the sky somewhere, pushing buttons.”
Made In officially launched in September 2017 — our interview comes hot on the heels of the brand’s first anniversary celebrations — and that first year has been an impressive one. Beyond shipping out more than 15,000 pieces of cookware in their first year, the company has enjoyed a lot of respect from industry professionals. Just prior to our chat, Made In announced their partnership with celebrity chef Tom Colicchio, who’s come on board as an investor and advisor. “We have a solid network of professionals who use our products on a daily basis,” Chip says, clearly and deservedly proud.
In that one short year, Chip and Jake have discovered that they have two very distinct types of customers: those who start as skeptics, and buy just one pan but then return after they’ve used it to buy the whole set; and those two trust the reviews they’ve read and go all-in from the first purchase. And why wouldn’t you trust the reviews? 98% of them are 5 stars.
But still, education is paramount, especially because Made In’s pans hold heat so well. Almost _too_ well, in fact: some first-time customers often find they “burn the shit out of their first meal” according to Chip. “People come from using cast iron, which doesn’t hold heat well, or an old non-stick. It’s a different experience. But once people get the hang of it, they’re automatically a better cook.”
Did you know that non-stick pans should be used as the exception rather than the rule? Neither did we, until we read Made In’s extremely informative blog, Dinner Party. Seriously, go and read it — you’ll love it.
However, what sets Made In apart is the actual process of the products’ creation, which goes all the way back to sourcing. “We wanted to have a big focus on the supply chain from day one,” Chip explains. “Not just go to China and white-label a product and throw a brand on it. It meant finding people who were experts in their craft — who had honed it for generations — to build the products for us.” Unique to Made In is the intimate relationship the company has with its suppliers, with Chip and Jake buying the raw metals and handling the shipping of them to their metal-cladders.
Asked what’s changed since Made In’s launch a year ago, Chip cites the emotional attachment to cooking that they’ve found in their customers — the reasons _why_ people cook. The grandmother’s recipe that’s been handing down for generations. Inviting their friends over for dinner. A way of expressing creativity. “We launched with a very cool image,” Chip explains, “but we’ve moved towards these simpler, more down-to-earth elements. A little more depth and authenticity rather than the snazzy brand stuff.”
This quest for authenticity has recently led Chip and Jake to a small town in France that has been making knives for the last 700 years. “We’ve partnered with fifth-generation knife-makers,” Chip explains. “It’s one of the few places in the world that creates a full knife from one single piece of metal.” The result is a new product — their first made outside the US — that’s helping to redefine the very message behind the brand name. It’s now “Made In as in ‘made where it should be made in’,” Chip explains. “So we have ‘Made In America’ cookware and ‘Made In France’ knives. They all follow this philosophy of us doing the research, sourcing the manufacturers, and designing the product with them to make something awesome.”
Made In’s cookware is used in the kitchen of our restaurant Prim and Proper, and is available to buy in-store and online. Asked why they decided to partner with Neighborhood Goods, Chip says, “Surrounding ourselves with like-minded brands that are unique and innovative and inline with the retail concept we’re trying to do… It makes sense on every level.” He believes that our generation appreciates subtlety in marketing, and that having an offline presence presents unique opportunities. “It’s important to establish ourselves as not being an amorphous group of internet people up in the sky somewhere, pushing buttons.” | 2024-02-10T01:26:51.906118 | https://example.com/article/5012 |
Ubiquilin2 as a novel marker for detection of urothelial carcinoma cells in urine.
Ubiquilin 2 (UBQLN2), an ubiquitin-related protein, is strongly expressed in urothelial carcinoma cells, in contrast to no or less expression in non-neoplastic cells; it protects cancer cells from reactive oxygen species (ROS)-induced cytotoxicity. In this study, we investigated whether UBQLN2 immunostaining, using liquid-based cytology sample could improve the accuracy of cytological urine diagnosis. Two-hundred and forty-five urinary samples, including 143 negative controls and 102 urothelial carcinomas, consisting of 42 low-grade and 60 high-grade urothelial carcinomas, were used for immunocytochemical analysis of UBQLN2. Urothelial carcinoma cells were positive for UBQLN2-staining, while non-neoplastic cells, including renal tubular cells and degenerative atypical cells, were negative. Interestingly, percentage of nuclear stain immunopositive for UBQLN2 was significantly higher in carcinoma cells with high grade/invasive phenotype than in those with low grade/noninvasive phenotype. UBQLN2 immunostaining had an overall sensitivity of 87.6%, specificity of 98.6%, positive predictive value of 97.8% and negative predictive value of 92.8% for the detection of urothelial carcinoma. UBQLN2 immunostaining is a practical test for urine cytology, even in samples with few cells, with slight atypia or severe degenerative changes. In addition, it allows prediction of tumor grade and stage by examining the cellular localization of UBQLN2. | 2024-05-01T01:26:51.906118 | https://example.com/article/2449 |
Q:
How to append no. of bytes to a byte array?
I am doing a project in 'Steganography' in which I want to encrypt the contents of file using 'Blowfish' algorithm and then want to embed the encrypted text in the image and do the reverse procedure for extracting the image.
The 'update' method from class 'Cipher' encrypts only some no. of bytes but, here I want all the bytes(encrypted contents) of the file in only one array. Same is the case with 'update' method in decryption. This array later will be passed to a method in which I embed the text in the image and extract when required.So what can be the better approach towards this problem?
Thank you.
A:
Most ciphers are streaming ciphers. They can take blobs of data and stream out results as it encrypt/decrypts them. The Java Cipher class works this way. You call update(..) with a block of data, and it returns a block of encrypted data. When you reach the end of your input data, you call the final(...) method.
Now, if you wish to accumulate all of your data in to a single binary buffer, and encrypt it all at once, that works fine also. But in the end, either way works, the cipher doesn't care if it encrypts 1 byte at a time or 1MB at a time.
If you simply want to know how to append byte arrays, you simply create a new byte array that has a length equal to the sum of the sizes of the arrays you wish to append, then use System.arraycopy to move copy the original arrays.
byte[] newbuf = new byte[oldbuf1.length + oldbuf2.length];
System.arraycopy(oldbuf1, 0, newbuf, 0, oldbuf1.length);
System.arraycopy(oldbuf2, 0, newbuf, oldbuf1.length, oldbuf2.length);
If you're going to do that a lot, and you have the memory to spare, it's better to accumulate your chunks of data in to disparate byte buffers, stuff them in a List, and then do your final merge just once.
int sum = 0;
for(byte[] ba : arraysList) {
sum = sum + ba.length;
}
byte[] newbuf = new byte[sum];
int curpos = 0;
for(byte[] ba : arraysList) {
System.arraycopy(ba, 0, newbuf, curpos, ba.length);
curpos = curpos + ba.length;
}
(Code not tested, should work, don't think there's any 1-offs in there.)
| 2023-08-14T01:26:51.906118 | https://example.com/article/5115 |
1. Field
Embodiments of the disclosure relate generally to the field of aircraft fuel systems and more particularly to embodiments for a fuel scavenge water removal system employing flow direction change and fluid velocity reduction.
2. Background
Large commercial aircraft often employ a center fuel tank and separate wing tanks. Weight and balance requirements as well as fuel usage by the engines or other operational considerations may require fuel from the center tank to be burned prior to fuel in the wing tanks. Since the center tank fuel pumps are not able to completely drain the center, a separate fuel scavenge system is installed to transfer the small amount of fuel remaining to the wing tanks. The temperatures outboard from the fuselage are much colder than the temperatures inboard which may cause any water present in fact being moved outboard into the wing, tanks to freeze and impair fuel transfer.
It is therefore desirable to provide a fuel scavenge water removal system which prevents water from leaving the warmer center tank. | 2023-08-08T01:26:51.906118 | https://example.com/article/3760 |
Description:Stewart v. Cendant Mobility Services Corp.; a promise that the promisor should reasonably expect to induce action or forbearance and does is binding if injustice can be avoided only by enforcement of the promise. | 2024-04-02T01:26:51.906118 | https://example.com/article/9921 |
Mereswine
Mereswine may refer to:
Dolphins, aquatic mammals related to Porpoises and Whales
Porpoises, small Cetaceans of the family Phocoenidae
Category:Animal common name disambiguation pages | 2023-10-17T01:26:51.906118 | https://example.com/article/9023 |
NASA's Kepler Mission is designed to determine the frequency of Earth-size and larger planets in the habitable zone of solar-like stars. It uses transit photometry from space to determine planet size relative to its star and orbital period. From these measurements, and those of complementary ground-based observations of planet-hosting stars, and from Kepler's third law, the actual size of the planet, its position relative to the habitable zone, and the presence of other planets can be deduced. The Kepler photometer is designed around a 0.95 m aperture wide field-of-view (FOV) Schmidt type telescope with a large array of CCD detectors to continuously monitor 100,000 stars in a single FOV for four years. To detect terrestrial planets, the photometer uses differential relative photometry to obtain a precision of 20 ppm for 12th magnitude stars. The combination of the number of stars that must be monitored to get a statistically significant estimate of the frequency of Earth-size planets, the size of Earth with respect to the Sun, the minimum number of photoelectrons required to recognize the transit signal while maintaining a low false-alarm rate, and the areal density of target stars of differing brightness are all critical to the photometer design. | 2023-11-24T01:26:51.906118 | https://example.com/article/7723 |
Statutes that prohibit secret detention in black-hole prisons, surveillance of the American people without warrant and torture have all been ignored or redefined out of existence. The protections afforded by habeas corpus and the Geneva Conventions have been taken out the back and shot.
Like Louis XIV before him, Bush says, "L'Etat, c'est moi" (I am the state). He could declare anyone, anywhere, to be an illegal enemy combatant, even though they had committed no war crime or fought in any war. Outside the normal laws of war, or even the criminal law, they could be sent to a black-hole prison, where they could be tortured, and face trial on charges based on "coerced testimony" and hearsay. The accused could not even testify they had been tortured because to say so would violate a classified secret.
Bush said his prisoners were beyond the reach of the US court system. The Supreme Court said no, they are not. Bush thought he could suspend habeas corpus for his detainees. The Supreme Court said he was wrong about that. Bush thought he alone had power to create military commissions. The Supreme Court again said he was mistaken and that Congress had to legislate for such a process. The previous Australian government thought all of this skew-whiff lawyering was just fine. Obama has a monumental task ahead of him to repair the damage done to America's standing in the free world by lawyers who delivered incredibly poor advice. To name a few: David Addington, Vice-President Cheney's chief of staff and legal adviser and the main proponent of "L'Etat, c'est moi". John Yoo, who worked in the Justice Department and formulated the torture memos. William "Jim" Haines, the Pentagon's top lawyer who oversaw the enforcement of the interrogation techniques. Alberto Gonzales, former attorney-general and Bush crony from Texas, who obligingly implemented the Rovian plan to sack US attorneys who prosecuted Republican heavyweights. Harriet Miers, an obedient functionary and underqualified lawyer who Bush wanted to foist on the Supreme Court.
That's enough. The federal courts under Bush have been stacked with ideological clones, approved by an ultraconservative legal lobby called the Federalist Society. Just before the election The New York Times ran a story about how the federal appeal courts have been pushed to the right under the Bush Administration.
Of course, this is not "judicial activism". That term only applies if the judges push things to the left or, more probably, the centre. The Times recounted one story about a South Dakota law that forced doctors to tell women seeking abortions that the procedure would "terminate the life of a whole, separate, unique living human being". Those exact words had to be used to patients, as though something like that might never have occurred to them.
A federal trial judge ruled that the state could not enforce the law because to do so might violate doctors' first amendment rights. An appeals court upheld that decision. In June, the full US Court of Appeals for the Eighth Circuit swung into action. In a 7-4 decision it overturned the earlier findings and said the legislation should take effect immediately. The state can force doctors to say that life begins at conception because that is "objectively true". Six of the seven majority judges were appointed by Bush.
Conservative judges now make up 62 per cent of the federal bench. When Bush took office the figure was closer to 50 per cent. The trend is clear. Judges appointed by Republican administrations tend to favour corporations over regulators, state or local authorities over the rights of the citizen, and are more likely to throw out cases on technical grounds.
This is not to say there is always a unanimity of view among conservative jurists. For instance, there is a split on pressing issues such as whether mentally retarded people should be executed. You let a bunch of swivel-eyed lawyers loose in the paddock and they can wreak an awful lot of damage on the world. justinian@lawpress.com.au | 2024-07-29T01:26:51.906118 | https://example.com/article/8752 |
Unilateral thenar hypoplasia.
This report documents a patient with unilateral hypoplasia of the thenar eminence. The clinical, electrodiagnostic, and radiological findings indicated a developmental abnormality which must be considered in the differential diagnosis of carpal tunnel syndrome. | 2023-11-19T01:26:51.906118 | https://example.com/article/3258 |
What Does Being Cool Really Mean?
If James Dean was in his prime today, would we still consider him cool? According to a new survey, maybe not — seems the very definition of what’s cool and what’s not could be changing.
In a three-year study, researchers from the University of Rochester Medical Center surveyed about 1,000 young Canadian adults on their perception of cool and found qualities like “friendly,” “warm,” “smart” and “trendy” have replaced the leather-jacketed, cigarette-smoking aloof rebel of Dean’s heyday.
“Even if you hear how the word ‘cool’ is being used to describe things today, it’s not being used to reflect counterculture rebellion, it’s being used to described as a way of saying, ‘I like you,’” said lead study author Ilan Dar-Nimrod.
Of course, this may not be true worldwide — and since this particular study only involved “mostly educated, young, Canadian, ethnically white and Asian, [and] predominantly female” participants, what’s cool elsewhere could vary dramatically.
Still, Dar-Nimrod said even nerdiness may now be considered cool, since geeks these days fall “under that counterculture umbrella of edginess.”
“[Being] cool by definition requires a reference point — what is boring, normal, or even uncool,” said Kevin Lewis, a doctoral student in Harvard’s Department of Sociology. “The day culture stops changing is the day our notions of coolness will also be frozen in time.” | 2023-10-09T01:26:51.906118 | https://example.com/article/5698 |
I read on line about other such ovens doing the same thing mine was doing, absolutely nothing!
I even read stories of a major retailer telling customers to throw the microwave away. There's nothing you can do to fix it. After replacing a simple fuse that I ordered from you, the Advantium is as good as new. It took a grand total of 5 minutes to make the repair. The shipping cost more than the part, but it was all very worthwhile.
After purchasing the replacement bulb I had a lot of problem removing the cover.Turns out that three of the six screws in the back required a special tool. After trying different types of screw drivers to no avail, I took a picture of the screw and went to my local hardware store for some help. I had previously tried different sizes of Torx screw bits but none worked. It turns out that the screw was a Security Torx (has a center post in the middle of the screw) and required a TT20 bit, I was able to open the microwave cover and replace the lamp,by removing just two screws that held it in place and installing the new lamp in less than 5-minutes. I now have a security Torx bit set for toolbox for future use on other things. I almost threw in the towel and thought about calling in an appliance repair man due to the time spent (2 hours) going to several different hardware stores looking for the the right tool. | 2024-04-08T01:26:51.906118 | https://example.com/article/5973 |
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| 2023-11-10T01:26:51.906118 | https://example.com/article/6336 |
Fisch was the Bruins' offensive coordinator and quarterbacks coach last season, markedly improving the Bruins' offense during his only year in charge. He also developed a strong bond with star quarterback Josh Rosen, who had a bounce-back season before declaring for the NFL draft. | 2024-01-23T01:26:51.906118 | https://example.com/article/9320 |
The general features of the proteolytic fragmentation of fibrinogen have been established by our work and others previous work. Further studies will focus on details, as the fate of the thrombin susceptible bonds during the fragmentation. Some physicochemical studies will be performed to characterize the isolated D and E fragments. The data on their unfolding by heat, obtained by differential scanning calorimetry, will be supplemented by studies of unfolding by acid, alkali, and denaturing agents, using difference spectroscopy and fluorescence for this purpose. The structural rigidity of the native fibrinogen molecule will be studied by nanosecond fluorimetry of derivatives labeled by fluorescent chromophores. | 2024-07-12T01:26:51.906118 | https://example.com/article/6983 |
Magyarab people
The Magyarab are a people living along the Nile River in Egypt and Sudan. They are of Hungarian ancestry, probably dating back to the late 16th century, when both parts of Hungary and Egypt were part of the Ottoman Empire.
Name
The name "Magyarab" is not a portmanteau of the words "Magyar" and "Arab" as is commonly assumed. Rather, the name is a concatenation of "Magyar" (Hungarian) and "Ab" which in Nubian simply means "tribe". So Magyarab combined translates to "Tribe of the Magyars." In fact, to the Magyarab people, their Hungarian identity specifically sets them apart from the surrounding Egyptians.
History
According to legend, Christian Hungarians who had only recently been brought under the control of the Ottoman Empire formed a part of the Ottoman army that was fighting in southern Egypt. Evidently, a portion or the entirety of the fighting unit remained there and intermarried with the local Nubian women.
According to local Magyarabs, their ancestor was Ibrahim el-Magyar, a general who came from Buda (present-day Budapest) in 1517, he married with a local Nubian woman, they had a son called Ali. Ali had five sons (Selami, Mustafa, Djelal Eddin, Musa and Iksa), and Ali's five sons were the ancestor of all Magyarabs. Magyar Abs have been members of the World Federation of Hungarians (Magyarok Világszövetsége) since 1992 and still consider themselves as Hungarians.
They were not discovered by Europeans until 1935, when László Almásy, himself Hungarian, and his co-worker, the German engineer and explorer Hansjoachim von der Esch, happened upon the tribe in the Nubian region. Representatives of the tribes had attempted to make contact with Hungarian officials, but were unable to do so because of the outbreak of World War II.
These people now have a mixed race appearance due to the intermarriage with the local Nubian population and no longer speak the Hungarian language. Around 1934, however, Esch, who spent several weeks with the population of the Magyarab island at Wadi Halfa, put together a list of non-Arabic words used only on that island and which, according to him, were recognized by Almásy as similar to Hungarian words. His notes show that all Magyarab in Wadi Halfa were convinced that their ancestors came from "Nemsa" (the Arabic word for Austria), which might refer to any region of the Austro-Hungarian Empire. He was told by the chief of the Magyarab island village that their ancestors arrived in Egypt/Sudan as a group of "Austrian" soldiers led by a man called Shenghal Sendjer, which Esch assumes to be originally General Sendjer or Senger.
Magyarab communities
Magyarabs live along the Nile, in Sudan around Wadi Halfa, in Egypt around Aswan in the villages of Magyarab-irki, Magyararti, Magyariyya, Magyar-nirki, Hillit el-Magyarab and about 400 Magyarabs live in Cairo. There is also a very small diaspora in the U.S.A., Western Europe, Hungary and Romania.
Proverbs about the Magyarab
The people of many different ethnicities neighboring the Magyarab have proverbs that tell us more about the historical Magyarab people.
Al-majāri lā jisālli fil-mesjīd. – The Hungarian does not pray in the mosque.
Rá'sz el-mágyár zejj el-hágyár. – The Hungarian's head is as hard as a stone.
El-mágyárí jilbisz burnétá. – The Hungarian wears a hat.
References and notes
Detailed report about a Hungarian expedition:
Islands on the Nile - The Csángós of Africa, the Magyarabs (1), Magyar Nemzet, Budapest, 10 03 2007
Islands on the Nile - The Csángós of Africa, the Magyarabs (2), Magyar Nemzet, Budapest, 17 03 2007
Islands on the Nile - The Csángós of Africa, the Magyarabs (3), Magyar Nemzet, Budapest, 24 03 2007
Other references:
Hungarians along the Nile, Demokrata, Budapest, 17 07 1997 (Archive)
External links
Topographic map of the Wadi Halfa region in 1958 (prior to the filling of Lake Nasser/Nubia) which shows "Magarab I." (i.e., Magyarab Island) near the top. Published by the British War Office and Air Ministry in 1960.
Category:Hungarian diaspora
Category:Ethnic groups in Sudan
Category:Ottoman period in Hungary | 2023-09-19T01:26:51.906118 | https://example.com/article/7631 |
Picky Eaters
I found it interesting and weird that people who grow up in the same family have totally different taste and preference for food.
My son Andy eats most of the food we prepare at home, vegetables and meat, except seafood. He loves and eats a lot of fruit, except banana from its original package, I mean peel.
My daughter, on the other hand, eats some seafood, but she does not like vegetables and fruit. There are only a few vegetables that she eats, and she eats vegetables only because she has to eat some no matter what. Normally we have two or three different kinds of vegetables on the dinner table, she eats only from one of them. She tries to eat as less as possible while I want her to eat as much as possible.
When it comes to fruit, Amy is even more picky. She only eats banana and doesn’t like anything else. Banana is all her fruit intake. She doesn’t even want to try other kinds of fruit. So one of my daily tasks is to make sure that she at least eats her banana every day. That’s what she has been doing for her whole life (she is almost 11 now).
What’s weird is Amy likes her banana right out of its peel, unlike my son who hates banana out of the peel.
My son and daughter come from the same family background, yet have so totally different preferences. I don’t know why.
I tried to think of some reasons that might have caused this difference, and look for something/someone to blame.
“What did I do wrong when they were babies?”
“What was different when they were little?”
The only difference I could think of was my son was born in Chicago, Illinois and my daughter was born in Twin Cities, Minnesota.
Chinese people believe that kids become smarter when they eat more seafood. So when my son was born, I ate fish and had fish soup almost every day. The soup helped to increase the breast milk.
Chicago has Chinatown and it was easy to buy live fish. That’s what I had, a lot of fish and fish soup. I had more breast mild that my son could consume. I breastfed him for about 11 months.
My daughter was born after we moved to Twin Cities. I did not eat a lot of live fish and had fish soup when I breast fed her. The breast milk fried out much faster. My daughter was on breastmild for almost 6 months. I remember I made my own baby food puree with carrots and other vegetables for her, as I did for my son. But my daughter definitely had more vegetables than seafood as a baby.
Could it be that when you eat too much of something as a baby, you develop a dislike for it when you grow up?
Is our preference for food something we were born with or is it determined by the environment?
Nature or nurture, which one is the determining factor?
I really don’t know the answer.
Lately I have been making smoothies for my kids every day. I use bananas, apples, strawberries or other fruit to make the smoothies. This way, my son gets to eat banana that he normally doesn’t eat and my daughter gets to eat fruit other than banana that she normally doesn’t eat. It’s a good solution. I am glad that Amy is willing to drink smoothies now. Before I made smoothies only for my son. Amy was never interested in it.
The only good thing about my kids’ picky eating behavior is that they never fight for food. They each can eat as much as veggies or fruit as they want, it doesn’t bother the other one, because they don’t like the same thing.
Candies and snacks are a different story though.
By the way, it turned out that my daughter is actually as smart as my son, if not smarter. So the Chinese saying that seafood makes people smarter has not proved to be true in our family.
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ABOUT
My name is Qin Tang.
USANA Associate, Librarian & Writer.
I have a passion for healthy living - body, mind and spirit. As a USANA Associate, I love to help you live healthy and well through life style changes and through high quality nutritional supplements from USANA.
Take the free USANA True Health Assessment at http://qintang.usana.com/ and find out what you might need to reach your optimal health. | 2024-06-08T01:26:51.906118 | https://example.com/article/9413 |
Introduction {#s1}
============
The pathological angiogenesis is a critical hallmark of human diseases such as the cancer [@pone.0070544-Grothey1] and the wet form of age-related macular degeneration (AMD) [@pone.0070544-Bressler1] -- the leading cause of blindness in the elderly population. Compelling evidences have demonstrated that vascular endothelial growth factor (VEGF) plays a pivotal role in the abnormal angiogenesis process [@pone.0070544-Folkman1]. Therefore VEGF has become a key target in antiangiogenic therapy [@pone.0070544-Campochiaro1]. There are five members in VEGF family: VEGF-A, -B, -C, -D and placental growth factor (PlGF) [@pone.0070544-Ferrara1]. Among them, VEGF-A is the first discovered and the most well-studied member [@pone.0070544-Takahashi1]. Alternative exon splicing and proteolytic cleavage generated several distinct VEGF-A isoforms, respectively named VEGF121, VEGF165, and VEGF162. VEGF-A isoforms are all active as dimers, differing principally in their size and ability to bind heparin or neuropilins. Isoforms of VEGF-B and PlGF, which differ in their capacity to bind heparin, are also produced by alternative splicing.
Several therapeutic drugs against VEGF isoforms and PlGF have been developed by different companies. Pegaptanib (Macugen™, Eye- tech, Inc.) was the first anti-VEGF drug approved for the treatment of wet AMD [@pone.0070544-Gragoudas1], [@pone.0070544-Ng1]. Bevacizumab (Avastin®, Genentech, Inc.) is a recombinant humanized monoclonal antibody [@pone.0070544-Avery1], which has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer, non-small-cell lung cancer, glioblastoma [@pone.0070544-Ferrara2]. And ranibizumab (Lucentis®, Genentech, Inc.), a Fab fragment similar to Bevacizumab, has been also approved for the treatment of wet AMD [@pone.0070544-Ferrara3].VEGF Trap (aflibercept, Regeneron Pharmaceuticals, Inc.) is a novel soluble decoy receptor generated with Trap technology. It employs the fusion of components from multiple endogenous receptors [@pone.0070544-Economides1]. Although pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancer and various eye diseases [@pone.0070544-Miao1], presently, little information is reported on the binding kinetics and affinity of various VEGF inhibitors.
Conbercept is a recombinant fusion protein composed of the second Ig domain of VEGFR1 and the third and fourth Ig domain of VEGFR2 to the constant region (Fc) of human IgG1 ([Figure 1](#pone-0070544-g001){ref-type="fig"}).The structural characterization of conbercept was reported not long ago [@pone.0070544-Wu1]. It is designed as a receptor decoy with high affinity for all VEGF isoforms and PlGF. The inhibitory effects of conbercept to VEGF have been evaluated in vitro and vivo, indicating that conbercept exerts potent anti-angiogenic and anti-tumor effects [@pone.0070544-Jin1]. The surface plasmon resonance (SPR) biosensor system is widely used to determine binding affinity between proteins due to the advantages of direct and label-free detection with dispersionless microfluidics [@pone.0070544-Wang1]. In a previous work, based on BIACORE 3000 instrument (Uppsala, Sweden; GE), we have assessed the pre-clinical immunogenicity on the rhesus monkeys administrated with intravenous conbercept [@pone.0070544-Wang2]. Subsequently, in the phase I clinical trial, we continued to detect the serum immunogenicity on the cancer and AMD patients cured with conbercept (data to be published). In this study, we not only evaluated the kinetics and affinity characteristics of conbercept and Avastin with VEGF isoforms using Biacore and ELISA, but proved the anti-angiogenic effects of conbercept in choridal neovasularization (CNV) growth and permeability experiments by animal models. These results strongly support the pre-clinical and sequential phase clinical trials of conbercept.
{#pone-0070544-g001}
Materials and Methods {#s2}
=====================
1. Reagents {#s2a}
-----------
The conbercept protein used in this study was produced from Chinese hamster ovary cells and supplied by Chengdu Kanghong Biotechnology Co. Ltd. (Chengdu, China, 610036). VEGF-A165, VEGF-A121, VEGF-B167 and PlGF were purchased from R&D Company. CM5 microchips and Amine Coupling Kit were obtained from GE. ELISA reagents were purchased from BETHYL and R&D. 5-FU was purchased from Tianjin Jinyao Amino Acid Co. Ltd. M200 medium and low serum growth supplement (LSGS) used for the growth of human umbilical vein endothelial cells (HUVEC) were ordered from Cascade (Carlsbad, CA, USA).
2. The binding efficiency analysis by ELISA assay {#s2b}
-------------------------------------------------
ELISA: Antigens (VEGF-A 165 or VEGF-B 167 or PlGF) were diluted to a final concentration of 4 nM in PBS. The wells of a PVC microtiter plate were coated with the antigen by pipeting 100 µl of the antigen dilution in the top wells of the plate and incubated at 4°C overnight. The coating solution was removed and the plate was washed three times by filling the wells with 200 µl PBS. The remaining protein-binding sites were blocked by adding 200 µl blocking buffer containing 1%BSA in PBS and then the plate was incubated at 37°C for 2 hours. The plate was washed three times by filling the wells with 200 µl PBS. 100 µl of diluted primary antibody (conbercept or Avastin) was added into each well, the plate was covered with an adhesive plastic and incubated for 2 h at room temperature. The plate was washed four times with PBS. 100 µl of conjugated goat anti-human secondary antibody labeled with horse radish peroxidase (HRP) was added, diluted at 1∶50000 in blocking buffer before use. The plate was covered with an adhesive plastic and incubated for 1 h at 37°C. The plate was washed four times with PBS. 100 µl of the substrate solution was dispensed per well. After 10 min incubation at 37°C, 100 µl of stop solution was added into the wells. The absorbance of each well was read with a plate reader at 450 nM as the detection wave length.
3. Kinetics and Affinity detection by BIACORE {#s2c}
---------------------------------------------
The kinetics and affinity of conbercept with VEGF isoforms were analyzed by surface plasmon resonance technology using a BIACORE 3000 instrument (Uppsala, Sweden, GE). VEGF-A isoforms and PlGF (in 10 mM sodium acetate) were set as ligands to be immobilized onto the CM5 biosensor microchips by the amine coupling method using N-ethyl-N-dimethylaminopropyl carbodimide and N-hydroxy-succinimide. About 5,000±500 response units (RUs) per flow cell were immobilized to the channel FC2-4, and the FC1 channel was set as the blank control. Microchip sensor surfaces were conditioned with three cycles of five injections of 5 µl of 15 mM HCl, followed by three injections of 10 µl of 1.0 M NaCl, and finally by three cycles of five injections of 10 µl of HBS buffer (10 mM HEPES, 0.15 M sodium chloride, 3.4 mM EDTA, and 0.005% surfactant P20) prior to the kinetics and affinity analysis. The affinity detective process was performed by the written wizard program of the BIAcontrol software. The kinetic curve and affinity data were acquired by injecting conbercept and Avastin onto the CM5 chips immobilized with VEGF isoforms. Microchip sensor surfaces were regenerated with 10 µl of 20 mM NaOH prior to every new injection cycle enabling microchip surfaces to be stable for 30--40 cycles. The alterations in the refractory index were recorded as relative response unit (RU) as described by the manufacturer (Uppsala, Sweden, GE). The dissociation rate constant (kd), the association rate constant (ka), the dissociation equilibrium constant (KD), and the association equilibrium constant (KA) were automatically calculated with the BIAevaluation Software3.0 (Uppsala, Sweden, GE).
4. Endothelial Cell Proliferation Assay {#s2d}
---------------------------------------
The proliferation of HUVEC is in response to recombinant VEGF165, which can bind conbercept and Avastin selectively. Thus the potency of conbercept and Avastin can be measured based on the ability to inhibit the proliferation of HUVEC.
To measure proliferation, HUVEC cells were thawed and resuspended at 2×104 cells/ml in ECM with growth factor and FBS supplementation. About 100 µl of the cells suspension was seeded into each well of a 96-well tissue culture plate and the growth medium in each well was aspired after 24 hours. For conbercept and Avastin inhibition, serial dilutions of conbercept and Avastin were mixed with 40 ng/ml of VEGF165 at 37°C for 3 hours. 100 µl of the mixture was then added to HUVEC cells per well after aspirated supernatant. The plate was continuously incubated at 37°C with 5% CO2 for 4 days. At the end of incubation, 20 µl of CCK-8 was added to each well and the plate was incubated for an additional 4 hours under the same condition. Then the plate was read at 490 nm on a plate reader.
5. Animals and ethics statement {#s2e}
-------------------------------
All necessary permits were obtained for the animal experiments. This study was approved by Institutional Ethics Review Committee of Beijing Institute of Microbiology and Epidemiology, China. All procedures on the animals were carried out in strict accordance with the regulations of the Beijing Institute of Microbiology and Epidemiology Animal Care and Use Committee (2010215). Animals were maintained under specific pathogen-free conditions (25∼28°C, relative humidity 55±15%, 12-hr light/dark cycles). All animals were handled under the care and supervision of a veterinarian. The mice were sacrificed by cervical dislocation at the end of the experiment.
6. Oxygen-Induced Retinopathy Suppression Experiments {#s2f}
-----------------------------------------------------
Ten KunMing timed-pregnant mice were obtained from Sichuan University laboratory animal center and were housed in the animal care facilities of Sichuan University. In the newborn mouse model of oxygen-induced retinopathy (OIR), 7-day-old mice were placed with their maternal mice in a (75±3)% oxygen atmosphere for 5 days (D7--D11), and then returned to normoxia for further treatment.
The neonatal mice were divided into 3 groups. Group 1 was set as normal control. Group 2 and 3 were OIR models, treated with normal saline and conbercept (25 mg/kg) (40 µL) intraperitoneally every other day. All animals were euthanatized on D21. Vascular perfusion of fluorescein (FITC-dextran) and retinal stretched preparation were used to observe the retinal vessels. The sections of eyeballs with H&E staining were used for counting the endothelial cells of new vessels beyond the inner limiting membrane under the microscopy (6 µm-thin sections were cut sagittally parallel to the optic nerve, and 38 sections were extracted discontinuously from an eyeball) [@pone.0070544-Liang1].
7. Tumor Growth Experiments {#s2g}
---------------------------
Fifty-six female BALB/c nude mice (5∼8 w, 16∼18 g) were obtained from Shanghai SLRC laboratory animal Co. Ltd. Human colon cancer cells (LOVO) were injected subcutaneously in the axilla (1×10^7^ cells/0.2 ml each mouse) at the start of the study. The animals were divided into 7 groups, each group had 8 mice. Group 1 received normal saline (NS) as a control. Group 2--4 received conbercept at 2, 6 and 18 mg/kg, respectively. Group 5 received Avastin at 6 mg/kg. Group 6 received 5-FU at 50 mg/kg. Group 7 received 5-FU (50 mg/kg) and conbercept (6 mg/kg). Dosing began 24 hours after tumor implantation. Each animal received injections of test material twice a week for a total of 10 doses. The tumors (big enough to be measured by vernier caliper) were measured weekly till week 6. The evaluation criteria were tumor weight,tumor volume and anti-tumor rate. At the end of study, the tumors were weighted after sacrifice of the animals. Tumor volume (TV) = a×b2/2 (a, b means the length and width of the tumor). Anti-tumor rate(%) = (The mean tumor weights of negative control group -- The mean tumor weights of treatment group)/The mean tumor weights of negative control group×100%.
8. Data availability statement {#s2h}
------------------------------
The methods used in this paper were validated for selectivity, linearity, accuracy, precision, recovery and stability according to the FDA guidelines for the validation of bioanalytical methods (USFDA, <http://www.fda.gov/downloads/Drugs/Guidance> Compliance Regulatory Information/Guidances/ucm070107.pdf, 2001).
9. Statistics {#s2i}
-------------
Statistical analysis was carried out using SPSS version 11.0 (SPSS Inc., Chicago, Illinois, USA). All results are expressed as the mean ± standard deviation. The comparison of baseline OD value was performed by Student\'s t test. A probability of P\<0.05 was considered to be statistically significant.
Results {#s3}
=======
1. The binding efficiency comparison of conbercept and Avastin with VEGF isoforms and PlGF by ELISA {#s3a}
---------------------------------------------------------------------------------------------------
The binding specificity and efficiency of conbercept and Avastin with VEGF isoforms and PlGF were first examined by ELISA ([Figure 2](#pone-0070544-g002){ref-type="fig"}). In this experiment, both conbercept (EC~50~, concentration for 50% of maximal effect, EC50 = 0.1 nM) and Avastin (EC50 = 0.15 nM) showed high binding affinity with VEGF-A 165. Conbercept binds VEGF-B and PlGF with relative affinity of 2 nM and 52 nM respectively, whereas Avastin shows no detectable binding to VEGF-B and PlGF. Avastin, as a human antibody against VEGF-A, is not expected to bind other VEGF isoforms. However, conbercept composed of portions of VEGF receptors, is expected to bind VEGF-B and PlGF as well.
{#pone-0070544-g002}
2. The affinity comparison of conbercept and Avastin with VEGF-A isoforms by Biacore {#s3b}
------------------------------------------------------------------------------------
VEGF-A isoforms were set as ligands to be immobilized to the channel FC2-4. The FC1 channel was set as the blank control. The final curves and data results were automatically presented as FC2-1, FC3-1, and FC4-1 by the BIAevaluation Software3.0. Conbercept and Avastin were set as analytes to be injected onto the surface of CM5 biosensor microchips immobilized by VEGF-A isoforms. The analytes were all two-fold diluted into eight concentrations with HBS buffer ranging from 1.25 nM to 160 nM. The dynamic reactive process between analytes and ligands was automatically recorded by the BIAcontrol software. The curve and data results were analyzed by the BIAevaluation 3.0 software according to the 1∶1 binding with baseline drift model. The dynamic association and dissociation curves were displayed from [Figure 3A](#pone-0070544-g003){ref-type="fig"} to [Figure 3D](#pone-0070544-g003){ref-type="fig"}. The kinetics and affinity constants between analytes and ligands were listed in [Table 1](#pone-0070544-t001){ref-type="table"}. The data indicated that conbercept had high affinity to VEGF-A165 (5.4 nM) and VEGF-A121 (5.26 nM). As reference, Avastin showed binding affinity to VEGF-A165 (24.3 nM) and VEGF-A121 (20.3 nM).
{#pone-0070544-g003}
10.1371/journal.pone.0070544.t001
###### The detected kinetics constants comparison of different VEGF inhibitors with VEGF isoforms and PlGF.
{#pone-0070544-t001-1}
Analytes Kinetics Constant Ligands
---------------- ------------------- --------- --------- --------- ---------
**Conbercept** ka (1/Ms) 1.94e5 1.99e5 6.83e4 1.14e5
kd (1/s) 1.05e-3 1.05e-3 5.58e-3 5.81e-3
KD (M) 5.40e-9 5.26e-9 8.18e-8 5.12e-8
**Avastin** ka (1/Ms) 2.67e4 3.40e4 NA NA
kd (1/s) 6.48e-4 6.88e-4 NA NA
KD (M) 2.43e-8 2.03e-8 NA NA
NA: No binding data was acquired by Biacore.
3. The multi-targets binding ability of conbercept with VEGF-B167 and PlGF {#s3c}
--------------------------------------------------------------------------
VEGF-B167 and PlGF were set as ligands to be immobilized to the channel FC2-4. The FC1 channel was set as the blank control. The final curves and data results were automatically presented as FC2-1, FC3-1 and FC4-1 by the BIAevaluation Software3.0. Conbercept was set as analyte to be injected onto the surface of CM5 biosensor microchips immobilized by VEGF-B167 and PlGF. Conbercept was two-fold diluted into eight concentrations with HBS buffer ranging from 31.25 nM to 4000 nM. The dynamic curves of conbercept with VEGF-B167 and PlGF were recorded in [Figure 3E, 3F](#pone-0070544-g003){ref-type="fig"}. Biacore data showed that the KDs of conbercept with VEGF-B167 and PlGF were 81.8 nM and 51.2 nM, respectively, about 10 times lower than it with VEGF-A isoforms.
4. Comparison of bioactivity between Avastin and conbercept {#s3d}
-----------------------------------------------------------
The growth of endothelial cells is induced by a lot of factors including VEGF. To determine whether conbercept binding with VEGF could effectively block the ability of VEGF-induced endothelial cells proliferation. The inhibitory effect of conbercept was evaluated by endothelial cell proliferation assay. Both Avastin and conbercept could completely block VEGF-induced HUVEC growth at the concentration of 100 ng/ml. Conbercept had a lower plateau than Avastin, as shown in [Figure 4](#pone-0070544-g004){ref-type="fig"}, probably due to higher inhibition potency.
{#pone-0070544-g004}
5. Inhibition of oxygen-induced CNV growth and permeability {#s3e}
-----------------------------------------------------------
There was no permeability and CNV detectable in the normal group. Heavy leakages were observed in OIR models treated with normal saline (NS) indicating the generation of new vessels. Whereas, less leakage and fewer neovasularizations were observed in OIR models treated with conbercept ([Figure 5](#pone-0070544-g005){ref-type="fig"}). The results of H&E staining also showed that the number of vascular endothelial cells beyond the inner limiting membrane was less in conbercept treated group than NS treated group(p\<0.01) ([Table 2](#pone-0070544-t002){ref-type="table"}).
{ref-type="fig"}). Less leakage and fewer neovasularizations were observed in OIR models treated with conbercept (the arrow pointing in the [Figure 5C](#pone-0070544-g005){ref-type="fig"}). (A) Negative control group. (B) Model control group. (C) Medicated group.](pone.0070544.g005){#pone-0070544-g005}
10.1371/journal.pone.0070544.t002
###### The numbers of vascular endothelial cells beyond the inner limiting membrane ().
{#pone-0070544-t002-2}
Group Number of eyeball Number of sections Number of vascular endothelial cells beyond the inner limiting membrane Number of vascular endothelial cells beyond the inner limiting membrane in a section
--------- ------------------- -------------------- ------------------------------------------------------------------------- --------------------------------------------------------------------------------------
Group 1 10 380 15 0.04±0.20
Group 2 10 380 14060 37±12.20[\*](#nt103){ref-type="table-fn"}
Group 3 10 380 1900 5±2.80[\*](#nt103){ref-type="table-fn"} [Δ](#nt104){ref-type="table-fn"}
Group 1: Normal control; Group 2: OIR models treated with NS; Group 3: OIR models treated with Conbercept.
Statistical differences were significant compared to group 1 (p\<0.01);
Statistical differences were significant compared to group 2 (p\<0.01).
6. Anti-tumor effects of conbercept in vivo {#s3f}
-------------------------------------------
There was a sigmoidal relationship between the mean tumor volume per group and time after tumor implantation ([Figure 6A](#pone-0070544-g006){ref-type="fig"}). Tumor volumes in all treatment groups were significantly smaller than in the control group (p\<0.05).
{#pone-0070544-g006}
Compared with the NS group, the tumor weights in the low, middle and high Conbercept dosage groups became obviously lower, which were 0.791 g, 0.253 g and 0.128 g respectively ([Figure 6B](#pone-0070544-g006){ref-type="fig"}). The positive control Avastin group was 0.488 g. The tumor weight was 0.98 g in the group given 5-FU, in contrast, the group given 5-FU plus conbercept was only 0.077 g.
Anti-tumor rates were calculated according to the formula mentioned in the method section. The anti-tumor rates were 48.70%, 83.63% and 91.73% respectively in the low, middle and high conbercept dosage groups, indicating dose-dependent anti-tumor effect. The anti-tumor rate was 36.46% in the group given 5-FU, as compared with 94.98% in the group given 5-FU plus conbercept ([Figure 6C](#pone-0070544-g006){ref-type="fig"}). As positive control, Avastin showed 67.85% anti-tumor rate.
Discussion {#s4}
==========
Many studies have demonstrated that VEGF family factors, especially VEGF-A isoforms, are the major promoters of pathological angiogenesis process characterized by an increase in the number of proliferating endothelial and stromal cells, and altered morphology of the vasculature [@pone.0070544-Folkman2], [@pone.0070544-Baluk1]. Abnormal angiogenesis does not stimulate tumor growth, but could cause vascular leak in the ocular vascular diseases such as the wet AMD and ischemic retinopathies [@pone.0070544-Carmeliet1]. Therefore, it has been important strategy to find blockers of VEGF isoforms for cancers and eye diseases therapy.
For a therapeutic drug, the binding affinity, half-life, bioavailability, molecular size, stability, and effectiveness should be evaluated [@pone.0070544-Shibuya1]. Above all, the binding affinity is the key of the drug\'s efficacy. The equilibrium dissociation constant (KD) of Avastin for VEGF-A was 1.8 nM [@pone.0070544-Presta1] or 20 nM [@pone.0070544-Chen1] determined by SPR technology (Biacore). Recently, Wiegand *et al.* reported that the KD of Lucentis for VEGF- A165 was 46 pM. In contrast, KD of VEGF Trap was less than 1 pM for VEGF-A121 and VEGF-A165 [@pone.0070544-Papadopoulos1].
Besides VEGF, some other factors are also involved in abnormal angiogenesis, such as PlGF and angiopoietins [@pone.0070544-Augustin1]. Researchers have demonstrated that the drugs with high binding affinity with multiple antigens exhibit the most effective blockade of tumor angiogenesis and vascular leakage, and thereby prevent tumor growth and metastasis. In this study, we employed Biacore and ELISA assays to study the kinetic and affinity of conbercept with VEGF isoforms and PlGF. Both technologies showed that conbercept could bind VEGF-A, VEGF-B and PlGF whereas Avastin could only bind VEGF-A. The Biacore result of Avastin with VEGF-A was in close agreement with earlier reports [@pone.0070544-Chen1], but different from the other research [@pone.0070544-Papadopoulos1]. It is probably due to different experimental setups from study to study. Only in the same experiment, the relative values of the binding affinity are considered comparable. In previous study, conbercept was examined for the inhibitory effect in the choroidal neovascularization (CNV) monkey model. It has been proved that Conbercept can effectively inhibit leakage and growth of the CNV in rhesus monkeys without evidence of toxicity [@pone.0070544-Zhang1]. In this study, we proved that conbercept present high inhibitory activity on the proliferation of human umbilical vein endothelial cells (HUVECs) induced by VEGF. Oxygen-induced retinopathy model also demonstrate the anti-angiogenic activity of conbercept. The results indicated that conbercept could suppress the formation of CNV, which was confirmed by the histological assessment, and thus could reduce vascular leakage subsequently. We concluded that VEGF and PlGF may play an important role in mediating the formation of new vessels, so conbercept could be effective in the animal models of retinopathy.
Furthermore, tumor-bearing nude mice were used to evaluate the biological activity of conbercept in vivo. As one of the most successful antiangiogenic drugs, Avastin has been proven to be effective in many preclinical and clinical studies [@pone.0070544-Mordenti1], [@pone.0070544-Braghiroli1]. And in this study, Avastin was taken as reference to evaluate effectiveness of biological activity of conbercept in vivo. The results showed that tumor suppression was dose-dependent and could be achieved at each dose level. The middle-dose (6 mg/kg) conbercept plus 5-FU showed the best efficacy, in agreement with the clinical data: combination of antiangiogenesis with chemotherapy was more effective in cancer treatment. The possible reason is that the antiangiogenic drugs induce functional normalization of tumor vasculature resulting in tumor cell exposuring to co-administered cytotoxic drugs [@pone.0070544-Ma1]. In this study, 6 mg/kg of conbercept showed better anti-tumor activity than the same dosage group of Avastin (p\<0.05). One possible reason is that conbercept can effectively block VEGF with higher affinity in human colon cancer cells or in mice. Another possible reason is that conbercept can also bind PlGF and VEGF-B other than VEGF-A. Although the main function of conbercept was to block VEGF-A, the slight suppression of VEGF-B and PlGF might assist the action of anti-VEGF-A according to previous articles [@pone.0070544-Loges1]. Therefore, it might be more active for the treatment of cancer than anti-VEGF-A antibody.
In summary, as a novel chimeric decoy receptor, conbercept can bind to multiple targets (VEGF-A, VEGF-B and PlGF) for antiangiogenic therapy and consequently suppress tumor growth very effectively in vivo. These attributes give strong support for the preclinical and further clinical trials of conbercept, and can be beneficial in treating various ocular disorders and cancers.
[^1]: **Competing Interests:**All authors of the paper declare that there are no competing commercial interests in relation to the present work. Although one or more of the authors are employed by Chengdu Kanghong Biotechnology Co. Ltd., this does not alter the authors\' adherence to all of the PLOS ONE policies on sharing data and materials.
[^2]: Conceived and designed the experiments: HW DL. Performed the experiments: Q. Wang TL Q. Wu XK. Analyzed the data: HW Q. Wang ZW DL. Contributed reagents/materials/analysis tools: Q. Wang Q. Wu. Wrote the paper: Q. Wang ZW HW.
| 2024-01-09T01:26:51.906118 | https://example.com/article/3855 |
jQuery is the most popular JavaScript library today. It’s used on hundreds of thousands of websites, and yet it’s not the only library JavaScript developers use. In fact, thousands of JavaScript libraries and utilities are available, and each one can typically be categorized into two groups: general and specialty.
The aim of general frameworks is to balance the differences between browsers by creating a new, unified API to perform general tasks like DOM manipulation and Ajax functionality (jQuery is a general framework). Specialty frameworks, on the other hand, focus on a specific ability, such as feature detection. So identify what it is you want to achieve and choose a framework based on that. For example, if you wanted to perform animations and only animations, the script.aculo.us framework (http://script.aculo.us/) could be a good choice for you.
This chapter looks at both general and specific frameworks. When deciding ...
Get Beginning JavaScript, 5th Edition now with O’Reilly online learning. | 2024-04-05T01:26:51.906118 | https://example.com/article/9727 |
Facebook Under Fire for Temporarily Blocking Pages in Pakistan
Facebook said on Friday that it had blocked users in Pakistan from access to the pages of a popular Pakistani rock band and several left-wing political pages, drawing sharp criticism from free-speech activists who accused the American company of caving in to government censors.
A spokeswoman for Facebook in London said the company’s policy was to adhere to local laws, and that it blocked the pages after receiving an official request from the Pakistan Telecommunications Authority, which regulates Internet content in Pakistan.
“While we never remove this type of content from the site entirely, like most Internet services, we may restrict people from accessing it in the countries where it is determined to be illegal,” the spokeswoman said, adding that questions about why specific pages were blocked were “best addressed to the authorities who issue these orders.”
The spokeswoman declined to be named, citing company policy.
Facebook was banned entirely in Pakistan for several months in 2010, during a controversy over a page that encouraged people to draw cartoons of the Prophet Muhammad.
The company says it regularly weeds out pages that promote hate or extremism. According to a report published on its website, Facebook restricted access to 162 pieces of content in Pakistan between July and December 2013, and many more in some other countries, including India, where it restricted access to more than 4,700 pages in the same period.
But activists said on Friday that the latest blocks in Pakistan affected pages that spoke out against extremism, while several extremist pages in the country were left untouched.
“This is ridiculous,” said Taimur Rahman, the lead singer of Laal, speaking before the ban on his group’s page was lifted. “None of our content could be construed as anti-state or anti-religious, in any shape or form.”
The Facebook actions come at a time when freedom of speech is under increasing pressure in Pakistan. Extremists have been bringing criminal accusations of blasphemy against journalists, and the army has been cracking down on criticism of itself in the media. The government media regulator suspended broadcasts of the country’s most popular news channel, Geo News, on Friday and fined it $104,000, on accusations that Geo News had defamed the military’s Inter-Services Intelligence spy agency.
Continue reading the main storyContinue reading the main storyAle Natiq, 31, the administrator of the Urdu-language page Roshni Pakistan, speculated that the military was behind the blocking of the page this week. “We’re not anti-state or anti-religion,” Mr. Natiq said. “But we’ve been very vocal on the Baluchistan issue, which is sensitive to the military, so that might have done it.”
Several activists questioned why Facebook had not blocked other Pakistani pages that incite sectarian violence, religious extremism or hatred against minorities. As examples, they pointed to pages administrated by supporters of Ahle Sunnat Wal Jamaat, a notorious sectarian groups that has supported attacks on Shiites; the sectarian militant group Lashkar e Jhangvi;and the Red Mosque, where a violent stand-off between extremists and government forces in 2007 left over 100 people dead, and where a recently opened library is named for Osama bin Laden.
“These pro-Taliban pages are spewing hatred, and we are the people they shut down,” said Mr. Rahman, the singer. “It’s insanity.”
Facebook officials say that they resist censorship as much as possible, but their leverage is limited in countries like Pakistan where the government imposes constraints with little public debate.
">
Members of the band, Laal, whose members have frequently spoken out against the Taliban, confirmed that their Facebook page, which had over 400,000 “likes,” had been blocked.
Following an outcry on social media and inquiries by reporters to the Pakistani government and to Facebook, the government reversed itself and Facebook restored access to Laal’s page.
But advocates said late on Friday that at least six other Facebook pages that promoted progressive debate in Pakistan and that had been blocked during the week remained inaccessible.
“Facebook claims to be in favor of free speech, and talks about protecting political expression, but they are not,” said Shahzad Ahmad of the group Bytes for All Pakistan, which campaigns for Internet freedom and has gone to court several times seeking to lift government restrictions in Pakistan."For the sake of their own profits and business, they are caving in to anything the government demands.”
A spokeswoman for Facebook in London said the company’s policy was to adhere to local laws, and that it blocked the pages after receiving an official request from the Pakistan Telecommunications Authority, which regulates Internet content in Pakistan.
“While we never remove this type of content from the site entirely, like most Internet services, we may restrict people from accessing it in the countries where it is determined to be illegal,” the spokeswoman said, adding that questions about why specific pages were blocked were “best addressed to the authorities who issue these orders.”
The spokeswoman declined to be named, citing company policy.
Facebook was banned entirely in Pakistan for several months in 2010, during a controversy over a page that encouraged people to draw cartoons of the Prophet Muhammad.
The company says it regularly weeds out pages that promote hate or extremism. According to a report published on its website, Facebook restricted access to 162 pieces of content in Pakistan between July and December 2013, and many more in some other countries, including India, where it restricted access to more than 4,700 pages in the same period.
But activists said on Friday that the latest blocks in Pakistan affected pages that spoke out against extremism, while several extremist pages in the country were left untouched.
“This is ridiculous,” said Taimur Rahman, the lead singer of Laal, speaking before the ban on his group’s page was lifted. “None of our content could be construed as anti-state or anti-religious, in any shape or form.”
The Facebook actions come at a time when freedom of speech is under increasing pressure in Pakistan. Extremists have been bringing criminal accusations of blasphemy against journalists, and the army has been cracking down on criticism of itself in the media. The government media regulator suspended broadcasts of the country’s most popular news channel, Geo News, on Friday and fined it $104,000, on accusations that Geo News had defamed the military’s Inter-Services Intelligence spy agency.
Continue reading the main storyContinue reading the main storyAle Natiq, 31, the administrator of the Urdu-language page Roshni Pakistan, speculated that the military was behind the blocking of the page this week. “We’re not anti-state or anti-religion,” Mr. Natiq said. “But we’ve been very vocal on the Baluchistan issue, which is sensitive to the military, so that might have done it.”
Several activists questioned why Facebook had not blocked other Pakistani pages that incite sectarian violence, religious extremism or hatred against minorities. As examples, they pointed to pages administrated by supporters of Ahle Sunnat Wal Jamaat, a notorious sectarian groups that has supported attacks on Shiites; the sectarian militant group Lashkar e Jhangvi;and the Red Mosque, where a violent stand-off between extremists and government forces in 2007 left over 100 people dead, and where a recently opened library is named for Osama bin Laden.
“These pro-Taliban pages are spewing hatred, and we are the people they shut down,” said Mr. Rahman, the singer. “It’s insanity.”
Facebook officials say that they resist censorship as much as possible, but their leverage is limited in countries like Pakistan where the government imposes constraints with little public debate. | 2023-10-01T01:26:51.906118 | https://example.com/article/5255 |
Rangoon - A Sombre Anniversary
As president Trump flies in to Singapore to attend an unprecedented summit meeting with Kim Jong-un the political leader of North Korea, a sombre anniversary will go almost totally unnoticed and unremarked by the world’s press.
Thirty-five years ago on 9th October 1983, a large delegation of South Korean politicians led by prime minister Chun Doo-hwan were on a state visit to Rangoon, the capital of Burma. The visitors were attending a ceremony to lay a wreath at the Martyr’s Mausoleum to commemorate Aung San, one of the founding political leaders of Burma who was assassinated in 1947.
As the party waited for the ceremony to begin, a massive bomb exploded in the roof of the building. 21 people were killed and another 46 were injured. Four senior members of the South Korean cabinet were killed including foreign minister Lee Beom-Suk and deputy prime minister Suh Suk Joon. 14 South Korean presidential advisers, journalists and security officals were killed; four Burmese nationals including three journalists were also among the dead. The Prime minister of South Korea Chun Doo-hwan who was the real target of the bomb only escaped because his car had been delayed by traffic and was still a minute away from arriving at the memorial.
Burmese security forces quickly traced three suspects. Two of the suspects tried to commit suicide by detonating a grenade, but survived and were arrested, while the third was hunted down by the Burmese army and shot dead in a gun-battle in which two Burmese soldiers were also killed. One of the surviving assassins Kang Min-chul chose to co-operate with his interrogators and confessed that he was a North Korean People’s Army major, and that his companions were both army captains.
The Burmese police investigation revealed that the trio had slipped off a ship docked in Rangoon port and had received explosives in a North Korean diplomatic mission. Kang Min-chul claimed they had been trained and sent by the North Korean leadership to assassinate the prime minister of South Korea. He was sentenced to life imprisonment and died in prison in 2008. His companion was hanged. | 2023-11-19T01:26:51.906118 | https://example.com/article/5813 |
Review: ‘TT3D: Closer to the Edge’
"If it doesn't excite you, you're not alive," says one motorcycling enthusiast in 3D Brit docu "TT3D: Closer to the Edge," and even the most racing-averse auds will have to agree this entertaining whiz around the 2010 Isle of Man TT racing event puts across the thrill of the sport.
“If it doesn’t excite you, you’re not alive,” says one motorcycling enthusiast in 3D Brit docu “TT3D: Closer to the Edge,” and even the most racing-averse auds will have to agree this entertaining whiz around the 2010 Isle of Man TT racing event puts across the thrill of the sport. A mosaic of interviews, background coverage and, most importantly, footage of bikes going really fast, this competently made assemblage will be high octane fuel for fans. Nevertheless, crossover appeal to other demographics looks much more iffy. Starting gun for the pic’s wide release goes off April 21 in Blighty.
Predicted hot weather over the long holiday weekend when the pic opens will also work against it, but ancillary should rev high.
Aware of auds’ need for human interest and drama, sports docu and commercials helmer Richard De Aragues, making his feature debut, starts off by interviewing about a dozen of the key protagonists as they prepare for the TT (the initials stand for “tourist trophy”) in June 2010. Those intro’ed include soft-spoken but determined racer Ian Hutchinson (who will have a good year), frequent champion John McGuinness, ill-fated hopeful Paul Dobbs and his family, and various mechanics and pit-crew personal. But by far the most screen time is devoted to Guy Martin, an outspoken maverick motorcyclist who’s yet to win a TT race, but whose charisma, popularity with the fans, and shaggy-haired good looks prove irresistible to the filmmakers. Martin comes across initially as a charmer, but is later less sympathetic when things don’t go quite so well for him.
Beverley Mills’ deft editing of the TT — not just one race, but several around the Isle of Man over the course of a week — assembles the action that’s been recorded via a wide range of rigs, from helicopter-mounted 3D cameras to sports channel archive footage to tiny HD recording devices strapped to various riders’ bikes and helmets.
The course is a famously treacherous one that frequently claims riders’ lives, and the pic conveys this danger as it delivers the adrenalin rush riders experience as they go streaking through the island’s usually sleepy villages, often at amazingly close angles to the road. A few droll static shots record peaceful tableaux — a church surrounded by trees, or a suburban duplex whose owners are enjoying a cup of tea in the front yard — whose quietude is broken by the screaming sound of the racers flashing by in a blur.
Auds less than passionate about motorcycle racing may start to get antsy about three-quarters of the way through, as yet another race kicks off around the same circuit, but some awful accidents revive interest in the same ghoulish way they do when races are seen live.
By the end, coverage feels a little unbalanced given so much screen time allotted to Martin rather than some of the riders who perform better. Hardly more than a minute is spent on femme rider Jenny Tinmouth, for instance, whom distaff auds dragged along by their partners might liked to have learned more about.
Tech credits are pro across the board, although Jared Leto’s narration makes the docu feel more like fodder for niche sports cable channels. | 2023-08-01T01:26:51.906118 | https://example.com/article/1161 |
Q:
iOS 8.1.2 Calendar Timezone Problem
I use my calendars very often to keep track of things. Ever since I upgraded to iOS 8.1.2 (or possibly 8.1.1) the phone lets me create a new event with my timezone, but as soon as I create the event and try to edit it, the times are converted to GST (which is not my timezone).
Is there a way to fix or disable this so that iPhone Calendar is easier to use like before?
A:
Go to Settings/General/Date and Time.
Choose Set Automatically and choose your Time Zone.
Next go to Settings/Mail, Contacts, and Calendars. Page down to the Calendars section.
Set Time Zone Override to OFF if you want you calendar to display with times converted to the Time Zone where you are currently standing.
Or, set Time Zone Override to ON if you want to force the times in your calendar to be displayed in the home Time Zone that you set above.
| 2023-08-13T01:26:51.906118 | https://example.com/article/2143 |
Hillary's calculated move away from Democrat party
http://www.NewsAndOpinion.com |
Hillary Clinton is likely to be the 2008 Democratic presidential nominee because she is so much smarter than rivals now on the horizon. Once in the Senate, she made a beeline for the Armed Services Committee because she understood that the first female President will have to be a hawk, just as the first Catholic President (JFK) had to be adamant about not aiding Catholic schools, and the first Jewish President will have to voice doubts about Israel.
When she ran against young Rick Lazio for the Senate, my wife and I had dinner with friends, including four liberal Democratic women who were bitterly anti-Hillary, mostly because they thought she was an enabler for Bill Clinton's self-destruction. But they all voted for her, partly because Lazio was a poor choice, but mostly because she ran a strong campaign.
She startled a lot of analysts by running so well upstate, an area that's traditionally Republican and reliably hostile to urban liberals. Hillary Clinton lost the area only by a slim margin. People tell me she now knows more and responds better to upstate New Yorkers than any other statewide politician ever has. Imagine this ability going national?
Clinton seems to be on the move, laying the groundwork for a centrist campaign in 2008. She has come out in favor of immigration reform, in effect saying: close the borders. She has demanded a role for religion and faith-based programs in the public square. And last week, while clearly underlining her pro-choice position, she expressed many sentiments firmly held by the anti-abortion movement, including putting in a good word for abstinence.
On all three issues, Clinton is bucking the Democratic elites and the base of her party. She also is answering the big question currently bothering Democratic head scratchers: what do we have to do to win nationwide elections? Hillary's sensible answer seems to be: stop trying to overcome and stigmatize huge majorities of voters.
The number of Americans who want to seal our borders is in the 70% range. Three-quarters of Americans believe abortion should be restricted. Fewer than 25% would allow it in all cases. And America is lopsidedly religious, with believers in the 90% range. Yet the Democratic elite is conducting a relentless and escalating campaign against any public expression of faith. So far Hillary Clinton seems to be one of the few to recognize the scope of the anti-religion problem. She is a religious person but said recently, "There is no contradiction between support for faith-based initiatives and upholding our constitutional principles."
And, once considering the opponents of abortion to be sinister and sneaky, she's now more moderate.
You don't have to be overwhelmed by Hillary Clinton's sincerity to conclude that she is making some smart moves now. She is beginning to distance herself from Democratic dogma.
Every weekday JewishWorldReview.com publishes what many in Washington
and in the media consider "must reading." Sign up for the daily JWR update. It's free. Just click here. | 2023-11-16T01:26:51.906118 | https://example.com/article/2814 |
Description
The evil night things that prowl Cincinnati despise witch and bounty hunter Rachel Morgan. Her new reputation for the dark arts is turning human and undead heads alike with the intent to possess, bed, and kill her -- not necessarily in that order.
Now a mortal lover who abandoned Rachel has returned, haunted by his secret past. And there are those who covet what Nick possesses -- savage beasts willing to destroy the Hollows and everyone in it if necessary.
Forced to keep a low profile or eternally suffer the wrath of a vengeful demon, Rachel must nevertheless act quickly. For the pack is gathering for the first time in millennia to ravage and to rule. And suddenly more than Rachel's soul is at stake. | 2023-08-10T01:26:51.906118 | https://example.com/article/9198 |
Q:
Django HStore: How to override a key-value model field's __getattr__ and __setattr__
I've been getting my feet wet with using hstore in Django, through the django-hstore module. A big advantage to using hstore is that it allows for key-values to be stored in a field while providing decent indexing in Postgresql. A big disadvantage to django-hstore (and hstore in general) is that you can only store values as strings.
To overcome this, I thought it would be nice to override the model field (hstore.DictionaryField) so that any data entered in to the field is automatically encoded in JSON and any data retrieved is automatically decoded from JSON. I've attempted to do this by overriding the __setattr__ method but this causes tons of errors (when all the properties of the field are being set). Any ideas of the right way to do this?
What I have so far (I've commented out the getter portions while focusing on the setter, but left it in to show what I had in mind):
import simplejson as json
from django.db import models
from django_hstore import hstore
def _unpack_json(value):
try:
value = json.loads(value)
except TypeError:
pass
return value
class HStoreJsonDict(hstore.DictionaryField):
@staticmethod
def _load_json(value):
try:
value = json.dumps(value)
except Exception as e:
# Is this needed?
print(value, e)
pass
return value
# def __getattribute__(self, key):
# print('__getattribute__')
# value = super(HStoreJsonDict, self).__getattribute__(key)
# return _unpack_json(value)
# def __getitem__(self, key):
# print('__getitem__')
# value = super(HStoreJsonDict, self).__getitem__(key)
# return _unpack_json(value)
def __setattr__(self, key, value):
print('__setattr__', key, value)
value = self._load_json(value)
return super(HStoreJsonDict, self).__setattr__(key, value)
class TestModel(models.Model):
name = models.CharField(max_length=64)
data = HStoreJsonDict(db_index=True)
objects = hstore.HStoreManager()
def __unicode__(self):
return '%s - %s' % (self.name, self.data)
A:
At the end of the day, I found it easiest to fork the django-hstore module and to put serialization/deserialization in the DictionaryField's get_prep_value() and to_python() methods (see here for code).
For anyone else looking to manipulate data on entry-to/retrieval-from the database when using Django, I highly recommend checking Django's docs on to_python() and get_prep_value().
| 2024-03-26T01:26:51.906118 | https://example.com/article/5224 |
return {
track_winter = {}
}
| 2023-12-09T01:26:51.906118 | https://example.com/article/5092 |
Q:
Trying to create a tabbed, popup, rising, footer
I'm wanting to create a similar menu effect to the footer at crackerbarrel.com, where the tabs at the bottom roll up when you hover over them. It keeps the tab on the top and the whole thing slides up, with room for additional content.
I found a similar effect at CSSplay. I guess my main question is, what is this effect called, so I can find tutorials?
I've been searching "rising," "pull-up," "drop-down variants," and have found a lot of cool CSS tricks today, but not anything about this effect specifically.
Thanks for your help!
A:
Jquery SlideUp. Here: Jquery SlideUp
Example:
http://www.w3schools.com/jquery/tryit.asp?filename=tryjquery_eff_slideup_slidedown
The examples you gave can be made with a hover handler registered to the target element.
jquery .hover()
A more complete demo, from scratch:
http://www.mkyong.com/jquery/jquery-slideup-slidedown-and-slidetoggle-example/
| 2023-09-26T01:26:51.906118 | https://example.com/article/4526 |
The Glenwood Area Chamber of Commerce believes it’s time to bring the colorful bicyclists back to town.
Linda Washburn, executive director of the chamber of commerce, has been putting the finishing touches on the city’s formal application to serve as a RAGBRAI host city in 2011. The application must be submitted by Aug. 15 for Glenwood to be considered for next year’s ride across the state of Iowa.
“The new high school is done and the chamber board has decided that somebody would have to take the initiative,” Washburn said. “The route for next year won’t be announced until Janaury, but we want to be ready if we’re selected.”
In addition to completing the application, the chamber has secured letters of support for hosting the ride from the City of Glenwood, Mills County Board of Supervisors and the Mills County Historical Museum.
Washburn said the chamber board believes there are many “positives” associated with having RAGBRAI come to the community.
“This is the longest-standing and largest bicycle ride in the world. I think we look at it to showcase Glenwood, southwest Iowa and the Loess Hills,” Washburn said. “There are also some economic benefits. I certainly hope it would be financially beneficial for our local businesses, organizations and clubs to have RAGBRAI in Glenwood.
“RAGBRAI also gives people in our community the opportunity to work together with other people in our community who they might not get to know normally.”
Washburn said should Glenwood be selected to be a host city for RAGBRAI, public safety will be the top priority for the community.
Later this year, probably in the fall, the chamber plans to host a public meeting to gauge interest in RAGBRAI and to recruit potential volunteers that might want to serve on the various committees needed to host the event.
“We have a list already of people who want to assist,” Washburn said. “We feel like there’s a level of enthusiasm building.”
Glenwood has served as the starting point for RAGBRAI five times, most recently in 2003. The ride also came to Glenwood in 1980, 1984, 1989 and 1992.
Washburn said the chamber wanted to wait until the new high school was completed before attempting to host the ride again. In past years, the area that now houses the high school has served as a campground site for RAGBRAI. | 2023-08-06T01:26:51.906118 | https://example.com/article/6296 |
Introduction {#Sec1}
============
Discrete molecular architectures, especially those organic cage compounds, have received intensive attention in recent years^[@CR1]--[@CR8]^. These intriguing compounds featuring aesthetic geometry and intrinsic cavities display potential applications in gas or organic molecular separation^[@CR9]--[@CR14]^, catalysis^[@CR15]--[@CR18]^, porous liquids^[@CR19],[@CR20]^ and detection^[@CR21]--[@CR23]^. Synthetic control on the formation of versatile cages with given topologies is crucial before exploring their applications. Due to the characteristic of self-healing, dynamic covalent chemistry has been demonstrated as a powerful approach to synthesize these sophisticated cages from simple precursors. Among them, imine condensation, boronicester or boroxine formation and alkyne metathesis are the most frequently used type of dynamic bond formation^[@CR24]^.
Using reversible covalent chemistry to construct organic molecular cages (OMCs), external stimuli, such as solvent, pH, temperature, catalysts, steric and electronic factors, are all worthy of enough attention^[@CR25]^. Sometimes, different solvents could govern the self-assembly behavior to form cage products with different geometry. For example, Liu and Warmuth described a solvent-dependent method to selectively synthesize tetrahedral, octahedral and square antiprismatic cages from the same sub-components^[@CR26]^. On the other hand, choice of appropriate building blocks or precursors in the self-assembly process is believed as a key and important factor to access the desired and functionalized OMCs^[@CR27],[@CR28]^. In the family of tritopic building blocks or precursors, 1,3,5-triformylbenzene and triptycene triamine occupy a special status owing to their excellent ability to form various OMCs with different partners^[@CR1],[@CR29]--[@CR31]^.
A semi-flexible phosphate based trialdehyde had been proved to be a practicable precursor containing P=O functional site and a functionalized \[2 + 3\] imine OMC was successfully obtained by our group^[@CR32]^. As a part of our ongoing research on OMCs, we aim to further investigate and demonstrate that the semi-flexible precursor could also satisfy the requirements of different geometrical organic cage assembly. So we have changed the amine component from previous ditopic linker (cyclohexanediamine) to a flexible tritopic linker \[tris(2-aminoethyl)amine\]. For multi-component systems comprising competitive reactions, increasing the number of reactive ending groups and the flexibility of the amine linker is bound to complicate the self-assembly process. To address this challenge, a solvent-controlled method was tried and applied to simplify the self-assembly process towards the desired OMC in this paper.
Results and Discussion {#Sec2}
======================
Schiff-base condensation generally has great compatibility with different solvents, and different solvents have large influences on the final molecular crystallization and solid-state crystal packing^[@CR33],[@CR34]^. Acetonitrile/chloroform (v/v = 5:1) was adopted as a mixed-solvent in the synthesis of previous \[2 + 3\] phosphate cage just because of its suitability to grow single crystals. Actually, both acetonitrile and chloroform were effective solvents to yield the \[2 + 3\] cage. However, in the following self-assembly reaction between two tritopic precursors \[phosphate trialdehyde and tris(2-aminoethyl)amine\], it is found that the type of reaction solvents could dramatically impact the self-assembled outcomes (Fig. [1](#Fig1){ref-type="fig"}). In our experiments, acetonitrile as a single solvent for equimolar self-assembly is firstly tried since two tritopic precursors with a 1:1 molar ratio could theoretically form a \[4 + 4\] molecular cage. Nevertheless, the ESI-MS spectrum does not give the expected \[4 + 4\] assembled results, in which two positive peaks at *m/z* = 1415.67 and 708.58 are present corresponding to the full and half peaks of a \[2 + 3\] molecular cage with three unreacted aldehyde groups (Fig. [2a](#Fig2){ref-type="fig"}). Furthermore, the ^1^H NMR spectrum of this species evidences the existence of the aldehyde group (Fig. [S1](#MOESM2){ref-type="media"}). The combination of ESI-MS and ^1^H NMR analyses suggests that one aldehyde group from every phosphate trialdehyde precursor is not involved in the cage construction and six-fold imine condensation produces a credible \[2 + 3\] cage structure. This half-way self-assembly could be ascribed to the poor solubility for the \[2 + 3\] cage product in acetonitrile, which tends to precipitate from the reaction solution and terminate the further imine condensation.Figure 1Different OMCs based on the phosphate trialdehyde.Figure 2Solvent Effects on the cage assembly. **(a)** EIS-MS in acetonitrile; **(b)** EIS-MS in mixture of acetonitrile and chloroform; **(c)** EIS-MS in chloroform; **(d)** MALDI-TOF-MS in chloroform.
Considering that chlorohydrocarbon solvents are often used in the cage syntheses^[@CR11],[@CR16],[@CR21]--[@CR23],[@CR35],[@CR36]^, a mixture of 1:1 acetonitrile and chloroform is then used for this reaction. Although the formation of partial \[2 + 3\] cage still occurs, the successful assembly of a \[4 + 4\] molecular age is achieved which can be verified by the presence of new ESI-MS peaks at *m/z* = 1006.17, 671.25 and 503.67 with the isotopic distribution patterns separated by 0.50 ± 0.01, 0.33 ± 0.01 and 0.25 ± 0.01 Da (Figs. [2b](#Fig2){ref-type="fig"} and [S2](#MOESM2){ref-type="media"}), corresponding to 1/2, 1/3 and 1/4 of the molecular weight of the \[4 + 4\] cage. In order to improve the yield of \[4 + 4\] cage, pure chloroform is explored, where the ESI-MS spectrum clearly exhibits three positive peaks originating from the \[4 + 4\] cage excluding the peaks of half-way \[2 + 3\] cage (Fig. [2c](#Fig2){ref-type="fig"}). The formation of \[4 + 4\] cage was further confirmed by a peak at *m/z* = 2012.64 in the MALDI-TOF-MS spectrum (Fig. [2d](#Fig2){ref-type="fig"}). In addition, ^1^H NMR spectrum provides reliable proofs for the formation of this \[4 + 4\] cage, where only one set of signals could be observed for this symmetrical structure (Fig. [S3](#MOESM2){ref-type="media"}).
The molecular structure of \[4 + 4\] cage was further verified by single-crystal X-ray diffraction studies. Slow evaporation of the reaction solution affords the suitable single crystals for the X-ray diffraction determination. Crystallographic analysis shows that this \[4 + 4\] cage has a tetrapodal structure with symmetry (Fig. [3](#Fig3){ref-type="fig"}). The shape of the cage could also be regarded as tetrahedral shape with the tertiary amine nitrogens of the amine linkers as four vertexes. In both \[4 + 4\] cage and previously reported \[2 + 3\] cage, the phosphate tetrahedron comprised by four oxygen atoms is very rigid (Fig. [3a](#Fig3){ref-type="fig"}). However, three P-O single bonds of the phosphate tetrahedron could be rotated along the axial direction freely, which would result in the three benzene rings pointing toward different orientations during the construction of OMCs with cyclohexanediamine and tris(2-aminoethyl)amine. Herein we use the distance between the O atom of P=O double bond and the centroid of benzene ring to illustrate the discrepancy between the conformation of the cages. This parameter is the same as 3.85 Å for three benzene rings in the previous \[2 + 3\] cage exhibiting the typical tripod configuration, while it changes to 3.94, 4.10 and 5.13 Å in the current \[4 + 4\] cage indicating two different orientations in forming a more complicated cage with flexible tris(2-aminoethyl)amine. Unlike the previous \[2 + 3\] cage, the P=O bonds does not point straight toward the cage centre in this \[4 + 4\] cage and the window of the cage cavity was partially occupied by the oxygen atoms of the P=O units (Fig. [3b](#Fig3){ref-type="fig"}). In addition, a cavity with a 4.0 Å diameter taking into account the van der Waals radii of the atoms is found in the cage, which is comparable with that of some gas molecules such as CO~2~, CH~4~ and N~2~^[@CR37]^. In addition, the thermal stability of this \[4 + 4\] cage is evaluated by thermogravimetric analysis (TGA), in which the decomposition temperature is high up to 300 °C (Fig. [S4](#MOESM2){ref-type="media"}). This work is believed to give a representative example to illustrate the semi-flexible and versatile traits of this phosphate trialdehyde.Figure 3(**a**) Crystal structure of the cage (phosphate units are represented by four tetrahedrons); **(b)** the size of the cage (represented by a green ball in a radius of 2.0 Å).
Given that gas sorption phenomena have been revealed on discrete organic molecular solids, gas adsorption properties of this \[4 + 4\] cage were explored. After thermal activation for 12 h at 80 °C under the high vacuum, the crystalline sample has lost its crystallinity/solvents and became amorphous (Figs. [S5](#MOESM2){ref-type="media"} and [S6](#MOESM2){ref-type="media"}). The N~2~ adsorption isotherms of the cage at 77 K indicate a low BET surface area (less than 10 m^2^/g), which is similar to other discrete cage compounds^[@CR38]--[@CR41]^. Gas adsorption experiments at 273 and 298 K reveal that the cage has selective adsorption of CO~2~ over CH~4~. As illustrated in Fig. [4](#Fig4){ref-type="fig"}, it can absorb 12.46 and 5.71 cm^3^ g^−1^ of CO~2~ at 273 and 298 K and 1.0 bar, whereas small amounts of CH~4~ uptake can be observed at 1 bar (2.36 and 0.68 cm^3^ g^−1^ at 273 and 298 K). The selectivities of CO~2~ over CH~4~ estimated from Henry's constants are 7.10 and 6.52 at 298 and 273 K (Table [S2](#MOESM2){ref-type="media"}), respectively, which are comparable with other previously reported OMCs (For CO~2~ vs CH4 adsorption and separation of some selected OMCs, see Table [S3](#MOESM2){ref-type="media"}). The reason for the high selectivities of CO~2~ over CH~4~ is probably due to the presence of polar functional P=O groups for CO~2~ adsorption^[@CR12],[@CR42],[@CR43]^.Figure 4CO~2~ (red) and CH~4~ (blue) adsorption isotherms at 273 (left) and 298 K (right).
Conclusion {#Sec3}
==========
In summary, one novel \[4 + 4\] phosphate OMC can be efficiently synthesized in a one pot reaction through solvent-controlled multicomponent imine condensation between tris(4-formylphenyl)phosphate and tris(2-aminoethyl)amine. It is concluded that acetonitrile is beneficial to the assembly of \[2 + 3\] halfway cage, while chloroform can promote the full conversion of the functional groups on two reactants. Structurally, this cage possesses one distinctive cavity constituted by four phosphate units. Furthermore, this \[4 + 4\] phosphate OMC displays good selectivity of CO~2~ adsorption over CH~4~. Thus, the strategy we offered here to synthesize the \[4 + 4\] phosphate cage is believed to be instructive for designing new type functionalized organic cages and host molecules in supramolecular chemistry.
Supplementary information
=========================
{#Sec4}
Supplementary information Supplementary information2
**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
=========================
is available for this paper at 10.1038/s41598-020-61813-6.
This work was supported by National Natural Science Foundation of China (No. 21871133), National Natural Science Foundation of Jiangsu Province (No. BK20171334), and Science, Technology and Innovation Commission of Shenzhen Municipality (No. JCYJ20180307153251975).
Gen-Feng Feng synthesized the complexes, performed the characterization and wrote the first draft of the manuscript. Jiao Geng and Fen-Da Feng analyzed the results. Wei Huang designed the experiments and corrected the manuscript. All authors reviewed the manuscript.
The authors declare no competing interests.
| 2023-09-29T01:26:51.906118 | https://example.com/article/5693 |
[Laser beam protection in research, technology and the theater].
Detailed limiting values are indicated for inoffensive exposition of eyes and skin to laser radiation. In order to have a simple method of judging the risk, laser classes have been introduced which are briefly described. The most important technical principles for a secure handling of lasers are presented. Their application in laboratory is discussed. Within the field of industrial production, a complete encapsulation of lasers is desirable. Surveying lasers are problematic because the laser hazard area can hardly be limited. If lasers are applied in theaters or performances, the mounted unit has mostly to be submitted to an expert. | 2023-10-29T01:26:51.906118 | https://example.com/article/2247 |
Publications
This case describes how the Honduran Ministry of Health developed and implemented a Chagas disease control program with the assistance of the Japan International Cooperation Agency (JICA) and others from 2003 to 2012. After providing background information about Honduras and Chagas disease, the case examines the work of the Guatemalan Ministry of Health and JICA to implement a Chagas disease control program that provided the template for the program in Honduras. The case then describes the adaptation of this model for the Honduran context, including details of the surveillance model and vector control interventions. The case concludes with the program considering how it would maintain its success in spite of decreased funding and changes in leadership.
Main vector species of Chagas disease in Central America. Source: Biblioteca Virtual en Salud de Honduras.
Training community members for indoor residual spraying in the first trial in Intibucá 2004. Source: Case writers.
Learning Objectives: A productive class discussion will allow students to appreciate strategies in control of neglected tropical diseases; Chagas disease vector control and surveillance; the role of bilateral cooperation to strengthen health systems management; and how regional disease control initiatives are implemented locally.
This case takes place in the United States (US) and traces the inception and growth of Project Extension for Community Healthcare Outcomes (Project ECHO)—a web-based "guided practice" model for primary care providers—from 2003 to 2016. After providing background on the US health system, including medical education, health care financing, and the supply and distribution of primary care and specialist providers, the case explores what motivated Project ECHO founder and liver specialist Sanjeev Arora, MD to train primary care providers in rural New Mexico in hepatitis C treatment and management. It describes early replication of the ECHO model in the US and across medical conditions and what the Project ECHO model entailed—including leveraging technology to expand access to specialty resources, best practices, case-based learning, and outcome monitoring, as well as good will among participants. A professional communications campaign, ongoing research, and persistence supported Project ECHO’s growth. The case displays three dimensions of Project ECHO’s early work: creating a new mode to redistribute the expertise of specialists to primary care practitioners, scaling this new care delivery model and measuring its impact, and identifying sustainable funding sources. The case concludes with the US Congress passing the ECHO Act to promote research on the model and Arora contemplating what else he might need to continue to scale to reach his goal of touching 1 billion lives.
Learning Objectives: To understand what is needed to design a service model; the potential for redistribution of expertise among practitioners to enhance value; the role of operational effectiveness in enabling scale up; and the importance of measuring impact for stakeholders.
This case traces the development of the voluntary medical male circumcision (VMMC) campaign in Nyanza Province, Kenya as it transformed from the subject of a randomized clinical trial into national policy. After providing some background on the cultural, political, and scientific context surrounding male circumcision, the case traces the PEPFAR-funded implementers' advances in delivering male circumcision in Nyanza. It examines the various delivery models used in Nyanza and the evolution of the relationship between implementers as well as on the development of the national strategic plan for VMMC released in 2009. The case ends with the implementers having come together successfully for two rapid, aggressive, 30-day implementation campaigns and the head of Kenya's National AIDS and Sexually Transmitted Infections Control Programme wrestling with how to make such campaigns sustainable and what lessons from the campaign to pass on to the national program. This is a condensed version of the case Voluntary Medical Male Circumcision in Nyanza Province, Kenya.
Learning Objectives: To understand how a randomized controlled trial may be translated into a large-scale public health program; how a surgical campaign was designed and implemented for rapid impact; the role of national and international collaboration in large-scale health delivery; and the ethical tradeoffs that arise in large-scale public health programs.
This case demonstrates what it takes to address a chronic, intergenerational public health issue. It explores the drivers behind the reduction of malnutrition in Maharashtra State, India, from 2001–2013. Specifically, the case examines the strategies and management decisions of leaders of the government-established Rajmata Jijau Mother-Child Health and Nutrition Mission as they worked to reduce the incidence of malnutrition in children and women through a multi-sectoral collaborative approach.
Learning Objectives: A productive class discussion will allow students to appreciate how to configure specific interventions and indicators to ameliorate and measure malnutrition for a local setting; the complexity and importance of crafting policies and generating political will across sectors in support of nutrition programs; and the role of a strong community workforce in enabling nutrition programs to reach the target population.
This case traces the development of the voluntary medical male circumcision (VMMC) campaign in Nyanza Province, Kenya as it transformed from the subject of a randomized clinical trial into national policy. After providing some background on the cultural, political, and scientific context surrounding male circumcision, the case traces the PEPFAR-funded implementers' advances in delivering male circumcision in Nyanza. It examines the various delivery models used in Nyanza and the evolution of the relationship between implementers as well as on the development of the national strategic plan for VMMC released in 2009. The case ends with the implementers having come together successfully for two rapid, aggressive, 30-day implementation campaigns and the head of Kenya's National AIDS and Sexually Transmitted Infections Control Programme wrestling with how to make such campaigns sustainable and what lessons from the campaign to pass on to the national program.
Learning Objectives: To understand how a randomized controlled trial may be translated into a large-scale public health program; how a surgical campaign was designed and implemented for rapid impact; the role of national and international collaboration in large-scale health delivery; and the ethical tradeoffs that arise in large-scale public health programs.
This case reviews the changes in national policy and the subsequent interventions used to reduce the incidence of malaria in Zambia from 2005 to 2010. After providing contextual information on Zambia-including historical, demographic, social, and health information-the case delves into the history of malaria control efforts worldwide and in Zambia. Though Zambia was at the forefront of malaria control-changing policy, adopting new treatment, and aggressively pursuing comprehensive malaria control efforts-in the early 2000s, by 2005 the Zambian government was still falling short of its targets. The National Malaria Control Center (NMCC) resolved to intensify its efforts by developing one national plan to improve coordination, data collection, and partner involvement, and ultimately, to scale up interventions rapidly in order to meet the national malaria targets. The new NMCC director, Dr. Elizabeth Chizema, guided the program toward success through several key interventions described in the case. With basic improvements in monitoring and evaluation, Chizema could demonstrate progress in malaria control. Nonetheless, she worried that partners might lose interest in helping Zambia given the decreasing burden even though the program still had many challenges to overcome.
Learning Objectives: To understand the development of a successful malaria control program over time and the components that led to its success, including the value of setting bold national goals, the merits of a health system with centralized governance and decentralized implementation, the importance of multiple coordinated interventions as opposed to a "silver bullet" approach for malaria control, and the use of data as an outcome measure, planning tool, and fundraising tool.
The case delves into the history of malaria control efforts in Zambia, including control and treatment policy changes in the in the early 2000s that set Zambia apart from other countries. Because by 2005 Zambia was still falling short of its targets, the National Malaria Control Center (NMCC) resolved to intensify its efforts by developing one national plan to improve coordination, data collection, partner involvement, and ultimately, rapidly scale-up interventions to meet the national malaria targets. The new NMCC director, Dr. Elizabeth Chizema, helped the program achieve success through several key interventions described in the case. With improved monitoring and evaluation, Chizema could demonstrate progress in malaria control, but she worried that partners might lose interest in helping Zambia given the low burden, and the program still had many challenges to overcome. This is a condensed version of the case Malaria Control in Zambia.
Learning Objectives: To understand the development of a successful malaria control program over time and the components that led to its success including the value of setting bold national goals, the merits of a health system with centralized governance and decentralized implementation, the importance of multiple coordinated interventions as opposed to a "silver bullet" approach for malaria control, and the use of data as an outcome measure, planning tool, and fundraising tool.
This case documents Indonesia’s progress in developing a coordinated national HIV/AIDS response. Within the context of a new democratic government, a weak civil society sector, a newly decentralized and underfunded public health system, and a religiously conservative environment, the case describes how international donors financed and directed HIV/AIDS-related efforts for the first 15 years of the epidemic. In 2006 the National AIDS Commission (NAC) was restructured and awarded funding from the United Kingdom’s Department for International Development (DFID). The case documents how DFID’s flexible financing enabled the NAC to develop a single national strategy, a national monitoring and evaluation framework, and a system of local AIDS commissions. The case ends in 2009 with the NAC preparing to assume a new role as one of three Principal Recipients of the Global Fund to Fight, AIDS, Tuberculosis and Malaria. The NAC leadership must contemplate how to sustain and further the progress made in scaling up HIV prevention services while taking on new responsibilities as a Global Fund Principal Recipient.
Learning Objectives: To understand the impact of external financing, donor-driven agendas, and a national champion in creating a multisectoral response to HIV in a religiously conservative, lower middle-income country.
This case is the second in a two-part series describing the Avahan Indian AIDS Initiative (Avahan), a large-scale HIV prevention delivery program of the Bill & Melinda Gates Foundation (Gates Foundation). The case examines Avahan's choice of intervention strategies in the face of the HIV epidemic of India in 2002. It describes Avahan's structure, operations, and execution style, as well as how Avahan's management system for its seven "state lead partners" and 137 district-level nongovernmental organizations was applied initially to scale and later to sustain the delivery model. The case ends with Avahan's director planning to transfer program ownership to the Government of India.
Learning Objectives: To understand the strategies needed to deliver HIV prevention services at scale; how the configuration of management activities can enable rapid scale up of HIV prevention programming; and how these management activities must evolve to sustain delivery at scale.
This case examines the development of a tuberculosis (TB) treatment program in Bangladesh by the non-governmental organization, BRAC, from 1984 to 2006. After providing background about Bangladesh, the burden of TB there, and BRAC, the case examines how this program was piloted and grew to cover a population of 80 million people. It details how BRAC was able to create a TB control program that utilized community health workers to perform most of its essential functions including case finding, directly-observed therapy, identification of complications, and record keeping. The case concludes with a brief summary of BRAC’s expansion to Afghanistan and recently, Africa, and asks the reader to consider the feasibility of this TB care model in other contexts and in other conditions, such as HIV/AIDS.
Timeline of BRAC TB Program Expansions. Source: From One to Many: Scaling Up Health Programs in Low-Income Countries. Edited by Richard A Cash, A Mushtaque R. Chowdhury, George B. Smith, and Faruque Ahmed (2010). Ch 13. Islam A and May MA. Decentralized Management in the Expansion of BRAC's Rural Tuberculosis Program (DOTS). Pgs. 207-214. (Exhibit 3 in "BRAC’s Tuberculosis Program: Pioneering DOTS Treatment for TB in Rural Bangladesh" case.)
Learning Objectives: To understand effective strategies for effectively engaging community health workers to deliver complex medical and public health interventions to large populations in low resource settings.
This case examines BRAC’s experience expanding its rural TB program to the urban environment of Dhaka between 2002 and 2008. The case provides background information about Dhaka and describes what TB services existed at the time. The case then describes the expansion of BRAC’s TB program into Dhaka and details innovations in the Urban program. Students should gain an understanding of how these program modifications were a response to the specific challenges the program faced in the urban setting. The case allows an exploration of how successful health care delivery program adapt to new environments.
This case traces the development of The AIDS Support Organization (TASO), a Ugandan non-governmental organization, from 2001 to 2006. One of the first organizations to become involved in HIV/AIDS in the late 1980s, TASO began as a meeting place for people infected and affected by HIV/AIDS, helping people to live positively. The organization provided free counselling, social support, limited medical care, community mobilizing, advocacy and networking. TASO worked alongside government facilities and trained government medical personnel in HIV counselling. After many years, TASO got a new director who brought management skills, a commitment to professionalizing the organization, and a drive to expand services. TASO began incorporating antiretroviral therapy (ART) into its offerings. The ART delivery model combined home and clinic-based care in order to maximize patient adherence. The case follows the development of the organization and scale up of services and raises the question of how to deliver care most cost effectively while maintaining its values and meeting the changing needs of the population and clients.
Learning Objectives: Students should learn how a healthcare delivery organization can expand and evolve over time in response to changes in external context and the needs of its clients; how public and private organizations can coordinate to meet the varied needs of a population; and the importance of leadership, management, and strategic vision in creating successful global health programs. | 2024-01-27T01:26:51.906118 | https://example.com/article/5486 |
This photo of the curry is the most popular of all menu. Homemade european “torotoro” beef belly curry, ￥1200
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Why don't you stay M's inn ♪ | 2024-04-29T01:26:51.906118 | https://example.com/article/7713 |
Hum Tum
After his raggedly likable supporting turn in the aces "Kal ho naa ho," Saif Ali Khan proves he's more than capable of carrying a romantic comedy in "Hum tum," the latest colorful piece of candy floss from veteran producer Yash Chopra. Otherwise, this Westernized tale of mismatched friends who just can't fess up to their real feelings is a couple of notches below the Chopra par, with so-so dialogue and lack of strong chemistry between leads Khan and Rani Mukherjee.
After his raggedly likable supporting turn in the aces “Kal ho naa ho,” Saif Ali Khan proves he’s more than capable of carrying a romantic comedy in “Hum tum,” the latest colorful piece of candy floss from veteran producer Yash Chopra. Otherwise, this Westernized tale of mismatched friends who just can’t fess up to their real feelings is a couple of notches below the Chopra par, with so-so dialogue and lack of strong chemistry between leads Khan and Rani Mukherjee. Pic opened well in Indian metros May 28, but looks set for only OK returns in the long term.
Film is one huge flashback, as well-known cartoonist Karan Kapoor (Khan) reminisces about the love of his life, Rhea Prakash (Mukherjee), at the launch of his first novel, based on his popular battle-of-the-sexes comic strip “Hum tum” (literally, “Me and You”). Structured as a series of episodes, as the pair meets in various locations (Delhi, New York, Amsterdam, Paris) across nine years, pic is never less than an easy sit, but fails to deliver the emotional goods in its latter stages.
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Playboy Karan and seriously studious Rhea meet cute on a plane from Delhi to Gotham, where both are going to study. Despite his attempts to charm her during an Amsterdam stopover, the Western-hip lothario fails to impress the over-serious prude, and when he plonks a kiss on her, she slaps his face.
Six months later, they bump into each other in Central Park, where he’s romancing his g.f., Shalini (Shenaz Treasurywala), who turns out to be an old school-chum of Rhea’s. That meeting also ends badly.
Three years on, back in Delhi, Karan is now a well-known cartoonist with a shaggy “Tom Cruise haircut,” and at a mehndi (engagement party) arranged by his mom, Anju (Rati Agnihotri), Karan discovers the bride is none other than Rhea. When he tells Rhea that her husband, Sameer (Abhishek Bachchan, cameoing), sounds boring and asks if they’ve had sex yet, Rhea’s ire is raised again. However, her mom, Parminder (Kiron Kher, eating up the role of a colorful Punjabi mother), takes a liking to him.
Following a minor reversal prior to the intermission, as they meet on a train outside Paris, pic’s second half fans out into a more conventional romance, with Parminder playing discreet matchmaker and Karan’s friend, Mihir (Jimmy Shergill), entering the mix.
Both Kher and fellow vet Rishi Kapoor (as Karan’s estranged dad) bring some character heft to Part 2, but the central duo’s relationship doesn’t gain the necessary depth to click emotionally with the viewer. Khan is very good as the jokey womanizer who can’t put the lessons of his cartoon strip into personal practice, but Mukherjee’s Rhea remains a one-note, reactive character who’s difficult to like or understand. Instead of sparking, their scenes together simply coast along in well-worn Bollywood grooves.
Helmer-writer Kunal Kohli, whose super-fluffy “Mujhse dosti karoge!” showcased the gravel-voiced Mukherjee far better, here directs competentlyrather than at full throttle, and musical numbers are lively and tuneful without ever really taking off. (Rhea’s mehndi, staged as a comic battle of the sexes, is a case in point.) Copious Yank-style animated segs — showing the cute boy and girl from Karan’s comic strip — basically repeat what’s just happened between Karan and Rhea in the movie.
Production values are OK, without being super-glossy. However, Amsterdam doubling as the French capital won’t fool anyone familiar with Paris for a second. One musical number is even shamelessly staged in front of the famous Concertgebouw building.
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After his raggedly likable supporting turn in the aces “Kal ho naa ho,” Saif Ali Khan proves he’s more than capable of carrying a romantic comedy in “Hum tum,” the latest colorful piece of candy floss from veteran producer Yash Chopra. Otherwise, this Westernized tale of mismatched friends who just can’t fess up to their […]
After his raggedly likable supporting turn in the aces “Kal ho naa ho,” Saif Ali Khan proves he’s more than capable of carrying a romantic comedy in “Hum tum,” the latest colorful piece of candy floss from veteran producer Yash Chopra. Otherwise, this Westernized tale of mismatched friends who just can’t fess up to their […]
After his raggedly likable supporting turn in the aces “Kal ho naa ho,” Saif Ali Khan proves he’s more than capable of carrying a romantic comedy in “Hum tum,” the latest colorful piece of candy floss from veteran producer Yash Chopra. Otherwise, this Westernized tale of mismatched friends who just can’t fess up to their […]
After his raggedly likable supporting turn in the aces “Kal ho naa ho,” Saif Ali Khan proves he’s more than capable of carrying a romantic comedy in “Hum tum,” the latest colorful piece of candy floss from veteran producer Yash Chopra. Otherwise, this Westernized tale of mismatched friends who just can’t fess up to their […]
After his raggedly likable supporting turn in the aces “Kal ho naa ho,” Saif Ali Khan proves he’s more than capable of carrying a romantic comedy in “Hum tum,” the latest colorful piece of candy floss from veteran producer Yash Chopra. Otherwise, this Westernized tale of mismatched friends who just can’t fess up to their […]
After his raggedly likable supporting turn in the aces “Kal ho naa ho,” Saif Ali Khan proves he’s more than capable of carrying a romantic comedy in “Hum tum,” the latest colorful piece of candy floss from veteran producer Yash Chopra. Otherwise, this Westernized tale of mismatched friends who just can’t fess up to their […]
After his raggedly likable supporting turn in the aces “Kal ho naa ho,” Saif Ali Khan proves he’s more than capable of carrying a romantic comedy in “Hum tum,” the latest colorful piece of candy floss from veteran producer Yash Chopra. Otherwise, this Westernized tale of mismatched friends who just can’t fess up to their […] | 2024-06-20T01:26:51.906118 | https://example.com/article/4839 |
1. Introduction {#sec1-sensors-18-03621}
===============
Wireless Sensor Networks are being actively adopted as enablers for context aware communication capabilities within multiple scenarios, such as Smart Cities and Smart Regions \[[@B1-sensors-18-03621],[@B2-sensors-18-03621]\]. Within Smart City/Region concept, developments in the management of healthcare systems, water resources and waste, energy and transportation systems have been published in recent years \[[@B3-sensors-18-03621],[@B4-sensors-18-03621],[@B5-sensors-18-03621],[@B6-sensors-18-03621],[@B7-sensors-18-03621]\]. Among these, agricultural management is gaining relevance since it concerns a fundamental aspect of human survival: feeding. As in the other mentioned cases, information and communication technologies have also been adopted in order to improve multiple aspects of agriculture \[[@B8-sensors-18-03621]\]. In this context, WSNs play a key role, given to the fact that they constitute inherent distributed systems, in which current platforms allow the inclusion of multiple analogue/digital input/output ports. Furthermore, the use of wireless communication systems enables ubiquity as well as ease of deployment. Multiple challenges must also be handled, such as compact form factors, reduced energy consumption, interference handling and variable node density allocation. In this sense, HetNet solutions as well as incumbent 5G systems provide user access/interference control mechanisms, which rely on radio propagation characteristics in site-specific fashion, such as Self Optimizing Networks, Cloud RAN or Cooperative MAC schemes \[[@B9-sensors-18-03621]\]. Adequate network operation and design require wireless channel analysis and optimization in order to minimize interference, energy consumption and enhance overall quality of service. This is of particular interest in the case of wireless sensor networks, given inherent restrictions in their operating conditions, as well as in the potentially large number of nodes present in the network.
All these advancements lead to the so-called Precision Agriculture and Smart Agriculture, where the information gathered by sensors (such as environmental parameters \[[@B10-sensors-18-03621]\] or chemical component and soil water detection \[[@B11-sensors-18-03621]\]) provide support to decision systems \[[@B12-sensors-18-03621]\], facilitating the adoption of measures in order to optimize resources such as water or fertilizers \[[@B13-sensors-18-03621],[@B14-sensors-18-03621],[@B15-sensors-18-03621],[@B16-sensors-18-03621]\], control and manage plant growth \[[@B17-sensors-18-03621]\], as well as to detect, prevent and treat diseases \[[@B18-sensors-18-03621],[@B19-sensors-18-03621]\]. One of the main advantages that this kind of systems can provide is the possibility to control and act from a location far away from the crops. This is feasible by means of IoT systems, which send to a Cloud (through a gateway) the information gathered by the WSN deployed on the crops \[[@B20-sensors-18-03621]\]. Thus, the information can be stored and managed from any device connected to the Internet. In fact, there are a few works which present Cloud-based solutions for agricultural environment applications \[[@B21-sensors-18-03621]\], a FIWARE-Based IoT platform for Precision Agriculture \[[@B22-sensors-18-03621]\] and for hydroponic precision farming \[[@B23-sensors-18-03621]\]. At this point, it is worth noting that commercial Smart Agriculture solutions are already in the market \[[@B24-sensors-18-03621]\].
Regarding the communication between these devices, in most of the cases wireless technologies to deploy WSNs and IoT-based systems for Precision Agriculture and Smart Agriculture are used \[[@B25-sensors-18-03621]\], such as Bluetooth \[[@B26-sensors-18-03621]\] or GSM and Infrared communications \[[@B27-sensors-18-03621]\]. But due to its ideal characteristics to deploy WSNs (low power consumption, low cost and high number of devices allowed per network), ZigBee is the most employed wireless technology \[[@B28-sensors-18-03621],[@B29-sensors-18-03621],[@B30-sensors-18-03621],[@B31-sensors-18-03621],[@B32-sensors-18-03621],[@B33-sensors-18-03621]\], where transceivers are mounted and controlled by Arduino and Raspberry Pi boards in most cases. Even for precision agriculture based on mobile UAVs (Unmanned Aerial Vehicles) communicating with ground sensors, ZigBee has been used \[[@B34-sensors-18-03621]\].
In this context, this work presents an educational application based on the combination of the capabilities provided by WSNs with parameter observation in a school garden in order to enhance the outcomes within the learning process of students in primary school. The novelty of the proposed system lies in two aspects of our work: On the one hand, since clean energy consumption for Smart Agriculture is gaining importance \[[@B35-sensors-18-03621]\], Energy Harvesting (EH)-based EnOcean sensors have been used instead of the mostly used Raspberry Pi and Arduino-based devices. The main advantages of the commercial EnOcean devices are the much-reduced size of the motes and the EH system they have embedded. The drawback comparing to the Raspberry Pi and Arduino-based solutions present in the literature could be, for some applications, that the wireless network topology is limited to star topology type but in the presented application it is not a drawback due to the fact that all the motes are at a similar distance from the central node. On the other hand, the educational application itself is the second novel aspect of the presented study, since no other similar applications have been reported in the literature. Specifically, in this work wireless EnOcean transceivers with energy harvesting capabilities are employed in order to provide autonomous system operation, combined with an ad-hoc implemented application called MySchoolGardenApp. Information is retrieved in a cloud enable environment, providing remote data access and off-line processing capabilities, in order to adapt content to specific classroom needs. MySchoolGardenApp follows the trend marked by multiple initiatives within the educational community in which development environments such as Arduino/Genuino or Raspberry Pi are being employed in order to enhance learning outcomes in multiple disciplines, with a clear focus on Science, Technology, Engineering and Mathematics (STEM) \[[@B36-sensors-18-03621],[@B37-sensors-18-03621],[@B38-sensors-18-03621]\].
The paper is organized as follows: [Section 2](#sec2-sensors-18-03621){ref-type="sec"} presents the scenario where the experiments have been done, the 3D Ray Launching simulation technique that has been used for the radio planning and the employed EnOcean devices for the creation of the WSN. [Section 3](#sec3-sensors-18-03621){ref-type="sec"} focuses on the radio planning simulation results and their analysis. In [Section 4](#sec4-sensors-18-03621){ref-type="sec"} the developed MySchoolGardenApp is presented and finally, in [Section 5](#sec5-sensors-18-03621){ref-type="sec"} the conclusions of the obtained results are commented.
2. Materials and Methods {#sec2-sensors-18-03621}
========================
The experiments have been carried out in the orchard of the 'Camino de Santiago' primary school, located near the city of Pamplona. The orchard has an educational role, as the students learn how to grow different kind of vegetables such as cucumbers, pumpkins, onions, garlic, tomatoes, beans, zucchini, corn and so forth. The orchard is 25 m long and 9.5 m width and it is located within the school yard, near the school building, as can be seen in [Figure 1](#sensors-18-03621-f001){ref-type="fig"}a, where the orchard is delimited by a red rectangle. The 18 yellow dots within the red rectangle that can be seen in the figure represent the positions where the sensor devices of the proposed WSN have been placed. [Figure 1](#sensors-18-03621-f001){ref-type="fig"}b shows a real picture of the orchard under study.
The proposed WSN for monitoring the orchard has been built based on EnOcean's energy harvesting modules. Specifically, the STM 330 modules have been employed, which employ the ISO/IEC 14543-3-1X proprietary standard for wireless communications. The STM 330 module makes use of the European operating frequency (868 MHz), receiver sensitivity value of −96 dBm\@125 kbps and expected current consumption values ranging from 0.6 µA to 130 µA depending on charging and luminosity conditions. These wireless modules have integrated a 16 MHz 8051 CPU with 32 kB FLASH and 2 kB SRAM. They also have incorporated a temperature sensor (range 0 to 40 °C) and provide the possibility of equipping them with a humidity sensor, which has been used in this study as it provides interesting information for the purpose of the presented application. The humidity sensor is HSM 100 module, which has a measurement range from 0% to 100% with a resolution of 0.4% and a typical accuracy of ±5% (for values between 30--70%). In [Figure 2](#sensors-18-03621-f002){ref-type="fig"}a a simplified device block diagram is presented. [Figure 2](#sensors-18-03621-f002){ref-type="fig"}b shows a picture of a STM 330 module alongside the optional humidity sensor. In the same way, [Figure 2](#sensors-18-03621-f002){ref-type="fig"}c shows a picture of the opposite side of the same module, where the solar cell used for the energy harvesting can be seen. The power supplied by the solar cell is managed by an energy management circuit to bridge periods of darkness. Specifically, if the energy storage is fully charged, the operation time in darkness is typically 4 days (which could vary depending on the temperature), when the information transmissions are made every 1000 s. The module also provides user configurable cyclic wake-up functionality. After wake-up, a radio message is transmitted in case of a significant change of measured data is detected. Besides the reduced size of the modules, which provides an easy-to-deploy feature, it is very important to note that the energy harvesting technology of the devices (they are self-powered by the small solar cell) avoids the maintenance task of replacing batteries that common WSNs usually need. This is a very important feature of the EnOcean devices and it is worth noting that from the literature, there are very few solutions where self-powered devices are employed \[[@B13-sensors-18-03621],[@B33-sensors-18-03621]\], the rest need to be powered externally as the use development boards such as Arduino or Raspberry Pi.
Regarding the radio characteristics of the STM 330 modules, they operate at 868.3 MHz, which can provide longer distances than common devices operating at 2.4 GHz (such as ZigBee and Bluetooth) due to lower radio propagation losses. They provide a low data rate of 125 kbps (in comparison, ZigBee at 2.4 GHz transmits 256 kbps), which is enough in order to transmit the required information. The transmitted power level is between 5 and 8 dBm. The available network topology is much more restricted than other wireless technologies in terms of packets routing, as the only possible topology is the star topology (although the coverage of the network can be extended programming a device as a repeater), which means that each of the deployed STM 330 modules communicates only with a central module, usually connected to a PC or laptop via USB. Anyway, for the presented application, the benefits that provide these modules (size-deployment ease and energy harvesting system) make the EnOcean devices more interesting than those based on Arduino and Raspberry boards shown in the literature. [Figure 3](#sensors-18-03621-f003){ref-type="fig"} shows a schematic description of the star topology of the network with the USB Gateway central module, which in this study case will be connected to a PC inside the school building. The Gateway records the temperature, humidity and RSSI value sent by each of the deployed STM 330 modules. The employed version of the Gateway has an internal chip antenna.
Before the implantation of the proposed system and the EnOcean-based WSN, a radio planning study has been performed in order to obtain data of the coverage of the WSN. This is particularly important in this case since the employed wireless devices have to be directly connected to the USB Gateway placed inside the building due to the restrictions of the star topology, that is, there are no routing elements in the network. For this task, an in-house developed simulation tool, called 3D Ray Launching, has been used. It is a deterministic method as it is based on the resolution of Maxwell's equations but comparing to other deterministic methods it provides a good trade-off between precision and required computational time since it is simplified by ray launching and ray tracing techniques, based on geometrical optics. For the present study, the 3D Ray Launching technique will provide the RF power distribution for the whole 3D simulated scenario. This simulation tool has been broadly used and validated in both indoor and outdoor large scenarios \[[@B39-sensors-18-03621],[@B40-sensors-18-03621]\]. It has also been tested satisfactorily for smart viticultural management \[[@B41-sensors-18-03621]\].
3. Results {#sec3-sensors-18-03621}
==========
As previously mentioned, a radio planning study has been performed in order to obtain information about the feasibility of the proposed EnOcean-based WSN for the monitoring of the school orchard. The scenario under analysis has been presented in [Figure 1](#sensors-18-03621-f001){ref-type="fig"} and the created scenario for the simulations by means of the 3D Ray Launching tool is presented in [Figure 4](#sensors-18-03621-f004){ref-type="fig"}a. The simulated scenario is composed by the 'Camino de Santiago' public school building and the orchard which is part of its facilities. They are distributed in a 2470 m^2^ area scenario, where the orchard occupies 237.5 m^2^. The building has dimensions of 40 m long, 28 m width and 9 m height. It is worth noting that important elements in terms of its effect on radio propagation have been taken into account such as the interior of the school building, which has been filled approximately like the real building (see [Figure 4](#sensors-18-03621-f004){ref-type="fig"}b) and the metallic fence that surrounds the orchard (see [Figure 4](#sensors-18-03621-f004){ref-type="fig"}c). The material properties (dielectric constant and conductivity) of all the elements within the scenario, including organic materials for trees and orchard have also been considered.
The main results provided by the 3D Ray Launching simulation tool are the RF power distribution planes. A transmitter is located within the created scenario and parameters such as transmission power level and antenna type are defined. Then, results for the whole volume of the scenario are obtained for each of the deployed wireless transmitters. As an illustrative example, [Figure 5](#sensors-18-03621-f005){ref-type="fig"} shows the estimated values for a bi-dimensional plane at 5 m height for the simulation of one of the wireless sensors deployed on the orchard (represented by a red dot). The typical RF power distribution due to multipath propagation can be seen in the figure, which is caused by the morphology and topology of the considered scenario. Instead of the required process for 3D Ray Launching simulations, a faster methodology to obtain the received RF power at one point of the scenario has been also used, by means of empirical radio propagation models such as COST-231. These methods are based on measurement campaigns and provide very fast estimations. However, they lack precision since they do not take into account the multipath propagation which is specific for each scenario due to the elements within them such as furniture, columns, fences and so forth. In order to see clearer the difference between empirical methods and the 3D Ray Launching method, three linear path RF power distributions are shown in [Figure 6](#sensors-18-03621-f006){ref-type="fig"}. They correspond to the linear path marked by a white dashed line in [Figure 5](#sensors-18-03621-f005){ref-type="fig"} and the presented heights (1.2 m, 4.25 m and 7.25 m) are equivalent to the tables' heights of the first, second and third floor of the building, that is, the potential locations of the EnOcean gateway. As can be seen in all the graphs of [Figure 6](#sensors-18-03621-f006){ref-type="fig"}, the estimations provided by the 3D Ray Launching follow the tendencies of the other radio propagation models but they reflect the typical rapid variations generated by the multipath propagation, giving more precise results for an optimized radio planning.
One of the issues which were taken into account when wireless sensors were chosen, apart from the self-powered feature, was the operation frequency of the transceivers. As presented in the Introduction section, in the literature almost all WSNs deployed for Smart Agriculture use ISM 2.4 GHz band for the wireless communication. The EnOcean STM 330 devices (EnOcean GmbH, Oberhaching, Germany) used in this work operates at 868.3 MHz, which means that in same conditions (same transmitted power level and antenna), the coverage or reach of these nodes is higher than those operating at higher frequencies. This could be a key aspect in a star topology WSN since it is mandatory to have direct communication between the gateway and each of the wireless sensors of the network. In this way, further simulations have been performed in order to compare the performance between EnOcean STM 330 modules and a common ZigBee module operating at 2.4 GHz. The used simulation parameters are summarized in [Table 1](#sensors-18-03621-t001){ref-type="table"}. The obtain simulation results for a wireless sensor placed in the centre of the orchard are shown in [Figure 7](#sensors-18-03621-f007){ref-type="fig"}. The RF power distribution planes at the height of the three floors of the school building are presented. As expected, 868.3 MHz shows better performance in terms of RF power level, both outside and inside the school building.
This kind of results give a valuable information for a correct deployment of the proposed WSN, as the central node of the network will be deployed within the building. Since the sensitivity of the EnOcean USB 300 central node is −96 dBm, sensitivity fulfilment planes can be obtained based on the RF power distribution planes. In this case, at 868.3 MHz, the sensitivity threshold is never exceeded inside the building. This means that there are not restricted areas where the central node can be placed inside the building. But there is another important issue that has not been taken into account yet: the presence of human beings. It is well known that the presence of human body affects significantly the radio propagation due to its absorption properties, which creates the also well-known shadowing effect \[[@B42-sensors-18-03621]\]. Depending on how many human beings are within a scenario (i.e., human body density), propagation losses vary greatly in indoor environments \[[@B43-sensors-18-03621]\]. Based on this loss variability, in [Figure 8](#sensors-18-03621-f008){ref-type="fig"} sensitivity fulfilment planes for approximated losses for different human body densities are presented. Three human body densities have been defined: LD (Low Density), MD (Medium Density) and HD (High Density), with their corresponding propagation losses: 10 dB, 20 dB and 30 dB respectively. The areas/zones that do not comply with the sensitivity requirements are highlighted in red, whereas the blue zone indicates that the EnOcean gateway could be deployed as the received power level is higher than the sensitivity threshold. Obtaining the sensitivity fulfilment planes for each of the deployed wireless sensors on the orchard, an optimum location for the gateway can be estimated. If the location of the gateway is restricted to specific classes or laboratories (which is usually the case), it can be assessed whether they are adequate places for the deployment or not. In this work, after obtaining all the sensitivity fulfilment planes, a laboratory and a teachers' room in the second floor have been selected as the best choices to deploy the gateway of the WSN. It is worth noting that the first-floor areas beside the orchard were also a good option but they were discarded since they were common classrooms and were defined as inappropriate.
For an in-depth performance analysis, BER (Bit Error Rate) values can be calculated for both EnOcean and ZigBee options. [Figure 9](#sensors-18-03621-f009){ref-type="fig"} shows the obtained BER for the linear path depicted in [Figure 5](#sensors-18-03621-f005){ref-type="fig"}. For the estimations, a noise level of −70 dBm has been considered for both communication schemes. ZigBee shows a better performance in terms of BER when considering the same noise level, due to its bandwidth and modulation scheme (3 MHz, Q-PSK) in contrast to EnOcean's 70 KHz bandwidth and ASK modulation. It is worth noting that the error probability is almost zero outdoor and it starts to be higher for locations within the building, which is expected. But in general, the obtained error probability is very low except in locations at the far end of the building, as it happened for the received power distributions (see [Figure 7](#sensors-18-03621-f007){ref-type="fig"}).
4. Application Design and System Validation {#sec4-sensors-18-03621}
===========================================
This section presents the developed educational application based on the EnOcean WSN deployed on school gardens. School gardens are becoming increasingly popular in urban districts as they are a very useful educational resource for urban schools. They boost students' interest in learning specific botanical concepts by allowing them to engage in agricultural practices on a small scale and they help students become responsible caretakers by teaching them the responsibilities and impacts of land cultivation. Besides, the students start using and learning technological concepts such as sensors, wireless communications and clouds. But the benefits of school gardens as complementary educational tools do not stop there. The application presented in this work, called MySchoolGardenApp, covers a large number of educational impact areas in addition to those previously presented. For instance, it increases students' interest in several topics including the following: the value of the natural environment and its importance in human life, the history of different crops, mathematics for the calculus of surfaces, weights collected, number of fruits and, in higher courses, the use and interpretation of graphs on time and the Internet search on different cultivation methods. [Figure 10](#sensors-18-03621-f010){ref-type="fig"} describes the areas MySchoolGardenApp has the largest impact on.
A simple system architecture is required to support the application (see [Figure 11](#sensors-18-03621-f011){ref-type="fig"}). EnOcean's STM 330 nodes gather the information and transfer it wirelessly (868.3 MHz) to a gateway node located in the building. This USB-based gateway is connected to a PC, which is in charge of the collection and management of data and its transmission to the cloud. This channel is also used to provide control commands to the sensor nodes when needed. The used PC is an Ubuntu 16.4 Linux computer that uses a RESTful API to transfer data to the cloud (Amazon) by means of a web service. Basically, the periodically collected information is transferred to the cloud. In addition, meteorological information obtained from a web service run by the Government of Navarre (<http://meteo.navarra.es>) is used to complement the locally collected data (temperature). Through this efficient data acquisition process, all the information the application needs (including the meteorological information and the harvested data) is statistically merged and processed using Amazon's RDS (Relational Database Service) and RStudio Server. Finally, access to the generated reports, statistical data analysis tools and all user process capabilities and features (restricted by the user profile) are available through mobile devices (smartphones and tablets), electronic boards and computers using the Wi-Fi network of the building.
From a software level view, MySchoolGardenApp has different Graphical User Interfaces (GUIs) to accommodate different user types. The different GUIs allow the system to restrict data access and function usage based on a given user's user type. An Administrator profile is available to control the performance of the application by monitoring features and accounts and making adjustments if necessary. The Administrator is also responsible for the management and maintenance of the hardware infrastructure sensor network, the gateway, communications and the software licenses required for data processing (Amazon RDS and RStudio Server). At the operational level, Teacher and Student profiles are available. Teachers are able to exploit the application's features to design activities, set and manage schedules and alerts and analyse data to assess students' performance. Students, similarly, can benefit greatly from the application by using its interactive learning tools. The students are further broken into the following three categories based on their grade level: basic, intermediate and advanced. This division allows the system to be a much more customizable tool for teachers, who can then assign content suitable for the educational needs of their students based on their students' levels of understanding. User profiles and their general tasks are presented in [Figure 12](#sensors-18-03621-f012){ref-type="fig"}.
MySchoolGardenApp is designed to be as simple and intuitive as possible. Teachers can assert their charge of the maintenance of the urban school garden by using the application's activities management system to assign tasks to students. They can interact in real-time with their students, creating, sending or evaluating activities, alerts or homework through the application's interface that they can access using their own personal portable devices. Some panels from the applications' Teacher GUIs are shown in [Figure 13](#sensors-18-03621-f013){ref-type="fig"}a. Students can query information on the app through their own devices. The content made available to a given student by the app depends on the age and knowledge level of that student. For example, the system provides easy-to-understand pictograms appropriate for younger students (Basic Student Profile) whereas it provides comparative tables of the evolution of multiple variables measured by sensors, advanced graphs and even regressions and trends for older students (Advanced Student Profile). [Figure 13](#sensors-18-03621-f013){ref-type="fig"}b shows some panels from Student profiles' GUIs including those for results queries, activities and alerts. The graphs presented are aimed at students who are already able to understand graphs of a certain complexity with their knowledge of statistics.
5. Conclusions {#sec5-sensors-18-03621}
==============
In this work, an environment to enhance School Garden observation for educational purposes in primary school has been presented. The system is formed by a set of autonomous wireless sensor nodes, which transmit information to a cloud capable platform. The selected nodes, the EnOcean STM 330 modules, present very interesting features compared to the typical ISM 2.4 GHz ZigBee nodes used in the literature in order to monitor agricultural tasks: They are self-powered by an incorporated small solar cell, the whole wireless node (sensors plus wireless transceiver) is very small and the operation frequency of 868.3 MHz gives a longer range of direct communication.
Pre-deployment deterministic wireless channel analysis results have been obtained by means of 3D Ray Launching in-house simulations in order to estimate coverage relations for the proposed wireless communication system. Operation is feasible for both operating frequencies, in which the communications between point to point links for the employed star network configuration are fulfilled in terms of receiver sensitivity thresholds. Moreover, the influence of persons within the school environment has also been taken into account, revealing that it is a key issue since the overall losses due to human body presence reduces significantly the effective coverage range of the system.
On the other hand, an ad-hoc application called MySchoolGardenApp has been implemented, in order to monitor and process the obtained observation data from the sensors located on a garden located within the school yard of a primary school. The app offers different GUIs and possibilities depending on the user's profile (Administrator, Teacher or Student), which make the app flexible and simple to use. Initial testbed results have been obtained, showing the feasibility of the proposed system, which can provide multiple and adaptive results, tailored to the specific classroom needs.
It is important to note that feedback regarding the system operation and the MySchoolGardenApp is missing for the case when academic activities are being carried out, which will be determinant in order to validate the proposed solution and develop further work. Future developments of this work are the application of the presented system to higher educational levels, such as university courses, monitoring the crops used for agronomical engineering studies (which will have more difficulties due mainly to the big surfaces they occupy) and the adaptation of the application to such university course levels.
Conceptualization, P.L.-I. and F.F.; Methodology, P.L.-I., L.A. and F.F.; Software, M.C.-E. and J.J.A.; Validation, P.L.-I., E.A. and J.J.A.; Investigation, P.L.-I.; Data Curation, P.L.-I. and L.A.; Writing-Original Draft Preparation, P.L.-I. and M.C.-E.; Writing-Review & Editing, P.L.-I. and F.F.; Visualization, E.A. and M.C.-E.; Supervision, F.F.; Funding Acquisition, F.F. and J.V.
The authors would like to acknowledge the support and funding of the project PRO-UPNA17 (6100).
The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript and in the decision to publish the results.
{#sensors-18-03621-f001}
{#sensors-18-03621-f002}
{#sensors-18-03621-f003}
{#sensors-18-03621-f004}
{#sensors-18-03621-f005}
######
Linear path RF power distribution, corresponding to the white dashed line of [Figure 5](#sensors-18-03621-f005){ref-type="fig"}. (**a**) First floor height; (**b**) Second floor height; (**c**) Third floor height.
{#sensors-18-03621-f007}
{#sensors-18-03621-f008}
######
Performance comparison between EnOcean and ZigBee in terms of BER for the linear path depicted in [Figure 5](#sensors-18-03621-f005){ref-type="fig"}. (**a**) First floor; (**b**) Second floor; (**c**) Third floor.
{#sensors-18-03621-f010}
{#sensors-18-03621-f011}
{#sensors-18-03621-f012}
{#sensors-18-03621-f013}
sensors-18-03621-t001_Table 1
######
3D Ray Launching simulation parameters.
Parameter 868.3 MHz 2.4 GHz
-------------------------- ----------------- -----------------
Output power level 8 dBm 8 dBm
Antenna type Whip antenna Whip Monopole
Antenna Gain (average) 0.2 dB 0.2 dB
Permitted reflections 6 6
Cuboid resolution 2 m × 2 m × 2 m 2 m × 2 m × 2 m
Launched Rays resolution 1° 1°
Data rate 125 kbps 250 kbps
| 2024-03-15T01:26:51.906118 | https://example.com/article/6476 |
Strategy for efficient detection of respiratory viruses in pediatric clinical specimens.
Direct immunofluorescence (IF) with a polyclonal respiratory syncytial virus (RSV)-specific antibody preparation was used for antigen detection during the 1982-1983 RSV season (155 specimens) and gave an overall sensitivity of 94% with 87% specificity compared with viral culture. Indirect IF was used in the 1983-1984 season (265 specimens) and exhibited sensitivity of 96% with specificity of 79%. During these two seasons, 42 of 224 (18.8%) specimens that were IF-negative for RSV grew viruses other than RSV. In the winter of 1984-1985, we screened 297 specimens for RSV by IF and 80 (27%) were positive. Forty-four (20%) of the IF-negative specimens were culture-positive for RSV(2) or other viruses(44). We conclude that, in the interest of cost reduction and expeditious detection of respiratory viruses, once a properly equipped laboratory has become thoroughly familiar with IF techniques, pediatric respiratory specimens can be screened for RSV by IF and only the IF-negative specimens need be inoculated into cell cultures for isolation of virus during the winter respiratory season. | 2024-03-23T01:26:51.906118 | https://example.com/article/3496 |
Introduction {#s0001}
============
The FDI World Dental Federation vision 2020 defines oral health as:
> multi-faceted and includes the ability to speak, smile, smell, taste, touch, chew, swallow and convey a range of emotions through facial expressions with confidence and without pain, discomfort and disease of the craniofacial complex.^[@CIT0001]^
The definition connects with Locker and Allen's concept of oral health-related quality of life (OHRQoL), which is explained simply and loosely as 'impact of oral conditions on daily functioning and well-being'.^[@CIT0002]^ Oral health-related quality of life deals with effects and symptoms that vary in intensity and importance. 'Some maybe life threatening (e.g. oral cancers), some chronic (caries, periodontitis), some aesthetic (malocclusion, fluorosis), while some are acute and painful (toothache, pulpitis, oral mucosal lesions, extractions)', according to Hernández et al.^[@CIT0003]^ Conceptualisation of OHRQoL is context-reliant as culture and society shapes an individual's belief system and influences how health and illness is viewed.^[@CIT0004]^ Studies conducted on children's oral conditions have generally reported a poorer OHRQoL because of the oral conditions.^[@CIT0005],[@CIT0006],[@CIT0007],[@CIT0008]^ Herdman et al. purport that OHRQoL measurement domains important to one culture may not be equally relevant in all cultures.^[@CIT0009]^
Recently, research on children's oral conditions and OHRQoL globally has described the factors influencing OHRQoL.^[@CIT0010],[@CIT0011],[@CIT0012],[@CIT0013]^ Oral health-related quality of life research in children is fairly recent in Africa.^[@CIT0014],[@CIT0015],[@CIT0016],[@CIT0017]^ Existing children tools that measure OHRQoL have been developed in a non-African setting; however, some have been adapted and tested in the African setting. According to Traebert et al., different existing tools showed discrepancies when applied to different cultural backgrounds when probing the concept of ethnicity and socialisation despite translation.^[@CIT0018]^ With the amount of OHRQoL literature available on children in the African setting, no consolidating integrative review has been conducted regarding the factors influencing OHRQoL. It is, thus, necessary to probe whether the factors influencing OHRQoL are context-reliant.
Consideration of sociocultural contexts and factors affecting children's OHRQoL is important as OHRQoL is a social construct. The majority of health-related quality of life (HRQoL) models are based on the biomedical and psychological dimensions of health such as those in the International Classification of Impairments, Disabilities and Handicaps model by the World Health Organization (ICIDH, 1980). The Locker model is a type of such HRQoL model that is based on the WHO-ICIDH.^[@CIT0019]^ The Locker model is the dental adaptation of the WHO-ICIDH, and the model hypothesises that oral disease will result in 'pain', 'impairment' and functional limitation. These constructs will, in turn, lead to physical and psychological disability, handicap, and thus affect the overall OHRQoL.^[@CIT0019]^ The Locker model places its emphasis on multidimensionality of health positioned around the biomedical model and incorporates a psychosocial dimension.
In 2005, Ferrans et al. developed an OHRQoL conceptual framework which posits that the biological--symptom--functional status complex is directly influenced by both individual and environmental characteristics and together they influence the general perceptions of health and overall OHRQoL ([Figure 1](#F0001){ref-type="fig"}).^[@CIT0020]^ Sischo and Broder even unpack the Ferrans et al.'s model further when applying it to oral health by expanding on the individual and environmental characteristics.^[@CIT0013],[@CIT0020]^ On the contrary, a newer model, such as the International Classification of Functioning, Disability and Health (ICF), has an elaborate classification which includes holistic non-sick-based dimensions such as functioning and health. These models and theories provide a guiding point of view when interrogating the factors that may influence OHRQoL among African children.
{#F0001}
Oral health-related quality of life in children is particularly important as childhood development involves phases that are dominated by life changes notwithstanding the added burden of living with oral diseases.^[@CIT0004],[@CIT0021],[@CIT0022]^ Wallander et al. noted that HRQoL has a dual subjective--objective elements underlined by a time in one's life.^[@CIT0004]^ Children generally tend to have higher prevalence of oral conditions.^[@CIT0023]^ A review of the life stages before adulthood has not been thoroughly investigated in the broad field of OHRQoL in general and in the African context in particular.
This review will be the first to our knowledge that seeks to explore and integrate available literature on the factors influencing OHRQoL in children in the African setting. The review will provide more insight into understanding the phenomenon and to add a voice to the integrated management of children's oral conditions and the related impact on HRQoL.
Methods {#s0002}
=======
This review addresses the following question: What are the determinant factors that influence OHRQoL among children in Africa? It seeks to establish, through the available literature, factors influencing OHRQoL in children in Africa. The objective is to integrate and summarise the factors influencing OHRQoL in children diagnosed with oral conditions or problems throughout Africa. The systematic review was registered with PROSPERO number: CRD42017056759. The inclusion requirements, as shown in [Table 1](#T0001){ref-type="table"}, were followed. No publication date limit was set as this type of review has not been done before.
######
Inclusion exclusion criteria of articles in the review.
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Article characteristics Included Excluded
------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------ -----------------------------------------------------------------------------------------------------------------------------------------------
Publication type Peer-reviewed, full-text, English language articles dated till 2017 Non-English articles\
Editorials, review articles, letters, practice guidelines, other guideline documents, conference abstracts, conference reports, news articles
Study design Any study design with the measurement or assessment of OHRQoL using validated tools \-
Study population and study setting All children's studies and where mothers were used as a proxy for young children\ Any study with adult participants only\
Studies with overlap up to adulthood (e.g. 21 years) were included and the outcome referring to children only was used in the data extraction\ The study setting was not Africa
The study site was anywhere in Africa
Condition of interest Factors influencing OHRQoL Factors pertaining to dental anxiety, satisfaction and any related topic other than OHRQoL
Outcome OHRQoL using validated measures Did not use validated measures for OHRQoL
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OHRQoL, Oral health-related quality of life.
A systematic literature search of multiple databases with published English language articles in PubMed, CINAHL, EMBASE (Excerpta Medical Database), MEDLINE, EBSCOhost, OVID and PsychINFO was performed with key words: \#1 'oral health'; and \#2 'quality of life', 'health-related quality of life', 'patient-reported outcomes', 'well-being'; and \#3 'child\*', 'adolescents', 'teen\*', 'youth'; and 4\# 'determinants', 'factors', 'predictors'; and \#5 'oral health quality of life tools/instruments/scales'; and \#6 'Africa\*'.
Data synthesis {#s20003}
--------------
A multi-level search process was used starting with the screening which included an independent review of titles by three of the authors of this article (Y.M.-K., C.B.N., T.R.D.R.). This was followed by a review of abstracts and full articles selected after the abstract review. Thereafter a reference list of selected full articles was reviewed to retrieve more articles. Identified studies that met the publication criteria were grouped into one of the following categories: experimental studies, cohort studies, case control studies and cross-sectional observational studies. These studies were then assessed independently for methodological validity by three reviewers, prior to inclusion in the review, using the corresponding checklist developed by the Joanna Briggs Institute tool for cross-sectional, random controlled trials and cohort studies. Each of the tools has the components related to selection criteria, validity and reliability of exposure and outcome variables, confounders, objective measurement of outcome and appropriate statistical tests used. Any disagreements that arose between the reviewers were resolved through discussion among the three reviewers. Where required, a consensus of two out of three was the deciding factor. Following assessment of methodological quality, the papers were grouped according to whether they are quantitative, qualitative designs or opinion-based. A data extraction tool was developed specifically for quantitative research data. None of papers retrieved used qualitative study designs. Three reviewers independently performed data extraction.
Quantitative studies were classified using a table noting publication year, study setting, participants' age, sample size, study design, OHRQoL outcome and the underpinning predictors or factors or determinants, odds ratio (OR) and corresponding confidence intervals (CIs) ([Table 2](#T0002){ref-type="table"}). If more than one study reported the same factors influencing OHRQoL, the results were pooled into a statistical meta-analysis. Where statistical pooling was not possible, the findings were presented in the form of a narrative analysis. The initial step of meta-analysis was to assess the heterogeneity of the studies to be pooled. When studies were heterogeneous, a random effect model was assumed to account for unequal weighting of the studies. Heterogeneity was quantified using *I*^2^ statistic. A variation of 25% or less meant that there was a low heterogeneity of studies, 26% -- 50% meant moderate and 56% -- 75% implied high heterogeneity. Thereafter a final outcome of interest was read from ORs. Forest plots were created displaying the results from individual studies, together with the summary and 95% CI estimated in the meta-analyses. Random effect models were assumed because of the following reasons: (1) the studies had a wide age range of child participants, (2) the studies were conducted in different African countries and (3) studies used different validated tools measuring OHRQoL. Meta-analyses were conducted separately for the same factors. For instance, all studies where dental caries, area of residence, oral problems and socio-economic status (SES) were factors were analysed separately.
######
List of studies retrieved from the database search.
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Authors Publication year Study setting Facility Sample age Sample size Study design OHRQoL outcome (%) OHRQoL tool ([Box 1](#B0001){ref-type="boxed-text"})
---------------------------------------------------------------------- ------------------ ---------------------- -------------------------------- ------------------------------------ ------------- -------------- -------------------- --------------------------------------------------------
Åstrøm et al.^[@CIT0015]^ 2016 Tanzania School 12--15; 16--21 years 2412 Cohort study 50.7% OIDP
Birungi et al.^[@CIT0028]^ 2016 Uganda Community-based Mother--child pairs (5 years) 863--765 RCT 23.1 and -26.4 ECOHIS
Chukwumah et al.^[@CIT0025]^ 2016 Nigeria Local government area schools 12--15 years 1790 C-S study 56.5 C-OIDP
Tagelsir et al.^[@CIT0029]^ 2013 Sudan School 6--18 years 79 of 92 C-S study 15.9 C-OIDP
Masumo et al.^[@CIT0032]^ 2012 Tanzania and Uganda Mother and child health clinic Mother--child pairs (6--36 months) 1221 C-S study 32.5--36.5 ECOHIS
Mbawalla et al.^[@CIT0007]^ 2011 Tanzania School 12--17 years 2678 C-S study 39.65 C-OIDP
Nurelhuda et al.^[@CIT0030]^ 2010 Sudan School 12 years 1109 C-S study 54.6 C-OIDP
Mashoto et al.^[@CIT0031]^ 2009 Tanzania School 10--14; 15--19 years 2465 C-S study 36.2 OIDP
Mtaya et al.^[@CIT0008]^ 2007 Tanzania School 13 years 1601 C-S study 28.6 C-OIDP
Åstrøm and Okullo^[@CIT0016]^ 2003 Uganda \- 13--15; 16--19 years 1146 C-S study 62 OIDP
Mashoto et al.^[@CIT0024]^[†](#TFN0001){ref-type="table-fn"} 2010 Tanzania School 10--14; 15--19 years 1306 RCT 35.6 C-OIDP
Hobdell et al.^[@CIT0026]^[†](#TFN0001){ref-type="table-fn"} 2009 South Africa, UK, US Schools 15--16; 11--12; 40+ years 525 C-S study SA: 49.5\ OIDP
US: 52.6\
UK: 28.8
Wandera et al.^[@CIT0027]^[†](#TFN0001){ref-type="table-fn"} 2009 Uganda Mother and child health clinic Mother--child pairs (6--36 months) 816 C-S study Child : 37.7\ ECOHIS
Family: 47.1
Robinson et al. (2005)^[@CIT0060]^[†](#TFN0001){ref-type="table-fn"} 2005 Uganda School 12 years 174 C-S study Sum: 39.9 CPQ~11--14~
Åstrøm and Mashoto^[@CIT0014]^[†](#TFN0001){ref-type="table-fn"} 2002 Tanzania School 12--20 years 492 C-S study \- OIDP\
Dissatisfaction (oral condition and dental appearance)
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
UK, United Kingdom; US, United States
, Excluded from meta-analysis but included in narrative analysis.
C-S, cross-sectional study; RCT, randomised controlled trial; OHRQoL, oral health-related quality of life; OIDP, Oral Impacts on Daily Performances; C-OIDP, Child-Oral Impacts on Daily Performances; ECOHIS, Early Childhood Oral Health Impact Scale; CPQ~11--14~, Child Perceptions Questionnaire.
Ethical considerations {#s20004}
----------------------
Ethical approval was obtained from the Human Research Ethics Committee of the University of the Witwatersrand (Clearance certificate no. M141150).
Results {#s0005}
=======
A total of 337 articles were retrieved from all databases. Following identification and screening, only 15 articles were assessed for eligibility ([Figure 2](#F0002){ref-type="fig"}). Of the 15 eligible articles, four were excluded from the narrative or meta-analysis despite using validated OHRQoL tools because they did not perform regression analysis to report on the factors influencing OHRQoL.^[@CIT0024],[@CIT0025],[@CIT0026],[@CIT0027]^ The regression analysis was crucial to ascertain the likelihood of independent variables influencing OHRQoL. One article was also excluded because it reported ORs, but the OHRQoL was not the dependant variable in the regression model but the presence or absence of dental fluorosis.^[@CIT0014]^ The study reported dissatisfaction with oral condition (dental fluorosis) and appearance as the outcome in the logistic regression instead of OHRQoL.^[@CIT0014]^ Finally, only 10 articles were included for analysis.
{#F0002}
Characteristics of the studies finally included in the review {#s20006}
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The main characteristics of the studies in the review are shown in [Table 2](#T0002){ref-type="table"}. All of the 10 studies used validated tools to measure OHRQoL outcomes ([Box 1](#B0001){ref-type="boxed-text"}). All studies were quantitative in design; nine were conducted in the East African region (Tanzania, Uganda and Sudan); they were also similar in sharing the same authors or co-authors.^[@CIT0007],[@CIT0008],[@CIT0015],[@CIT0016],[@CIT0025],[@CIT0028],[@CIT0029],[@CIT0030],[@CIT0031]^ Only one study was conducted in West Africa (Nigeria).^[@CIT0025]^ The study designs were biased towards cross-sectional studies with eight out of 10 (80%) using that design. The measure of association of interest was OR and the related CIs.
######
Studies that used validated tools measuring oral health-related quality of life.
Family Impact Scale (FIS) (Locker et al. 2002)^[@CIT0061]^Child Perceptions Questionnaire (CPQ~6--7~); (CPQ~8--10~) and (CPQ~11--14~) (Jokovic et al. 2004a; Jokovic et al. 2004b; Jokovic et al.2002)^[@CIT0062],[@CIT0063],[@CIT0064]^Child-Oral Impacts on Daily Performances (Child-OIDP) (Gherunpong et al. 2004)^[@CIT0065]^Early Childhood Oral Health Impact Scale (ECOHIS) (Pahel et al. 2007)^[@CIT0066]^
Note: With reference to [Table 2](#T0002){ref-type="table"}.
Factors influencing oral health-related quality of life where studies were fitted into forest plots for meta-analysis {#s20007}
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### Dental caries {#s30008}
Six studies in this review reported the presence of dental caries as a factor influencing OHRQoL.^[@CIT0007],[@CIT0015],[@CIT0025],[@CIT0030],[@CIT0031],[@CIT0032]^ Four of the studies were performed in Tanzania with a total of 7617 children and they reported the variable dental caries experience measured by DMFT/dmft (Decayed Missing Filled Teeth/decayed missing filled teeth) index. In both primary and secondary dentition, the caries index ranged from being 1.5 times more likely to up to 5.2 times more likely to lead to a poorer OHRQoL among children. Studies based in the Sudan and Uganda reported mid-range ORs of 2.0 (95% CI: 1.4--2.6) and 1.8 (95% CI: 1.2--3.0), respectively (*n* combined = 1874) ([Figure 3](#F0003){ref-type="fig"}).
{#F0003}
Dental caries, when fitted for meta-analysis, showed an overall high level of influence with regard to OHRQoL in total combined studies of 9491 child participants. However, the results of the *I*^2^ statistics showed that the studies were heterogeneous (88%, *p* = 0.000) ([Figure 2](#F0002){ref-type="fig"}). This implies that the studies cannot be pooled because of high heterogeneity. Even though studies all used validated OHRQoL ([Table 2](#T0002){ref-type="table"}), responses are still subjective heterogeneity and the overall conclusion from meta-analysis is explained later in the discussion.
### Oral conditions other than dental caries {#s30009}
Mashoto et al. in their Tanzanian study reported, with a total of 1745 children with a mean age of 13.8 years (s.d. 1.67), that having any oral condition other than dental caries increased the odds of a poorer OHRQoL (OR: 3.8, 95% CI: 2.8--5.2).^[@CIT0031]^ The results were the same as those of Mtaya et al. in Tanzania (*n* = 387) (OR: 3.9, 95% CI: 2.9--5.2).^[@CIT0008]^ These authors, using the Child-OIDP validated tools ([Table 2](#T0002){ref-type="table"}), suggested that the oral problems were stronger influencers than other dimensions in the OHRQoL tool used, such as emotional and social well-being.^[@CIT0008],[@CIT0031]^ When these studies were included in the meta-analysis, having oral problems (excluding dental caries) was still a factor likely to influence OHRQoL among children ([Figure 3](#F0003){ref-type="fig"}). Both the *I*^2^ test for heterogeneity favoured homogeneity of the studies (0.0%, *p* = 0.9) ([Figure 4](#F0004){ref-type="fig"}).
{#F0004}
### Socio-economic status {#s30010}
From the only longitudinal study in the review, with a sample of 2412 children in Tanzania, the authors concluded that an SES was 2.3 times more likely (95% CI: 1.12--4.78) to result in poorer OHRQoL ([Figure 4](#F0004){ref-type="fig"}), both used C-OIDP and OIDP tools ([Table 2](#T0002){ref-type="table"})^[@CIT0015]^ Åstrøm et al. concluded that having parents who could afford dental care was a significant predictor of positive OHRQoL. Equally, in 2010 Nurelhuda et al. in their Sudanese study (*n* = 1109) found that SES, albeit in a cross-sectional study, was 1.9 times more likely (95% CI: 1.1--1.3) to influence OHRQoL.^[@CIT0015],[@CIT0030]^ Meta-analysis of the two studies was displayed in the forest plot and supported the fact that a higher SES is 2.03 times more likely to influence OHRQoL outcomes ([Figure 5](#F0005){ref-type="fig"}).
{#F0005}
### Area of residence {#s30011}
The Tanzanian and Ugandan studies found the area of residence (district, rural and urban) to influence children's oral HRQoL.^[@CIT0008],[@CIT0016]^ Nurelhuda et al. reached a similar conclusion in the Sudanese study.^[@CIT0030]^ The meta-analysis of these studies, with a combined sample of 3202 participants, supported the notion that the area or residence is a significant predictor of OHRQoL ([Figure 6](#F0006){ref-type="fig"}).
{#F0006}
### Satisfaction with oral health {#s30012}
In the Sudanese and Tanzanian studies those children who were satisfied with their oral health status were less likely to report lower OHRQoL using the Child-OIDP tool (OR: 0.4, 95% CI: 0.3--0.6).^[@CIT0008],[@CIT0030]^ However, the studies demonstrated moderate heterogeneity and the meta-analysis yielded contrasting findings. The overall effect was not significant with OR = 0.87 (95% CI: 0.19--4.00) with equal weighting of the studies ([Figures 7](#F0007){ref-type="fig"}--[9](#F0009){ref-type="fig"}).
{#F0007}
{#F0008}
{#F0009}
### Dental attendance and gingival infection {#s30013}
Both dental attendance and gingival infection were identified by Mtaya et al., Mashoto et al. and Nurelhuda et al. as factors influencing OHRQoL in their Tanzanian and Sudanese samples, respectively.^[@CIT0008],[@CIT0030],[@CIT0031]^ The meta-analysis and pooling of results did not support their argument. Dental attendance had an overall effect of 1.30 (0.48--3.50), while gingival infection had an overall effect of 1.40 (0.88--2.24) ([Figures 7](#F0007){ref-type="fig"}--[9](#F0009){ref-type="fig"}).
Seven more reported factors influencing oral health-related quality of life {#s20014}
---------------------------------------------------------------------------
Four studies, in addition to reporting factors similar to each other, also reported individual factors that were not cited by any other authors in this review. In the Sudan, among the visually challenged school attendants, it was found that *visual impairment* (*n* = 79, OR: 6.3, 95% CI: 1.7--22.7 \[Results are significant\]) significantly influenced OHRQoL.^[@CIT0029]^ *Low self-efficacy* (*n* = 610, OR: 0.41, 95% CI: 0.19--0.89 \[Results are significant; paper was included in meta-analyses\]) and *depressed mental status n* = 428. OR: 3.23 (95% CI: 1.37--7.63 \[Results are significant\]) (paper was included in meta-analyses) were reported to be significant predictors of OHRQoL in the secondary schools learners in Tanzania.^[@CIT0015]^ A Ugandan study by Åstrøm and Okullo cited that *religious affiliation* (*n* = 256, OR: 0.5, 95% CI: 0.3--0.9 \[Results are significant; paper was included in meta-analyses\]) and *missing teeth* (*n* =372, OR: 1.8, 95% CI: 1.0--3.2 \[Results are significant; paper was included in meta-analyses\]) significantly influenced the OHRQoL of adolescents using the OIDP tool, and were significantly influenced by OHRQoL instead.^[@CIT0015],[@CIT0016],[@CIT0030]^
Of interest is that a study conducted among the Sudanese sample of 12-year-old school attendees showed a significant association between OHRQoL and behavioural factors, such as irregular tooth brushing and eating sugar sweetened snacks. ^\[[@CIT0016],[@CIT0030]\]^ The findings included *tooth brushing frequency (irregular)* (OR: 1.0, 95% CI: 0.6--1.7), *plaque index* (*n* = 1045, OR: 1.3, 95% CI: 0.9--1.8) and *sugar sweetened snack intake* (*n* = 1045, OR: 1.4, 95% CI: 0.9--1.8), respectively.
Discussion {#s0015}
==========
This systematic review is the first aimed to critically analyse the factors influencing OHRQoL in African child populations. Oral health-related quality of life outcomes are usually assessed by measurement tools based on a conceptual framework which postulates that individual factors (demographic, personal biological and psychological status) and environmental factors (SES, dental access, caregivers status, education, type of residence and utilisation, and more) influence general health perceptions and the overall OHRQoL as postulated by Ferrens et al.^[@CIT0020]^
All 10 articles included studies that used validated tools to measure OHRQoL in children ([Table 2](#T0002){ref-type="table"}). The studies used good methods with regard to selection criteria of participants, validity and reliability of exposure and outcome variables as objectively assessed by the review involved (Y.M.-K., C.B.N., and T.R.D.R.). There was also a predisposition towards cross-sectional study designs in the studies selected. Cross-sectional studies cannot determine causality but only associations. However, these associations were rigorously determined especially when studies adjusted for confounders using regression analysis. Longitudinal studies including randomised controlled trials are obviously preferred as these designs have the potential to follow up on the exposure variable and can be used to determine causality.
The bias of studies towards East Africa could be attributed to one key author who contributed to eight of the 10 articles. The reason could be that the field on OHRQoL in dentistry is still at its development stage in Africa and the author is an expert author in the field.
*Dental caries*, the most common dental condition that affects 60% -- 90% of school-aged children, in children more often results in pain and functional limitation.^[@CIT0031]^ Thus, pain from severe dental decay can exert an impact on OHRQoL.^[@CIT0033]^ The analysis in this review revealed an unexpected result regarding dental caries where it was not conclusively a factor that influenced OHRQoL. The result may be described by several explanations. Firstly, there was a high level of variation in the studies that reported on dental caries as a factor influencing OHRQoL. Heterogeneity in the studies within a systematic review is expected because a review combines studies that may be methodologically diverse; hence, it is more important to determine the extent to which heterogeneity affects the conclusions to the studies.^[@CIT0034]^ A high percentage of *I*^2^ statistic (\> 75%) indicates that there is an increased level of variability among the studies that could be because of the differences in their OHRQoL tools, studies adjusting for different confounders as well as the high number of studies included in meta-analysis which increases the percentage of the *I*^2^ statistic.^[@CIT0035]^ Although all tools used were validated in the study settings, two tools (Child-OIDP and OIDP)^[@CIT0007],[@CIT0015],[@CIT0025],[@CIT0030],[@CIT0031],[@CIT0032]^ were used where dental caries was reported to be a factor. Secondly, the heterogeneity could be attributed to the subjective nature of the design of OHRQoL tools that may be affected by cultural variation and differences in these East African countries. Thirdly, reporting of caries experience through DMFT/dmft without severity does not factor the element of pain. Indices such as Pulpal involvement, Ulcerations, Fistula and Abscess (PUFA) index do factor in the pain element, and thus may be useful in OHRQoL measurements.^[@CIT0036]^ Fourthly, the DMFT/dmft index measures caries experience and is diluted by the filled and missing components related to treatment. It would be preferable for the analysis to single out the DMFT/dmft component to assess the active decay status when association analysis is performed. Lastly, the East African region is characterised by high fluoride content in the water source which makes teeth mottled and prone enough to initiation of dental caries, but the lesions are not severe because of the protective nature of fluorosis teeth.^[@CIT0037]^
Dental caries was reported as a predictor of pain only if the prevalence and severity is high which tends to be common in the poorer communities who consume more refined carbohydrates diet as is common in South Africa.^[@CIT0023]^ A Norwegian study by Koposovo et al. also supports the notion that the impact of dental caries on OHRQoL can be weak, and they attribute this finding to low general prevalence of caries in their Norwegian adolescent population.^[@CIT0038]^
*Oral conditions other than dental caries* were a significant determinant of OHRQoL in this systematic review. These oral conditions maybe gingival or mucosal conditions, related to aesthetics or dental treatments. This is plausible as OHRQoL dimensions include pain, functional, psychological or emotional factors as well the social impacts. Malocclusion, which is an oral problem where there is misalignment or an incorrect relationship between the two dental arches, may result in aesthetic and functional problems. This is more likely to lead to a self-perceived treatment need which is common in malocclusion cases. It heightens the way the children perceive their own oral health. The children tend to have a worsened OHRQoL when they perceive that they ought to receive treatment, a perception that is shaped by the societal expectations. Appearance, which is affected in malocclusion cases, is very important in children's lives particularly as they approach puberty. The notion is supported by Koposova et al.'s study in Europe among 12-year-olds where it was concluded that dental aesthetics was found to influence their OHRQoL.^[@CIT0038]^
*Socio-economic status* measured by attending private versus public school was found to play an important role in influencing OHRQoL in the review. A higher SES may result in preventive visits and better access to dental health services and, thus, is likely to result in improved dental health, no pain, no early extraction and resulting malocclusion and a better OHRQoL. Thus, a better SES increases access to aesthetic services and may possibly influence the non-clinical dimensions (behavioural and social) of OHRQoL. Issues such as missing teeth, early extraction and later malocclusion are averted early, and thus improve oral health perceptions of adolescents. This finding in this review is congruent with literature where parents' low-income is closely related to the availability of resources and children from low-income families are likely to have a lower OHRQoL.^[@CIT0039],[@CIT0040]^ In addition, the study among 12-year-olds in Norway and Russia reported a poorer OHRQoL for the less privileged Russian children than their Norwegian counterparts.^[@CIT0038]^ Furthermore, a study of 12-year-old Thai children of low socio-economic status found that they were likely to have a high level of dental caries with subsequent negative OHRQoL impact.^[@CIT0041]^ So, this review in the African setting characterised by low-income countries with few resources also confirmed that resources will invariably influence OHRQoL. These findings highlight the context-related dimensions of most OHRQoL frameworks. Unfavourable social conditions and poor SES have a negative impact on children's OHRQoL.^[@CIT0042]^ Locker states that in the Canadian study, low SES scored worse than high SES.^[@CIT0043]^
There was evidence linking *area of residence* with negative outcomes on OHRQoL in African child populations from this review. Mtaya et al. and Åstrøm and Okullo,^[@CIT0008],[@CIT0016]^ in their Tanzanian and Ugandan studies, found the area of residence (rural vs. urban) to influence children's OHRQoL.^[@CIT0006],[@CIT0016]^ Nurelhuda et al. reached a similar conclusion in their Sudanese study.^[@CIT0030]^ Rural districts tend to have poor availability and less access to dental facilities. Reduced access is likely to result in less preventive and curative services which might affect OHRQoL outcomes on various levels such as pain, functional and psychological impact. Children in urban dwellings tended to have or report better OHRQoL outcomes because of socio-demographic characteristics such as better parental education.^[@CIT0008]^ One can argue that SES will be a mediating factor to the area (urban or rural) where children reside. If both factors have a strong relationship with the dependant variable, then there is a chain of risk factors that an even worse-off outcome regarding OHRQoL may prevail.^[@CIT0044]^
*Satisfaction with oral health* is likely to result in a good self-rating on oral health and it is influenced by attitudes towards oral health. The result from this review showed moderate heterogeneity, and meta-analysis showed that this factor did not influence OHRQoL from the only two studies in the review. Satisfaction with oral health usually results from the individual's attitudes; these attitudes are shaped by socialisation and context. In contrast, studies conducted outside Africa from literature have shown that oral health perceptions and attitudes of the caregiver or parents and of children themselves can influence the OHRQoL in children.^[@CIT0033],[@CIT0045]^ Shaghaghian et al. reported that parental attitude to children's oral hygiene habits influences children's oral health status and their OHRQoL.^[@CIT0045]^ Gomes et al. conclude that those caregivers who viewed their children's oral health as poor were more likely to report a greater impact on OHRQoL.^[@CIT0033]^ Different children in different geographical areas such as Saudi Arabia, Brazil and the United Kingdom responded differently especially on the social well-being and emotional well-being constructs of OHRQoL instruments, despite the translation and adaptation of the tool.^[@CIT0046],[@CIT0047],[@CIT0048],[@CIT0049]^ The difference can be explained by embedded cultural influences. It is for this reason that the development of a conceptual equivalence of OHRQoL measurement tools is recommended before it can be used in settings different from those in which it originated.^[@CIT0009]^
More factors influencing oral health-related quality of life {#s20016}
------------------------------------------------------------
*Physical handicap such as visual impairment* will impart an element of physical limitation, thus it may result in restrictive action and lack of visual--manual coordination. Despite the low sample in the reviewed study, of note among these visually impaired school attendees, those who were boarders had a poorer oral hygiene compared with non-boarders. Therefore, lack of assistance and supervision by caregivers may have mediated the resulting poorer oral hygiene. Less or no assistance with oral hygiene practices (e.g. toothbrushing and use of mouth guards) may thus lead to poor oral health states such as poor oral hygiene and traumatic dental injuries. A poor oral health status and the associated oral conditions may cause a negative reporting on OHRQoL.^[@CIT0029]^ Irregular toothbrushing among the 12-year-old non-visually disabled Sudanese children in a similar setting did, however, not lead to a poor OHRQoL, perhaps the traumatic injures carried more weight in the OHRQoL reporting rather limited manual--visual brushing coordination.^[@CIT0030]^
*Mental status is closely related to perception of self*; if individuals have less confidence and suffer from *depression* then their attitudes are generally negative.^[@CIT0050]^ The reporting of OHRQoL is subjective in nature, thus the psychological dimension of the OIDP tool used among the Tanzanian school learners carried more weight than the clinical factors because of their depressive symptoms.^[@CIT0015]^ The authors caution against a conclusion based on the mediating factor related to dental care utilisation, which was generally poor in the Tanzanian setting. However, a prerequisite for good oral health behaviour is self-efficacy to, for example, use floss, regular brushing and proper diet, according to the theory of planned behaviour.^[@CIT0051]^ Self-efficacy may be lacking in the depressive states situations.
*Behavioural factors such as poor dietary habits and irregular brushing* on their own failed to make an impact on these African child populations; however, they may be mediated by the level of adolescents' self-efficacy^[@CIT0015]^ or by assistance or support in self-care.^[@CIT0029]^ Socio-economic status is an important mediator or moderator in this instance because it will increase the dental attendance patterns and enhance preventive behaviour.
*Religion* such as reporting being Muslim was an important factor in the Ugandan adolescent sample as they were less likely to report oral impacts.^[@CIT0016]^ Religion and spirituality are rarely reported in the health-related patient-reported outcomes. O'Connell and Skevington pointed out in their review that when the idea of spiritually is visited, it is usually as part of the social or psychological phenomenon of HRQoL outcomes and not a stand-alone dimension. Not enough is reported about religion, and it tends to be a salient concept in the OHRQoL.^[@CIT0052]^
The issue of a *child's age* as a determinant factor did not come up in the African studies in this systematic review, although Barbosa and Gaviao argue that the child's age, development and gender influence and affect their well-being.^[@CIT0053]^ Studies included in the review did adjust for age and gender, and in both instances there were no significant predictors. Except for two studies that used caregiver reports, most used adolescents groups of comparable ages ([Table 2](#T0002){ref-type="table"}). Genderson et al. argues that the issue of self-concept is age-dependent and is heightened and important during adolescence because oral health is 'strongly age-dependent',^[@CIT0054]^ hence there are differences between children and adults in OHRQoL measures.^[@CIT0055]^
*Dental utilisation and access* did not influence OHRQoL in this review when results were pooled; this is in contrast to the Indian study by Kumar et al. which found that OHRQoL was better for participants who had been to the dentist within the past 12 months.^[@CIT0056]^ Dental utilisation increases when dental access is enhanced. However, unlike in Kumar et al.'s^[@CIT0056]^ Indian study, it was surprising in the Ugandan study that there was an inverse relationship where higher utilisation led to poorer OHRQoL reports.^[@CIT0016]^ Nonetheless, following pooling the results in the meta-analysis, dental utilisation was not an influencing factor in this review. Introduction of free primary services in other African settings has shown the increased work operator load experience and thus poor services.^[@CIT0057]^ In Uganda, the Lira District has a free user-fee policy for a public oral service in place. User-free policies may lead to poor services, thus affecting OHRQoL directly as the perceptions are rated by experience during dental visits.
A key finding in the articles reviewed was that factors influencing OHRQoL in children were environmental in nature (family SES and area of residence), but depended on the individual biological status and symptoms from oral problems. These oral problems, however, did not include dental caries, the most common oral condition. When assessing the findings against the Ferrans et al.^[@CIT0020]^ and Sischo and Broder's^[@CIT0013]^ conceptual frameworks on OHRQoL, individual characteristics pertained only to the biological status and not the demographic factors. Sischo and Broder's framework goes further to unpack the individual characteristics ([Figure 1](#F0001){ref-type="fig"}).^[@CIT0013],[@CIT0020]^ There seems to be congruence with the Sischo and Broder explanation of the framework in this African setting where oral medical condition, psyche status (low self-efficacy and depressive states) and physical disability of the children were the significant individual factors to influence. However, the environmental issues arising from the review were the area of residence and SES only. The parent or caregiver status was implied by the family's SES status.
The factors in the review were balanced between the environmental and individuals' oral problems, but the pathway did not necessarily fit the models ([Figure 1](#F0001){ref-type="fig"}). Overall perceptions with oral health were not evident. Other factors such as oral health behaviour, perception or satisfaction with oral health and dental access were significant in other settings in high-income countries but not evident in the African setting. This may be related to contextual importance of factors or perhaps these factors were reported by few studies.^[@CIT0058]^ It is evident from the review that the OHRQoL measurement tools do not tease out in the setting what is reported in high-income country settings. The form and degree of impacts could vary between populations with different cultural backgrounds.^[@CIT0059]^ The question is: How are issues framed and from whose point of view that they fail to capture or be relevant in the setting?
Moreover, these systematic review findings are in contrast with the Locker model of OHRQoL, which suggests that mainly physical symptoms and functional limitation dimensions will carry weight rather than environmental dimensions in influencing OHRQoL.^[@CIT0019]^ The biomedical Locker model hypothesised that oral disease will result in 'pain', 'impairment' and functional limitation. These constructs will, in turn, lead to physical and psychological disability, handicap, and thus affect the overall OHRQoL.^[@CIT0019]^ Thus, in this African setting context the contributing factors spanned the socio-environmental context in nature and biomedical dimensions.
Oral health-related quality of life does not exist in a vacuum, but is influenced by interplay of socio-economical, biological and personal psychosocial factors. Herdman et al. argue convincingly that cross-cultural adaptation is warranted as it guards against automatic assumptions that OHRQoL domains important to one culture will be equally relevant in all cultures.^[@CIT0009]^ Comprehension of this interplay will begin a process to assess the OHRQoL impacts, hence the importance of studying the factors of OHRQoL. Understanding influencing factors will assist in planning so that measures to reduce OHRQoL impacts are incorporated in the integrated management of children's oral health in Africa.
Limitations {#s20017}
-----------
Mostly cross-sectional studies were retrieved from this review given that research into OHRQoL is fairly recent in Africa. However, data analysis included accounting for possible confounders when looking for associated factors related to OHRQoL in children. The reporting of ORs implied that authors dichotomised the OHRQoL outcome describing the absence or presence of a negative impact. Reporting the presence of OHRQoL impacts in binary form makes it impossible to see the intensity of the OHRQoL impacts.
Conclusion {#s0018}
==========
There is preliminary evidence to suggest that in Africa there is an association between individual factors such as children's psyche and oral problems, excluding dental caries, and contextual social determinants such as area of residence and SES and children's OHRQoL in African contexts. Thus, in this African setting context the contributing factors spanned the socio-environmental context in nature and biomedical dimensions. There seemed to be a contextual viewpoint underpinning the current OHRQoL frameworks and OHRQoL was context-reliant.
There is evidence of rigorous work in the field of OHRQoL in Africa. However, most literature is dominated by quantitative prevalence studies. More work in qualitative and longitudinal studies can assess causality in this field in the setting to see if factors related to OHRQoL are context-reliant.
The authors would like to acknowledge all the support from the Faculty of Health Science and the School of Oral Health Sciences at Wits University. In addition, the first author Y.M.-K. is a PhD candidate and a Consortium for Advanced Research Training in Africa (CARTA) fellowship recipient. This systematic review was supported by the CARTA, which is jointly led by the African Population and Health Research Center and the University of the Witwatersrand.
Competing interests {#s20019}
===================
The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.
Authors' contributions {#s20020}
======================
Y.M.-K., the project leader, conceptualised the article; searched databases, undertook the critical appraisal and data synthesis of papers included in the review data collection, analysis and discussion synthesis of the review. V.Y. supported the data analysis and synthesis with discussion. J.I. supported conceptualisation, analysis and synthesis with discussion. C.B.N. and T.R.D.R. were responsible for database search, critical appraisal and data synthesis of papers included in the review. All authors read and approved the final manuscript.
Funding information {#s20021}
===================
This study was funded by the Wellcome Trust (UK) (Grant no.: 087547/Z/08/Z), the Carnegie Corporation of New York (Grant no.: B 8606.R02) and Sida (Grant no.: 54100029).
Data availability statement {#s20022}
===========================
Data sharing is not applicable to this article as no new data were created or analysed in this study.
Disclaimer {#s20023}
==========
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.
**How to cite this article:** Malele-Kolisa Y, Yengopal V, Igumbor J, Nqcobo CB, Ralephenya TRD. Systematic review of factors influencing oral health-related quality of life in children in Africa. Afr J Prm Health Care Fam Med. 2019;11(1), a1943. <https://doi.org/10.4102/phcfm.v11i1.1943>
| 2023-08-18T01:26:51.906118 | https://example.com/article/6086 |
--
-- This file and its contents are supplied under the terms of the
-- Common Development and Distribution License ("CDDL"), version 1.0.
-- You may only use this file in accordance with the terms of version
-- 1.0 of the CDDL.
--
-- A full copy of the text of the CDDL should have accompanied this
-- source. A copy of the CDDL is also available via the Internet at
-- http://www.illumos.org/license/CDDL.
--
--
-- Copyright (c) 2016 by Delphix. All rights reserved.
--
-- This program should work with LUAI_MAXCCALLS=20
i = 0
if true then
if true then
if true then
if true then
if true then
if true then
if true then
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i = i + 1
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i = i + 1
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i = i + 1
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i = i + 1
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i = i + 1
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i = i + 1
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i = i + 1
end
i = i + 1
end
i = i + 1
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i = i + 1
end
return i
| 2024-04-07T01:26:51.906118 | https://example.com/article/8182 |
Balakrishna's 100th Movie " Gautamiputra Satakarni " Shooting Began
Tollywood's Legendary Actor Balakrishna has began the shoot of his 100th film "GautamiputraSatakarni" Some sources revealed that the story is based on the life of the Andhra ruler who is said to have ruled over, mainly vast parts of southern India.
Telangana Chief Minister K Chandrasekhar Rao, Megastar Chiranjeevi, Venkatesh and a host of prominent personalities from the world of film and politics attended the Muhurtham event of the film.
Chiranjeevi expressed his confidence on director Krish & added that Balakrishna is going to create a history with his 100th film.
Seeing Legendary Chiranjeevi, Venkatesh and Balakrishna on same stage, the audiences were very happy & it was also a great moment for their respective fans! | 2024-04-09T01:26:51.906118 | https://example.com/article/6619 |
Performance Bugs (2011) [video] - AndreyKarpov
https://www.youtube.com/watch?v=89qiHoDjeDg
======
nodesocket
Really good talk. In today's modern web apps the most common types of
performance bugs tend to be either external http requests (buried inside of
APIs that often times you're not even aware of the multiple round-trips), or
inefficient DB queries (mostly thanks to abstractions by ORM's). There are
exceptions, but in most typical modern web apps performance bugs live in i/o
and network calls, not in native code.
| 2024-06-04T01:26:51.906118 | https://example.com/article/9036 |
#import <Foundation/Foundation.h>
#import "sqlite3.h"
#ifndef __has_feature // Optional.
#define __has_feature(x) 0 // Compatibility with non-clang compilers.
#endif
#ifndef NS_RETURNS_NOT_RETAINED
#if __has_feature(attribute_ns_returns_not_retained)
#define NS_RETURNS_NOT_RETAINED __attribute__((ns_returns_not_retained))
#else
#define NS_RETURNS_NOT_RETAINED
#endif
#endif
@class FMDatabase;
@class FMStatement;
@interface FMResultSet : NSObject
{
FMDatabase *parentDB;
FMStatement *statement;
NSString *query;
NSMutableDictionary *columnNameToIndexMap;
BOOL columnNamesSetup;
}
+ (id)resultSetWithStatement: (FMStatement *)statement usingParentDatabase: (FMDatabase *)aDB;
- (void)close;
- (NSString *)query;
- (void)setQuery: (NSString *)value;
- (FMStatement *)statement;
- (void)setStatement: (FMStatement *)value;
- (void)setParentDB: (FMDatabase *)newDb;
- (BOOL)next;
- (BOOL)hasAnotherRow;
- (int)columnIndexForName: (NSString *)columnName;
- (NSString *)columnNameForIndex: (int)columnIdx;
- (int)intForColumn: (NSString *)columnName;
- (int)intForColumnIndex: (int)columnIdx;
- (long)longForColumn: (NSString *)columnName;
- (long)longForColumnIndex: (int)columnIdx;
- (long long int)longLongIntForColumn: (NSString *)columnName;
- (long long int)longLongIntForColumnIndex: (int)columnIdx;
- (int64_t)int64ForColumn: (NSString *)columnName;
- (int64_t)int64ForColumnIndex: (int)columnIdx;
- (BOOL)boolForColumn: (NSString *)columnName;
- (BOOL)boolForColumnIndex: (int)columnIdx;
- (double)doubleForColumn: (NSString *)columnName;
- (double)doubleForColumnIndex: (int)columnIdx;
- (NSString *)stringForColumn: (NSString *)columnName;
- (NSString *)stringForColumnIndex: (int)columnIdx;
- (NSDate *)dateForColumn: (NSString *)columnName;
- (NSDate *)dateForColumnIndex: (int)columnIdx;
- (NSData *)dataForColumn: (NSString *)columnName;
- (NSData *)dataForColumnIndex: (int)columnIdx;
- (NSNumber *)numberForColumn: (NSString *)columnName;
- (NSNumber *)numberForColumnIndex: (int)columnIdx;
- (const unsigned char *)UTF8StringForColumnIndex: (int)columnIdx;
- (const unsigned char *)UTF8StringForColumnName: (NSString *)columnName;
/*
If you are going to use this data after you iterate over the next row, or after you close the
result set, make sure to make a copy of the data first (or just use dataForColumn:/dataForColumnIndex:)
If you don't, you're going to be in a world of hurt when you try and use the data.
*/
- (NSData *)dataNoCopyForColumn: (NSString *)columnName NS_RETURNS_NOT_RETAINED;
- (NSData *)dataNoCopyForColumnIndex: (int)columnIdx NS_RETURNS_NOT_RETAINED;
- (BOOL)columnIndexIsNull: (int)columnIdx;
- (BOOL)columnIsNull: (NSString *)columnName;
- (void)kvcMagic: (id)object;
- (NSDictionary *)resultDict;
- (id)objectForColumnIndex: (int)columnIdx;
- (id)objectForColumnName: (NSString *)columnName;
@end
| 2024-05-17T01:26:51.906118 | https://example.com/article/2048 |
Minnesota Had No Answer For The Big Kiwi
By: A. Suave Francisco
If you would've heard that Oklahoma City's Steven Adams would outscore Russell Westbrook and Carmelo Anthony combined in a game against the (13-9) Minnesota Timberwolves, you'd probably bet your pocket that the (8-12) Thunder lost that game.
Well, hopefully, you didn't place that bet because Steven Adams finished Friday night's game with 27 points, on a perfect 11-of-11 shooting.
Russell Westbrook played the facilitator role, only notching 15 points, but almost equally getting assists with 14 and nine rebounds. Carmelo Anthony didn't have a bad game by any means, but he didn't shoot the ball as much, just 4-of-7 for 9 points on the night.
Westbrook and Anthony, two very ball-dominant players, sacrificed their individual games for Adams at an early juncture in which they saw a monumental mismatch in the paint.
Early in the game, Karl Anthony-Towns and Andre Roberson butted heads, which landed them in the locker room to get stitches. Adams used that time to use and abuse Minnesota's front-court while Towns was getting attended to, scoring 9 points in the first period.
Nothing changed when Towns re-entered the game. By the second quarter, Adams built his confidence to the point where no one on the T-Wolves could out-play or out-hustle him. Towns' energy level simply never matched Adams'.
Adams having the game he had opened things up on the perimeter, due to the focus being on him. Paul George was the player that benefitted the most. Notching a game-high 36 points, George was getting more uncontested shot attempts than he has all season and shot an impressive 5-of-9 from long distance. Not to mention, his 11-of-11 shooting from the free-throw line.
Oklahoma City fans had to be satisfied with the way OKC's star-power sacrificed their game for the betterment of the team and seeing the bigger picture. Forgoing a high scoring night because of a clear mismatch.
Regardless the outcome of Friday night's game, Oklahoma City has to play the (15-7) San Antonio Spurs on Sunday evening. In OKC lost their first game against the Spurs, 104-101 in another comeback effort by an opponent. Steven Adams finished with 16 points on 6-of-8 shooting, so maybe he can use this game as a confidence builder and capitalize on any potential matchup advantages on Sunday. | 2024-01-09T01:26:51.906118 | https://example.com/article/9764 |
The spectrum of endocrinocarcinomas of the larynx.
The authors discuss the terminology, classification, pathology, diagnosis, treatment and prognosis of the endocrinocarcinomas of the larynx. | 2023-08-14T01:26:51.906118 | https://example.com/article/9637 |
Introduction {#s1}
============
Overactive bladder symptom complex (OABS) is one of the most frequently encountered urological disorders. In the western world, the number of people suffering from OABS has been evaluated at almost 100 million (Stewart et al., [@B82]; Irwin et al., [@B51]; Hashim and Abrams, [@B48]). The complex is defined as a medical condition encompassing urgency, increased daytime frequency, nocturia and urgency urinary incontinence (i.e., involuntary loss of urine associated with urgency) either isolated or in any combination (Abrams et al., [@B3]). Although this is not considered as a severe health condition, it has a significant impact on personal autonomy, self-esteem, quality of life, quality of sleep and mental health and it creates an enormous economic burden (Irwin et al., [@B51]; Onukwugha et al., [@B72]).
Nowadays, the first line treatment for OABS relies on the application of antimuscarinic drugs (Madhuvrata et al., [@B61]; Veenboer and Bosch, [@B90]). The second line therapies include botulinum toxin injection into the detrusor muscle (Chapple et al., [@B24]; Nitti et al., [@B69]; Mangera et al., [@B62]; Giannantoni et al., [@B39]), sacral neuromodulation (Peters et al., [@B75], [@B74]; Sukhu et al., [@B85]) or invasive surgical interventions such as an augmentation cystoplasty (Reyblat and Ginsberg, [@B76]). However, these therapeutic interventions are only effective in a subset of patients and their effectiveness is limited in the remainder. One of the key elements of OABS is related to faulty sensory signaling of the filling status of the bladder. Knowledge about structures within the central nervous system involved in the micturition pathway can aid in developing novel rationally-designed treatment modalities and can help to identify patients, which are good candidates for specific lines of treatment.
The two functions of the lower urinary tract (LUT), i.e., urinary bladder and urethra, to store and periodically expel urine, are dependent upon central and local neural circuits located in the brain, the spinal cord and the peripheral ganglia (Fowler, [@B36]; Fowler et al., [@B37]; Birder et al., [@B15]; de Groat et al., [@B27]). Altered reflexes and sensory perceptions within the bladder---brain axis have emerged as a generally accepted model to explain pathologies such as OABS (Abrams, [@B2]). The modulation of sensory afferent functioning by means of neuromodulation could be considered a promising option for the treatment of OABS. However, in order to reach maximal efficacy and minimal side effects targets need to be identified.
One vital structure in the central pathway of the micturition pathway is the periaqueductal gray matter (PAG). The PAG receives ascending sensory fibers from the bladder, which pass through the dorsal horn of the spinal cord. The PAG is connected to the pontine micturition center (PMC; also called Barrington's nucleus). The PAG, in turn, is connected to other supraspinal structures of which some belong to the limbic system (such as the amygdala, insula) but also the prefrontal cortex and the thalamus (Vizzard et al., [@B91]; Blok et al., [@B21], [@B20]; Athwal et al., [@B9]; Griffiths et al., [@B41]; Griffiths and Tadic, [@B43]; Fowler and Griffiths, [@B38]; Tai et al., [@B86]).
It is generally believed that all ascending signals (such as mechanosensation, Griffiths and Tadic, [@B43]) are relayed through the PAG to the PMC. The PMC is the site for the initiation of the micturition reflex (Blok and Holstege, [@B18]; Matsuura et al., [@B64]; Taniguchi et al., [@B88]). Therefore the PAG is considered to be at the crossroads of ascending sensory information and inputs from higher centers that modulate these processes and plays the role of coordination center (Blok et al., [@B19]). Inputs from higher cortical systems are related to emotions, i.e., anxiety, and interpretation of social aspects (Mantyh, [@B63]; Griffiths et al., [@B44]; Griffiths and Fowler, [@B45]).
Based on neuroanatomical and cytoarchitectural features the PAG has been subdivided into four longitudinal columns spanning in the rostro-caudal direction, which are classified as the dorsomedial, dorsolateral, lateral and ventrolateral column (Beitz, [@B12]; Carrive, [@B23]; Bandler and Shipley, [@B10]; Linnman et al., [@B58]; Menant et al., [@B65]). Besides, their neuroanatomical distinction, these columns are also involved in different physiological processes. It has been described that the PAG is involved in autonomic (respiration and cardiovascular functions) as well as pain related functioning.
Several studies have investigated neuronal connections to and from the PAG by means of imaging or neuronal tracing. However, functional connectivity in response to afferent sensory stimuli and in particular stretch-related mechanoperception have---to our knowledge---never been investigated in a physiological manner.
Therefore, the present manuscript describes three groups of experiments. First, we identified an optimal stimulus applied to the bladder, in order to provoke sensory afferent stimulation in the absence of voiding. Second, we evaluated what behavioral consequences this stimulus has. We evaluated these consequences in the light of the different functions (i.e., anxiety and pain) that the PAG is mediating. Third, we investigated the pattern of neuronal activation in different parts of the central nervous system and in particular in the PAG. We did so by localizing and quantifying the amount of cFos positive cells in the various columns of the PAG, the PMC, the locus coeruleus, and several nuclei of the sacral spinal cord after urinary bladder stimulation in freely moving rats, with the previously optimized parameters.
Materials and Methods {#s2}
=====================
Subjects {#s2-1}
--------
Adult, male *Sprague-Dawley* rats (body weight 300--350 g at the time of surgery) from Charles River were housed in the Central Animal Facility (Maastricht University, Netherlands). Rats were individually placed in Makrolon™ cages. Housing conditions for temperature (21 ± 1°C) and light (reversed 12 h light/dark cycle, 7 a.m.--7 p.m. lights off, music on) were controlled and food and water were provided *ad libitum*. All experimental animal procedures were executed during the dark phase, under red light, when rodents are most active.
Bipolar Stimulation Electrode Implantation {#s2-2}
------------------------------------------
For the purpose of these experiments we developed a novel methodology for the electrical stimulation of the detrusor muscle. The idea is derived from the principle of transurethral intravesical electrostimulation (IVES), which has been used to initiate non-voiding contractions, which result in the depolarization of afferent sensory nerve fibers and subsequently a strong centrally-induced detrusor contraction (Madersbacher, [@B60]; Ebner et al., [@B31]; Buyle et al., [@B22]; Jiang, [@B53]; Streng et al., [@B84]).
We implanted rats chronically with a custom-made bipolar stimulation construct, which consists of two pacing wires (Streamline™, Medtronic, France) that were surgically implanted in the bladder wall. The wires were tunneled transdermally and a platform attached to the head was used as plug in order to easily connect an external power source.
For the surgical procedure, anesthesia was achieved by isoflurane inhalation (IsoFlo^®^, Abbott Laboratories Ltd., Great Britain; induction: 4%, maintenance: 1.5%) and the temperature was monitored using a rectal temperature probe and maintained within one degree of 37°C using a heating blanket. The abdomen, the neck and the head were shaved and disinfected using Betadine^®^. A small incision was made in the neck of the animal to subcutaneously tunnel the wires. A midline laparotomy was made to expose the urinary bladder and insert the exposed pacing wires between the serosa and the muscular layer. Two configurations have been used for the implantation of the bipolar electrode: (i) one pacing wire at the level of the dome and the other one at the level of the neck of the bladder, close to the urethra (hereafter abbreviated as: D-N); and (ii) both pacing wires at the level of the neck of the bladder (hereafter abbreviated as: N-N). To keep the electrode in place, to insulate the tips and protect the surrounding tissues from scratching, pieces of polyethylene tubing were sealed at the free end of wires. The abdominal incision was then closed. After installing the rat in the stereotactic apparatus (Stoelting model 51950, Stoelting Co., Wood Dale, IL, USA), a dermal incision and periostomy were performed to facilitate anchoring of the construct to the skull by using miniature screws (stainless steel, 1 × 2 mm). The platform was positioned on top of them and fixed with dental cement (Paladur, Heraeus Kulzer GmbH, Germany). For cFos immunostaining and behavioral experiments, a recovery period of 2 weeks was given before stimulation and testing.
Optimization of Stimulation Parameters {#s2-3}
--------------------------------------
### Electrical Stimulation of the Urinary Bladder and *in Vivo* Cystometry {#s2-3-1}
To evaluate which parameters were optimal for electrical stimulation of the urinary bladder, an experiment was performed combining electrical stimulation and *in vivo* cystometry in five rats under terminal anesthesia with urethane (1.5 g/kg). Besides the two electrodes, a catheter was implanted at the dome of the bladder in order to measure intravesical pressure. For this reason, electrodes were implanted at opposing sides in the lateral bladder wall for all animals in this experiment. The catheter was made of PE-50 tubing (BD Medical, USA) with a cuff and inserted into the bladder dome during the laparatomy through the low abdominal incision and held in place with a purse-string suture.
After the recovery period, the bladder catheter was connected via a T-tube to a pressure transducer and an infusion pump. Saline solution was infused into the bladder at a flow rate of 90 μl/min. The bladder was filled with saline up to 0.6 ± 0.2 ml and the grade of bladder filling was kept stable during the stimulation protocol. The intravesical pressure was recorded continuously using a disposable IBP pressure transducer (DPT-6000, Codan pvb Medical GmbH, Germany) and the MP150 data acquisition system equipped with an amplifier module and acquired with the AcqKnowledge software (AcqKnowledge 4.2 version, BIOPAC system Inc., Goleta, CA, USA). Simultaneously, stimulation was applied by connecting animals to a stimulus isolator (DS100, WPI Europe, Germany) driven by a digital stimulator (DS8000, WPI Europe, Germany). After bladder stabilization, electrical stimulation was given with constant current biphasic square wave pulses of 0.5 ms. Studies showed that sensory nerves were more effectively stimulated with a pulse width of 0.5 ms whereas motor fibers were preferentially activated at shorter pulse duration (0.05--0.4 ms; Jiang and Lindström, [@B54]; Tsui, [@B89]). Additionally, longer pulse duration (\>2 ms) might cause tissue damage.
We aimed at establishing optimal stimulation frequency (ranging from 10 Hz to 200 Hz) and intensity (ranging from 2 mA to 3 mA) in order to induce intravesical pressure augmentation. In order to prevent confounding, a randomized stimulation paradigm with different frequencies was applied with electrical stimulations lasting 30 s followed by a stimulation-off period of 60 s to allow intravesical pressure to return to baseline.
After the experiment rats were sacrificed by means of decapitation and no further post-mortem analysis took place.
Stimulation Induced Behavioral Changes {#s2-4}
--------------------------------------
To assess locomotor activity, anxiety and voiding pattern changes in rats during electrical stimulation of the urinary bladder, the following behavioral tests were performed: Open Field (OF), Elevated Zero Maze (EZM) and Voiding behavior tasks (VBTs). Five rats underwent all behavioral tests in a repeated design after a period of habituation to the handler and experimental environment at the following time points: at baseline prior to the surgical procedure (Control condition), 2 weeks after the electrode implantation in the presence (Stimulated condition) and absence (Sham condition) of electrical stimulation. For all behavioral experiments the electrodes were implanted in the D-N configuration.
At the end of the experiments rats were sacrificed and their tissue was not used for further *post-mortem* investigations due to the potential confounding influence of repeated stimulation.
### Open Field Task {#s2-4-1}
Spontaneous locomotor activity was measured in the OF, which consists of a large Plexiglas square arena (100 × 100 cm) with 40 cm high transparent Plexiglas walls and a dark Plexiglas floor. The trials were recorded under low light conditions and the total distance moved was automatically assessed via a video camera connected to a video tracking system (Ethovision, Noldus, Netherlands).
### Elevated Zero Maze Task {#s2-4-2}
Anxiety was evaluated in the EZM, a black plastic circular runway (100 cm in diameter, 10 cm path width) placed 70 cm above the floor level and equally divided into two opposite open and two opposite enclosed parts with 50 cm high side walls. To prevent falls, a 7-mm high rim surrounds the open arms. Animals were placed into one of the open arms facing a closed part and allowed to explore the maze for 5 min. Time spent in the open parts was automatically quantified by means of the Ethovision setup under low light conditions through an infrared video camera connected to a video tracking system.
### Voiding Behavior {#s2-4-3}
Voiding behavior was assessed with a filter paper assay in combination with video-assisted tracing as previously described for mice (Biallosterski et al., [@B14]). We adapted the procedure to the body size of rats by changing the size of the cage and re-calculating a standard curve for estimating the relation between spot size and volume of urine voided.
All rats were assessed at the same time of the day to minimize the effect of the circadian cycle on micturition frequency and volume. Testing started 24 h after a habituation period lasting for 5 h in which the animal was placed into the cage in which the measurement took place.
Animals were placed on an elevated mesh floor, in a standard cage with its floor covered by filter paper. For 1-h, voiding behavior of freely moving rats was observed using a video camera placed below the cage. Thereafter, the number of spots, and the volume of voided urine were assessed as indicators for the voiding frequency, and the total of discharged urine. For this purpose, the filter paper was exposed to ultraviolet light and spot quantity and size were measured in ImageJ.
Neuronal Activation in the Central Nervous System {#s2-5}
-------------------------------------------------
### Experimental Groups {#s2-5-1}
Rats were randomly assigned to one of the five experimental groups: (I) Control group without electrode implantation (*n* = 6), (II) Sham D-N group (*n* = 6), (III) Sham N-N group (*n* = 6), (IV) Stim D-N group (*n* = 7) and (V) Stim N-N group (*n* = 7). Sham animals underwent the same surgical procedure with electrode implantation and were connected to the stimulator without stimulation being performed.
### cFos Immunohistochemistry {#s2-5-2}
Following a 2-week recovery period, 1-h continuous electrical stimulation of the bladder in freely moving rats was administrated using the previously optimized stimulation parameters.
For this purpose, rats were placed in custom-made cages that had equal dimensions as their home cages. These cages were modified in a way that the top of the cage allowed the connection of the head-mounted connector to the stimulator. Before the start of the stimulation rats were habituated for 1 h.
Ninety minutes after the end of stimulation (Rodella et al., [@B77]; Baulmann et al., [@B11]; Haller et al., [@B47]; Arout et al., [@B6]), rats were transcardiac perfused with Tyrode's buffer and with fixation solution containing 4% paraformaldehyde, 15% picric acid, 0.05% glutaraldehyde in 0.1 M phosphate buffer (pH 7.6; Somogyi and Takagi, [@B80]). Thirty-two brains and six spinal cords (Control *n* = 2, Sham D-N *n* = 2 and Stim D-N *n* = 2) were removed rapidly and post-fixed in fresh fixative solution (Fixation solution without glutaraldehyde) for 2 h at 4°C prior to overnight immersions in an ascending series of sucrose (10% and 20% sucrose in 0.1 M phosphate buffer) at 4°C. Finally, tissue was snap-frozen in solid carbon dioxide and stored at −80°C until being sectioned coronally into 30 μm serial slices using a cryostat (Leica, Germany). Brains sections were collected into cups to be processed immunohistochemically as free-floating sections whereas spinal cord sections were mounted on gelatin-coated glass slides. Serial sections were kept at −80°C before staining.
We applied two different ways of visualizing cFos. For the brain sections, we used the indirect immunohistochemical (3,3′-Diaminobenzidine, DAB) staining method employing amplification by means of streptavidin and nickel-diaminobenzidine chromogen enhancement according to previous protocols (Tang et al., [@B87]) whereas for spinal cord sections we chose fluorescent visualization. Because brain sections are known for possessing auto-fluorescence after formaldehyde fixation (Clancy and Cauller, [@B25]; Schnell et al., [@B79]; Spitzer et al., [@B81]) and we expected low cFos epitope expression, we opted for the indirect immunohistochemical visualization in the brain. In the spinal cord, the secondary aim was to perform double labeling techniques, which is facilitated by the use of fluorophores.
Brain sections containing the PAG (Bregma AP: −6.3 to −8.3 mm) and the pons (Bregma: AP: −9.6 to 10.0 mm) were incubated overnight at 4°C with monoclonal mouse anti-cFos primary antibody (1:2000 dilution, Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), washed with Tris-buffered saline (TBS) and TBS-Triton X-100, and then incubated with the biotinylated donkey anti-mouse secondary antibody (1:400 dilution, Jackson Immunoresearch Laboratories, USA) for 1 h. This was followed by exposure to avidin-biotin-peroxidase complex (1:800, Elite ABC-kit, Vestastatin, Vector Laboratories, USA) for 2 h. The staining was visualized using a DAB solution and nickel intensification. Brain sections were mounted on gelatin-coated glass slides, dehydrated and cover-slipped with Pertex mounting medium (Histolab Products AB, Sweden). Spinal cord sections (L6 to S2 segments) were incubated overnight at room temperature with monoclonal mouse anti-cFos primary antibody (1:2000 dilution, Santa Cruz Biotechnology Inc., USA) and rinsed following the same protocol as for brain sections. Subsequently, a 2-h incubation with the secondary antibody Alexa Fluor^®^ 488-conjugated donkey anti-mouse (1:100 dilution, Thermo Fisher Scientific, NY, USA) was followed by three washing steps with TBS and by coverslipping in 80% glycerol/TBS).
Photographs of the stained brain sections were taken (4× and 10× magnification) using a U-CMAD-2 digital camera mounted on an Olympus AX70 bright-field microscope (analySIS, Imaging System, Germany) and evaluated with ImageJ analysis software (ImageJ software, NIH, USA). We assessed results for the caudal and rostral regions of the PAG separately. In the rostral part of the PAG no ventrolateral (vl) column can be found and therefore results are based on the dorsomedial (dm), dorsolateral (dl) and lateral column of the PAG. In the caudal portion of the PAG all four columns are present (Lawrenson et al., [@B57]; Supplementary Figure [S1](#SM1){ref-type="supplementary-material"}). Columns were delineated from similar Bregma levels of two rostral (AP: −6.7 mm and −7.0 mm) and two caudal (AP: −7.7 mm and −8.0 mm) PAG images per rat. The locus coeruleus (LC) and PMC were delineated on the two hemispheres from one pontine region image per rat.
We assessed the quantity of cFos positive cells in the brain in the following way. First, we acquired pictures from the region of interest with a low magnification (4×). Second, we delineated the region or columnar areas with a higher magnification (10×), which resulted in an area, which was used for the quantification of the cell number (Supplementary Figure [S2](#SM2){ref-type="supplementary-material"}). In all cases, the delineation was based on standard anatomical hallmarks for the PAG (i.e., an angle of the circumference) or corresponding histological stainings of the consecutive section (Nissl staining for the PMC and LC) and the anatomical descriptions of these regions according to the standard rat brain atlas of Paxinos and Watson ([@B500]). Consequently, a thresholding method was applied in the delineated sections, which identified all cells, which had an intensity that exceeded the background (Hescham et al., [@B49]). Cells were then manually counted by two independent observers. Observers were blinded for treatment groups. The values were expressed as cells per area to correct for potential differences in the delineation of the areas and expressed as cells/mm^2^.
A different workstation was used for the acquisition of pictures for the activation of cFos positive cells in the segments L6-S2 of the spinal cord. The analysis was performed online using a stereology workstation, i.e., a modified Olympus BX50 fluorescence microscope controlled by the Stereo Investigator software (MBF Bioscience, Williston, VT, USA). Delineations of the regions of interest (Laminae I to III of the dorsal horn, Medial gray region with the DCM, Lateral gray subdivision including the SPN and the ventral horn) were made on the microscopic images displayed on a monitor using 4× objective and adjusted at a higher magnification (10×). Within the delineated areas, the total number of cFos positive cells was evaluated using a 40× objective and the optical fractionator of the Stereo Investigator software by manually counting cFos positive cells. Because of the limited number of sections per region of interest, we did not extrapolate the data into a 2D volume but chose to present results per slice.
Electrode Localization {#s2-6}
----------------------
The location of the electrode was assessed in a sample of the implanted animals by performing a macroscopic *post-mortem* examination. This was accompanied by the microscopic assessment of cryosection of the bladder. For this purpose, bladder strips were prepared, which were cut and rapidly assessed under bright field illumination. No staining procedures or quantifications were performed. This method revealed no overt signs of fibrosis, dis-location or inflammation in the assessed bladders.
Statistics {#s2-7}
----------
Data were presented as mean ± SEM values. For the evaluation of stimulation parameters, a one-way ANOVA was employed, followed by a Fisher PLSD *post hoc* test. Histological and behavioral data were analyzed statistically with inter-group comparisons using *t*-test. All statistical analyses were performed with Sigma Plot 11.0 version for Windows (Systat Software). *P-values* lower than 0.05 were considered statistically significant.
Ethical Approval {#s2-8}
----------------
All procedures were in line with local and national guidelines and laws on animal welfare. This study was carried out in accordance with the recommendations of Guidelines for Ethical Conduct in the Care and Use of Nonhuman Animals in Research. The protocol was approved by the "Animal ethical committee of Maastricht University" and all procedures performed were in accordance with ethical standards of Maastricht University.
Results {#s3}
=======
Cystometric Investigation for Electrical Stimulation Parameter Optimization {#s3-1}
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The effect of different combinations of parameters (i.e., frequency and intensity) on the induced non-voiding detrusor contraction was evaluated to find the most effective setting for 1-h continuous electrical stimulation of the bladder with the bipolar electrode. Pressure responses were observed during electrical stimulation when the current intensity was higher than 2 mA, for a frequency range of 20--200 Hz. For 10 Hz-stimulations, an intensity of 3 mA was required to trigger an intravesical pressure increase. In all animals, the pressure increase, and the stimulus amplitude were positively correlated (Figure [1A](#F1){ref-type="fig"}). In five animals, the maximal pressure response (4.55 cm H~2~O ± 1.07) was obtained with a current intensity of 3 mA. The response to electrical stimulation of the bladder with a current intensity of 2 mA was characterized by a rise in pressure to reach a plateau and then a decrease towards the baseline (Figure [1A](#F1){ref-type="fig"}). Higher current intensities (2.5 mA and 3 mA) elicited an acute increase of pressure, showed as a sharp peak, and followed by a decrease of pressure to the plateau level (Figure [1A](#F1){ref-type="fig"}). However, in order to avoid tissue injury and at the same time to avoid inducing a micturition contraction during long-term electrical stimulation, the current intensity of 2 mA, the lowest current intensity capable of inducing a response, was chosen. Because the intravesical pressure responses could depend on the position of the electrode, we standardize the statistical analysis, by normalizing the data and expressed these as percentage of the maximal intravesical pressure response per animal. With the current intensity set at 2 mA, the intravesical pressure responses obtained upon electrical stimulation were frequency-dependent (One-way ANOVA, *F*~(4,24)~ = 61.175, *p* \< 0.001; Figure [1B](#F1){ref-type="fig"}). With a frequency of 10 Hz, low intravesical pressure responses were induced (6.08% ± 1.28). At 20 Hz, the response was maximal (54.4% ± 5.2) and was not significantly different from the responses found using higher frequencies (NS, 20 vs. 50 Hz, *p* = 0.396; 20 vs. 100 Hz, *p* = 0.963; 20 vs. 200 Hz, *p* = 0.175, Fischer PLSD). The observed response to electrical stimulation with 200 Hz was lower than with the intermediate frequencies (50 Hz vs. 200 Hz, 56.7% ± 4.4 vs. 48.04% ± 2.2, *p* = 0.034). To minimize tissue damage due to continuous electrical stimulation, we opted for the frequency of 20 Hz, the lowest frequency stimulation giving a maximal pressure response. Therefore, the optimal combination of both parameters inducing an adequate sensation inducing contraction of the bladder following electrical stimulation was determined as having a frequency of 20 Hz and an amplitude of 2 mA and has been used for the subsequent set of experiments.
{#F1}
Behavioral Measurements During Electrical Stimulation of the Urinary Bladder {#s3-2}
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After the electrode implantation, in both stimulated and non-stimulated animals, characteristic behavioral signs of visceral pain were assessed. No behavioral modifications including lacrimation, piloerection, tail hyperextension, abdominal contraction, arched posture, lower abdomen licking and backward withdrawal movements were displayed in neither the sham nor the stimulated conditions.
Previous works suggested that stress and pain are related to the activation of specific columns in the PAG (Carrive, [@B23]; Bandler and Shipley, [@B10]). For instance, the dorsal PAG is linked to avoidance behavior, the lateral PAG is correlated to fight and flight whereas the ventrolateral PAG is associated with freezing and immobility. To confirm that the neuronal activation observed in the PAG related to bladder-related functioning and was not triggered by confounding behaviors potentially generated by electrode implantation or electrical stimulation of the urinary bladder, the locomotor behavior was evaluated in the OF. Analysis of the behavioral data in the OF showed that the total distance traveled was not significantly different in stimulated animals compared to sham animals (Sham vs. Stim, 5063.8 cm ± 135.9 vs. 5271.3 cm ± 559.2, *p* = 0.753). Therefore, neither the implantation of the bipolar electrode nor the electrical stimulation of the bladder alters spontaneous locomotor activity.
Moreover, animals were tested in the EZM to determine whether anxiety level was affected by the experimental procedure. No significant effect was found between the control and sham conditions (*t*-test, NS, *p* \> 0.05). Moreover, the time spent in open arms of the EZM was comparable between the sham and stimulated conditions (Sham vs. Stim, 95.7 ± 34.8 vs. 106.1 ± 18.6, *p* = 0.805) indicating no change in terms of anxiety-like behavior.
Also, we assessed whether stimulation changed voiding behavior (Figure [2A](#F2){ref-type="fig"}). The quantification of voiding spots reveals no following electrode implantation (Control vs. Sham, 4.7 ± 0.3 vs. 6.0 ± 0.6, *p* = 0.116; Figure [2B](#F2){ref-type="fig"}). However, electrical stimulation of the bladder caused a significant increase of voiding frequency compared to the un-stimulated condition (Sham vs. Stim, 6.0 ± 0.6 vs. 11.0 ± 1, *p* = 0.012).
{#F2}
We estimated the total volume of voided urine during the VB by means of a volumetric calibration, which revealed a linear relation between spot size and volume voided. Video recordings were used to discriminate between overlapping urine spots. We found that the total volume of voided urine was comparable before and after surgery (Control vs. Sham, 0.61 ml ± 0.08 vs. 0.72 ml ± 0.07, *p* = 0.33; Figure [2C](#F2){ref-type="fig"}). Moreover, the total volume of voided urine was not altered in stimulated rats (Sham vs. Stim, 0.72 ml ± 0.07 vs. 0.78 ml ± 0.12, *p* = 0.652). The duration of the test we used resulted in a few voids at baseline. Therefore, we could not reliably quantify whether changes in the voiding pattern occurred in the different experimental conditions.
In summary our behavioral results indicate that there were no factors such as anxiety or pain, that could explain the activation of PAG columns. However, stimulation induced a higher frequency of voiding with smaller volumes per void.
Effect of Electrical Stimulation of the Urinary Bladder on cFos Immunoreactivity in the PAG {#s3-3}
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The cFos expression and its topographical localization in the PAG following electrical stimulation of the bladder were investigated to detect induced neuronal activation. Sham groups were used to test whether the presence of the electrode or the procedure of the electrode implantation *per se* were able to induce cFos expression in the PAG. In all sham groups, the cFos expression did not differ from control animals (Control vs. Sham, *t*-test, NS, *p* \> 0.05; Figures [3](#F3){ref-type="fig"}, [4](#F4){ref-type="fig"}). No effect of electrode implantation (control vs. sham), regardless of pacing wires configuration, i.e., N-N vs. D-N, was observed on neuronal activation in any column of the PAG. Electrical stimulation of the urinary bladder upregulated cFos expression in several PAG columns compared to sham animals. This effect will be discussed separately for the rostral and caudal part of the PAG below.
{#F3}
{#F4}
Activation of Neurons in the Rostral Part of the PAG {#s3-4}
----------------------------------------------------
In both electrode configurations there was a significant increase of cFos positive cells in all columns of rostral part of the PAG except for a non-significant difference between sham and stimulated animals in the N-N configuration in the dl PAG. For N-N stimulated animals, the number of cFos positive cells in the lPAG and dmPAG was higher compared to sham control animals (Sham vs. Stim, lPAG and dmPAG, \**p* = 0.044 and \**p* = 0.046, respectively; Figures [3A--C](#F3){ref-type="fig"}). Electrical stimulation of the urinary bladder in D-N group increased the number of activated neurons in the lPAG, dlPAG and dmPAG (Sham vs. Stim, lPAG, dmPAG and dmPAG, \*\*\**p* \< 0.001, \**p* = 0.044 and \*\*\**p* = 0.001, respectively; Figures [3D--F](#F3){ref-type="fig"}).
Activation of Neurons in the Caudal Part of the PAG {#s3-5}
---------------------------------------------------
For N-N electrode configuration, no statistically significant difference in the number of cFos positive neurons was found in the caudal PAG between stimulated and sham groups (*t*-test, NS, *p* \> 0.05; Figures [4A--D](#F4){ref-type="fig"}). For D-N electrode implantation, cFos counts in the ventrolateral subdivision of the caudal PAG were significantly greater in stimulated compared to sham rats (Sham vs. Stim, 48.8 ± 11.9 vs. 177.4 ± 23.1 cells/mm^2^; *p* = 0.003; Figure [4E](#F4){ref-type="fig"}). This was also the case for lateral and dorsomedial subdivisions of the caudal PAG (Sham vs. Stim, lPAG and dmPAG, \**p* = 0.012 and \**p* = 0.024, respectively; Figures [4F,H](#F4){ref-type="fig"}). The strongest effect size was seen in the caudal vlPAG compared to the other columns of the PAG (Figure [4](#F4){ref-type="fig"}). Moreover, the ventrolateral aspects of the caudal PAG close to the aqueduct in stimulated compared to sham D-N rats seemed to be more densely populated with activated neurons (Figure [5](#F5){ref-type="fig"}). Indeed, this observation was quantitatively confirmed by cFos cells counting, showing that the majority (53.8% ± 7.8%) of activated neurons were located in the central one third closest to the aqueduct of the vlPAG area. We did not observe the clustering of neurons in other columns.
![Distribution of cFos immunoreactive cells in the caudal PAG. **(A)** Coronal diagram of the rat brain at corresponding Bregma level AP −8.00 mm (Rat brain atlas, Paxinos and Watson, [@B500]). Representative low power photomicrographs of coronal brain sections stained for cFos showing the PAG of **(B)** non-stimulated (Sham) rat and **(C)** stimulated rat (Stim) with bipolar stimulation electrode implanted in the bladder wall at the dome and neck levels. The higher power photomicrographs in the lower right corners focus on the central region of the vlPAG column. Aq, aqueduct; DRN, dorsal raphe nucleus; dlPAG, dorsolateral PAG; dmPAG, dorsomedial PAG; lPAG, lateral PAG; vlPAG, ventrolateral PAG. Scale bar = 100 μm.](fncel-12-00133-g0005){#F5}
Effect of Electrical Stimulation of the Urinary Bladder on cFos Immunoreactivity in the Pons {#s3-6}
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The changes in cFos expression in the PMC and the LC were examined following electrical stimulation of the urinary bladder for the D-N group only, because this configuration showed the biggest effect size for the PAG. The numbers of cFos positive cells for both pontine structures was similar in control and sham animals (Control vs. Sham, *t*-test, NS, *p* \> 0.05; Figures [6A,B](#F6){ref-type="fig"}). By contrast, electrical stimulation of the urinary bladder significantly increased the number of activated neurons in the PMC and LC (Sham vs. Stim, PMC and LC, \*\*\**p* \< 0.001, \*\**p* = 0.004, respectively; Figures [6](#F6){ref-type="fig"}, [7](#F7){ref-type="fig"}). Interestingly, whereas the activated neurons were distributed homogeneously throughout PMC, the cFos labeled neurons were mainly located in the dorsal part of the LC (Figure [7C](#F7){ref-type="fig"}).
{#F6}
![Distribution of cFos immunoreactive cells in the pontine structures. **(A)** Coronal diagram of the rat brain at corresponding Bregma level AP −9.68 mm (Rat brain atlas, Paxinos and Watson, [@B500]). Representative low power photomicrographs of coronal brain sections stained **(B)** with Nissl staining and for cFos showing the dorsal pons of **(C)** non-stimulated (Sham) rat and **(D)** stimulated rat (Stim) with bipolar stimulation electrode implanted in the bladder wall at the dome and neck levels. The higher power photomicrographs in the lower right corners show the PMC and locus coeruleus. 4V, fourth ventricle; PMC, Pontine micturition center or Barrington's nucleus; LC, locus coeruleus; Me5, mesencephalic trigeminal tract. Scale bar = 150 μm.](fncel-12-00133-g0007){#F7}
Effect of Electrical Stimulation of the Urinary Bladder on cFos Immunoreactivity in the Spinal Cord {#s3-7}
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A quantitative assessment of cFos expression in the sacral parasympathetic nucleus (SPN), in the central canal region (DCM) and in laminae I and II of the dorsal horn (I--II) of the lumbosacral spinal cord (L6-S2) of D-N animals was done in a smaller sample size pilot study (Figure [8A](#F8){ref-type="fig"}; *n* = 2 per experimental group). No increase was seen in these structures between control and sham groups (Control vs. Sham, *t*-test, NS, *p* \> 0.05; Figures [8B--D](#F8){ref-type="fig"}). However, cFos positive cells counts were significantly higher in stimulated compared to non-stimulated D-N animals (Sham vs. Stim, SPN, DCM and laminae I--II, \*\*\**p* \< 0.001, \**p* = 0.006 and \*\**p* = 0.004, respectively; Figures [8B--D](#F8){ref-type="fig"}).
![Expression of cFos immunoreactive cells in the lumbosacral spinal cord. **(A)** Coronal diagram of the rat lumbosacral spinal cord (L6) showing the location of the dorsal horn (i.e., laminae I and II), the sacral parasympathetic nucleus and the dorsal commissure (Rat brain atlas, Paxinos and Watson, [@B500]) and a corresponding photomicrograph showing a spinal cord section stained for cFos of stimulated rat with bipolar stimulation electrode implanted in the bladder wall in the D-N configuration. The higher power photomicrograph in the right corner shows the dorsal horn of the spinal cord. Abbreviations: I--II: laminae I and II, DCM: dorsal commissure, SPN: sacral parasympathetic nucleus. Scale bar = 200 μm. Cumulative data showing the means and SEM for the optical density of cFos expression for D-N group in the **(B)** SPN, **(C)** DCM and **(D)** I--II of L6-S2 spinal cord. Control *n* = 4, Sham D-N *n* = 4 and Stim D-N *n* = 4. *t*-test, \**p* \< 0.05, \*\**p* \< 0.005 and \*\*\**p* \< 0.001.](fncel-12-00133-g0008){#F8}
Macroscopic Evaluation of Urinary Bladder Tissue and Electrode Implantation {#s3-8}
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No sign of erosion, presence of excessive scar tissue or obvious change in tissue architecture in the urinary bladder and the surrounding tissues due to electrode implantation and chronic electrical stimulation performed during behavioral tests was revealed during *post-mortem* histological examination. Moreover, for all animals, the electrode wires remained correctly implanted in the bladder wall until the end of the experiments.
Discussion {#s4}
==========
To our knowledge this study is the first that investigates the response of sensory afferent mechanosensitive fibers in the bladder in isolation in order to evaluate their distinct supraspinal neuronal response.
Stimulation Parameter Choice {#s4-1}
----------------------------
It has been shown by tracing studies that the PAG receives projections from the sacral spinal cord. Also, electrophysiologically this connection has been established in several studies. Yet, the studies performed mostly made use of nociceptive stimuli to prove this connection. The majority of afferent signaling from the bladder is however related to its filling status, which is signaled by mechanosensitization from stretch-receptors. We have spent a fair amount of work into optimizing the stimulus used to mimic mechanosensitization, because it is essential for the interpretation of the results and draw solid scientific conclusions (Buyle et al., [@B22]).
For the optimization of the stimulation parameters a duration of 30 s was used. Yet, for the final experiment we stimulated bladders for 1 h. We did not evaluate the effect of long-lasting stimulation on bladder contractility. Yet, it is known from electrical skeletal muscle stimulation, that frequencies in the range of 20--50 Hz produce smooth contractions, that could be sustained over long periods (Bhadra and Peckham, [@B13]; Doucet et al., [@B29]). Moreover, it has been shown, that high stimulation frequencies can cause the activation of motor neurons in the central nervous system. We aimed at triggering sensory fibers, which in turn could lead to the activation of motor neurons in the PMC. This will be discussed in more detail in the following paragraph. Low frequencies in combination with a short pulse width (around 500 μs) are less likely resulting in fatigue. In the case of 20 Hz stimulation it is unlikely, that a tetanus occurred, and that the bladder remained contracted during the stimulation phase. Tetany is generally known to occur at frequencies above 60 Hz. So, in the present experiment we expect, that continuous contraction and relaxation occurred during the stimulation period in the form of detrusor "twitches".
Interestingly, somatosensory evoked potentials have been investigated in relation to different stimulation paradigms for anal sensory signaling. It has been shown, that low stimulation frequencies needed to be applied for longer durations in order to evoke the same somatosensory stimulation (Evers et al., [@B33]) than with higher frequencies. We therefore safely assume, that a stimulation period lasting 1 h activated central perceptions. Moreover, low to intermediate frequencies are considered more appropriate to stimulate Aδ-fibers of the LUT (Jiang, [@B53]; Langille et al., [@B56]).
Both charge transfer and heat dissipation due to electrical current can contribute to cell injury at the electrode-tissue interface (Crago et al., [@B26]). Thus, for minimal tissue damage during chronic stimulation, the amplitude should be set at a value causing minimum heat dissipation and charge transfer. Moreover, stimulation waveforms should be charge-balanced to reduce the possibility of tissue damage. In our case biphasic stimulation was considered most adequate. Intravesical pressure measurements showed that electrical stimulation with frequency of 20 Hz and amplitude of 2 mA was suitable and high enough to generate contractions of the urinary bladder, but these amplitudes did not cause voiding contractions.
As a critical note, one needs to realize that the simulation of a sensory stimulus is very challenging in rodents, because perceptions are nearly impossible to measure. However, studies investigating this in humans (i.e., functional magnetic resonance imaging) are very difficult to perform or miss the temporal or spatial resolution and therefore do not allow columnar analyses.
Electrode Position {#s4-2}
------------------
To evaluate PAG activity linked to urinary bladder sensation, the most appropriate parameter to stimulate the afferent nervous system of the LUT would be to initiate the sensation of bladder fullness by artificial bladder filling. However, functionally mapping of cFos needs to be applied carefully and critically (Dragunow and Faull, [@B30]), because cFos expression requires a prolonged and strong stimulation session, it is affected by anesthetic agents and can be induced non-specifically. Therefore, the introduction of a catheter for bladder filling, the measurement of bladder pressure and residual urine volume could induce cFos expression. This led us to opt for electrical stimulation of the urinary bladder in awake rats as a paradigm to study bladder sensation processing. Electrical stimulation is not a physiological stimulus, yet mimicking bladder sensation in a preclinical setting by electrical stimulation is a valid method. There is an added values of this stimulus for this type of sensory testing especially since it has been shown recently that afferent fibers detect bladder pressure or bladder wall stretch rather than bladder volume (Andersson, [@B5]; Janssen et al., [@B52]).
For the current set of experiments a custom-made bipolar electrode construction has been designed to be chronically implanted into the bladder wall of rats. The position for the implantation of the two wires within the bladder wall was determined in the line with the general distribution of mechanosensitive afferent fibers in the rat bladder. The myelinated Aδ fibers, described as afferent fibers responding to bladder filling and detrusor stretch and communicating filling sensation to the central nervous system, are mainly present in the smooth muscle layer of the urinary bladder (Iggo, [@B50]; Xu and Gebhart, [@B92]; Birder et al., [@B15]). Moreover, previous studies in rodents have revealed that the afferent fibers are notably more dense in the bladder neck and the dome (Grol et al., [@B46]). Accordingly, we placed the two wires at the level of the neck on both sides for the N-N group and at the level of the neck and the dome for the D-N group, between the outer muscular and serosal layers of the urinary bladder wall.
From a theoretical point of view in the N-N configuration the electrodes are closer to the location that has a high density of afferent neurons. It is unclear however whether sensory afferent neurons located at the bladder neck are Aδ or c-fibers. However, when stimulating a bigger area, which is the case in the D-N position, it is more likely that the whole detrusor muscle contracts rather than local contractions which leads to stretch-induced afferent activation of sensory neurons. However, as mentioned previously the stimulation parameters used---especially a pulse width of 0.5 ms---preferentially activate sensory afferents independently of their effect on contractility and or stretch. The difference in the density and eventually type of neurons in the different stimulation locations, might contribute to the differential activation of the rostral dlPAG and most columns of the caudal PAG, which did not respond to N-N but D-N stimulation. From a hypothetical point of view, activation stretch caused by bladder filling is exerting its effect on the whole detrusor muscle and does not occur at distinct locations such as the bladder neck. So theoretically speaking the D-N configuration seems to be more physiological. Based on these data not the density of neurons but rather the type and location in the bladder determine the activation of central nervous system structures. In the future, the identification of neurons that are responsible for PAG activation in transgenic animal models or in models with (transient) local lesion might reveal novel targeted treatment approaches for bladder disorders, with aberrant sensory processing.
Behavioral Findings {#s4-3}
-------------------
There is a vast body of evidence that the PAG plays an important role in pain control (Young and Chambi, [@B94]; Bandler and Shipley, [@B10]; Rosen et al., [@B78]). Moreover, the dorsomedial and dorsolateral columns of the PAG have been demonstrated to be involved in anxiety-related behavior (dlPAG for the flight reaction and dmPAG for defensive behavior; Carrive, [@B23]; Keay and Bandler, [@B55]).
This raises the question whether electrical stimulation increases anxiety or pain and thus induced cFos expression in dorsal columns of the PAG. To exclude the possibility that cFos expression was induced by non-stimulation related effects, behavioral signs of pain and anxiety were analyzed in rats. There were no behavioral signs of pain nor did animals show anxiety-related behavior during the stimulation, which lead us to the conclusion, that cFos expression in the (dorsal) PAG, was not attributable to increased pain and anxiety.
However, in our study, an increase of urination frequency was found. In accordance with recent findings concerning afferents dysfunction in the development of bladder activity disorders such as OABS, the increased urinary frequency is likely to result from (hyper)excitation of the sensory system.
If---like applied in this experiment sensory afferent stimulation---results in a higher voiding frequency, this supports the hypothesis that OABS is in part related to faulty sensory signaling of bladder filling status. OAB is characterized by an increased frequency of voiding and urgency. Both are potentially related to faulty sensory signaling. From a neuromodulatory perspective it would be therefore interesting to test if it is possible by applying different stimulation parameters (i.e., high vs. low frequency) to ameliorate OAB symptoms by inhibiting sensory processing at the level of the bladder or even in the central nervous system.
Finally, before analyzing the results from cFos immunostaining, great care was taken to exclude that the observed changes were due to a displacement in the level of the electrode that would lead to unintentional stimulation of somatosensory receptors in the abdominal musculature and parietal peritoneum.
Neuronal Activation in the Central Nervous System Upon Electrical Stimulation {#s4-4}
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Previous studies showed a key role for the PAG in the regulatory system of urinary bladder (Blok et al., [@B21], [@B20]; Matsuura et al., [@B64]; Athwal et al., [@B9]; Taniguchi et al., [@B88]; Griffiths et al., [@B41]; Tai et al., [@B86]; Griffiths and Fowler, [@B45]). This structure is therefore seen as an interesting target to invoke treatment strategies to restore the normal function of the urinary bladder in urological disorders such as OABS. However, little is known about the relationship between the urinary bladder sensation and more specific PAG columnar activity.
The findings of the current set of experiments with regard to supraspinal activation upon sensory afferent stimulation are summarized in Figure [9](#F9){ref-type="fig"}.
{#F9}
Neuronal Activation of the PAG by Electrical Stimulation {#s4-5}
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Tracing studies have been performed earlier showing, that indeed there is a connection between the bladder and the PAG---more specially the ventrolateral column (Morrison, [@B501]). These results are in line with the current study. Whereas tracing studies are excellent to show neuroanatomical connection they cannot be used for functional connectivity assessment. The present study has the potential to combine neuroanatomical evidence with functional activation of neurons. To our knowledge there is no study investigating, which physiological stimulus activates neurons in brain structures such as the PAG. The studies that have been investigating (mainly by means of neurophysiological measurements) the activation of the PAG made use of noxious stimuli, which cannot be considered physiological. Considering that the PAG also plays a strong role in anxiety and pain-related functioning the use of noxious stimuli is biasing the results of earlier performed studies.
In control, Sham D-N and Sham N-N animals, few cFos immunoreactive cells were scattered throughout the PAG. These observations correspond to cFos basal expression and confirm that the presence of wires implanted in the bladder wall did not induce non-stimulation related cFos expression.
After electrical stimulation, the number of cFos positive cells was significantly greater than in non-stimulated animals. In the stimulated D-N group, cFos in the dorsomedial, lateral and ventrolateral regions of the caudal PAG was significantly increased compared to non-stimulated sham D-N group, with the biggest effect size in the vlPAG. Also, Marson ([@B502]) showed, that the bladder projects to a very localized area in the vmPAG. Even though, the terminology used (ventromedial vs. ventrolateral) is different the location and pattern of labeled neurons they show is identical with the activated area that we found. In their study they used a tracer that was injected into the EUS. This distinct localization in combination with the knowledge that neurons are connected to the EUS offers opportunities for selective treatment options. Even though, we did not observe obvious clusters of neurons in other columns it might be interesting in future experiments to identify if there are neuronal subpopulations within the columns of the PAG.
A previous study on cFos expression following activation of bladder afferents by noxious stimuli (acetic acid) to the urinary bladder reported cFos positive cells in the lateral area of the vlPAG (Mitsui et al., [@B67]). The difference in columnar activation could be explained by the stimulation of different types of afferent fibers. Indeed, in the case of acetic acid infusion, mainly unmyelinated c-fibers respond to noxious stimuli (Aizawa et al., [@B4]). Electrically evoked (sub-micturition threshold) contractions generated increased activity through central pathways that control the urinary bladder, initiated by activation of sensory axons. In previous studies, various stimulation protocols of the LUT caused changes in the central pathways such as PAG, PMC and spinal cord (Birder and de Groat, [@B16]; Birder et al., [@B17]; Mitsui et al., [@B66], [@B67]; Yamada et al., [@B93]).
It has been hypothesized, that the PAG receives information about the bladder filling status (Griffiths et al., [@B42]). To our knowledge this study is the first study proofing the concept that afferent bladder signaling is indeed received by the PAG and functionally activates neurons.
Neuronal Activation of the PMC by Electrical Stimulation {#s4-6}
--------------------------------------------------------
The PMC has a well-documented role in the control of micturition and urinary bladder function (Noto et al., [@B70], [@B71]; Fowler et al., [@B37]; Griffiths and Fowler, [@B45]). It is known that activation of PMC initiates a complete synergic micturition response by inducing detrusor contractions and the relaxation of the external urethral sphincter resulting in micturition. Since the ventrolateral and lateral caudal PAG are known to project specifically to the PMC and activate its premotor interneurons (Blok and Holstege, [@B18]; Fowler et al., [@B37]), activation of the PAG should result in dense cFos immunoreactive cells in PMC. Considering, that the PAG was activated minimally in the N-N configuration and the fact that activation of the PMC depends on PAG activation we investigated the expression of cFos in the D-N configuration only. CFos expression in the sham stimulated group showed a sparse and random distribution of cells expressing cFos whereas in D-N Stim group cFos positive cells were upregulated and consistently distributed.
Interestingly, we noticed in the nearby region, the LC, an increase in cFos immunoreactivity after electrical stimulation compared to non-stimulated animals presenting a low cFos level expression. Moreover, cFos positive neurons were primarily present in the dorsal half of the LC. We can conclude that the LC is activated upon bladder stimulation. Activation of LC neurons has been implicated in arousal and attention (Foote et al., [@B35]; Aston-Jones, [@B7]). In monkeys, cats and rats, sensory stimuli of various modalities can activate the LC-noradrenergic system (Foote et al., [@B34]; Aston-Jones and Bloom, [@B8]; Abercrombie and Jacobs, [@B1]). Visceral stimuli increase LC discharge rate and are important in initiating a forebrain response (Elam et al., [@B32]; Page et al., [@B73]). The LC has been previously identified to be connected anatomically to the bladder by means of tracing (Marson, [@B502]).
Spinal Cord Activation {#s4-7}
----------------------
Previous studies have revealed that the caudal lateral, ventrolateral and dorsal divisions of the PAG receive many projections from the lumbosacral cord and that stimulation of the afferent bladder nerves in the rat evokes short latency potentials in the most caudal part of the PAG (Noto et al., [@B71]; Ding et al., [@B28]). Because neurons located in the laminae I and II, SPN and DCM of lumbosacral spinal cord project to the PAG, the visceroceptive inputs are likely to be propagated to the PAG through these spinal-PAG projections. We measured the cFos expression at the spinal levels of the L6-S2, since it corresponds to spinal entry sites of the pelvic nerve and to the regions of bladder afferent connections (Morgan et al., [@B68]; Ding et al., [@B28]; Xu and Gebhart, [@B92]). The present study demonstrated that bladder stimulation increases cFos expression in the superficial layers of the dorsal horn (laminae I and II), in the SPN and the central canal region in accordance with previous observations with noxious stimuli (Birder and de Groat, [@B16]; Birder et al., [@B17]; Mitsui et al., [@B66]). It should be noted that an increased cFos expression in the SPN may also be related to changes in the motor control of the vesical sphincters. The current study indicates strong neural activation consistent with mechanoceptive input in the spinal cord supports and validates the model of bladder electrical stimulation.
We optimized the parameters for the stimulation so that an intravesical pressure would occur caused by detrusor contractility in the absence of voiding. We applied the stimulation directly to the bladder muscle through the implanted electrode. There is no reason to believe that direct stimulation at the detrusor muscle itself causes the activation of efferent motor neurons in the central nervous system directly. Likely, efferent motor neurons were activated as a consequence of the bladder-spinal cord reflex network. One example of this is the guarding reflex, which occurs once there is a sudden rise in abdominal pressure in order to prevent leakage of urine resulting in the contraction of the EUS to prevent urine from leaking. Augmentations of intravesical pressure can lead to either the activation of the guarding reflex (short reflex loop at the level of the spinal cord) in order to prevent leakage of urine or the initiation of voiding (long reflex loop mediated via the brain).
In the spinal cord, the efferent system is exclusively located in the ventral horn, whereas the sensory part is located in the dorsal horn. Furthermore, motor neurons can be easily distinguished in the spinal cord due to their size and shape. It is indeed true that some motoneurons stained positive for cFos (see Figure [8A](#F8){ref-type="fig"}, which shows incidentally a motoneuron stained in the ventral horn). Due to the fact that we quantified cFos positive neurons in the dorsal part of the spinal cord only, we can surely say that these are related to sensory activity.
This means that we could: (i) proof that sensory activation took place in our setup; and (ii) exclusively focus on the sensory component by delineating and quantifying a neuroanatomical region, which is supposedly only involved in sensory information processing. As we were unable to assess if animals were aware of a sensory perception we proof a sensory component in our experiments by the activation of sensory neurons in a region of the spinal cord that is exclusively mediating sensory signals.
Technical Considerations {#s4-8}
------------------------
For the purpose of identifying sensory processing upon sensory bladder related signals in the central nervous system, we used immunohistochemical detection of the cFos protein in the CNS of rats after urinary bladder electrical stimulation.
It is important to realize that cFos expression is a marker of neuronal activity but not a marker for the efferent result (such as the contraction of a muscle) or the effect on a distant neuronal target (such as the PMC, which is under the control of the PAG). The activation of inhibitory neurons (i.e., GABAergic interneurons) results in distinctive actions at the distant side than the activation of excitatory neurons. In this study, we did not differentiate between the type of neuron that was activated. However, we did follow-up on this question in a study, which was recently published studying the co-expression of cFos and neuronal markers in the PAG (Zare et al., [@B95]). Also, like described in the above diagram, due to input of various regions to the PAG, we cannot make a difference which neuronal activation resulted from afferent sensory or cortico-limbic inputs.
Staining of cFos does not allow to differentiate in temporal terms. Therefore, our study does not allow to differentiate the temporal sequence in which neuronal activation occurred. Even stronger rather than considering PAG columns as isolated entities it is possible that those interact and modulate their function. For instance, Noto et al. ([@B71]) showed that stimulation of the pelvic nerve afferents induced evoked-potentials in the dorsal PAG. The optimal site for inducing bladder contractions was in the ventral PAG. This suggests, that afferent and efferent pathways are distinct in the PAG. Based on their results they suggest, that it is unlikely that the PAG is a relay station, but raise the possibility that the dorsal part of the PAG may have modulatory effects on micturition (Noto et al., [@B71]).
Moreover, it appeared that the location of the stimulation activated the caudal, but not the rostral (dl)PAG. The meaning of this differential activation is unknown. The focus with regard to functional differences in the PAG has mostly been on the columnar structure rather than functional difference in the rostro-caudal direction. It has been shown, that specific projections from one PAG column to other brain areas (i.e., rostral ventromedial medulla) differ in the rostro-caudal axis (Loyd and Murphy, [@B59]).
These regional differences cannot be investigated by exposure to noxious compounds because they are not applied in distinct parts of the bladder. Therefore, our experimental setup provides unique insights into the columnar activation of the PAG.
Future Perspectives {#s4-9}
-------------------
To characterize and elucidate the function of the receptors involved in the activated neurons playing a role in the propagation of signals generated by the bladder, additional investigations by immunohistochemistry and *in vivo* electrophysiological experiments are required. Since several levels of the central nervous system are involved in the control of micturition, a cFos study in structures such as the prefrontal cortex, the insula and the anterior cingulate cortex should be considered to evaluate their potential influence in the processing of urinary bladder sensation elicited by electrical stimulation.
A deep understanding of complex neural circuits controlling the urinary bladder can be offer opportunities for novel modalities for OABS. Among the innovative therapeutic approaches to restore the correct functioning of the urinary bladder in OABS patients, deep brain stimulation (DBS) seems to be an attractive alternative treatment modality (Green et al., [@B40]; Stone et al., [@B83]).
Author Contributions {#s5}
====================
CM, AJ, LB, YT and GK: designing research studies. CM: conducting experiments. MC, RH and SS: acquiring data. CM, RH, SS and AZ: analyzing data. YT and GK: providing reagents. CM, SS and GK: writing the manuscript. CM, RH, AZ, AJ, LB, SS, YT and GK: reviewing the manuscript.
Conflict of Interest Statement {#s6}
==============================
CM is a Marie Skłodowska-Curie postdoctoral fellow. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We gratefully acknowledge T. Camps and J. Robinet from Medtronic for providing pacing wires. We thank HE. Steinbusch and M. Philippens for their technical support and Dr. M. Lagière for her assistance with the statistical analysis of the results.
**Funding.** This study was funded by the EU---FP7 Marie Skłodowska-Curie ITN---TRUST program.
Supplementary Material {#s7}
======================
The Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fncel.2018.00133/full#supplementary-material>
######
Schematic diagram of the dorsomedial (dm), dorsolateral (dl), lateral (l) and ventrolateral (vl) longitudinal neuronal columns of periaqueductal gray matter (PAG) along the rostro-caudal axis (from left to right on the figure) and associated representative photomicrographs of coronal brain sections stained for cFos and delineated for the PAG. Note that the dark spot on bottom left side of photomicrographs is due to an imperfection in the 4× objective but did not interfer with delineation of the columns and the quantification of the cell number performed on photomicrographs taken with 10× magnification.
######
Click here for additional data file.
######
Methodological process for the quantification of cFos immunoreactive cells. Acquisition of the photomicrographs from the region of interest with a low magnification (4x) **(A)** for the delineation of the PAG **(B)**. **(C)** Delineation of the columns of the PAG with a higher magnification (10x). **(D)** Application of a thresholding method on the delineated sections. **(E)** Manual counting of cFos positive cells.
######
Click here for additional data file.
[^1]: Edited by: Sergey M. Korogod, Bogomoletz Institute of Physiology, Ukraine
[^2]: Reviewed by: Thelma Anderson Lovick, University of Bristol, United Kingdom; Yu-Qiang Ding, Tongji University, China
[^3]: ^†^Present address: Céline Meriaux, INSERM UMR-S1172, Research group "Alzheimer and Tauopathies", Jean-Pierre Aubert Research Centre, University of Lille Nord de France, Lille, France
[^4]: ^‡^These authors have contributed equally to this work.
| 2023-09-29T01:26:51.906118 | https://example.com/article/6293 |
Tuesday, March 23, 2010
The first time I saw the Maple Leafs play live was in April 1977. They tied the Sabres 1-1. I sat in the greens near centre ice. My father wore a tie.
It was the first time I’d been in Maple Leaf Gardens and my dad must have taken me down early as we had enough time to wander around the ground level to look at all the old photos of the Leafs. Teeder Kennedy and the Queen. George Armstrong embracing the Cup.
My dad was a big Dave Keon fan and I’m sure he pointed out a few photos of #14, but Keon to me was a foreign entity, a guy with a big moustache who played in the WHA. I was so Leaf obsessed that Keon might as well have been a cricket player.
I’d like to think I remember the startling site of the bright white ice that you could glimpse through the doors in the reds or the size of the score clock hanging over centre ice. I certainly remember the skinny stuttering single file escalators with their crenulated round tube-like handles that took you up from the golds through the reds and into the greens. I doubt those memories came from that first game but they’re certainly something I still carry with me.
I do know we were in our seats for the warm up. So many pucks on the ice, the silence of shots hitting mesh, maybe a little Jimmy Holstrom on the organ.
I don’t recall much about the game. I have no idea who scored, who started in net or who carried the play. I can picture the Sabres in their road blues and the Leafs in their beautiful home whites with those giant silver TV lights shining down…
Tonight, I’m taking my six year old daughter to her very first Leaf game.
We’ve been to the ACC for the Leafs skills competition and a Raptors game, but somehow those events don’t carry the same weight. They don’t seem like milestones in the life of a Toronto kid.
I won’t be wearing a tie, but we will get down to the rink early. I’ll show her pictures of Sittler and Salming; hopefully I’ll be able to find one of Palmateer, my favourite boyhood Leaf. If there’s one of Keon, I’ll be sure to point him out too. Her grandfather might like that. I know she’ll look for one of Mats Sundin, who remains her favourite Leaf.
We’ll take the thoroughly modern and boring escalators up to the Purples in time to watch the warm-up.
I don’t know if she’ll manage to stay-awake for the whole game, I don't even think that matters. I do hope the night creates a strong memory or two that she’ll carry with her the way I carry that memory of a long ago night in a hockey rink, sitting in the greens with my dad. | 2024-05-20T01:26:51.906118 | https://example.com/article/2818 |
Intelligent Mail is a linear postal barcode symbology, which is also named as USPS Intelligent Mail Barcode, OneCode 4CB, USPS 4CB, USPS OneCode Solution Barcode, USPS IM. It is widely used in sorting and tracking mails.
To add the created barcodes in html or aspx pages, insert the following image tag into your web pages. <img src = "http://localhost/barcode/barcode.aspx?symbology=32&code-to-encode=12345678901234567890"/> | 2023-12-31T01:26:51.906118 | https://example.com/article/9646 |
Treatment of small vessel primary CNS vasculitis in children: an open-label cohort study.
There is no treatment protocol or standardised documentation of neurological outcome for patients with small vessel childhood primary angiitis of the CNS, a rare inflammatory brain disease. We aimed to assess a treatment regimen and describe long-term neurological outcomes in a cohort of children with this disorder. We did a single-centre open-label cohort study in children with small vessel childhood primary angiitis of the CNS who were less than 18 years old at diagnosis. The treatment protocol consisted of induction therapy with steroids and pulses of intravenous cyclophosphamide followed by maintenance therapy with either azathioprine or mycophenolate mofetil. Clinical and neurological assessments, quality of life measures, and laboratory markers were done at baseline, 3, 6, 9, 12, 18, and 24 months, and every year thereafter. Brain imaging was done at baseline, 6, 12, 18, and 24 months. The primary outcome was the paediatric stroke outcome measure (PSOM) score at 24 months. From January, 2002, to December, 2009, 127 patients were enrolled, 19 of whom met the inclusion criteria and were given induction therapy. Median age at diagnosis was 9·8 years (range 5·5-17·8) and median follow-up was 33 months (range 1-86). 14 patients completed induction and received maintenance therapy with azathioprine (n=9) or mycophenolate mofetil (n=5). 13 patients completed 24 months' follow-up, nine of whom had a good neurological outcome by PSOM. Eight of 19 patients experienced disease flares. Four patients achieved remission of disease off medication. This treatment protocol of immunosuppressive therapy may improve long-term neurological outcome in children with small vessel childhood primary angiitis of the CNS. Identification and appropriate diagnosis of children with the disorder is crucial because with standardised treatment good neurological outcome is a realistic goal. None. | 2024-07-01T01:26:51.906118 | https://example.com/article/5589 |
Newsweek
Newsweek is a weekly news magazine covering current events and politics in America. Newsweek magazine is published by Newsweek, Inc. and is headquartered in New York, N.Y. It has been published since 1933 and is currently owned by Sidney Harman. Newsweek covers national news and is the second largest weekly news magazine in the United States, behind Time Magazine. Newsweek was founded in 1933 as News-Week by Thomas J.C. Martyn, a former foreign Time magazine editor. At that time, the magazine cost 10 cents a copy and $4 per year. The name changed to Newsweek in 1937 and it merged with Raymond Moley's weekly magazine, Today. Moley was a member of Franklin D. Roosevelt's "Brain Trust" and to distinguish itself from its competition, Time, which had a similar format, Newsweek carved a reputation for itself as being more liberal and serious in tone. It was the first to assign writer by-lines for its editorial columns. The Washington Post Company bought the magazine in 1961 and its liberal publisher, Katharine Graham, continued to set the publication apart from its two main competitors (Time and U.S. News & World Report). Starting in 2008, the company went through massive restructuring and suffered a reported 50 percent in subscriber rate loss in one year and $28 million in revenue in 2009. The magazine was sold to stereo pioneer Sidney Harman, who is husband to California Congresswoman Jane Harman, in August 2010. Newsweek's editor Jon Meacham's resignation from the magazine coincided with the sale. 52 percent of the readership are men and 47 percent are women. The average age of readers is 52 and 88 percent have either attended or graduated from college. The average personal income of its readers is $99,792.In the 1950s, Newsweek became a leader in in-depth reporting of racial diversity and in the 1960s, under then-editor Osborn Elliott, it became a voice for advocacy journalism, where subjective political positions are countebalanced with facts. In August 1976, Newsweek reported that federal investigators had enough evidence to prove that former Teamsters Union boss James Hoffa was strangled to death July 30, 1974, the day he disappeared outside a suburban Detroit restaurant. The article further reported that the murder was planned and executed outside Michigan. In 1998, Newsweek killed a story about White House intern Monica Lewinsky's sexual relationship with President Bill Clinton. The story broke on news aggregate website, the Drudge Report, which reported that Newsweek's reporter, Michael Isikoff, had gathered enough evidence from sources to publish the story and name Lewinsky, when at the last minute the magazine decided to pull it. Newsweek eventually published the story after the Drudge Report made it public. The magazine is reknowned for its investigative war reporting, most recently in Iraq and Afghanistan. Daniel Klaidman is the Managing Editor.
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Byline: Tarek Masoud As Egypt's democracy fights for its life, Hosni Mubarak is at death's door. There will be no dramatic moment of closure on the era of Muhammad Hosni al-Sayyid Mubarak, the man who ruled and misruled Egypt for 30 years before...
Byline: Abigail Pesta The battle for 'personhood' heats up. It's an awkward moment at the Cheesecake Factory for Keith Mason. Over dinner in Denver recently, his wife, Jennifer, mentions she'll be giving birth to their fourth child in August....
Byline: Tina Brown Two wild men hang out together. One insane celebrity deserves another. The writer of the piece this week on Charlie Sheen is Michael Ware, the blaspheming, crooked-nosed Australian war correspondent whose unnerving reporting... | 2024-03-12T01:26:51.906118 | https://example.com/article/8330 |
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