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Elucidation of multiple-point interactions of pyranine fluoroprobe during the gelation.
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We have studied the multiple-point interactions of the pyranine (8-hydroxypyrene-1,3,6-trisulfonic acid, trisodium salt; 3sPyOH) fluoroprobe with polymer chains during the free-radical polymerization of acrylamide (AAm) by using the steady state fluorescence measurements. We observed a considerable blue shift from 515nm to 406nm in the emission spectra due to a C-O ether bond formation between the hydroxylic oxygen of 3sPyOH and a terminal C-atom of the growing AAm chain. Furthermore ionic (electrostatic) interactions occur between the three ionized sulfonic acid groups (SO(3)(-)) of 3sPyOH and protonated amide groups on the AAm chains. These electrostatic interactions also cause a gradual red shift in the maximum of the short-wavelength-peak, from 406nm to 430nm. The results showed that the pyranine can be used as a probe for real time monitoring of the polymerization process of AAm system since it monitors both the progression of the polymerization via chemical binding over OH group and the change in the local density of the polymerizing sample by means of the gradual red shift in the short-wavelength-peak via ionic interactions over SO(3)(-) groups.
| 19,010,726
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Computerized Provider Order Entry--what are health professionals concerned about? A qualitative study in an Australian hospital.
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To identify the main concerns of a broad range of hospital staff about the implementation of a new Computerized Provider Order Entry (CPOE) system for medication management. The study was conducted in a large Australian teaching hospital using semi-structured interviews (n=20) and focus groups (six focus groups involving a total of 30 participants) from a broad section of health professionals including doctors, nurses, managers, pharmacists and senior health executives. Systematic concurrent analysis of the data was undertaken by a team of researchers. We identified 20 recurrent themes related to nine areas of shared concern including work practices, software/hardware, relationships/communication, education and training, inexperienced staff and de-skilling. A higher level of analysis identified four interrelated constructs that highlight what people are concerned about: (1) Will it help? (2) Will it work? (3) Will we cope? (4) Will it impair existing interaction? The research provides a snapshot overview of perceptions from a range of hospital personnel in the lead up to CPOE implementation. Generalizability is limited by the size of the sample and the contextual circumstances of the hospital being studied. This work contributes valuable evidence about an often-neglected dimension in the evaluation of computer systems in hospitals, namely the pre-implementation concerns of staff. These pre-conceptions can have a significant effect on how technology is implemented and utilised. Acknowledging and addressing people's concerns can contribute to the establishment of durable channels of negotiation and communication. Further research informed by the findings of this study will help advance this process.
| 19,010,728
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Assessing controlled substance prescribing errors in a pediatric teaching hospital: an analysis of the safety of analgesic prescription practice in the transition from the hospital to home.
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Iatrogenic errors producing serious and often preventable injury occur frequently in hospitalized patients, particularly in children. Little is known about the epidemiology of analgesic medication errors in patients being discharged from the hospital. The goal of this study was to describe the epidemiology of controlled substance prescription errors by physicians-in-training for children being discharged from the hospital. We conducted a prospective, observational study of the analgesic prescriptions and discharge forms of 241 pediatric patients discharged from a Children's Center of a major urban teaching hospital from November 2003 to April 2004. All patients who were actively followed by the Pediatric Pain Service at the time of their discharge and were discharged with an analgesic prescription were included in the study. Primary outcome variables were the percentage of prescriptions that contained at least 1 medication error or potential adverse drug event. Errors were defined using the Institute for Safe Medication Practices' (ISMP) List of Error-Prone Abbreviations, Symbols, and Dose Designations, literature review, expert panel consensus, and the Johns Hopkins Department of Pharmacy hospital formulary. Two hundred forty-one patients who received 314 prescriptions were included in this study. Prescription errors were common; 257 of 314 (82%) of the prescriptions examined contained 1 or more errors. The most common errors were missing or wrong patient weight (n = 127, 77%), incomplete dispensing information (n = 167, 53%), and no or wrong date on prescription (n = 19, 6%). Nine prescriptions (2.9%) had the potential for significant medical injury and were considered potential adverse drug events. Discharge prescription errors for children requiring potent, opioid analgesic drugs in the management of pain are common, and nearly 3% could cause significant harm. The high rate of prescribing errors highlights the importance of developing, testing and implementing effective error-prevention strategies, especially in high-risk medications such as narcotics. Narcotic prescriptions written by trainees at discharge from a pediatric hospital are error prone and nearly 3% have the potential to cause significant harm. With a low therapeutic profile, the hospital may consider a review/verification process to reduce the risk of patient harm.
| 19,010,736
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Acupoint stimulation with diluted bee venom (apipuncture) potentiates the analgesic effect of intrathecal clonidine in the rodent formalin test and in a neuropathic pain model.
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Although intrathecal (i.t.) administration of the alpha(2)-adrenoceptor agonist clonidine has a pronounced analgesic effect, the clinical use of clonidine is limited by its side effects. Previously, our laboratory has demonstrated that the subcutaneous injection of diluted bee venom (DBV) into an acupoint (termed apipuncture) produces significant analgesic effect in various pain animal models. The present study was designed to examine whether DBV injection into the Zusanli acupoint (ST-36) could enhance lower-dose clonidine-induced analgesic effects without the development of hypotension, bradycardia, or sedation. In the mouse formalin test, DBV injection produced a dramatic leftward shift in the dose-response curve for clonidine-induced analgesia. In a rat neuropathic pain model i.t. clonidine dose dependently suppressed chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia, and this clonidine-induced analgesic effect was significantly potentiated by apipuncture pretreatment. DBV apipuncture alone or in combination with a low dose of i.t. clonidine produced an analgesic effect similar to that of the high dose of clonidine, but without significant side effects. The analgesic effect produced by the combination of i.t. clonidine and apipuncture was completely blocked by pretreatment with an alpha(2)-adrenoceptor antagonist. These data show that DBV-apipuncture significantly enhances clonidine-induced analgesia and suggest that a combination of low dose clonidine with acupuncture therapy represents a novel strategy for pain management that could eliminates clonidine's side effects. This study demonstrated that intrathecal clonidine-induced analgesia is significantly enhanced when it is combined with chemical acupuncture treatment. The administration of low-dose clonidine in combination with acupuncture produced a potent analgesic effect without significant side effects and thus represents a potential novel strategy for the management of chronic pain.
| 19,010,737
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Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy: a double-blind, randomized, placebo-controlled study.
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Recent evidence has demonstrated analgesic, anti-inflammatory, and anxiolytic properties of melatonin. Taking into account that higher anxiety makes the control of postoperative pain more difficult, one can hypothesize that melatonin anxiolytic and analgesic effects improve the control of postoperative pain. Thus, we conducted a randomized, double-blind, placebo-controlled study with 59 patients undergoing abdominal hysterectomy to test the hypothesis that melatonin is as effective as clonidine and that both are more effective than placebo in reducing postoperative pain. Additionally, we compared their anxiolytic effects on postoperative pain. Patients were randomly assigned to receive oral melatonin (5 mg) (n = 20), clonidine (100 microg) (n = 19), or placebo (n = 20) orally. In addition to primary outcomes of pain intensity and analgesic consumption, secondary outcome measures included postoperative state anxiety. In anxious patients 6 hours after surgery, the number of patients needed to be to prevent moderate to intense pain during the first 24 hours after surgery was 1.52 (95% CI, 1.14 to 6.02) and 1.64 (95% CI, 1.29 to 5.93), respectively, in the melatonin and clonidine groups compared with placebo. Also, the anxiolytic effect of melatonin and clonidine resulted in reduced postoperative morphine consumption by more than 30%. However, in the mildly anxious, it was not observed the treatment effect on pain. The preoperative anxiolysis with melatonin or clonidine reduced postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy. The effects these 2 drugs were equivalent and greater than with placebo.
| 19,010,741
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General strategy to humanize a camelid single-domain antibody and identification of a universal humanized nanobody scaffold.
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Nanobodies, single-domain antigen-binding fragments of camelid-specific heavy-chain only antibodies offer special advantages in therapy over classic antibody fragments because of their smaller size, robustness, and preference to target unique epitopes. A Nanobody differs from a human heavy chain variable domain in about ten amino acids spread all over its surface, four hallmark Nanobody-specific amino acids in the framework-2 region (positions 42, 49, 50, and 52), and a longer third antigen-binding loop (H3) folding over this area. For therapeutic applications the camelid-specific amino acid sequences in the framework have to be mutated to their human heavy chain variable domain equivalent, i.e. humanized. We performed this humanization exercise with Nanobodies of the subfamily that represents close to 80% of all dromedary-derived Nanobodies and investigated the effects on antigen affinity, solubility, expression yield, and stability. It is demonstrated that the humanization of Nanobody-specific residues outside framework-2 are neutral to the Nanobody properties. Surprisingly, the Glu-49 --> Gly and Arg-50 --> Leu humanization of hallmark amino acids generates a single domain that is more stable though probably less soluble. The other framework-2 substitutions, Phe-42 --> Val and Gly/Ala-52 --> Trp, are detrimental for antigen affinity, due to a repositioning of the H3 loop as shown by their crystal structures. These insights were used to identify a soluble, stable, well expressed universal humanized Nanobody scaffold that allows grafts of antigen-binding loops from other Nanobodies with transfer of the antigen specificity and affinity.
| 19,010,777
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Opposing roles of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase in the cellular response to ionizing radiation in human cervical cancer cells.
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Exposure of cells to ionizing radiation induces activation of multiple signaling pathways that play critical roles in determining cell fate. However, the molecular basis for cell death or survival signaling in response to radiation is unclear at present. Here, we show opposing roles of the c-jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in the mitochondrial cell death in response to ionizing radiation in human cervical cancer cells. Ionizing radiation triggered Bax and Bak activation, Bcl-2 down-regulation, and subsequent mitochondrial cell death. Inhibition of JNK completely suppressed radiation-induced Bax and Bak activation and Bcl-2 down-regulation. Dominant-negative forms of stress-activated protein kinase/extracellular signal-regulated kinase kinase 1 (SEK-1)/mitogen-activated protein kinase kinase-4 (MKK-4) inhibited JNK activation. Radiation also induced phosphoinositide 3-kinase (PI3K) activation. Interestingly, inhibition of PI3K effectively attenuated radiation-induced mitochondrial cell death and increased clonogenic survival. Inhibition of PI3K also suppressed SEK-1/MKK-4 and JNK activation, Bax and Bak activation, and Bcl-2 down-regulation. In contrast, inhibition of p38 MAPK led to enhanced Bax and Bak activation and mitochondrial cell death. RacN17, a dominant-negative form of Rac1, inhibited p38 MAPK activation and increased Bax and Bak activation. Exposure of cells to radiation also induced selective activation of c-Src among Src family kinases. Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation-induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death. Our results support the notion that the PI3K-SEK-1/MKK-4-JNK pathway is required for the mitochondrial cell death in response to radiation, whereas the c-Src-Rac1-p38 MAPK pathway plays a cytoprotective role against mitochondrial cell death.
| 19,010,820
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Antisense MDM2 enhances E2F1-induced apoptosis and the combination sensitizes androgen-sensitive [corrected] and androgen-insensitive [corrected] prostate cancer cells to radiation.
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We have previously shown in separate studies that MDM2 knockdown via antisense MDM2 (AS-MDM2) and E2F1 overexpression via adenoviral-mediated E2F1 (Ad-E2F1) sensitized prostate cancer cells to radiation. Because E2F1 and MDM2 affect apoptosis through both common and independent pathways, we hypothesized that coupling these two treatments would result in increased killing of prostate cancer cells. In this study, the effect of Ad-E2F1 and AS-MDM2 in combination with radiation was investigated in three prostate cancer cell lines: LNCaP cells, LNCaP-Res cells [androgen insensitive with functional p53 and androgen receptor (AR)], and PC3 cells (androgen insensitive, p53(null), and AR(null)). A supra-additive radiosensitizing effect was observed in terms of clonogenic inhibition and induction of apoptosis (caspase-3 + caspase-7 activity) in response to Ad-E2F1 plus AS-MDM2 treatments in all three cell lines. In LNCaP and LNCaP-Res, these combination treatments elevated the levels of phospho-Ser(15) p53 with significant induction of p21(waf1/cip1), phospho-gammaH2AX, PUMA, and Bax levels and reduction of AR and bcl-2 expression. Similarly, AR(null) and p53(null) PC-3 cells showed elevated levels of Bax and phospho-gammaH2AX expression. These findings show that the combination of Ad-E2F1 and AS-MDM2 significantly increases cell death in prostate cancer cells exposed to radiation and that this effect occurs in the presence or absence of AR and p53.
| 19,010,821
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Nuclear factor-kappaB modulation in patients undergoing induction chemotherapy for acute myelogenous leukemia.
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Nuclear factor-kappaB (NF-kappaB) is constitutively expressed in many acute myelogenous leukemia (AML) cells and AML stem cells. Ex vivo treatment of AML cells with inhibitors of NF-kappaB results in diminished AML cell survival and enhances the cytotoxic effects of chemotherapeutic agents. The purpose of this study was to determine if standard anti-inflammatory agents modulate AML cell nuclear NF-kappaB when administered in conjunction with induction chemotherapy. Patients with newly diagnosed AML were treated with dexamethasone, choline magnesium trisalicylate, or both for 24 hours prior to and 24 hours following initiation of standard induction chemotherapy. AML cell nuclear NF-kappaB was measured at baseline, 24, and 48 hours. Choline magnesium trisalicylate +/- dexamethasone decreased nuclear NF-kappaB, whereas dexamethasone alone was associated with an increase in nuclear NF-kappaB in AML cells. These results show the feasibility of NF-kappaB modulation in conjunction with induction chemotherapy for patients with AML using inexpensive readily available medications. A follow-up study to determine the effects of NF-kappaB modulation on clinical end points is warranted.
| 19,010,875
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Does the renin-angiotensin system participate in regulation of human vasculogenesis and angiogenesis?
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Several lines of evidence suggest that hypertension and angiogenesis may be related phenomena but a functional link remains elusive. Here, we propose that the renin-angiotensin system (RAS), in addition to its central role in arterial hypertension, also regulates blood vessel formation during normal development and cancer. This mechanistic hypothesis is based on reports of biochemical, genetic, clinical, and epidemiologic data reviewed herein. Species differences between the RAS of rodents and humans likely account for why such a fundamental role in angiogenesis went unrecognized for so long. If proven correct, this hypothesis carries many implications for the medical practices of cardiology, oncology, and neonatology.
| 19,010,879
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Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth.
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Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. Symptoms are usually evident after blockage of the bile duct by the tumor, and at this late stage, they are relatively resistant to chemotherapy and radiation therapy. Therefore, it is imperative that alternative treatment options are explored. We present novel data indicating that the metabolism of serotonin is dysregulated in cholangiocarcinoma cell lines, compared with normal cholangiocytes, and tissue and bile from cholangiocarcinoma patients. Specifically, there was an increased expression of tryptophan hydroxylase 1 and a suppression of monoamine oxidase A expression (enzymes responsible for the synthesis and degradation of serotonin, respectively) in cholangiocarcinoma. This resulted in an increased secretion of serotonin from cholangiocarcinoma and increased serotonin in the bile from cholangiocarcinoma patients. Increased local serotonin release may have implications on cholangiocarcinoma cell growth. Serotonin administration increased cholangiocarcinoma cell growth in vitro, whereas inhibition of serotonin synthesis decreases tumor cell growth both in vitro and in vivo. The data presented here represent the first evidence that serotonin metabolism is dysregulated in cholangiocarcinoma and that modulation of serotonin synthesis may represent an alternative target for the development of therapeutic strategies.
| 19,010,890
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A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo.
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The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously shown that tumor cells can be targeted by EphA2 monoclonal antibodies and that these antibodies function, in part, by inducing EphA2 internalization and degradation. In this report, we describe the isolation and characterization of a fully human monoclonal antibody (1C1) that selectively binds both the human and rodent EphA2 receptor. After cell binding, the antibody induces rapid tyrosine phosphorylation, internalization, and degradation of the EphA2 receptor. Because monoclonal antibodies that selectively bind tumor cells and internalize provide a vehicle for targeted delivery of cytotoxics, 1C1 was conjugated to the microtubule inhibitor monomethylauristatin phenylalanine using a stable maleimidocaproyl linker. The anti-EphA2 antibody-drug conjugate [1C1-maleimidocaproyl-MMAF (mcMMAF)] stimulated the activation of caspase-3/caspase-7 and the death of EphA2-expressing cells with IC(50) values as low as 3 ng/mL. Similarly, the conjugate induced degradation of the EphA2 receptor and inhibited tumor growth in vivo. Administration of 1C1-mcMMAF at doses as low as 1 mg/kg once weekly resulted in significant growth inhibition of EphA2-expressing tumors without any observable adverse effects in mouse xenograft and rat syngeneic tumor models. Our data support the use of an antibody-drug conjugate approach to selectively target and inhibit the growth of EphA2-expressing tumors.
| 19,010,911
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Type 2 Bias of T cells expanded from the blood of melanoma patients switched to type 1 by IL-12p70 mRNA-transfected dendritic cells.
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Melanoma patients may exhibit a T(H)2-skewed cytokine profile within blood and tumor-infiltrating lymphocytes. Therapies that induce beneficial T(H)1-type tumor-specific immune responses, therefore, are highly desirable. Dendritic cells (DC) are widely used as immune adjuvants for cancer. Before their administration, DC are generally induced to mature with a cocktail of recombinant cytokines [interleukin (IL)-1beta, tumor necrosis factor alpha, and IL-6] and prostaglandin E(2) (PGE(2)), which is added to preserve the ability of DC to migrate to draining lymph nodes. However, PGE(2) suppresses the production of IL-12p70, a cytokine essential for differentiation of T(H)1 responses. In this study, human DC were transfected with IL-12p70 mRNA and tested for their ability to alter the T(H)2 type bias manifested by blood T cells of patients with melanoma. Transfected DC secreted high levels of bioactive IL-12p70, as indicated by their capacity to enhance natural killer cell activity, skew T(H)1 responses in allogeneic mixed lymphocyte reactions through reduction of IL-4 and IL-5, and prime CD8(+) T cells to the melanoma-associated antigen Melan A/MART-1. Furthermore, T-cell lines primed in vitro from the blood of melanoma patients showed strong type 2 skewing that was dramatically reversed by IL-12p70 transfection of autologous DC. Thus, IL-12p70 transfection of clinical DC preparations may enhance type 1 antitumor responses and may thereby contribute to effective immune-based therapy.
| 19,010,919
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Effect of fenretinide and low-dose tamoxifen on insulin sensitivity in premenopausal women at high risk for breast cancer.
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The prevalence of metabolic syndrome is increasing along with breast cancer incidence worldwide. Because fenretinide improves insulin action and glucose tolerance in insulin-resistant obese mice and because tamoxifen has shown to regulate several markers involved in metabolic syndrome, we sought to investigate the effect of fenretinide or tamoxifen at low dose on features linked to insulin resistance in premenopausal women at risk for breast cancer. We randomized 235 women to low-dose tamoxifen (5 mg/daily), fenretinide (200 mg/daily), or their combination or placebo for 2 years. We used the homeostasis model assessment (HOMA; fasting insulin x glucose/22.5) to estimate insulin sensitivity. Women were considered to improve insulin sensitivity when they shifted from a HOMA >/=2.8 to <2.8. There was no effect of fenretinide or tamoxifen on HOMA overall, but overweight women (body mass index, >or=25 kg/m(2)) had a 7-fold greater probability to normalize HOMA after 2 years of fenretinide treatment [odds ratio (OR), 7.0; 95% confidence interval (95% CI), 1.2-40.5], with 25% of women improving their insulin sensitivity, whereas tamoxifen decreased insulin sensitivity by almost 7 times compared with subjects not taking tamoxifen (OR, 0.15; 95% CI, 0.03-0.88). In this group only, 5% improved their insulin sensitivity. Interestingly, women with intraepithelial or microinvasive neoplasia had higher HOMA (3.0) than unaffected subjects (2.8; P = 0.07). Fenretinide can positively balance the metabolic profile in overweight premenopausal women and this may favorably affect breast cancer risk. Furthermore, features of the metabolic syndrome should be taken into consideration before proposing tamoxifen for breast cancer prevention. The clinical implications of these results require further investigations.
| 19,010,927
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Membrane type 1 matrix metalloproteinase-mediated stromal syndecan-1 shedding stimulates breast carcinoma cell proliferation.
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Mounting evidence implicates stromal fibroblasts in breast carcinoma progression. We have recently shown in three-dimensional coculture experiments that human mammary fibroblasts stimulate the proliferation of T47D breast carcinoma cells and that this activity requires the shedding of the heparan sulfate proteoglycan syndecan-1 (Sdc1) from the fibroblast surface. The goal of this project was to determine the mechanism of Sdc1 ectodomain shedding. The broad spectrum matrix metalloproteinase (MMP) inhibitor GM6001 specifically blocked Sdc1-mediated carcinoma cell growth stimulation, pointing toward MMPs as critical enzymes involved in Sdc1 shedding. MMP-2 and membrane type 1 MMP (MT1-MMP) were the predominant MMPs expressed by the mammary fibroblasts. Fibroblast-dependent carcinoma cell growth stimulation in three-dimensional coculture was abolished by MT1-MMP expression silencing with small interfering RNA and restored either by adding recombinant MT1-MMP catalytic domain or by expressing a secreted form of Sdc1 in the fibroblasts. These findings are consistent with a model where fibroblast-derived MT1-MMP cleaves Sdc1 at the fibroblast surface, leading to paracrine growth stimulation of carcinoma cells by Sdc1 ectodomain. The relevance of MT1-MMP in paracrine interactions was further supported by coculture experiments with T47D cells and primary fibroblasts isolated from human breast carcinomas or matched normal breast tissue. Carcinoma-associated fibroblasts stimulated T47D cell proliferation significantly more than normal fibroblasts in three-dimensional coculture. Function-blocking anti-MT1-MMP antibody significantly inhibited the T47D cell growth stimulation in coculture with primary fibroblasts. In summary, these results ascribe a novel role to fibroblast-derived MT1-MMP in stromal-epithelial signaling in breast carcinomas.
| 19,010,933
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Evidence for direct contact between the RPA3 subunit of the human replication protein A and single-stranded DNA.
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Replication Protein A is a single-stranded (ss) DNA-binding protein that is highly conserved in eukaryotes and plays essential roles in many aspects of nucleic acid metabolism, including replication, recombination, DNA repair and telomere maintenance. It is a heterotrimeric complex consisting of three subunits: RPA1, RPA2 and RPA3. It possesses four DNA-binding domains (DBD), DBD-A, DBD-B and DBD-C in RPA1 and DBD-D in RPA2, and it binds ssDNA via a multistep pathway. Unlike the RPA1 and RPA2 subunits, no ssDNA-RPA3 interaction has as yet been observed although RPA3 contains a structural motif found in the other DBDs. We show here using 4-thiothymine residues as photoaffinity probe that RPA3 interacts directly with ssDNA on the 3'-side on a 31 nt ssDNA.
| 19,010,961
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The protein structure initiative structural genomics knowledgebase.
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The Protein Structure Initiative Structural Genomics Knowledgebase (PSI SGKB, http://kb.psi-structuralgenomics.org) has been created to turn the products of the PSI structural genomics effort into knowledge that can be used by the biological research community to understand living systems and disease. This resource provides central access to structures in the Protein Data Bank (PDB), along with functional annotations, associated homology models, worldwide protein target tracking information, available protocols and the potential to obtain DNA materials for many of the targets. It also offers the ability to search all of the structural and methodological publications and the innovative technologies that were catalyzed by the PSI's high-throughput research efforts. In collaboration with the Nature Publishing Group, the PSI SGKB provides a research library, editorials about new research advances, news and an events calendar to present a broader view of structural biology and structural genomics. By making these resources freely available, the PSI SGKB serves as a bridge to connect the structural biology and the greater biomedical communities.
| 19,010,965
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Threat and anxiety affect visual contrast perception.
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Threat cues activate the visual cortex and are detected faster than neutral cues as evidenced by functional brain imaging during viewing of visual threat and neutral stimuli. The functional visual processes underlying these phenomena have not been determined. Pattern visual evoked potentials were elicited in a baseline and a verbal threat condition with two stimulus contrasts in subjects with high and low trait anxiety. Threat reduced the latency of the early P100 wave in the low but not the high anxious group. The reduction was greater with increasing stimulus contrasts. The dependence of the P100 latency on trait anxiety is reminiscent of the Yerkes-Dodson inverted U-shape curve, which relates anxiety to behavioural responses. These results show that threat affects perceptual processes and suggest that data based on the effects of threat in visual search studies should be reappraised to include acceleration of contrast perception.
| 19,010,976
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Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia.
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Bronchopulmonary dysplasia (BPD) is characterised by impaired alveolarisation, inflammation and aberrant vascular development. Phosphodiesterase (PDE) inhibitors can influence cell proliferation, antagonise inflammation and restore vascular development and homeostasis, suggesting a therapeutic potential in BPD. The aim of the present study was to investigate PDE expression in the lung of hyperoxia-exposed mice, and to assess the viability of PDE4 as a therapeutic target in BPD. Newborn C57BL/6N mice were exposed to normoxia or 85% oxygen for 28 days. Animal growth and dynamic respiratory compliance were reduced in animals exposed to hyperoxia, paralleled by decreased septation, airspace enlargement and increased septal wall thickness. Changes were evident after 14 days and were more pronounced after 28 days of hyperoxic exposure. At the mRNA level, PDE1A and PDE4A were upregulated while PDE5A was downregulated under hyperoxia. Immunoblotting confirmed these trends in PDE4A and PDE5A at the protein expression level. Treatment with cilomilast (PDE4 inhibitor, 5 mg.kg(-1).day(-1)) between days 14 and 28 significantly decreased the mean intra-alveolar distance, septal wall thickness and total airspace area and improved dynamic lung compliance. Pharmacological inhibition of phosphodiesterase improved lung alveolarisation in hyperoxia-induced bronchopulmonary dysplasia, and thus may offer a new therapeutic modality in the clinical management of bronchopulmonary dysplasia.
| 19,010,982
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High-sensitive C-reactive protein is associated with reduced lung function in young adults.
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Systemic inflammation has been associated with reduced lung function. However, data on the interrelationships between lung function and inflammation are sparse, and it is not clear if low-grade inflammation leads to reduced lung function. Associations between high-sensitive C-reactive protein (CRP) and spirometric lung function were assessed in a population-based cohort of approximately 1,000 Danes aged 20 yrs. In males, the average decline in forced expiratory volume in one second (FEV(1)) in the highest CRP quintile was 23 mL.yr(-1) versus 1.6 mL.yr(-1) in the lowest quintile. In females, the average decline was 6.2 mL.yr(-1) in the highest CRP quintile versus an increase of 1.8 mL.yr(-1) in the lowest CRP quintile. In a multiple regression analysis adjusted for sex, body mass index, cardiorespiratory fitness, smoking, asthma, airway hyperresponsiveness and serum eosinophil cationic protein, higher levels of CRP at age 20 yrs were associated with a greater reduction in both FEV(1) and forced vital capacity between ages 20 and 29 yrs. The findings show that higher levels of C-reactive protein in young adults are associated with subsequent decline in lung function, suggesting that low-grade systemic inflammation in young adulthood may lead to impaired lung function independently of the effects of smoking, obesity, cardiorespiratory fitness, asthma and eosinophilic inflammation.
| 19,010,993
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Amifostine reduces lung vascular permeability via suppression of inflammatory signalling.
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Despite an encouraging outcome of antioxidant therapy in animal models of acute lung injury, effective antioxidant agents for clinical application remain to be developed. The present study investigated the effect of pre-treatment with amifostine, a thiol antioxidant compound, on lung endothelial barrier dysfunction induced by Gram-negative bacteria wall-lipopolysaccharide (LPS). Endothelial permeability was monitored by changes in transendothelial electrical resistance. Cytoskeletal remodelling and reactive oxygen species (ROS) production was examined by immunofluorescence. Cell signalling was assessed by Western blot. Measurements of Evans blue extravasation, cell count and protein content in bronchoalveolar lavage fluid were used as in vivo parameters of lung vascular permeability. Hydrogen peroxide, LPS and interleukin-6 caused cytoskeletal reorganisation and increased permeability in the pulmonary endothelial cells, reflecting endothelial barrier dysfunction. These disruptive effects were inhibited by pre-treatment with amifostine and linked to the amifostine-mediated abrogation of ROS production and redox-sensitive signalling cascades, including p38, extracellular signal regulated kinase 1/2, mitogen-activated protein kinases and the nuclear factor-kappaB pathway. In vivo, concurrent amifostine administration inhibited LPS-induced oxidative stress and p38 mitogen-activated protein kinase activation, which was associated with reduced vascular leak and neutrophil recruitment to the lungs. The present study demonstrates, for the first time, protective effects of amifostine against lipopolysaccharide-induced lung vascular leak in vitro and in animal models of lipopolysaccharide-induced acute lung injury.
| 19,010,997
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Colocalization of increased transforming growth factor-beta-induced protein (TGFBIp) and Clusterin in Fuchs endothelial corneal dystrophy.
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To investigate the differential expression of TGFBIp in normal human and Fuchs endothelial corneal dystrophy (FECD) endothelial cell-Descemet's membrane (HCEC-DM) complex, and to asses the structural role of TGFBIp and clusterin (CLU) in guttae formation. HCEC-DM complex was dissected from stroma in normal and FECD samples. Proteins were separated by 2-D gel electrophoresis and subjected to proteomic analysis. N-terminal processing of TGFBIp was detected by Western blot analysis with two separate antibodies against the N- and C-terminal regions of TGFBIp. Expression of TGFBI mRNA was compared by using real-time PCR. Subcellular localization of TGFBIp and CLU in corneal guttae was assessed by fluorescence confocal microscopy. A major 68-kDa fragment and a minor 39-kDa fragment of TGFBIp were identified on 2-D gels. Western blot analysis revealed an age-dependent proteolytic processing of the TGFBIp N terminus resulting in the increased formation of 57-kDa (P = 0.04) and 39-kDa (P = 0.03) fragments in older donors. FECD HCEC-DM showed a significant increase in the 68-kDa (P = 0.04), 57-kDa (P = 0.01), and 39- kDa (P = 0.03) fragments of TGFBIp. Real-time PCR analysis revealed that TGFBI mRNA was significantly increased (P = 0.04) in FECD samples. TGFBIp formed aggregates at the lower portions of guttae, next to Descemet's membrane, whereas CLU localized mostly on top of the TGFBIp-stained areas at the level of the endothelial cell nuclear plane. The overexpression of proaggregative protein CLU, and proadhesive protein TGFBIp, have been colocalized in the guttae. Such findings provide us with a better understanding of the major contributors involved in the aberrant cell-extracellular matrix interactions seen in the guttae of patients with FECD.
| 19,011,008
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1,3-Propanediol dehydrogenase from Klebsiella pneumoniae: decameric quaternary structure and possible subunit cooperativity.
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Klebsiella pneumoniae is a nosocomial pathogen frequently isolated from opportunistic infections, especially in clinical environments. In spite of its potential pathogenicity, this microorganism has several metabolic potentials that could be used in biotechnology applications. K. pneumoniae is able to metabolize glycerol as a sole source of carbon and energy. 1,3-Propanediol dehydrogenase is the core of the metabolic pathway for the use of glycerol. We have determined the crystallographic structure of 1,3-propanediol dehydrogenase, a type III Fe-NAD-dependent alcohol dehydrogenase, at 2.7-A resolution. The structure of the enzyme monomer is closely related to that of other alcohol dehydrogenases. The overall arrangement of the enzyme showed a decameric structure, formed by a pentamer of dimers, which is the catalytic form of the enzyme. Dimers are associated by strong ionic interactions that are responsible for the highly stable in vivo packing of the enzyme. Kinetic properties of the enzyme as determined in the article would suggest that this decameric arrangement is related to the cooperativity between monomers.
| 19,011,020
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Dynamic association of the replication initiator and transcription factor DnaA with the Bacillus subtilis chromosome during replication stress.
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DnaA functions as both a transcription factor and the replication initiator in bacteria. We characterized the DNA binding dynamics of DnaA on a genomic level. Based on cross-linking and chromatin immunoprecipitation data, DnaA binds at least 17 loci, 15 of which are regulated transcriptionally in response to inhibition of replication (replication stress). Six loci, each of which has a cluster of at least nine potential DnaA binding sites, had significant increases in binding by DnaA when replication was inhibited, indicating that the association of DnaA with at least some of its target sites is altered after replication stress. When replication resumed from oriC after inhibition of replication initiation, these high levels of binding decreased rapidly at origin-proximal and origin-distal regions, well before a replication fork could pass through each of the regulated regions. These findings indicate that there is rapid signaling to decrease activation of DnaA during replication and that interaction between DnaA bound at each site and the replication machinery is not required for regulation of DnaA activity in response to replication stress.
| 19,011,033
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Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor.
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It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptor-positive tumours in vitro and in vivo through activation of the androgen receptor.
| 19,011,039
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NADPH oxidase has a directional response to shear stress.
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Vessel regions with predilection to atherosclerosis have negative wall shear stress due to flow reversal. The flow reversal causes the production of superoxides (O(2)(-)), which scavenge nitric oxide (NO), leading to a decrease in NO bioavailability and endothelial dysfunction. Here, we implicate NADPH oxidase as the primary source of O(2)(-) during full flow reversal. Nitrite production and the degree of vasodilation were measured in 46 porcine common femoral arteries in an ex vivo system. Nitrite production and vasodilation were determined before and after the inhibition of NADPH oxidase, xanthine oxidase, or mitochondrial oxidase. NADPH oxidase inhibition with gp91ds-tat or apocynin restored nitrite production and vasodilation during reverse flow. Xanthine oxidase inhibition increased nitrite production at the highest flow rate, whereas mitochondrial oxidase inhibition had no effect. These findings suggest that the NADPH oxidase system can respond to directional changes of flow and is activated to generate O(2)(-) during reverse flow in a dose-dependent fashion. These findings have important clinical implications for oxidative balance and NO bioavailability in regions of flow reversal in a normal and compromised cardiovascular system.
| 19,011,040
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Chronic stimulation of farnesoid X receptor impairs nitric oxide sensitivity of vascular smooth muscle.
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Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily that is highly expressed in enterohepatic tissue, is implicated in bile acid, lipid, and glucose metabolisms. Although recent studies showed that FXR is also expressed in vascular endothelial cells and smooth muscle cells, its physiological and/or pathological roles in vasculature tissue remain unknown. The aim of this study is to examine the chronic effect of synthetic FXR agonist GW4064 on vascular contraction and endothelium-dependent relaxation using tissue culture procedure. In cultured rabbit mesenteric arteries, the treatment with 0.1-10 microM GW4064 for 7 days did not influence vascular contractility induced by high K(+) (15-65 mM), norepinephrine (0.1-100 microM), and endothelin-1 (0.1-100 nM). However, the chronic treatment with GW4064 (1-10 microM for 7 days) dose dependently impaired endothelium-dependent relaxation induced by substance P (0.1-30 nM). In hematoxylin-eosin cross sectioning and en face immunostaining, GW4064 had no effects on the morphology of endothelial and smooth muscle cells. In endothelium-denuded arteries treated with GW4064 (1-10 microM) for 7 days, 3 nM-100 microM sodium nitroprusside-induced vasorelaxation, but not membrane-permeable cGMP analog 8-bromoguanosine-cGMP (8-Br-cGMP; 1-100 microM)-induced vasorelaxation, was significantly impaired. In these GW4064-treated arteries, 1 muM sodium nitroprusside-induced intracellular cGMP elevations were impaired. In RT-PCR, any changes were detected in mRNA expression level of alpha(1)- and beta(1)-subunit of soluble guanylyl cyclase. These results suggest that chronic stimulation of FXR impairs endothelium-dependent relaxation, which is due to decreased sensitivity of smooth muscle cells to nitric oxide.
| 19,011,043
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Na+/H+ exchanger isoform 1 facilitates cardiomyocyte embryonic stem cell differentiation.
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Embryonic stem cells provide one potential source of cardiomyocytes for cardiac transplantation; however, after differentiation of stem cells in vitro, cardiomyocytes usually account for only a minority of cells present. To gain insights into improving cardiomyocyte development from stem cells, we examined the role of the Na(+)/H(+) exchanger isoform 1 (NHE1) in cardiomyocyte differentiation. NHE1 protein and message levels were induced by treatment of CGR8 cells to form embryoid bodies and cardiomyocytes. The NHE1 protein was present on the cell surface and NHE1 inhibitor-sensitive activity was detected. Inhibition of NHE1 activity during differentiation of CGR8 cells prevented cardiomyocyte differentiation as indicated by decreased message for transcription factors Nkx2-5 and Tbx5 and decreased levels of alpha-myosin heavy chain protein. Increased expression of NHE1 from an adenoviral vector facilitated cardiomyocyte differentiation. Similar results were found with cardiomyocyte differentiation of P19 embryonal carcinoma cells. CGR8 cells were treated to induce differentiation, but when differentiation was inhibited by dispersing the EBs, myocardial development was inhibited. The results demonstrate that NHE1 activity is important in facilitating stem cell differentiation to cardiomyocyte lineage. Elevated NHE1 expression appears to be triggered as part of the process that facilitates cardiomyocyte development.
| 19,011,045
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Investigating feedforward neural regulation of circulation from analysis of spontaneous arterial pressure and heart rate fluctuations in conscious rats.
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It has been suggested in anesthetized animals that the occurrence of sequences of consecutive beats characterized by systolic arterial pressure (SAP) and RR or pulse interval (PI) changing in the opposite direction (SAP(+)/RR(-) and SAP(-)/RR(+), nonbaroreflex sequences) might represent the expression of neural cardiovascular regulatory mechanisms operating with feedforward characteristics. The aim of the present study was to study nonbaroreflex sequences in a more physiological experimental model, i.e., in conscious freely moving rats. We studied conscious rats before and after 1) complete autonomic blockade (n = 12), 2) sympathetic blockade (n = 10), 3) alpha (n = 7)- and beta (n = 8)-adrenergic blockade, and 4) parasympathetic blockade (n = 10). Nonbaroreflex sequences were defined as three or more beats in which SAP and PI of the following beat changed in the opposite direction. Complete autonomic blockade reduced the number of nonbaroreflex sequences (95.6 +/- 9.0 vs. 45.2 +/- 4.1, P < 0.001), as did sympathetic blockade (80.9 +/- 12.6 vs. 30.9 +/- 6.1, P < 0.001). The selective alpha-receptor blockade did not induce significant changes (80.9 +/- 12.5 in baseline vs. 79.0 +/- 14.7 after prazosin), whereas beta-receptor blockade significantly reduced nonbaroreflex sequence occurrence (80.9 +/- 12.5 in baseline vs. 48.9 +/- 15.3 after propranolol). Parasympathetic blockade produced a significant increase of nonbaroreflex sequences (95.1 +/- 6.9 vs. 136.0 +/- 12.4, P < 0.01). These results demonstrate the physiological role of the nonbaroreflex sequences as an expression of a feedforward type of short-term cardiovascular regulation able to interact dynamically with the feedback mechanisms of baroreflex origin in the neural control of the sinus node.
| 19,011,047
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Xylella fastidiosa afimbrial adhesins mediate cell transmission to plants by leafhopper vectors.
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The interactions between the economically important plant-pathogenic bacterium Xylella fastidiosa and its leafhopper vectors are poorly characterized. We used different approaches to determine how X. fastidiosa cells interact with the cuticular surface of the foreguts of vectors. We demonstrate that X. fastidiosa binds to different polysaccharides with various affinities and that these interactions are mediated by cell surface carbohydrate-binding proteins. In addition, competition assays showed that N-acetylglucosamine inhibits bacterial adhesion to vector foregut extracts and intact wings, demonstrating that attachment to leafhopper surfaces is affected in the presence of specific polysaccharides. In vitro experiments with several X. fastidiosa knockout mutants indicated that hemagglutinin-like proteins are associated with cell adhesion to polysaccharides. These results were confirmed with biological experiments in which hemagglutinin-like protein mutants were transmitted to plants by vectors at lower rates than that of the wild type. Furthermore, although these mutants were defective in adhesion to the cuticle of vectors, their growth rate once attached to leafhoppers was similar to that of the wild type, suggesting that these proteins are important for initial adhesion of X. fastidiosa to leafhoppers. We propose that X. fastidiosa colonization of leafhopper vectors is a complex, stepwise process similar to the formation of biofilms on surfaces.
| 19,011,051
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Autoinducer-2 production in Campylobacter jejuni contributes to chicken colonization.
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Inactivation of luxS, encoding an AI-2 biosynthesis enzyme, in Campylobacter jejuni strain 81-176 significantly reduced colonization of the chick lower gastrointestinal tract, chemotaxis toward organic acids, and in vitro adherence to LMH chicken hepatoma cells. Thus, AI-2 production in C. jejuni contributes to host colonization and interactions with epithelial cells.
| 19,011,073
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Phylogenetic relationships of yessotoxin-producing dinoflagellates, based on the large subunit and internal transcribed spacer ribosomal DNA domains.
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Yessotoxin (YTX) is a globally distributed marine toxin produced by some isolates of the dinoflagellate species Protoceratium reticulatum, Lingulodinium polyedrum, and Gonyaulax spinifera within the order Gonyaulacales. The process of isolating cells and testing each isolate individually for YTX production during toxic blooms are labor intensive, and this impedes our ability to respond quickly to toxic blooms. In this study, we used molecular sequences from the large subunit and internal transcribed spacer genomic regions in the ribosomal operon of known YTX-producing dinoflagellates to determine if genetic differences exist among geographically distinct populations or between toxic and nontoxic isolates within species. In all analyses, all three YTX-producing species fell within the Gonyaulacales order in agreement with morphological taxonomy. Phylogenetic analyses of available rRNA gene sequences indicate that the capacity for YTX production appears to be confined to the order Gonyaulacales. These findings indicate that Gonyaulacoloid dinoflagellate species are the most likely to produce YTX and thus should be prioritized for YTX screening during events. Dinoflagellate species that fall outside of the Gonyaulacales order are unlikely to produce YTX. Although the rRNA operon offers multiple sequence domains to resolve species level diversification within this dinoflagellate order, these domains are not sufficiently variable to provide robust markers for YTX toxicity.
| 19,011,074
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The ferritin Fe2 site at the diiron catalytic center controls the reaction with O2 in the rapid mineralization pathway.
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Oxidoreduction in ferritin protein nanocages occurs at sites that bind two Fe(II) substrate ions and O(2), releasing Fe(III)(2)-O products, the biomineral precursors. Diferric peroxo intermediates form in ferritins and in the related diiron cofactor oxygenases. Cofactor iron is retained at diiron sites throughout catalysis, contrasting with ferritin. Four of the 6 active site residues are the same in ferritins and diiron oxygenases; ferritin-specific Gln(137) and variable Asp/Ser/Ala(140) substitute for Glu and His, respectively, in diiron cofactor active sites. To understand the selective functions of diiron substrate and diiron cofactor active site residues, we compared oxidoreductase activity in ferritin with diiron cofactor residues, Gln(137) --> Glu and Asp(140) --> His, to ferritin with natural diiron substrate site variations, Asp(140), Ser(140), or Ala(140). In Gln(137) --> Glu ferritin, diferric peroxo intermediates were undetectable; an altered Fe(III)-O product formed, DeltaA(350) = 50% of wild type. In Asp(140) --> His ferritin, diferric peroxo intermediates were also undetectable, and Fe(II) oxidation rates decreased 40-fold. Ferritin with Asp(140), Ser(140), or Ala(140) formed diferric peroxo intermediates with variable kinetic stabilities and rates: t(1/2) varied 1- to 10-fold; k(cat) varied approximately 2- to 3-fold. Thus, relatively small differences in diiron protein catalytic sites determine whether, and for how long, diferric peroxo intermediates form, and whether the Fe-active site bonds persist throughout the reaction cycle (diiron cofactors) or break to release Fe(III)(2)-O products (diiron substrates). The results and the coding similarities for cofactor and substrate site residues-e.g., Glu/Gln and His/Asp pairs share 2 of 3 nucleotides-illustrate the potential simplicity of evolving active sites for diiron cofactors or diiron substrates.
| 19,011,101
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Antioxidants reduce endoplasmic reticulum stress and improve protein secretion.
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Protein misfolding in the endoplasmic reticulum (ER) contributes to the pathogenesis of many diseases. Although oxidative stress can disrupt protein folding, how protein misfolding and oxidative stress impact each other has not been explored. We have analyzed expression of coagulation factor VIII (FVIII), the protein deficient in hemophilia A, to elucidate the relationship between protein misfolding and oxidative stress. Newly synthesized FVIII misfolds in the ER lumen, activates the unfolded protein response (UPR), causes oxidative stress, and induces apoptosis in vitro and in vivo in mice. Strikingly, antioxidant treatment reduces UPR activation, oxidative stress, and apoptosis, and increases FVIII secretion in vitro and in vivo. The findings indicate that reactive oxygen species are a signal generated by misfolded protein in the ER that cause UPR activation and cell death. Genetic or chemical intervention to reduce reactive oxygen species improves protein folding and cell survival and may provide an avenue to treat and/or prevent diseases of protein misfolding.
| 19,011,102
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Genome-wide analyses of Geraniaceae plastid DNA reveal unprecedented patterns of increased nucleotide substitutions.
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Angiosperm plastid genomes are generally conserved in gene content and order with rates of nucleotide substitutions for protein-coding genes lower than for nuclear protein-coding genes. A few groups have experienced genomic change, and extreme changes in gene content and order are found within the flowering plant family Geraniaceae. The complete plastid genome sequence of Pelargonium X hortorum (Geraniaceae) reveals the largest and most rearranged plastid genome identified to date. Highly elevated rates of sequence evolution in Geraniaceae mitochondrial genomes have been reported, but rates in Geraniaceae plastid genomes have not been characterized. Analysis of nucleotide substitution rates for 72 plastid genes for 47 angiosperm taxa, including nine Geraniaceae, show that values of dN are highly accelerated in ribosomal protein and RNA polymerase genes throughout the family. Furthermore, dN/dS is significantly elevated in the same two classes of plastid genes as well as in ATPase genes. A relatively high dN/dS ratio could be interpreted as evidence of two phenomena, namely positive or relaxed selection, neither of which is consistent with our current understanding of plastid genome evolution in photosynthetic plants. These analyses are the first to use protein-coding sequences from complete plastid genomes to characterize rates and patterns of sequence evolution for a broad sampling of photosynthetic angiosperms, and they reveal unprecedented accumulation of nucleotide substitutions in Geraniaceae. To explain these remarkable substitution patterns in the highly rearranged Geraniaceae plastid genomes, we propose a model of aberrant DNA repair coupled with altered gene expression.
| 19,011,103
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Phospholipase A2 structure/function, mechanism, and signaling.
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Tremendous advances in understanding the structure and function of the superfamily of phospholipase A2 (PLA2) enzymes has occurred in the twenty-first century. The superfamily includes 15 groups comprising four main types including the secreted sPLA2, cytosolic cPLA2, calcium-independent iPLA2, and platelet activating factor (PAF) acetyl hydrolase/oxidized lipid lipoprotein associated (Lp)PLA2. We review herein our current understanding of the structure and interaction with substrate phospholipids, which resides in membranes for a representative of each of these main types of PLA2. We will also briefly review the development of inhibitors of these enzymes and their roles in lipid signaling.
| 19,011,112
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A new, major C27 biliary bile acid in the red-winged tinamou (Rhynchotus rufescens):25R-1beta, 3alpha,7alpha-trihydroxy-5beta-cholestan-27-oic acid.
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The chemical structures of the three major bile acids present in the gallbladder bile of the Red-winged tinamou (Rhynchotus rufescens), an early evolving, ground-living bird related to ratites, were determined. Bile acids were isolated by preparative reversed-phase HPLC. Two of the compounds were identified as the taurine N-acylamidates of 25R-3alpha,7alpha-dihydroxy-5beta-cholestan-27-oic acid (constituting 22% of biliary bile acids) and 25R-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-27-oic acid (constituting 51%). The remaining compound, constituting 21% of biliary bile acids, was an unknown C27 bile acid. Its structure was elucidated by LC/ESI-MS/MS and NMR and shown to be the taurine conjugate of 25R-1beta, 3alpha, 7alpha-trihydroxy-5beta-cholestan-27-oic acid, a C27 trihydroxy bile acid not previously reported. Although C27 bile acids with a 1beta-hydroxyl group have been identified as trace bile acids in the alligator, this is the first report of a major biliary C27 bile acid possessing a 1beta-hydroxyl group.
| 19,011,113
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Skin exposure to aliphatic polyisocyanates in the auto body repair and refinishing industry: III. A personal exposure algorithm.
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Isocyanate skin exposure may play an important role in sensitization and the development of isocyanate asthma, but such exposures are frequently intermittent and difficult to assess. Exposure metrics are needed to better estimate isocyanate skin exposures. The goal of this study was to develop a semiquantitative algorithm to estimate personal skin exposures in auto body shop workers using task-based skin exposure data and daily work diaries. The relationship between skin and respiratory exposure metrics was also evaluated. The development and results of respiratory exposure metrics were previously reported. Using the task-based data obtained with a colorimetric skin exposure indicator and a daily work diary, we developed a skin exposure algorithm to estimate a skin exposure index (SEI) for each worker. This algorithm considered the type of personal protective equipment (PPE) used, the percentage of skin area covered by PPE and skin exposures without and underneath the PPE. The SEI was summed across the day (daily SEI) and survey week (weekly average SEI) for each worker, compared among the job title categories and also compared with the respiratory exposure metrics. A total of 893 person-days was calculated for 232 workers (49 painters, 118 technicians and 65 office workers) from 33 auto body shops. The median (10th-90th percentile, maximum) daily SEI was 0 (0-0, 1.0), 0 (0-1.9, 4.8) and 1.6 (0-3.5, 6.1) and weekly average SEI was 0 (0-0.0, 0.7), 0.3 (0-1.6, 4.2) and 1.9 (0.4-3.0, 3.6) for office workers, technicians and painters, respectively, which were significantly different (P < 0.0001). The median (10th-90th percentile, maximum) daily SEI was 0 (0-2.4, 6.1) and weekly average SEI was 0.2 (0-2.3, 4.2) for all workers. A relatively weak positive Spearman correlation was found between daily SEI and time-weighted average (TWA) respiratory exposure metrics (microg NCO m(-3)) (r = 0.380, n = 893, P < 0.0001) and between weekly SEI and TWA respiratory exposure metrics (r = 0.482, n = 232, P < 0.0001). The skin exposure algorithm developed in this study provides task-based personal daily and weekly average skin exposure indices that are adjusted for the use of PPE. These skin exposure indices can be used to assess isocyanate exposure-response relationships.
| 19,011,126
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Relationship between overnight rostral fluid shift and Obstructive Sleep Apnea in nonobese men.
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The cause of increased pharyngeal collapsibility in patients with obstructive sleep apnea is incompletely understood. In awake healthy subjects, we showed that fluid displacement from the legs into the neck induced by lower body positive pressure reduces upper airway size and increases its collapsibility. Prolonged sitting leads to dependent fluid accumulation in the legs. To test the hypotheses that the apnea-hypopnea index (AHI) during sleep will be related to the amount of fluid spontaneously displaced from the legs overnight, and that this will, in turn, be related to the time spent sitting the previous day. In 23 nonobese healthy men referred for sleep studies for suspected obstructive sleep apnea, we assessed the changes in leg fluid volume and in neck circumference from the beginning to the end of the night, and the time spent sitting during the previous day. The overnight change in leg fluid volume correlated strongly with the AHI (r = -0.773, P < 0.001), the change in neck circumference (r = -0.792, P < 0.001), and the time spent sitting (r = -0.588, P = 0.003). Multivariate analysis showed that the only significant independent correlates of the AHI were the overnight changes in leg fluid volume and neck circumference, which together explained 68% of the variability in the AHI among subjects. These novel findings suggest that overnight rostral fluid displacement from the legs, related to prolonged sitting, may play a previously unrecognized role in the pathogenesis of obstructive sleep apnea in nonobese men that is independent of body weight.
| 19,011,149
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Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review.
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It is commonly stated that mortality from acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is decreasing. To systematically review the literature assessing ARDS mortality over time and to determine patient- and study-level factors independently associated with mortality. We searched multiple databases (MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL) for prospective observational studies or randomized controlled trials (RCTs) published during the period 1984 to 2006 that enrolled 50 or more patients with ALI/ARDS and reported mortality. We pooled mortality estimates using random-effects meta-analysis and examined mortality trends before and after 1994 (when a consensus definition of ALI/ARDS was published) and factors associated with mortality using meta-regression models. Of 4,966 studies, 89 met inclusion criteria (53 observational, 36 RCTs). There was a total of 18,900 patients (mean age 51.6 years; 39% female). Overall pooled weighted mortality was 44.3% (95% confidence interval [CI], 41.8-46.9). Mortality decreased with time in observational studies conducted before 1994; no temporal associations with mortality were demonstrated in RCTs (any time) or observational studies (after 1994). Pooled mortality from 1994 to 2006 was 44.0% (95% CI, 40.1-47.5) for observational studies, and 36.2% (95% CI, 32.1-40.5) for RCTs. Meta-regression identified study type (observational versus RCT, odds ratio, 1.36; 95% CI, 1.08-1.73) and patient age (odds ratio per additional 10 yr, 1.27; 95% CI, 1.07-1.50) as the only factors associated with mortality. A decrease in ARDS mortality was only seen in observational studies from 1984 to 1993. Mortality did not decrease between 1994 (when a consensus definition was published) and 2006, and is lower in RCTs than observational studies.
| 19,011,152
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UK research staff perspectives on improving recruitment and retention to primary care research; nominal group exercise.
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Primary care studies often encounter recruitment difficulties, but there is little evidence to inform solutions. As part of a National Institute for Health Research School for Primary Care Research and UK Clinical Research Network programme, we elicited research staff perspectives on factors facilitating or obstructing recruitment. To identify factors that experienced research staff consider important in successful recruitment and retention and their confidence in achieving them. An iterative series of three workshops was held. The third used a modified nominal group technique to categorize whether factors related to the 'context' in which the research took place, the 'content' of the study or the recruitment 'process' and to prioritize them by their importance to success. Eighteen research staff participated in the prioritization workshop. They prioritized positive attitudes of primary care staff towards research and trust of researchers by potential participants as major contextual factors affecting recruitment. Studies needed to be considered safe and relevant by staff and fit with practice systems. They proposed that researchers strengthen relationships with staff and participants and minimize workload for primary care teams. Although confident in many recruitment processes, respondents remained uncertain how to achieve cultural change so that research became part of normal practice activity and how best to motivate patients to participate. Research workers taking part identified factors which might be important in recruitment, several of which they expressed little confidence in addressing. Understanding how to improve recruitment is crucial if current efforts to strengthen primary care research are to bear fruit.
| 19,011,173
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Discrepancy rates of radiology resident interpretations of on-call neuroradiology MR imaging studies.
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To determine the discrepancy rates of radiology residents interpreting emergent neuroradiology magnetic resonance (MR) imaging studies and to assess any adverse clinical outcomes. Three hundred sixty-one brain and spine MR imaging and MR angiographic examinations that were ordered emergently after hours and given preliminary interpretations by radiology residents were retrospectively reviewed from December 1, 2006 to May 31, 2007 with institutional review board approval. Discrepancies between the interpretations of radiology residents and the final reports of attending neuroradiologists were classified as either false-negative (FN, failure to recognize abnormalities) or false-positive (FP, misinterpreting normal images as abnormal). Discrepancies that could affect patient care or clinical outcome were considered major. Overall, the agreement rate was 92.8%, the overall discrepancy rate was 7.2%, the major disagreement rate was 4.2%, and the minor disagreement rate was 2.2%. Misinterpretations among 1st-year residents on call were significant (P < .04) when compared with more senior-level residents. There were 23 FN interpretations. The most common misses were acute stroke (n = 3), aneurysm (n = 3), vascular occlusion (n = 3), and disk herniation (n = 2). There were only three FP interpretations (misdiagnoses of syrinx, arachnoiditis, and acute infarct). There was no adverse clinical outcome as a result of misinterpretations, owing in part to rapid turnaround time for final reporting. Level of residency training has a significant effect on the rate of discrepancy, which may be mitigated by recent changes regarding 1st-year radiology residents' overnight call.
| 19,011,191
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The connection between landscapes and the solar ephemeris in honeybees.
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Honeybees connect the sun's daily pattern of azimuthal movement to some aspect of the landscape around their nests. In the present study, we ask what aspect of the landscape is used in this context--the entire landscape panorama or only sectors seen along familiar flight routes. Previous studies of the solar ephemeris memory in bees have generally used bees that had experience flying a specific route, usually along a treeline, to a feeder. When such bees were moved to a differently oriented treeline on overcast days, the bees oriented their communicative dances as if they were still at the first treeline, based on a memory of the sun's course in relation to some aspect of the site, possibly the familiar route along the treeline or possibly the entire landscape or skyline panorama. Our results show that bees lacking specific flight-route training can nonetheless recall the sun's compass bearing relative to novel flight routes in their natal landscape. Specifically, we moved a hive from one landscape to a differently oriented twin landscape, and only after transplantation under overcast skies did we move a feeder away from the hive. These bees nonetheless danced accurately by memory of the sun's course in relation to their natal landscape. The bees' knowledge of the relationship between the sun and landscape, therefore, is not limited to familiar flight routes and so may encompass, at least functionally, the entire panorama. Further evidence suggests that the skyline in particular may be the bees' preferred reference in this context.
| 19,011,213
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Short-term hematologic and hemodynamic effects of osteopathic lymphatic techniques: a pilot crossover trial.
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Research into the physiologic effects of osteopathic lymphatic techniques has been somewhat limited. To assess the short-term hematologic and hemodynamic effects of a comprehensive lymphatic treatment protocol. Randomized crossover design that included 10-minute lymphatic treatment and rest (control) protocols delivered 1 week apart for a small pilot group of healthy men (N=15). At baseline, albumin, hematocrit, hemoglobin and platelet count , total protein, and white blood cell count were measured, as were systolic and diastolic blood pressure. All measures were repeated 20, 50, and 80 minutes after baseline data were gathered. Significant condition x time interaction effects were observed, indicating a decrease in platelet counts and an increase in diastolic blood pressure after the lymphatic treatment protocol [corrected]. Statistically significant differences by time were observed in all hemotologic measures and in systolic blood pressure. No adverse events or complications from the treatment protocol were observed in this population. Lymphatic techniques may decrease platelet counts and increase diastolic blood pressure during the first hour after treatment.
| 19,011,227
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Promoter cloning and characterization of the anti-vascular proliferation gene, R-ras: role of Ets- and Sp-binding motifs.
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The R-ras gene encodes a small GTPase of the ras family that is closely related to H-ras and K-ras. Unlike the prototypic ras genes, the disruption of the R-ras gene in mice results in enhanced angiogenesis in tumor implants and sustained neointimal hyperplasia in response to arterial injury, indicating the in vivo role of R-ras as a negative regulator of vascular proliferation. R-ras is abundantly expressed in normal mature blood vessels but significantly down-regulated in pathologically regenerating vasculature. In this study, we investigated the roles of cis-acting elements in the transcription of the human R-ras gene, as well as the transcription factors that interact with these sequences in cultured endothelial cells and arterial smooth muscle cells. The findings from vascular cells were then compared with findings from epithelial tumor cells that aberrantly express R-ras. Deletion analyses on 5 kb of 5'-flanking DNA of the human R-ras gene revealed the functional importance of the region between -727/-476, which contains two Ets and one Sp1 consensus binding motifs. Mutation analyses of various consensus binding motifs within this region suggest both cell type-dependent and -independent regulatory mechanisms for the R-ras gene transcription. Electrophoretic mobility shift and antibody disruption assays demonstrated that an Ets transcription factor family protein, GA-binding protein (GABP), binds to the R-ras-derived sequence. Chromatin immunoprecipitation analyses determined the association of endogenous GABP as well as Sp3 proteins with the -727/-476 region of the R-ras promoter in intact cells grown in culture. Forced expression of GABP significantly enhanced R-ras mRNA expression level in endothelial cells. These results map the functional elements in the R-ras promoter sequence and suggest that the GABP may be critical for transcription of R-ras and for maintenance of normal blood vessel functions through the regulation of this gene.
| 19,011,236
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A retrospective analysis of patients treated for superficial vein thrombosis.
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The absolute risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) as well as extension and/or recurrence in superficial vein thrombosis (SVT) of the leg is considerable and underestimated. We retrospectively evaluated therapeutic management, thrombophilic risk factors and clinical outcome of SVT. A database search was performed for consecutive patients with a suspected SVT of the lower extremities referred to our institution between 1 January 1999 and 31 December 2004. The primary outcome measure was pain reduction at follow-up. Secondary outcome measures were progression or recurrence of SVT in the leg and the occurrence of (a)symptomatic DVT or symptomatic PE at follow-up. In 73 patients follow-up information was present (3/76 non-evaluable patients). In 9/32 (28%) of the patients treated with carbasalate calcium, there was progression of SVT as assessed by ultrasonographic evaluation, compared with 3/11 (27%) in the low-molecular-weight heparin (LMWH) group and 3/6 (50%) in the no treatment group. DVT was diagnosed in 5/36 (14%) of the patients treated with carbasalate calcium compared with 1/13 (1%) in the LMWH and 1/3 (33%) in the other treatment groups at follow-up. Furthermore, 34 were tested for thrombophilic defects, 27 of whom had one or more thrombophilic defect. The results of our study show that SVT may be prone to venous thromboembolism and therefore needs to be treated or carefully followed up.
| 19,011,268
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Current guidelines for the diagnosis of testosterone deficiency.
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Hypogonadism in males is a clinical syndrome complex which comprises symptoms with or without signs as well as biochemical evidence of testosterone deficiency. The diagnosis of hypogonadism thus includes both clinical history and examination as well as biochemical assessment of serum testosterone levels. Hypogonadal symptoms depend on the age at onset of hypogonadism, severity of the deficiency, its duration and sensitivity to androgen action. Prepubertal onset results in lack of virilization and pubertal development and produces features such as eunuchoid body proportions and undeveloped secondary sex characteristics. Development of hypogonadism in adult life is characterized by a loss of androgen-dependent functions such as reduction in muscle mass, a shift in body composition towards more adipose tissue, decreased sexual function with diminished libido, depressed mood, loss of psychological energy osteoporosis and several other possible symptoms. The majority of men who suffer from hypogonadism do not have classical endocrine disorders. These men present with concomitant disease such as metabolic syndrome or type 2 diabetes, chronic infections, inflammatory disease, COPD, or cardiovascular disease. All these conditions are associated with a high prevalence of hypogonadism. Pharmacological therapy with opiates and corticosteroids are also known to cause hypogonadism. Hypogonadal symptoms are precipitated at different testosterone levels. Total testosterone levels of less than 8 nmol/l highly support a diagnosis of hypogonadism whereas levels greater than 12 nmol/l are likely to be normal. The grey zone between 8 and 12 nmol/l requires further evaluation and assessment of free or non-sex hormone-binding globulin-bound (bioavailable) testosterone. A trial period of testosterone treatment may be required.
| 19,011,285
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Advances in testosterone replacement therapy.
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The major goal of androgen substitution is to replace testosterone at levels as close to physiological concentrations as is possible. The mainstay of testosterone susbstitution are parenteral testosterone esters (enanthate and cypionate) to be administered every 2-3 weeks. A major disadvantage is the strongly fluctuating levels of plasma testosterone which are at least 50% of the time not in the physiological range. A significant improvement is parenteral testosterone undecanoate producing normal plasma testosterone for 12 weeks. Subcutaneous testosterone implants provide the patient, depending on the dose of implants, with normal plasma testosterone for 3-6 months. Its use is, however, not widespread. Oral testosterone undecanoate dissolved in oil bypasses the liver via its lymphatic absorption, but resulting plasma levels are erratic. Transdermal testosterone preparations have already been available for two decades. Transdermal testosterone gel produces attractive pharmocokinetic serum testosterone profiles and offers greater flexibility in dosing. Transdermal gel has been recommended in elderly males. In case of complications its use can be discontinued immediately. Oromucosal testosterone preparations are being developed. Testosterone replacement is usually of long duration, and patient compliance is of utmost importance. Therefore, the patient must be involved in the selection of the type of testosterone preparation.
| 19,011,287
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The role of the CAG repeat androgen receptor polymorphism in andrology.
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A dysfunctional androgen receptor is able to cause variable phenotypes of androgen insensitivity or androgenicity in humans. In addition, also a polymorphism, the CAG repeat polymorphism in exon 1 of the androgen receptor gene (CAG)n, modulates androgen effects: androgen-induced target activities are attenuated corresponding to the length of triplet residues. Clinically, the (CAG)n polymorphism causes marked modulations of androgenicity in eugonadal men in various tissues and psychological traits and may cause the clinical picture of hypogonadism in the presence of normal testosterone concentrations. Also pharmacogenetic implications might exist in this regard: there appears to be a significant role of testosterone treatment of hypogonadal men as treatment effects have been demonstrated to be modulated by the number of (CAG)n in retrospective approaches.
| 19,011,288
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Testosterone in obesity, metabolic syndrome and type 2 diabetes.
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Testosterone levels are reduced in obesity, the metabolic syndrome and type 2 diabetes. Low testosterone levels are now being recognised as an independent risk factors for these conditions. Findings from men undergoing androgen suppression as treatment for prostate cancer confirm that the hypogonadal state increases body fat mass and serum insulin and there is a high rate of developing new diabetes in this population. Clinical trial data are consistent in showing reductions in body fat mass during testosterone replacement therapy. There are also trials showing improvements in insulin resistance and glycaemic control with testosterone. Most of the trials in this area to date have been of small size and the promising results require confirmation in larger trials, which are underway. In the longer term, large trials should be conducted to assess the potentially beneficial effects of testosterone on cardiovascular risk in this and other patient groups. In the meantime physicians involved in the care of men with diabetes should remain vigilant for the symptoms and signs of hypogonadism. Testosterone replacement therapy should be considered for those men with subsequently confirmed hypogonadism.
| 19,011,290
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Automatic recognition of pathological phoneme production.
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Proper diagnosis and therapy of pathological pronunciation of phonemes play an important role in modern logopedics. To enhance the efficiency of diagnosis and therapy an automatic recognition of pathological phoneme pronunciation is addressed in this paper. The authors focus on the therapy of phoneme substitution disorders. Recognized speech samples come from speech-impaired Polish children and partially from persons imitating speech disorders. Recognized speech disorders were substitutions in pairs (for the correct phonetic charactors please see online article) embedded in Polish carrier words. In order to detect substitutions in the recognized words, recently proposed human factor cepstral coefficients (HFCC) have been implemented. Efficiency of the HFCC approach was compared to the application of standard mel-frequency cepstral coefficients (MFCC) as a feature vector. Both dynamic time warping (DTW), working on whole words or embedded phoneme patterns, and hidden Markov models (HMM) were used as classifiers. The HMM classifier was based on whole-word models as well as phoneme models. Results present a comparative analysis of DTW and HMM methods. The superiority of HFCC features over those of MFCC was demonstrated. Results obtained by DTW methods, mainly by modified phoneme-based DTW classifier, were slightly better in comparison with the HMM classifier. Results obtained for the detection of substitution in pairs (for the correct phonetic charactors please see online article) are very promising. The methods developed for these cases can be integrated into computer systems for speech therapy. For substitutions in pairs (for the correct phonetic charactors please see online article) further research is necessary.
| 19,011,305
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[Radiobiological basis for hyperfractionated radiation therapy].
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Hyperfractionated radiation therapy has been established as a radical treatment for head and neck cancer. The radiobiological hypothesis for hyperfractionation has been derived from that of fractionated radiation therapy, and it enables us to improve therapeutic gain by delivering a small fraction dose at optimal interfraction intervals, i. e., 1) reduction of normal tissue complication while maintaining tumor control probability, 2)improvement of tumor control probability while maintaining the incidence of normal tissue complications within an acceptable level. The understanding of radiobiological hypothesis or theory is important in clinical application of hyperfractionation.
| 19,011,328
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[A case of metastatic lung and liver tumors from rectal cancer treated with oral UFT and CPT-11 by hepatic arterial infusion followed by FOLFOX and FOLFIRI].
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The patient was a 62-year-old male who underwent a high anterior resection for rectal cancer with multiple liver metastases in June 2004. After the operation, 66 courses of weekly hepatic arterial infusion(HAI)therapy of 5-FU/Leucovorin( LV)were performed. Thereafter 14 courses of FOLFOX 4, 5 courses of FOLFIRI and 5 courses of FOLFOX 4 therapy were also sequentially performed. As a result of the CT examination, which revealed a new metastatic lesion in the liver and lung metastases, combination chemotherapy consisting of UFT and HAI of low-dose CPT-11 was administered in July 2007. After 1 cycle of this therapy, metastatic liver and lung tumors showed a reduction rate of 8.5% and 27.0%, respectively, without any adverse events. The elevated serum CEA (2,055 ng/mL)and CA19-9 (924 U/mL) levels decreased to 623 ng/mL and 332U /mL, respectively, after 1 cycle of the treatment. The combination of oral UFT and HAI of CPT-11 may therefore be a useful treatment for patients after FOLFOX and FOLFIRI therapy.
| 19,011,353
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[A case of osteonecrosis of the lower jaw due to bisphosphonates in a breast cancer patient with bone metastasis].
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Recently, osteonecrosis of the jaw (ONJ) with bisphosphonates is frequently reported. ONJ due to bisphosphonate is an adverse event in the treatment of breast cancer with bone metastasis. We report a case of ONJ due to bisphosphonates. A 66-year-old woman was admitted to our hospital due to right advanced breast cancer with bone metastasis. She received neo-adjuvant chemotherapy consisting of paclitaxel 70 mg/m2, qw, trastuzumab 2 mg/m2, qw. After chemotherapy, we performed modified mastectomy for local control. Postoperative adjuvant chemotherapy was added with bisphosphonate for bone metastasis of breast cancer. After bisphosphonate was used 14 times, she had a pain and pus-discharge in her lower jaw. The dentists' diagnosis was ONJ. We treated her with antibiotics and local minor curettage. The inflammatory symptoms almost disappeared. In this case, the administration of bisphosphonates was thought to be a major risk factor for ONJ. We think that special precautions for ONJ should be taken in patients administered bisphosphonates for bone metastasis of breast cancer.
| 19,011,355
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Ghrelin control of GH secretion and feeding behaviour: the role of the GHS-R1a receptor studied in vivo and in vitro using novel non-peptide ligands.
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Energy homeostasis is controlled by a complex regulatory system of molecules that affect food intake and that are critical for maintaining a stable body weight during life. Ghrelin is a peptide of 28 amino acid synthesized predominantly by the stomach and the gut, which activate the type 1a growth hormone (GH) secretagogue receptor (GHS-R1a), a G-protein coupled receptor. The acylated form of ghrelin potently stimulates GH secretion both in vitro and in vivo in several animal species, including humans. Beside the endocrine effect, ghrelin shows also extraendocrine activities, including stimulation of feeding behaviour. Several classes of small synthetic peptide and non-peptide ligands of the GHS-R1a have been described and are able to release GH and stimulate food intake. However, in time, it appeared that the stimulating effects on GH secretion could be divorced from those on food intake, suggesting that more than a single receptor might be involved. Several experimental data have even questioned the physiological role of ghrelin in the control of GH secretion and energy metabolism. By using novel agonists, partial agonists, and antagonists for the GHS-R1a receptor, we have studied whether the stimulation of this receptor could account for the purported physiological role of ghrelin. Our results demonstrate that the ability to bind in vitro the GHS-R1a is not predictive of the in vivo biological activity of the compounds and that the endocrine and extraendocrine effects could be mediated also by receptors different from the GHS-R1a.
| 19,011,367
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Safety of Tdap-IPV given one month after Td-IPV booster in healthy young adults: a placebo-controlled trial.
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In France, the only vaccines available for use as a pertussis booster in adults are combined vaccines containing adsorbed tetanus, diphtheria (adult formulation), acellular pertussis and inactivated poliovirus (Tdap-IPV). Adults may require a pertussis booster relatively soon after having received vaccines containing tetanus-diptheria antigens (Td) (occupational or familial circumstances such as new job, childbirth in recent past or future), although the safety of Tdap-IPV when administered soon after vaccination with Td is undocumented. In this randomized, double-blind, multi-centre study, we assessed the safety of Tdap-IPV administered one month after vaccination with tetanus, diphtheria (adult formulation), inactivated poliovirus vaccination (Td-IPV) in healthy adults vaccinated according to the French vaccination calendar (seven tetanus-diphtheria vaccinations by age 18 years). Subjects received either Td-IPV (n = 249) or placebo (n = 251) followed 1 month later by Tdap-IPV. Any adverse events (AEs) were recorded. The safety of Tdap-IPV was similar when Tdap-IPV vaccine was administered one month after either Td-IPV or placebo: at seven days, 85.1% versus 93.4% subjects reported at least one reaction at the injection site, mainly pain (82.6% versus 92.1%); 40.5% versus 45.0%, at least one systemic AE (mainly headache: 26.4% versus 26.0%); fever concerned 1.7% of both groups. No serious vaccine-related AEs were reported. Both safety profiles corresponded to documented product characteristics. Tdap-IPV may be administered to adults one month after Td-IPV without exacerbating post-vaccination side-effects.
| 19,011,374
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Colorectal polyps: the scope and management of the problem.
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Colorectal cancer affects over 150,000 individuals yearly, and accounts for over 50,000 deaths. Much of the benefit of colorectal cancer screening has been attributed to detection and removal of adenomatous polyps, highlighting the importance of colorectal polyps as targets for intervention and as biomarkers for colorectal cancer risk. This review details the epidemiology of sporadic colorectal polyps, rationale behind use of polyps as an important surrogate for colorectal cancer risk, the benefits and limitations of secondary prevention of colorectal polyps through chemopreventive and dietary interventions, as well as colon surveillance.
| 19,011,398
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Striatal and extrastriatal D2/D3-receptor-binding properties of ziprasidone: a positron emission tomography study with [18F]Fallypride and [11C]raclopride (D2/D3-receptor occupancy of ziprasidone).
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To elucidate the "atypicality" of ziprasidone, its striatal and extrastriatal D2/D3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls. [F]fallypride positron emission tomography (PET) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose. Binding potentials were calculated for striatal and extrastriatal regions. D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel [C]raclopride-PET study, striatal D2/D3-receptor occupancy was measured in healthy subjects after single oral doses of 40 mg ziprasidone or 7.5 mg haloperidol. Ziprasidone plasma concentrations correlated significantly with D2/D3-receptor occupancies in all volumes of interests. Occupancy in extrastriatal regions was approximately 10% higher than in striatal regions. Half maximal effective concentration values were consistently higher in striatal than in extrastriatal regions (temporal cortex: 39 ng/mL; putamen: 64 ng/mL), irrespective of the time between last dosing and scan. Single ziprasidone doses resulted in higher occupancies exceeding the 95% prediction limits of the occupancy versus plasma concentrations for chronic dosing. Ziprasidone shares moderate preferential extrastriatal D2/D3-receptor binding with some other atypicals. D2/D3-receptor occupancy is rapidly attuning to the daily course of ziprasidone plasma levels, suggesting relatively high intraday variations of D2/D3-receptor binding. The discrepancies between single-dose and steady-state results are important for the future design of dose-finding PET occupancy studies of novel antipsychotics. Single-dose studies may not be totally relied on for final dose selection.
| 19,011,428
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Pharmacokinetics of sertraline across pregnancy and postpartum.
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Insufficient data inform dosing of antidepressants and clinical monitoring for major depressive disorder (MDD) during the perinatal period. The objectives were to assess the pharmacokinetics of sertraline (SER) across pregnancy and postpartum. Participants treated with SER for MDD underwent serial sampling to measure steady-state concentrations of SER and norsertraline during the second and third trimesters and postpartum (total of 3 assessments). Blood was drawn before observed SER administration and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. A sensitive high-performance liquid chromatography/mass spectrometric method for simultaneous determination of serum concentrations of SER and norsertraline was developed and validated. For each sampling period for SER, area under the serum concentration versus time curve, maximal serum concentration (Cmax), and the time at which Cmax occurred (Tmax) were determined. Of 11 women initially enrolled, 6 completed second- and third-trimester assessments, and 3 completed all 3 assessments (including the postpartum assessment). Mean changes on all pharmacokinetic parameters were nonsignificant between assessments, although there was a marked heterogeneity among individuals. Results were not significantly altered by incorporation of body weights into the analyses. The range of pharmacokinetic changes between individuals was broad, indicating heterogeneity regarding the impact of pregnancy on SER metabolism. Overall, lowest observed SER area under the curve and Cmax occurred in the third trimester (observed in 5 of 6 participants). Despite nonsignificant mean pharmacokinetic changes, the range of pharmacokinetic changes across pregnancy warrants careful monitoring of depressive symptoms in women with MDD in late pregnancy and further study.
| 19,011,433
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Late side effects of high-dose steroid therapy on skeletal system in children with idiopathic thrombocytopenic purpura.
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Corticosteroids have been widely used in the treatment of idiopathic thrombocytopenic purpura (ITP). We evaluated the late side effects of high-dose methylprednisolone (HDMP) therapy on bone metabolism in children with ITP. Twenty-eight children with acute ITP treated with HDMP (30 mg/kg/d for 3 d then 20 mg/kg/d for 4 d) and 28 controls were enrolled in the study. Bone mineral density (BMD), urinary calcium creatinine ratio, urinary levels of deoxypyridinoline, serum levels of calcium, phosphate, parathyroid hormone, total alkaline phosphatase, and bone-specific alkaline phosphatase were measured in both groups. Magnetic resonance imaging of the femoral head was performed only in study group. The mean levels of serum phosphate, parathyroid hormone, urinary deoxypyridinoline, and calcium creatinine ratio were significantly increased in the study group. There was no significant difference between the 2 groups in terms of serum calcium, total alkaline phosphatase, bone-specific alkaline phosphatase, and BMD values. There was a statistically significant negative correlation between cumulative steroid dose and BMD values in study group (r = -0.379). Osteonecrosis was observed in 3 of 25 patients by magnetic resonance imaging. In conclusion, HDMP therapy, especially in high cumulative doses, increases the bone resorption and may cause osteonecrosis in children with ITP.
| 19,011,472
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Kaposiform hemangioendothelioma presenting antenatally with a pericardial effusion.
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We describe an infant presenting with fetal pericardial effusion requiring in utero pericardiocentesis. Important postnatal clinical features included recurrent pericardial effusion, progressive stridor, thrombocytopenia, anemia, and a mediastinal mass surrounding the heart and coronary arteries. Investigations and management consisted of repeat pericardiocentesis, platelet and red blood cell transfusions, laryngoscopy, creation of a pericardial window, and biopsy of the mediastinal mass. Diagnosis was made of Kaposiform hemangioendothelioma surrounding the base of the heart, trachea, and esophagus as well as Kasabach-Merritt phenomenon. The infant responded well to treatment with vincristine and prednisone.
| 19,011,475
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Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome.
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The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), one of the autoinflammatory syndromes, is caused by mutations in the gene coding for mevalonate kinase (MVK). We conducted the current study to assess the genetic, laboratory, and clinical features as well as the complications and course of disease in patients with genetically confirmed HIDS. In addition, we studied the quality of life and course of life in a selection of patients. Follow-up data were obtained by a questionnaire sent to all physicians of patients in the International HIDS Database. In addition, we assessed the course of life and quality of life in Dutch patients aged >16 years using validated quality of life instruments. Data were obtained from 103 patients from 18 different countries. The median age of first attack was 6 months (range, 0-120 mo), with a median period of 9.9 years from onset of disease to diagnosis. The most frequent symptoms that accompanied attacks of fever were lymphadenopathy, abdominal pain, arthralgia, diarrhea, vomiting, skin lesions, and aphthous ulcers. Amyloidosis was a severe but infrequent complication (2.9%). The median serum IgD level was 400 U/mL. IgD levels were normal in 22% of patients. The 4 most prevalent mutations (V377I, I268T, H20P/N, P167L) accounted for 71.5% of mutations found. The frequency of attacks decreased with the patient's increasing age, although 50% of patients over the age of 20 years still had 6 or more attacks per year. Many drugs have been tried in HIDS. Some patients responded to high-dose prednisone (24.4% response). Anakinra and etanercept can also be effective (33.3% response). Quality of life was determined in a subgroup of patients (n = 28). Social functioning, general health perception, and vitality were significantly lower in patients with HIDS than in controls, as were autonomy and social development. In addition, HIDS had an adverse impact on educational achievements and employment status. In conclusion, HIDS is an early-onset disease that is accompanied by an array of inflammatory symptoms. Although the frequency of attacks decreases during the patient's life, many patients continue to have frequent attacks. HIDS impairs several aspects of quality of life.
| 19,011,501
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STAT5 contributes to antiapoptosis in melanoma.
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Malignant melanoma is a cancer whose incidence is rising rapidly. Extensive studies of primary tumors and tumor-derived cell lines revealed that inappropriate activation of signal transducer and activator of transcription (STAT) proteins, particularly of STAT3 and 5, occurs with high frequency in various human cancers. We reported that in the Xiphophorus fish melanoma model, constitutive activation of STAT5 correlates with the aggressiveness of melanoma. Investigations in human melanoma mainly focussed on the function of STAT1, but we have shown recently that STAT5 is also activated in human melanoma. The objectives of this investigation were to get more information about the function of STAT5 in melanoma. Here we demonstrate that in murine melanocytes activation of STAT5 measured by its tyrosine phosphorylation and translocation to the nucleus parallels upregulation with its target gene bcl-XL. This indicates a role for STAT5 in antiapoptotic signaling in pigment cells. In human melanoma cell lines, we found that constitutive activation of STAT5 correlates with expression of bcl-XL. Expression of dominant negative STAT5 in the human melanoma cell line A375 leads to a reduced bcl-XL expression and a dramatic increase of apoptotic cells. In contrast to STAT1, which is known to transduce antiproliferative effects of interferons, our data support a significant role for STAT5 in melanoma cell proliferation and survival via the activation of the antiapoptotic protein bcl-XL. Keeping in mind that interferons activate both STAT proteins, STAT5 activation could be of importance in interferon resistance of melanoma.
| 19,011,510
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Relationship between screw trajectory of C1 lateral mass screw and internal carotid artery.
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Evaluation of diagnostic imaging. To comprehend anatomic relationships between the internal carotid artery (ICA) and bicortical purchase of C1 lateral mass screws from the perspective of avoiding ICA injury. No studies have evaluated safety trajectory of atlantal lateral mass screw that would avoid the ICA injury in relation to its location, although previous studies have indicated concern about ICA injury by the screw tip at the anterior surface of the lateral mass of the atlas. From 149 of 177 human 3-dimensional computed tomography reconstruction images, 6 distance and 2 angle parameters related to both atlas and ICA were measured on the plane 15 degrees cephalad to the transverse plane. In addition, angle of error during screw insertion from intended trajectory was checked. The ICA was located in front of the C1 lateral mass in 64.4% of cases and faced the lateral one third of the C1 lateral mass in 54.6% of cases. None were located in front of the medial one third of the C1 lateral mass. The maximum inward screw trajectory that would violate the ICA was 8.6 degrees . Mean angle of preoperative C1/2 rotation and angle of error from intended trajectory was about 5 degrees , respectively. The possibility of ICA injury can be excluded by correct insertion of the screw 10 degrees inward. Although bicortical purchase with adequately medially angulated trajectory might be safe enough, we must remember the possibility to violate the ICA in bicortical purchase, because the intended screw trajectory never be assured.
| 19,011,539
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The action of resveratrol, a phytoestrogen found in grapes, on the intervertebral disc.
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Basic science, biologic study. To determine the potential benefits of using resveratrol (RSV) for intervertebral disc (IVD) matrix repair and regeneration. The phytoestrogen RSV is a natural compound found in various plants including grapes and red wines. RSV has been reported to provide a protective effect on articular cartilage in rabbit models for arthritis, but its effect on spine cartilage is unknown. METHODS.: We studied the effect of RSV on bovine IVD cartilage homeostasis by assessing MMP-13 (potent catabolic factor) production, proteoglycan (PG) accumulation and synthesis, and the interaction between RSV and known catabolic factors such as bFGF or IL-1. To understand the molecular mechanisms by which RSV modulates MMP-13 and PG production, we also investigated its downstream target regulatory molecules. Stimulation of bovine disc cells cultured in monolayer with bFGF or IL-1 augmented the production of MMP-13 and ADAMTS-4 at the transcriptional level and this augmentation was blocked by RSV. Incubation of nucleus pulposus cells with RSV for 21 days significantly increased PG accumulation per cell in a dose-dependent manner, increased PG synthesis, rescued PG losses induced by catabolic reagents bFGF and IL-1, and promoted cell survival to levels seen after incubation with the anabolic protein BMP7 100 ng/mL. Protein-DNA interaction array results suggest that RSV effectively suppresses downstream target molecules of bFGF and IL-1 responsible for oxidative stress, proliferation, and apoptosis. Resveratrol is a potent anabolic mediator of bovine IVD cartilage homeostasis, revealing its potential as a unique biologic treatment to slow the progression of IVD degeneration. These data suggests RSV may have considerable promise in the treatment of disc degeneration.
| 19,011,540
|
Overview of existing cartilage repair technology.
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Currently, autologous chondrocyte implantation and osteochondral grafting bridge the gap between palliation of cartilage injury and resurfacing via arthroplasty. Emerging technologies seek to advance first generation techniques and accomplish several goals including predictable outcomes, cost-effective technology, single-stage procedures, and creation of durable repair tissue. The biologic pipeline represents a variety of technologies including synthetics, scaffolds, cell therapy, and cell-infused matrices. Synthetic constructs, an alternative to biologic repair, resurface a focal chondral defect rather than the entire joint surface. Scaffolds are cell-free constructs designed as a biologic "net" to augment marrow stimulation techniques. Minced cartilage technology uses stabilized autologous or allogeneic fragments in 1-stage transplantation. Second and third generation cell-based methods include alternative membranes, chondrocyte seeding, and culturing onto scaffolds. Despite the promising early results of these products, significant technical obstacles remain along with unknown long-term durability. The vast array of developing technologies has exceptional promise and the potential to revolutionize the cartilage treatment algorithm within the next decade.
| 19,011,550
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Cartilage repair: third-generation cell-based technologies--basic science, surgical techniques, clinical outcomes.
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The goal of all cartilage replacement techniques is the reformation of mature organized hyaline cartilage. However, currently cartilage repair techniques lead principally to production of fibrocartilage, which has material properties that are inferior to hyaline cartilage. Cell-based therapies such as autologous chondrocyte implantation hold promise for cartilage regeneration; however, these techniques still do not predictably result in hyaline cartilage formation. The newest, "third-generation techniques" have been developed to address the limitations of earlier techniques. These new procedures use 3 novel approaches: chondro-inductive or chondro-conductive matrix; use of allogeneic cells, both of which may allow a single-stage surgical approach; and techniques to mechanically condition the developing tissue before surgical application to improve the material properties and maturation of the implant. However, at this time there is very limited clinical data available on the nature and outcomes of these procedures.
| 19,011,555
|
Insulinomatosis: a multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia.
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Multicentric insulinoma disease was characterized with regard to its histopathology, multiple endocrine neoplasia type 1 (MEN1) status, precursor lesions, and the risk of hyperinsulinemic hypoglycemia recurrence. Fourteen patients with multicentric insulinoma disease were compared with 267 patients with sporadic and familial insulinomas. The tumors were classified according to the World Health Organization (WHO) criteria. The MEN1 status was defined clinically and by germline mutation analysis. Detection of the MEN1 gene locus was performed using fluorescence in situ hybridization. The surgical interventions and the duration of disease-free survival were recorded. Fourteen patients (5%) without evidence of MEN1 showed 53 macrotumors and 285 microtumors expressing exclusively insulin. In addition, they had small proliferative insulin-expressing monohormonal endocrine cell clusters (IMECCs). No allelic loss of the MEN1 locus was detected in 64 tumors. All but one patient had benign disease. Recurrent hypoglycemia occurred in 6/14 patients (11 recurrences; mean time to relapse 8.4 y). Thirteen patients with MEN1 (4.6%) showed 41 insulinomas and 133 tumors expressing islet hormones other than insulin. IMECCs were not detected. Allelic loss of the MEN1 locus was found in 17/19 insulinomas. Recurrent hypoglycemia occurred in 4/13 patients (4 recurrences; mean time to relapse 14.5 y). Solitary insulinomas were found in 254/281 patients (90.4%). IMECCs were absent. There was no recurrent hypoglycemia in 84 patients with benign insulinomas. Insulinomatosis is characterized by the synchronous and metachronous occurrence of insulinomas, multiple insulinoma precursor lesions, and rare development of metastases, but common recurrent hypoglycemia. This disease differs from solitary sporadic and MEN1-associated insulinomas.
| 19,011,561
|
Serous tubal intraepithelial carcinoma and the dominant ovarian mass: clues to serous tumor origin?
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Pelvic serous cancer is a diverse disease, and the assignment of primary site -- ovarian, tubal, or peritoneal -- is often problematic. Recent studies indicate that a proportion of these tumors arise from the distal fallopian tube, originating as serous tubal intraepithelial carcinoma (STIC). This study examined the relationship of 2 parameters for assigning origin -- endosalpingeal involvement and dominant ovarian mass -- in the context of STIC. Endometrioid carcinomas served as a reference. Eighty-seven consecutive pelvic serous cancers in which the tubes and ovaries were completely examined (SEE-FIM protocol) were analyzed. The presence of a dominant ovarian mass (DOM+), involvement of the fimbrial mucosa (FIM+), and STIC were correlated. In addition, tumor categories were compared with respect to PAX8, p73, p53, and p16 immunohistochemistry. Of the 27 DOM+ cases, 13 (48%) were FIM+ and a STIC was present in 3 (11%). Of the 60 DOM(-) cases, 48 (78%) were FIM+ and 28 (45%) harbored a STIC. In 92% of all cases, tumor distribution was extensive with bilateral ovarian and extraovarian peritoneal involvement. All tumor categories were immunophenotypically similar. In contrast, DOM+, FIM+, and STIC were found in 81%, 19%, and 0% of ovarian endometrioid carcinomas. In conclusion, there is a significant inverse relationship between DOM+ and STIC (P=0.001), indicating both parameters are of value in grouping pelvic serous carcinomas more likely to be ovarian [DOM+/FIM(-)] versus fimbrial [DOM(-)/STIC], and ovarian or peritoneal surface (DOM-/FIM-) in origin. Nevertheless, the shared immunophenotype suggests a common cell of origin for all categories, irrespective of site.
| 19,011,565
|
CD3-positive large B-cell lymphoma.
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It is not uncommon for some B-lineage non-Hodgkin lymphomas (NHLs) to aberrantly coexpress T-cell markers, particularly CD5, as well as CD7, CD2, CD4, and/or CD8 in rare cases. Cases of CD3-positive B-cell NHL, however, have not previously been described in the literature. We present 4 cases of large B-cell lymphoma aberrantly coexpressing T-cell marker CD3 and B-lineage markers as well as demonstrating clonal rearrangement of the immunoglobulin genes but not the gamma T-cell receptor gene. To our knowledge, this represents the first series report of B-cell NHL coexpressing T-lineage-specific marker CD3. The identification of such cases indicates that the use of CD3 antibody alone in paraffin sections may lead to an incorrect determination of cell lineage in some B-cell NHL. Immunohistochemistry using additional cell lineage specific markers or molecular analysis for antigen receptor gene rearrangements are necessary for correct determination of the cell lineage in such cases.
| 19,011,566
|
TTF-1 expression in nephroblastoma.
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The unexpected observation of nuclear immunoreactivity for thyroid transcription factor-1 (TTF-1) associated with an apparent lack of nuclear immunoreactivity for Wilms tumor-1 protein (WT1) in the pulmonary metastasis of a morphologically typical case of nephroblastoma affecting a 6.5-year-old male prompted us to examine the expression of these 2 markers (and CD56) in a series of 48 nephroblastomas, 5 adult metanephric adenomas, and 1 pediatric cystic nephroma. TTF-1 was found to be positive in 8 of 48 (16.6%) nephroblastomas and negative in all 5 metanephric adenomas. WT1 was positive in 43 of 48 (89.6%) nephroblastomas and 4 of 5 (80.0%) metanephric adenomas. CD56 was positive in 45 of 47 cases that were so tested (95.74%), but negative in all metanephric adenomas. The single cystic nephroma was TTF-1-negative, WT1-negative, and CD56-positive. The finding of TTF-1 expression in one sixth of nephroblastomas constitutes a potential source of misdiagnosis. The biologic significance of this surprising finding is unclear. It may reflect the embryonal nature of these tumors and may conceivably result-directly or indirectly-in interference with the transcriptional control of target genes and other molecular events in the pathway leading to the development of nephroblastoma.
| 19,011,567
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X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility.
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Inhibitor of apoptosis proteins (IAP) are evolutionarily conserved anti-apoptotic regulators. C-RAF protein kinase is a direct RAS effector protein, which initiates the classical mitogen-activated protein kinase (MAPK) cascade. This signalling cascade mediates diverse biological functions, such as cell growth, proliferation, migration, differentiation and survival. Here we demonstrate that XIAP and c-IAPs bind directly to C-RAF kinase and that siRNA-mediated silencing of XIAP and c-IAPs leads to stabilization of C-RAF in human cells. XIAP binds strongly to C-RAF and promotes the ubiquitylation of C-RAF in vivo through the Hsp90-mediated quality control system, independently of its E3 ligase activity. In addition, XIAP or c-IAP-1/2 knockdown cells showed enhanced cell migration in a C-RAF-dependent manner. XIAP promotes binding of CHIP (carboxy terminal Hsc70-interacting protein), a chaperone-associated ubiquitin ligase, to the C-RAF-Hsp90 complex in vivo. Interfering with CHIP expression resulted in stabilization of C-RAF and enhanced cell migration, as observed in XIAP knockdown cells. Our data show an unexpected role of XIAP and c-IAPs in the turnover of C-RAF protein, thereby modulating the MAPK signalling pathway and cell migration.
| 19,011,619
|
The forkhead protein Foxj1 specifies node-like cilia in Xenopus and zebrafish embryos.
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It has been proposed that ciliated cells that produce a leftward fluid flow mediate left-right patterning in many vertebrate embryos. The cilia on these cells combine features of primary sensory and motile cilia, but how this cilia subtype is specified is unknown. We address this issue by analyzing the Xenopus and zebrafish homologs of Foxj1, a forkhead transcription factor necessary for ciliogenesis in multiciliated cells of the mouse. We show that the cilia that underlie left-right patterning on the Xenopus gastrocoel roof plate (GRP) and zebrafish Kupffer's vesicle are severely shortened or fail to form in Foxj1 morphants. We also show that misexpressing Foxj1 is sufficient to induce ectopic GRP-like cilia formation in frog embryos. Microarray analysis indicates that Xenopus Foxj1 induces the formation of cilia by upregulating the expression of motile cilia genes. These results indicate that Foxj1 is a critical determinant in the specification of cilia used in left-right patterning.
| 19,011,629
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Cooperative three-step motions in catalytic subunits of F(1)-ATPase correlate with 80 degrees and 40 degrees substep rotations.
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Rotation of the central shaft gamma subunit in a molecular motor F(1)-ATPase is assumed to correlate with and probably be driven by domain motions of the three catalytic beta subunits. Here we observe directly these beta motions through an attached fluorophore, concomitantly with 80 degrees and 40 degrees substep rotations of gamma in the same single molecules. We show the sequence of conformations that each beta subunit undergoes in three-step bending, a approximately 40 degrees counterclockwise turn followed by two approximately 20 degrees clockwise turns, occurring in synchronization with two substep rotations of gamma. The results indicate that most previous crystal structures mimic the conformational set of three beta subunits in the catalytic dwells. Moreover, a previously undescribed set of beta conformations, open, closed and partially closed, is revealed in the ATP-waiting dwells. The present study thus bridges the gap between the chemical and mechanical steps in F(1)-ATPase.
| 19,011,636
|
p53 in mitochondria enhances the accuracy of DNA synthesis.
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Mitochondrial localization of p53 was observed in stressed and unstressed cells. p53 is involved in DNA repair and apoptosis. It exerts physical and functional interactions with mitochondrial DNA and DNA polymerase gamma (pol gamma). The functional cooperation of p53 and pol gamma during DNA synthesis was examined in the mitochondrial fraction of p53-null H1299 cells, as the source of pol gamma. The results show that p53 may affect the accuracy of DNA synthesis in mitochondria: (1) the excision of a misincorporated nucleotide increases in the presence of (a) recombinant wild-type p53 (wtp53); (b) cytoplasmic fraction of LCC2 cells expressing endogenous wtp53 (but not specifically pre-depleted fraction); (c) cytoplasmic extract of H1299 cells overexpressing wtp53, but not exonuclease-deficient mutant p53-R175H. (2) Mitochondrial extracts of HCT116(p53+/+) cells display higher exonuclease activity compared with that of HCT116(p53-/-) cells. Addition of exogenous p53 complements the HCT116(p53-/-) mitochondrial extract mispair excision. Furthermore, the misincorporation was lower in the mitochondrial fraction of HCT116(p53+/+) cells as compared with that of HCT116(p53-/-) cells. (3) Irradiation-induced mitochondrial translocation of endogenous p53 in HCT116(p53+/+) cells correlates with the enhancement of error-correction activities. Taken together, the data suggest that p53 in mitochondria may be a component of an error-repair pathway and serve as guardian of the mitochondrial genome. The function of p53 in DNA repair and apoptosis is discussed.
| 19,011,642
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Socioeconomic questionnaire and clinical assessment in the HELENA Cross-Sectional Study: methodology.
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Environmental factors such as dietary habits, breastfeeding, socioeconomic conditions and educational factors are strong influences on nutritional and puberty status, physical activity, food choices and their interactions. Several diseases of adulthood seem to be linked to, or to originate from, lifestyle in childhood and adolescence. The aims of this study are to describe birth parameters and socioeconomic factors and to assess clinical status in adolescents aged 13-16 years from 10 European countries participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Cross-Sectional Study (CSS). A self-report questionnaire on the socioeconomic status, a parental questionnaire concerning neonatal period and also a case report form (CRF), in which clinical items during clinical examination (such as medical history, treatments, anthropometry, Tanner staging, blood pressure, heart rate) were assessed. To develop these documents, first a list of items was established, a search of existing documents was performed and the advice of local and international experts was taken. All documents (questionnaires and an operations manual) were discussed in plenary HELENA meetings; a final version of these documents was fixed, and the process of translation and back translation was performed. The questionnaires and CRF were tested for validation in all 10 participant cities; 208 adolescents were enrolled during the pilot study. All items that caused problems or questions in one or more participating centers or were completed by < 85% of the adolescents were reviewed before the beginning of the HELENA-CSS. These final questionnaires and CRF will contribute to better understanding of the inequalities in nutrition, behavior and health in the European adolescent population. The experience and process should be useful for other multicenter studies.
| 19,011,648
|
Early outcomes after allogeneic hematopoietic SCT in pediatric patients with hematologic malignancies following single fraction TBI.
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Fractionated TBI (FTBI) followed by allogeneic hematopoietic SCT results in donor engraftment and improves survival in children with high-risk hematologic malignancies. However, acute toxicities (skin, lung and mucosa) are common after FTBI. Late complications include cataracts, endocrine dysfunction, sterility and impaired neurodevelopment. Instead of FTBI, we used low-dose single fraction TBI (550 cGy) with CY as transplant conditioning for pediatric hematologic malignancies. GVHD prophylaxis included CYA and short-course MTX; methylprednisolone was added for unrelated donor transplants. A total of 55 children in first (40%) or second remission and beyond (60%) underwent transplantation from BM (65%) or peripheral blood; 62% from unrelated donors; 22% were mismatched. Median follow-up was 18.5 months (1-68). Overall survival and disease-free survival at 1 year were 60 and 47%, respectively. Acute toxicities included grade 3-4 mucositis (18%), invasive infections (11%), multiorgan failure/shock (11%), hemolytic anemia (7%), veno-occlusive disease (4%) and renal failure (4%). TRM was 11% at 100 days. Non-relapse mortality was 6% thereafter. Graft rejection occurred in 2%. Three patients (5%) died of GVHD. The regimen was well tolerated even in heavily pretreated children and supported donor cell engraftment; long-term follow up is in progress.
| 19,011,666
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Altered PI3-kinase/Akt signalling in skeletal muscle of young men with low birth weight.
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Low birth weight (LBW) is associated with increased future risk of insulin resistance and type 2 diabetes mellitus. The underlying molecular mechanisms remain poorly understood. We have previously shown that young LBW men have reduced skeletal muscle expression of PI3K p85alpha regulatory subunit and p110beta catalytic subunit, PKCzeta and GLUT4 in the fasting state. The aim of this study was to determine whether insulin activation of the PI3K/Akt and MAPK signalling pathways is altered in skeletal muscle of young adult men with LBW. Vastus lateralis muscle biopsies were obtained from 20 healthy 19-yr old men with BW< or = 10th percentile for gestational age (LBW) and 20 normal birth weight controls (NBW), matched for physical fitness and whole-body glucose disposal, prior to (fasting state) and following a 4-hr hyperinsulinemic euglycemic clamp (insulin stimulated state). Expression and phosphorylation of selected proteins was determined by Western blotting. Insulin stimulated expression of aPKCzeta (p<0.001) and Akt1 (p<0.001) was decreased in muscle of LBW men when compared to insulin stimulated controls. LBW was associated with increased insulin stimulated levels of IRS1 (p<0.05), PI3K p85alpha (p<0.001) and p110beta (p<0.05) subunits, while there was no significant change in these proteins in insulin stimulated control muscle. In addition LBW had reduced insulin stimulated phospho-Akt (Ser 473) (p<0.01), indicative of reduced Akt signalling. Insulin stimulated expression/phosphorylation of all the MAPK proteins studied [p38 MAPK, phospho-p38 MAPK (Thr180/Tyr182), phospho-ERK (Thr 202/Tyr204), JNK1, JNK2 and phospho-JNK (Thr 183/Tyr185)] was not different between groups. We conclude that altered insulin activation of the PI3K/Akt but not the MAPK pathway precedes and may contribute to development of whole-body insulin resistance and type 2 diabetes in men with LBW.
| 19,011,679
|
Assessment of determinants for osteoporosis in elderly men.
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The aim of this cross-sectional study was to determine and quantify some determinants associated to low bone mineral density (BMD) in elderly men. This study showed that ageing, a lower body mass index (BMI), a higher blood level of C-terminal cross-linking telopeptides of type I collagen (CTX-1), family history of osteoporosis, and/or fracture and prior fracture were associated with bone mineral density. Our aims were to identify some determinants associated to low bone mineral density in men and to develop a simple algorithm to predict osteoporosis. A sample of 1,004 men aged 60 years and older was recruited. Biometrical, serological, clinical, and lifestyle determinants were collected. Univariate, multivariate, and logistic regression analyses were performed. Receiver operating characteristic analysis was used to assess the discriminant performance of the algorithm. In the multiple regression analysis, only age, BMI, CTX-1, and family history of osteoporosis and/or fracture were able to predict the femoral neck T-score. When running the procedure with the total hip T-score, prior fracture also appeared to be significant. With the lumbar spine T-score, only age, BMI, and CTX-1 were retained. The best algorithm was based on age, BMI, family history, and CTX-1. A cut-off point of 0.25 yielded a sensibility of 78%, a specificity of 59% with an area under the curve of 0.73 in the development and validation cohorts. Ageing, a lower BMI, higher CTX-1, family history, and prior fracture were associated with T-score. Our algorithm is a simple approach to identify men at risk for osteoporosis.
| 19,011,728
|
Medium- and short-chain dehydrogenase/reductase gene and protein families : Dual functions of alcohol dehydrogenase 3: implications with focus on formaldehyde dehydrogenase and S-nitrosoglutathione reductase activities.
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Alcohol dehydrogenase 3 (ADH3) is highly conserved, ubiquitously expressed in mammals and involved in essential cellular pathways. A large active site pocket entails special substrate specificities: shortchain alcohols are poor substrates, while medium-chain alcohols and particularly the glutathione adducts S-hydroxymethylglutathione (HMGSH) and S-nitrosoglutathione (GSNO) are efficiently converted under concomitant use of NAD(+)/NADH. By oxidation of HMGSH, the spontaneous glutathione adduct of formaldehyde, ADH3 is implicated in the detoxification of formaldehyde. Through the GSNO reductase activity, ADH3 can affect the transnitrosation equilibrium between GSNO and S-nitrosated proteins, arguing for an important role in NO homeostasis. Recent findings suggest that ADH3-mediated GSNO reduction and subsequent product formation responds to redox states in terms of NADH availability and glutathione levels. Finally, a dual function of ADH3 is discussed in view of its potential implications for asthma.
| 19,011,746
|
Medium- and short-chain dehydrogenase/reductase gene and protein families : Medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism.
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Retinoic acid (RA), the most active retinoid, is synthesized in two steps from retinol. The first step, oxidation of retinol to retinaldehyde, is catalyzed by cytosolic alcohol dehydrogenases (ADHs) of the medium-chain dehydrogenase/reductase (MDR) superfamily and microsomal retinol dehydrogenases (RDHs) of the short-chain dehydrogenase/reductase (SDR) superfamily. The second step, oxidation of retinaldehyde to RA, is catalyzed by several aldehyde dehydrogenases. ADH1 and ADH2 are the major MDR enzymes in liver retinol detoxification, while ADH3 (less active) and ADH4 (most active) participate in RA generation in tissues. Several NAD(+)- and NADP(+)-dependent SDRs are retinoid active. Their in vivo contribution has been demonstrated in the visual cycle (RDH5, RDH12), adult retinoid homeostasis (RDH1) and embryogenesis (RDH10). K(m) values for most retinoid-active ADHs and RDHs are close to 1 microM or lower, suggesting that they participate physiologically in retinol/retinaldehyde interconversion. Probably none of these enzymes uses retinoids bound to cellular retinol-binding protein, but only free retinoids. The large number of enzymes involved in the two directions of this step, also including aldo-keto reductases, suggests that retinaldehyde levels are strictly regulated.
| 19,011,747
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Peroxynitrite affects lidocaine by acting on membrane-constituting lipids.
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Inflammation frequently decreases local anesthetic effects, especially in dental anesthesia in patients with pulpitis and periodontitis. The pharmacokinetics and the mode of action of local anesthetics are closely associated with the hydrophobic interactions between these drugs and lipid bilayers that change the membrane physicochemical property, fluidity. A lipid oxidant, peroxynitrite, is produced by inflammatory cells, and it may act on nerve cell membranes and affect anesthetic efficacy. With respect to this speculated action, we addressed whether peroxynitrite acted on membrane-constituting lipids to decrease the membrane interactivity of lidocaine. Membrane fluidity changes were determined by measuring the fluorescence polarization of liposomes prepared with different phospholipids. Peroxynitrite (0.1-50 microM) rigidified nerve-cell model membranes consisting of unsaturated phospholipids, as well as liposomal membranes consisting of 1,2-dioleoylphosphatidylcholine and 1-stearoyl-2-arachidonylphosphatidylcholine, but peroxynitrite did not rigidify 1, 2-dipalmitoylphosphatidylcholine liposomal membranes. The pretreatment of nerve-cell model membranes with peroxynitrite (0.1-50 microM) decreased the membrane-fluidizing effects of lidocaine (5.0 mg x ml(-1)) to 63%-86% of the control (not treated with peroxynitrite) depending on the peroxynitrite concentration. As one of the mechanisms of the local anesthetic failure associated with inflammation, inflammatory peroxynitrite may affect local anesthesia by acting on membrane-constituting unsaturated phospholipids.
| 19,011,794
|
[Perioperative discontinuation of antiplatelet therapy of patients with coronary stents. Reevaluating the risks].
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According to the present guidelines, patients with coronary stents are to be treated with dual antiplatelet therapy. In case surgery is needed, the risk of a fatal stent thrombosis by withdrawing antithrombotics needs to be balanced in each individual case against the risk of haemorrhagic complications on continued antiplatelet medication. We present a case of fatal stent thrombosis and discuss the current evidence regarding perioperative continuation and interruption of antiplatelet therapy for this patient population. In summary the haemorrhagic risk with acetylsalicylic acid for secondary prevention seems very low, and it should be discontinued only in selected cases. Continued dual anticoagulation concepts are also discussed.
| 19,011,817
|
[Oropharyngeal pathologies].
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The oropharynx is an interface between the airway and the digestive tract. Clinical evaluation and endoscopy suffice for the diagnosis of a variety of lesions, but tumors require cross-sectional imaging to assess local infiltration depth and lymphatic spread. This article discusses different lesions of the oropharynx with respect to imaging characteristics of CT and MRI, with a focus on resectability issues and decision-making.
| 19,011,829
|
When we enhance cognition with Adderall, do we sacrifice creativity? A preliminary study.
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Adderall (mixed amphetamine salts) is used by healthy normal individuals to enhance attention. Research with healthy normal participants and those with attention deficit hyperactivity disorder indicate a possible inverse relationship between attentional function and creativity. This raises the possibility that Adderall could decrease creativity in people using it for cognitive enhancement. This study was designed to find out whether Adderall impairs creativity in healthy young adults. In a double-blind placebo-controlled study, the effects of Adderall on the performance of 16 healthy young adults were measured on four tests of creativity from the psychological literature: two tasks requiring divergent thought and two requiring convergent thought. Adderall affected performance on the convergent tasks only, in one case enhancing it, particularly for lower-performing individuals, and in the other case enhancing it for the lower-performing and impairing it for higher-performing individuals. The preliminary evidence is inconsistent with the hypothesis that Adderall has an overall negative effect on creativity. Its effects on divergent creative thought cannot be inferred with confidence from this study because of the ambiguity of null results. Its effects on convergent creative thought appear to be dependent on the baseline creativity of the individual. Those in the higher range of the normal distribution may be unaffected or impaired, whereas those in the lower range of the normal distribution experience enhancement.
| 19,011,838
|
Pseudointercondylar notch sign: manifestation of osteochondritis dissecans of the trochlea.
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Osteochondritis dissecans (OCD) is an idiopathic condition affecting the articular epiphysis. Initially described in the knee, this entity affects several other parts of the body such as the talar dome, tarsal navicular, and femoral capital epiphysis. OCD of the elbow primarily involves the capitellum. OCD involving the trochlea has rarely been reported. We describe an unusual and interesting case of OCD affecting the trochlea, mimicking a pseudointercondylar notch.
| 19,011,851
|
Influence of light intensity and selection scheme on regeneration time of transgenic flax plants.
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This study aimed at establishing a protocol to increase the number of regenerated shoots and to limit the recovery of "escapes" during the regeneration of transgenic flax plants (cv Barbara). Here, we describe how light, adapted media and selection scheme could stimulate the transformation process, the organogenic potentiality of calli (by a factor of 3.2) and accelerate the transgenic shoot regeneration (by a factor of about 2). On comparison of the transformation rate observed while using low light (LL) and high light (HL) a considerable enhancement from 0.12 to 5.7% was evident. The promotive effect of light might also had a direct beneficial effect on transgenic plant production time leading to a reduction of more than 4 months in the time need to obtain transgenic seeds. All data indicate that HL plays a role on growth and on protein, rubisco and pigment contents by stimulating the gene implicated in photosynthetic and Calvin cycle processes.
| 19,011,860
|
Sonographic anatomy and dynamic study of the normal iliopsoas musculotendinous junction.
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The objective of the study was to document the anatomy of the iliopsoas muscle at the level of the groin with the use of sonography. At the same time, behaviour of the muscle during external rotation-flexion and abduction was dynamically evaluated. Forty-two hips in 21 asymptomatic volunteers were studied in static and dynamic conditions. Four bundles of the iliopsoas muscle were identified in all patients. A fifth one was found in only two hips. During dynamic study, a snap was explained by the sudden release of the most medial fibres of the ilacus from an entrapment between the tendon and the superior pubic ramus in 40% of our asymptomatic hips. Anatomy of the iliopsoas muscle can be accurately depicted by sonography at the level of the groin. Snapping of the muscle is often encountered as a physiological finding.
| 19,011,866
|
Integral assessment of estrogenic potentials in sediment-associated samples: Part 2: Study of estrogen and anti-estrogen receptor-binding potentials of sediment-associated chemicals under different salinity conditions using the salinity-adapted enzyme-linked receptor assay.
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The enzyme-linked receptor assay (ELRA) detects estrogenic and anti-estrogenic effects at the molecular level of receptor binding and is a useful tool for the integrative assessment of ecotoxicological potentials caused by hormonally active agents (HAA) and endocrine disrupting compounds (EDC). The main advantage of the ELRA is its high sample throughput and its robustness against cytotoxicity and microbial contamination. After a methodological adaptation to salinity of the ELRA, according to the first part of this study, which increased its salinity tolerance and sensitivity for 17-beta-estradiol, the optimised ELRA was used to investigate 13 native sediments characterised by different levels of salinity and chemical contamination. The applicability of the ELRA for routine analysis in environmental assessment was evaluated. Salinity is often a critical factor for bioassays in ecotoxicological sediment assessment. Therefore, salinity of the samples was additionally adjusted to different levels to characterise its influence on elution and binding processes of receptor-binding substances. The ELRA was carried out with the human estrogen receptor alpha (ER) in a 96-well microplate format using the experimental setup known from the competitive immunoassay based on ligand-protein interaction. It is an important improvement that a physiologically relevant receptor was used as a linking protein instead of an antibody. The microplates were coated with a 17-beta-estradiol-BSA conjugate, and dilution series of estradiol and of native sediment samples were added and incubated with the ER. After a washing step, a biotinylated mouse anti-ER antibody was added to each well. Receptor binding to estradiol, agonistic and antagonistic receptor binding, were determined by a streptavidin-POD-biotin complex with subsequent measurement of the peroxidase activity at the wavelength of 450 nm using a commercial ELISA multiplate reader. The sediment elutriates and pore water samples of sediments were tested in a dilution series to evaluate at which dilution step the receptor-binding potential ends. In the elution process (see Section 2.1 to 2.2), a method was developed to adjust the salinity to the levels of the reference testings, which offers an appropriate option to adjust the salinity in both directions. Statistical evaluation was made with a combination of the Mann-Whitney U test and the pT-method. This part of the study characterised the environmental factor 'salinity' for prospective applications of the ELRA. Using reference substances such as 17-beta-estradiol, the ELRA showed sigmoid concentration-effect relations over a broad range from 0.05 mug/l to 100 mug/l under physiological conditions. After methodological optimisation, both sensitivity and tolerance of the assay against salinity could be significantly raised, and the ELRA became applicable under salinity conditions up to concentrations of 20.5 per thousand. The mean relative inter-test error (n = 3) was around 11% with reference substances and below 5% for single sediments elutriates in three replicates each. For sediment testings, the pore water and different salinity-adjusted elutriates of 13 sediments were used. A clear differentiation of the receptor-binding potential could be reached by application of the pT-method. Thereby, pT-values from one to six could be assigned to the sediments, and the deviation caused by the different salinity conditions was one pT-value. The mean standard deviation in the salinity adaptation procedure of the elutriates was below 5%. Although the ELRA has already been used for assessments of wastewater, sludge and soil, its applicability for samples to different salinity levels has not been investigated so far. Even if the ELRA is not as sensitive as the E-screen or the YES-assay, with regard to reference substances like 17-beta-estradiol, it is a very useful tool for pre-screening, because it is able to integrate both estrogenic as well as anti-estrogenic receptor-binding effects. According to the results of sediment testing, and given the integrative power to detect different directions of effects, the ELRA shows sufficient sensitivity and salinity tolerance to discriminate receptor-binding potentials in environmental samples. The optimised ELRA assay is a fast, cost-effective, reliable and highly reproducible tool that can be used for high-throughput screening in a microplate format in detecting both estrogenic and anti-estrogenic effects. Additionally, the ELRA is robust against microbial contaminations, and is not susceptible towards cytotoxic interferences like the common cell-culture methods. The general applicability and sufficient sensitivity of the ELRA was shown in freshwater environments. Marine and brackish samples can be measured up to salinity levels of 20.5 per thousand. In view of the proven sensitivity, functionality and the fastness of the ELRA, it is recommendable to standardise the test method. At the moment, no adequate in vitro test procedure exists which is standardised to DIN or ISO levels. The E-screen and the yeast estrogen/androgen screens (YES/YAS) sometimes underlie strong cytotoxic effects, as reported in the first part of this study. Further development of an ELRA assay using human androgen receptors appears to be very promising to gain information about androgenic and anti-androgenic effects, too. This would offer a possibility to use the ELRA as a fast and reliable pre-screening tool for the detection of endocrine potentials, thus minimising time and cost-expensive animal experiments.
| 19,011,916
|
Association between EGF, TGF-beta1, VEGF gene polymorphism and colorectal cancer.
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Up to the present, EGF 61 A/G, TGF-beta1 -509 T/C, and VEGF 936 T/C gene polymorphisms have been analyzed in other cancer entities than colorectal cancer. We have now investigated the frequency of these gene polymorphisms among colorectal cancer patients. A total of 157 colorectal cancer patients and 117 cancer-free healthy people were recruited at the Surgical Department of the Universitätsklinikum Mannheim. All patients and healthy people are Caucasians. Genomic DNA was isolated from peripheral blood, and gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The distribution of EGF 61 G/G homozygotes among colorectal cancer patients was more frequent than that in the control group (33.1% versus 11.1%; Odds Ratio [OR]=3.962; 95% Confidence Interval [CI]=2.036-7.708). The frequency of the "G" allele in the colorectal cancer patient group was also higher than that in the control group (51.3% versus 33.3%; OR=2.105; 95% CI=1.482-2.988). No difference could be found for the TGF-beta1 and VEGF genotypes among colorectal cancer patients and healthy controls. The EGF 61 G/G genotype and the G allele are significantly related to colorectal cancer. The TGF-beta1 -509 T/C and VEGF 936 T/C gene polymorphisms are not related to colorectal cancer.
| 19,011,936
|
Medial meniscal cyst: a case report.
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Meniscal cysts are a rare disease constantly combined with a horizontal meniscal lesion. Currently, nuclear magnetic resonance (MRI) is the main diagnostic tool, because of its high sensitivity and specificity, and decompression arthroscopy combined with selective meniscectomy is the treatment of choice. The Authors report a case of a voluminous medial meniscal cyst where instrumental examination, MRI, was fundamental for the preoperative diagnosis of the horizontal meniscal lesion causing the cystic degeneration of the meniscus. The treatment performed was selective meniscectomy of the body and posterior horn of the medial meniscus and decompression of the voluminous cyst by arthroscopy. Physical examination after six months showed the complete resolution of swelling at the medial hemirima, no walking pain and normal range of motion.
| 19,011,952
|
The Comprehensive Muscular Activity Profile (CMAP): its high sensitivity, specificity and overall classification rate for detecting submaximal effort on functional capacity testing.
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A traditional problem faced by clinicians attempting to objectively measure musculoskeletal disorders such as low back pain, where there is often primarily soft tissue involvement, is that psychosocial factors (e.g., fear-avoidance, secondary gain) frequently influence the experience/reporting of pain. Nevertheless, there is still a great need for the quantification of physical function, with appropriate criteria in place, in order to help assess both physical impairment and therapeutic endpoint following treatment. One such potentially objective measure is surface electromyographic (sEMG) recordings during purposeful muscular activity and resting states. The present randomized controlled study assessed the potential validity of a new sEMG approach-the comprehensive muscular activity profile (CMAP)-by addressing the following question: can the CMAP accurately document whether a subject is exerting appropriate muscular effort during range-of-motion and lifting testing, or is submaximum effort being exerted? Eighty healthy volunteers were randomly assigned to either: (1) an instruction group encouraging maximum effort on the tests; or (2) an instruction group encouraging "faking" and not putting in maximum effort on the tests. Therapists, who then administered the CMAP protocol (range-of-motion and lifting tests), were kept blind to subject group assignment. They were also asked to complete a rating scale evaluating whether subjects were exerting maximum effort after all the tests were completed. In differentiating between the two instruction groups, the CMAP demonstrated high levels of sensitivity [predicting maximum effort on all tests (ranging from 84.6 to 94.9%)]. In contrast, the sensitivity of the therapists' ratings was much lower (ranging from only 72.5 to 80.0%). Most importantly, when the CMAP data and therapists' ratings were combined, logistic regression analyses revealed high rates of sensitivity (94.4-97.2%), specificity (84.6-92.3%), and overall classification (90.7-93.3%). The results of this study demonstrate the potential utility of the CMAP, combined with therapist ratings, as a valid method of objectively quantifying subject muscular performance and effort during lumbar range-of-motion and lifting tasks.
| 19,011,955
|
Noncontact evaluation of articular cartilage degeneration using a novel ultrasound water jet indentation system.
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We previously reported a noncontact ultrasound water jet indentation system for measuring and mapping tissue mechanical properties. The key idea was to utilize a water jet as an indenter as well as the coupling medium for high-frequency ultrasound. In this paper, the system was employed to assess articular cartilage degeneration, using stiffness ratio as an indicator of the mechanical properties of samples. Both the mechanical and acoustical properties of intact and degenerated bovine patellar articular cartilage (n = 8) were obtained in situ. It was found that the stiffness ratio was reduced by 44 +/- 17% after the articular cartilage was treated by 0.25% trypsin at 37 degrees C for 4 h while no significant difference in thickness was observed between the intact and degenerated samples. A significant decrease of 36 +/- 20% in the peak-to-peak amplitude of ultrasound echoes reflected from the cartilage surface was also found for the cartilage samples treated by trypsin. The results also showed that the stiffness obtained with the new method highly correlated with that measured using a standard mechanical testing protocol. A good reproducibility of the measurements was demonstrated. The present results showed that the ultrasound water jet indentation system may provide a potential tool for the non-destructive evaluation of articular cartilage degeneration by simultaneously obtaining mechanical properties, acoustical properties, and thickness data.
| 19,011,965
|
Negative opinions about cancer screening and contraceptive measures by female emergency department patients.
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We sought to determine the extent to which adult female emergency department participants viewed two women's cancer screening and two contraceptive measures negatively. The study also explored the relationship between having a negative opinion about these measures and participant demography, lack of knowledge, and lack of usage of these measures. Few women expressed negative opinions about these measures. Lack of knowledge about and lack of use of these measures were associated with having negative opinions on these cancer screening and contraceptive measures. Having any negative opinion about one cancer screening or contraceptive measure was associated with a higher risk of having any negative opinion on another measure. The results suggest that influencing opinion and knowledge about these measures might impact the success of emergency department-based cancer screening and contraceptive health programs. Editors' Strategic Implications: Emergency departments (and primary care settings) provide key opportunities for prevention. Replication is needed, but the authors present important data on knowledge, attitudes, and characteristics that might influence women's receptivity to consent to and engage in behaviors consistent with prevention, screening, and health promotion.
| 19,011,970
|
Organic and genetically modified soybean diets: consequences in growth and in hematological indicators of aged rats.
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The aim of this study was to evaluate the protein quality of organic and genetically modified soy by feeding specific diets to rats. Three groups of Wistar rats (n=10) were used, and each group was named according to the food that they ate. There was an organic soy group (OG), a genetically modified soy group (GG), and a control group (CG). All animals received water and diet ad libitum for 455 days. At the end of this period, the weight of the GG group was the same as that of the OG, and both were higher than CG. Protein intake was similar for the OG and GG, which were significantly lower (p<0.0005) than the CG. The growth rate (GR) of the rats, albumin levels, and total levels of serum protein were comparable for all groups. Hematocrit (p<0.04) and hemoglobin (p<0.03) for the OG and GG were less than the CG. Although the OG and GG demonstrated reduced hematocrit and hemoglobin, both types of soy were utilized in a way similar to casein. This result suggests that the protein quality of soy is parallel to the standard protein casein in terms of growth promotion but not hematological indicators.
| 19,011,971
|
Physical activity and premenopausal breast cancer: an examination of recall and selection bias.
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Compared with cohort studies, case-control investigations have tended to report clearer protective associations for the relationship between physical activity and premenopausal breast cancer risk. We conducted a case-control study within the Nurses' Health Study II cohort to examine whether recall or selection bias could explain the stronger protective associations. Self-reported total recreational physical activity during adulthood and over a woman's lifetime (ages 12 years to current) were assessed in 1997 before diagnosis and, again, from one to seven years after breast cancer diagnosis among the same women. Eighty-seven percent of cases (417 of 479) and 82% of controls (390 of 474) responded. Selection bias was observed for activity during adulthood but not for activity over a woman's lifetime. Recall bias was not observed in the direction we expected: the odds ratios (ORs) for breast cancer comparing the highest versus lowest quintile of prospectively reported total activity were not significantly different than the corresponding estimates from retrospective reports (e.g., lifetime activity: prospective OR = 0.58, 95% CI: 0.37, 0.93 versus retrospective OR = 0.80; 95% CI: 0.50, 1.29). Recall or selection bias may not have been accounted for protective associations among case-control investigations examining lifetime recreational physical activity and breast cancer. Selection bias related to recreational physical activity during adulthood and random error in the measurement of physical activity remain concerns.
| 19,011,977
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Expression profile of BRCA1 and BRCA2 genes in premenopausal Mexican women with breast cancer: clinical and immunohistochemical correlates.
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Low BRCA1 gene expression is associated with increased invasiveness and influences the response of breast carcinoma (BC) to chemotherapeutics. However, expression of BRCA1 and BRCA2 genes has not been completely characterized in premenopausal BC. We analyzed the clinical and immunohistochemical correlates of BRCA1 and BRCA2 expression in young BC women. We studied 62 women (mean age 38.8 years) who developed BC before the age of 45 years. BRCA1 and BRCA2 mRNA expression was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and that of HER-2 and p53 proteins by immunohistochemistry. Body mass index (BMI) > or = 27 (52%) and a declared family history of BC (26%) were the main risk factors. Ductal infiltrative adenocarcinoma was found in 86% of the cases (tumor size >5 cm in 48%). Disease stages I-IV occurred in 2, 40, 55, and 3%, respectively (73% implicating lymph nodes). Women aged < or = 35 years (24%) had more family history of cervical cancer, stage III/IV disease, HER-2 positivity, and lower BRCA1 expression than older women (P < 0.05). BRCA1 and BRCA2 expression correlated in healthy, but not in tumor tissues (TT). Neither BRCA1 nor BRCA2 expression was associated with tumor histology, differentiation, nodal metastasis or p53 and HER-2 expression. After multivariate analysis, only disease stage explained BRCA1 mRNA levels in the lowest quartile. Premenopausal BC has aggressive clinical and molecular characteristics. Low BRCA1 mRNA expression is associated mainly with younger ages and advanced clinical stage of premenopausal BC. BRCA2 expression is not associated with disease severity in young BC women.
| 19,012,002
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Common coding variant in the TCF7L2 gene and study of the association with type 2 diabetes in Japanese subjects.
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Genetic variants of the transcription factor 7-like 2 (TCF7L2) gene affect the risk of type 2 diabetes in populations with multiple ethnic groups. However, a comprehensive survey of this gene has not been done for a Japanese population. Thus, we conducted this gene-based association study, in which the common genetic variants were analyzed. Using 24 Japanese type 2 diabetic subjects, we first screened a 9.5 kb region, which included the entire coding sequence, to assess potential functional variants of TCF7L2. Sequencing revealed a common coding variant (Pro477Thr) in exon 14 of TCF7L2 that was not enrolled in the public SNP database. Nineteen SNPs and the microsatellite DG10S478 were genotyped across the gene in 2,877 unrelated Japanese subjects. This independent screen identified the previously reported rs7903146 with a strongest association (allele P = 0.0001, odds ratio = 1.59 [95% confidence interval 1.25-2.01]), but there was no significant association between Pro477Thr and type 2 diabetes (allele P = 0.64). Expression of the Pro477Thr variant did not alter TCF7L2 expression in 30 lymphoblast cells. Although a genotypic effect of Pro477Thr on expression of TCF7L2 was not apparent, Pro477Thr was identified as a common variant of TCF7L2 in 2,877 Japanese subjects. Further functional studies are required to determine the possible effect of this coding variant on type 2 diabetes.
| 19,012,045
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Invasive, paediatric, vaccine strains of Streptococcus pneumoniae: are there differences in clinical characteristics?
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Invasive pneumococcal infections in 777 adults caused by 'invasive' (1, 7; n=187), 'paediatric' (6, 9, 14, 19, 23; n=304) and other (n=286) serogroups were compared. Infections caused by 'invasive' strains caused pneumonia more often than other serogroups and were more often isolated from younger patients without concomitant conditions and had lower case-fatality rate than 'paediatric' and other strains. The 2 latter groups differed little from each other. Infections caused by strains in the 7-valent pneumococcal conjugate vaccine differed little from infections caused by non-vaccine types indicating that widespread use of this vaccine will not markedly change the clinical characteristics of invasive pneumococcal infections in adults.
| 19,012,056
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The management of the type 2 diabetic patient with hypertension - too late and too little: suggested improvements.
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Patients with comorbid hypertension and type 2 diabetes are common, have a greatly increased risk of premature cardiovascular and renal morbidity and mortality, and are likely to increase substantially in number over the next 10-15 years. We suggest the need for more aggressive management strategies for these patients, regardless of their baseline blood pressure, including the early use of combination therapy with blockers of the renin-angiotensin system.
| 19,012,063
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