Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.
Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate. At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426 .).


Poor air quality in classrooms related to asthma and rhinitis in primary schoolchildren of the French 6 Cities Study.
Relationships between indoor air quality (IAQ) found in schools and the allergic and respiratory health of schoolchildren have been insufficiently explored. A survey was conducted in a large sample of classrooms of primary schools in France to provide objective assessments of IAQ to which young schoolchildren are exposed in classrooms, and to relate exposure to major air pollutants found in classrooms to asthma and allergies of schoolchildren. Concentrations of fine particles with aerodynamic diameter ≤2.5 μm (PM(2.5)), nitrogen dioxide (NO(2)) and three aldehydes were objectively assessed in 401 randomly chosen classrooms in 108 primary schools attended by 6590 children (mean age 10.4 years, SD ±0.7) in the French 6 Cities Study. The survey incorporated a medical visit including skin prick testing (SPT) for common allergens, a test for screening exercise-induced asthma (EIA) and a standardised health questionnaire completed by parents. Children were differently exposed to poor air quality in classrooms, with almost 30% being highly exposed according to available standards. After adjusting for confounders, past year rhinoconjunctivitis was significantly associated with high levels of formaldehyde in classrooms (OR 1.19; 95% CI 1.04 to 1.36). Additionally, an increased prevalence of past year asthma was found in the classrooms with high levels of PM(2.5) (OR 1.21; 95% CI 1.05 to 1.39), acrolein (OR 1.22; 95% CI 1.09 to 1.38) and NO(2) (OR 1.16; 95% CI 0.95 to 1.41) compared with others. The relationship was observed mostly for allergic asthma as defined using SPT. A significant positive correlation was found between EIA and the levels of PM(2.5) and acrolein in the same week. In this random sample, air quality in classrooms was poor, varied significantly among schools and cities, and was related to an increased prevalence of clinical manifestations of asthma and rhinitis in schoolchildren. Children with a background of allergies seemed at increased risk.


Deafferentation-induced plasticity of visual callosal connections: predicting critical periods and analyzing cortical abnormalities using diffusion tensor imaging.
Callosal connections form elaborate patterns that bear close association with striate and extrastriate visual areas. Although it is known that retinal input is required for normal callosal development, there is little information regarding the period during which the retina is critically needed and whether this period correlates with the same developmental stage across species. Here we review the timing of this critical period, identified in rodents and ferrets by the effects that timed enucleations have on mature callosal connections, and compare it to other developmental milestones in these species. Subsequently, we compare these events to diffusion tensor imaging (DTI) measurements of water diffusion anisotropy within developing cerebral cortex. We observed that the relationship between the timing of the critical period and the DTI-characterized developmental trajectory is strikingly similar in rodents and ferrets, which opens the possibility of using cortical DTI trajectories for predicting the critical period in species, such as humans, in which this period likely occurs prenatally. Last, we discuss the potential of utilizing DTI to distinguish normal from abnormal cerebral cortical development, both within the context of aberrant connectivity induced by early retinal deafferentation, and more generally as a potential tool for detecting abnormalities associated with neurodevelopmental disorders.


Drugs in the news: an analysis of Canadian newspaper coverage of new prescription drugs.
Patients routinely cite the media, after physicians and pharmacists, as a key source of information on new drugs, but there has been little research on the quality of drug information presented. We assessed newspaper descriptions of drug benefits and harms, the nature of the effects described and the presence or absence of other important information that can add context and balance to a report about a new drug. We looked at newspaper coverage in the year 2000 of 5 prescription drugs launched in Canada between 1996 and 2001 that received a high degree of media attention: atorvastatin, celecoxib, donepezil, oseltamivir and raloxifene. We searched 24 of Canada's largest daily newspapers for articles reporting at least one benefit or harm of any of these 5 drugs. We recorded the benefits and harms reported and analyzed how such information was presented; we also determined whether clinical or surrogate outcomes were mentioned; if and how drug effects were quantified; whether contraindications, other treatment options and costs were mentioned; and whether any information on affiliations of quoted interviewees and potential conflicts of interest was presented. Our search yielded 193 articles reporting at least one benefit or harm for 1 of the 5 drugs. All of the articles mentioned at least one benefit, but 68% (132/193) made no mention of possible side effects or harms. Only 24% (120/510) of mentions of drug benefits and harms presented quantitative information. In 26% (31/120) of cases in which drug benefits and harms were quantified, the magnitude was presented only in relative terms, which can be misleading. Overall, 62% (119/193) of the articles gave no quantification of the benefits or harms. Thirty-seven (19%) of the 193 articles reported only surrogate benefits. Other information needed for informed drug-related decisions was often lacking: only 7 (4%) of the articles mentioned contraindications, 61 (32%) mentioned drug costs, 89 (46%) mentioned drug alternatives, and 30 (16%) mentioned nondrug treatment options (such as exercise or diet). Sixty-two percent (120/193) of the articles quoted at least one interviewee. After exclusion of industry and government spokespeople, for only 3% (5/164) of interviewees was there any mention of potential financial conflicts of interest. Twenty-six percent (15/57) of the articles discussing a study included information on study funding. Our results raise concerns about the completeness and quality of media reporting about new medications.


DNA Methylation Signatures of Depressive Symptoms in Middle-aged and Elderly Persons: Meta-analysis of Multiethnic Epigenome-wide Studies.
Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers. To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood. To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts. Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire. The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10-04) was associated with major depression. This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.


The prevalence of metabolic syndrome in patients with gout: a multicenter study.
It has been suggested that hyperuricemia and possibly gout are associated with the metabolic syndrome, but there have been no direct studies. This study was undertaken to obtain the prevalence of the metabolic syndrome in patients with gout and to compare it with those from the general population studies. This was a 4-institutional case-historical control study composed of 168 patients with gout. We assessed the prevalence of metabolic syndrome according to the ATP III criteria and compared the prevalence with that of the historical controls. To elucidate the factors in gout that were associated with metabolic syndrome, a multivariate analysis was done. The age-adjusted prevalence of metabolic syndrome in gout patients was 43.6%, which was significantly higher than that of the Korean control population (5.2%) from the previous studies. Patients with gout had more components of metabolic syndrome than did the controls. Body mass index (BMI, OR = 1.357 (95%CI 1.111-1.657)) and high density lipoprotein (HDL, OR = 0.774 (95%CI 0.705-0.850)) were the variables most significantly associated with the occurrence of metabolic syndrome in gout, but alcohol consumption did not show such associations. Gout is associated with the metabolic syndrome, and furthermore, obesity and dyslipidemia were the factors most associated with the syndrome in these patients.


Views of New Jersey teenagers about their state's policies for beginning drivers.
Three New Jersey licensing policies are unique in the United States: (a) minimum licensing age of 17; (b) applying full graduated driver licensing (GDL) rules to beginners younger than 21; and (c) requiring license status decals on vehicle plates of drivers in GDL. New Jersey 17-19 year-olds were surveyed by telephone and online. Eighty-four percent approved licensing at 17; 77% approved applying GDL to older novices; 23% approved the decal policy. Probationary licensees ages 18-19 were more likely than 17 year-olds to have multiple nighttime restriction violations in the past month. There were no age group differences in passenger restriction violations. All three policies have been considered in other states. Views of teenagers directly affected by the policies can be taken into account in considering their implementation. Views of licensing policies by affected teenagers indicate potential support or obstacles to their adoption in other states.


Sub-100 fs mode-locked erbium-doped fiber laser using a 45°-tilted fiber grating.
We demonstrate generation of sub-100 fs pulses at 1.5 µm in a mode-locked erbium-doped fiber laser using a 45°-tilted fiber grating element. The laser features a genuine all-fiber configuration. Based on the unique polarization properties of the 45°-tilted fiber grating, we managed to produce sub-100 fs laser pulses through proper dispersion management. To the best of our knowledge, this is the shortest pulse generated from mode-locked lasers with fiber gratings. The output pulse has an average power of 8 mW, with a repetition rate of 47.8 MHz and pulse energy of 1.68 nJ. The performance of laser also matches well the theoretical simulations.


Distribution of oxytocin-like and vasopressin-like immunoreactivities within the central nervous system of the cuttlefish, Sepia officinalis.
We have investigated the distribution of oxytocin/vasopressin (OT/VP) superfamily peptides in the central nervous system (CNS) of the cuttlefish, Sepia officinalis, by using antibodies raised against mammalian OT and VP. Several populations of OT-like and VP-like immunoreactive cell bodies and fibers were widely distributed in cerebral structures involved in learning processes (vertical lobe complex, optic lobes), behavioral communication (peduncle, lateral basal and chromatophore lobes), feeding behavior (inferior frontal, brachial and buccal lobes), sexual activity (dorsal basal, subpedunculate, olfactory lobes), and metabolism (visceral lobes). The two most remarkable findings of this study were the occurrence of OT-like immunoreactivity in many amacrine cells of the vertical lobe and the dense accumulation of VP-like immunoreactive cell bodies in the subpedunculate 1 lobe. No double-immunolabeled cell bodies or fibers were found in any lobes of the CNS, indicating, for the first time in a decapod cephalopod mollusc, the existence of distinct oxytocinergic-like and vasopressinergic-like systems. The widespread distribution of the immunoreactive neurons suggests that these OT-like and VP-like peptides act as neurotransmitters or neuromodulators.


State-space prior distribution for parameter of nonhomogeneous Poisson spatiotemporal models.
This article proposes a new class of nonhomogeneous Poisson spatiotemporal model. In this approach, we use a state-space model-based prior distribution to handle the scale and shape parameters of the Weibull intensity function. The proposed prior distribution enables the inclusion of changes in the behavior of the intensity function over time. In defining the spatial correlation function of the model, we include anisotropy via spatial deformation. We estimate the model parameters from a Bayesian perspective, employ the Markov chain Monte Carlo approach, and validate this estimation procedure through a simulation exercise. Finally, the extreme rainfall in the southern semiarid region in northeastern Brazil is analyzed using the R10mm index. The proposed model showed better fit and prediction ability than did other nonhomogeneous Poisson spatiotemporal models available in the literature. This improvement in performance is mainly due to the flexibility of the intensity function that is achieved by allowing the incorporation, in time, of the climatic characteristics of this region.


Dynamics of vitellogenin and vitellogenesis-inhibiting hormone levels in adult and subadult whiteleg shrimp, Litopenaeus vannamei: relation to molting and eyestalk ablation.
Levels of vitellogenin (VG) and vitellogenesis-inhibiting hormone (VIH) in the whiteleg shrimp, Litopenaeus vannamei, were measured by time-resolved fluoroimmunoassay in relation to the molting cycle and ovarian maturation induced by eyestalk ablation. During the molt cycle, VG mRNA expression levels and VG concentrations showed similar patterns of fluctuation. VG levels increased significantly at early intermolt (stage C0) in adults, but not in subadults. Unilateral and bilateral eyestalk ablation increased VG levels in adults, whereas only bilateral eyestalk ablation affected subadults. VIH levels showed contrasting patterns between adults and subadults. In adults, levels were high in late postmolt adults (stage B) and then low thereafter, whereas they increased from postmolt (stage A) to intermolt (stage C0) in subadults and remained high. Unilateral eyestalk ablation increased VIH levels 10 days following ablation in adults, after which levels decreased at 20 days. VIH levels decreased from 10 to 20 days after bilateral ablation. Both unilateral and bilateral ablation led to increased VIH levels in subadults. Eyestalk ablation induced ovarian maturation, but did not reduce VIH concentrations in the hemolymph. This phenomenon was perhaps due to other crustacean hyperglycemic hormone peptides having cross-reactivity with VIH antibodies. This is the first report to quantify concentrations of VG and VIH together in L. vannamei hemolymph, and to examine their relative dynamics.


Levels of complexity in scale-invariant neural signals.
Many physical and physiological signals exhibit complex scale-invariant features characterized by 1/f scaling and long-range power-law correlations, indicating a possibly common control mechanism. Specifically, it has been suggested that dynamical processes, influenced by inputs and feedback on multiple time scales, may be sufficient to give rise to 1/f scaling and scale invariance. Two examples of physiologic signals that are the output of hierarchical multiscale physiologic systems under neural control are the human heartbeat and human gait. Here we show that while both cardiac interbeat interval and gait interstride interval time series under healthy conditions have comparable 1/f scaling, they still may belong to different complexity classes. Our analysis of the multifractal scaling exponents of the fluctuations in these two signals demonstrates that in contrast to the multifractal behavior found in healthy heartbeat dynamics, gait time series exhibit less complex, close to monofractal behavior. Further, we find strong anticorrelations in the sign and close to random behavior for the magnitude of gait fluctuations at short and intermediate time scales, in contrast to weak anticorrelations in the sign and strong positive correlation for the magnitude of heartbeat interval fluctuations-suggesting that the neural mechanisms of cardiac and gait control exhibit different linear and nonlinear features. These findings are of interest because they underscore the limitations of traditional two-point correlation methods in fully characterizing physiological and physical dynamics. In addition, these results suggest that different mechanisms of control may be responsible for varying levels of complexity observed in physiological systems under neural regulation and in physical systems that possess similar 1/f scaling.


An FRMD4B variant suppresses dysplastic photoreceptor lesions in models of enhanced S-cone syndrome and of Nrl deficiency.
Photoreceptor dysplasia, characterized by formation of folds and (pseudo-)rosettes in the outer retina, is associated with loss of functional nuclear receptor subfamily 2 group E member 3 (NR2E3) and neural retina leucine-zipper (NRL) in both humans and mice. A sensitized chemical mutagenesis study to identify genetic modifiers that suppress photoreceptor dysplasia in Nr2e3rd7mutant mice identified line Tvrm222, which exhibits a normal fundus appearance in the presence of the rd7 mutation. The Tvrm222 modifier of Nr2e3rd7/rd7 was localized to Chromosome 6 and identified as a missense mutation in the FERM domain containing 4B (Frmd4b) gene. The variant is predicted to cause the substitution of a serine residue 938 with proline (S938P). The Frmd4bTvrm222 allele was also found to suppress outer nuclear layer (ONL) rosettes in Nrl-/- mice. Fragmentation of the external limiting membrane (ELM), normally observed in rd7 and Nrl-/-mouse retinas, was absent in the presence of the Frmd4bTvrm222 allele. FRMD4B, a binding partner of cytohesin 3, is proposed to participate in cell junction remodeling. Its biological function in photoreceptor dysplasia has not been previously examined. In vitro experiments showed that the FRMD4B938P variant fails to be efficiently recruited to the cell surface upon insulin stimulation. In addition, we found a reduction in protein kinase B phosphorylation and increased levels of cell junction proteins, Catenin beta 1 and tight junction protein 1, associated with the cell membrane in Tvrm222 retinas. Taken together, this study reveals a critical role of FRMD4B in maintaining ELM integrity and in rescuing morphological abnormalities of the ONL in photoreceptor dysplasia.


Obinutuzumab in Combination with Chemotherapy for the First-Line Treatment of Patients with Advanced Follicular Lymphoma : An Evidence Review Group Evaluation of the NICE Single Technology Appraisal.
The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1-3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was <£20,000 per quality-adjusted life-year (QALY) gained. Although the ERG concluded that the economic model met the NICE reference case to a reasonable extent, some errors were identified and several assumptions made by the company were challenged. A new base-case scenario produced by the ERG suggested an ICER that was higher than the company base case, but still below £30,000 per QALY gained. However, some ERG scenario analyses were close to or even above the threshold. This was the case in particular for assuming a treatment effect that did not extend beyond trial follow-up. These results led to an initial negative recommendation by the appraisal committee. Subsequently, the company submitted a revised base case focusing on patients at intermediate or high risk of premature mortality. Simultaneously, a further price discount for obinutuzumab was granted. In addition to the company's revised base case, the ERG suggested a restriction of the treatment effect to 5 years and implemented biosimilar uptake and cheaper prices for rituximab. All of these adjustments did not exceed £30,000 per QALY gained and therefore the use of obinutuzumab for patients with advanced FL and a Follicular Lymphoma International Predictive Index (FLIPI) score of two or more could be recommended.


An evaluation of the efficacy of topical application of salicylic acid for the treatment of familial cylindromatosis.
Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of NF-kappaB, a transcription factor having antiapoptotic activity. This provides a possible explanation for the deregulated growth of cylindromas. In cell-based assays, salicylate can prevent NF-kappaB activation caused by loss of the cylindromatosis gene, suggesting that salicylic acid application might be a potential treatment for cylindromatosis. To assess the effectiveness of topical application of salicylic acid on familial cylindromas. Cylindromas in five patients from four different cylindromatosis families were treated with twice daily and then once daily topical salicylic acid. Clinical response was determined by serial tumour measurements. In total 17 cylindromas in five patients were studied: 12 target lesions and five control lesions. The median size of the cylindromas was 1.0 cm (range, 0.6-2.8 cm). Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission. The control lesions remained stable or increased in size. Salicylic acid is a well-tolerated and potential new treatment for cylindromatosis.


Investigation of model stacking for drug sensitivity prediction.
A significant problem in precision medicine is the prediction of drug sensitivity for individual cancer cell lines. Predictive models such as Random Forests have shown promising performance while predicting from individual genomic features such as gene expressions. However, accessibility of various other forms of data types including information on multiple tested drugs necessitates the examination of designing predictive models incorporating the various data types. We explore the predictive performance of model stacking and the effect of stacking on the predictive bias and squared error. In addition we discuss the analytical underpinnings supporting the advantages of stacking in reducing squared error and inherent bias of random forests in prediction of outliers. The framework is tested on a setup including gene expression, drug target, physical properties and drug response information for a set of drugs and cell lines. The performance of individual and stacked models are compared. We note that stacking models built on two heterogeneous datasets provide superior performance to stacking different models built on the same dataset. It is also noted that stacking provides a noticeable reduction in the bias of our predictors when the dominant eigenvalue of the principle axis of variation in the residuals is significantly higher than the remaining eigenvalues.


Modification of an RBF ANN-Based Temperature Compensation Model of Interferometric Fiber Optical Gyroscopes.
This paper presents modification of Radial Basis Function Artificial Neural Network (RBF ANN)-based temperature compensation models for Interferometric Fiber Optical Gyroscopes (IFOGs). Based on the mathematical expression of IFOG output, three temperature relevant terms are extracted, which include: (1) temperature of fiber loops; (2) temperature variation of fiber loops; (3) temperature product term of fiber loops. Then, the input-modified RBF ANN-based temperature compensation scheme is established, in which temperature relevant terms are transferred to train the RBF ANN. Experimental temperature tests are conducted and sufficient data are collected and post-processed to form the novel RBF ANN. Finally, we apply the modified RBF ANN based on temperature compensation model in two IFOGs with temperature compensation capabilities. The experimental results show the proposed temperature compensation model could efficiently reduce the influence of environment temperature on the output of IFOG, and exhibit a better temperature compensation performance than conventional scheme without proposed improvements.


Bigendothelin-1 via p38-MAPK-dependent mechanism regulates adult rat ventricular myocyte contractility in sepsis.
We tested the hypothesis that exogenous administration of the ET-1 precursor, bigET-1, would regulate adult rat ventricular myocyte (ARVM) contractility in a p38-mitogen activated protein kinase (p38-MAPK)-dependent mechanism during sepsis. Ventricular myocytes from adult rat hearts (both sham and septic) were stimulated to contract at 0.5 Hz and mechanical properties were evaluated using an IonOptix Myocam system. Immunoblot analysis was used to determine the phosphorylation of p38-MAPK and extracellular signal-regulated kinase 1/2 (ERK1/2). ARVMs were treated with vehicle, bigET-1 and inhibitors for 24 h and then subjected to functional and biochemical estimations. Septic ARVM displayed a distorted cell membrane and irregular network within the cells along with increased cell contractility as evidenced by elevated peak shortening (PS), maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt) in comparison to sham ARVM. BigET-1 treatment caused ARVM enlargement in both sham and sepsis groups. BigET-1 (100 nM) produced an increase in ARVM contractility in sham group as compared to vehicle treatment. However, septic ARVM treated with bigET-1 exhibited unaltered ARVM contractility, and upregulated ET(B) receptors as compared to respective sham group. BigET-1 increased the concentration of ET-1 and upregulated phosphorylation of p38-MAPK but not of ERK1/2 in sham and septic ARVM. Furthermore, inhibition of p38-MAPK by SB203580 (10 microM) increased ARVM contractility in sham but not in sepsis group. BigET-1 reversed SB203580-induced increase in PS in sham group but accentuated it in sepsis group. BigET-1 also reversed SB203580-induced inhibition of p38-MAPK phosphorylation in sham but not in septic ARVM. SB203580 pretreatment followed by bigET-1 administration significantly decreased p38-MAPK phosphorylation and downregulated ET(B) receptor expression as compared to bigET-1 treatment per se in sepsis group but not in sham. We concluded that a bigET-1-induced non-responsive effect on septic ARVM contractile function could be due to upregulation of p38-MAPK phosphorylation and ET(B) receptor expression.


Short term effects of cocoa consumption on blood pressure.
Hypertension, defined as diastolic pressure ≥ 90 mmHg and systolic pressure ≥ 140 mmHg, is a major cause of morbidity and mortality among black populations globally. Several studies have shown that prolonged consumption of cocoa or cocoa containing products leads to decreased blood pressure (BP) in hypertensives. In this study, we investigated the flavonoid content of the top selling cocoa/cocoa based products in Trinidad and Tobago and attempted to determine if consumption of cocoa had any immediate impact on blood pressure levels. The flavonoid content of three 100% cocoa powder products and four cocoa based formulas was measured using a modified Folin-Ciocalteu procedure. The brand with the highest flavonoid content, 372 gallic acid equivalents, was selected to evaluate the short-term impact of cocoa consumption on blood pressure. Thirty-six participants comprising nineteen hypertensives and seventeen persons with normal blood pressure had their blood pressure recorded on three separate days using ambulatory blood pressure monitors; the blood pressure was recorded every half hour for eight hours. On the first day, the participants received no intervention but on the second and third days, they received either the intervention (5 g cocoa in 125 ml water) or a placebo, in any order. Statistical analysis conducted using t-test statistic and a 95% confidence interval revealed that whether participants regularly took antihypertensive medication or not, a single intervention of cocoa induced decreases in both the diastolic and systolic BPs that were significant (p = 0.0001). Mean decreases of between 8 mmHg and 18 mmHg were observed.


Clinical comparison of difco ESP, Wampole isolator, and Becton Dickinson Septi-Chek aerobic blood culturing systems.
The ESP 80A aerobic blood culture of the ESP automated blood culture system (Difco Laboratories. Detroit, Mich.) was compared with two manual aerobic blood culture systems, the Isolator (Wampole Laboratories, Cranbury, N.J.) and the Septi-Chek (Becton Dickinson, Cockeysville, Md.) systems, for the detection of bloodstream microorganisms from 5,845 blood samples for culture collected from adult patients with suspected septicemia. The bottles were incubated for 7 days, and the sediment from the Isolator tube was inoculated onto solid medium and this medium was incubated for 72 h. A total of 609 microorganisms were recovered from 546 blood cultures. There was no statistically significant difference in the total recovery of microorganisms for the ESP 80A system when compared with that for the Septi-Chek system (P = 0.083); however, the Isolator system recovered significantly more microorganisms overall than either the ESP 80A (P < 0.001) or the Septi-Chek (P < 0.001) system. When assessing individual probable pathogens, the Isolator system detected statistically significantly more Staphylococcus aureus and Candida spp. than either the ESP 80A or the Septi-Chek system (P < 0.05). Similarly, the Isolator system detected statistically significantly more bloodstream infections (septic episodes) caused by S. aureus and Candida spp. than either the ESP 80A or the Septi-Chek system (P < 0.05). In blood culture sets which produced growth of the same probable pathogens in the ESP 80A and the Isolator systems, there was no statistically significant difference in the median times to detection for all pathogens combined (P = 0.067). However, a similar comparison showed the Isolator and the ESP 80A systems to have statistically significantly shorter median detection times for all pathogens combined (P < 0.001) when they were independently compared with the Septi-Chek system. The ESP 80A system had 29 (0.5%) false-positive signals. The ESP system required less processing time than the Isolator system and eliminates the hands-on time for the detection of positive cultures required by the manual systems.


Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses.
Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.


Endogenous retrovirus insertion in the KIT oncogene determines white and white spotting in domestic cats.
The Dominant White locus (W) in the domestic cat demonstrates pleiotropic effects exhibiting complete penetrance for absence of coat pigmentation and incomplete penetrance for deafness and iris hypopigmentation. We performed linkage analysis using a pedigree segregating White to identify KIT (Chr. B1) as the feline W locus. Segregation and sequence analysis of the KIT gene in two pedigrees (P1 and P2) revealed the remarkable retrotransposition and evolution of a feline endogenous retrovirus (FERV1) as responsible for two distinct phenotypes of the W locus, Dominant White, and white spotting. A full-length (7125 bp) FERV1 element is associated with white spotting, whereas a FERV1 long terminal repeat (LTR) is associated with all Dominant White individuals. For purposes of statistical analysis, the alternatives of wild-type sequence, FERV1 element, and LTR-only define a triallelic marker. Taking into account pedigree relationships, deafness is genetically linked and associated with this marker; estimated P values for association are in the range of 0.007 to 0.10. The retrotransposition interrupts a DNAase I hypersensitive site in KIT intron 1 that is highly conserved across mammals and was previously demonstrated to regulate temporal and tissue-specific expression of KIT in murine hematopoietic and melanocytic cells. A large-population genetic survey of cats (n = 270), representing 30 cat breeds, supports our findings and demonstrates statistical significance of the FERV1 LTR and full-length element with Dominant White/blue iris (P < 0.0001) and white spotting (P < 0.0001), respectively.


Determining health-care facility catchment areas in Uganda using data on malaria-related visits.
To illustrate the use of a new method for defining the catchment areas of health-care facilities based on their utilization. The catchment areas of six health-care facilities in Uganda were determined using the cumulative case ratio: the ratio of the observed to expected utilization of a facility for a particular condition by patients from small administrative areas. The cumulative case ratio for malaria-related visits to these facilities was determined using data from the Uganda Malaria Surveillance Project. Catchment areas were also derived using various straight line and road network distances from the facility. Subsequently, the 1-year cumulative malaria case rate was calculated for each catchment area, as determined using the three methods. The 1-year cumulative malaria case rate varied considerably with the method used to define the catchment areas. With the cumulative case ratio approach, the catchment area could include noncontiguous areas. With the distance approaches, the denominator increased substantially with distance, whereas the numerator increased only slightly. The largest cumulative case rate per 1000 population was for the Kamwezi facility: 234.9 (95% confidence interval, CI: 226.2-243.8) for a straight-line distance of 5 km, 193.1 (95% CI: 186.8-199.6) for the cumulative case ratio approach and 156.1 (95% CI: 150.9-161.4) for a road network distance of 5 km. Use of the cumulative case ratio for malaria-related visits to determine health-care facility catchment areas was feasible. Moreover, this approach took into account patients' actual addresses, whereas using distance from the facility did not.


The economic costs of child maltreatment in UK.
Child maltreatment is a major public health problem with significant consequences for individual victims and for society. In this paper, we quantify for the first time the economic costs of fatal and nonfatal child maltreatment in the UK in relation to several short-, medium-, and long-term outcomes ranging from physical and mental health problems to labor market outcomes and welfare use. We combine novel regression analysis of rich data from the National Child Development Study and the English Longitudinal Study of Aging with secondary evidence to produce an incidence-based estimate of the lifetime costs of child maltreatment from a societal perspective. The discounted average lifetime incidence cost of nonfatal child maltreatment by a primary caregiver is estimated at £89,390 (95% uncertainty interval £44,896 to £145,508); the largest contributors to this are costs from social care, short-term health, and long-term labor market outcomes. The discounted lifetime cost per death from child maltreatment is estimated at £940,758, comprising health care and lost productivity costs. Our estimates provide the first comprehensive benchmark to quantify the costs of child maltreatment in the UK and the benefits of interventions aimed at reducing or preventing it.


The effects of orthodontic treatment on isometric bite forces and mandibular motion in patients before orthognathic surgery.
Little is known about the effects of orthodontic treatment on oral motor function. The objective of this report is to evaluate changes in mandibular motion and maximum bite force that occur between the initiation of presurgical orthodontics and its completion before surgery. Fifteen patients (9 women, 6 men) with a variety of dentofacial deformities were examined before and after presurgical orthodontics. Mechanical advantage of the muscles and bite points, mandibular range of motion, maximum isometric bite force, and levels of electromyographic (EMG) activity in the anterior and posterior temporalis and masseter muscles during isometric bites were recorded on all subjects over time. Data obtained before and after completion of presurgical orthodontics were statistically compared. Presurgical orthodontics reduced mandibular mobility somewhat, but the amount was not significant. Statistically significant reductions in bite force were noted after orthodontics for incisor, canine, premolar, and molar bite positions. No significant difference in the EMG/bite force slopes was obtained, nor was there any difference in the moment arms of the bite points or the muscles of mastication from orthodontics. This study showed significant changes in measures of oral motor function resulting from orthodontic treatment. A larger study is needed to confirm that these results will be similar in all orthodontic patients. There is no indication that these changes are the result of physiologic alterations of the muscles of mastication. The best current explanation is that these changes result from the pain and discomfort of the orthodontic appliances and the induced malocclusion.


The Wilms' tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis.
The Wilms' tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1(GFP/+)) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (<1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ETO+TEL/PDGFbetaR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit(+)lin(-)Sca-1(+) (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1(GFP/+) mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.


GlnK Facilitates the Dynamic Regulation of Bacterial Nitrogen Assimilation.
Ammonium assimilation in Escherichia coli is regulated by two paralogous proteins (GlnB and GlnK), which orchestrate interactions with regulators of gene expression, transport proteins, and metabolic pathways. Yet how they conjointly modulate the activity of glutamine synthetase, the key enzyme for nitrogen assimilation, is poorly understood. We combine experiments and theory to study the dynamic roles of GlnB and GlnK during nitrogen starvation and upshift. We measure time-resolved in vivo concentrations of metabolites, total and posttranslationally modified proteins, and develop a concise biochemical model of GlnB and GlnK that incorporates competition for active and allosteric sites, as well as functional sequestration of GlnK. The model predicts the responses of glutamine synthetase, GlnB, and GlnK under time-varying external ammonium level in the wild-type and two genetic knock-outs. Our results show that GlnK is tightly regulated under nitrogen-rich conditions, yet it is expressed during ammonium run-out and starvation. This suggests a role for GlnK as a buffer of nitrogen shock after starvation, and provides a further functional link between nitrogen and carbon metabolisms.


An international bioinformatics infrastructure to underpin the Arabidopsis community.
The future bioinformatics needs of the Arabidopsis community as well as those of other scientific communities that depend on Arabidopsis resources were discussed at a pair of recent meetings held by the Multinational Arabidopsis Steering Committee and the North American Arabidopsis Steering Committee. There are extensive tools and resources for information storage, curation, and retrieval of Arabidopsis data that have been developed over recent years primarily through the activities of The Arabidopsis Information Resource, the Nottingham Arabidopsis Stock Centre, and the Arabidopsis Biological Resource Center, among others. However, the rapid expansion in many data types, the international basis of the Arabidopsis community, and changing priorities of the funding agencies all suggest the need for changes in the way informatics infrastructure is developed and maintained. We propose that there is a need for a single core resource that is integrated into a larger international consortium of investigators. We envision this to consist of a distributed system of data, tools, and resources, accessed via a single information portal and funded by a variety of sources, under shared international management of an International Arabidopsis Informatics Consortium (IAIC). This article outlines the proposal for the development, management, operations, and continued funding for the IAIC.


Quinpirole induces compulsive checking behavior in rats: a potential animal model of obsessive-compulsive disorder (OCD).
Rats treated chronically with the dopamine agonist quinpirole (0.5 mg/kg, twice weekly x 10) met 5 criteria for performance of compulsive checking. Specifically, in a large open-field with single small objects in 4 of 25 locales, quinpirole rats revisited two places/objects excessively often and rapidly, compared with other locations in the environment or saline controls. They performed a ritual-like set of behavioral acts at these two places/objects and stopped in relatively few locales before returning to the preferred places/objects. Finally, they shifted their behavior to a new location when the object was moved there. Clomipramine (10 mg/kg, daily) postponed but did not prevent the development of the quinpirole effect. Quinpirole-induced compulsive checking may be an exaggeration of normal checking of home site in rats. Results suggest an animal model of obsessive-compulsive disorder and a role for dopamine in this disorder.


Seasonal influenza vaccination delivery through community pharmacists in England: evaluation of the London pilot.
To evaluate the effectiveness and cost of the pan-London pharmacy initiative, a programme that allows administration of seasonal influenza vaccination to eligible patients at pharmacies. We analysed 2013-2015 data on vaccination uptake in pharmacies via the Sonar reporting system, and the total vaccination uptake via 2011-2015 ImmForm general practitioner (GP) reporting system data. We conducted an online survey of London pharmacists who participate in the programme to assess time use data, vaccine choice, investment costs and opinions about the programme. We conducted an online survey of London GPs to assess vaccine choice of vaccine and opinions about the pharmacy vaccine delivery programme. All London boroughs. London-based GPs, and pharmacies that currently offer seasonal flu vaccination. Not applicable. Comparison of annual vaccine uptake in London across risk groups from years before pharmacy vaccination introduction to after pharmacy vaccination introduction. Completeness of vaccine uptake reporting data. Cost to the National Health Service (NHS) of flu vaccine delivery at pharmacies with that at GPs. Cost to pharmacists of flu delivery. Opinions of pharmacists and GPs regarding the flu vaccine pharmacy initiative. No significant change in the uptake of seasonal vaccination in any of the risk groups as a result of the pharmacy initiative. While on average a pharmacy-administered flu vaccine dose costs the NHS up to £2.35 less than a dose administered at a GP, a comparison of the 2 recording systems suggests there is substantial loss of data. Flu vaccine delivery through pharmacies shows potential for improving convenience for vaccine recipients. However, there is no evidence that vaccination uptake increases and the use of 2 separate recording systems leads to time-consuming data entry and missing vaccine record data.


Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function.
Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N = 406), the Argentinean Andes (N = 198), and Italy (N = 238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N = 101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort. The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, P = .027) and Italy (10.6%, P = .012), but not as clear in Bangladesh (3.4%, P = .21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, P = .033; adjusted for age and sex) and reduced SLC30A10 expression (-24.6%, P = .029). In contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (-18.4%, P = .04), and increased finger-tapping speed (8.7%, P = .025). We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in 3 unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels.


Identification of the Risk HLA-A Alleles and Autoantigen in Han Chinese Vitiligo Patients and the Association of CD8+T Cell Reactivity with Disease Characteristics.
BACKGROUND Multiple studies have implicated a role for CD8+T cell-mediated immune response to autoantigens in vitiligo. However, the antigen-specific T lymphocyte reactivity against the peptide epitopes is diverse among different world populations. This study aimed to identify the risk HLA-A allele in vitiligo and study CD8+ T cell reactivity to 5 autoantigenic peptides in Han Chinese populations, and to analyze the association of CD8+ T cell reactivity with disease characteristics. MATERIAL AND METHODS The risk HLA-A allele was analyzed by case-control study. Enzyme linked immunospot (ELISPOT) assay was used to compare T cell reactivity to the 5 autoantigenic peptides between vitiligo patients and healthy controls, then we analyzed the association of CD8+ T cell reactivity to 2 positive peptides with disease activity and area of skin lesions. RESULTS The results indicated that the most frequent allele in the Han Chinese vitiligo patients was the HLA-A*02: 01 allele with a significantly higher frequency compared to controls (20.20% versus 13.79%, P=6.64×10-5). The most frequently encountered epitopes were 2 gp100 modified peptides, IMDQVPFSV and YLEPGPVTV, whereas a weak T cell reactivity against tyrosinase and Melan-A/MART-1 were evaluated. Moreover, we demonstrated that T cell reactivity against the 2 positive peptides was significantly associated with disease characteristics including disease activity and area of skin lesions. CONCLUSIONS Our findings showed that the HLA-A*02: 01 allele was the major risk HLA-A allele, and 2 gp100 modified peptides were identified as autoantigens and were found to be closely related to disease characteristics which might play a critical role in Han Chinese vitiligo patients.


Battling illness with wellness: a qualitative case study of a young rapper's experiences with music therapy.
Mental health difficulties are connected with major interpersonal and social challenges. Recent qualitative research indicates that music therapy can facilitate many of the core elements found to promote social recovery and social inclusion, findings also reflected in results from a growing body of effect studies. The objective of this study was to explore how music therapy might afford possibilities for social recovery to one man with psychosis admitted to a psychiatric intensive care unit. This was achieved by means of a qualitative case study featuring a description of the music therapeutic process alongside first-hand accounts of the participant's subjective experiences. The data were analysed using interpretative phenomenological analysis (IPA). The findings are presented in a narrative form reflecting processes and activities considered particularly important for the process of social recovery. Theoretical perspectives from the recovery literature and current perspectives in music therapy are discussed with a view to the possible use of music therapy for strengthening agency, (re)building identity, developing positive relationships, and expanding social networks.


Risk factors and the role of bedside colonoscopy for lower gastrointestinal hemorrhage in critically ill patients.
We designed this study to determine the clinical characteristics of critically ill patients with lower gastrointestinal hemorrhage (LGIH) and to evaluate the effectiveness of bedside colonoscopy in diagnosing and managing LGIH in the intensive care unit (ICU) setting. We retrospectively reviewed the medical records of patients who underwent bedside colonoscopy for LGIH that developed while in the ICU at Severance Hospital from January 1999 to June 2006. The control group was a random sampling of patients hospitalized in the ICU without GIH. A total of 28,101 patients were hospitalized in ICU during the study period. Of these, 43 patients were included in each group. There were no significant differences in age, sex, and primary and underlying diseases between the two groups. Hypoalbuminemia and high BUN levels were found to be risk factors for LGIH in ICU patients. Bleeding focus was recognized in 28 patients (65.1%) through bedside colonoscopy. Major endoscopic diagnoses were ischemic colitis (13, 30.2%), rectal ulcer (7, 20.9%), and hemorrhoids (6, 13.9%). Primary endoscopic hemostasis was achieved in 11 of 28 diagnosed patients (39.3%). Our data suggest that patients' underlying conditions may affect LGIH in the ICU setting. Moreover, urgent bedside colonoscopy may be effective in diagnosing and guiding appropriate treatments for LGIH in critically ill patients.


Impairment of auditory spatial localization in congenitally blind human subjects.
Several studies have demonstrated enhanced auditory processing in the blind, suggesting that they compensate their visual impairment in part with greater sensitivity of the other senses. However, several physiological studies show that early visual deprivation can impact negatively on auditory spatial localization. Here we report for the first time severely impaired auditory localization in the congenitally blind: thresholds for spatially bisecting three consecutive, spatially-distributed sound sources were seriously compromised, on average 4.2-fold typical thresholds, and half performing at random. In agreement with previous studies, these subjects showed no deficits on simpler auditory spatial tasks or with auditory temporal bisection, suggesting that the encoding of Euclidean auditory relationships is specifically compromised in the congenitally blind. It points to the importance of visual experience in the construction and calibration of auditory spatial maps, with implications for rehabilitation strategies for the congenitally blind.


Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study.
Terbufos is the fourth most commonly used organophosphate insecticide (OP) in the United States. Terbufos has not been demonstrated to be carcinogenic in rodents, although non-arsenical insecticides, including OPs, have been associated with excess cancer in epidemiologic studies. We investigated associations between use of terbufos and the incidence of cancer. The Agricultural Health Study is a prospective cohort study of 57,310 licensed pesticide applicators from Iowa and North Carolina. Detailed information about 50 pesticides, including terbufos, and potential confounders was obtained from self-administered questionnaires. Terbufos intensity-weighted lifetime exposure-days were defined as (lifetime exposure-days) x (exposure intensity score). Cases include all first primary cancers diagnosed between enrollment and December 31, 2005. Hazard ratios (HR) and 95% CI were calculated with Cox proportional hazards models, adjusting for potential confounders. Overall cancer risk was slightly increased among terbufos users [HR 1.21 (1.06-1.37)]. Suggestive associations were observed between terbufos use and cancers of the prostate (HR(highest tertile) = 1.21; 95% CI = 0.99-1.47) and lung (HR(middle tertile) = 1.45; 95% CI = 0.95-2.22) and leukemia (HR(middle tertile) = 2.38; 95% CI = 1.35-4.21) and non-Hodgkin's lymphoma (HR(middle tertile) = 1.94; 95% CI = 1.16-3.22), although the exposure-response gradients were non-monotonic and p for trends were not significant. We found suggestive associations between occupational terbufos use and several cancer sites. However, cautious interpretation of these results is warranted by the lack of existing experimental and epidemiologic evidence to support carcinogenic effects of terbufos.


Neonatally measured immunoglobulins and risk of autism.
Previous studies indicate that prenatal exposure to infections is a possible pathway through which autism spectrum disorders (ASD) could be initiated. We investigated whether immunoglobulin levels in archived specimens obtained from newborns subsequently diagnosed with ASD are different from levels in newborn specimens from controls. Children with ASD born in six California counties in 1994 were ascertained through records of the California Department of Developmental Services (DDS) and Kaiser Permanente; controls were randomly selected using birth certificates. Archived newborn blood specimens were obtained from the California Genetic Disease Screening Program (GDSP) for N = 213 cases and N = 265 controls and assayed to determine levels of total IgG, antigen-specific IgG to selected common pathogens, total IgM, total IgA, and C-reactive protein (CRP). We did not find measurable levels of total IgM or IgA in any neonate and measurable CRP was present in only a few. No antigen-specific IgG antibodies were elevated in cases compared to controls and total IgG levels were lower. In adjusted models, a 10-unit increase in total IgG yielded an OR = 0.72 (95% CI 0.56, 0.91); a significantly decreasing trend in risk of ASD was observed across increasing exposure quartiles of total IgG (P = 0.01). The finding of lower IgG in cases may indicate maternal immune dysfunction during gestation and/or impaired transplacental transfer of immunoglobulins. Further investigation of IgG levels in newborns and the mechanisms by which they might be associated with ASD are warranted.


Naloxegol and Postoperative Urinary Retention: A Randomized Trial.
Naloxegol antagonizes peripheral opioid-related side effects without preventing opioid-related analgesia. However, the effect of naloxegol on opioid-induced bladder dysfunction remains unknown. patients given naloxegol have lower residual bladder urine volume than those given placebo. 136 patients scheduled for elective hip and knee surgery were randomized to oral naloxegol or placebo given the morning of surgery, and on the first two postoperative mornings. Residual urine volume was measured ultrasonographically within 30 min after voiding once in the morning and once in the afternoon for two postoperative days. Opioid-related Symptom Distress Scale (ORSDS), the need for indwelling urinary catheterization, and quality of recovery (QoR) score were secondary outcomes. 67 were randomized to naloxegol and 64 to placebo. We did not identify a significant effect on urine residual volume, with an estimated ratio of geometric means of 0.9 (0.3, 2.6), p = 0.84. There were no significant differences in ORSDS or QoR. There were 19 (29%) patients assigned to naloxegol who needed indwelling urination catheterization versus 7 (11%) patients in the placebo group, p = 0.012. Our results do not support use of naloxegol for postoperative urinary retention after hip and knee surgery.


Cholesterol-independent effects of methyl-β-cyclodextrin on chemical synapses.
The cholesterol chelating agent, methyl-β-cyclodextrin (MβCD), alters synaptic function in many systems. At crayfish neuromuscular junctions, MβCD is reported to reduce excitatory junctional potentials (EJPs) by impairing impulse propagation to synaptic terminals, and to have no postsynaptic effects. We examined the degree to which physiological effects of MβCD correlate with its ability to reduce cholesterol, and used thermal acclimatization as an alternative method to modify cholesterol levels. MβCD impaired impulse propagation and decreased EJP amplitude by 40% (P<0.05) in preparations from crayfish acclimatized to 14 °C but not from those acclimatized to 21 °C. The reduction in EJP amplitude in the cold-acclimatized group was associated with a 49% reduction in quantal content (P<0.05). MβCD had no effect on input resistance in muscle fibers but decreased sensitivity to the neurotransmitter L-glutamate in both warm- and cold-acclimatized groups. This effect was less pronounced and reversible in the warm-acclimatized group (90% reduction in cold, P<0.05; 50% reduction in warm, P<0.05). MβCD reduced cholesterol in isolated nerve and muscle from cold- and warm-acclimatized groups by comparable amounts (nerve: 29% cold, 25% warm; muscle: 20% cold, 18% warm; P<0.05). This effect was reversed by cholesterol loading, but only in the warm-acclimatized group. Thus, effects of MβCD on glutamate-sensitivity correlated with its ability to reduce cholesterol, but effects on impulse propagation and resulting EJP amplitude did not. Our results indicate that MβCD can affect both presynaptic and postsynaptic properties, and that some effects of MβCD are unrelated to cholesterol chelation.


Effect of aquatic exercise on ankylosing spondylitis: a randomized controlled trial.
Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease that affects mainly the axial skeleton and causes significant pain and disability. Aquatic (water-based) exercise may have a beneficial effect in various musculoskeletal conditions. The aim of this study was to compare the effectiveness of aquatic exercise interventions with land-based exercises (home-based exercise) in the treatment of AS. Patients with AS were randomly assigned to receive either home-based exercise or aquatic exercise treatment protocol. Home-based exercise program was demonstrated by a physiotherapist on one occasion and then, exercise manual booklet was given to all patients in this group. Aquatic exercise program consisted of 20 sessions, 5× per week for 4 weeks in a swimming pool at 32-33 °C. All the patients in both groups were assessed for pain, spinal mobility, disease activity, disability, and quality of life. Evaluations were performed before treatment (week 0) and after treatment (week 4 and week 12). The baseline and mean values of the percentage changes calculated for both groups were compared using independent sample t test. Paired t test was used for comparison of pre- and posttreatment values within groups. A total of 69 patients with AS were included in this study. We observed significant improvements for all parameters [pain score (VAS) visual analog scale, lumbar flexion/extension, modified Schober test, chest expansion, bath AS functional index, bath AS metrology index, bath AS disease activity index, and short form-36 (SF-36)] in both groups after treatment at week 4 and week 12 (p < 0.05). Comparison of the percentage changes of parameters both at week 4 and week 12 relative to pretreatment values showed that improvement in VAS (p < 0.001) and bodily pain (p < 0.001), general health (p < 0.001), vitality (p < 0.001), social functioning (p < 0.001), role limitations due to emotional problems (p < 0.001), and general mental health (p < 0.001) subparts of SF-36 were better in aquatic exercise group. It is concluded that a water-based exercises produced better improvement in pain score and quality of life of the patients with AS compared with home-based exercise.


The Effect of Utilizing Organizational Culture Improvement Model of Patient Education on Coronary Artery Bypass Graft Patients' Anxiety and Satisfaction: Theory Testing.
Due to the increasing prevalence of arteriosclerosis and the mortality caused by this disease, Coronary Artery Bypass Graft (CABG) has become one of the most common surgical procedures. Utilization of patient education is approved as an effective solution for increasing patient survival and outcomes of treatment. However, failure to consider different aspects of patient education has turned this goal into an unattainable one. The objective of this research was to determine the effect of utilizing the organizational culture improvement model of patient education on CABG patients' anxiety and satisfaction. The present study is a randomized controlled trial. This study was conducted on eighty CABG patients. The patients were selected from the CCU and Post-CCU wards of a hospital affiliated with Iran University of Medical Sciences in Tehran, Iran, during 2015. Eshpel Burger's Anxiety Inventory and Patients' Satisfaction Questionnaire were used to collect the required information. Levels of anxiety and satisfaction of patients before intervention and at the time of release were measured. The intervention took place after preparing a programmed package based on the organizational culture improvement model for the following dimensions: effective communication, participatory decision-making, goal setting, planning, implementation and recording, supervision and control, and improvement of motivation. After recording the data, it was analyzed in the chi-square test, t-independent and Mann-Whitney U tests. The significance level of tests was assumed to be 0.05. SPSS version 18 was also utilized for data analysis. Research results revealed that variations in the mean scores of situational and personality anxiety of the control and experiment group were descending following the intervention, but the decrease was higher in the experiment group (p≤0.0001). In addition, the variations of the mean scores of patients' satisfaction with education were higher in the experiment group than the control group (p≤0.0001). Utilization of the organizational culture improvement model of patient education reduces stress in CABG patients and increases their satisfaction with the provided education considering the factors involved in patient education, which were incorporated in the designed model.


Optical oversampled analog-to-digital conversion.
A new approach to optical analog-to-digital (A/D) conversion based on oversampling and interpolative coding techniques is described, and both interferometric and noninterferometric architectures based on this method are presented. This new approach combines the high resolution of classical oversampled A/D conversion with the high speed of optical processing technology to extend the resolution and conversion rates beyond that currently possible with other electronic or optical converters. The proposed optical converters are simple, consisting of multiple quantum well self-electro-optic effect devices, photodetectors, and common optical components that are capable of operating at sampling rates of up to 15 Gbits/s and that can provide scalable resolutions of 16 and 8 bits at a conversion rate of 117 and 938 MHz, respectively.


Suppression of Cisplatin-Induced Vomiting by Cannabis sativa in Pigeons: Neurochemical Evidences.
Cannabis sativa (CS, family Cannabinaceae) has been reported for its anti-emetic activity against cancer chemotherapy-induced emesis in animal models and in clinics. The current study was designed to investigate CS for potential effectiveness to attenuate cisplatin-induced vomiting in healthy pigeons and to study the impact on neurotransmitters involved centrally and peripherally in the act of vomiting. High-performance liquid chromatography system coupled with electrochemical detector was used for the quantification of neurotransmitters 5-hydroxytryptamine (5HT), dopamine (DA) and their metabolites; Di-hydroxy Phenyl Acetic acid (Dopac), Homovanillic acid (HVA), and 5-hydroxy indole acetic acid (5HIAA) centrally in specific brain areas (area postrema and brain stem) while, peripherally in small intestine. Cisplatin (7 mg/kg i.v.) induce emesis without lethality across the 24 h observation period. CS hexane fraction (CS-HexFr; 10 mg/kg) attenuated cisplatin-induced emesis ∼ 65.85% (P < 0.05); the reference anti-emetic drug, metoclopramide (MCP; 30 mg/kg), produced ∼43.90% reduction (P < 0.05). At acute time point (3rd h), CS-HexFr decreased (P < 0.001) the concentration of 5HT and 5HIAA in the area postrema, brain stem and intestine, while at 18th h (delayed time point) CS-HexFr attenuated (P < 0.001) the upsurge of 5HT caused by cisplatin in the brain stem and intestine and dopamine in the area postrema. CS-HexFr treatment alone did not alter the basal neurotransmitters and their metabolites in the brain areas and intestine except 5HIAA and HVA, which were decreased significantly. In conclusion the anti-emetic effect of CS-HexFr is mediated by anti-serotonergic and anti-dopaminergic components in a blended manner at the two different time points, i.e., 3rd and 18th h in pigeons.


Early-onset type 2 diabetes impairs skeletal acquisition in the male TALLYHO/JngJ mouse.
Type 2 diabetes (T2D) incidence in adolescents is rising and may interfere with peak bone mass acquisition. We tested the effects of early-onset T2D on bone mass, microarchitecture, and strength in the TALLYHO/JngJ mouse, which develops T2D by 8 weeks of age. We assessed metabolism and skeletal acquisition in male TALLYHO/JngJ and SWR/J controls (n = 8-10/group) from 4 weeks to 8 and 17 weeks of age. Tallyho mice were obese; had an approximately 2-fold higher leptin and percentage body fat; and had lower bone mineral density vs SWR at all time points (P < .03 for all). Tallyho had severe deficits in distal femur trabecular bone volume fraction (-54%), trabecular number (-27%), and connectivity density (-82%) (P < .01 for all). Bone formation was higher in Tallyho mice at 8 weeks but lower by 17 weeks of age vs SWR despite similar numbers of osteoblasts. Bone marrow adiposity was 7- to 50-fold higher in Tallyho vs SWR. In vitro, primary bone marrow stromal cell differentiation into osteoblast and adipocyte lineages was similar in SWR and Tallyho, suggesting skeletal deficits were not due to intrinsic defects in Tallyho bone-forming cells. These data suggest the Tallyho mouse might be a useful model to study the skeletal effects of adolescent T2D.


Pancytopenia: a clinico hematological study.
Pancytopenia is a relatively common hematological entity. It is a striking feature of many serious and life-threatening illnesses, ranging from simple drug-induced bone marrow hypoplasia, megaloblastic anemia to fatal bone marrow aplasias and leukemias. The severity of pancytopenia and the underlying pathology determine the management and prognosis. Thus, identification of the correct cause will help in implementing appropriate therapy. To study the clinical presentations in pancytopenia due to various causes; and to evaluate hematological parameters, including bone marrow aspiration. It was a prospective study, and 104 pancytopenic patients were evaluated clinically, along with hematological parameters and bone marrow aspiration in Hematology Unit, Department of Pathology, JJMMC, Davanagere, during the period of September 2005 to September 2007. Among 104 cases studied, age of patients ranged from 2 to 80 years with a mean age of 41 years, and male predominance. Most of the patients presented with generalized weakness and fever. The commonest physical finding was pallor, followed by splenomegaly and hepatomegaly. Dimorphic anemia was the predominant blood picture. Bone marrow aspiration was conclusive in all cases. The commonest marrow finding was hypercellularity with megaloblastic erythropoiesis. The commonest cause for pancytopenia was megaloblastic anemia (74.04%), followed by aplastic anemia (18.26%). Thepresent study concludes that detailed primary hematological investigations along with bone marrow aspiration in cytopenic patients are helpful for understanding disease process and to diagnose or to rule out the causes of cytopenia. These are also helpful in planning further investigations and management.


Genome assembly of Nannochloropsis oceanica provides evidence of host nucleus overthrow by the symbiont nucleus during speciation.
The species of the genus Nannochloropsis are unique in their maintenance of a nucleus-plastid continuum throughout their cell cycle, non-motility and asexual reproduction. These characteristics should have been endorsed in their gene assemblages (genomes). Here we show that N. oceanica has a genome of 29.3 Mb consisting of 32 pseudochromosomes and containing 7,330 protein-coding genes; and the host nucleus may have been overthrown by an ancient red alga symbiont nucleus during speciation through secondary endosymbiosis. In addition, N. oceanica has lost its flagella and abilities to undergo meiosis and sexual reproduction, and adopted a genome reduction strategy during speciation. We propose that N. oceanica emerged through the active fusion of a host protist and a photosynthesizing ancient red alga and the symbiont nucleus became dominant over the host nucleus while the chloroplast was wrapped by two layers of endoplasmic reticulum. Our findings evidenced an alternative speciation pathway of eukaryotes.


Recurrence of renosplenic entrapment after renosplenic space ablation in a seven-year-old stallion.
A 7-year-old mixed-breed stallion was admitted because of colic. Entrapment of the left colon in the renosplenic space was diagnosed via rectal palpation and ultrasonographic examination, despite a renosplenic space ablation 6.5 years earlier. The renosplenic entrapment was corrected with a combination of phenylephrine administration, rolling, and ballottement of the horse's abdomen during general anesthesia. The following week, left flank laparoscopic renosplenic space ablation was performed with the horse standing. On examination of the previous surgical site, only 4 bands of fibrous adhesion remained of the original space ablation. The renosplenic space was again closed by suturing the perirenal fascia and renosplenic ligament to the splenic capsule. The horse was discharged from the hospital and recovered at home. No complications or recurrence of entrapment was reported following the procedure. There have been no previous reports of recurrence of renosplenic entrapment following procedures to permanently ablate the renosplenic space. Recurrence in this patient may be attributed to the horse's young age at the time of initial surgery or inadequate size or spacing of the sutures through the perirenal fascia and splenic capsule.


Preparing alpha,beta-unsaturated Fischer-type carbene complexes via an unforeseen route.
Four 4-(NH-amino)-1-metalla-1,3-diene carbene complexes, two of which contain novel 4-membered heterometallacycles, formed regioselectively from the reaction of a mixture of [(CH(3))(2)(CH(3)S)S][BF(4)], the acetonitrilium electrophile, CH(3)CNCH(3)(+), and the deprotonated alkoxycarbene complexes, (CO)(5)M=C(OCH(3))CH(2)Li (M = Cr, W). The preferred Z-configurations of the alkoxy and amino groups are determined by strong H-bonding in the products. The metal-carbene bonds in the chelates are shorter by 0.08 A than those in the acyclic compounds.


Innate immunity to adenovirus.
Human adenoviruses are the most widely used vectors in gene medicine, with applications ranging from oncolytic therapies to vaccinations, but adenovirus vectors are not without side effects. In addition, natural adenoviruses pose severe risks for immunocompromised people, yet infections are usually mild and self-limiting in immunocompetent individuals. Here we describe how adenoviruses are recognized by the host innate defense system during entry and replication in immune and nonimmune cells. Innate defense protects the host and represents a major barrier to using adenoviruses as therapeutic interventions in humans. Innate response against adenoviruses involves intrinsic factors present at constant levels, and innate factors mounted by the host cell upon viral challenge. These factors exert antiviral effects by directly binding to viruses or viral components, or shield the virus, for example, soluble factors, such as blood clotting components, the complement system, preexisting immunoglobulins, or defensins. In addition, Toll-like receptors and lectins in the plasma membrane and endosomes are intrinsic factors against adenoviruses. Important innate factors restricting adenovirus in the cytosol are tripartite motif-containing proteins, nucleotide-binding oligomerization domain-like inflammatory receptors, and DNA sensors triggering interferon, such as DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 and cyclic guanosine monophosphate-adenosine monophosphate synthase. Adenovirus tunes the function of antiviral autophagy, and counters innate defense by virtue of its early proteins E1A, E1B, E3, and E4 and two virus-associated noncoding RNAs VA-I and VA-II. We conclude by discussing strategies to engineer adenovirus vectors with attenuated innate responses and enhanced delivery features.


What and How Can Physical Activity Prevention Function on Parkinson's Disease?
This study was aimed at investigating the effects and molecular mechanisms of physical activity intervention on Parkinson's disease (PD) and providing theoretical guidance for the prevention and treatment of PD. Four electronic databases up to December 2019 were searched (PubMed, Springer, Elsevier, and Wiley database), 176 articles were selected. Literature data were analyzed by the logic analysis method. (1) Risk factors of PD include dairy products, pesticides, traumatic brain injury, and obesity. Protective factors include alcohol, tobacco, coffee, black tea, and physical activity. (2) Physical activity can reduce the risk and improve symptoms of PD and the beneficial forms of physical activity, including running, dancing, traditional Chinese martial arts, yoga, and weight training. (3) Different forms of physical activity alleviate the symptoms of PD through different mechanisms, including reducing the accumulation of α-syn protein, inflammation, and oxidative stress, while enhancing BDNF activity, nerve regeneration, and mitochondrial function. Physical activity has a positive impact on the prevention and treatment of PD. Illustrating the molecular mechanism of physical activity-induced protective effect on PD is an urgent need for improving the efficacy of PD therapy regimens in the future.


Genetic susceptibility to diabetes mellitus: the distribution of properdin factor B (Bf) and glyoxalase (GLO) phenotypes.
The distribution of phenotypes controlled by two loci on chromosome 6 has been studied in a series of 239 patients with type 1 (insulin-dependent) and 297 patients with type 2 (non-insulin-dependent) diabetes mellitus. At the properdin factor B (Bf) locus there is a significant increase in the frequency of the BfSu and BfF1 alleles for type 1 patients, and the combined inc;rease in frequency of BfS1 and BfF1 in those patients is highly significant. The relative risk for F1 is 6.2 and for F1 and S1 combined is 5.3. These results confirm the association with F1 reported recently by Raum and co-workers in Boston. The two rare alleles BfS1 and BfF1 are in significant negative disequilibrium with HLA B8. For the glyoxalase (GLO) locus there is a slight but nonsignificant increase in the frequency of the GLO2 allele, but a significant disturbance in the distribution of the GLO phenotypes for type 2 patients. These results for the GLO alleles may be due to stratification in our series of type 2 patients. Further studies are in progress to test this hypothesis.


Bacterial infections in Lilongwe, Malawi: aetiology and antibiotic resistance.
Life-threatening infections present major challenges for health systems in Malawi and the developing world because routine microbiologic culture and sensitivity testing are not performed due to lack of capacity. Use of empirical antimicrobial therapy without regular microbiologic surveillance is unable to provide adequate treatment in the face of emerging antimicrobial resistance. This study was conducted to determine antimicrobial susceptibility patterns in order to inform treatment choices and generate hospital-wide baseline data. Culture and susceptibility testing was performed on various specimens from patients presenting with possible infectious diseases at Kamuzu Central Hospital, Lilongwe, Malawi. Between July 2006 and December 2007 3104 specimens from 2458 patients were evaluated, with 60.1% from the adult medical service. Common presentations were sepsis, meningitis, pneumonia and abscess. An etiologic agent was detected in 13% of patients. The most common organisms detected from blood cultures were Staphylococcus aureus, Escherichia coli, Salmonella species and Streptococcus pneumoniae, whereas Streptococcus pneumoniae and Cryptococcus neoformans were most frequently detected from cerebrospinal fluid. Haemophilus influenzae was rarely isolated. Resistance to commonly used antibiotics was observed in up to 80% of the isolates while antibiotics that were not commonly in use maintained susceptibility. There is widespread resistance to almost all of the antibiotics that are empirically used in Malawi. Antibiotics that have not been widely introduced in Malawi show better laboratory performance. Choices for empirical therapy in Malawi should be revised accordingly. A microbiologic surveillance system should be established and prudent use of antimicrobials promoted to improve patient care.


[Recommendations from a panel of experts on the usefulness of fidaxomicin for the treatment of infections caused by Clostridium difficile].
Clostridium difficile infections have a high recurrence rate, which can complicate the prognosis of affected patients. It is therefore important to establish an early detection and an appropriate therapeutic strategy. The objective of this manuscript was to gather the opinion of an expert group about the predictive factors of poor progression, as well as when to use fidaxomicin in different groups of high-risk patients. A scientific committee of three experts in infectious diseases reviewed the most recent literature on the management of C. difficile infections, and the use of fidaxomicin. They developed a questionnaire of 23 items for consensus by 15 specialists in this type of infection using a modified Delphi method. The consensus reached by the panelists was 91.3% in terms of agreement. The most important agreements were: recurrence is a risk criterion per se; fidaxomicin is effective and safe for the treatment of infections caused by C. difficile in critical patients, immunosuppressed patients, or patients with chronic renal failure; fidaxomicin is recommended from the first episode of infection to ensure maximum efficacy in patients with well-contrasted recurrence risk factors. The experts consulted showed a high degree of agreement on topics related to the selection of patients with poorer prognosis, as well as on the use of fidaxomicin in groups of high-risk patients, either in the first line or in situations of recurrence.


Randomized Trial Evaluating Percutaneous Coronary Intervention for the Treatment of Chronic Total Occlusion.
Procedural results for percutaneous coronary intervention (PCI) in coronary vessels with chronic total occlusion (CTO) have improved in recent years, and PCI strategies have moved toward more complete revascularization with more liberal use of CTO-PCI. However, evidence evaluating CTO-PCI is limited to observational studies and small clinical trials. In this open-label, multicenter, randomized, noninferiority trial, PCI-eligible patients were assigned to receive either 1 of 2 strategies: PCI or no PCI for the qualifying de novo CTO lesion with the option for PCI of obstructive non-CTO lesions at the discretion of the operator. The primary end point was a composite of death, myocardial infarction, stroke, or any revascularization. Health-related quality of life was assessed at baseline and at 1, 6, 12, 24, and 36 months. Because of slow recruitment, the trial was stopped before completion of the 1284 planned enrollments. Between March 2010 and September 2016, 834 patients were randomly assigned to the CTO-PCI (n=417) or no CTO-PCI (n=398) strategy. Among the patients assigned to the no CTO-PCI strategy, 78 (19.6%) crossed over to receive staged CTO-PCI within 3 days of randomization. The overall CTO-PCI success rate was 90.6%. Serious nonfatal complications associated with CTO-PCI occurred in 3 patients (1 stroke, 1 cardiac tamponade, and 1 patient with recurrent episodes of ventricular tachyarrhythmia induced by intracoronary thrombus). Approximately half of the patients in each group underwent PCI for an average of 1.3 non-CTO lesions, resulting in a comparable residual SYNTAX score (Synergy Between PCI With TAXUS and Cardiac Surgery; 3.7±5.4 versus 4.0±5.9, P=0.42) confined to non-CTO vessels. During a median follow-up of 4.0 years (interquartile range, 2.4 to 5.1 years), there was no significant difference between the CTO-PCI and the no CTO-PCI strategies in the incidence of the primary end point (22.3% versus 22.4%, hazard ratio, 1.03; 95% CI, 0.77 to 1.37; P=0.86). Both CTO-PCI and no CTO-PCI strategy were associated with significant improvements but without between-group differences in disease-specific health status that was sustained through 36 months. CTO-PCI was feasible with high success rates. There was no difference in the incidence of major adverse cardiovascular events with CTO-PCI versus no CTO-PCI, but the study was limited by low power for clinical end points and high crossover rates between groups. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01078051.


Plasma metabolomic biomarker panel to distinguish patients with amyotrophic lateral sclerosis from disease mimics.
Our objective was to identify plasma biomarkers of ALS that can aid in distinguishing patients with ALS from those with disease mimics. In this multi-center study, plasma samples were collected from 172 patients recently diagnosed with ALS, 50 healthy controls, and 73 neurological disease mimics. Samples were analyzed using metabolomics. Using all identified biochemicals detected in > 50% of all samples in the metabolomics analysis, samples were classified as ALS or mimic with 65% sensitivity and 81% specificity by LASSO analysis (AUC of 0.76). A subset panel of 32 candidate biomarkers classified these diagnosis groups with a specificity of 90%/sensitivity 58% (AUC of 0.81). Creatinine was lower in subjects with lower revised ALS Functional Rating Scale (ALSFRS-R) scores. In conclusion, ALS can be distinguished from neurological disease mimics by global biochemical profiling of plasma samples. Our analysis identified ALS versus mimics with relatively high sensitivity. We identified a subset of 32 metabolites that identify patients with ALS with a high specificity. Interestingly, lower creatinine correlates significantly with a lower ALSFRS-R score. Finally, molecules previously reported to be important in disease pathophysiology, such as urate, are included in our metabolite panel.


Evaluating the impact of Mexico's drug policy reforms on people who inject drugs in Tijuana, B.C., Mexico, and San Diego, CA, United States: a binational mixed methods research agenda.
Policymakers and researchers seek answers to how liberalized drug policies affect people who inject drugs (PWID). In response to concerns about the failing "war on drugs," Mexico recently implemented drug policy reforms that partially decriminalized possession of small amounts of drugs for personal use while promoting drug treatment. Recognizing important epidemiologic, policy, and socioeconomic differences between the United States-where possession of any psychoactive drugs without a prescription remains illegal-and Mexico-where possession of small quantities for personal use was partially decriminalized, we sought to assess changes over time in knowledge, attitudes, behaviors, and infectious disease profiles among PWID in the adjacent border cities of San Diego, CA, USA, and Tijuana, Baja California, Mexico. Based on extensive binational experience and collaboration, from 2012-2014 we initiated two parallel, prospective, mixed methods studies: Proyecto El Cuete IV in Tijuana (n = 785) and the STAHR II Study in San Diego (n = 575). Methods for sampling, recruitment, and data collection were designed to be compatible in both studies. All participants completed quantitative behavioral and geographic assessments and serological testing (HIV in both studies; hepatitis C virus and tuberculosis in STAHR II) at baseline and four semi-annual follow-up visits. Between follow-up assessment visits, subsets of participants completed qualitative interviews to explore contextual factors relating to study aims and other emergent phenomena. Planned analyses include descriptive and inferential statistics for quantitative data, content analysis and other mixed-methods approaches for qualitative data, and phylogenetic analysis of HIV-positive samples to understand cross-border transmission dynamics. Investigators and research staff shared preliminary findings across studies to provide feedback on instruments and insights regarding local phenomena. As a result, recruitment and data collection procedures have been implemented successfully, demonstrating the importance of binational collaboration in evaluating the impact of structural-level drug policy reforms on the behaviors, health, and wellbeing of PWID across an international border. Our prospective, mixed methods approach allows each study to be responsive to emerging phenomena within local contexts while regular collaboration promotes sharing insights across studies. The strengths and limitations of this approach may serve as a guide for other evaluations of harm reduction policies internationally.


A missense mutation of the Dhh gene is associated with male pseudohermaphroditic rats showing impaired Leydig cell development.
Development of the male gonads is a complex process with interaction of various cells in the gonads including germ, Sertoli, Leydig, and myoid cells. TF is a mutant rat strain showing male pseudohermaphroditism, with agenesis of Leydig cells and androgen deficiency controlled by an autosomal single recessive gene (mp). The mp locus was mapped on the distal region of rat chromosome 7 by linkage analysis, but the gene responsible for the mp mutation has not been identified. In this study, we performed fine linkage mapping and sequence analysis to determine the causative gene of the mp mutation, and performed an immunohistochemical study using a Leydig cell-specific marker to investigate detailed phenotypes of the mutant rats during the testicular development. As a result, we found a missense mutation of the gene encoding Desert hedgehog (Dhh) in the mutant rat, which could result in loss of function of the DHH signaling pathway. Histochemical examination revealed remarkably reduced number of fetal Leydig cells and lack of typical spindle-shaped adult Leydig cell in the mp/mp rats. These phenotypes resembled those of the Dhh-null mice. Additionally, testosterone levels were significantly lower in the mp/mp fetus, indicating androgen deficiency during embryonic development. These results indicate that the mutation of the Dhh gene may be responsible for the pseudohermaphrodite phenotypes of the mutant rat, and that the Dhh gene is probably essential for the development of Leydig cells.


Is intercalation a critical factor in the covalent binding of mutagenic and tumorigenic polycyclic aromatic diol epoxides to DNA?
The tumorigenic and mutagenic effects induced by polycyclic aromatic diol epoxides are widely believed to involve the covalent binding of these electrophilic metabolites of polycyclic aromatic hydrocarbons to DNA. Here the relationships between the formation of non-covalent intercalation complexes with DNA, the DNA-catalyzed reaction rates, the formation of tetraols (which constitutes a detoxification pathway) and the level of covalent binding to DNA, are examined critically within the context of available experimental results. When the rates of reaction of the diol epoxide molecules at DNA binding sites dominate over those in the external aqueous solution, the level of covalent binding is independent of the intercalative non-covalent binding (association constant K, M-1) which precedes the covalent binding reaction. However, under conditions in which DNA does not catalyze or enhance the reaction rate of diol epoxide molecules (e.g. at high salt concentrations), or when there are efficient competitive reaction pathways in the solution external to the DNA, the level of covalent binding to DNA is predicted to be directly proportional to K. Since these latter reaction conditions are expected to prevail in a cellular environment, the ability of a given diol epoxide derivative to form intercalative non-covalent complexes with DNA prior to covalent binding should be an important factor in determining the biological activities of these compounds. The experimental conditions which are suitable for testing the relationships between non-covalent intercalative complex formation and covalent binding to DNA in vitro are described.