title stringlengths 0 901 | abstract stringlengths 3 9.89k | PMID int64 22 25.3M | embedding listlengths 768 768 |
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Acupuncture and relaxation response for craving and anxiety reduction among military veterans in recovery from substance use disorder. | Substance use disorder (SUD) is a major health issue, especially among military veterans. We previously reported the effects of auricular acupuncture and the relaxation response (RR) on reducing craving and anxiety following 10-week interventions among veterans who were in recovery from SUDs. Our current analysis examines effects following each intervention session and RR daily practice. We conducted a three-arm randomized controlled trial on residents of a homeless veteran rehabilitation program. Sixty-Seven enroled participants were randomly assigned to acupuncture (n=23), RR (n=23), or usual care (n=21). Participants in the two intervention groups rated their degree of craving for substance on a scale of 1-10 and anxiety levels on a scale of 1-4 (total score 20-80) before and after each intervention session. Mixed effects regression models were used for analysis. Craving and anxiety levels decreased significantly following one session of acupuncture (-1.04, p=.0001; -8.83, p<.0001) or RR intervention (-.43, p=.02; -4.64, p=.03). The level of craving continued to drop with additional intervention sessions (regression coefficient b=-.10, p=.01, and b=-.10, p=.02 for acupuncture and RR groups, respectively). Number of daily practice days of RR-eliciting techniques is also associated with reduction in craving ratings (b=-.02, p=.008). Findings demonstrate the value of attending regular acupuncture and RR-eliciting intervention sessions, as well as the daily practice of RR-eliciting techniques. Substance addiction is a complex disease and effective treatment remains a challenge. Our study findings add to the scientific evidence of these two non-pharmaceutical approaches for SUD. | 25,187,049 | [
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Posttraumatic stress symptoms and alcohol problems: self-medication or trait vulnerability? | Posttraumatic stress symptoms (PTSD) and problem alcohol use (ALC) commonly co-occur, but the nature of this co-occurrence is unclear. Self-medication explanations have been forwarded, yet traits such as tendency toward negative emotionality and behavioral disconstraint also have been implicated. In this study we test three competing models (Self-Medication, Trait Vulnerability, Combined Dual Pathway) of PTSD-ALC prospectively in a college sample. Participants (N=659; 73% female, M age=18) provided data at college matriculation (Time 1) and 1 year later (Time 2). Structural equation models showed disconstraint to meditate the path from PTSD symptoms to alcohol problems, supporting a trait vulnerability conceptualization. Findings regarding negative emotionality and self-medication were more mixed. Negative emotionality played a stronger role in cross-sectional than in prospective analyses, suggesting the importance of temporal proximity. Self-regulation skills may be an important focus for clinicians treating PTSD symptoms and alcohol misuse disorders concurrently. | 25,187,046 | [
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Silicon-core glass fibres as microwire radial-junction solar cells. | Vertically aligned radial-junction solar cell designs offer potential improvements over planar geometries, as carrier generation occurs close to the junction for all absorption depths, but most production methods still require a single crystal substrate. Here, we report on the fabrication of such solar cells from polycrystalline, low purity (99.98%) p-type silicon starting material, formed into silicon core, silica sheath fibres using bulk glass draw techniques. Short segments were cut from the fibres, and the silica was etched from one side, which exposed the core and formed a conical cavity around it. We then used vapour deposition techniques to create p-i-n junction solar cells. Prototype cells formed from single fibres have shown conversion efficiencies up to 3.6%, despite the low purity of the starting material. This fabrication method has the potential to reduce the energy cost and the silicon volume required for solar cell production. Simulations were performed to investigate the potential of the conical cavity around the silicon core for light collection. Absorption of over 90% of the incident light was predicted, over a wide range of wavelengths, using these structures in combination with a 10% volume fraction of silicon. | 25,187,060 | [
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Expanding the indications for single-incision laparoscopic cholecystectomy to all patients with biliary disease: is it safe? | The safety of single-incision laparoscopic cholecystectomy (SILC) has been proven in well-selected patients. The objective of this study was to determine whether SILC can be offered to all patients with any indication for cholecystectomy. A total of 173 consecutive SILCs were performed between January 2010 and November 2012 with no exclusion criteria. Demographic data, operative, and postoperative outcomes were prospectively collected and analyzed. Patients with acute cholecystitis and gallstone pancreatitis had longer operative times and a higher conversion to 4-port cholecystectomy than patients with biliary colic. Similar relationships were seen when comparing patients with obesity to nonobese patients. There were no differences in complication rates between the groups. SILC can be safely offered to patients with a wide spectrum of biliary disease with the understanding that this may result in increased operative times and a higher likelihood of conversion to multiport laparoscopy. | 25,187,074 | [
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HIV is an independent predictor of aortic stiffness. | Patients with treated Human Immunodeficiency Virus-1 (HIV) infection are at increased risk of cardiovascular events. Traditionally much of this risk has been attributed to metabolic and anthropometric abnormalities associated with HIV, which are similar to the metabolic syndrome (MS), an established risk factor for cardiovascular mortality. It remains unclear whether treated HIV infection is itself associated with increased risk, via increase vascular stiffness. 226 subjects (90 with HIV) were divided into 4 groups based on HIV and MS status: 1) HIV-ve/MS-ve, 2) HIV-ve/MS + ve, 3) HIV + ve/MS-ve and 4)HIV + ve/MS + ve. CMR was used to determine aortic pulse wave velocity (PWV) and regional aortic distensibility (AD). PWV was 11% higher and regional AD up to 14% lower in the HIV + ve/MS-ve group when compared to HIV-ve/MS-ve (p < 0.01 all analyses). PWV and AD in the HIV + ve/MS-ve group was similar to that observed in the HIV-ve/MS + ve group (p > 0.99 all analyses). The HIV + ve/MS + ve group had 32% higher PWV and 30-34% lower AD than the HIV-ve/MS-ve group (all p < 0.001), and 19% higher PWV and up to 31% lower AD than HIV + ve/MS-ve subjects (all p < 0.05). On multivariable regression, age, systolic blood pressure and treated HIV infection were all independent predictors of both PWV and regional AD. Across multiple measures, treated HIV infection is associated with increased aortic stiffness and is also an independent predictor of both PWV and regional AD. The magnitude of the effect of treated HIV and MS are similar, with additive detrimental effects on central vascular elasticity. | 25,187,084 | [
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Brugada electrocardiogram pattern "unmasked" by amiodarone infusion. | Brugada syndrome predisposes individuals to ventricular arrhythmias and sudden cardiac death, in the absence of structural heart disease. The typical Brugada electrocardiogram (ECG) phenotype is often concealed in affected population, and the existing genetic testing is capable of detecting just about 20% of cases. Therefore, the diagnosis largely requires various pharmacological provocative agents like class I antiarrhythmic drugs to unmask the unique features of Brugada ECG phenotype. We report an unusual case of "unmasking" of Brugada ECG pattern with ventricular tachycardia brought out by amiodarone infusion. | 25,187,091 | [
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Canagliflozin-Associated Acute Pancreatitis. | Canagliflozin is a new drug in class of sodium-glucose cotransporter 2 inhibitors used for treatment of type 2 diabetes mellitus. We describe a patient who developed moderately severe acute pancreatitis as an untoward consequence after being initiated on this drug. To the best of our knowledge, this is the first reported case of canagliflozin-associated acute pancreatitis in clinical literature. | 25,187,092 | [
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Electrochemical, spectroscopic, and (1)O2 sensitization characteristics of 10,10-dimethylbiladiene complexes of zinc and copper. | The synthesis, electrochemistry, and photophysical characterization of a 10,10-dimethylbiladiene tetrapyrrole bearing ancillary pentafluorophenyl groups at the 5- and 15-meso positions (DMBil1) is presented. This nonmacrocyclic tetrapyrrole platform is robust and can serve as an excellent ligand scaffold for Zn(2+) and Cu(2+) centers. X-ray diffraction studies conducted for DMBil1 along with the corresponding Zn[DMBil1] and Cu[DMBil1] complexes show that this ligand scaffold binds a single metal ion within the tetrapyrrole core. Additionally, electrochemical experiments revealed that all three of the aforementioned compounds display an interesting redox chemistry as the DMBil1 framework can be both oxidized and reduced by two electrons. Spectroscopic and photophysical experiments carried out for DMBil1, Zn[DMBil1], and Cu[DMBil1] provide a basic picture of the electronic properties of these platforms. All three biladiene derivatives strongly absorb light in the visible region and are weakly emissive. The ability of these compounds to sensitize the formation of (1)O2 at wavelengths longer than 500 nm was probed. Both the free base and Zn(2+) 10,10-dimethylbiladiene architectures show modest efficiencies for (1)O2 sensitization. The combination of structural, electrochemical, and photophysical data detailed herein provides a basis for the design of additional biladiene constructs for the activation of O2 and other small molecules. | 25,187,099 | [
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Observational outcome results following a randomized controlled trial of early amino acid administration in preterm infants. | Several reports have investigated amino acid administration in premature infants during the early postnatal phase. Most of these previous studies, however, have only evaluated short-term in-hospital outcomes. Our aim was to describe long-term outcomes in premature infants previously subjected to different nutritional regimens in a randomized controlled trial. The primary outcome was survival without major disabilities, and the secondary outcomes included anthropometry and mental development. Infants born <32 weeks' gestation and <1500 g were randomized to receive glucose (n = 69) or glucose with 2.4 g · kg(-1) · day(-1 amino acids) (n = 63) from birth. From postnatal day 3 onward, the nutritional intake was similar. At 2 years of corrected age, the surviving infants were assessed for neurodevelopmental outcome and anthropometry. Ninety-seven percent of the surviving infants were examined at follow-up, with no overall effect on survival without major disabilities. Boys, however, had a normal outcome significantly more often if amino acids were administered from birth onward (crude odds ratio 3.8, 95% confidence interval 1.3-11.4) and following adjustment for confounders (odds ratio 6.2, 95% confidence interval 1.0-38.0). The secondary outcomes exhibited no differences in anthropometric data. The mental developmental index was lower in the small number of girls who survived without major disabilities following the early administration of amino acids. In this hypothesis-generating outcome study, premature boys, but not girls, benefited from amino acid administration directly following birth. The observed lower mental developmental index in a subgroup of girls, however, warrants further studies. | 25,187,104 | [
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Choice of Health Options In prevention of Cardiovascular Events for people with Atrial Fibrillation (CHOICE-AF): A pilot study. | Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with high risk of stroke and significant health burden. Recent emerging evidence suggests that modifying risk factor profiles of people with AF may assist to reduce stroke risk and health burden. The purpose of this study was to test the feasibility of a brief telephone-based program targeted at improving cardiovascular risk, and health-related quality of life (HRQoL) in patients with AF METHODS: This was a pilot study of a brief three-month telephone-based intervention for patients with diagnosed AF. During an initial face-to-face consultation participants were assisted to set individualized risk factor reduction goals and a treatment plan. Participants received phone-based follow-up for three months, with final assessment at three months. Nineteen participants with AF were recruited, with age range 35-82 years (mean 65±13 years) and 53% were male. No changes were observed in either body mass index (BMI) or waist circumference measures. Participation was associated with significant improvement in reported symptom severity (p=0.005). There were non-significant improvements in physical activity, sedentary behavior, HRQoL, anxiety and depression. Participation in the CHOICE-AF pilot study did not improve BMI or waist circumference: however, it was associated with significant improvement in reported symptom severity. Further research is required to determine the most appropriate model of care for addressing risk factor management for people with AF. | 25,187,121 | [
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ITS1: a DNA barcode better than ITS2 in eukaryotes? | A DNA barcode is a short piece of DNA sequence used for species determination and discovery. The internal transcribed spacer (ITS/ITS2) region has been proposed as the standard DNA barcode for fungi and seed plants and has been widely used in DNA barcoding analyses for other biological groups, for example algae, protists and animals. The ITS region consists of both ITS1 and ITS2 regions. Here, a large-scale meta-analysis was carried out to compare ITS1 and ITS2 from three aspects: PCR amplification, DNA sequencing and species discrimination, in terms of the presence of DNA barcoding gaps, species discrimination efficiency, sequence length distribution, GC content distribution and primer universality. In total, 85 345 sequence pairs in 10 major groups of eukaryotes, including ascomycetes, basidiomycetes, liverworts, mosses, ferns, gymnosperms, monocotyledons, eudicotyledons, insects and fishes, covering 611 families, 3694 genera, and 19 060 species, were analysed. Using similarity-based methods, we calculated species discrimination efficiencies for ITS1 and ITS2 in all major groups, families and genera. Using Fisher's exact test, we found that ITS1 has significantly higher efficiencies than ITS2 in 17 of the 47 families and 20 of the 49 genera, which are sample-rich. By in silico PCR amplification evaluation, primer universality of the extensively applied ITS1 primers was found superior to that of ITS2 primers. Additionally, shorter length of amplification product and lower GC content was discovered to be two other advantages of ITS1 for sequencing. In summary, ITS1 represents a better DNA barcode than ITS2 for eukaryotic species. | 25,187,125 | [
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Reuse of waste beer yeast sludge for biosorptive decolorization of reactive blue 49 from aqueous solution. | Reactive blue 49 was removed from aqueous solution by biosorption using powder waste sludge composed of Saccharomyces cerevisiae from the beer-brewing industry. The effect of initial pH, temperature and the biosorption thermodynamics, equilibrium, kinetics was investigated in this study. It was found that the biosorption capacity was at maximum at initial pH 3, that the effect of temperature on biosorption of reactive blue 49 was only slight in relation to the large biosorption capacity (25°C, 361 mg g(-1)) according as the biosorption capacity decreased only 43 mg g(-1) at the temperature increased from 25 to 50°C. The biosorption was spontaneous, exothermic in nature and the dye molecules movements decreased slightly in random at the solid/liquid interface during the biosorption of dye on biosorbents. The biosorption equilibrium data could be described by Freundich isotherm model. The biosorption rates were found to be consistent with a pseudo-second-order kinetics model. The functional group interaction analysis between waste beer yeast sludge and reactive blue 49 by the aid of Fourier transform infrared (abbr. FTIR) spectroscopy indicated that amino components involved in protein participated in the biosorption process, which may be achieved by the mutual electrostatic adsorption process between the positively charged amino groups in waste beer yeast sludge with negatively charged sulfonic groups in reactive blue 49. | 25,187,128 | [
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Biodegradation of malachite green by strain Pseudomonas sp. K9 and cloning of the tmr2 gene associated with an ISPpu12. | A bacterial strain K9 capable of degrading malachite green was isolated from the sludge of the wastewater treatment system of a chemical plant. It was identified preliminarily as Pseudomonas sp. Strain K9 was also able to degrade other triphenylmethane dyes, such as Crystal Violet and Basic Fuchsin. The gene tmr2, encoding the triphenylmethane reductase, was cloned from strain K9, and functionally expressed in E. coli. A 5946-bp DNA fragment including the tmr2 gene was cloned from the genomic DNA of strain K9 by chromosome walking. Its sequence analysis showed that tmr2 was associated with a typical mobile element ISPpu12 consisting of tnpA (encoding a transposase), lspA (encoding a lipoprotein signal peptidase) and orf1 (encoding a putative MerR family regulator), orf2 (encoding a CDF family heavy metal/H(+) antiporter). This association was also found in another malachite green-degrading strain Pseudomonas sp. MDB-1, which indicated that the tmr2 gene might be a horizontally transferable gene. | 25,187,131 | [
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MutS-mediated enrichment of mutated DNA produced by directed evolution in vitro. | Directed evolution in vitro is a powerful tool in the study and design of protein function. However, screening the desired mutants is a difficult task. To facilitate the screening, a method is proposed to eliminate wild type sequences and increase mutated DNA sequences, which is based on the preferential binding of MutS protein to heteroduplex DNA. Following error-prone PCR, amplified products are denatured and re-annealed to form heteroduplex and homoduplex DNA. Heteroduplexes are selectively bound to an engineered MutS protein and immobilized on a Strep-Tactin column. Homoduplexes are effectively removed by washing, and the final elution is enriched in mutated DNA sequences. One round of mutated DNA enrichment resulted in an about 2.3-fold of increase in mutation frequency compared to the control. The percentage of mutants rose from 44% in the control sample to 72% in the enrichment sample. Fluorescent assay by flow cytometry showed that the enrichment method increased the mutants with changed fluorescent activity by about 2.2-fold, which strongly justified the efficiency of enrichment in increasing mutants with functional changes. With reduced workload of screening and increased possibility of obtaining mutants with functional changes, the overall efficiency was improved by MutS-mediated enrichment of mutated DNA. | 25,187,136 | [
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Thermoactive β-N-acetylhexosaminidase production by a soil isolate of Penicillium monoverticillium CFR 2 under solid state fermentation: parameter optimization and application for N-acetyl chitooligosaccharides preparation from chitin. | Two fungal strains were evaluated for β-N-acetylhexosaminidase production by solid state fermentation using different agro-industrial residues such as commercial wheat bran (CWB) and shrimp shell chitin waste (SSCW), of which Penicillium monoverticillium CFR 2 a local soil isolate showed significantly (P ≤ 0.001) higher β-N-acetylhexosaminidase activity on CWB medium as compared with the activity of Fusarium oxysporum CFR 8. Fermentation parameters such as incubation temperature, incubation time, initial moisture content and inoculum concentration were optimized by statistically designed experiments, using 3**(4-1) fractional factorial design of Response Surface Methodology. The high R(2) (0.9512) observed during validation experiment showed the usefulness of the model. Highest level of enzyme activity (311.84 U/g IDS) was predicted at 75% (w/w) initial moisture content, 26 °C incubation temperature, 168 h incubation time and initial inoculum, at the highest concentration tested (2.95 ml spore suspension/5 g substrate). Statistical optimization yielded a 4.5 fold increase in β-N-acetylhexosaminidase activity. The crude β-N-acetylhexosaminidase showed optimum temperature of 57 ± 1 °C and pH of 3.6 and retained 50% activity after 1 h of incubation at 57 ± 1 °C. SDS-PAGE zymogram revealed crude enzyme was a monomer with an apparent molecular weight ~110 kDa. The crude enzyme formed 6.81 ± 0.03 mM/l of N-acetyl chitooligosaccharides from colloidal chitin in 24 h of incubation. HPLC analysis revealed hydrolysate contained 37.57% N-acetyl chitotriose and 62.43% N-acetyl chitohexose, indicating its potential for specific N-acetyl chitooligosaccharides production. | 25,187,143 | [
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Heat and phosphate starvation effects on the proteome, morphology and chemical composition of the biomining bacteria Acidithiobacillus ferrooxidans. | Acidithiobacillus ferrooxidans is a Gram negative, acidophilic, chemolithoautotrophic bacterium that plays an important role in metal bioleaching. During bioleaching, the cells are subjected to changes in the growth temperature and nutrients starvation. The aim of this study was to gather information about the response of the A.ferrooxidans Brazilian strain LR to K2HPO4 starvation and heat stress through investigation of cellular morphology, chemical composition and differential proteome. The scanning electron microscopic results showed that under the tested stress conditions, A. ferrooxidans cells became elongated while the Fourier transform infrared spectroscopy (FT-IR) analysis showed alterations in the wavenumbers between 850 and 1,275 cm(-1), which are related to carbohydrates, phospholipids and phosphoproteins. These findings indicate that the bacterial cell surface is affected by the tested stress conditions. A proteomic analysis, using 2-DE and tandem mass spectrometry, enabled the identification of 44 differentially expressed protein spots, being 30 due to heat stress (40°C) and 14 due to K2HPO4 starvation. The identified proteins belonged to 11 different functional categories, including protein fate, energy metabolism and cellular processes. The upregulated proteins were mainly from protein fate and energy metabolism categories. The obtained results provide evidences that A. ferrooxidans LR responds to heat stress and K2HPO4 starvation by inducing alterations in cellular morphology and chemical composition of the cell surface. Also, the identification of several proteins involved in protein fate suggests that the bacteria cellular homesostasis was affected. In addition, the identification of proteins from different functional categories indicates that the A. ferrooxidans response to higher than optimal temperatures and phosphate starvation involves global changes in its physiology. | 25,187,146 | [
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The impact of exposure model misspecification on signal detection in prospective pharmacovigilance. | Pharmacovigilance monitors the safety of drugs after their approval and marketing. Timely detection of adverse effects is important. The true relationship between time-varying drug use and the adverse event risk is typically unknown. Yet, most current pharmacovigilance studies rely on arbitrarily chosen exposure metrics such as current exposure or use in the past 3 months. The authors used simulations to assess the impact of a misspecified exposure model on the timeliness of adverse effect detection. Prospective pharmacovigilance studies were simulated assuming different true relationships between time-varying drug use and the adverse event hazard. Simulated data were analyzed by fitting conventional parametric and more complex spline-based estimation models at multiple, pre-specified testing times. The 'signal' was generated on the basis of the corrected model-specific p-value selected to ensure a 5% probability of incorrectly rejecting the null hypothesis of no association. Results indicated that use of an estimation model that diverged substantially from the true underlying association-reduced sensitivity and increased the time to detection of a clinically important association. Time to signal detection in pharmacovigilance may depend strongly on the method chosen to model the exposure. No single estimation model performed optimally across different simulated scenarios, suggesting the need for data-dependent criteria to select the model most appropriate for a given study. | 25,187,155 | [
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Differences in immunogenicity of HLA antigens and the impact of cross-reactivity on the humoral response. | Information about differences in immunogenicity of various HLA antigens may help guide donor selection and identify mismatches to avoid for patients likely to need retransplantation. To date, antibody responses to a wide array of individual mismatched antigens have not been evaluated. Frequencies of antibodies to mismatched HLA-A, HLA-B, HLA-DR, and HLA-DQ antigens were determined for 703 renal transplant patients who had no detectable donor-specific antibody before transplantation. The impact of cross-reactive group matching and production of antibodies cross-reactive with mismatched antigens were also assessed. Antibodies were identified using multiplexed bead assays. The overall mean frequencies were similar for HLA-A (53.2%), HLA-DR (52.6%), and HLA-DQ (59.0%) antibodies, but significantly lower for HLA-B antibodies (42.4%). However, the response to individual antigens ranged from 15.0% to 76.2%. Antibody frequencies were reduced significantly for 54 of 62 specificities when the patient possessed an antigen cross-reactive with the donor mismatch, but the magnitude of the effect was variable and ranged from 8% to 83%. Moreover, there was directionality in the protective effect of cross-reactive group matching. Overall mean donor-specific antibody frequencies were comparable for men and women except for a significantly higher frequency of antibodies to HLA-DR among men (56.6% vs. 47.8%, P=0.004). Overall mean frequencies in blacks were higher than, or comparable to those of, whites, but differences were not significant. There is considerable variability in the immunogenicity of different HLA antigens that is impacted by the presence or absence of cross-reactive antigens in the patient's phenotype. This information can be used to augment the immunologic evaluation of donor-recipient pairs. | 25,187,165 | [
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Expression of ZAT12 transcripts in transgenic tomato under various abiotic stresses and modeling of ZAT12 protein in silico. | ZAT12 a C2H2-zinc-finger protein is an abiotic stress-responsive transcription factor in plants having less information about their structure. Transcription analysis proved that ZAT12 transcripts over-expressed during drought, heat and salt stress conditions which led to an interest in 3-D structural studies of ZAT12in Brassica carinata. Over-expression of BcZAT12 in transformed tomato plants under abiotic stresses, suggest role of ZAT12 in conferring stress-tolerance in tomato. Sequence analysis of ZAT12 protein (Accession No. ABB55254.1) from B. carinata revealed it as a 161 amino acid long protein with short conserved motif (140)LDLXL(144) in C-terminal, a leucine rich L-Box with-(14)EXXAXCLXXL(23) motif in N-terminal region and presence of two conserved Zinc-Finger motifs "CXXCXXXXXXXQALGGHXXXH" between positions 42-62 and 85-105. The two zinc finger motifs have presence of two conserved glutamic acid (Glu) and phenylalanine (Phe) residues. Two methionine (Met) residues at position 94 and 102 present in ZF-motif-2 were absent in ZF-motif-1. The (94)Met and (97)Ala in ZF-motif-2 were found to be replaced by serine (Ser) in ZF-motif-1. Homology and ab initio structural modeling of ZAT12 encoded BcZAT12 protein of B. carinata resulted in robust 3-D models and were evaluated for structural motifs, associated GO terms and protein-DNA interactions. The BcZAT12 protein model, was of good quality, reliable, stable and is deposited in PMDB database (PMDB ID: PM0078213). BcZAT12 is annotated as an intracellular protein having molecular function in Zn-binding which in turn regulates signal transduction/translation processes in response to abiotic stresses in plants. Results suggest BcZAT12 protein to interact directly with one strand of dsDNA via electrostatic and H-bonds. | 25,187,181 | [
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Sequential Bi-C bond activation reactions of BiEt₃ via insertion reactions of RE {R = HC[C(Me)N(2,6-i-Pr₂C₆H₃)]₂; E = Al, Ga, In}. | Two of the Bi-C bonds of BiEt3 are sequentially activated by mono-valent RM {R = HC[C(Me)N(2,6-i-Pr2C6H3)]2; M = Al, Ga, In}. The first Bi-C bond activation leads to the formation of insertion complexes, [RMEt(BiEt2)] (M = Al 1; Ga 2; In 3), whereas the consecutive second activation proceeds through a reductive elimination of RMEt2 (M = Al 4, Ga 5), elemental Bi and BiEt3. | 25,187,200 | [
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Cellular damage suffered by equine embryos after exposure to cryoprotectants or cryopreservation by slow-freezing or vitrification. | Equine embryos are cryopreserved by slow-freezing or vitrification. While small embryos (<300 μm) survive cryopreservation reasonably well, larger embryos do not. It is not clear if slow-freezing or vitrification is less damaging to horse embryos. To compare the type and extent of cellular damage suffered by small and large embryos during cryopreservation by slow-freezing vs. vitrification. Sixty-three Day 6.5-7 embryos were subdivided by size and assigned to one of 5 treatments: control, exposure to slow-freezing or vitrification cryoprotectants (CPs), and cryopreservation by either technique. After thawing/CP removal, embryos were stained with fluorescent stains for various parameters of cellular integrity, and assessed by multiphoton microscopy. Exposing large embryos to vitrification CPs resulted in more dead cells (6.8 ± 1.3%: 95% confidence interval [CI], 3.1-10.4%) than exposure to slow-freezing media (0.3 ± 0.1%; 95% CI 0.0-0.6%: P = 0.001). Cryopreservation by either technique induced cell death and cytoskeleton disruption. Vitrification of small embryos resulted in a higher proportion of cells with fragmented or condensed (apoptotic) nuclei (P = 0.002) than slow-freezing (6.7 ± 1.5%, 95% CI 3.0-10.4% vs. 5.0 ± 2.1%, 95% CI 4.0-14.0%). Slow-freezing resulted in a higher incidence of disintegrated embryos (P = 0.01) than vitrification. Mitochondrial activity was low in control embryos, and was not differentially affected by cryopreservation technique, whereas vitrification changed mitochondrial distribution from a homogenous crystalline pattern in control embryos to a heterogeneous granulated distribution in vitrified embryos (P = 0.05). Cryopreservation caused more cellular damage to large embryos than smaller ones. While vitrification is more practical, it is not advisable for large embryos due to a higher incidence of dead cells. The choice is less obvious for small embryos, as vitrification led to occasionally very high percentages of dead or damaged cells, but a lower incidence of embryo disintegration. Modifications that reduce the level of cellular damage induced by vitrification are required before it can be considered the method of choice for cryopreserving equine embryos. | 25,187,202 | [
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Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells. | Endothelial glucose transporter 1 (GLUT1) is a definitive and diagnostic marker for infantile hemangioma (IH), a vascular tumor of infancy. To date, GLUT1-positive endothelial cells in IH have not been quantified nor directly isolated and studied. We isolated GLUT1-positive and GLUT1-negative endothelial cells from IH specimens and characterized their proliferation, differentiation, and response to propranolol, a first-line therapy for IH, and to rapamycin, an mTOR pathway inhibitor used to treat an increasingly wide array of proliferative disorders. Although freshly isolated GLUT1-positive cells, selected using anti-GLUT1 magnetic beads, expressed endothelial markers CD31, VE-Cadherin, and vascular endothelial growth factor receptor 2, they converted to a mesenchymal phenotype after 3 weeks in culture. In contrast, GLUT1-negative endothelial cells exhibited a stable endothelial phenotype in vitro. GLUT1-selected cells were clonogenic when plated as single cells and could be induced to redifferentiate into endothelial cells, or into pericytes/smooth muscle cells or into adipocytes, indicating a stem cell-like phenotype. These data demonstrate that, although they appear and function in the tumor as bona fide endothelial cells, the GLUT1-positive endothelial cells display properties of facultative stem cells. Pretreatment with rapamycin for 4 days significantly slowed proliferation of GLUT1-selected cells, whereas propranolol pretreatment had no effect. These results reveal for the first time the facultative nature of GLUT1-positive endothelial cells in IH. | 25,187,207 | [
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A performance comparison of the paediatric i-gel with other supraglottic airway devices. | We performed a review of published literature comparing the i-gel with other supraglottic airway devices in children. Sixty-two articles were identified following a literature search; we included data from 14 randomised controlled trials and eight observational studies that compared i-gel sizes 1-2.5 with other commonly used, equivalently-sized, devices. The primary outcome in most studies was oropharyngeal leak pressure. In the 14 randomised trials the i-gel performed the same as the comparator device in five trials, significantly better in eight studies (p < 0.05) and significantly worse in one (p < 0.01). Seven studies assessed fibreoptic views of the larynx through the device; two found significantly better views through the i-gel. Three studies reported a shorter insertion time for the i-gel, whereas two reported a longer time. Insertion success rate, gastric tube placement and complications were similar for all the devices. Seven of the eight observational studies measured average oropharyngeal leak pressures of 20-27 cmH2O and all had first-time insertion success rates exceeding 90%. We conclude that the i-gel is at least equivalent to other supraglottic airway devices currently available for use in children, and may enable a higher oropharyngeal leak pressure and an improved fibreoptic view of the glottis. | 25,187,212 | [
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Measuring extracellular pH in a lung fibrosis model with acidoCEST MRI. | A feed-forward loop involving lactic acid production may potentially occur during the formation of idiopathic pulmonary fibrosis. To provide evidence for this feed-forward loop, we used acidoCEST MRI to measure the extracellular pH (pHe), while also measuring percent uptake of the contrast agent, lesion size, and the apparent diffusion coefficient (ADC). We developed a respiration-gated version of acidoCEST MRI to improve the measurement of pHe and percent uptake in lesions. We also used T2-weighted MRI to measure lesion volumes and diffusion-weighted MRI to measure ADC. The longitudinal changes in average pHe and % uptake of the contrast agent were inversely related to reduction in lung lesion volume. The average ADC did not change during the time frame of the study. The increase in pHe during the reduction in lesion volume indicates a role for lactic acid in the proposed feed-forward loop of IPF. | 25,187,227 | [
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'True' null allele detection in microsatellite loci: a comparison of methods, assessment of difficulties and survey of possible improvements. | Null alleles are alleles that for various reasons fail to amplify in a PCR assay. The presence of null alleles in microsatellite data is known to bias the genetic parameter estimates. Thus, efficient detection of null alleles is crucial, but the methods available for indirect null allele detection return inconsistent results. Here, our aim was to compare different methods for null allele detection, to explain their respective performance and to provide improvements. We applied several approaches to identify the 'true' null alleles based on the predictions made by five different methods, used either individually or in combination. First, we introduced simulated 'true' null alleles into 240 population data sets and applied the methods to measure their success in detecting the simulated null alleles. The single best-performing method was ML-NullFreq_frequency. Furthermore, we applied different noise reduction approaches to improve the results. For instance, by combining the results of several methods, we obtained more reliable results than using a single one. Rule-based classification was applied to identify population properties linked to the false discovery rate. Rules obtained from the classifier described which population genetic estimates and loci characteristics were linked to the success of each method. We have shown that by simulating 'true' null alleles into a population data set, we may define a null allele frequency threshold, related to a desired true or false discovery rate. Moreover, using such simulated data sets, the expected null allele homozygote frequency may be estimated independently of the equilibrium state of the population. | 25,187,238 | [
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Oxidative stress and cannabinoid receptor expression in type-2 diabetic rat pancreas following treatment with Δ⁹-THC. | The objectives of study were (a) to determine alteration of feeding, glucose level and oxidative stress and (b) to investigate expression and localization of cannabinoid receptors in type-2 diabetic rat pancreas treated with Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Rats were randomly divided into four groups: control, Δ(9)-THC, diabetes and diabetes + Δ(9)-THC groups. Diabetic rats were treated with a single dose of nicotinamide (85 mg/kg) 15 min before injection of streptozotocin (65 mg/kg). Δ(9)-THC was administered intraperitoneally at 3 mg/kg/day for 7 days. Body weights and blood glucose level of rats in all groups were measured on days 0, 7, 14 and 21. On day 15 after the Δ(9)-THC injections, pancreatic tissues were removed. Blood glucose levels and body weights of diabetic rats treated with Δ(9)-THC did not show statistically significant changes when compared with the diabetic animals on days 7, 14 and 21. Treatment with Δ(9)-THC significantly increased pancreas glutathione levels, enzyme activities of superoxide dismutase and catalase in diabetes compared with non-treatment diabetes group. The cannabinoid 1 receptor was found in islets, whereas the cannabinoid 2 receptor was found in pancreatic ducts. Their localization in cells was both nuclear and cytoplasmic. We can suggest that Δ(9) -THC may be an important agent for the treatment of oxidative damages induced by diabetes. However, it must be supported with anti-hyperglycaemic agents. Furthermore, the present study for the first time emphasizes that Δ(9)-THC may improve pancreatic cells via cannabinoid receptors in diabetes. The aim of present study was to elucidate the effects of Δ(9)-THC, a natural cannabinoid receptor agonist, on the expression and localization of cannabinoid receptors, and oxidative stress statue in type-2 diabetic rat pancreas. Results demonstrate that the cannabinoid receptors are presented in both Langerhans islets and duct regions. The curative effects of Δ(9)-THC can be occurred via activation of cannabinoid receptors in diabetic rat pancreas. Moreover, it may provide a protective effect against oxidative damage induced by diabetes. Thus, it is suggested that Δ(9)-THC can be a candidate for therapeutic alternatives of diabetes symptoms. | 25,187,240 | [
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WS₂ 2D nanosheets in 3D nanoflowers. | In this work it has been established that 3D nanoflowers of WS2 synthesised by chemical vapour deposition are composed of few layer WS2 along the edges of the petals. An experimental study in order to understand the evolution of these nanostructures shows the nucleation and growth along with the compositional changes they undergo. | 25,187,313 | [
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Ameliorative effects of docosahexaenoic acid on the toxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in cultured rat hepatocytes. | The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant toxicant that mediates carcinogenic effects associated with oxidative DNA damage. Docosahexaenoic acid (DHA) with antioxidant functions has many biochemical, cellular, and physiological functions for cells. The present study assessed, for the first time, the ameliorative effect of DHA in alleviating the toxicity of TCDD on primary cultured rat hepatocytes (HEPs). In vitro, isolated HEPs were incubated with TCDD (5 and 10 μM) in the presence and absence of DHA (5, 10, and 20 μM) for 48 h. The cell viability was detected by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) release. DNA damage was analyzed by liver micronucleus assay and 8-oxo-2-deoxyguanosine (8-OH-dG) level. In addition, total antioxidant capacity (TAC) and total oxidative stress (TOS) were assessed to determine the oxidative injury in HEPs. The results of MTT and LDH assays showed that TCDD decreased cell viability but not DHA. On the basis of increasing treatment concentrations, the dioxin caused significant increases of micronucleated HEPs and 8-OH-dG as compared to control culture. TCDD also led to significant increases in TOS content. On the contrary, in cultures treated with DHA, the level of TAC was significantly increased during treatment in a concentration-dependent fashion. DHA showed therapeutic potential against TCDD-mediated cell viability and DNA damages. As conclusion, this study provides the first evidence that DHA has protective effects against TCDD toxicity on primary cultured rat hepatocytes. | 25,187,318 | [
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Mutagenicity of automobile workshop soil leachate and tobacco industry wastewater using the Ames Salmonella fluctuation and the SOS chromotests. | Environmental management of industrial solid wastes and wastewater is an important economic and environmental health problem globally. This study evaluated the mutagenic potential of automobile workshop soil-simulated leachate and tobacco wastewater using the SOS chromotest on Escherichia coli PQ37 and the Ames Salmonella fluctuation test on Salmonella typhimurium strains TA98 and TA100 without metabolic activation. Physicochemical parameters of the samples were also analyzed. The result of the Ames test showed mutagenicity of the test samples. However, the TA100 was the more responsive strain for both the simulated leachate and tobacco wastewater in terms of mutagenic index in the absence of metabolic activation. The SOS chromotest results were in agreement with those of the Ames Salmonella fluctuation test. Nevertheless, the E. coli PQ37 system was slightly more sensitive than the Salmonella assay for detecting genotoxins in the tested samples. Iron, cadmium, manganese, copper, nickel, chromium, arsenic, zinc, and lead contents analyzed in the samples were believed to play significant role in the observed mutagenicity in the microbial assays. The results of this study showed that the simulated leachate and tobacco wastewater showed strong indication of a genotoxic risk. Further studies would be required in the analytical field in order to identify and quantify other compounds not analyzed for in this study, some of which could be responsible for the observed genotoxicity. This will be necessary in order to identify the sources of toxicants and thus to take preventive and/or curative measures to limit the toxicity of these types of wastes. | 25,187,319 | [
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The effect of radiofrequency turbinoplasty vs two other methods in the management of polypoid changes of the middle turbinate: a randomized trial. | The aim of this study was to evaluate the effectiveness of middle turbinate radiofrequency (RF) turbinoplasty for the management of the polypoid middle turbinate compared to middle turbinate resection and middle turbinate medialization. The study was performed on 90 patients at a tertiary referral hospital with nasal polyposis resistant to maximal medical treatment. At the time of functional endoscopic sinus surgery (FESS), patients were randomized into 3 groups with respect to the management of the middle turbinate: middle turbinate turbinoplasty by RF; partial resection of the middle turbinate; and medialization of the middle turbinate by scarification to the septum. We evaluated the patients' symptoms according to the 22-item Sino-Nasal Outcome Test (SNOT-22) preoperatively and 1 year after surgery. Additionally, polyp recurrence and complications were compared among the 3 groups. One year after surgery, there was no significant difference in SNOT-22 scores between the groups. However, the RF group had a significantly lower polyp recurrence rate when compared to other groups (p < 0.05). RF middle turbinate turbinoplasty could be considered an alternative to other common approaches, but it needs further long-term studies before widespread usage. | 25,187,345 | [
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Temporal triangular alopecia: significance of trichoscopy in differential diagnosis. | There are only two case reports in literature regarding the trichoscopic features of temporal triangular alopecia (TTA). Differential diagnosis of other types of localized alopecia such as alopecia areata is necessary in some cases. To evaluate the potential benefit of trichoscopy in the clinical diagnosis of TTA. Nine patients with a clinical diagnosis of TTA were included in the study. Trichoscopic examination was performed by a polarized-light handheld dermatoscope with a 10-fold magnification. The images were obtained by a digital camera that produced imagery with a 3-fold optical zoom. Short vellus hairs, vellus hair length diversity and white hairs were encountered in all subjects, while white dots, honeycomb pigment pattern, arborising red lines and epidermal scale were noted in 22%-33% of them. None of the cases showed trichoscopic features such as tapering hairs, yellow dots or loss of follicular openings. We suggest that it seems possible to differentiate TTA by a handheld dermatoscope. Short vellus hairs with length diversity and white hairs in the absence of diagnostic features of other types of localized alopecia should be considered in favour of TTA. | 25,187,354 | [
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Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes. | Six skin collagen advanced glycation end products (AGEs) originally measured near to the time of the Diabetes Control and Complications Trial (DCCT) closeout in 1993 may contribute to the "metabolic memory" phenomenon reported in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. We have now investigated whether the addition of four originally unavailable AGEs (i.e., glucosepane [GSPNE], hydroimidazolones of methylglyoxal [MG-H1] and glyoxal, and carboxyethyl-lysine) improves associations with incident retinopathy, nephropathy, and neuropathy events during 13-17 years after DCCT. The complete 10-AGE panel is associated with three-step Early Treatment of Diabetic Retinopathy Study scale worsening of retinopathy (P ≤ 0.002), independent of either mean DCCT or EDIC study A1C level. GSPNE and fructose-lysine (furosine [FUR]) correlate with retinopathy progression, independently of A1C level. The complete panel also correlates with microalbuminuria (P = 0.008) and FUR with nephropathy independently of A1C level (P ≤ 0.02). Neuropathy correlates with the complete panel despite adjustment for A1C level (P ≤ 0.005). MG-H1 and FUR are dominant, independent of A1C level (P < 0.0001), whereas A1C loses significance after adjustment for the AGEs. Overall, the added set of four AGEs enhances the association of the original panel with progression risk of retinopathy and neuropathy (P < 0.04) but not nephropathy, while GSPNE and MG-H1 emerge as the principal new risk factors. Skin AGEs are robust long-term markers of microvascular disease progression, emphasizing the importance of early and sustained implementation of intensive therapy. | 25,187,362 | [
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Assessment of β-cell mass and α- and β-cell survival and function by arginine stimulation in human autologous islet recipients. | We used intravenous arginine with measurements of insulin, C-peptide, and glucagon to examine β-cell and α-cell survival and function in a group of 10 chronic pancreatitis recipients 1-8 years after total pancreatectomy and autoislet transplantation. Insulin and C-peptide responses correlated robustly with the number of islets transplanted (correlation coefficients range 0.81-0.91; P < 0.01-0.001). Since a wide range of islets were transplanted, we normalized the insulin and C-peptide responses to the number of islets transplanted in each recipient for comparison with responses in normal subjects. No significant differences were observed in terms of magnitude and timing of hormone release in the two groups. Three recipients had a portion of the autoislets placed within their peritoneal cavities, which appeared to be functioning normally up to 7 years posttransplant. Glucagon responses to arginine were normally timed and normally suppressed by intravenous glucose infusion. These findings indicate that arginine stimulation testing may be a means of assessing the numbers of native islets available in autologous islet transplant candidates and is a means of following posttransplant α- and β-cell function and survival. | 25,187,365 | [
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Stress response protein cirp links inflammation and tumorigenesis in colitis-associated cancer. | Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and is reported to be associated with refractory inflammatory bowel disease (IBD). Defective apoptosis of inflammatory cell populations seems to be a relevant pathogenetic mechanism in refractory IBD. We assessed the involvement of stress response protein cold-inducible RNA-binding protein (Cirp) in the development of intestinal inflammation and CAC. In the colonic mucosa of patients with ulcerative colitis, expression of Cirp correlated significantly with the expression of TNFα, IL23/IL17, antiapoptotic proteins Bcl-2 and Bcl-xL, and stem cell markers such as Sox2, Bmi1, and Lgr5. The expression of Cirp and Sox2 was enhanced in the colonic mucosae of refractory ulcerative colitis, suggesting that Cirp expression might be related to increased cancer risk. In human CAC specimens, inflammatory cells expressed Cirp protein. Cirp(-/-) mice given dextran sodium sulfate exhibited decreased susceptibility to colonic inflammation through decreased expression of TNFα, IL23, Bcl-2, and Bcl-xL in colonic lamina propria cells compared with similarly treated wild-type (WT) mice. In the murine CAC model, Cirp deficiency decreased the expression of TNFα, IL23/IL17, Bcl-2, Bcl-xL, and Sox2 and the number of Dclk1(+) cells, leading to attenuated tumorigenic potential. Transplantation of Cirp(-/-) bone marrow into WT mice reduced tumorigenesis, indicating the importance of Cirp in hematopoietic cells. Cirp promotes the development of intestinal inflammation and colorectal tumors through regulating apoptosis and production of TNFα and IL23 in inflammatory cells. | 25,187,386 | [
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Surgical treatment of intrahepatic cholangiocarcinoma in the USA. | Cholangiocarcinoma (CC) is a malignancy that arises from the epithelial cells of the biliary system (ductules as well as large ducts, and likely from progenitor cells, as well). Intrahepatic CC (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC), and accounts for 10-15% of primary liver cancers. ICC differs from both extrahepatic and CC and HCC and has unique risk factors, histological features, genetic alterations and clinical outcomes. The natural history and results of surgical intervention are not well described as ICC is a relatively uncommon tumor, especially in the USA. This article reviews the literature relevant to the surgical management and outcome of patients with ICC in the USA. | 25,187,408 | [
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Arsenic trioxide and microRNA-204 display contrary effects on regulating adipogenic and osteogenic differentiation of mesenchymal stem cells in aplastic anemia. | Our previous studies have demonstrated that arsenic trioxide (ATO) had the clinical efficacy in treating patients with aplastic anemia (AA). However, the mechanisms remain to be elucidated. The important components of the bone marrow hematopoietic microenvironment, bone marrow mesenchymal stem cells (BMSCs), are often altered in AA patients. In this study, it was found that AA BMSCs were prone to be induced into adipocytes rather than osteoblasts. ATO treatment can at least partially restore the differentiation imbalance of AA BMSCs. We further identified miR-204 as a key regulator in AA BMSC differentiation. Luciferase reporter assay showed that miR-204 could directly bind to the 3'-untranslated region of Runx2 mRNA, a key transcription factor regulating osteogenesis. Moreover, adipogenic differentiation was promoted and osteogenic differentiation was inhibited in miR-204 over-expressed cells, whereas osteogenesis was enhanced and adipocyte formation was inhibited in cells that lost miR-204 function, which suggested its endogenous function. Together we showed that ATO could inhibit adipogenic differentiation, but promote osteogenic differentiation in AA BMSCs, providing a possible explanation for ATO clinical efficacy in AA patients. MiR-204 plays a key role in regulating BMSCs differentiation, and down-regulating miR-204 expression might be a novel strategy to treat AA. | 25,187,411 | [
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Rostafuroxin protects from podocyte injury and proteinuria induced by adducin genetic variants and ouabain. | Glomerulopathies are important causes of morbidity and mortality. Selective therapies that address the underlying mechanisms are still lacking. Recently, two mechanisms, mutant β-adducin and ouabain, have been found to be involved in glomerular podocytopathies and proteinuria through nephrin downregulation. The main purpose of the present study was to investigate whether rostafuroxin, a novel antihypertensive agent developed as a selective inhibitor of Src-SH2 interaction with mutant adducin- and ouabain-activated Na,K-ATPase, may protect podocytes from adducin- and ouabain-induced effects, thus representing a novel pharmacologic approach for the therapy of podocytopathies and proteinuria caused by the aforementioned mechanisms. To study the effect of rostafuroxin on podocyte protein changes and proteinuria, mice carrying mutant β-adducin and ouabain hypertensive rats were orally treated with 100 μg/kg per day rostafuroxin. Primary podocytes from congenic rats carrying mutant α-adducin or β-adducin (NB) from Milan hypertensive rats and normal rat podocytes incubated with 10(-9) M ouabain were cultured with 10(-9) M rostafuroxin. The results indicated that mutant β-adducin and ouabain caused podocyte nephrin loss and proteinuria in animal models. These alterations were reproduced in primary podocytes from NB rats and normal rats incubated with ouabain. Treatment of animals, or incubation of cultured podocytes with rostafuroxin, reverted mutant β-adducin- and ouabain-induced effects on nephrin protein expression and proteinuria. We conclude that rostafuroxin prevented podocyte lesions and proteinuria due to mutant β-adducin and ouabain in animal models. This suggests a potential therapeutic effect of rostafuroxin in patients with glomerular disease progression associated with these two mechanisms. | 25,187,430 | [
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Pattern of underreporting falls in a general psychiatric hospital in Japan. | To examine the pattern of underreporting of fall incidents in a general psychiatric hospital in Japan. All fall incidents were analyzed and stratified by ward. A discrepancy in fall rates was found in acute psychiatric and dementia wards. The following indicators were suggestive of underreporting: "zero fall/1,000 patient-days," "proportion of falls without injury," and "proportion of falls identified as occurring in the bedroom as a fall location during certain time periods." Ward-specific fall rates, with further stratifications by time and location of the fall, were useful for identifying a pattern of underreporting. | 25,187,446 | [
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"Providing structure" as a psychiatric nursing intervention: a review of the literature. | The focus is on a nursing intervention called "providing structure" (PS). This label does not exist in the Nursing Interventions Classification. The following three questions were asked: (a) How is PS defined? (b) What are the goals of PS? and (c) What is the evidence regarding the effectiveness of PS? A systematic literature review. Forty articles, predominantly qualitative studies of PS, were selected for review. Regarding PS, three elements were mentioned: to impose and maintain rules and limits; to assess the condition of the patient; and to interact with the patient. The goals for PS related to patient security, making expectations explicit, and recovering from illness. Major findings were reviewed, but little was found about the effectiveness of PS. | 25,187,449 | [
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Factors that influence the diagnoses of Asian Americans in mental health: an exploration. | This 10-year review of Asian Americans focuses on factors that impede adequate psychiatric diagnosis and treatment. Asian Americans are the fastest growing ethnic group in the United States, with a high prevalence of domestic violence, alcohol abuse, and significant distress. However, Asian Americans consistently underutilize mental health services because of stigma, misconceptions of Western treatment, and cultural interpretations of mental health problems. Knowledge of the diversity of the Asian American population and an understanding of cultural interpretations of psychiatry will better prepare clinicians to treat and engage these patients. | 25,187,450 | [
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Histological insights into the pathogenesis of post-Roux-en-Y hyperinsulinaemic hypoglycaemia. | β-cell hyperplasia has been implicated in the aetiology of post Roux-en-Y gastric bypass hyperinsulinaemic hypoglycaemia, but the pathogenesis of this condition is still unclear. We report a case of a 52-year-old man with post-Roux-en-Y gastric bypass hyperinsulinaemic hypoglycaemia who underwent distal pancreatectomy to alleviate his symptoms. Pancreatic histopathology showed chronic pancreatitis with a corresponding loss of exocrine tissue and islet retention. Amyloid deposition was found in pancreatic islets. These features are more typically associated with Type 2 diabetes. This case highlights the potential multifactorial pathogenesis of symptomatic hypoglycaemia after Roux-en-Y gastric bypass. | 25,187,473 | [
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Image-based high-throughput field phenotyping of crop roots. | Current plant phenotyping technologies to characterize agriculturally relevant traits have been primarily developed for use in laboratory and/or greenhouse conditions. In the case of root architectural traits, this limits phenotyping efforts, largely, to young plants grown in specialized containers and growth media. Hence, novel approaches are required to characterize mature root systems of older plants grown under actual soil conditions in the field. Imaging methods able to address the challenges associated with characterizing mature root systems are rare due, in part, to the greater complexity of mature root systems, including the larger size, overlap, and diversity of root components. Our imaging solution combines a field-imaging protocol and algorithmic approach to analyze mature root systems grown in the field. Via two case studies, we demonstrate how image analysis can be utilized to estimate localized root traits that reliably capture heritable architectural diversity as well as environmentally induced architectural variation of both monocot and dicot plants. In the first study, we show that our algorithms and traits (including 13 novel traits inaccessible to manual estimation) can differentiate nine maize (Zea mays) genotypes 8 weeks after planting. The second study focuses on a diversity panel of 188 cowpea (Vigna unguiculata) genotypes to identify which traits are sufficient to differentiate genotypes even when comparing plants whose harvesting date differs up to 14 d. Overall, we find that automatically derived traits can increase both the speed and reproducibility of the trait estimation pipeline under field conditions. | 25,187,526 | [
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Molecular characterization of a novel temperate sinorhizobium bacteriophage, ФLM21, encoding DNA methyltransferase with CcrM-like specificity. | ΦLM21 is a temperate phage isolated from Sinorhizobium sp. strain LM21 (Alphaproteobacteria). Genomic analysis and electron microscopy suggested that ΦLM21 is a member of the family Siphoviridae. The phage has an isometric head and a long noncontractile tail. The genome of ΦLM21 has 50,827 bp of linear double-stranded DNA encoding 72 putative proteins, including proteins responsible for the assembly of the phage particles, DNA packaging, transcription, replication, and lysis. Virion proteins were characterized using mass spectrometry, leading to the identification of the major capsid and tail components, tape measure, and a putative portal protein. We have confirmed the activity of two gene products, a lytic enzyme (a putative chitinase) and a DNA methyltransferase, sharing sequence specificity with the cell cycle-regulating methyltransferase (CcrM) of the bacterial host. Interestingly, the genome of Sinorhizobium phage ΦLM21 shows very limited similarity to other known phage genome sequences and is thus considered unique. Prophages are known to play an important role in the genomic diversification of bacteria via horizontal gene transfer. The influence of prophages on pathogenic bacteria is very well documented. However, our knowledge of the overall impact of prophages on the survival of their lysogenic, nonpathogenic bacterial hosts is still limited. In particular, information on prophages of the agronomically important Sinorhizobium species is scarce. In this study, we describe the isolation and molecular characterization of a novel temperate bacteriophage, ΦLM21, of Sinorhizobium sp. LM21. Since we have not found any similar sequences, we propose that this bacteriophage is a novel species. We conducted a functional analysis of selected proteins. We have demonstrated that the phage DNA methyltransferase has the same sequence specificity as the cell cycle-regulating methyltransferase CcrM of its host. We point out that this phenomenon of mimicking the host regulatory mechanisms by viruses is quite common in bacteriophages. | 25,187,538 | [
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A histidine residue of the influenza virus hemagglutinin controls the pH dependence of the conformational change mediating membrane fusion. | The conformational change of the influenza virus hemagglutinin (HA) protein mediating the fusion between the virus envelope and the endosomal membrane was hypothesized to be induced by protonation of specific histidine residues since their pKas match the pHs of late endosomes (pK(a) of ∼ 6.0). However, such critical key histidine residues remain to be identified. We investigated the highly conserved His184 at the HA1-HA1 interface and His110 at the HA1-HA2 interface of highly pathogenic H5N1 HA as potential pH sensors. By replacing both histidines with different amino acids and analyzing the effect of these mutations on conformational change and fusion, we found that His184, but not His110, plays an essential role in the pH dependence of the conformational change of HA. Computational modeling of the protonated His184 revealed that His184 is central in a conserved interaction network possibly regulating the pH dependence of conformational change via its pKa. As the propensity of histidine to get protonated largely depends on its local environment, mutation of residues in the vicinity of histidine may affect its pK(a). The HA of highly pathogenic H5N1 viruses carries a Glu-to-Arg mutation at position 216 close to His184. By mutation of residue 216 in the highly pathogenic as well as the low pathogenic H5 HA, we observed a significant influence on the pH dependence of conformational change and fusion. These results are in support of a pK(a)-modulating effect of neighboring residues. The main pathogenic determinant of influenza viruses, the hemagglutinin (HA) protein, triggers a key step of the infection process: the fusion of the virus envelope with the endosomal membrane releasing the viral genome. Whereas essential aspects of the fusion-inducing mechanism of HA at low pH are well understood, the molecular trigger of the pH-dependent conformational change inducing fusion has been unclear. We provide evidence that His184 regulates the pH dependence of the HA conformational change via its pK(a). Mutations of neighboring residues which may affect the pK(a) of His184 could play an important role in virus adaptation to a specific host. We suggest that mutation of neighboring residue 216, which is present in all highly pathogenic phenotypes of H5N1 influenza virus strains, contributed to the adaptation of these viruses to the human host via its effect on the pKa of His184. | 25,187,542 | [
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Characterization of simian immunodeficiency virus (SIV) that induces SIV encephalitis in rhesus macaques with high frequency: role of TRIM5 and major histocompatibility complex genotypes and early entry to the brain. | Although nonhuman primate models of neuro-AIDS have made tremendous contributions to our understanding of disease progression in the central nervous system (CNS) of human immunodeficiency virus type 1 (HIV-1)-infected individuals, each model holds advantages and limitations. In this study, in vivo passage of SIVsmE543 was conducted to obtain a viral isolate that can induce neuropathology in rhesus macaques. After a series of four in vivo passages in rhesus macaques, we have successfully isolated SIVsm804E. SIVsm804E shows efficient replication in peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) in vitro and induces neuro-AIDS in high frequencies in vivo. Analysis of the acute phase of infection revealed that SIVsm804E establishes infection in the CNS during the early phase of the infection, which was not observed in the animals infected with the parental SIVsmE543-3. Comprehensive analysis of disease progression in the animals used in the study suggested that host major histocompatibility complex class I (MHC-I) and TRIM5α genotypes influence the disease progression in the CNS. Taken together, our findings show that we have successfully isolated a new strain of simian immunodeficiency virus (SIV) that is capable of establishing infection in the CNS at early stage of infection and causes neuropathology in infected rhesus macaques at a high frequency (83%) using a single inoculum, when animals with restrictive MHC-I or TRIM5α genotypes are excluded. SIVsm804E has the potential to augment some of the limitations of existing nonhuman primate neuro-AIDS models. Human immunodeficiency virus (HIV) is associated with a high frequency of neurologic complications due to infection of the central nervous system (CNS). Although the use of antiviral treatment has reduced the incidence of severe complications, milder disease of the CNS continues to be a significant problem. Animal models to study development of neurologic disease are needed. This article describes the development of a novel virus isolate that induces neurologic disease in a high proportion of rhesus macaques infected without the need for prior immunomodulation as is required for some other models. | 25,187,546 | [
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Remodeling of a delivery complex allows ClpS-mediated degradation of N-degron substrates. | The ClpS adaptor collaborates with the AAA+ ClpAP protease to recognize and degrade N-degron substrates. ClpS binds the substrate N-degron and assembles into a high-affinity ClpS-substrate-ClpA complex, but how the N-degron is transferred from ClpS to the axial pore of the AAA+ ClpA unfoldase to initiate degradation is not known. Here we demonstrate that the unstructured N-terminal extension (NTE) of ClpS enters the ClpA processing pore in the active ternary complex. We establish that ClpS promotes delivery only in cis, as demonstrated by mixing ClpS variants with distinct substrate specificity and either active or inactive NTE truncations. Importantly, we find that ClpA engagement of the ClpS NTE is crucial for ClpS-mediated substrate delivery by using ClpS variants carrying "blocking" elements that prevent the NTE from entering the pore. These results support models in which enzymatic activity of ClpA actively remodels ClpS to promote substrate transfer, and highlight how ATPase/motor activities of AAA+ proteases can be critical for substrate selection as well as protein degradation. | 25,187,555 | [
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Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. | Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma. | 25,187,556 | [
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Voltage-sensitive dye imaging of transcranial magnetic stimulation-induced intracortical dynamics. | Transcranial magnetic stimulation (TMS) is widely used in clinical interventions and basic neuroscience. Additionally, it has become a powerful tool to drive plastic changes in neuronal networks. However, highly resolved recordings of the immediate TMS effects have remained scarce, because existing recording techniques are limited in spatial or temporal resolution or are interfered with by the strong TMS-induced electric field. To circumvent these constraints, we performed optical imaging with voltage-sensitive dye (VSD) in an animal experimental setting using anaesthetized cats. The dye signals reflect gradual changes in the cells' membrane potential across several square millimeters of cortical tissue, thus enabling direct visualization of TMS-induced neuronal population dynamics. After application of a single TMS pulse across visual cortex, brief focal activation was immediately followed by synchronous suppression of a large pool of neurons. With consecutive magnetic pulses (10 Hz), widespread activity within this "basin of suppression" increased stepwise to suprathreshold levels and spontaneous activity was enhanced. Visual stimulation after repetitive TMS revealed long-term potentiation of evoked activity. Furthermore, loss of the "deceleration-acceleration" notch during the rising phase of the response, as a signature of fast intracortical inhibition detectable with VSD imaging, indicated weakened inhibition as an important driving force of increasing cortical excitability. In summary, our data show that high-frequency TMS changes the balance between excitation and inhibition in favor of an excitatory cortical state. VSD imaging may thus be a promising technique to trace TMS-induced changes in excitability and resulting plastic processes across cortical maps with high spatial and temporal resolutions. | 25,187,557 | [
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High CO2 concentration increases relative leaf carbon gain under dynamic light in Dipterocarpus sublamellatus seedlings in a tropical rain forest, Malaysia. | Understory plants in tropical forests often experience a low-light environment combined with high CO2 concentration. We hypothesized that the high CO2 concentration may compensate for leaf carbon loss caused by the low light, through increasing light-use efficiency of both steady-state and dynamic photosynthetic properties. To test the hypothesis, we examined CO2 gas exchange in response to an artificial lightfleck in Dipterocarpus sublamellatus Foxw. seedlings under contrasting CO2 conditions: 350 and 700 μmol CO2 mol(-1) air in a tropical rain forest, Pasoh, Malaysia. Total photosynthetic carbon gain from the lightfleck was about double when subjected to the high CO2 when compared with the low CO2 concentration. The increase of light-use efficiency in dynamic photosynthesis contributed 7% of the increased carbon gain, most of which was due to reduction of photosynthetic induction to light increase under the high CO2. The light compensation point of photosynthesis decreased by 58% and the apparent quantum yield increased by 26% at the high CO2 compared with those at the low CO2. The study suggests that high CO2 increases photosynthetic light-use efficiency under both steady-state and fluctuating light conditions, which should be considered in assessing the leaf carbon gain of understory plants in low-light environments. | 25,187,569 | [
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Comparison of ultrasound and electrodiagnostic testing for diagnosis of carpal tunnel syndrome: study using a validated clinical tool as the reference standard. | Ultrasound examination is both accurate and cost-effective for the confirmation of a clinical diagnosis of carpal tunnel syndrome. Previous studies have shown electrodiagnostic testing and ultrasound to be similar with regard to sensitivity and specificity. The purpose of this study was to compare the sensitivity and specificity of ultrasound and electrodiagnostic testing by using a validated clinical diagnostic tool as the reference standard. All consecutive patients referred to an upper-extremity practice for electrodiagnostic testing for any reason over a three-month period were recruited to participate in this study. All patients were evaluated with the use of the Carpal Tunnel Syndrome 6 (CTS-6) clinical diagnostic tool, and a score of ≥12 was considered positive for carpal tunnel syndrome. A positive finding on ultrasound was considered to be a cross-sectional area of the median nerve, measured just proximal to the level of the pisiform, of ≥10 mm(2). A positive finding on electrodiagnostic testing was a distal motor latency of ≥4.2 ms and/or a distal sensory latency of ≥3.2 ms. Sensitivity, specificity, and accuracy were calculated for ultrasound and electrodiagnostic testing with use of the CTS-6 as the reference standard. With use of the CTS-6 as the reference standard, ultrasound had a sensitivity of 89% and a specificity of 90% in our series of eighty-five patients. Electrodiagnostic testing had a sensitivity of 89% and a specificity of 80%. The positive predictive value of ultrasound was 94% compared with 89% for electrodiagnostic testing. The negative predictive value of ultrasound was 82% compared with 80% for electrodiagnostic testing. Ultrasound was accurate in seventy-six (89%) of the eighty-five cases whereas electrodiagnostic testing was accurate in seventy-three (86%) of the eighty-five cases (p = 0.5). While ultrasound will not replace electrodiagnostic testing in complicated or unclear cases, in a select group of patients with a positive CTS-6, ultrasound can be used to confirm the diagnosis of carpal tunnel syndrome with better specificity and equal sensitivity as compared with those of electrodiagnostic testing. Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. | 25,187,592 | [
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Assessment of moral reasoning skills in the orthopaedic surgery resident applicant. | Assessing orthopaedic surgery residency applicants is a complex process. One important applicant characteristic not commonly measured during the interview process is moral behavior, a key component of the guidelines of the Accreditation Council for Graduate Medical Education for professionalism competency. We sought to determine whether a relationship exists between the results of residency selection interviews, as measured by match rank order, and moral reasoning skills, as measured by the revised version of the Defining Issues Test (DIT-2). The DIT-2, a psychological tool that has been validated in assessing moral reasoning in >30,000 subjects, was administered to orthopaedic surgery residency candidates on a voluntary basis during their interview day. Data were collected annually from four applicant classes (2009 to 2012) at one institution. Each candidate was interviewed by an orthopaedic faculty team and was ranked comparatively with the other interviewing applicants. The five-part aggregate interview method for ranking applicants for the match list included a focused interview station presenting ethical dilemmas as one part of determining rank order. One hundred and twenty-four fourth-year medical students interviewing for orthopaedic surgery residency were assessed with the DIT-2. The results from the DIT-2 produced a postconventional score, which correlates with various levels of moral development. Each applicant's postconventional score was then compared with the patient's overall rank order. Applicants had highly variable moral reasoning skills, with no relationship to the final rank list. Despite a wide range of DIT-2 scores, the interview process did not differentiate applicants based on moral reasoning skills. It remains unclear whether the DIT-2 could (or should) be used as an additional data point to help stratify orthopaedic residency applicants and to predict their performance. | 25,187,595 | [
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Transgenerational impaired male fertility with an Igf2 epigenetic defect in the rat are induced by the endocrine disruptor p,p'-DDE. | What are the epigenetic mechanisms underlying the transgenerational effect of p,p'-DDE on male fertility? Impaired male fertility with an Igf2 epigenetic defect is transgenerationally inherited upon exposure of p,p'-DDE. p,p'-Dichlorodiphenoxydichloroethylene (p,p'-DDE) is one of the primary metabolite products of the ancestral organochlorine pesticide dichlorodiphenoxytrichloroethane. As it is a known anti-androgen endocrine disruptor, it could cause harmful effects on the male reproductive system. Pregnant rats (F0) were administered with p,p'-DDE or corn oil at the critical time of testis development, i.e. from gestation days 8 to 15. Male and female rats of the F1 generation were mated with each other to produce F2 progeny. To reveal whether the transgenerational phenotype is produced by the maternal or paternal line, F3 progeny were generated by intercrossing control (C) and treated (DDE) males and females of the F2 generation according to the following groups: (i) C♂-C♀, (ii) DDE♂-DDE♀, (iii) DDE♂-C♀ and (iv) C♂-DDE♀. Mature sperm and testes were collected from male offspring of the F1-F3 generations for the examination of male fertility parameters, i.e. sperm count and motility, testis histology and apoptosis. Expression of the imprinted genes, H19 and Igf2, was detected by real-time PCR. Igf2 DMR2 methylation was analyzed by bisulfite genomic sequencing. Upon exposure of p,p'-DDE, the male F1 generation showed impaired male fertility and altered imprinted gene expression caused by Igf2 DMR2 hypomethylation. These defects were transferred to the F3 generation through the male germline. This study has examined the effect of p,p'-DDE only on the sperm number and motility and the possible mechanism of Igf2 DMR2 methylation in vivo and thus has some limitations. Further investigation is necessary to focus on the epigenetic effects of p,p'-DDE at the genome level and to include a more detailed semen quality analysis including sperm morphology assessment. Impaired male fertility with epigenetic alterations is transgenerationally inherited after environmental exposure of p,p'-DDE, posing significant implications in the etiology of male infertility. The present research was supported by National Natural Science Fund for Young Scholar (81102161), the Natural Science Fund of Zhejiang Province (LY14H260004) and funding from the Health Department of Zhejiang Province (201475777). No competing interests are declared. | 25,187,598 | [
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Combination of contrast-enhanced wall motion analysis and myocardial deformation imaging during dobutamine stress echocardiography. | The combination of deformation analysis with conventional wall motion scoring (WMS) has been shown to increase the diagnostic sensitivity of dobutamine stress echocardiography (DSE). The feasibility and diagnostic power of WMS is largely improved by contrast agents; however, they are not used in combination with deformation analysis, as contrast agents are generally considered to render strain measurement unfeasible. To assess the feasibility of tissue velocity (TVI)- and 2D speckle tracking (ST)-based strain analysis during contrast-enhanced DSE; and to show whether there is an incremental value in combining deformation analysis with contrast-enhanced WMS. DS echocardiograms containing native, tissue Doppler, and contrast-enhanced loops of 60 patients were analysed retrospectively. The feasibility of WMS, TVI-, and ST-strain measurement was determined in 40 patients according to pre-defined criteria. The diagnostic ability of a combined protocol integrating data from contrast-WMS and TVI-strain measurement was then compared with contrast-WMS alone in all 60 patients, using coronary angiograms as a gold standard. Both TVI- and ST-based strain analysis were feasible during contrast-DSE (feasibility at peak stress: 87 and 75%). At the patient level, the diagnostic accuracy of the combined method did not prove superior to contrast-WMS (82 vs. 78%); a trend towards improved sensitivity and specificity for detecting coronary artery disease in the right coronary artery circulation (sensitivity: 85 vs. 77%, P = NS; specificity: 96 vs. 94%) was, however, observed. Both TVI- and ST-based myocardial deformation analysis are feasible during contrast-enhanced DSE, however, our results fail to demonstrate a clear diagnostic benefit of additional strain analysis over expert WMS alone. | 25,187,604 | [
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Canine blastomycosis in Wisconsin: a survey of small-animal veterinary practices. | The disease burden and impact of canine blastomycosis in Wisconsin is uncertain. We surveyed small-animal veterinary practices to obtain estimates of disease incidence, determine patient outcomes, and investigate variation in diagnostic and treatment strategies used by veterinarians. Veterinarians representing small-animal practices in Wisconsin were contacted by mail with the option to complete a paper or online questionnaire. Questionnaires were returned from 68 of 443 veterinary practices (15%) that estimated diagnosing 239 cases of canine blastomycosis annually, with an overall mortality of 36%. Annual incidence rates of canine blastomycosis were calculated for 43 individual veterinary clinics and differed significantly between clinics in endemic and nonendemic counties (P = 0.01), with the mean in endemic counties being 204/100,000/yr and nonendemic counties being 72/100,000/yr. Veterinarians reported an increase in canine blastomycosis cases from April through August. A wide variety of methods were used for diagnosis, ranging from clinical signs alone to antigen testing and "in-house" cytology. Of note, fungal culture was used rarely for diagnosis. In addition, veterinarians at these 68 clinics estimated diagnosing 36 cases of feline blastomycosis annually. The incidence of canine blastomycosis is high but quite variable among veterinary practices in Wisconsin. Diagnosis is based frequently on clinical signs exclusively due, in part, to the perceived high cost of laboratory tests. Similarly, the mortality associated with blastomycosis is likely negatively impacted because some dog owners defer therapy due to the cost of antifungal drugs. | 25,187,628 | [
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Hepatitis E virus of subtype 3i in chronically infected kidney transplant recipients in southeastern France. | Hepatitis E virus (HEV) is a leading cause of waterborne acute hepatitis in developing countries. In Europe, HEV causes a zoonotic disease and is hyperendemic in southern France. Four HEV genotypes (1 to 4) have been defined, and the most used classification divides them into 24 subtypes. Autochthonous European HEV strains belong in majority to genotype 3. Subtypes 3c, 3f, and 3e are representative of the HEV diversity in France. HEV causes chronic hepatitis in solid-organ transplant recipients in Europe, and viral characteristics associated with chronicity are poorly documented. We sequenced 343-nucleotide-long HEV genomic fragments from the serum of eight chronically infected kidney transplant recipients and a near-full-length genome in one case. We identified in four patients (50%) HEV of subtype 3i, not described previously in France. If shorter genomic fragments were used in phylogenetic analyses, these HEV sequences were clustered with open reading frame 2 (ORF2) fragments labeled as subtype 3c. At least five of the eight HEV 3i sequences recovered from humans in our phylogenetic analyses were from chronically infected kidney transplant recipients. These data show that the description of the prevalence and geographical distribution of HEV subtypes may be partially inaccurate and that criteria for classification as 3i and 3c should be clarified. Extended molecular virology analyses are required to improve knowledge of HEV epidemiology and determinants of chronic HEV infection. | 25,187,634 | [
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Characterization and multicentric validation of a common standard for Toxoplasma gondii detection using nucleic acid amplification assays. | The molecular diagnosis of toxoplasmosis essentially relies upon laboratory-developed methods and suffers from lack of standardization, hence the large diversity of performances between laboratories. Moreover, quantifications of parasitic loads differ among centers, a fact which prevents the possible prediction of the severity of this disease as a function of parasitic loads. The objectives of this multicentric study performed in eight proficient laboratories of the Molecular Biology Pole of the French National Reference Center for Toxoplasmosis (NRC-T) were (i) to assess the suitability of a lyophilized preparation of Toxoplasma gondii as a common standard for use in this PCR-based molecular diagnosis and (ii) to make this standard available to the community. High-quality written procedures were used for the production and qualification of this standard. Three independent batches of this standard, containing concentrations ranging from 10(4) to 0.01 T. gondii genome equivalents per PCR, were first assessed: the linear dynamic range was ≥ 6 log, the intra-assay coefficients of variation (CV) from a sample containing 10 T. gondii organisms per PCR were 0.3% to 0.42%, and the interassay CV over a 2-week period was 0.76% to 1.47%. A further assessment in eight diagnostic centers showed that the standard is stable, robust, and reliable. These lyophilized standards can easily be produced at a larger scale when needed and can be made widely available at the national level. To our knowledge, this is the first quality control assessment of a common standard which is usable both for self-evaluation in laboratories and for accurate quantification of parasitic loads in T. gondii prenatal infections. | 25,187,637 | [
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The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases. | The Norwegian nationwide MCTD cohort was established to obtain unbiased data on key disease issues, and thereby reappraise the concept of MCTD. In the current study, the aims were to obtain detailed HLA profile data on the large Norwegian MCTD cohort and compare these with the HLA profiles of ethnically matched healthy controls and related CTD controls. HLA profiles, determined by sequence-based typing of HLA-B* and DRB1*, were compared between four control groups of Norwegian ancestry, SLE (n = 96), SSc (n = 95), PM/DM (n = 84), healthy individuals (n = 282), the complete MCTD cohort (n = 155) and MCTD subsets defined by key clinical parameters. HLA-B*08 [odds ratio (OR) 2.05, P = 1.31 × 10(-4)) and DRB1*04:01 (OR 2.82, P = 3.64 × 10(-8)) were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE and PM/DM were B*08 and DRB1*03:01. SSc risk was associated with DRB1*08:01. Analyses of MCTD subsets identified B*18 [OR 3.32 (95% CI 1.38, 8.01)] and DRB1*03:01 [OR 1.83 (95% CI 1.03, 3.25)] as independent risk factors for lung fibrosis. Novel HLA alleles associated with MCTD and disease subsets were identified and DRB1*04:01 was confirmed as a major risk allele. Altogether, the data reinforce the notion of MCTD as a disease entity distinct from SLE, SSc and PM/DM. | 25,187,641 | [
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Impact on short-term glycaemic control of initiating diabetes care versus leaving diabetes untreated among individuals with newly screening-detected diabetes in Japan. | The impact of early initiation of diabetes care soon after the identification of hyperglycaemia rather than leaving diabetes untreated on changes in glycaemic control has not been fully clarified. We aimed to quantify the effect of initiating and continuing diabetes care compared with not starting management of diabetes on short-term changes in glycaemic control among the Japanese with newly screening-detected diabetes. We retrospectively reviewed data from a nationwide claims database to assess histories of physician-diagnosed diabetes or hyperglycaemia, as well as the use of antidiabetic agents, blood testing for hyperglycaemia or dietary advice among individuals without a history of diabetes care. Changes in glycated haemoglobin (HbA1c) concentrations were evaluated using baseline data and data from a health examination during the following year. Among 1393 individuals with newly screening-detected diabetes, 62% (n=864) did not initiate diabetes management during the follow-up period; 49.2% (n=425) of the untreated group had poor glycaemic control (HbA1c ≥7%) at the baseline examination. Only 38% (n=529) began diabetes management in medical settings. Individuals who remained untreated had a 1.87 (95% CI 1.38 to 2.52) or 1.63 (1.10 to 2.41) times higher risk of absolute increases in HbA1c ≥0.5% or ≥1%, respectively, compared with the treated patients, a difference that was significant. Making more frequent clinic visits especially after the first visit was dose-dependently associated with improved HbA1c levels compared with no diabetes management. In comparison with a lack of management of diabetes, immediately initiating and continuing diabetes care after identification of hyperglycaemia in a screening setting would contribute to clinically meaningful, improved glycaemic control in the Japanese. | 25,187,645 | [
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Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin. | A long-standing issue in the field of signal transduction is to understand the cross-talk between receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major and distinct signaling hubs that control eukaryotic cell behavior. Although stimulation of many RTKs leads to activation of trimeric G proteins, the molecular mechanisms behind this phenomenon remain elusive. We discovered a unifying mechanism that allows GIV/Girdin, a bona fide metastasis-related protein and a guanine-nucleotide exchange factor (GEF) for Gαi, to serve as a direct platform for multiple RTKs to activate Gαi proteins. Using a combination of homology modeling, protein-protein interaction, and kinase assays, we demonstrate that a stretch of ∼110 amino acids within GIV C-terminus displays structural plasticity that allows folding into a SH2-like domain in the presence of phosphotyrosine ligands. Using protein-protein interaction assays, we demonstrated that both SH2 and GEF domains of GIV are required for the formation of a ligand-activated ternary complex between GIV, Gαi, and growth factor receptors and for activation of Gαi after growth factor stimulation. Expression of a SH2-deficient GIV mutant (Arg 1745→Leu) that cannot bind RTKs impaired all previously demonstrated functions of GIV-Akt enhancement, actin remodeling, and cell migration. The mechanistic and structural insights gained here shed light on the long-standing questions surrounding RTK/G protein cross-talk, set a novel paradigm, and characterize a unique pharmacological target for uncoupling GIV-dependent signaling downstream of multiple oncogenic RTKs. | 25,187,647 | [
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Short-term n-3 fatty acid supplementation but not aspirin increases plasma proresolving mediators of inflammation. | Resolution of inflammation is an active process involving specialized proresolving mediators (SPM) formed from the n-3 fatty acids. This study examined the effect of n-3 fatty acid supplementation and aspirin on plasma SPMs in healthy humans. Healthy volunteers (n = 21) were supplemented with n-3 fatty acids (2.4g/day) for 7 days with random assignment to take aspirin (300 mg/day) or placebo from day 5 to day 7. Blood was collected at baseline (day 0), day 5, and day 7. Plasma 18R/S-HEPE, E-series resolvins, 17R/S-HDHA, D-series resolvins, 14R/S-HDHA, and MaR-1 were measured by LC/MS/MS. At baseline concentrations of E- and D- series resolvins and the upstream precursors 18R/S-HEPE, 17R/S-HDHA ranged from 0.1nM to 0.2nM. 14R/S-HDHA was 3-fold higher than the other SPMs at baseline but MaR-1 was below the limit of detection. Supplementation with n-3 fatty acids significantly increased RvE1, 18R/S-HEPE, 17R/S-HDHA, and 14R/S-HDHA but not other SPMs. The addition of aspirin after 5 days of n-3 fatty acids did not affect concentrations of any SPM. N-3 fatty acid supplementation for 5 days results in concentrations of SPMs that are biologically active in healthy humans. Aspirin administered after n-3 fatty acids did not offer any additional benefit in elevating the levels of SPMs. | 25,187,667 | [
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From early markers to neuro-developmental mechanisms of autism. | A fast growing field, the study of infants at risk because of having an older sibling with autism (i.e. infant sibs) aims to identify the earliest signs of this disorder, which would allow for earlier diagnosis and intervention. More importantly, we argue, these studies offer the opportunity to validate existing neuro-developmental models of autism against experimental evidence. Although autism is mainly seen as a disorder of social interaction and communication, emerging early markers do not exclusively reflect impairments of the "social brain". Evidence for atypical development of sensory and attentional systems highlight the need to move away from localized deficits to models suggesting brain-wide involvement in autism pathology. We discuss the implications infant sibs findings have for future work into the biology of autism and the development of interventions. | 25,187,673 | [
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An open-label, one-year, noncomparative study to evaluate the safety and tolerability of intravitreal pegaptanib sodium in patients with diabetic macular edema. | The purpose of this study was to evaluate the safety and tolerability of pegaptanib in patients with diabetic macular edema. An open-label, multicenter, noncomparative, one-year study of approximately 500 patients was planned. Recruitment was terminated after enrollment of 46 patients. Enrolled patients were fully informed and reconsented; 12 patients elected to complete the study. Patients received intravitreal injections of pegaptanib 0.3 mg once every 6 weeks or less frequently, as determined by the investigator. Clinical benefit was evaluated after the patient received two or more injections. Ocular and nonocular adverse events were closely monitored throughout the study. Compared with baseline, mean best-corrected visual acuity increased by week 6. Ten patients reported ocular-related adverse events, none of which were severe, and eight patients reported nonocular adverse events, two of which were severe but unrelated to study treatment. Three serious adverse events, unrelated to study treatment, were reported. In this limited set of patients with diabetic macular edema, pegaptanib appeared to be well tolerated with evidence of efficacy. | 25,187,694 | [
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High infiltration of tumor-associated macrophages in triple-negative breast cancer is associated with a higher risk of distant metastasis. | Triple-negative breast cancer (TNBC) is associated with poor prognosis and high probability of distant metastases. Tumor microenvironments play a pivotal role in tumor metastasis. Tumor-associated macrophages (TAMs) are one of the main cell components, and they are correlated with increasing metastatic risk. The aim of this study is to analyze the prognostic significance of the infiltration of TAMs in patients with TNBC. Immunohistochemical staining for cluster of differentiation (CD)68 (a marker for macrophages) was performed on tissue microarrays of operable breast cancer among 287 patients with TNBC, and the number of infiltrating TAMs was correlated with clinicopathological parameters. We found that TNBC with a large number of infiltrating TAMs had a significantly higher risk of distant metastasis, as well as lower rates of disease-free survival and overall survival than those with a smaller number of infiltrating TAMs. Multivariate analysis indicated that the number of infiltrating TAMs was a significant independent prognostic factor of disease-free survival (P=0.001) in all patients. Our results suggested that high infiltrating TAMs are a significantly unfavorable prognostic factor for patients with TNBC, and they could become a potentially useful prognostic marker for TNBC. | 25,187,727 | [
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B-type (brain) natriuretic peptide and pruritus in hemodialysis patients. | While pruritus is a common complication in hemodialysis patients, the pathophysiological mechanisms remain obscure. Recently, B-type (brain) natriuretic peptide (BNP) has been defined as an itch-selective neuropeptide in pruriceptive neurons in mice, and higher serum levels of BNP are frequently observed in hemodialysis patients. The objective of the present study was to evaluate the role of serum BNP in pruritus in patients undergoing hemodialysis. The current cross-sectional study was performed on 43 patients undergoing maintenance hemodialysis. A visual analog scale (VAS) measuring the general severity of pruritus (values from 0 to 10, with higher values indicating more severe pruritus) in daytime and at night was self-reported by patients. Each patient's background and laboratory tests, including serum BNP in the post-hemodialysis period, were collected. The correlation between VAS and clinical parameters was evaluated. Both daytime and nighttime VAS scores in diabetic patients were significantly less than those in nondiabetic patients. Multiple regression analysis revealed that pruritus in daytime was worsened by serum BNP (β=2.0, t=2.4, P=0.03), calcium (β=4.4, t=5.2, P<0.0001), and β2-microglobulin (β=2.0, t=3.0, P=0.007), while it was eased by age (β=-2.2, t=-3.2, P=0.0004). Nocturnal pruritus was severe in nondiabetic patients (β=1.7, t=3.8, P=0.0005) and weakened by the total iron binding capacity (β=-2.9, t=-3.1, P=0.004). It is suggested that a higher level of serum BNP increases the pruritus of hemodialysis patients in daytime and that diabetic patients are less sensitive to itch, especially at nighttime. | 25,187,733 | [
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A successful case of dose reduction in etizolam dependence using fine granules: a case report. | The prevalence of benzodiazepine consumption in Japan is one of the highest worldwide. Etizolam is the most abused drug of the benzodiazepine class. The treatment of benzodiazepine dependence is difficult. We report a case of successful dosage reduction in a 24-year-old female patient with etizolam dependence. She was diagnosed with etizolam dependence at the age of 22 years old. We proposed a benzodiazepine dependence treatment that involved replacing etizolam with a long-acting benzodiazepine class drug in conjunction with a long-term weaning plan. However, the patient refused the treatment and insisted that reducing the number of tablets would increase her anxiety. After providing a detailed explanation and receiving consent from the patient, a treatment regimen consisting of fine granules of etizolam mixed with lactose granules was begun with the aim of reducing the percentage of etizolam at a rate of 0.3 mg/week. The treatment of etizolam dependence in this patient was successful. This treatment strategy may be an effective option for patients who are difficult to treat with conventional methods, or who have anxiety regarding the reduction of the amount of the drug itself. | 25,187,742 | [
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Aborted sudden cardiac death and a mother with suspected metabolic myopathy. | Aborted sudden cardiac death (SCD) has not been reported as initial manifestation of cardiac involvement in metabolic myopathy (MM). A 20-year-old female with a previous history of three syncopes, hyperhidrosis, and recurrent tick bites experienced aborted SCD. Her mother presented with MM, and a history of pituitary adenoma, nephroptosis, arterial hypertension, depression, migraine, goiter, pancreatitis, osteoporosis, hyperhidrosis, multiple muscle ruptures, and hyperlipidemia. After a few days of disorientation and amnesia, the young female recovered completely. Clinical neurological examination was noticeable for partial ophthalmoparesis and mild hyperprolactinemia. She received an implantable cardioverter defibrillator, which did not discharge so far. Recurrent syncopes and aborted SCD may be the initial manifestation of MM with multiple organ involvement. The family history is important in cases with aborted SCD to guide the diagnostic work-up. Phenotypic heterogeneity between the family members may be an indicator of MM. | 25,187,745 | [
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Effect of vitamin d3 on untreated graves' disease with vitamin d deficiency. | Besides its classical role in calcium and bone homeostasis, vitamin D is considered a potent immunomodulator that can affect the pathogenesis of several autoimmune diseases. Our aim is to evaluate the effect of vitamin D correction to a patient with new onset Graves' disease (GD) with an underlying vitamin D deficiency. We describe the effect of vitamin D3 on untreated Graves' disease with vitamin D deficiency. A healthy Saudi woman in her 40s sought consultation with a three-month history of palpitation. She denied any history of heat intolerance, weight loss, menstrual irregularity or sweating. She has a history of chronic muscle aches and pains. Physical examination revealed a mild diffusely enlarged and non-tender thyroid gland with no bruit. She had no signs of Graves' ophthalmopathy. In laboratory examinations, the initial thyroid function test, which was done in an outside hospital, revealed a TSH, 0.01 mIU/L; FT4, 22.5 pmol/L and FT3, 6.5 pmol/L. Vitamin D 25-OH level was done in our hospital and showed a result of 26.0 nmol/L with a TSH, 0.013 mIU/L; FT4, 16.7 pmol/L; and FT3, 3.8 pmol/L. TSH receptor antibody was positive. TC-99 m thyroid scintigraphy demonstrated an enlarged thyroid gland with increased radiotracer trapping and heterogeneous distribution. The patient was given only oral cholecalciferol 4000 IU per day since November 2012 (prescribed by an outside hospital) then from May 2013 onwards she was given 50,000 IU per month. Follow-up laboratory exams revealed improved vitamin D levels as well as TSH and FT4. She eventually improved both clinically and biochemically with a satisfactory outcome. Vitamin D deficiency may exacerbate the onset and/or development of GD and correction of the deficiency may be able to reverse it. However, further prospective clinical studies will be needed to define the role of vitamin D treatment in GD. | 25,187,748 | [
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Beyond the time window of intravenous thrombolysis: standing by or by stenting? | Intravenous administration of tissue plasminogen activator within 4.5 h of symptom onset is presently the 'golden rule' for treating acute ischemic stroke. However, many patients miss the time window and others reject this treatment due to a long list of contraindications. Mechanical embolectomy has recently progressed as a potential alternative for treating patients beyond the time window for IV thrombolysis. In this paper, recent progress in mechanical embolectomy, angioplasty, and stenting in acute stroke is reviewed. Despite worries concerning the long-term clinical outcomes and increased risk of intracranial hemorrhage, favorable clinical outcomes may be achieved after mechanical embolectomy in carefully selected patients even 4.5 h after stroke onset. Potential steps should be prepared and attempted in these patients whose opportunity for recovery will elapse in a flash. | 25,187,761 | [
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Carotid plaque hemodynamics. | Internal carotid artery (ICA) plaques constitute one major source of retinal and cerebral brain embolism. Current guidelines recommend optimal treatment of cardiovascular risk factors and recanalization based on the degree of ICA stenosis. However, ICA plaque composition, motion, vascularization, and local hemodynamics have only received limited attention as potential and independent risk factors for plaque rupture. The European Carotid Surgery Trial (ECST) showed an increased risk of stroke recurrence even in moderate stenosis if the plaque surface was ulcerated in angiography. Further indicators of plaque instability and thus vulnerability were established by native or contrast-enhanced two-dimensional duplex ultrasound, CT, and MRI. Due to high soft tissue contrast, multi-contrast MRI seems to be ideally suited to identify plaque compositions that are prone to rupture, although data from large clinical trials proving the independent predictive value of plaque morphology are lacking. The role of cardiovascular risk factors for atherosclerosis of the common carotid artery is well established. Nevertheless, little is known concerning the impact of local hemodynamics on plaque development, progression, and rupture. Wall shear stress, the friction force acting on the endothelium of the vessel wall, was shown to be able to induce local atherosclerosis and vulnerable plaques in animal models. Plaque movement and deformation was limited to investigations using ultrasound in order to identify plaques at risk. Similarly, models to calculate tensile plaque stress seem to be able to identify peak mechanical stress acting on plaque surfaces that make such regions susceptible to rupture. In this review, current evidence regarding the correlation of plaque location, composition, and local hemodynamics at the carotid artery bifurcation will be presented. Moreover, the potential benefit of a future comprehensive and individual risk assessment will be discussed. | 25,187,766 | [
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Ischemia-reperfusion injury in stroke. | Despite ongoing advances in stroke imaging and treatment, ischemic and hemorrhagic stroke continue to debilitate patients with devastating outcomes at both the personal and societal levels. While the ultimate goal of therapy in ischemic stroke is geared towards restoration of blood flow, even when mitigation of initial tissue hypoxia is successful, exacerbation of tissue injury may occur in the form of cell death, or alternatively, hemorrhagic transformation of reperfused tissue. Animal models have extensively demonstrated the concept of reperfusion injury at the molecular and cellular levels, yet no study has quantified this effect in stroke patients. These preclinical models have also demonstrated the success of a wide array of neuroprotective strategies at lessening the deleterious effects of reperfusion injury. Serial multimodal imaging may provide a framework for developing therapies for reperfusion injury. | 25,187,778 | [
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Sanmiao formula inhibits chondrocyte apoptosis and cartilage matrix degradation in a rat model of osteoarthritis. | Sanmiao formula (SM) is a basic prescription for the treatment of gouty and rheumatoid arthritis that has been used in China over a long period of history. However, there is no evidence associating SM with the treatment of osteoarthritis (OA). In this study, a characterization of the anti-OA effect of SM was conducted using an <iin vivo</i rat model induced by anterior cruciate ligament transection and medial meniscus resection (ACLT plus MMx), together with <iin vitro</i studies using chondrocytes for further molecular characterization. Rats subjected to ACLT plus MMx were treated with SM at doses of 0.63, 1.25 and 2.5 g/kg per day for three or six weeks. SM treatment significantly inhibited the histopathological changes of articular cartilage damage and synovial inflammation in the rats following ACLT plus MMx. SM (2.5 g/kg) clearly inhibited chondrocyte apoptosis and prevented cartilage matrix degradation, which was indicated by the increased proteoglycan and collagen content, particularly with regard to type II collagen expression in articular cartilage. Furthermore, SM (2.5 g/kg) markedly inhibited the release of interleukin (IL)-1β, tumor necrosis factor-α and nitric oxide in serum, while simultaneously increasing the levels of bone morphogenetic protein-2 and transforming growth factor-β in the circulation. Notably, SM (2.5 g/kg) clearly attenuated the OA-augmented expression of matrix metalloproteinase (MMP)-13 and augmented the OA-reduced expression of tissue inhibitor of metalloproteinase (TIMP)-1 in the knee joints. In addition, SM significantly reduced the proportion of early and late apoptotic and sub-G<sub1</sub phase cells, and clearly decreased the expression of MMP-13 and increased that of TIMP-1 at the mRNA and protein levels in IL-1β-induced chondrocytes. These findings provide the first evidence that SM effectively treats OA by inhibiting chondrocyte apoptosis, cartilage matrix degradation and the inflammatory response. | 25,187,798 | [
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Combination therapy with low molecular weight heparin and Adriamycin results in decreased breast cancer cell metastasis in C<sub>3</sub>H mice. | The aim of this study was to investigate the effect of low molecular weight heparin (LMWH) against breast cancer cell invasion and metastasis in C<sub3</subH mice and the underlying mechanism. The C<sub3</subH mouse breast cancer model was established, and the mice were then randomly divided into four groups: normal saline group, LMWH group, Adriamycin positive control group and the combination group (LMWH combined with Adriamycin). Twelve days after inoculation, drug treatment was initiated. During the one-month period of drug administration, tumor growth curves were recorded. At the end of the treatment period, the mice were sacrificed and the solid tumor tissue and lung were removed. Hematoxylin and eosin (H&E) staining was used to observe the overall changes in tumor cell morphology and lung metastasis following the treatment. A terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay was used for detection of apoptosis in tumor cells, and immunohistochemical (IHC) analysis was used to determine the expression of vascular endothelial growth factor (VEGF). The tumor growth curves demonstrated that the overall growth of the combination group was less compared with that of the other three groups, indicating that LMWH inhibited the growth of the tumors. H&E staining showed that the area of tumor cell necrosis in the combination group was significantly greater compared with that in the other groups, and less metastasis was observed in the lung. The results from the TUNEL staining demonstrated that there was an increase in the number of blue-black apoptotic cells, and the expression of VEGF was significantly reduced in the combination group compared with the other three groups. Therefore, this indicates that LMWH, combined with Adriamycin significantly reduced the growth of breast cancer cells in C<sub3</subH mice. The results suggest that the mechanism may be associated with breast cancer cell apoptosis and inhibition of VEGF expression. | 25,187,827 | [
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Pre-ischemic exercise alleviates oxidative damage following ischemic stroke in rats. | Physical exercise has been proved to be neuroprotective in clinical trials and animal experiments. However, the exact mechanism underlying this neuroprotective effect remains unclear. The aim of the present study was to explore whether pre-ischemic treadmill training could act as a form of ischemic preconditioning in a rat following ischemic stroke by reducing oxidative damage. Fifty-four rats were randomly divided into three groups (n=18 per group): Sham surgery, middle cerebral artery occlusion (MCAO) without exercise and MCAO with exercise. Subsequent to treadmill training, ischemic stroke was induced by occluding the MCA for 1.5 h, followed by reperfusion. Six rats in each group were evaluated for neurological deficits and then sacrificed by decapitation to calculate the infarct volume. The remaining rats in each group were sacrificed to detect the level of superoxide dismutase (SOD) activity (n=6) and malondialdehyde (MDA) concentration (n=6). The results indicated that pre-ischemic exercise training reduced brain infarct volume and neurological deficits, increased SOD activity and decreased the concentration of MDA following ischemic stroke. In conclusion, treadmill exercise training prior to MCAO/reperfusion increased the antioxidant ability and decreased the oxidative damage in the brain subsequent to ischemic stroke. | 25,187,848 | [
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Association of adiponectin protein and ADIPOQ gene variants with lumbar disc degeneration. | Lumbar disc degeneration (LDD) is a widespread public health problem that may lead to disability and loss of productivity. Adiponectin is an adipokine secreted by adipose tissue and has been shown to be involved in cartilage homeostasis. In the present study, the association between the rs266729 (-11377C/G) and rs2241766 (45T/G) single nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ) and LDD was investigated. In addition, the correlation between the plasma adiponectin level and LDD was examined. A total of 289 subjects, 168 patients with LDD and 122 healthy individuals, were recruited in the study. All subjects were genotyped for rs266729 and rs2241766 SNPs using polymerase chain reaction-restriction fragment length polymorphism. Circulating levels of adiponectin protein were measured using the ELISA technique. A strong association was found between adiponectin level and LDD (P<0.01), where high levels of adiponectin were found in patients compared with healthy controls. The increase in adiponectin level was not affected by gender. However, no significant differences were found in the genotype distribution or allelic frequency of the two examined polymorphisms between patients with LDD and healthy controls (P>0.05). In conclusion, adiponectin appears to be elevated in patients with LDD. The rs266729 and rs2241766 SNPs in the ADIPOQ gene are not associated with LDD. | 25,187,851 | [
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Lumbar morphometry: a study of lumbar vertebrae from a pakistani population using computed tomography scans. | A cross-sectional study. To describe the characteristics of lumbar vertebrae of Pakistani patients reporting at a tertiary care hospital and compare with studies from other populations. Several studies have been conducted to determine morphometry of lumbar vertebrae. Most of the studies involve Caucasian populations, still data on other populations still sparse. This is the first study describing lumbar morphometry of a Pakistani population. An observational study was conducted based on a review of thin-cut (3 mm) computed topographic images of lumbar vertebrae. Two-hundred and twenty vertebrae from forty-nine patients were studied, and various dimensions were analyzed. Generally, the size of the vertebrae, vertebral canals and recesses were found to be greater in male patients. The difference was statistically significant for transverse and anteroposterior diameters of the vertebral bodies and sagittal diameter of pedicles on the left side (p<0.05). Comparison of populations revealed statistically significant differences in pedicle dimensions between Pakistani population and others. This study provides anatomical knowledge of the lumbar region in a sample population of Pakistan. There were significant differences in various dimensions of lumbar vertebrae between female and male patients. This would prove to be critical for performing a safe operation. | 25,187,858 | [
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An extremely giant lumbar schwannoma: new classification (kotil) and mini-open microsurgical resection. | Purely extradural giant lumbar schwannomas are rare lesions. Classification of these tumors is performed according to the sizes and spills and is named the modified Sridhar's classification. The management of these tumors has traditionally been performed by combined antero-posterior large or two-stage exposures. This combined exposure has many disadvantages. Recent reports have demonstrated the safety and efficacy of removal of these tumors using mini-open micro surgical resection for the schwannomas, but the safety and efficacy have not been established for extremely large giant tumors. We report a case of a giant L4 dumb-bell schwannoma successfully resected through a mini-open micro surgical resection. These neoplasms can be safely and effectively treated with mini-open techniques. Reduction in blood loss, hospitalization, and tissue disruption may be potential benefits of this approach. We discuss the technical details of this surgical approach along with the limitations and possible complications. In addition, this study is included in the current schwannoma (Kotil) classification. | 25,187,870 | [
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Accuracy of clinical tests in the diagnosis of anterior cruciate ligament injury: a systematic review. | Numerous clinical tests are used in the diagnosis of anterior cruciate ligament (ACL) injury but their accuracy is unclear. The purpose of this study is to evaluate the diagnostic accuracy of clinical tests for the diagnosis of ACL injury. Systematic review. The review protocol was registered through PROSPERO (CRD42012002069). Electronic databases (PubMed, MEDLINE, EMBASE, CINAHL) were searched up to 19th of June 2013 to identify diagnostic studies comparing the accuracy of clinical tests for ACL injury to an acceptable reference standard (arthroscopy, arthrotomy, or MRI). Risk of bias was appraised using the QUADAS-2 checklist. Index test accuracy was evaluated using a descriptive analysis of paired likelihood ratios and displayed as forest plots. A total of 285 full-text articles were assessed for eligibility, from which 14 studies were included in this review. Included studies were deemed to be clinically and statistically heterogeneous, so a meta-analysis was not performed. Nine clinical tests from the history (popping sound at time of injury, giving way, effusion, pain, ability to continue activity) and four from physical examination (anterior draw test, Lachman's test, prone Lachman's test and pivot shift test) were investigated for diagnostic accuracy. Inspection of positive and negative likelihood ratios indicated that none of the individual tests provide useful diagnostic information in a clinical setting. Most studies were at risk of bias and reported imprecise estimates of diagnostic accuracy. Despite being widely used and accepted in clinical practice, the results of individual history items or physical tests do not meaningfully change the probability of ACL injury. In contrast combinations of tests have higher diagnostic accuracy; however the most accurate combination of clinical tests remains an area for future research. Clinicians should be aware of the limitations associated with the use of clinical tests for diagnosis of ACL injury. | 25,187,877 | [
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The 24-h FEV1 time profile of olodaterol once daily via Respimat® and formoterol twice daily via Aerolizer® in patients with GOLD 2-4 COPD: results from two 6-week crossover studies. | These studies evaluated the 24-h forced expiratory volume in 1 sec (FEV1) profile of once-daily (QD) olodaterol compared to placebo and twice-daily (BID) formoterol in patients with moderate to very severe chronic obstructive pulmonary disease. In two replicate, randomized, double-blind, double-dummy, four-way crossover studies, patients received olodaterol 5 and 10 μg QD, formoterol 12 μg BID, or placebo for 6 weeks in addition to usual-care background maintenance therapy. Co-primary end points were FEV1 area under the curve from 0-12 h (AUC0-12) response (change from baseline) and FEV1 AUC from 12-24 h (AUC12-24) response after 6 weeks, with FEV1 AUC from 0-24 h response identified as a key secondary end point. Other secondary end points included FEV1 AUC from 0-3 h and trough FEV1 responses, as well as corresponding forced vital capacity responses. With both olodaterol doses, FEV1 increased to near-maximal 30 min post-morning dose, which was sustained over 24 h. FEV1 also increased within 30 min post-morning dose of formoterol and was sustained over 12 h; the second formoterol dose resulted in a further increase, sustained for an additional 12 h. FEV1 AUC0-12 and AUC12-24 responses with both QD olodaterol doses and BID formoterol were significantly greater than placebo at 6 weeks (P < .0001). Secondary end-point outcomes were consistent with those of the co-primary end points. These data, together with those from the wider phase III clinical program, provide evidence for the 24-h bronchodilator efficacy of olodaterol QD in this patient population. ClinicalTrials.gov; NCT00931385 and NCT00932646. | 25,187,881 | [
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Profile of ocular trauma in the Solomon Islands. | The objective of this study was to characterize the causes of ocular trauma and determine the risk factors for infection and vision loss following ocular trauma in the Solomon Islands. A prospective clinic-based study. A total of 507 patients with ocular trauma who were reviewed at the National Referral Hospital in Honiara or one of five provincial eye clinics were included. An interview-based questionnaire to determine the circumstances of ocular trauma, and an ocular examination to elicit the trauma sustained,infectious sequelae and the visual outcome. Visual acuity. Males were significantly more likely to have ocular trauma than females (P = 0.01). The major cause of ocular trauma in young boys and girls was being poked by a stick, followed by lime burns in young boys. For both genders, physical violence resulted in most injuries across all adult age groups. Microbial keratitis complicated 4.4% of ocular trauma. Monocular vision impairment (<6/18) occurred in 5.5% of participants and was more likely to occur if female (P = 0.02). Ocular trauma is a significant cause of visual morbidity in the Solomon Islands. The results from this prospective study provide a basis for planning blindness prevention programmes in the Western Pacific. | 25,187,927 | [
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Noninvasive assessment of endothelial function and vascular parameters in patients with familial and nonfamilial hypercholesterolemia. | Endothelial dysfunction is one of the markers of atherosclerosis. The aim of the study was to evaluate endothelial function by assessing flow-mediated dilation (FMD) and to measure the parameters of brachial arterial stiffness in patients with familial hypercholesterolemia (FH) and those with high low-density lipoprotein (LDL) cholesterol levels without FH mutations (nonfamilial hypercholesterolemia - non-FH). The study involved 60 patients (mean age, 41.9 ±7.7 y) without documented cardiovascular events and clinical symptoms of cardiovascular diseases: 21 patients with elevated plasma LDL cholesterol levels and genetically confirmed FH, 19 patients with elevated LDL cholesterol levels and without FH mutations, and 20 healthy controls. In each patient, ultrasound imaging was used to assess endothelium-dependent FMD and nitroglycerin-induced endothelium-independent dilation (EID) in the brachial artery. In addition, echo-tracking and photoplethysmography were used to assess the parameters of arterial stiffness. FMD was significantly lower in patients with FH (11.0% ±9.9% vs. 21.0% ±14.3%, P <0.01) and non-FH (14.2% ±10.1% vs. 21.0% ±14.3%, P <0.05) compared with controls. EID and arterial stiffness parameters were similar between the groups. Reduced FMD may suggest endothelial dysfunction. A lack of significant differences in arterial stiffness parameters may indicate that vascular remodeling is not advanced in patients with elevated LDL cholesterol levels. A lack of significant differences in FMD and arterial stiffness between patients with and without FH may indicate that FH mutation itself is not the main determinant of endothelial dysfunction and vascular remodeling in younger patients with hypercholesterolemia. | 25,187,945 | [
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Na+K+-ATPase activity and K+ channels differently contribute to vascular relaxation in male and female rats. | Gender associated differences in vascular reactivity regulation might contribute to the low incidence of cardiovascular disease in women. Cardiovascular protection is suggested to depend on female sex hormones' effects on endothelial function and vascular tone regulation. We tested the hypothesis that potassium (K+) channels and Na+K+-ATPase may be involved in the gender-based vascular reactivity differences. Aortic rings from female and male rats were used to examine the involvement of K+ channels and Na+K+-ATPase in vascular reactivity. Acetylcholine (ACh)-induced relaxation was analyzed in the presence of L-NAME (100 µM) and the following K+ channels blockers: tetraethylammonium (TEA, 2 mM), 4-aminopyridine (4-AP, 5 mM), iberiotoxin (IbTX, 30 nM), apamin (0.5 µM) and charybdotoxin (ChTX, 0.1 µM). The ACh-induced relaxation sensitivity was greater in the female group. After incubation with 4-AP the ACh-dependent relaxation was reduced in both groups. However, the dAUC was greater in males, suggesting that the voltage-dependent K+ channel (Kv) participates more in males. Inhibition of the three types of Ca2+-activated K+ channels induced a greater reduction in Rmax in females than in males. The functional activity of the Na+K+-ATPase was evaluated by KCl-induced relaxation after L-NAME and OUA incubation. OUA reduced K+-induced relaxation in female and male groups, however, it was greater in males, suggesting a greater Na+K+-ATPase functional activity. L-NAME reduced K+-induced relaxation only in the female group, suggesting that nitric oxide (NO) participates more in their functional Na+K+-ATPase activity. These results suggest that the K+ channels involved in the gender-based vascular relaxation differences are the large conductance Ca2+-activated K+ channels (BKCa) in females and Kv in males and in the K+-induced relaxation and the Na+K+-ATPase vascular functional activity is greater in males. | 25,187,951 | [
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Brain-targeted delivery of trans-activating transcriptor-conjugated magnetic PLGA/lipid nanoparticles. | Magnetic poly (D,L-lactide-co-glycolide) (PLGA)/lipid nanoparticles (MPLs) were fabricated from PLGA, L-α-phosphatidylethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-amino (polyethylene glycol) (DSPE-PEG-NH2), and magnetic nanoparticles (NPs), and then conjugated to trans-activating transcriptor (TAT) peptide. The TAT-MPLs were designed to target the brain by magnetic guidance and TAT conjugation. The drugs hesperidin (HES), naringin (NAR), and glutathione (GSH) were encapsulated in MPLs with drug loading capacity (>10%) and drug encapsulation efficiency (>90%). The therapeutic efficacy of the drug-loaded TAT-MPLs in bEnd.3 cells was compared with that of drug-loaded MPLs. The cells accumulated higher levels of TAT-MPLs than MPLs. In addition, the accumulation of QD-loaded fluorescein isothiocyanate (FITC)-labeled TAT-MPLs in bEnd.3 cells was dose and time dependent. Our results show that TAT-conjugated MPLs may function as an effective drug delivery system that crosses the blood brain barrier to the brain. | 25,187,980 | [
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An siRNA screen of membrane trafficking genes highlights pathways common to HIV-1 and M-PMV virus assembly and release. | The assembly and release of retroviruses from the host cells requires a coordinated series of interactions between viral structural proteins and cellular trafficking pathways. Although a number of cellular factors involved in retrovirus assembly have been identified, it is likely that retroviruses utilize additional trafficking factors to expedite their assembly and budding that have not yet been defined. We performed a screen using an siRNA library targeting host membrane trafficking genes in order to identify new host factors that contribute to retrovirus assembly or release. We utilized two retroviruses that follow very distinct assembly pathways, HIV-1 and Mason-Pfizer monkey virus (M-PMV) in order to identify host pathways that are generally applicable in retrovirus assembly versus those that are unique to HIV or M-PMV. Here we report the identification of 24 host proteins identified in the screen and subsequently validated in follow-up experiments as contributors to the assembly or release of both viruses. In addition to identifying a number of previously unsuspected individual trafficking factors, we noted multiple hits among proteins involved in modulation of the actin cytoskeleton, clathrin-mediated transport pathways, and phosphoinositide metabolism. Our study shows that distant genera of retroviruses share a number of common interaction strategies with host cell trafficking machinery, and identifies new cellular factors involved in the late stages of retroviral replication. | 25,187,981 | [
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Polarization holograms in a bifunctional amorphous polymer exhibiting equal values of photoinduced linear and circular birefringences. | Light-controlled molecular alignment is a flexible and useful strategy introducing novelty in the fields of mechanics, self-organized structuring, mass transport, optics, and photonics and addressing the development of smart optical devices. Azobenzene-containing polymers are well-known photocontrollable materials with large and reversible photoinduced optical anisotropies. The vectorial holography applied to these materials enables peculiar optical devices whose properties strongly depend on the relative values of the photoinduced birefringences. Here is reported a polarization holographic recording based on the interference of two waves with orthogonal linear polarization on a bifunctional amorphous polymer that, exceptionally, exhibits equal values of linear and circular birefringence. The peculiar photoresponse of the material coupled with the holographic technique demonstrates an optical device capable of decomposing the light into a set of orthogonally polarized linear components. The holographic structures are theoretically described by the Jones matrices method and experimentally investigated. | 25,187,982 | [
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Genetic diversity of Salmonella pathogenicity islands SPI-5 and SPI-6 in Salmonella Newport. | Salmonella enterica subspecies enterica serotype Newport is one of the common serotypes causing foodborne salmonellosis outbreaks in the United States. Salmonella Newport consists of three lineages exhibiting extensive genetic diversity. Due to the importance of Salmonella pathogenicity islands 5 and 6 (SPI-5 and SPI-6) in virulence of pathogenic Salmonella, the genetic diversity of these two SPIs may relate to different potentials of Salmonella Newport pathogenicity. Most Salmonella Newport strains from North America belong to Salmonella Newport lineages II and III. A total 28 Salmonella Newport strains of lineages II and III from diverse sources and geographic locations were analyzed, and 11 additional Salmonella genomes were used as outgroup in phylogenetic analyses. SPI-5 was identified in all Salmonella Newport strains and 146 single nucleotide polymorphisms (SNPs) were detected. Thirty-nine lineage-defining SNPs were identified, including 18 nonsynonymous SNPs. Two 40-kb genomic islands (SPI5-GI1 and SPI5-GI2) encoding bacteriophage genes were found between tRNA-ser and pipA. SPI5-GI1 was only present in Salmonella Newport multidrug-resistant strains of lineage II. SPI-6 was found in all strains but three Asian strains in Salmonella Newport lineage II, whereas the three Asian strains carried genomic island SPI6-GI1 at the same locus as SPI-6 in other Salmonella. SPI-6 exhibited 937 SNPs, and phylogenetic analysis demonstrated that clustering of Salmonella Newport isolates was a reflection of their geographic origins. The sequence diversity within SPI-5 and SPI-6 suggests possible recombination events and different virulence potentials of Salmonella Newport. The SNPs could be used as biomarkers during epidemiological investigations. | 25,188,010 | [
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Innovative care model for patients with complex muscle diseases. | Many neuromuscular disorders require complex multisystem management. This is especially true for the rapidly growing numbers of young adults surviving congenital and childhood onset conditions following improved multidisciplinary care and the routine use of home ventilation. Surveys from the United Kingdom and Netherlands indicate that neuromuscular disorder patients report their services to be at best 'average' and more often 'poor' in quality. Centralization of care to a small number of specialist centres to increase critical mass and thus improve the expertise of clinical teams has been recommended. A recent audit of unplanned hospital admissions for neuromuscular disorder patients has substantiated data from patient surveys. Patients often had no access to a neuromuscular specialist or had fragmented care; 37.5% of 359 unplanned neuromuscular disorder emergency admissions were identified as potentially avoidable. A Neuromuscular Complex Care Centre has recently opened in the United Kingdom to provide holistic patient-centred care in a purpose built adapted environment with high staff to patient ratio. Elective multisystem assessments will be co-ordinated into a 'one stop' admission, bringing the specialists to the patient. The centre will provide first point of contact with 24-h telephone access 7 days a week and will advise and support local hospitals on the management of acutely unwell patients. Regular multidisciplinary meetings of specialized consultants and therapists will improve communication and maximize outcomes. In the long term, we anticipate this high-quality development to be cost-effective in reducing the frequency of outpatient appointments and emergency/critical care admissions. | 25,188,015 | [
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Co-molten solvothermal method for synthesizing chalcopyrite CuFe(1-x)Cr(x)S₂ (x ≤ 0.4): high photocatalytic activity for the reduction of nitrate ions. | In literature, it is very difficult to obtain sulfides with Cr(3+) in tetrahedral coordination. Here, a thiourea-oxalic acid co-molten solvothermal method was applied to synthesize chalcopyrite CuFe(1-x)Cr(x)S2 (x ≤ 0.4) solid solutions. We propose that oxalic acid plays an important role in the crystallization of CuFe(1-x)Cr(x)S2 and can considerably restrain the formation of other undesirable impurities. The successful incorporation of Cr(3+) was confirmed by powder XRD, SEM and EDX mapping (2D elemental distribution). The UV-Vis reflectance spectra of CuFe(1-x)Cr(x)S2 suggest that the bandgap energies decrease from 0.80 to 0.61 eV along with an increase in the Cr(3+) concentration. All the CuFe(1-x)Cr(x)S2 (0 ≤ x ≤ 0.4) samples show considerably higher photocatalytic activities than P25 toward the reduction of nitrate ions in aqueous solution. We speculate that the thiourea-oxalic acid co-molten method may not only be effective to synthesize Fe(3+)-Cr(3+) sulfides, but can also be helpful to incorporate Cr(3+) to other sulfide systems with MS4 tetrahedra. | 25,188,017 | [
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Interdependency of subsurface carbon distribution and graphene-catalyst interaction. | The dynamics of the graphene-catalyst interaction during chemical vapor deposition are investigated using in situ, time- and depth-resolved X-ray photoelectron spectroscopy, and complementary grand canonical Monte Carlo simulations coupled to a tight-binding model. We thereby reveal the interdependency of the distribution of carbon close to the catalyst surface and the strength of the graphene-catalyst interaction. The strong interaction of epitaxial graphene with Ni(111) causes a depletion of dissolved carbon close to the catalyst surface, which prevents additional layer formation leading to a self-limiting graphene growth behavior for low exposure pressures (10(-6)-10(-3) mbar). A further hydrocarbon pressure increase (to ∼10(-1) mbar) leads to weakening of the graphene-Ni(111) interaction accompanied by additional graphene layer formation, mediated by an increased concentration of near-surface dissolved carbon. We show that growth of more weakly adhered, rotated graphene on Ni(111) is linked to an initially higher level of near-surface carbon compared to the case of epitaxial graphene growth. The key implications of these results for graphene growth control and their relevance to carbon nanotube growth are highlighted in the context of existing literature. | 25,188,018 | [
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Causes of death among adults in northern Ethiopia: evidence from verbal autopsy data in health and demographic surveillance system. | In countries where registration of vital events is lacking and the proportion of people who die at home without medical care is high, verbal autopsy is used to determine and estimate causes of death. We conducted 723 verbal autopsy interviews of adult (15 years of age and above) deaths from September 2009 to January 2013. Trained physicians interpreted the collected verbal autopsy data, and assigned causes of death according to the international classification of diseases (ICD-10). We did analysis of specific as well as broad causes of death (i.e. non-communicable diseases, communicable diseases and external causes of death) by sex and age using Stata version 11.1. We performed logistic regression to identify socio-demographic predictors using odds ratio with 95% confidence interval and a p-value of 0.05. Tuberculosis, cerebrovascular diseases and accidental falls were leading specific causes of death accounting for 15.9%, 7.3% and 3.9% of all deaths. Two hundred sixty three (36.4% [95% CI: 32.9, 39.9]), 252 (34.9% [95% CI: 31.4, 38.4]) and 89 (12.3% [95% CI: 10.1, 14.9]) deaths were due to non-communicable, communicable diseases, and external causes, respectively. Females had 1.5 times (AOR = 1.53 [95% CI: 1.10, 2.15]) higher odds of dying due to communicable diseases than males. The odds of dying due to external causes were 4 times higher among 15-49 years of age (AOR = 4.02 [95% CI: 2.25, 7.18]) compared to older ages. Males also had 1.7 times (AOR = 1.70 [95% CI: 1.01, 2.85]) higher odds of dying due to external causes than females. Tuberculosis, cerebrovascular diseases and accidental falls were the top three causes of death among adults. Efforts to prevent tuberculosis and cerebrovascular diseases related deaths should be improved and safety efforts to reduce accidents should also receive attention. | 25,188,025 | [
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"New drug" designations for new therapeutic entities: new active substance, new chemical entity, new biological entity, new molecular entity. | This Perspective addresses ambiguities in designations of "new drugs" intended as new therapeutic entities (NTEs). Designation of an NTE as a new drug is significant, as it may confer regulatory exclusivity, an important incentive for development of novel compounds. Such designations differ between jurisdictions according to their drug laws and drug regulations. Chemical, biological, and innovative drugs are addressed in turn. The terms new chemical entity (NCE), new molecular entity (NME), new active substance (NAS), and new biological entity (NBE) as applied in worldwide jurisdictions are clarified. Differences between them are explored through case studies showing why new drugs have different periods of exclusivity in different jurisdictions or none at all. Finally, this Perspective recommends that in future, for the purpose of new drug compilations, NME is used for a new chemical drug, NBE for a new biological drug, and the combined designation NTE should refer to either an NME or an NBE. | 25,188,028 | [
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American Thyroid Association statement on preoperative imaging for thyroid cancer surgery. | The success of surgery for thyroid cancer hinges on thorough and accurate preoperative imaging, which enables complete clearance of the primary tumor and affected lymph node compartments. This working group was charged by the Surgical Affairs Committee of the American Thyroid Association to examine the available literature and to review the most appropriate imaging studies for the planning of initial and revision surgery for thyroid cancer. Ultrasound remains the most important imaging modality in the evaluation of thyroid cancer, and should be used routinely to assess both the primary tumor and all associated cervical lymph node basins preoperatively. Positive lymph nodes may be distinguished from normal nodes based upon size, shape, echogenicity, hypervascularity, loss of hilar architecture, and the presence of calcifications. Ultrasound-guided fine-needle aspiration of suspicious lymph nodes may be useful in guiding the extent of surgery. Cross-sectional imaging (computed tomography with contrast or magnetic resonance imaging) may be considered in select circumstances to better characterize tumor invasion and bulky, inferiorly located, or posteriorly located lymph nodes, or when ultrasound expertise is not available. The above recommendations are applicable to both initial and revision surgery. Functional imaging with positron emission tomography (PET) or PET-CT may be helpful in cases of recurrent cancer with positive tumor markers and negative anatomic imaging. | 25,188,202 | [
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The interaction between aggrecan gene VNTR polymorphism and obesity in predicting incident symptomatic lumbar disc herniation. | An association between aggrecan gene variable number of tandem repeats polymorphism (VNTR) and symptomatic lumbar disc herniation (LDH) has been reported in Chinese Han of Northern China, and obesity had previously been suspected of causing severe LDH. However, the interaction between aggrecan VNTR and obesity in symptomatic LDH has not been well studied. To examine the interaction between aggrecan VNTR and obesity in the susceptibility of symptomatic LDH, 259 participants participated in this study and donated a blood sample. The disease group comprised 61 patients already diagnosed with symptomatic LDH. The control group consisted of 198 healthy blood donors without symptoms of LDH who were not diagnosed with LDH. The aggrecan gene VNTR region was analyzed using polymerase chain reaction. The data indicated that between the two groups, participants carrying one or two alleles ≤25 repeats who were non-obese people showed a 1.057-fold increase in risk for symptomatic LDH (p = 0.895, changing the number of repeat alleles to <25 repeats alone did not demonstrably change the risk of LDH), and participants carrying two alleles >25 repeats who were obese people showed an 1.061-fold higher risk (p = 0.885, adding obesity to the mix alone did not demonstrably increase the risk of LDH), while participants carrying one or two alleles ≤25 repeats who were obese people showed a 4.667-fold increase in risk for symptomatic LDH (p = 0.0003, adding obesity plus changing the repeat allele number significantly increased the risk of LDH by 4.667). Overall, the findings suggest an underlying interaction between aggrecan VNTR and obesity in symptomatic LDH. | 25,188,217 | [
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Phase transitions in the multi-cellular regulatory behavior of pancreatic islet excitability. | The pancreatic islets of Langerhans are multicellular micro-organs integral to maintaining glucose homeostasis through secretion of the hormone insulin. β-cells within the islet exist as a highly coupled electrical network which coordinates electrical activity and insulin release at high glucose, but leads to global suppression at basal glucose. Despite its importance, how network dynamics generate this emergent binary on/off behavior remains to be elucidated. Previous work has suggested that a small threshold of quiescent cells is able to suppress the entire network. By modeling the islet as a Boolean network, we predicted a phase-transition between globally active and inactive states would emerge near this threshold number of cells, indicative of critical behavior. This was tested using islets with an inducible-expression mutation which renders defined numbers of cells electrically inactive, together with pharmacological modulation of electrical activity. This was combined with real-time imaging of intracellular free-calcium activity [Ca2+]i and measurement of physiological parameters in mice. As the number of inexcitable cells was increased beyond ∼15%, a phase-transition in islet activity occurred, switching from globally active wild-type behavior to global quiescence. This phase-transition was also seen in insulin secretion and blood glucose, indicating physiological impact. This behavior was reproduced in a multicellular dynamical model suggesting critical behavior in the islet may obey general properties of coupled heterogeneous networks. This study represents the first detailed explanation for how the islet facilitates inhibitory activity in spite of a heterogeneous cell population, as well as the role this plays in diabetes and its reversal. We further explain how islets utilize this critical behavior to leverage cellular heterogeneity and coordinate a robust insulin response with high dynamic range. These findings also give new insight into emergent multicellular dynamics in general which are applicable to many coupled physiological systems, specifically where inhibitory dynamics result from coupled networks. | 25,188,228 | [
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A predictive model combining fecal calgranulin B and fecal occult blood tests can improve the diagnosis of colorectal cancer. | Current fecal screening tools for colorectal cancer (CRC), such as fecal occult blood tests (FOBT), are limited by their low sensitivity. Calgranulin B (CALB) was previously reported as a candidate fecal marker for CRC. This study investigated whether a combination of the FOBT and fecal CALB has increased sensitivity and specificity for a diagnosis of CRC. Patients with CRC (n = 175), and healthy individuals (controls; n = 151) were enrolled into the development (81 cases and 51 controls) and validation (94 cases and 100 controls) sets. Stool samples were collected before bowel preparation. CALB levels were determined by western blotting. FOBT and fecal CALB results were used to develop a predictive model based on logistic regression analysis. The benefit of adding CALB to a model with only FOBT was evaluated as an increased area under the receiver operating curve (AUC), partial AUC, and reclassification improvement (RI) in cases and controls, and net reclassification improvement (NRI). Mean CALB level was significantly higher in CRC patients than in controls (P<0.001). CALB was not associated with tumor stage or cancer site, but positivity on the FOBT was significantly higher in advanced than in earlier tumor stages. At a specificity of 90%, the cross-validated AUC and sensitivity were 89.81% and 82.72%, respectively, in the development set, and 92.74% and 79.79%, respectively, in the validation set. The incremental benefit of adding CALB to the model, as shown by the increase in AUC, had a p-value of 0.0499. RI in cases and controls and NRI all revealed that adding CALB significantly improved the prediction model. A predictive model using a combination of FOBT and CALB may have greater sensitivity and specificity and AUC for predicting CRC than models using a single marker. | 25,188,229 | [
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Evolution of the F0F1 ATP synthase complex in light of the patchy distribution of different bioenergetic pathways across prokaryotes. | Bacteria and archaea are characterized by an amazing metabolic diversity, which allows them to persist in diverse and often extreme habitats. Apart from oxygenic photosynthesis and oxidative phosphorylation, well-studied processes from chloroplasts and mitochondria of plants and animals, prokaryotes utilize various chemo- or lithotrophic modes, such as anoxygenic photosynthesis, iron oxidation and reduction, sulfate reduction, and methanogenesis. Most bioenergetic pathways have a similar general structure, with an electron transport chain composed of protein complexes acting as electron donors and acceptors, as well as a central cytochrome complex, mobile electron carriers, and an ATP synthase. While each pathway has been studied in considerable detail in isolation, not much is known about their relative evolutionary relationships. Wanting to address how this metabolic diversity evolved, we mapped the distribution of nine bioenergetic modes on a phylogenetic tree based on 16S rRNA sequences from 272 species representing the full diversity of prokaryotic lineages. This highlights the patchy distribution of many pathways across different lineages, and suggests either up to 26 independent origins or 17 horizontal gene transfer events. Next, we used comparative genomics and phylogenetic analysis of all subunits of the F0F1 ATP synthase, common to most bacterial lineages regardless of their bioenergetic mode. Our results indicate an ancient origin of this protein complex, and no clustering based on bioenergetic mode, which suggests that no special modifications are needed for the ATP synthase to work with different electron transport chains. Moreover, examination of the ATP synthase genetic locus indicates various gene rearrangements in the different bacterial lineages, ancient duplications of atpI and of the beta subunit of the F0 subcomplex, as well as more recent stochastic lineage-specific and species-specific duplications of all subunits. We discuss the implications of the overall pattern of conservation and flexibility of the F0F1 ATP synthase genetic locus. | 25,188,293 | [
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Direct costs of dengue hospitalization in Brazil: public and private health care systems and use of WHO guidelines. | Dengue, an arboviral disease, is a public health problem in tropical and subtropical regions worldwide. In Brazil, epidemics have become increasingly important, with increases in the number of hospitalizations and the costs associated with the disease. This study aimed to describe the direct costs of hospitalized dengue cases, the financial impact of admissions and the use of blood products where current protocols for disease management were not followed. To analyze the direct costs of dengue illness and platelet transfusion in Brazil based on the World Health Organization (WHO) guidelines, we conducted a retrospective cross-sectional census study on hospitalized dengue patients in the public and private Brazilian health systems in Dourados City, Mato Grosso do Sul State, Brazil. The analysis involved cases that occurred from January through December during the 2010 outbreak. In total, we examined 8,226 mandatorily reported suspected dengue cases involving 507 hospitalized patients. The final sample comprised 288 laboratory-confirmed dengue patients, who accounted for 56.8% of all hospitalized cases. The overall cost of the hospitalized dengue cases was US $210,084.30, in 2010, which corresponded to 2.5% of the gross domestic product per capita in Dourados that year. In 35.2% of cases, blood products were used in patients who did not meet the blood transfusion criteria. The overall median hospitalization cost was higher (p = 0.002) in the group that received blood products (US $1,622.40) compared with the group that did not receive blood products (US $550.20). The comparative costs between the public and the private health systems show that both the hospitalization of and platelet transfusion in patients who do not meet the WHO and Brazilian dengue guidelines increase the direct costs, but not the quality, of health care. | 25,188,295 | [
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48-week efficacy and safety of dolutegravir relative to commonly used third agents in treatment-naive HIV-1-infected patients: a systematic review and network meta-analysis. | A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1-infected patients. A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed. Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions. Three clinical trials of DTG have demonstrated comparable or superior efficacy and safety to DRV, RAL, and EFV in HIV-1-infected treatment-naive patients. This network meta-analysis suggests DTG is also favorable or comparable to other commonly used third agents (ATV/r, LPV/r, RPV, and EVG/c). | 25,188,312 | [
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Application of optimal designs to item calibration. | In computerized adaptive testing (CAT), examinees are presented with various sets of items chosen from a precalibrated item pool. Consequently, the attrition speed of the items is extremely fast, and replenishing the item pool is essential. Therefore, item calibration has become a crucial concern in maintaining item banks. In this study, a two-parameter logistic model is used. We applied optimal designs and adaptive sequential analysis to solve this item calibration problem. The results indicated that the proposed optimal designs are cost effective and time efficient. | 25,188,318 | [
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Is the link from working memory to analogy causal? No analogy improvements following working memory training gains. | Analogical reasoning has been hypothesized to critically depend upon working memory through correlational data, but less work has tested this relationship through experimental manipulation. An opportunity for examining the connection between working memory and analogical reasoning has emerged from the growing, although somewhat controversial, body of literature suggests complex working memory training can sometimes lead to working memory improvements that transfer to novel working memory tasks. This study investigated whether working memory improvements, if replicated, would increase analogical reasoning ability. We assessed participants' performance on verbal and visual analogy tasks after a complex working memory training program incorporating verbal and spatial tasks. Participants' improvements on the working memory training tasks transferred to other short-term and working memory tasks, supporting the possibility of broad effects of working memory training. However, we found no effects on analogical reasoning. We propose several possible explanations for the lack of an impact of working memory improvements on analogical reasoning. | 25,188,356 | [
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Salinity and bacterial diversity: to what extent does the concentration of salt affect the bacterial community in a saline soil? | In this study, the evaluation of soil characteristics was coupled with a pyrosequencing analysis of the V2-V3 16S rRNA gene region in order to investigate the bacterial community structure and diversity in the A horizon of a natural saline soil located in Sicily (Italy). The main aim of the research was to assess the organisation and diversity of microbial taxa using a spatial scale that revealed physical and chemical heterogeneity of the habitat under investigation. The results provided information on the type of distribution of different bacterial groups as a function of spatial gradients of soil salinity and pH. The analysis of bacterial 16S rRNA showed differences in bacterial composition and diversity due to a variable salt concentration in the soil. The bacterial community showed a statistically significant spatial variability. Some bacterial phyla appeared spread in the whole area, whatever the salinity gradient. It emerged therefore that a patchy saline soil can not contain just a single microbial community selected to withstand extreme osmotic phenomena, but many communities that can be variously correlated to one or more environmental parameters. Sequences have been deposited to the SRA database and can be accessed on ID Project PRJNA241061. | 25,188,357 | [
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