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Characterization of a whole smoke in vitro exposure system (Burghart Mimic Smoker-01).
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In vitro systems are frequently used to study mechanisms of mainstream cigarette smoke (MS)-induced lung injury. Traditional methods of exposure involve the capture of MS particulate phase with filter pads or bubbling MS through phosphate buffered saline (PBS) or cell culture medium. Although useful for in vitro experiments, these exposure methods may fail to capture potential interactions between the gas and particulate phases. To better understand the effect of MS on the human airway, in vitro whole smoke exposure systems that utilize freshly generated whole smoke are needed. Here we report the characterization of a new in vitro whole smoke exposure system (Burghart Mimic Smoker-01 (MSB-01)). This system uses a smoke distribution manifold to simultaneously deliver MS to each well of a 96-well plate. Intraday and interday variations for particulate matter deposition were less than 5% and 13% respectively. Cytotoxicity measurements using lung epithelial BEAS-2B cells indicate variations in calculated EC(50) (half maximal effective concentration) values of 13% intraday and 20% interday. Smoke particulate losses and changes in particle size distribution were also analyzed. The data indicate that 45-50% of the MS generated at the smoking ports is lost within the system prior to delivery into the exposure chamber; however, no changes in particle size distribution were detected throughout the system. Overall, the MSB-01 reproducibly delivered mainstream cigarette smoke in a dose dependent manner across the multiwell plate. The MSB-01 is a high throughput system capable of exposing cells to both the MS particulate and gas/vapor phases simultaneously.
| 19,016,061
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Critical parameters in the pegylation of gold nanoshells for biomedical applications: an in vitro macrophage study.
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Pegylation of gold nanoshells provides an effective means to reduce their reticuloendothelial system (RES) clearance in body. In this study, we perform a parametric investigation on the factors that would affect the macrophage uptake of gold nanoshells with the aim to optimize their pegylation and minimize their macrophage uptake. We synthesized and pegylated the gold nanoshells using methoxy-poly(ethylene glycol)-thiol and employed an in vitro macrophage assay to examine the effect of surface density of poly(ethylene glycol) (PEG), chain length of the PEG, and size of the gold nanoshells on their macrophage uptake. We have shown that a saturated surface density would minimize macrophage uptake, which could be obtained by experimental titration-based Ellman's reagent. Our results suggest that the chain length of PEG and size of gold nanoshells influence the surface density of PEG. We have also shown that PEG with molecular weight of around 2000Da and a size range larger than 186nm would be appropriate for facilitating a high surface density. Our in vitro macrophage system thus provides a good model to accurately predict the RES response to different pegylation parameters.
| 19,016,072
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Mechanisms of recombination: lessons from E. coli.
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The genetics and biochemistry of genetic recombination in E. coli has been studied for over four decades and provides a useful model system to understand recombination in other organisms. Here we provide an overview of the mechanisms of recombination and how such processes contribute to DNA repair. We describe the E. coli functions that are known to contribute to these mechanisms, step by step, and summarize their biochemical properties in relation to the role these proteins play in vivo. We feature areas of investigation that are newly emerging, as well as work that provides a historical perspective to the field. Finally, we highlight some of the questions that remain unanswered.
| 19,016,098
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The effect of alefacept on T-cell subsets and cells expressing NK receptors in lesional psoriatic skin: the effects of monotherapy and combination treatment with calcipotriol.
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To investigate the effect of weekly alefacept monotherapy 15 mg i.m. on epidermal hyperproliferation, keratinization, T-cell subsets and cells expressing NK receptors during 12 weeks of treatment. Furthermore, the addition of calcipotriol cream to alefacept treatment was studied and compared with alefacept monotherapy. Five patients participated in this study, and used weekly alefacept 15 mg i.m. combined with calcipotriol cream up to a maximum of 100 g per week. Biopsies from two lesions (one treated and another lesion not treated with calcipotriol cream) were taken at week 0 and week 12. We investigated the number of T-cell subsets (CD4, CD8, CD45RO, CD45RA, CD2, CD25), cells expressing NK receptors (CD94 and CD161), the proliferation marker Ki-67 and the keratinization marker keratin-10. Alefacept monotherapy induced a statistically significant reduction of CD4+, CD45RO+ and CD2+ cells in dermis and epidermis and CD8+ cells in epidermis at week 12. Furthermore, the keratin-10 positive epidermal surface was significantly increased at week 12. The combination of alefacept and calcipotriol cream induced a statistically significant reduction of only CD4+ and CD45RO+ cells at week 12. The number of memory effector T-cells in the psoriatic lesion is significantly decreased by alefacept, and calcipotriol cream does not seem to have an additional effect on this reduction. Cells expressing NK receptors are virtually not targeted by alefacept monotherapy or the combination.
| 19,016,104
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Occupation as described by occupational therapy students in Sweden: a follow-up study.
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This study is the second in a series of studies carried out in Sweden concerning the dimensions of the concept occupation. The specific aim of this study was to explore new and confirm previously found dimensions of the concept of occupation in the context of occupational therapy. Occupational therapy students, a few weeks from their completion of studies, were asked to write down spontaneously what they personally considered to be occupation. Forty-two women and three men, aged between 25 and 33 years, participated. Grounded theory with the constant comparative method was used to analyse the data. A coding scheme of 40 codes was used to compare new data with previously found data concerning the concept of occupation as described by occupational therapy students. Six new codes concerning occupation expanded the dimensions of the concept. Five of those were found within the doing and context dimensions. These codes defined occupation as something that depends on who is performing the occupation and where the occupation is performed. Thus, occupation is not a permanent state but also very much depends on subjective experience. Additional studies with experienced occupational therapists have been planned to further expand these findings and aim to give a stronger foundation to the concept of occupation built on empirical grounds.
| 19,016,110
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Spontaneous reduction of intracranial arachnoid cysts: a complete review.
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The aetiopathology, clinical features and treatment of arachnoid cysts (AC) are still extremely controversial topics. The posterior fossa is the second most common site of these lesions, since they are often detected in the cerebellar or cerebellar-cistern region. Despite this, almost all the cases of non-surgical reduction of an AC reported in literature concern cysts of the middle fossa, whereas only two cases of spontaneous reduction of a posterior fossa AC has been described in literature. A complete review of the literature regarding this topic has been collected and discussed. The authors present a case of spontaneous reduction of an arachnoid cyst situated along the midline of the posterior cranial fossa with regression of all neurological symptoms. This 43-year-old man presented increasing nuchal headache with vomiting and nausea, simulating subarachnoid haemorrhage. CT and MRI documented an arachnoid cyst along the midline of the posterior fossa compressing the mesencephalon. The patient did not present any family history of this pathology nor had suffered head trauma. The patient was only given analgesics to relieve painful symptoms. After 30 days, spontaneous resolution of all the neurological symptoms took place. A 2 months, MRI control documented marked reduction of the cyst without any evident brain compression. The feasibility of a wait and see policy in such cases is discussed.
| 19,016,115
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Exclusion of cervical spine instability in patients with blunt trauma with normal multidetector CT (MDCT) and radiography.
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The objective of the study was to determine if negative multidetector computed tomography (MDCT) and lateral radiography of the cervical spine effectively excludes patients with unstable cervical spine injuries. Over a period of 40 months, 6558 people were admitted to our trauma service with blunt injury and 447 (6.8%) were found to have cervical fractures. Fractures were identified by CT and/or lateral radiography. In order to rule out clinically significant instability in the absence of fracture, we identified nine patients who required any type of stabilization of the cervical spine including anterior fusion, posterior fusion and external orthosis. These patients also underwent MR of the cervical spine. Radiography, CT, and MR images and reports of these nine patients were reviewed. Nine patients without a fracture required cervical stabilization. These patients had the following abnormalities: disc herniation with canal stenosis in three, unilateral jumped facet in three, and various other soft tissue abnormalities in three, all of which were evident on CT or radiography. All nine patients had evidence for cervical spine injury or instability by MDCT. Normal MDCT and radiography appears adequate to 'clear' the cervical spine. We recommend that patients requiring cervical spine clearance undergo a complete MDCT and lateral radiograph of the cervical spine. If these studies are entirely normal, then the cervical spine may be cleared. If any abnormalities, including disc herniation, soft tissue swelling and bony malalignments are noted by radiography and/or MDCT, further studies, including MR, are indicated prior to clearance of the cervical spine.
| 19,016,118
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Effects of low-dose gamma irradiation on artemisinin content and amorpha-4,11-diene synthase activity in Artemisia annua L.
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This research work aimed to create in vitro plantlet variants of Artemisia annua through gamma irradiation. The obtained variants were then evaluated for the correlation between their artemisinin content and enzyme activity of amorpha-4,11-diene synthase (ADS), the first enzyme of the artemisinin pathway. Shoot tips from plantlets of A. annua were exposed to gamma rays at a low-dose range and transferred to hormone-free MS medium for in vitro cultivation. A dose-response curve and the value of 50% of lethal dose (LD50) were then obtained. This LD50 dose of gamma rays was used for treating another batch of shoot tips. The surviving plantlets after four subsequent subcultures were evaluated for their ability to accumulate artemisinin in correlation with the enzyme activity of ADS. The dose-response curve showed that the LD50 value was at 8 Gray (Gy). The surviving irradiated plantlets from this dose treatment had artemisinin content ranging from 0.03-0.70% (w/w) of dry weight, comparing with only 0.18% present in the original non-irradiated samples. Their correlation coefficient between the ADS activity and the artemisinin content appeared to be R2 = 0.090 for all the 18 samples tested, although, selectively, more than half of these (11 samples) showed their R2 value of as high as 0.851. There was no correlation between the artemisinin content and ADS activity found in the whole population, but the correlation was observed in the main subpopulation of the irradiated A. annua plantlets.
| 19,016,136
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A 60-Hz sinusoidal magnetic field induces apoptosis of prostate cancer cells through reactive oxygen species.
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To explore the effects of power frequency magnetic fields (MF) on cell growth in prostate cancer, DU145, PC3, and LNCaP cells were examined in vitro. The cells were exposed to various intensities and durations of 60-Hz sinusoidal MF in combination with various serum concentrations in the media. To analyze MF effects on cell growth, cell counting, trypan blue exclusion assay, Western blot analysis, flow cytometry, enzyme-linked immunosorbent assay (ELISA), semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), fluorescence microscopy, and spectrofluorometry were used. MF exposure induced significant cell growth inhibition and apoptosis in an intensity- and time-dependent manner, in which cell cycle arrest, cleaved Caspase-3, and reactive oxygen species (ROS) increased. Pretreatment with a Caspase-3 inhibitor or antioxidant, N-acetyl-L-cysteine (NAC), significantly attenuated MF-induced cell growth inhibition and cell death. Media replacement experiments failed to show any notable change in the MF effects. These results demonstrate 60-Hz sinusoidal MF-activated cell growth inhibition of prostate cancer in vitro. Apoptosis together with cell cycle arrest were the dominant causes of the MF-elicited cell growth inhibition, mediated by MF-induced ROS. These results suggest that a possibility of using 60-Hz MF in radiation therapy of prostate cancer could usefully be investigated.
| 19,016,143
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Effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on streptozotocin-induced diabetic nephropathy.
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The aim of this study was designed to investigate the possible beneficial effects of the angiotensin-converting enzyme (ACE) inhibitor, Quinapril (Q) and, the angiotensin (ang) II T(1) (AT1) receptor blocker, irbesartan (Irb), in streptozotocin (STZ)-induced diabetes in rats. The rats were randomly allotted into one of five experimental groups: A (control), B (diabetic untreated), C (diabetic treated with Q), D (diabetic treated with Irb), and E (diabetic treated with Q&Irb), each group containing 10 animals. Groups B-E received STZ. Diabetes was induced in four groups by a single intraperitoneal (i.p) injection of STZ (50 mg/kg, freshly dissolved in 5 mmol/L citrate buffer, pH 4.5). Two days after STZ treatment, development of diabetes in four experimental groups was confirmed by measuring blood glucose levels in a tail vein blood samples. Rats with blood glucose levels of 250 mg/dL or higher were considered to be diabetic. The rats in Q-, Irb-, and Q&Irb-treated groups were given Q (in a dose of 3 mg/kg body weight), Irb (5 mg/kg body weight), and Q&Irb (in a dose of 1.5 mg/kg + 2.5 mg/kg body weight) once a day orally by using intra-gastric intubation for 12 weeks starting two days after STZ injection. Treatment of Q and especially Irb reduced the glomerular size and thickening of capsular, glomerular, and tubular basement membranes; and increased amounts of mesangial matrix and tubular dilatation and renal function as compared with diabetics untreated. Notably, the better effects were obtained when Q and Irb given together. We conclude that Q, Irb, and especially Q+Irb therapy causes renal morphologic and functional improvement after STZ-induced diabetes in rats. We believe that further preclinical research into the utility of Q and Irb treatment, alone or its combination, may indicate its usefulness as a potential treatment in diabetic nephropathy (DNp).
| 19,016,156
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Policies and laws affecting Mexican-origin immigrant access and utilization of substance abuse treatment: obstacles to recovery and immigrant health.
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This article reports the results of a study carried out with 30 Mexican-origin immigrants in drug user treatment in the United States-Mexico Border city of El Paso, Texas during 2007. Qualitative, semi-structured interviews were implemented to assess the dynamic social and economic factors that affect the delivery and utilization of treatment services, with emphasis on the impact of recent immigration-related laws and policies. The research provides initial data for evidence-based intervention and reinforces the need for culturally and gender appropriate treatment services for poor immigrants and their families. The study's limitations are noted.
| 19,016,163
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Effectiveness of dual focus mutual aid for co-occurring substance use and mental health disorders: a review and synthesis of the "Double Trouble" in Recovery evaluation.
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Over 5 million adults in the United States have a co-occurring substance use disorder and serious psychological distress. Mutual aid (self-help) can usefully complement treatment, but people with co-occurring substance use and psychiatric disorders often encounter a lack of empathy and acceptance in traditional mutual aid groups. Double Trouble in Recovery (DTR) is a dual focus fellowship whose mission is to bring the benefits of mutual aid to persons recovering from co-occurring disorders. An evaluation of DTR was conducted by interviewing 310 persons attending 24 DTR meetings in New York City (NYC) in 1998 and following them up for 2 years, in 1999 and 2000. The evaluation produced 13 articles in 12 peer-reviewed journals, the main results of which are summarized here. The sample's characteristics were as follows: mean age, 40 years; women, 28%; black, 59%; white, 25%; Hispanic, 14%; never married, 63%; live in supported community residence, 53%; high school graduate or GED, 60%; arrested as adult, 63%; diagnoses of: schizophrenia, 39%; major depression, 21%; or bipolar disorder, 20%; currently prescribed psychiatric medication, 92%; primary substance used, current or past: cocaine/crack, 42%; alcohol 34%; or heroin, 11%. Overall, the findings indicate that DTR participation has both direct and indirect effects on several important components of recovery: drug/alcohol abstinence, psychiatric medication adherence, self-efficacy for recovery, and quality of life. The study also identified several "common" therapeutic factors (e.g., internal motivation and social support) and unique mutual aid processes (helper-therapy and reciprocal learning) that mediate the influence of DTR participation on recovery. For clinicians, these results underline the importance of fostering stable affiliation with specialized dual focus 12-step groups for their patients with co-occurring disorders, as part of a comprehensive recovery-oriented treatment approach.
| 19,016,171
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A comparative clinical study of the effects of the traditional Chinese medicine Jinniu capsules and lofexidine on acute heroin withdrawal symptoms.
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Jinniu capsules, comprised of herbs and marine product extracts, are traditionally used in Chinese medicine. In this randomized multicenter clinical trial we evaluated the efficacy and safety of Jinniu capsules used to treat the symptoms of heroin withdrawal, as compared with lofexidine. Two hundred and twelve patients with heroin dependence were randomly assigned to the Jinniu capsule or lofexidine treatment groups during a 10-day double-blind clinical trial. The severity of their opiate withdrawal symptoms was measured daily for 10 days. Anxiety was measured on days 0, 5, and 10. Safety assessment of the drugs included measurement of vital signs and side effects, as well as laboratory tests. Withdrawal symptom and anxiety scores decreased gradually over the treatment period, and no significant differences were found between two groups. No severe adverse events occurred during the treatment. Jinniu capsules may be an effective and safe agent in the management of opiate withdrawal.
| 19,016,185
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Sickness absence and workplace levels of satisfaction with psychosocial work conditions at public service workplaces.
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The objective of this study was to examine the impact of psychosocial work conditions on sickness absence while addressing methodological weaknesses in earlier studies. The participants were 13,437 employees from 698 public service workplace units in Aarhus County, Denmark. Satisfaction with psychosocial work conditions was rated on a scale from 0 (low) to 10 (high). Individual ratings were aggregated to workplace scores. Analysis of variance was used to compare the average number of days of yearly sickness absence in three groups with different levels of satisfaction with psychosocial work conditions. Sickness absence was 30.8% lower in the most satisfied group (11.7 days/year (CI 95%: 10.2; 13.1)) than in the least satisfied group (16.9 days/year (CI 95%: 15.3; 18.6)) adjusted for the covariates included. Satisfaction with psychosocial work conditions has a strong and independent impact on sickness absence. Am. J. Ind. Med. 52:153-161, 2009. (c) 2008 Wiley-Liss, Inc.
| 19,016,235
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Cognition following bilateral deep brain stimulation surgery of the subthalamic nucleus for Parkinson's disease.
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Parkinson's disease (PD) is a neurodegenerative disorder characterized by significant motor dysfunction and various non-motor disturbances, including cognitive alterations. Deep brain stimulation (DBS) is an increasingly utilized therapeutic option for patients with PD that yields remarkable success in alleviating disabling motor symptoms. DBS has additionally been associated with changes in cognition, yet the evidence is not consistent across studies. The following review sought to provide a clearer understanding of the various cognitive sequelae of bilateral subthalamic nucleus (STN) DBS while taking into account corresponding neuroanatomy and potential confounding variables. A literature search was performed using the following inclusion criteria: (1) at least five subjects followed for a mean of at least 3 months after surgery; (2) pre- and postoperative cognitive data using at least one standardized measure; (3) adequate report of study results using means and standard deviations. Two recent meta-analyses found mild post-operative impairments in verbal learning and executive function in patients who underwent DBS surgery. However, studies have revealed improved working memory and psychomotor speed in the 'on' vs 'off' stimulation state. A deficit in language may be a consequence of the surgical procedure. While cognitive decline has been observed in some domains, our review of the data suggests that STN DBS is a worthwhile and safe method to treat PD.
| 19,016,252
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The RelA/p65 subunit of NF-kappaB specifically regulates cyclin D1 protein stability: implications for cell cycle withdrawal and skeletal myogenesis.
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Studies support that NF-kappaB functions in cellular growth through the transcriptional regulation of cyclin D1, but whether such regulation is attributed to a single NF-kappaB subunit remains unclear. To address this issue we examined endogenous cyclin D1 levels during cell cycle re-entry in mouse embryonic fibroblasts (MEFs) lacking specific NF-kappaB signaling subunits. Results showed that each of these subunits were dispensable for regulating cyclin D1 transcription. However, we found that resulting cyclin D1 protein was severely reduced in MEFs lacking only RelA/p65. Cyclohexamide treatment revealed that this regulation was due to an increase in protein turnover. Similar downregulation of cyclin D1 protein, but not RNA, was observed in vivo in multiple tissues lacking RelA/p65. Co-immunoprecipitation analysis also showed that RelA/p65 and cyclin D1 were capable of interacting, thus providing a possible explanation for cyclin D1 protein stability. In addition, although the decrease in cyclin D1 in RelA/p65(-/-) MEFs was concomitant with lower CDK4 activity during cell cycle re-entry, this was not sufficient to affect S phase progression. Nevertheless, similar decreases in cyclin D1 protein in primary RelA/p65(-/-) myoblasts was adequate to accelerate cell cycle exit and differentiation of these cells. Based on these findings we conclude that RelA/p65 functions as a specific regulator of cyclin D1 protein stability, necessary for proper cell cycle withdrawal during skeletal myogenesis.
| 19,016,262
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Are antidepressants warranted in the treatment of patients who present suicidal behavior?
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The aim of the study was to ascertain the clinical course of patients admitted to a psychiatric intensive care unit (PICU) just after a suicide attempt (SA) and to evaluate the effectiveness of 2nd generation antipsychotics and mood stabilizers in these patients. We examined all the 129 patients discharged in a three-year period, who had been admitted after a SA and considered in the analysis the 82 cases non-transferred (in the first 72 h) to other PICUs for administrative or logistic reasons. Among them, 47 received a complete neuropsychiatric assessment. We distinguished between patients who had been treated with Antidepressants (AD) or not in the three months preceding hospitalization. We treated all patients with mood stabilizers and 2nd generation antipsychotics. Only one patient was treated with AD in the course of current hospitalization. Both cases treated and not treated with AD before admission improved significantly, especially in symptoms of anxiety and depression, as well as in suicidality. The suicidal risk abated without AD treatment. In patients with impending suicide risk, AD should not be considered standard treatment. Mood stabilizers and 2nd generation antipsychotics can be effective.
| 19,016,273
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Dosing patterns and outcomes in African American, Asian, and Hispanic patients with heparin-induced thrombocytopenia treated with argatroban.
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We retrospectively evaluated dosing patterns and 37-day outcomes in argatroban-treated African American (n = 52), Asian (n = 13), and Hispanic (n = 14) patients with heparin-induced thrombocytopenia (HIT). The Asians required a lesser median dose (1.0 microg/kg/min) than the other groups (1.9 microg/kg/min, each) to achieve comparable activated partial thromboplastin times (medians: 61-69 s). Durations of therapy were similar (medians: 4.0-5.5 days). New thrombosis occurred in 11 (21%) African Americans, 1 (8%) Asian, and 1 (7%) Hispanic; of these 13 patients, 9 (69%) had baseline HIT-related thrombosis. Amputation occurred in 6 (12%) African Americans and 3 (21%) Hispanics; of these nine patients, 6 (67%) had diabetes. One (2%) African American and 1 (7%) Hispanic died from thrombosis. The composite of death due to thrombosis, amputation due to ischemic complications of HIT, or new thrombosis occurred in 14 (27%) African Americans, 1 (8%) Asian, and 4 (29%) Hispanics. Two (4%) African Americans and none others (0%) had major bleeding. These findings suggest that despite argatroban anticoagulation, African Americans and Hispanics may have worse outcomes in HIT than Asians. In minority patients with adverse HIT outcomes, baseline HIT-related thrombosis or diabetes is often present.
| 19,016,311
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Purification and characterization of hieronymain III. Comparison with other proteases previously isolated from Bromelia hieronymi Mez.
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A new proteolytic enzyme, named hieronymain III, has been purified by ion-exchange chromatography from unripe fruits of Bromelia hieronymi Mez. The new peptidase belongs to the cysteine catalytic type, as well as hieronymain I and II, the other two peptidases previously isolated from this species. Hieronymain III showed optimum alkaline pH range (8.6-9.3) and the molecular mass (MALDI-TOF) was 23713 Da. The N-terminal sequence (AVPQSIDWRRYGAVTTSRNQG) exhibited a higher percentage identity with hieronymain II (93%) than with hieronymain I (71%). The three peptidases showed notable differences on synthetic substrates degradation: whereas hieronymain III was the only one able to hidrolyze Z-Arg-Arg-p-nitroanilide, hieronymain I and II could degrade Z-Phe-Arg-p-nitroanilide; on the other hand, PFLNA was only split by hieronymain I. Finally, the three proteases showed different preferences on N-alpha-CBZ-p-nitrophenyl aminoacid ester substrates. From a biotechnological point of view, cleavage specificity differences are significant enough to use these enzymes as potential tools in that area.
| 19,016,314
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IGF and insulin receptor signaling in breast cancer.
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Major molecular abnormalities in breast cancer include the deregulation of several components of the IGF system. It is well recognized that the epithelial breast cancer cells commonly overexpress the IGF-I receptor while IGF-II is expressed by the tumor stroma. In view to the fact that the IGF-IR has mitogenic, pro-invasive and anti-apoptotic effects and mediates resistance to a variety of anti-cancer therapies, breast cancer is expected to be a candidate to therapeutic approaches aimed to inhibit the IGF-IR. However, there is increasing awareness that IGF system in cancer undergoes signal diversification by various mechanisms. One of these mechanisms is the aberrant expression of insulin receptor (IR) isoform A (IR-A), which is a high affinity receptor for both insulin and IGF-II, in breast cancer cells. Moreover, overexpression of both IGF-IR and IR-A in breast cancer cells, leads to overexpression of hybrid IR/IGF-IR receptors (HRs) as well. Upon binding to IGF-II, both IR-A and HRs may activate unique signaling patterns, which predominantly mediate proliferative effects. A better understanding of IGF system signal diversification in breast cancer has important implications for cancer prevention measures, which should include control of insulin resistance and associated hyperinsulinemia. Moreover, in addition to the IGF-IR, both IR-A and HRs should be also considered as molecular targets for anti-cancer therapies.
| 19,016,312
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Potential of cyclodextrin complexation and liposomes in topical delivery of ketorolac: in vitro and in vivo evaluation.
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The objective of this investigation was to evaluate the effect of delivery strategies such as cyclodextrin complexation and liposomes on the topical delivery of ketorolac acid (KTRA) and ketorolac tromethamine. Ketorolac acid-hydroxypropyl-beta-cyclodextrin solid dispersions (KTRA-CD) were prepared by kneading method. The liposomes containing ketorolac tromethamine (KTRM) and KTRA-CD were prepared. The in vitro permeation of KTRM solution, KTRA solution, KTRA-CD, and liposomes containing KTRM or KTRA-CD through guinea pig skin was evaluated. The anti-inflammatory activity of the topically applied KTRA-CD gel (containing 1% w/w KTRA) was compared to that of orally delivered KTRM solution. The KTRA-CD demonstrated significantly higher transdermal transport of ketorolac as compared to all other systems whereas liposomes significantly reduced the transport of ketorolac. The anti-inflammatory activity of the topically applied KTRA-CD gel was similar to that of the orally administered KTRM. Thus, cyclodextrin complexation enabled effective transdermal delivery of the ketorolac.
| 19,016,331
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Seroprevalence of Neospora caninum antibodies in beef cattle in three southern states of Mexico.
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The aims of the present study were to examine the seroprevalence of neosporosis in beef herds from three southern states of Mexico and determine the association with several risk factors. A cross-sectional serological survey for Neospora caninum was carried out by sampling a total of 596 animals from 31 herds in Chiapas, Veracruz, and Yucatan States and tested using an ELISA assay (IDEXX) to detect anti-N. caninum antibodies. The overall prevalence was 11.6%, (95% CI: 0.93-0.14), however, the prevalence for Chiapas was 15% (30/200) (95% CI: 0.11-0.21), in Yucatan 11.3% (21/186) (95% CI: 0.07-0.17) and in Veracruz 8.6% (18/210) (95% CI: 0.05-0.13). Of the 596 serum samples taken, 578 were from females and 18 were bulls., Only one bull sample was found seropositive from one herd in Veracruz State. The overall herd-prevalence was 70.9% (22/31) (95% CI: 0.53-0.84), and by State was: Chiapas 90% (9/10) (95% CI: 0.60-0.98); Yucatan 72.7% (8/12) (95% CI: 0.39-0.86); and Veracruz 50% (5/10) (95% CI: 0.24-0.76), respectively. The highest age-prevalences were found in animals 1 yr old (19.4% [95% CI: 0.01-0.35]) and 4 yrs old (19.6% [95% CI: 0.12-0.29]), and the lowest in animals 3 -yrs of age (6.2%,[95% CI: 0.02-0.20]). No association was found among all the variables tested in this study since most of the ranches have similar management conditions. In conclusion, N. caninum infection is common among beef herds in the Mexican tropics.
| 19,016,341
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PCNA indexing as a preclinical immunohistochemical biomarker for testicular toxicity.
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It is well known that toxicants such as cyclophosphamide and ethanol can have deleterious effects on normal spermatogenesis. End points such as testis weight and sperm counts have been used widely to assess gross structural and functional changes in testes resulting from toxicant exposure. Histopathological assessments are more sensitive measures of testicular health, but generally they are neither quantitative nor sensitive enough to detect early toxicity. Recently, immunolabeling cells with proliferating cell nuclear antigen (PCNA) has been used to identify proliferating spermatogonia; however, there have been no systematic attempts to quantify these changes. We have developed a sensitive, reliable and quantitative assay using immunohistochemistry on formalin fixed, paraffin embedded rat testes to assess the degree of proliferation-related toxicity. An indexing scheme was derived based on the determination of radially positioned PCNA-positive cells within similarly staged seminiferous tubules presenting a single layer of PCNA-positive cells along the basement membrane of the basal tubular compartment. An average of 60 tubules in the testes were counted per animal. Our results show significant decreases in the PCNA index in rats treated with an experimental compound that has been shown to produce testicular histopathology. The analysis provides a quick, reliable, sensitive, and quantitative means for assessing early testicular toxicity. The assay has potential utility as an in vivo biomarker for detecting early testicular toxicity of experimental compounds in preclinical development as well as for refining follow-up compounds with reduced testicular toxicity.
| 19,016,366
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Zhangfei, a novel regulator of the human nerve growth factor receptor, trkA.
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The replication of herpes simplex virus (HSV) in epithelial cells, and during reactivation from latency in sensory neurons, depends on a ubiquitous cellular protein called host cell factor (HCF). The HSV transactivator, VP16, which initiates the viral replicative cycle, binds HCF as do some other cellular proteins. Of these, the neuronal transcription factor Zhangfei suppresses the ability of VP16 to initiate the replicative cycle. It also suppresses Luman, another cellular transcription factor that binds HCF. Interactions of nerve growth factor (NGF) and its receptor tropomyosin-related kinase (trkA) appear to be critical for maintaining HSV latency. Because the neuronal transcription factor Brn3a, which regulates trkA expression, has a motif for binding HCF, we investigated if Zhangfei had an effect on its activity. We found that Brn3a required HCF for activating the trkA promoter and Zhangfei suppressed its activity in non-neuronal cells. However, in neuron-like NGF-differentiated PC12 cells, both Brn3a and Zhangfei activated the trkA promoter and induced the expression of endogenous trkA. In addition, capsaicin, a stressor, which activates HSV in in vitro models of latency, decreased levels of Zhangfei and trkA transcripts in NGF-differentiated PC12 cells.
| 19,016,376
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[Alveolar ventilation and recruitment under lung protective ventilation].
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Goal of mechanical ventilation is to improve gas exchange and reduce work of breathing without contributing to further lung injury. Besides providing adequate EELV and thereby arterial oxygenation PEEP in addition to a reduction in tidal volume is required to prevent cyclic alveolar collapse and tidal recruitment and hence protective mechanical ventilation. Currently, there is no consensus if and if yes at which price alveolar recruitment with high airway pressures should be intended ("open up the lung"), or if it is more important to reduce the mechanical stress and strain to the lungs as much as possible ("keep the lung closed"). Potential of alveolar recruitment differs from patient to patient but also between lung regions. Potential for recruitment depends probably more on regional lung mechanics - especially on lung elastance - than on the underlying disease. Based on available data neither high PEEP nor other methods used for alveolar recruitment could demonstrate a survival benefit in patients with ARDS. These results may support an individualized titration of PEEP or other manoeuvres used for recruitment taking into consideration the regional effects. Bedside imaging techniques allowing titration of PEEP or other manoeuvres to prevent end-expiratory alveolar collapse (tidal recruitment) and inspiratory overinflation may be a promising development.
| 19,016,388
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[Lumbar spinal stenosis--claudicatio spinalis. Pathophysiology, clinical aspects and treatment].
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The lumbar spinal stenosis (LSS) is defined as a narrowing of the spinal canal together with neuronal and vascular structures via circumjacent bone and soft tissue. In patients aged over 65 years, the LSS is among the most frequent causes of lumbago, either with or without sciatica. The prevalence will continue to augment because of the increased life expectancy. The leading symptom is neurogenic claudicatio with lumbogluteal or sciatic pain, which occurs while walking and leads to a limitation of the walking distance. Its typical constellation of symptoms including subjective leg weakness is leading to the tentative diagnosis. Nowadays, the imaging technique of choice for the diagnosis is magnetic resonance imaging. A conservative treatment is initially sufficient in most cases. The indication for surgery is given, if the pain and limitation of walking distance are not tolerable any more. Additional fusion should be taken into account, when degenerative spondylolisthesis or other pathomorphological alterations result in an instability. Conservative and surgical therapeutic goals imply pain relief, amelioration of the physical functionality, mobility and general quality of life.
| 19,016,422
|
Activation of murine macrophages.
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Our understanding of cell mediated immunity (CMI) has revealed the importance of activated macrophages as key immune effector cells. Over the past decade, we have come to realize that macrophages exhibit remarkable plasticity, and different populations of macrophages with distinct physiologies can develop in response to different stimuli. In fact, it is likely that the number of different macrophage populations that can arise may be as diverse as the activating stimuli that induce them. Some of these stimuli can instruct macrophages to kill microbes (classical activation), lay down extracellular matrix components to promote wound healing (alternative activation), or secrete anti-inflammatory cytokines to terminate inflammation (regulatory macrophages). New ways to biochemically identify these cells have led to a better understanding of the heterogeneity of activated macrophages. As our understanding of the various macrophage populations increases, so does the potential for therapeutic intervention based on targeting specific populations of activated macrophages.
| 19,016,446
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Comparison between ticlopidine and clopidogrel in patients undergoing primary stenting in acute myocardial infarction: results from the CADILLAC trial.
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The aim of this article is to examine whether clopidogrel and ticlopidine treatments produce similar clinical outcomes for patients receiving primary stenting for acute myocardial infarction (AMI). Prior studies have yielded conflicting results on the relative safety and efficacy of clopidogrel and ticlopidine after stent implantation, warranting an evaluation in primary stenting for AMI. In the multicenter, prospective CADILLAC trial, patients undergoing primary infarct stenting were treated at operator discretion with either ticlopidine (931 patients) or clopidogrel (163 patients) and then followed for 1 year. Baseline clinical and angiographic characteristics were comparable except for baseline TIMI 0/1 flow (72.5% clopidogrel vs. 63.9% ticlopidine, P = 0.04). Patients receiving clopidogrel had more recurrent ischemia in hospital (6.1 vs. 2.8%, P = 0.02) and at 30 days (10.5 vs. 5.8%, P = 0.02), more moderate and severe bleeding at 30 days (7.4 vs. 2.7%, P = 0.002), and similar rates of stent thrombosis out to 1 year (P = 0.11). By multivariable analysis, clopidogrel use was an independent predictor for recurrent ischemia in hospital (P = 0.0002), and at 30 days (P = 0.012); and of moderate and severe bleeding in hospital (P = 0.002), and at 30 days (P = 0.001). Despite thienopyridines similarities, their efficacy may be different within the first 30 days of primary stenting for AMI. A prospective, randomized trial is required to confirm these findings.
| 19,016,469
|
Kir 2.2 inward rectifier potassium channels are inhibited by an endogenous factor in Xenopus oocytes independently from the action of a mitochondrial uncoupler.
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We previously showed inhibition of K(ir)2 inward rectifier K(+) channels expressed in Xenopus oocytes by the mitochondrial agents carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and sodium azide. Mutagenesis studies suggested that FCCP may act via phosphatidylinositol 4,5-bisphosphate (PIP(2)) depletion. This mechanism could be reversible in intact cells but not in excised membrane patches which preclude PIP(2) regeneration. This prediction was tested by investigating the reversibility of the inhibition of K(ir)2.2 by FCCP in intact cells and excised patches. We also investigated the effect of FCCP on K(ir)2.2 expressed in human embryonic kidney (HEK) cells. K(ir)2.2 current, expressed in Xenopus oocytes, increased in inside-out patches from FCCP-treated and untreated oocytes. The fraction of total current that increased was 0.79 +/- 0.05 in control and 0.89 +/- 0.03 in 10 microM FCCP-treated (P > .05). Following "run-up," K(ir)2.2 current was re-inhibited by "cramming" inside-out patches into oocytes. Therefore, run-up reflected not reversal of inhibition by FCCP, but washout of an endogenous inhibitor. K(ir)2.2 current recovered in intact oocytes within 26.5 h of FCCP removal. Injection of oocytes with 0.1 U apyrase completely depleted ATP (P < .001) but did not inhibit K(ir)2.2 and inhibited K(ir)2.1 by 35% (P < .05). FCCP only partially reduced [ATP] (P < .001), despite inhibiting K(ir)2.2 by 75% (P < .01) but not K(ir)2.1. FCCP inhibited K(ir)2.2 expressed in HEK cells. The recovery of K(ir)2.2 from inhibition by FCCP requires intracellular components, but direct depletion of ATP does not reproduce the differential inhibitory effect of FCCP. Inhibition of K(ir)2.2 by FCCP is not unique to Xenopus oocytes.
| 19,016,473
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Evidence for association between polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence.
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Genomic studies of cannabis use disorders have been limited. The cannabinoid receptor 1 gene (CNR1) on chromosome 6q14-15 is an excellent candidate gene for cannabis dependence due to the important role of the G-protein coupled receptor encoded by this gene in the rewarding effects of Delta9-tetrahydrocannabinol. Previous studies have found equivocal evidence for an association between SNPs in CNR1 and a general vulnerability to substance use disorders. We investigate the association between 9 SNPs spanning CNR1 and cannabis dependence in 1,923 individuals. Two SNPs that were previously associated with cannabis dependence in other studies were also significant with this phenotype in our analyses [rs806368 (P = 0.05) and rs806380 (P = 0.009)]. Haplotype analyses revealed the association to be largely driven by the SNP rs806380. These results suggest a role for the cannabinoid receptor 1 gene in cannabis dependence.
| 19,016,476
|
Tagging SNP association study of the IL-1beta gene (IL1B) and childhood-onset mood disorders.
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Given substantial evidence for IL-1beta involvement in the etiology of depression, the IL1B gene is a strong candidate for involvement in susceptibility to depressive disorders. However, association studies investigating this, to date, have been limited to just two polymorphisms (rs1143627[-31T/C] and rs16944[-511C/T]) that constitute only a fraction of the genetic variation that is actually present across this gene in the population. Here, in a family-based association study of childhood-onset mood disorders (COMD), characterized by onset of depression before the age of 15, we have used a gene-wide approach, employing a panel of five tagging SNPs spanning the entire gene. Based on TDT analyses of both individual alleles and haplotypes, in a study sample of 646 families (with 782 affected children), none of the SNPs, including those implicated in transcriptional regulation of the gene, showed evidence for association with COMD. This is the largest and most comprehensive study of IL1B in relation to mood disorders that has been carried out, to date. The results do not support the involvement of IL1B as a major factor in genetic risk for early-onset mood disorders.
| 19,016,479
|
Depression, anxiety, and functional impairment in children with trichotillomania.
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Trichotillomania (TTM) remains understudied in children. Adult research suggests that TTM is accompanied by significant depression, anxiety, and functional impairment. The purpose of this study is to examine the occurrence of depression and anxiety in a relatively large sample of youth with TTM and the extent to which these symptoms mediate the relationship between TTM severity and associated impairment. The study utilized data from the Child and Adolescent Trichotillomania Impact Project (CA-TIP), an internet-based sample of 133 youth aged 10-17 (inclusive) with TTM. Over 45% of children with TTM endorsed depressive symptoms and 40% endorsed anxiety symptoms in excess of one standard deviation (SD) above published community norms. More remarkably, 25% of our sample reported depressive and 20% reported anxiety symptoms in excess of 2 SD above these norms. Older participants reported more symptoms of depression and anxiety than younger ones; age of onset (children with later onset), but not duration of illness, was predictive of higher reports of both depressive and anxiety symptoms. Neither depressive nor anxiety symptoms were related to pulling site. Depressive symptoms partially mediated the relationship between TTM severity and functional impairment. Based on an internet sample recruited from the homepage of the Trichotillomania Learning Center, data from this study suggests that symptoms of depression and anxiety may be pervasive among youth with TTM and likely impact functional impairment. Longitudinal studies using directly assessed samples are needed to replicate and extend these findings.
| 19,016,486
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Acute and chronic effects of citalopram on 5-HT1A receptor-labeling by [18F]MPPF and -coupling to receptors-G proteins.
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Selective serotonin reuptake inhibitors take several weeks to produce their maximal therapeutic antidepressant effect. This delay has been attributed to the gradual desensitization of somatodendritic serotonin 5-HT(1A) autoreceptors. We evaluated adaptive changes of 5-HT(1A) receptors after acute and chronic citalopram challenges in rat. Small animal positron emission tomography trial and quantitative ex vivo autoradiography studies using [(18)F]MPPF were employed, as well as in vitro 8-OH-DPAT-stimulated [(35)S]-GTPgammaS binding assay. Additionally, 5-HT(1A) receptor knock-out mice were used to assess the specificity of [(18)F]MPPF. Acute treatment with citalopram did not alter [(18)F]MPPF binding in dorsal raphe nucleus (DR), frontal cortex, or hippocampus. The absence of [(18)F]MPPF binding in the brain of 5-HT(1A) knock-out mice demonstrates the specificity of MPPF for 5-HT(1A) receptor brain imaging, but the high affinity of [(18)F]MPPF compared to 5-HT suggests that it would only be displaced by dramatic increases in extracellular 5-HT. Chronic citalopram did not modify 5-HT(1A) receptor density in any of the brain regions studied. In addition, this treatment did not modify 8-OH-DPAT-stimulated [(35)S]-GTPgammaS binding in DR, although a significant increase was observed in frontal cortex and hippocampus. [(18)F]MPPF appears to be an efficient radioligand to quantify specifically 5-HT(1A) receptor density in brain imaging. The delayed therapeutic efficacy of citalopram did not appear to be linked to either a downregulation of 5-HT(1A) receptors or to a 5-HT(1A) receptor-G protein decoupling process in serotonergic neurons, but to increased functional sensitivity of postsynaptic 5-HT(1A) receptors.
| 19,016,488
|
Proteomics in South Africa: current status, challenges and prospects.
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Proteomics is a biotechnology research area that is generally defined as the large-scale study of protein expression, structure and functions. Primarily, proteomics is used to study relative cellular, subcellular and extracellular abundances of proteins expressed at a defined physiological state on a large scale. In contrast to the analysis of mRNA expression studies, generally referred to as transcriptomics, proteomics approaches take into consideration the post-transcriptional, translational and post-translational modifications of polypeptides. Over the past 10 years, the proteomics field has been growing tremendously and contributing positively to biotechnology, particularly in North America, Europe and Asia. Research output in Africa is still very low in comparison. This article reviews proteomics capacity as well as research activities in South Africa. We highlight, with examples, the potential that this technology has in the acceleration of disease biomarker discovery and its role in drug design. Our ultimate objective is to promote further developments, research and applications of proteomics in South Africa, aiming for the generation of new scientific knowledge for our continent and for the rest of the world.
| 19,016,510
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Modified cetyltrimethylammonium bromide method improves robustness and versatility: the benchmark for plant RNA extraction.
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A wide range of plant RNA extraction methods are available; however, many of these are limited in their application for a diverse range of plant species. With special emphasis on robustness and versatility, we have improved the cetyltrimethylammonium bromide (CTAB) method and isolated high-quality RNA from 16 different plant species. The major modifications made to the protocol described here were a reduction of sample treatment steps and an increase in beta-mercaptoethanol concentration (to 3%) resulting in a robust, rapid and reproducible plant RNA extraction protocol that can be used for a broad range of plant species and tissue types.
| 19,016,512
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Development, scope and mechanisms of multicomponent reactions of asymmetric electron-deficient alkynes with amines and formaldehyde.
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Based on the reactive behaviour of the substrates, two synthetic routes to polysubstituted pyrimidine derivatives are presented herein: 1) A catalyst-free multicomponent reaction of electron-deficient alkynes, aliphatic amines and formaldehyde and 2) Ag(I)-catalyzed synthesis of pyrimidines from electron-deficient alkynes, anilines and formaldehyde by a domino reaction. Under optimized conditions, the multicomponent reactions were accomplished with high regioselectivity and excellent yields. A computational study was carried out by using the B3LYP density functional theory to elucidate the mechanisms of the catalyst-free hydroamination reaction. Calculations showed the activation free energies of aliphatic amines were lower than those of anilines, which is consistent with the experimental results.
| 19,016,558
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Folding and anion-binding properties of fluorescent oligoindole foldamers.
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A series of oligoindole foldamers 1 a-d that are highly fluorescent were prepared by using a biindole derivative as the repeating unit, and their folding and anion-binding properties were revealed by (1)H NMR and fluorescence spectroscopy. The oligoindoles exist in an extended conformation, but adopt a compact helical structure in the presence of an anion. The anion is entrapped inside the tubular cavity of the helical strand, comprising four aryl units per turn, by multiple hydrogen bonds with the indole NHs. These structural features were confirmed by (1)H NMR and fluorescence spectroscopy. When folded by anion binding, 1 b-d show characteristic downfield shifts of the NH signals and upfield shifts of the aromatic CH signals by Deltadelta=0.1-1.0 ppm. The average chemical shift for all the aromatic signals of 1 a-d is more upfield shifted as the chain lengthens, as anticipated from the degree of overlapped aromatic surfaces in the helical strand. Moreover, 1 a-d are strongly fluorescent in the absence of an anion. Upon binding an anion such as a chloride, the shorter oligoindoles 1 a and b lead to negligible change in the emission spectra, whereas the longer ones 1 c and d result in dramatic changes, that is, large hypochromic and bathochromic shifts (Deltalambda=65 and 70 nm) of the emission band, confirming the helical folding. The association constants (K(a)) between oligoindoles and tetrabutylammonium chloride strongly depend on the chain length; <1 M(-1) for 1 a, 630 M(-1) for 1 b, 1.1x10(5) M(-1) for 1 c, and 2.9x10(5) M(-1) for 1 d in 20 % (v/v) MeOH/CH(2)Cl(2) at 24+/-1 degrees C. In addition, the association constants of 1 c and 1 d with other anions such as fluoride, bromide, iodide, azide, cyanide, acetate, and nitrate are determined to be in the order of 10(3)-10(6) M(-1) under the same conditions.
| 19,016,560
|
Analgo-sedation of patients with burns outside the operating room.
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Following the initial resuscitation of burn patients, the pain experienced may be divided into a 'background' pain and a 'breakthrough' pain associated with painful procedures. While background pain may be treated with intravenous opioids via continuous infusion or patient-controlled analgesia (PCA) and/or less potent oral opioids, breakthrough pain may be treated with a variety of interventions. The aim is to reduce patient anxiety, improve analgesia and ensure immobilization when required. Untreated pain and improper sedation may result in psychological distress such as post-traumatic stress disorder, major depression or delirium. This review summarizes recent developments and current techniques in sedation and analgesia in non-intubated adult burn patients during painful procedures performed outside the operating room (e.g. staple removal, wound-dressing, bathing). Current techniques of sedation and analgesia include different approaches, from a slight increase in background pain therapy (e.g. morphine PCA) to PCA with rapid-onset opioids, to multimodal drug combinations, nitrous oxide, regional blocks, or non-pharmacological approaches such as hypnosis and virtual reality. The most reliable way to administer drugs is intravenously. Fast-acting opioids can be combined with ketamine, propofol or benzodiazepines. Adjuvant drugs such as clonidine or NSAIDs and paracetamol (acetaminophen) have also been used. Patients receiving ketamine will usually maintain spontaneous breathing. This is an important feature in patients who are continuously turned during wound dressing procedures and where analgo-sedation is often performed by practitioners who are not specialists in anaesthesiology. Drugs are given in small boluses or by patient-controlled sedation, which is titrated to effect, according to sedation and pain scales. Patient-controlled infusion with propofol has also been used. However, we must bear in mind that burn patients often show an altered pharmacokinetic and pharmacodynamic response to drugs as a result of altered haemodynamics, protein binding and/or increased extracellular fluid volume, and possible changes in glomerular filtration. Because sedation and analgesia can range from minimal sedation (anxiolysis) to general anaesthesia, sedative and analgesic agents should always be administered by designated trained practitioners and not by the person performing the procedure. At least one individual who is capable of establishing a patent airway and positive pressure ventilation, as well as someone who can call for additional assistance, should always be present whenever analgo-sedation is administered. Oxygen should be routinely delivered during sedation. Blood pressure and continuous ECG monitoring should be carried out whenever possible, even if a patient is undergoing bathing or other procedures that may limit monitoring of vital pulse-oximetry parameters.
| 19,016,572
|
Focal adhesion kinase is important for fluid shear stress-induced mechanotransduction in osteoblasts.
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Mechanical loading of bone is important for maintenance of bone mass and structural stability of the skeleton. When bone is mechanically loaded, movement of fluid within the spaces surrounding bone cells generates fluid shear stress (FSS) that stimulates osteoblasts, resulting in enhanced anabolic activity. The mechanisms by which osteoblasts convert the external stimulation of FSS into biochemical changes, a process known as mechanotransduction, remain poorly understood. Focal adhesions are prime candidates for transducing external stimuli. Focal adhesion kinase (FAK), a nonreceptor tyrosine kinase found in focal adhesions, may play a key role in mechanotransduction, although its function has not been directly examined in osteoblasts. We examined the role of FAK in osteoblast mechanotransduction using short interfering RNA (siRNA), overexpression of a dominant negative FAK, and FAK(-/-) osteoblasts to disrupt FAK function in calvarial osteoblasts. Osteoblasts were subjected to varying periods oscillatory fluid flow (OFF) from 5 min to 4 h, and several physiologically important readouts of mechanotransduction were analyzed including: extracellular signal-related kinase 1/2 phosphorylation, upregulation of c-fos, cyclooxygenase-2, and osteopontin, and release of prostaglandin E(2). Osteoblasts with disrupted FAK signaling exhibited severely impaired mechanical responses in all endpoints examined. These data indicate the importance of FAK for both short and long periods of FSS-induced mechanotransduction in osteoblasts.
| 19,016,591
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Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing.
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The role of osteoclast-mediated resorption during fracture healing was assessed. The impact of two osteoclast inhibitors with different mechanisms of action, alendronate (ALN) and denosumab (DMAB), were examined during fracture healing. Male human RANKL knock-in mice that express a chimeric (human/murine) form of RANKL received unilateral transverse femur fractures. Mice were treated biweekly with ALN 0.1 mg/kg, DMAB 10 mg/kg, or PBS (control) 0.1 ml until death at 21 and 42 days after fracture. Treatment efficacy assessed by serum levels of TRACP 5b showed almost a complete elimination of TRACP 5b levels in the DMAB-treated animals but only approximately 25% reduction of serum levels in the ALN-treated mice. Mechanical testing showed that fractured femurs from both ALN and DMAB groups had significantly increased mechanical properties at day 42 compared with controls. muCT analysis showed that callus tissues from DMAB-treated mice had significantly greater percent bone volume and BMD than did both control and ALN-treated tissues at both 21 and 42 days, whereas ALN-treated bones only had greater percent bone volume and BMC than control at 42 days. Qualitative histological analysis showed that the 21-and 42-day ALN and DMAB groups had greater amounts of unresorbed cartilage or mineralized cartilage matrix compared with the controls, whereas unresorbed cartilage could still be seen in the DMAB groups at 42 days after fracture. Although ALN and DMAB delayed the removal of cartilage and the remodeling of the fracture callus, this did not diminish the mechanical integrity of the healing fractures in mice receiving these treatments. In contrast, strength and stiffness were enhanced in these treatment groups compared with control bones.
| 19,016,594
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Neural substrates of visuospatial processing in distinct reference frames: evidence from unilateral spatial neglect.
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There is evidence for different levels of visuospatial processing with their own frames of reference: viewer-centered, stimulus-centered, and object-centered. The neural locus of these levels can be explored by examining lesion location in subjects with unilateral spatial neglect (USN) manifest in these reference frames. Most studies regarding the neural locus of USN have treated it as a homogenous syndrome, resulting in conflicting results. In order to further explore the neural locus of visuospatial processes differentiated by frame of reference, we presented a battery of tests to 171 subjects within 48 hr after right supratentorial ischemic stroke before possible structural and/or functional reorganization. The battery included MR perfusion weighted imaging (which shows hypoperfused regions that may be dysfunctional), diffusion weighted imaging (which reveals areas of infarct or dense ischemia shortly after stroke onset), and tests designed to disambiguate between various types of neglect. Results were consistent with a dorsal/ventral stream distinction in egocentric/allocentric processing. We provide evidence that portions of the dorsal stream of visual processing, including the right supramarginal gyrus, are involved in spatial encoding in egocentric coordinates, whereas parts of the ventral stream (including the posterior inferior temporal gyrus) are involved in allocentric encoding.
| 19,016,599
|
Unification of speaker and meaning in language comprehension: an FMRI study.
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When interpreting a message, a listener takes into account several sources of linguistic and extralinguistic information. Here we focused on one particular form of extralinguistic information, certain speaker characteristics as conveyed by the voice. Using functional magnetic resonance imaging, we examined the neural structures involved in the unification of sentence meaning and voice-based inferences about the speaker's age, sex, or social background. We found enhanced activation in the inferior frontal gyrus bilaterally (BA 45/47) during listening to sentences whose meaning was incongruent with inferred speaker characteristics. Furthermore, our results showed an overlap in brain regions involved in unification of speaker-related information and those used for the unification of semantic and world knowledge information [inferior frontal gyrus bilaterally (BA 45/47) and left middle temporal gyrus (BA 21)]. These findings provide evidence for a shared neural unification system for linguistic and extralinguistic sources of information and extend the existing knowledge about the role of inferior frontal cortex as a crucial component for unification during language comprehension.
| 19,016,606
|
EEG activity underlying successful study of associative and order information.
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Two of the most well studied and ecologically relevant memory paradigms are memory for pairs ("associations") and ordered sequences ("serial lists"). Behavioral theories comprise two classes: those that use common mechanisms and those that use distinct mechanisms for study and retrieval of associations versus serial lists. We tested the common-mechanisms hypothesis by recording electroencephalographic activity related to successful study ("subsequent memory effect" [SME]) of pairs and short lists (triples) of nouns. Multivariate analysis identified four distributed patterns of brain activity: (1) right parietal activity throughout most of the study period that differentiated study of pairs from triples within subjects as well as exhibiting an SME that was significant for pairs but not for triples; (2) a left parietal and fronto-polar activity pattern that was reliable around 500 msec and later in the study trial, exhibiting an SME for pairs and a weaker, nonsignificant SME for triples; (3) a left frontal/right parietal topography in the middle of the study interval which covaried with speed and accuracy across subjects; and (4) a pattern resembling the late positive component preceded by an early potential which together covaried with accuracy in triples but slow response times for both pairs and triples. These patterns point to the relevance of three classic SME components (early, late positive, and slow components) from single-item memory to memory for structured information, but suggest that they reflect subsets of more complex spatio-temporal patterns. Our findings support common underlying mechanisms for study and recall of pairs and lists. However, existing models must be modified to account for differences in both the presence of certain study-relevant processes and in the relevance of these processes to performance measures for pairs versus serial lists.
| 19,016,609
|
[Tooth loss in diabetic patients with and without chronic kidney disease and dialysis].
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To compare tooth loss (TL) in ESRD (ESRD DM) and non-ESRD (DM) type 2 diabetic patients. Teeth loss was quantified, and dentition classified as: Non-Compromised (NCD) with > or = 25 teeth, partially compromised (PCD) with 9 to 24, and compromised (CD) with 0 to 8 teeth. ESRD DM and DM: n> or = 103 and 130, mean age 57.9 and 58.5 yr (p> or =0.716), and at diabetes diagnosis 38.5 and 47.8 yr (p<0.001). Edentulous 23.5% and 13.8% (p> or =0.057), NCD 24.5% and 35.4% (p> or =0.074). TL was strongly associated mainly to periodontal disease (p<0.001). For ESRD DM, a low serum albumin (<3.5 g/dl) was more prevalent in peritoneal dialysis cases (p> or =0.0014), women (p> or =0.0100), people reporting unpleasant taste (UT) (p> or =0.0174), and those with a CD (p> or =0.0242). There was a clear trend for more severe TL in ESRD DM cases, but no statistical difference was found. The association between low serum albumin, UT and CD imply a need for treatment of these conditions as a part of nutritional intervention in ESRD DM cases.
| 19,016,639
|
An essential role for the Glut1 PDZ-binding motif in growth factor regulation of Glut1 degradation and trafficking.
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Cell surface localization of the Glut (glucose transporter), Glut1, is a cytokine-controlled process essential to support the metabolism and survival of haemopoietic cells. Molecular mechanisms that regulate Glut1 trafficking, however, are not certain. In the present study, we show that a C-terminal PDZ-binding motif in Glut1 is critical to promote maximal cytokine-stimulated Glut1 cell surface localization and prevent Glut1 lysosomal degradation in the absence of growth factor. Disruption of this PDZ-binding sequence through deletion or point mutation sharply decreased surface Glut1 levels and led to rapid targeting of internalized Glut1 to lysosomes for proteolysis, particularly in growth factor-deprived cells. The PDZ-domain protein, GIPC (G(alpha)-interacting protein-interacting protein, C-terminus), bound to Glut1 in part via the Glut1 C-terminal PDZ-binding motif, and we found that GIPC deficiency decreased Glut1 surface levels and glucose uptake. Unlike the Glut1 degradation observed on mutation of the Glut1 PDZ-binding domain, however, GIPC deficiency resulted in accumulation of intracellular Glut1 in a pool distinct from the recycling pathway of the TfR (transferrin receptor). Blockade of Glut1 lysosomal targeting after growth factor withdrawal also led to intracellular accumulation of Glut1, a portion of which could be rapidly restored to the cell surface after growth factor stimulation. These results indicate that the C-terminal PDZ-binding motif of Glut1 plays a key role in growth factor regulation of glucose uptake by both allowing GIPC to promote Glut1 trafficking to the cell surface and protecting intracellular Glut1 from lysosomal degradation after growth factor withdrawal, thus allowing the potential for a rapid return of intracellular Glut1 to the cell surface on restimulation.
| 19,016,655
|
The serotonin transporter 5-HTTPR polymorphism is associated with current and lifetime depression in persons with chronic psychotic disorders.
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Variation in the serotonin transporter gene (SLC6A4) promoter region has been shown to influence depression in persons who have been exposed to a number of stressful life events. We evaluated whether genetic variation in 5-HTTLPR, influences current depression, lifetime history of depression and quantitative measures of depression in persons with chronic psychotic disorders. This is an association study of a genetic variant with quantitative and categorical definitions of depression conducted in the southwest US, Mexico and Costa Rica. We analyzed 260 subjects with a history of psychosis, from a sample of 129 families. We found that persons carrying at least one short allele had a statistically significant increased lifetime risk for depressive syndromes (P < 0.02, odds ratio 2.18, 95% CI 1.10-4.20). The 'ss' or 'sl' genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of psychotic individuals to develop major depression during the course of their illness.
| 19,016,667
|
Severe mental illness and criminal victimization: a systematic review.
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To estimate the prevalence of criminal victimization among people with severe mental illness and to explore risk factors. Four databases (MEDLINE, ScienceDirect, ERIC, and AMED) were searched for articles published between January 1966 and August 2007, supplemented with hand-search of reference lists from retrieved papers. The author and a Medical Doctor independently abstracted data and assessed study quality. Disagreements were resolved by consensus after review of the article and the review protocol. Nine studies, including 5195 patients, were identified. Prevalence estimates of criminal victimization ranged from 4.3% to 35.04%. Rates of victimization among severely mentally ill persons were 2.3-140.4 times higher than those in the general population. Criminal victimization was most frequently associated with alcohol and/or illicit drug use/abuse, homelessness, more severe symptomatology, and engagement in criminal activity. Prevention and intervention programs should target high-risk groups and improve patients' mental health and quality of life.
| 19,016,668
|
How many well vs. unwell days can you expect over 10 years, once you become depressed?
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Prognostic studies of major depression have mainly focused on episode remission and relapse, and only a limited number of studies have examined long-term course of depressive symptomatology at threshold and subthreshold levels. The Group for Longitudinal Affective Disorders Study has conducted prospective serial assessments of a cohort of heretofore untreated major depressive episodes for 10 years under naturalistic conditions. Of the 94 patients in the cohort, the follow-up rate was 70% of the 11,280 person-months. Around 77% of the follow-up months were spent in euthymia, 16% in subthreshold depression and 7% in major depression. Duration of the index episode before reaching recovery was the only significant predictor of the ensuing well time. On average, patients with major depression starting treatment today may expect to spend three quarters of the next decade in euthymia but the remaining one quarter in subthreshold or threshold depression.
| 19,016,670
|
Sexual activity and prostate cancer risk in men diagnosed at a younger age.
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To examine, in a case-control study, the association between the frequency of sexual activity (intercourse, masturbation, overall) and prostate cancer risk in younger men diagnosed at < or = 60 years old. In all, 431 prostate cancer cases and 409 controls participated and provided information on their sexual activity. In particular, the frequencies of intercourse and masturbation during the participants' different age decades (20s, 30s, 40s, 50s) were collected. Whereas frequent overall sexual activity in younger life (20s) increased the disease risk, it appeared to be protective against the disease when older (50s). Alone, frequent masturbation activity was a marker for increased risk in the 20s and 30s but appeared to be associated with a decreased risk in the 50s, while intercourse activity alone was not associated with the disease. These findings could imply different mechanisms by which sexual activity is involved in the aetiology of prostate cancer at different ages. Alternatively, there is a possibility of reverse causation in explaining part of the protective effect seen for men in their 50s.
| 19,016,689
|
Psoriasis: an opportunity to identify cardiovascular risk.
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Psoriasis is highly prevalent and is associated with skin-associated complaints as well as arthritis, depression and a lower quality of life. Recently, it has been demonstrated that not only do patients with psoriasis have an increased prevalence of cardiovascular risk factors, but an increased risk of myocardial infarction, and for those with severe disease, increased mortality. Dermatologists and other health professionals need to be cognizant of this association and ensure that cardiovascular risk factors are evaluated and treated appropriately in those patients with psoriasis. We review the association between psoriasis, atherosclerosis and inflammation, as well as some treatable cardiovascular risk factors that may prove beneficial in reducing a patient's cardiovascular risk.
| 19,016,698
|
Prevalence and types of androgenetic alopecia in Shanghai, China: a community-based study.
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There are ethnic differences in the prevalence and types of androgenetic alopecia (AGA). Although there have been several reports on the prevalence and types of AGA in caucasian and Asian populations, there are very few data on a Chinese population that have been derived from a sufficient number of samples. To estimate the prevalence and types of AGA in a Chinese population, and to compare the results with those in caucasians and Koreans reported previously in the literature. A population-based cross-sectional study was carried out in 7056 subjects (3519 men and 3537 women) from May 2006 to December 2006 in a community of Shanghai. Questionnaires were completed during face-to-face interviews at the subjects' homes. The degree of AGA was classified according to the Norwood and Ludwig classifications. The prevalence of AGA in Chinese men was 19.9%, and the prevalence of female pattern AGA in men was 0.1%. The most common type in men was type III vertex (3.5%). The prevalence of AGA in women was 3.1%, while male pattern AGA was found in those aged over 50 years (0.4%), and the most common type was type I (Ludwig classification) (1.4%). A family history of AGA was present in 55.8% of men and 32.4% of women with AGA. The prevalence of AGA in Chinese men was lower than in caucasian men but was similar to that in Korean men; however, over the age of 60 years it was approaching that in caucasian men but was higher than that in Korean men. The most common type in Chinese men with AGA was type III vertex. Interestingly, the prevalence of AGA in Chinese women was lower than that in Korean women and caucasian women, and type I was the most common type (Ludwig classification).
| 19,016,703
|
Histoid leprosy: a retrospective study of 40 cases from India.
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Rare variants of leprosy pose a diagnostic challenge even to astute clinicians and histoid leprosy is one such form of disease with unique clinical and histopathological features. There are very few large series on this entity, mainly reported from India. To study the epidemiological and clinical characteristics of patients with histoid leprosy. We undertook this retrospective study including patients registered with the leprosy clinic of our tertiary care referral centre from January 1991 to December 2006. Data regarding demographic details, clinical features, treatment, complications and course following treatment were extracted from the records of the leprosy clinic. The incidence of histoid leprosy among the registered patients of our clinic was 1.8% (40 of 2150). There was a significant male preponderance with a male/female ratio of 5.7 : 1. The anatomical areas of involvement were thighs/buttocks (67.5%), arms (62.5%), back (52.5%), face (47.5%), forearms (47.5%) and legs (35%) in descending order of frequency. This variety of leprosy was found most commonly in patients with a primary diagnosis of lepromatous leprosy (40%). De novo histoid lesions, i.e. lesions of histoid leprosy developing without evidence of lesions of other types of leprosy in the Ridley-Jopling classification, appeared in 12.5% of patients only. Only three patients had received antileprosy treatment before presentation. Episodes of erythema nodosum leprosum (ENL) had occurred in 40% of patients, although only one patient manifested ENL after the diagnosis of histoid leprosy. The disease responded satisfactorily to the respective World Health Organization multidrug therapy regimens in all except in one patient who relapsed with borderline lepromatous leprosy. As the bacillary load is very high in these patients, they can form a potential reservoir of the infection in the community especially in the postleprosy elimination era. Contrary to the earlier belief in the dapsone era, most of our patients manifested disease without any history of inadequate or incomplete antileprosy therapy.
| 19,016,704
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Medallion-like dermal dendrocyte hamartoma: the main diagnostic pitfall is congenital atrophic dermatofibrosarcoma.
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Medallion-like dermal dendrocyte hamartoma is a newly described and rare clinical and pathological entity. This congenital, round, erythematous and atrophic lesion in the thoracic area is histologically characterized by a CD34+ dermal and hypodermal spindle-cell infiltration. We describe the clinical, histopathological, cytological and molecular features of three cases of dermal dendrocyte hamartoma. In all the cases, atrophic congenital dermatofibrosarcoma protuberans (DFSP) was the first histological diagnosis. In one case, wide surgery had been performed on the basis of the clinical and histological presentation. The histological pattern was similar in all the cases: epidermal atrophy and a spindle to ovoid cell proliferation in the dermis and in the subcutaneous fat. Immunochemical staining for CD34 and factor XIIIa was positive. Cytogenetic and molecular studies were performed; no chromosomal abnormality nor translocation t(17;22)(q22;q13) was observed. Fluorescence in situ hybridization analysis did not reveal the DFSP fusion gene COL1A1-PDGFB. We observed that the main diagnostic pitfall of medallion-like dermal dendrocyte hamartoma is atrophic congenital DFSP due to clinical and histological similarities. We emphasize that molecular studies to eliminate the t(17;22)(q22;q13) translocation of DFSP may provide determinant elements for diagnosis in order to avoid unnecessary mutilating surgery.
| 19,016,705
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Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes.
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Epidermal keratinocytes are involved in the skin innate immunity and express toll-like receptors (TLRs) and other innate immune proteins. The epidermis is continuously exposed to pathogenic gram-positive bacteria or fungi. However, few studies have examined the function and expression of innate immune proteins in keratinocytes. Histamine, which is well known for itch and allergy, is closely associated with innate immunity, but its influence on epidermal innate immunity is still unclear. To clarify the expression of innate immune proteins in keratinocytes stimulated by ligand pathogen-associated molecules, and the function of histamine in this process. We investigated the effects of lipopeptide (MALP-2, 1-100 ng mL(-1); ligand for TLR2), peptidoglycan (PGN, 0.02-2 microg mL(-1); ligand for NOD2) and beta-glucan (1-100 microg mL(-1); ligand for dectin-1) in the presence or absence of histamine on mRNA expression of TLR2, NOD2 and dectin-1 as well as human beta-defensin 2 by quantitative real-time polymerase chain reaction in cultured normal human epidermal keratinocytes. TLR2 expression was also examined at the cell surface and intracellularly, as determined by flow cytometry and confocal microscopy. The quantities of interleukin (IL)-1alpha and IL-8 produced by keratinocytes were measured using enzyme-linked immunosorbent assay. At the mRNA level, TLR2 was enhanced by PGN but not by its ligand MALP-2 or by beta-glucan; NOD2 was easily induced by all three ligands; and dectin-1 was enhanced by its ligand beta-glucan. These enhanced expressions were further augmented by histamine at 1 microg mL(-1). While the surface expression of TLR2 was barely detectable by flow cytometry even after stimulation, the intracellular expression of TLR2 was apparently elevated by PGN and further promoted by histamine. A confocal microscopic analysis also revealed the enhanced expression of TLR2 in the cytoplasm. The expression of TLR2, NOD2 and dectin-1 was functional, as these pathogen-associated molecules induced the production of IL-1alpha, IL-8 and defensin, and again, histamine greatly enhanced this production. Our study demonstrated that the expression of functional innate immune receptors is augmented by the pathogen-associated molecules in a ligand-feed forward or nonrelated manner in keratinocytes, and histamine promotes their expression and the resultant production of cytokines and defensins.
| 19,016,710
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Interferon-related transcriptome alterations in the cerebrospinal fluid cells of Aicardi-Goutières patients.
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Aicardi-Goutières syndrome (AGS) is a rare interferon (IFN)-related encephalopathy with onset during the first year of life. AGS, is clinically characterized by progressive microcephaly, bilateral basal ganglia calcification, cerebral atrophy, cerebrospinal fluid (CSF), lymphocytosis, delayed development of psychomotor abilities with pyramidal-extrapyramidal syndrome and mimics congenital viral infections. Microarray analysis examining the expression of 18 880 human genes has been applied to the CSF lymphocytes of 20 AGS cases (age 4.5 +/- 4.4 years, mean +/- standard deviation) characterized by high IFN-alpha levels in CSF and 20 matched controls (age 4.4 +/- 4.3 years, mean +/- standard deviation). Gene-expression data reveal significant differences between AGS cases and controls for all controls and 18 AGS cases. The two AGS cases unclassified as compared with controls were both older than 7 years. AGS cases presented upregulation of genes involved in IFN-dependent pathways and lymphocyte functions, paralleled by the downregulation of genes encoding for angiopoietic activities. The cystatin F and DNAJ genes, having a negative feedback on IFN pathways, underwent a progressive age-related increase in their expression. These gene-expression signature parallels a progressive attenuation of clinical symptoms with age. Obtained results provide evidence that exposure to IFN-alpha is harmful for developing brain.
| 19,016,741
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Aberrant expression and demethylation of gamma-synuclein in colorectal cancer, correlated with progression of the disease.
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Recent evidence suggests that gamma-synuclein is abnormally expressed in a high percentage of tumor tissues of diversified cancer types, but rarely expressed in tumor-matched non-neoplastic adjacent tissues (NNAT). The molecular mechanism of CpG island demethylation may underlie aberrant gamma-synuclein expression. To fully understand the roles of aberrant gamma-synuclein expression and demethylation in the development of colorectal cancer (CRC), we examined the expression and methylation status of gamma-synuclein in 67 CRC samples, 30 NNAT samples, and five CRC cell lines as well. By using reverse transcription-polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry analyses, gamma-synuclein expression was detected in both HT-29 and HCT116 cells, and was much higher in CRC samples than in NNAT samples (P < 0.05). The demethylating agent, 5-aza-2 cent-deoxycytidine, can induce re-expression of gamma-synuclein in COLO205, LoVo, and SW480 cells. Unmethylated gamma-synuclein alleles were detected in HT-29, HCT116, and LoVo cells by nested methylation-specific PCR, and the demethylated status of gamma-synuclein was much higher in CRC samples than in NNAT samples by real-time quantitative methylation-specific PCR (P < 0.05). The results of genomic bisulfite DNA sequencing further confirmed that the aberrant gamma-synuclein expression in CRC was primarily attributed to the demethylation of CpG island. The protein expression and demethylation status of gamma-synuclein in 67 CRC samples correlated with clinical stage, lymph node involvement, and distant metastasis. These findings suggest an involvement of aberrant gamma-synuclein expression and demethylation in progression of CRC, especially in advanced stages.
| 19,016,751
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Differential entry of botulinum neurotoxin A into neuronal and intestinal cells.
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Botulinum neurotoxins (BoNTs) are often acquired from the digestive tract and specifically target neuromuscular junctions where they cause an inhibition of acetylcholine release. A transcytotic mechanism has been evidenced in epithelial intestinal cells, which delivers whole BoNTs across the intestinal barrier, whereas BoNTs enter motoneurons through a pathway that permits the translocation of light chain into the cytosol. We used fluorescent BoNT/A C-terminal part of H chain (Hc) that mediates toxin binding to cell receptors to monitor toxin entry into NG108-15 neuronal cells as well as into Caco-2 and m-IC(cl2) intestinal cells. BoNT/A Hc receptors were found to be distributed in membrane structures closely associated to cholesterol-enriched microdomains, but distinct from detergent-resistant microdomains in both cell types. BoNT/A Hc was trapped into endocytic vesicles, which progressively migrated to a perinuclear area in NG108-15 cells, and in a more scattered manner in intestinal cells. In both cell types, BoNT/A Hc entered through a dynamin- and intersectin-dependent pathway, reached an early endosomal compartment labelled with early endosome antigen 1. In neuronal cells, BoNT/A Hc entered mainly via a clathrin-dependent pathway, in contrast to intestinal cells where it followed a Cdc42-dependent pathway, supporting a differential toxin routing in both cell types.
| 19,016,790
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Increased levels of regulatory T cells (Tregs) in human immunodeficiency virus-infected patients after 5 years of highly active anti-retroviral therapy may be due to increased thymic production of naive Tregs.
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This study determines levels of regulatory T cells (T(regs)), naive T(regs), immune activation and cytokine patterns in 15 adult human immunodeficiency virus (HIV)-infected patients receiving prolonged highly active anti-retroviral therapy (HAART) who have known thymic output, and explores if naive T(regs) may represent recent thymic emigrant T(regs). HIV-infected patients treated with HAART with a median of 1 and 5 years were compared with healthy controls. Percentages of T(regs) (CD3(+)CD4(+)CD25(+)CD127(low)), naive T(regs) (CD3(+)CD4(+)CD25(+)CD45RA(+)) and activation markers (CD38(+)human leucocyte antigen D-related) were determined by flow cytometry. Forkhead box P3 mRNA expression and T cell receptor excision circles (T(REC)) content in CD4(+) cells were determined by polymerase chain reaction and cytokines analysed with Luminex technology. Levels of T(regs) were significantly higher in HIV-infected patients compared with controls, both after 1 and 5 years of HAART (P<0.001), despite fully suppressed HIV-RNA and normalization of both CD4 counts, immune activation and cytokine patterns. Furthermore, levels of naive T(regs) were elevated significantly in HIV-infected patients (P<0.001) and were associated with thymic output measured as the T(REC) frequency in CD4(+) cells (P=0.038). In summary, T(reg) levels in HIV-infected patients are elevated even after 5 years of HAART. Increased thymic production of naive T(regs) may contribute to higher T(reg) levels in HIV-infection.
| 19,016,807
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Functional deficits in early stage age-related maculopathy.
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It is of interest to examine paracentral functional deficits in early age-related maculopathy (ARM), as histopathological studies indicate that this is where the earliest changes occur. The purpose of this study is to detect the sensory functional deficits at chosen retinal areas around the fovea and at the fovea itself in patients with early age-related maculopathy and to determine the type of functional losses that are more pronounced in early ARM. Ten participants with early ARM and 10 age-matched controls took part. Crowded and uncrowded visual acuity and static and transient contrast sensitivity were measured in the same selected eye of each participant at eight predetermined retinal locations plus the fovea in patients with early ARM and controls. All measurements were made using computer-generated targets. A significant difference between the controls and subjects with ARM was found in low spatial frequency static contrast sensitivity (p = 0.05) but not for transient contrast sensitivity (p = 0.586). Visual acuity (uncrowded VA and crowded VA) showed a borderline difference (p = 0.072 and p = 0.084, respectively). Compared to controls, there was no evidence of increased contour interaction effects in early ARM (p = 0.595). The subjects with very early ARM showed significant loss of low spatial frequency static contrast sensitivity before the loss of high contrast VA, indicating that static contrast sensitivity may be one of the earliest functional losses in early ARM and this loss was found to extend across the central 10 degrees of the retina.
| 19,016,808
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Influence of energy drinks and alcohol on post-exercise heart rate recovery and heart rate variability.
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Media have anecdotally reported that drinking energy drinks in combination with alcohol and exercise could cause sudden cardiac death. This study investigated changes in the electrocardiogram (ECG) and heart rate variability after intake of an energy drink, taken in combination with alcohol and exercise. Ten healthy volunteers (five men and five women aged 19-30) performed maximal bicycle ergometer exercise for 30 min after: (i) intake of 0.75 l of an energy drink mixed with alcohol; (ii) intake of energy drink; and, (iii) no intake of any drink. ECG was continuously recorded for analysis of heart rate variability and heart rate recovery. No subject developed any clinically significant arrhythmias. Post-exercise recovery in heart rate and heart rate variability was slower after the subjects consumed energy drink and alcohol before exercise, than after exercise alone. The healthy subjects developed blunted cardiac autonomic modulation after exercising when they had consumed energy drinks mixed with alcohol. Although they did not develop any significant arrhythmia, individuals predisposed to arrhythmia by congenital or other rhythm disorders could have an increased risk for malignant cardiac arrhythmia in similar situations.
| 19,016,812
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Use of empirically derived source-destination models to map regional conservation corridors.
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The ability of populations to be connected across large landscapes via dispersal is critical to long-term viability for many species. One means to mitigate population isolation is the protection of movement corridors among habitat patches. Nevertheless, the utility of small, narrow, linear features as habitat corridors has been hotly debated. Here, we argue that analysis of movement across continuously resistant landscapes allows a shift to a broader consideration of how landscape patterns influence connectivity at scales relevant to conservation. We further argue that this change in scale and definition of the connectivity problem improves one's ability to find solutions and may help resolve long-standing disputes regarding scale and definition of movement corridors and their importance to population connectivity. We used a new method that combines empirically derived landscape-resistance maps and least-cost path analysis between multiple source and destination locations to assess habitat isolation and identify corridors and barriers to organism movement. Specifically, we used a genetically based landscape resistance model for American black bears (Ursus americanus) to identify major movement corridors and barriers to population connectivity between Yellowstone National Park and the Canadian border. Even though western Montana and northern Idaho contain abundant public lands and the largest wilderness areas in the contiguous United States, moving from the Canadian border to Yellowstone Park along those paths indicated by modeled gene flow required bears to cross at least 6 potential barriers. Our methods are generic and can be applied to virtually any species for which reliable maps of landscape resistance can be developed.
| 19,016,821
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Roles of adenine anchoring and ion pairing at the coenzyme B12-binding site in diol dehydratase catalysis.
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The X-ray structure of the diol dehydratase-adeninylpentylcobalamin complex revealed that the adenine moiety of adenosylcobalamin is anchored in the adenine-binding pocket of the enzyme by hydrogen bonding of N3 with the side chain OH group of Seralpha224, and of 6-NH(2), N1 and N7 with main chain amide groups of other residues. A salt bridge is formed between the epsilon-NH(2) group of Lysbeta135 and the phosphate group of cobalamin. To assess the importance of adenine anchoring and ion pairing, Seralpha224 and Lysbeta135 mutants of diol dehydratase were prepared, and their catalytic properties investigated. The Salpha224A, Salpha224N and Kbeta135E mutants were 19-2% as active as the wild-type enzyme, whereas the Kbeta135A, Kbeta135Q and Kbeta135R mutants retained 58-76% of the wild-type activity. The presence of a positive charge at the beta135 residue increased the affinity for cobalamins but was not essential for catalysis, and the introduction of a negative charge there prevented the enzyme-cobalamin interaction. The Salpha224A and Salpha224N mutants showed a k(cat)/k(inact) value that was less than 2% that of the wild-type, whereas for Lysbeta135 mutants this value was in the range 25-75%, except for the Kbeta135E mutant (7%). Unlike the wild-type holoenzyme, the Salpha224N and Salpha224A holoenzymes showed very low susceptibility to oxygen in the absence of substrate. These findings suggest that Seralpha224 is important for cobalt-carbon bond activation and for preventing the enzyme from being inactivated. Upon inactivation of the Salpha224A holoenzyme during catalysis, cob(II)alamin accumulated, and a trace of doublet signal due to an organic radical disappeared in EPR. 5'-Deoxyadenosine was formed from the adenosyl group, and the apoenzyme itself was not damaged. This inactivation was thus considered to be a mechanism-based one.
| 19,016,846
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Glutathione transferases in bacteria.
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Bacterial glutathione transferases (GSTs) are part of a superfamily of enzymes that play a key role in cellular detoxification. GSTs are widely distributed in prokaryotes and are grouped into several classes. Bacterial GSTs are implicated in a variety of distinct processes such as the biodegradation of xenobiotics, protection against chemical and oxidative stresses and antimicrobial drug resistance. In addition to their role in detoxification, bacterial GSTs are also involved in a variety of distinct metabolic processes such as the biotransformation of dichloromethane, the degradation of lignin and atrazine, and the reductive dechlorination of pentachlorophenol. This review article summarizes the current status of knowledge regarding the functional and structural properties of bacterial GSTs.
| 19,016,852
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Marine toxins and the cytoskeleton: a new view of palytoxin toxicity.
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Palytoxin is a marine toxin first isolated from zoanthids (genus Palythoa), even though dinoflagellates of the genus Ostreopsis are the most probable origin of the toxin. Ostreopsis has a wide distribution in tropical and subtropical areas, but recently these dinoflagellates have also started to appear in the Mediterranean Sea. Two of the most remarkable properties of palytoxin are the large and complex structure (with different analogs, such as ostreocin-D or ovatoxin-a) and the extreme acute animal toxicity. The Na(+)/K(+)-ATPase has been proposed as receptor for palytoxin. The marine toxin is known to act on the Na(+) pump and elicit an increase in Na(+) permeability, which leads to depolarization and a secondary Ca(2+) influx, interfering with some functions of cells. Studies on the cellular cytoskeleton have revealed that the signaling cascade triggered by palytoxin leads to actin filament system distortion. The activity of palytoxin on the actin cytoskeleton is only partially associated with the cytosolic Ca(2+) changes; therefore, this ion represents an important factor in altering this structure, but it is not the only cause. The goal of the present minireview is to compile the findings reported to date about: (a) how palytoxin and analogs are able to modify the actin cytoskeleton within different cellular models; and (b) what signaling mechanisms could be involved in the modulation of cytoskeletal dynamics by palytoxin.
| 19,016,862
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Transposition of an insertion sequence, ISTth7, in the genome of the extreme thermophile Thermus thermophilus HB8.
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We have identified an active insertion sequence (IS) in the genome of Thermus thermophilus HB8. Transposition was detected as insertional inactivation of a 16S rRNA methyltransferase gene, rsmG, resulting in streptomycin resistance. The IS element, ISTth7, is 1029 bp in length, encodes an imperfect 12 bp inverted repeat, and produces a 9 bp direct repeat of the target sequence. The sequence of a putative transposase encoded by ISTth7 indicates that it is a member of the IS427 group within the IS5 family of ISs. Nine intact copies and several partial copies were identified throughout the chromosome and the megaplasmid pTT27. ISTth7 was also detected in T. thermophilus strain IB-21 and Thermus igniterrae but not Thermus antranikianii, suggesting a widespread occurrence of ISTth7 among Thermus spp.
| 19,016,874
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A window of environmental dependence is evident in multiple phylogenetically distinct subgroups in the faecal community of piglets.
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Microbial colonization in neonates has a profound impact on host development. In pigs, we have observed that a window of environmental dependence occurs during neonatal development. This was evident by the sudden onset of faecal community similarity in cohoused neonatal piglets at 3 weeks of age. This effect is postulated to represent a general change in gut community structure. Here, three phylogenetic groups (Clostridium leptum subgroup, Bacteroides and enterobacteria) that were predicted to have distinct ecological roles were monitored using nested denaturing gradient gel electrophoresis to determine the extent to which this window of environmental dependence was exerted throughout the gut community. Colonization trends were found to be similar for all subgroups despite predicted differences in the functional role and niche, and increased similarity between cohabiting piglets occurred in multiple phylogenetic subgroups. This supports the hypothesis that a distinct phase in neonatal development commences after 2 weeks whereby multiple subcommunities of the gut are strongly influenced by the environment.
| 19,016,877
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Relatively strong automatic appetitive action-tendencies in male carriers of the OPRM1 G-allele.
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This study investigated whether automatic approach action tendencies for alcohol-related stimuli were associated with variation in the mu-opioid receptor gene (OPRM1), previously related to rewarding effects of alcohol and craving. An adapted approach avoidance task was used, in which participants pulled or pushed a joystick in reaction to the format of a picture shown on the computer screen (e.g. pull landscape pictures and push portrait pictures). Picture size on the screen changed upon joystick movement, so that upon a pull movement picture size increased (creating a sense of approach) and upon a push movement picture size decreased (avoidance). Participants reacted to four categories of pictures: alcohol-related, other appetitive, general positive and general negative. The sample consisted of 84 heavy drinking young men without a g-allele in the A118G (or A355G) single nucleotide polymorphism of the OPRM1 gene and 24 heavy drinking young men with at least one g-allele. Heavy drinking carriers of a g-allele showed relatively strong automatic approach tendencies for alcohol (approach bias). Unexpectedly, they also showed an approach bias for other appetitive stimuli. No approach bias was found for general positive or negative stimuli. These results suggest that automatic approach tendencies in response to appetitive stimuli could play a role in the etiology of addictive behaviors and related disorders. Further research is needed to investigate the specificity of this approach bias and possible gender differences.
| 19,016,889
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A simple, low-cost method to monitor duration of ground water pumping.
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Monitoring ground water withdrawals for agriculture is a difficult task, while agricultural development leads frequently to overexploitation of the aquifers. To fix the problem, sustainable management is required based on the knowledge of water uses. This paper introduces a simple and inexpensive direct method to determine the duration of pumping of a well by measuring the temperature of its water outlet pipe. A pumping phase is characterized by a steady temperature value close to ground water temperature. The method involves recording the temperature of the outlet pipe and identifying the different stages of pumping. It is based on the use of the low-cost and small-size Thermochron iButton temperature logger and can be applied to any well, provided that a water outlet pipe is accessible. The temperature time series are analyzed to determine the duration of pumping through manual and automatic posttreatments. The method was tested and applied in South India for irrigation wells using electricity-powered pumps. The duration of pumping obtained by the iButton method is fully consistent with the duration of power supply (1.5% difference).
| 19,016,895
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United Kingdom myeloma forum position statement on the use of lenalidomide in multiple myeloma.
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Lenalidomide is an immunomodulatory drug, which has anti-myeloma activity in vitro. Phase II clinical trials have demonstrated lenalidomide in combination with dexamethasone is effective for the treatment of both relapsed refractory myeloma and newly diagnosed patients. Two large phase III studies comparing lenalidomide and dexamethasone to dexamethasone alone in relapsed patients showed superiority in response, progression free and overall survival. It is administered orally for 21 days in a 28 day cycle. Side effects are manageable and include neutropenia and venous thrombotic events. It is currently approved, in combination with dexamethasone, for the treatment of multiple myeloma patients who have received at least one prior therapy. Studies in front line patients and with other drug combinations are ongoing. Given the strength of this data the UK Myeloma Forum believe that lenalidomide in combination with dexamethasone should be available for prescription by UK haematologists according to its licensed indication in patients with relapsed myeloma.
| 19,016,917
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Conceptual challenges and practical approaches to screening capacity for self-care and protection in vulnerable older adults.
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Identifying impairments in the capacity to make and execute decisions is critical to the assessment and remediation of elder self-neglect. Few capacity assessment tools are available for use outside of healthcare settings, and none have been validated in the context of elder self-neglect. Health and social services professionals are in need of validated tools to assess capacity for self-care and self-protection (SC&P) during initial evaluations of older adults with suspected self-neglect syndrome. Currently, legal and medical declarations of incapacity and guardianship rely on clinical evaluations and instruments developed to assess only decision-making capacity. This article first describes the conceptual and methodological challenges to assessing the capacity to make and execute decisions regarding safe and independent living. Second, the article describes the pragmatic obstacles to developing a screening tool for the capacity for SC&P. Finally, the article outlines the process for validation and field testing of the screening tool. Social services professionals can then use a valid and feasible screening tool during field assessments to screen for potential impairments in the capacity for SC&P in vulnerable older adults.
| 19,016,970
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The hybrid stent-graft technique: a solution to complex aortic problems and lessons learned.
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The frozen elephant trunk technique has been recently presented in the literature and has been considered as a novel surgical option for single-stage repair of complex aortic pathology such as combined arch and descending thoracic aortic aneurysms. The first patient, a 74-year-old male, was admitted severely symptomatic (interscapular pain), with aortic distal arch and proximal descending thoracic aortic aneurysm with a diameter of 6 cm. The second patient, a 72-year-old male, underwent descending aortic aneurysm stent grafting one year ago and was admitted gravely symptomatic (interscapular pain), with aortic arch aneurysm (diameter of 5.7 cm) and type I endoleak at the proximal end of the stent. The first patient developed paraplegia after the operation and died three months after the operation due to pneumonia while he was on a rehabilitation program. The second patient's recovery was uneventful and was discharged on postoperative day nine. This report summarizes our preliminary experience with this technique emphasizing two points: first, it offers the opportunity to manage efficiently complex aortic problems, and second, there is a potential risk of serious complications related to the limited stent sizes available of the device to match the patient's anatomical characteristics and pathology.
| 19,016,991
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Axillary artery perfusion in acute type A aortic dissection repair.
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We evaluated our experience with axillary artery perfusion technique in acute type A aortic dissection repair. Between September 2000 and July 2006, 41 consecutive patients with acute type A aortic dissection underwent surgical repair. In 35 of 41 patients (85.4%), arterial perfusion was performed through right axillary artery and in the remaining six patients (14.6%), arterial perfusion site was femoral artery. Indication for femoral artery perfusion was cardiac arrest and ongoing cardiopulmonary resuscitation in one and pulselessness of right upper limb in five patients. Mean age was 54.9 +/- 15.3 (16 to 90 years) and 28 were male. Unilateral antegrade cerebral perfusion (perfusate temperature 22 to 25 degrees C) through axillary artery was performed in all axillary artery perfused patients and in three patients who had femoral artery perfusion. Five patients died postoperatively (hospital mortality 12.2%). All of them had evidence of single or multiple organ malperfusion preoperatively. We did not experience any new transient or permanent neurologic deficit after the procedure in the unilateral antegrade cerebral perfusion patients. Complications related to axillary artery cannulation were observed in two patients (5.3%). One patient with femoral artery cannulation experienced femoral arterial thrombosis, postoperatively. Right axillary artery cannulation for repair of acute type A aortic dissection is a simple and safe procedure. In the case of pulselessness of right upper limb, femoral artery is still the choice of cannulation site.
| 19,016,993
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Acute presentation in adult in Bland-White-Garland syndrome: double-conduit, two-coronary repair.
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Adult presentation with myocardial infarction in anomalous origin of the left main coronary artery from the pulmonary artery is rare. We describe the different coronary flow physiology in the adult form. A double-conduit repair with a separate feeder vessel to each limb of the left coronary circulation may be necessary to balance the myocardial demand and supply in large systemic collateral coronary beds. The report describes the use of the left internal mammary and radial artery for repair.
| 19,016,998
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Late complex biventricular repair after bidirectional cavopulmonary shunt.
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A child diagnosed with transposition of great arteries, multiple (Swiss cheese) ventricular septal defects, and a small right ventricle underwent pulmonary artery banding and patent ductus arteriosus ligation at the age of six months. At the age of three years bidirectional cavopulmonary shunt was performed as a first stage for univentricular repair. However, the patient was lost follow-up for four years, following which further evaluation showed that the right ventricle was reasonably adequate to support pulmonary circulation if the ventricular septal defects (VSDs) were closed using percutaneous techniques. Four VSDs were then closed using Amplatzer devices (AGA Medical Corporation, Plymouth, MN, USA). At the age of eight years she underwent complex biventricular repair in the form of arterial switch, closure of atrial septal defect, take down of Glenn shunt, and reanastomosis of the distal end of the superior vena cava to the distal superior vena cava stump on the right atrium. One year later the patient is alive and well. In conclusion; biventricular repair may be considered before completion of Fontan whenever cardiac anatomy allows.
| 19,016,999
|
Surgical management of coarctation of the aorta in adults with concurrent cardiac and aortic disease.
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We evaluated our experience with the surgical management of aortic coarctation (ACo) in adults with concurrent cardiac and aortic disease approached via median sternotomy. Eight patients were presented using a variety of repair techniques including end-to-end anastomosis, transpericardial ascending aorta to descending aorta bypass, and stage 1 elephant trunk insertion. All patients were male and symptomatic at presentation. The average age was 41 years (range, 27-67 years). The systolic blood pressure decreased by a mean of 49 mmHg in the patients presenting with hypertension. The postoperative New York Heart Association functional class was I or II in all patients. Mean length of stay was 7.7 days. There were no perioperative complications, and overall survival was 100%. Operative repair of complex ACo can be safely accomplished through the mediastinum in patients in whom a conventional left thoracotomy may not be the preferred approach.
| 19,017,015
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Quality of child-parent attachment moderates the impact of antenatal stress on child fearfulness.
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Animal studies have shown that prenatal stress has persisting effects on several aspects of offspring development; more recent studies show that this effect may be eliminated by positive postnatal rearing. Human studies of prenatal anxiety/stress are now also beginning to document links between antenatal stress/anxiety and behavioural and cognitive development of the child; however, there is no human evidence as to whether the early caregiving environment moderates the effect of antenatal anxiety/stress on child outcomes. Antenatal and postnatal measures of stress were collected on 123 women who were recruited from an antenatal clinic. Laboratory-based assessment of the children's cognitive development and fearfulness were assessed when the children were aged 17 months. In addition, child-parent attachment quality was assessed using the Strange Situation. Attachment classification moderated the link between antenatal stress and observed fearfulness. The effect of antenatal stress on fearfulness was most accentuated in children with an Insecure/Resistant attachment classification; the significant antenatal stress x attachment classification interaction held after controlling for postnatal stress and obstetric, social and demographic factors. Attachment did not moderate the effects of antenatal anxiety on cognitive development. These findings provide the first human evidence that postnatal parenting may moderate the adverse effects of antenatal stress. These results raise developmental questions about the timing and effect of interventions to reduce the adverse effects of antenatal stress exposure.
| 19,017,025
|
Pre- and postnatal influences on preschool mental health: a large-scale cohort study.
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Methodological challenges such as confounding have made the study of the early determinants of mental health morbidity problematic. This study aims to address these challenges in investigating antenatal, perinatal and postnatal risk factors for the development of mental health problems in pre-school children in a cohort of Western Australian children. The Raine Study is a prospective cohort study of 2,868 live born children involving 2,979 pregnant women recruited at 18 weeks gestation. Children were followed up at age two and five years. The Child Behaviour Checklist (CBCL) was used to measure child mental health with clinical cut-points, including internalising (withdrawn/depressed) and externalising (aggressive/destructive) behaviours (n = 1707). Multinomial logistic regression analysis showed that the significant risk factors for behaviour problems at age two were the maternal experience of multiple stress events in pregnancy (OR = 1.20, 95% CI = 1.06, 1.37), smoking during pregnancy (OR = 1.30, 95% CI = 1.06, 1.59) and maternal ethnicity (OR = 3.34, 95% CI = 1.61, 6.96). At age five the experience of multiple stress events (OR = 1.17, 95% CI = 1.08, 1.27), cigarette smoking (OR = 1.19, 95% CI = 1.03, 1.37), male gender (OR = 1.43, 95% CI = 1.02, 2.00), breastfeeding for a shorter time (OR = .97, 95% CI = .94, .99) and multiple baby blues symptoms (OR = 1.08, 95% CI = 1.02, 1.14) were significant predictors of mental health problems. Early childhood mental health is significantly affected by prenatal events in addition to the child's later environment. Interventions targeting adverse prenatal, perinatal and postnatal influences can be expected to improve mental health outcomes for children in the early years.
| 19,017,026
|
Autistic symptomatology and language ability in autism spectrum disorder and specific language impairment.
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Autism spectrum disorders (ASD) and specific language impairment (SLI) are common developmental disorders characterised by deficits in language and communication. The nature of the relationship between them continues to be a matter of debate. This study investigates whether the co-occurrence of ASD and language impairment is associated with differences in severity or pattern of autistic symptomatology or language profile. Participants (N = 97) were drawn from a total population cohort of 56,946 screened as part of study to ascertain the prevalence of ASD, aged 9 to 14 years. All children received an ICD-10 clinical diagnosis of ASD or No ASD. Children with nonverbal IQ > or =80 were divided into those with a language impairment (language score of 77 or less) and those without, creating three groups: children with ASD and a language impairment (ALI; N = 41), those with ASD and but no language impairment (ANL; N = 31) and those with language impairment but no ASD (SLI; N = 25). Children with ALI did not show more current autistic symptoms than those with ANL. Children with SLI were well below the threshold for ASD. Their social adaptation was higher than the ASD groups, but still nearly 2 SD below average. In ALI the combination of ASD and language impairment was associated with weaker functional communication and more severe receptive language difficulties than those found in SLI. Receptive and expressive language were equally impaired in ALI, whereas in SLI receptive language was stronger than expressive. Co-occurrence of ASD and language impairment is not associated with increased current autistic symptomatology but appears to be associated with greater impairment in receptive language and functional communication.
| 19,017,030
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Evidence for three subtypes of repetitive behavior in autism that differ in familiality and association with other symptoms.
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Restricted repetitive behaviors (RRBs) are a core feature of autism and consist of a variety of behaviors, ranging from motor stereotypies to complex circumscribed interests. The objective of the current study was to examine the structure of RRBs in autism using relevant items from the Autism Diagnostic Interview-Revised in a sample of 316 individuals with autistic disorder. Using exploratory factor analysis, three distinct factors were identified: Repetitive Motor Behaviors (RMB), Insistence on Sameness (IS), and Circumscribed Interests (CI). RMB were found to be associated with a variety of subject characteristics such as IQ, age, social/communication impairments, and the presence of regression. IS was associated with social and communication impairments whereas CI appeared to be independent of subject characteristics, suggesting CI may be particularly useful in subsetting samples. Based on sib-pair correlations, IS and CI (but not RMB) appear to be familial. Analysis of the data at the case level suggests that the presence of multiple forms of RRB in an individual is associated with more impairment in the social and communication domains, suggesting a more severe presentation of autistic disorder. There appears to be considerable structure within repetitive behavior in autism. The finding that these behaviors are differentially related to subject characteristics and familiality adds to their validity.
| 19,017,031
|
Involvement of vascular endothelial growth factor, CD44 and CD133 in periodontal disease and diabetes: an immunohistochemical study.
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The aim of this study was to investigate the relationship between expression of angiogenic and regeneration markers and periodontal disease in subjects with/without diabetes mellitus. Immunohistochemical detection of vascular endothelial growth factor (VEGF), CD44 and CD133 was performed in 16 samples each of (1) healthy gingiva from non-diabetic subjects (controls), (2) gingiva from non-diabetic subjects with periodontitis, (3) gingiva from subjects with type 1 diabetes and periodontitis, (4) gingiva from subjects with type 2 diabetes and periodontitis. Diseased gingivae from patients with diabetes and periodontitis had greater clinical measures of periodontal disease than those with periodontitis only. VEGF expression was significantly enhanced in epithelial and endothelial cells from patients with periodontitis compared with controls (p<0.05). Epithelial CD44 expression was strong in all groups, while CD44 was significantly enhanced (p<0.05) in connective tissue cells from both diabetic groups. Epithelial and endothelial CD133 expression was comparable in all patients except those with type 2 diabetes and periodontitis, where it was not detected. Stromal CD133 expression was significantly lower in patients with type 2 diabetes and periodontitis and was increased in periodontitis patients (p<0.05). The involvement and high expression of VEGF, CD44 and CD133 in periodontal disease may predict a greater regeneration capacity of gingival tissue.
| 19,017,033
|
Action mechanisms of the secondary metabolite euplotin C: signaling and functional role in Euplotes.
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Among secondary metabolites, the acetylated hemiacetal sesquiterpene euplotin C has been isolated from the marine, ciliated protist Euplotes crassus, and provides an effective mechanism for reducing populations of potential competitors through its cytotoxic properties. However, intracellular signaling mechanisms and their functional correlates mediating the ecological role of euplotin C are largely unknown. We report here that, in E. vannus (an Euplotes morphospecies that does not produce euplotin C and shares with E. crasssus the same interstitial habitat), euplotin C rapidly increases the intracellular concentration of both Ca(2+) and Na(+), suggesting a generalized effect of this metabolite on cation transport systems. In addition, euplotin C does not induce oxidative stress, but modulates the electrical properties of E. vannus through an increase of the amplitude of graded action potentials. These events parallel the disassembling of the ciliary structures, the inhibition of cell motility, the occurrence of aberrant cytoplasmic vacuoles, and the rapid inhibition of phagocytic activity. Euplotin C also increases lysosomal pH and decreases lysosomal membrane stability of E. vannus. These results suggest that euplotin C exerts a marked disruption of those homeostatic mechanisms whose efficiency represents the essential prerequisite to face the challenges of the interstitial environment.
| 19,017,056
|
Evaluation of the INNO-LiPA mycobacteria v2 assay for identification of aquatic mycobacteria.
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Fifty-seven isolates of mycobacteria comprising 10 reference strains, 47 field isolates and one non-Mycobacterium isolate were screened using commercial INNO-LiPA v2 assay kits. All mycobacteria isolates tested hybridized with the Mycobacterium genus probe on the LiPA strip. All M. marinum, M. fortuitum and M. chelonae reference and field strains and three out of the four M. gordonae isolates hybridized to their corresponding species- or complex-specific probes. Two cultures (a type strain and a field isolate) yielded mixed growth of two mycobacterial species, i.e. M. chelonae and M. fortuitum. A Mycobacterium isolate from one of these cultures was subsequently purified and correctly identified with the kit. However, sequence analysis of the 16S-23S rRNA internal transcribed spacer (ITS) region of various mycobacteria isolates revealed a misidentification of M. shottsii and M. pseudoshottsii with the kit because these isolates reacted with the M. marinum/M. ulcerans probe. Moreover, nine of the 13 field isolates presumed to be M. fortuitum from the results of the kit had closer ITS sequence homology with M. conceptionense, a species which, to our knowledge, has never been reported in fish. These findings highlight the need to redesign the M. fortuitum-M. peregrinum probe included in the INNO-LiPA assay and to introduce additional complex-specific probes into the kit. Nevertheless, the kit proved to be a rapid and reliable method for identifying mycobacteria in the aquatic environment and would be particularly useful in laboratories without sequencing facilities.
| 19,017,069
|
Emotional and sexual infidelity offline and in cyberspace.
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This study investigated how men and women perceive online and offline sexual and emotional infidelity. Undergraduates from a large university in Northern Ireland participated in the study. It was found that men, when forced to decide, were more upset by sexual infidelity and women by emotional infidelity. It was also found that men were more likely to believe that women have sex when in love and that women believe that men have sex even when they are not in love. It was not, however, found that either men or women believed that having cybersex implied the other was also in love or that being in love online implied they were having cybersex. These results are explained through a social-cognitive lens.
| 19,017,185
|
Mirrored pyramidal wells for simultaneous multiple vantage point microscopy.
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We report a novel method for obtaining simultaneous images from multiple vantage points of a microscopic specimen using size-matched microscopic mirrors created from anisotropically etched silicon. The resulting pyramidal wells enable bright-field and fluorescent side-view images, and when combined with z-sectioning, provide additional information for 3D reconstructions of the specimen. We have demonstrated the 3D localization and tracking over time of the centrosome of a live Dictyostelium discoideum. The simultaneous acquisition of images from multiple perspectives also provides a five-fold increase in the theoretical collection efficiency of emitted photons, a property which may be useful for low-light imaging modalities such as bioluminescence, or low abundance surface-marker labelling.
| 19,017,196
|
Alignment with sub-pixel accuracy for images of multi-modality microscopes using automatic calibration.
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A biological specimen is often imaged with various imaging modalities, and it is crucial that such images are well aligned to best reveal physiological structures and functions of the specimen for in-depth analyses. In this paper, we present a methodology for automatic calibration of multiple optical imaging modalities within the x-y detector plane using a custom chrome-on-glass target and an automatic and accurate registration algorithm. The target contains lines crossing at random angles, and our method of registration is based on the alignment of salient features extracted from the lines within the individual images. Once spatial relationships are found between the various detectors and applied to the resultant images, no further registration is required for all static samples, and the registered images serve as the starting point for registration of dynamic samples, where the remaining misalignment is caused by sample movement. We have validated our algorithm with 40 inter-modal and 30 intra-modal image pairs, and the success rates are 95 and 100%, respectively, with sub-pixel accuracy. This methodology is widely applicable to any multi-modal microscope that combines a number of imaging modalities on a common platform assuming images of the target can be obtained.
| 19,017,214
|
In vivo imaging of neurodegeneration in Caenorhabditis elegans by third harmonic generation microscopy.
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In this study, neurodegeneration phenomena were investigated, by performing third harmonic generation imaging measurements on the nematode Caenorhabditis elegans, in vivo. The in vivo, precise identification of the contour of the degenerating neurons in the posterior part of the nematode and the monitoring, in real time, of the progression of degeneration in the worm, through third harmonic generation imaging measurements, were achieved. Femtosecond laser pulses (1028 nm) were utilized for excitation. Thus, the THG image contrast modality comprises a powerful diagnostic tool, providing valuable information and offering new insights into morphological changes and complex developmental processes in live biological specimens.
| 19,017,226
|
Immersion oil for high-resolution live-cell imaging at 37 degrees C: optical and physical characteristics.
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The use of normal immersion oil, developed for 23 degrees C, at 37 degrees C greatly compromises both axial resolution and signal intensity. We developed and characterized an immersion oil for optimal performance in live-cell imaging at 37 degrees C. We quantify the improvements in resolution and intensity obtained when using the new oil instead of its standard 23 degrees C counterparts.
| 19,017,234
|
Nurse prescribing as an aspect of future role expansion: the views of Irish clinical nurse specialists.
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Nurses and midwives are expanding the scope of their professional practice, assuming additional responsibilities including the management and prescribing of medications. The aim of the study was to discover the attitudes of clinical nurse specialists (CNSs) in Ireland to nurse prescribing and to examine perceived barriers to engaging in this aspect of future role expansion. The expansion of the nursing role in relation to nurse prescribing is an ongoing process and is subject to incremental iterations of legislation and professional policy. Nurse prescribing as an expanded role function has become a reality in many countries. Ireland has addressed the matter in a formal and systematic way through legislation. A questionnaire was administered to a sample of 283 CNSs practising in a variety of care settings in Ireland. Attitudes were measured using Likert-type attitudinal scales, designed specifically for the study. Findings indicate that the majority of clinical nurse specialists were positively disposed toward nurse prescribing as a future role expansion. The fear of litigation was identified as the most significant barrier to nurse prescribing. The majority of respondents equated nurse prescribing with increased autonomy and holistic care. The findings indicate that there is a need for further examination of the educational requirements of the CNS in relation to nurse prescribing. The legislative implications for nurse prescribing and fear of legal consequences need to be considered prior to any implementation of nurse prescribing. While senior clinicians are willing to embrace future role expansion in the area of nurse prescribing, their Nurse Managers should recognize that facilitation of nurse prescribing needs to address the legal and educational requirements for such activity. Failure to address these requirements can represent a barrier to role expansion. This paper offers new understandings on the views of senior clinicians concerning nurse prescribing at a time of ongoing professional policy iteration and practice change in the area.
| 19,017,243
|
Stability in shifting sands: contemporary leadership roles in critical care.
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Contemporary nursing leadership roles in critical care are a reflection of the changing environment in which critical care is provided. In the UK, critical care nursing faces challenges in the form of: reduced number and seniority of medical staff cover for acute wards; mandated responsibility for management of patients outside of critical care units, without corresponding responsibility for managing staff; increased public and political awareness of deficits in critical care; increased use of Assistant Practitioners; and emphasis on longer-term outcomes from intensive care. New leadership roles have met these challenges head on with two main foci: patient management across the acute/critical care interface and hospital wide policies and practice. The leadership roles examined in this paper highlight three underpinning goals: improved quality and safety of patient care; improved communication between professionals; and empowerment of junior nurses and doctors. There has been considerable investment in strategic leadership roles for critical care nursing; evidence is developing of the return on this investment for patient and service outcomes. Consideration must now be given to the preparation, mentorship and development of leadership roles for the next generation of nurse leaders.
| 19,017,246
|
Biochemical characterization of plasma-derived tissue factor pathway inhibitor: post-translational modification of free, full-length form with particular reference to the sugar chain.
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Tissue factor pathway inhibitor (TFPI) is a physiological protease inhibitor that inhibits the initial reactions of the extrinsic blood coagulation pathway. Most TFPI in human plasma is associated with lipoproteins; however, the most functionally active form is thought to be the free, full-length form (f-pTFPI). Cell culture derived TFPI and recombinant TFPI (rTFPI) exhibit variations in their respective anticoagulant activity, which may be caused by post-translational modifications, such as the frequent differences in sugar chain structures among recombinant proteins. Sugar chain structures in rTFPI expressed in Chinese hamster ovary (CHO) cells have been reported previously, but those of plasma TFPI have not been. To purify f-pTFPI and analyze the sugar chain structures. f-pTFPI was purified to homogeneity from blood plasma using a combination of anion-exchange, heparin affinity, immunoaffinity, and reversed-phase chromatographies, resulting in a yield of 76%. f-pTFPI showed a partially phosphorylated glycoprotein comprising a total of 276 amino acids by peptide mapping. The sugar chain structures were analyzed by two-dimensional sugar mapping combined with exoglycosidase digestion of the pyridylamino sugar chains and the following results were obtained. (Sialyl) Galbeta1-3GalNAc was linked to Thr(175), partially to Thr(14) and Ser(174); sialyl complex-type sugar chains to Asn(117) and Asn(167), whereas Asn(228) was not glycosylated. Neuraminidase-resistant acidic sugar chains including sulfated sugar chains were not observed significantly. The protease inhibitory activities of f-pTFPI towards activated factor (F) X and tissue factor-activated FVII complex were identical to those of full-length rTFPI expressed in CHO cells.
| 19,017,259
|
The histone methylase KMTox interacts with the redox-sensor peroxiredoxin-1 and targets genes involved in Toxoplasma gondii antioxidant defences.
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The ability of living cells to alter their gene expression patterns in response to environmental changes is essential for viability. Oxidative stress represents a common threat for all aerobic life. In normally growing cells, in which hydrogen peroxide generation is transient or pulsed, the antioxidant systems efficiently control its concentration. Intracellular parasites must also protect themselves against the oxidative burst imposed by the host. In this work, we have investigated the role of KMTox, a new histone lysine methyltransferase, in the obligate intracellular parasite Toxoplasma gondii. KMTox is a nuclear protein that holds a High Mobility Group domain, which is thought to recognize bent DNA. The enzyme methylates both histones H4 and H2A in vitro with a great preference for the substrate in reduced conditions. Importantly, KMTox interacts specifically with the typical 2-cys peroxiredoxin-1 and the binding is to some extent enhanced upon oxidation. It appears that the cellular functions that are primarily regulated by the KMTox are antioxidant defences and maintenance of cellular homeostasis. KMTox may regulate gene expression in T. gondii by providing the rapid re-arrangement of chromatin domains and by interacting with the redox-sensor TgPrx1 contribute to establish the antioxidant 'firewall' in T. gondii.
| 19,017,266
|
Glycosylation of the phosphate binding protein, PstS, in Streptomyces coelicolor by a pathway that resembles protein O-mannosylation in eukaryotes.
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Previously mutations in a putative protein O-mannosyltransferase (SCO3154, Pmt) and a polyprenol phosphate mannose synthase (SCO1423, Ppm1) were found to cause resistance to phage, phiC31, in the antibiotic producing bacteria Streptomyces coelicolor A3(2). It was proposed that these two enzymes were part of a protein O-glycosylation pathway that was necessary for synthesis of the phage receptor. Here we provide the evidence that Pmt and Ppm1 are indeed both required for protein O-glycosylation. The phosphate binding protein PstS was found to be glycosylated with a trihexose in the S. coelicolor parent strain, J1929, but not in the pmt(-) derivative, DT1025. Ppm1 was necessary for the transfer of mannose to endogenous polyprenol phosphate in membrane preparations of S. coelicolor. A mutation in ppm1 that conferred an E218V substitution in Ppm1 abolished mannose transfer and glycosylation of PstS. Mass spectrometry analysis of extracted lipids showed the presence of a glycosylated polyprenol phosphate (PP) containing nine repeated isoprenyl units (C(45)-PP). S. coelicolor membranes were also able to catalyse the transfer of mannose to peptides derived from PstS, indicating that these could be targets for Pmt in vivo.
| 19,017,269
|
Liver transplantation in children with fulminant hepatic failure: The UCL experience.
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The outcome of pediatric LT for FHF was shown to be poor in our center. To better understand such results, recipient and transplant parameters with a putative impact on post-transplant outcome were analyzed in LT for FHF. Between March 1984 and June 2002, 33 children with FHF received a primary liver allograft. The overall results in this series were studied with respect to pre-operative demographic and metabolic variables, peri-operative events, and outcome. Five-yr patient and graft survivals were 71% and 66%, respectively, with a retransplantation rate at 18%. Incidences of perioperative hemorrhage, of HAT and PVT were 14%, 8%, and 4%, respectively. Five-yr acute rejection-free survival rate was 55%. These data confirm the worse outcome following LT for FHF when compared with LT in elective, non-malignant indications such as BA; results in FHF could not be related to surgical or immunological complications in the post-transplant period and it is hypothesized that the MOF associated with FHF contributes to early post-transplant mortality which would justify special management, including aggressive renal and hepatic support.
| 19,017,285
|
Identification of the novel HLA-A*9250 allele by sequence-based typing in a Caucasian bone marrow donor from Italy.
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HLA-A*9250 allele was identified by SBT in a Caucasian bone marrow donor. It differs from the closest A*020101 by only one nucleotide (A-->G) at position 124 in exon 2 (Arg to Gly at codon 18); this is an uncommon variation at a highly conserved nucleotide position, located on the loop between S1-S2 beta-sheets in alpha1 domain.
| 19,017,303
|
Lamivudine or lamivudine combined with hepatitis B immunoglobulin in prophylaxis of hepatitis B recurrence after liver transplantation: a meta-analysis.
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There is a controversy over whether the different outcomes of prophylaxis of hepatitis B virus (HBV) recurrence are attributable to different treatments. A systematic review and a meta-analysis were conducted to evaluate lamivudine monotherapy and combined therapy of lamivudine and hepatitis B immunoglobulin (HBIG) in HBV infected liver recipients. A fixed effects model was used for statistical pooling of relative risks (RR) for the different outcomes. Six articles (551 patients) fulfilled the inclusion criteria. Statistically significant differences were observed between lamivudine monotherapy and lamivudine + HBIG therapy in hepatitis B recurrence [P < 0.0001; RR = 0.38; 95% CI (0.25, 0.58)], YMDD mutant [P = 0.002; RR = 0.40; 95% CI (0.23, 0.72)] and hepatitis B recurrence in HBV-DNA positive patients before orthotopic liver transplantation [P < 0.00001; RR = 0.31; 95% CI (0.21, 0.45)]. No significant differences were observed in patient survival [P = 0.59; RR = 1.02; 95% CI (0.95, 1.09)], graft survival [P = 0.56; RR = 1.02; 95% CI (0.95, 1.09)] and diseases leading to death between the two groups [HBV recurrence leading to death: P = 0.05; RR = 0.47; 95% CI (0.22, 1.02); hepatocellular carcinoma recurrence leading to death: P = 0.13; RR = 0.34; 95% CI (0.09, 1.36)]. In conclusion, combination of lamivudine and HBIG can effectively decrease the recurrence rate of HBV and the incidence of YMDD mutant, but it can not improve patient survival and graft survival significantly. Well-designed large-sample trials are needed to evaluate the efficiency of combined therapy of lamivudine and HBIG in prophylaxis of HBV recurrence in liver graft recipients.
| 19,017,304
|
Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection.
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Transcriptomics could contribute significantly to the early and specific diagnosis of rejection episodes by defining 'molecular Banff' signatures. Recently, the description of pathogenesis-based transcript sets offered a new opportunity for objective and quantitative diagnosis. Generating high-quality transcript panels is thus critical to define high-performance diagnostic classifier. In this study, a comparative analysis was performed across four different microarray datasets of heterogeneous sample collections from two published clinical datasets and two own datasets including biopsies for clinical indication, and samples from nonhuman primates. We characterized a common transcriptional profile of 70 genes, defined as acute rejection transcript set (ARTS). ARTS expression is significantly up-regulated in all AR samples as compared with stable allografts or healthy kidneys, and strongly correlates with the severity of Banff AR types. Similarly, ARTS were tested as a classifier in a large collection of 143 independent biopsies recently published by the University of Alberta. Results demonstrate that the 'in silico' approach applied in this study is able to identify a robust and reliable molecular signature for AR, supporting a specific and sensitive molecular diagnostic approach for renal transplant monitoring.
| 19,017,305
|
Micronutrient status indicators in individuals single- or double-infected with HIV and Wuchereria bancrofti before and after DEC treatment.
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To identify possible associations between selected micronutrient status indicators (serum ferritin, retinol, beta-carotene, alpha-tocopherol, and the acute phase reactant alpha-1 antichymotrypsin) and infection with human immunodeficiency virus (HIV) or Wuchereria bancrofti, and to assess the effect of the antifilarial drug diethylcarbamazine (DEC) on the micronutrient status indicators in individuals positive for one or both of the two infections. Serum concentrations of ferritin, retinol, beta-carotene, alpha-tocopherol and the acute phase reactant alpha-1 antichymotrypsin were examined in 59 individuals with HIV, W. bancrofti infection, or both, in Tanga Region, Tanzania, before and 12 weeks after treatment with DEC. HIV infection, but not W. bancrofti infection, was associated with higher serum ferritin concentrations and lower beta-carotene and alpha-tocopherol. Neither HIV infection nor W. bancrofti infection was associated with serum retinol. The four micronutrient status indicators and alpha-1 antichymotrypsin were generally lower at 12 weeks after treatment both in the DEC and the placebo groups. The negative association between HIV infection and the antioxidant vitamins beta-carotene and alpha-tocopherol may be due to infection-induced oxidative stress, whereas W. bancrofti infection seemed not to be associated with oxidative stress. The drop in antioxidant vitamin concentrations after treatment may be due to oxidative stress induced by HIV progression (HIV infected) and inflammation around dead adult worms and microfilariae (W. bancrofti infected) rather than to an effect of DEC.
| 19,017,312
|
Diverticulum of the posterior left atrial wall.
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Diverticula of the left atrium are very rare malformations of unknown etiology and may be associated with arrhythmias, thromboembolism, or mitral valve regurgitation. We report a patient with suspected coronary artery disease (CAD) in whom we performed a low-dose computed tomography coronary angiography using prospective electrocardiogram triggering. CAD could be ruled out. Incidentally, we found a diverticulum on the posterior wall of the left atrium combined with an interatrial septal aneurysm. The diagnosis was confirmed by transthoracic echocardiography.
| 19,017,313
|
Lack of association between obesity and left ventricular systolic dysfunction.
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Previous studies have demonstrated that obesity is one of the risk factors for congestive heart failure (CHF). By analyzing a large database, we investigated any association between body mass index (BMI) and left ventricular (LV) systolic dysfunction. We retrospectively analyzed 24,265 echocardiograms performed between 1984 and 1998. Fractional shortening (FS) and BMI were available for 13,382 subjects in this cohort which were used for data analysis. FS was stratified into four groups: (1) FS > 25%, (2) FS 17.5-25%, (3) FS 10-17.5%, and (4) FS < 10%. Furthermore, we also used final diagnosis that was coded by the reading cardiologist as mild, moderate, and severe LV dysfunction separately for data analysis. BMI was divided into four groups: BMI < 18.5 kg/m(2) (underweight), 18.5-24.9 kg/m(2) (normal), 25-30 kg/m(2) (overweight), and >30 kg/m(2) (obese). There was no association between different BMI categories and LV systolic function. The prevalence of mild, moderate, or severely decreased LV function (based on FS or subjective interpretation of reading cardiologists) was equally distributed between the groups. Obese patients (BMI > 30%) had normal FS of >25 in 16.9%, mildly decreased FS in 18%, moderately decreased FS in 18.4%, and severely decreased FS in 20.1% P = ns. Our study is consistent with previous trials suggesting that obesity is not related to systolic LV dysfunction. The underlying mechanism for the occurrence of congestive heart failure in obese patients needs further investigation.
| 19,017,327
|
Pacing-induced electromechanical ventricular dyssynchrony does not acutely influence right ventricular function and global hemodynamics in children with normal hearts.
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Right ventricular (RV) pacing may be detrimental to ventricular function. However, the acute effects of electromechanical dyssynchrony on RV function are not well characterized in children. We studied acute effects of electromechanical dyssynchrony, induced by RV apical and RV outflow pacing, in children with normal hearts, evaluating electromechanical synchrony, hemodynamic response, and RV function. Seventeen children (mean +/- SD, 12 +/- 4 years) with normal cardiac structure/function were paced after accessory pathway ablation, at baseline (AOO), and with AV pacing (DOO) from the RV apex and RV outflow. QRS duration was determined from surface ECG. Intra- and interventricular mechanical dyssynchrony and regional ventricular function were determined using tissue Doppler imaging. Global RV systolic and diastolic functions were assessed by RV dP/dT(max) and RV dP/dT(neg) using pressure-tipped transducers. Regional RV function was assessed by tissue Doppler imaging. Cardiac index (CI) and blood pressures were measured. RV apical and outflow pacing induced significant electromechanical dyssynchrony manifested by lengthening of the QRS duration, increased LV intraventricular delay (49 +/- 34 ms, 53 +/- 43 ms, respectively, P < 0.001), and increased interventricular delay (60 +/- 29 ms, 55 +/- 37 ms, P < 0.0001) versus AOO pacing. However, there was no change in blood pressure, CI, RV dp/dT(max), RV dP/dT(neg), or regional tissue Doppler velocities, indicating preserved hemodynamics and preserved global and regional RV systolic and diastolic function. In children with normal cardiac function and structure, pacing-induced electromechanical dyssynchrony did not acutely affect RV systolic and diastolic function and did not acutely alter global hemodynamics. Therefore, electromechanical dyssynchrony may only be an important therapeutic target in the setting of decreased RV function.
| 19,017,336
|
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