Kinetic analysis of 3'-deoxy-3'-18F-fluorothymidine in patients with gliomas.
3'-Deoxy-3'-fluorothymidine (FLT), a thymidine analog, is under investigation for monitoring cellular proliferation in gliomas, a potential measure of disease progression and response to therapy. Uptake may result from retention in the biosynthetic pathway or leakage via the disrupted blood-tumor barrier. Visual analysis or static measures of 18F-FLT uptake are problematic as transport and retention cannot be distinguished. Twelve patients with primary brain tumors were imaged for 90 min of dynamic 18F-FLT PET with arterial blood sampling. Total blood activity was corrected for labeled metabolites to provide an FLT input function. A 2-tissue compartment, 4-rate-constant model was used to determine blood-to-tissue transport (K1) and metabolic flux (K(FLT)). Modeling results were compared with MR images of blood-brain barrier (BBB) breakdown revealed by gadolinium (Gd) contrast enhancement. Parametric image maps of K1 and K(FLT) were produced by a mixture analysis approach. Similar to prior work with 11C-thymidine, identifiability analysis showed that K1 (transport) and K(FLT) (flux) could be estimated independently for sufficiently high K1 values. However, estimation of K(FLT) was less robust at low K1 values, particularly those close to normal brain. K1 was higher for MRI contrast-enhancing (CE) tumors (0.053 +/- 0.029 mL/g/min) than noncontrast-enhancing (NCE) tumors (0.005 +/- 0.002 mL/g/min; P < 0.02), and K(FLT) was higher for high-grade tumors (0.018 +/- 0.008 mL/g/min, n = 9) than low-grade tumors (0.003 +/- 0.003 mL/g/min, n = 3; P < 0.01). The flux in NCE tumors was indistinguishable from contralateral normal brain (0.002 +/- 0.001 mL/g/min). For CE tumors, K1 was higher than K(FLT). Parametric images matched region-of-interest estimates of transport and flux. However, no patient has 18F-FLT uptake outside of the volume of increased permeability defined by MRI T1+Gd enhancement. Modeling analysis of 18F-FLT PET data yielded robust estimates of K1 and K(FLT) for enhancing tumors with sufficiently high K1 and provides a clearer understanding of the relationship between transport and retention of 18F-FLT in gliomas. In tumors that show breakdown of the BBB, transport dominates 18F-FLT uptake. Transport across the BBB and modest rates of 18F-FLT phosphorylation appear to limit the assessment of cellular proliferation using 18F-FLT to highly proliferative tumors with significant BBB breakdown.


Spatial-temporal modeling of neighborhood sociodemographic characteristics and food stores.
The literature on food stores, neighborhood poverty, and race/ethnicity is mixed and lacks methods of accounting for complex spatial and temporal clustering of food resources. We used quarterly data on supermarket and convenience store locations from Nielsen TDLinx (Nielsen Holdings N.V., New York, New York) spanning 7 years (2006-2012) and census tract-based neighborhood sociodemographic data from the American Community Survey (2006-2010) to assess associations between neighborhood sociodemographic characteristics and food store distributions in the Metropolitan Statistical Areas (MSAs) of 4 US cities (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and San Francisco, California). We fitted a space-time Poisson regression model that accounted for the complex spatial-temporal correlation structure of store locations by introducing space-time random effects in an intrinsic conditionally autoregressive model within a Bayesian framework. After accounting for census tract-level area, population, their interaction, and spatial and temporal variability, census tract poverty was significantly and positively associated with increasing expected numbers of supermarkets among tracts in all 4 MSAs. A similar positive association was observed for convenience stores in Birmingham, Minneapolis, and San Francisco; in Chicago, a positive association was observed only for predominantly white and predominantly black tracts. Our findings suggest a positive association between greater numbers of food stores and higher neighborhood poverty, with implications for policy approaches related to food store access by neighborhood poverty.


Female teachers' math anxiety affects girls' math achievement.
People's fear and anxiety about doing math--over and above actual math ability--can be an impediment to their math achievement. We show that when the math-anxious individuals are female elementary school teachers, their math anxiety carries negative consequences for the math achievement of their female students. Early elementary school teachers in the United States are almost exclusively female (>90%), and we provide evidence that these female teachers' anxieties relate to girls' math achievement via girls' beliefs about who is good at math. First- and second-grade female teachers completed measures of math anxiety. The math achievement of the students in these teachers' classrooms was also assessed. There was no relation between a teacher's math anxiety and her students' math achievement at the beginning of the school year. By the school year's end, however, the more anxious teachers were about math, the more likely girls (but not boys) were to endorse the commonly held stereotype that "boys are good at math, and girls are good at reading" and the lower these girls' math achievement. Indeed, by the end of the school year, girls who endorsed this stereotype had significantly worse math achievement than girls who did not and than boys overall. In early elementary school, where the teachers are almost all female, teachers' math anxiety carries consequences for girls' math achievement by influencing girls' beliefs about who is good at math.


Factors affecting epilepsy development and epilepsy prognosis in cerebral palsy.
A study was conducted between November 2006 and October 2009 to determine the factors predicting the presence and prognosis of epilepsy in patients with cerebral palsy. We enrolled 2 groups of patients: 42 with cerebral palsy in group 1 and 56 patients with cerebral palsy and epilepsy in group 2. The subjects in group 2 were considered to have good epilepsy prognosis if they were free of seizures for the previous year; otherwise they were considered to have poor epilepsy prognosis. In group 2, neonatal epilepsy, family history of epilepsy, and moderate to severe mental retardation were significantly higher than in group 1 (P < 0.05). In univariate analysis, neonatal seizures, epileptic activity as measured by electroencephalography, and polytherapy were found to be predictors of poor epilepsy prognosis. Additionally, the need for long-term medication to control seizures unfavorably affects prognosis. In logistic regression analysis, neonatal seizure and interictal epileptic activity in electroencephalography were found to be independent predictors of poor epilepsy outcome. In addition, logistic regression analysis revealed that increasing age reduces the success of epilepsy treatment. Neonatal seizures, family history of epilepsy, and mental retardation were found to be important and independent predictors of development of epilepsy in patients with cerebral palsy.


Distributed patterns of occipito-parietal functional connectivity predict the precision of visual working memory.
Limitations in visual working memory (WM) quality (i.e., WM precision) may depend on perceptual and attentional limitations during stimulus encoding, thereby affecting WM capacity. WM encoding relies on the interaction between sensory processing systems and fronto-parietal 'control' regions, and differences in the quality of this interaction are a plausible source of individual differences in WM capacity. Accordingly, we hypothesized that the coupling between perceptual and attentional systems affects the quality of WM encoding. We combined fMRI connectivity analysis with behavioral modeling by fitting a variable precision and fixed capacity model to the performance data obtained while participants performed a visual delayed continuous response WM task. We quantified functional connectivity during WM encoding between occipital and parietal brain regions activated during both perception and WM encoding, as determined using a conjunction of two independent experiments. The multivariate pattern of voxel-wise inter-areal functional connectivity significantly predicted WM performance, most specifically the mean of WM precision but not the individual number of items that could be stored in memory. In particular, higher occipito-parietal connectivity was associated with higher behavioral mean precision. These results are consistent with a network perspective of WM capacity, suggesting that the efficiency of information flow between perceptual and attentional neural systems is a critical determinant of limitations in WM quality.


Systemic availability and lymphatic transport of human growth hormone administered by subcutaneous injection.
Degradation of human growth hormone (hGH) at the injection site has previously been implicated as the basis for its reduced systemic availability following subcutaneous (SC) administration. The goal of these studies was to develop an animal model which would allow mass balance calculations to (i) quantify the loss at the injection site and (ii) determine the role of the lymphatics in the transport of subcutaneously-administered hGH. The animal model utilized a sheep and enabled simultaneous sampling of blood and collection of either peripheral lymph (via the efferent duct of the popliteal lymph node draining the injection site) or central lymph (via the thoracic lymph duct). In non-lymph cannulated sheep, the systemic availability of hGH following SC dosing was 58.4 +/- 9.1% (mean +/- SEM) relative to an intravenous (IV) control. The availability of hGH decreased to approximately 30-40% when either peripheral or central lymph was collected indicating that a proportion of the dose was transported via the lymph. The fraction of the administered dose collected in peripheral lymph was 61.7 +/- 8.5% (mean +/- SEM), whereas only 8.6 +/- 1.3% was collected in central lymph. These results suggested that loss of hGH within the lymphatics contributed significantly to its reduced systemic availability following SC administration. The total recovery (sum of the systemic availability and the cumulative amount recovered in lymph) of hGH was approximately 93% of the dose in the peripherally-cannulated group indicating that loss at the injection site was minimal.


Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces.
It is now understood that the nonclassical major histocompatibility complex-I molecule FcRn binds albumin and retrieves it from an intracellular degradative fate. Whether FcRn in the liver modulates albumin turnover through effects on biosynthesis and production is not known. Thus we quantified the appearance of biosynthetically labeled albumin in plasma after an intravenous bolus injection of [(3)H]leucine in FcRn-deficient mice. The production rates for both albumin (FcRn substrate) and transferrin (nonsubstrate) are increased by approximately 20% in FcRn-deficient mice compared with normal mice, likely compensating for the lowered plasma oncotic pressure caused by hypoalbuminemia in FcRn-deficient mice. Determining the magnitude of FcRn-mediated effects on albumin turnover, we then measured the steady-state plasma concentrations of biosynthetically labeled albumin and transferrin during [(3)H]leucine infusion. The concentration of albumin was approximately 40% lower in FcRn-deficient mice compared with normal mice. Furthermore, the approximately 40% lower plasma albumin concentration in FcRn-deficient mice along with the approximately 20% increase in albumin production indicate, by the mass-balance equation, that albumin degradation in FcRn-deficient mice is twice that of normal mice. These studies of biosynthetically labeled, and thus native, albumin support our previous finding that FcRn protects albumin from degradation. Permitting quantification of the magnitude of FcRn-mediated recycling, they further indicate that FcRn has extraordinary capacity: the amount of albumin saved from degradation by FcRn-mediated recycling is the same as that produced by the liver.


UltraFast Doppler ultrasonography for hepatic vessels of liver recipients: preliminary experiences.
The purpose of this study was to investigate the value of UltraFast Doppler ultrasonography (US) for evaluating hepatic vessels in liver recipients. Thirty-nine liver Doppler US sessions were conducted in 20 liver recipients. Each session consisted of UltraFast and conventional liver Doppler US in a random order. We compared the velocities and phasicities of the hepatic vessels, duration of each Doppler study, occurrence of technical failures, and differences in clinical decisions. The velocities and resistive index values of hepatic vessels showed a strong positive correlation between the two Doppler studies (mean R=0.806; range, 0.710 to 0.924). The phasicities of the hepatic vessels were the same in both Doppler US exams. With respect to the duration of the Doppler US exam, there was no significant difference between the UltraFast (251±99 seconds) and conventional (231±117 seconds) Doppler studies (P=0.306). In five poor breath-holders, in whom the duration of conventional Doppler US was longer, UltraFast Doppler US (272±157 seconds) required a shorter time than conventional Doppler US (381±133 seconds; P=0.005). There was no difference between the two techniques with respect to technical failures and clinical decisions. UltraFast Doppler US is clinically equivalent to conventional Doppler US with advantages for poor breath-holders during the post-liver transplantation work-up.


FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes.
FTY720 is a sphingosine-derived immunosuppressant. Phosphorylated FTY720 promotes T cell homing from spleen and peripheral blood to LNs by acting as an agonist for sphingosine-1-phosphate (S1P) receptors. Here we demonstrate that FTY720 enhances the activity of the sphingosine transporter Abcb1 (Mdr1) and the leukotriene C(4) transporter Abcc1 (Mrp1). Both transporters must be active for FTY720-mediated T cell migration and LN homing. Migration and homing driven by FTY720, phosphorylated FTY720, or S1P also require 5-lipoxygenase-mediated synthesis of cysteinyl leukotrienes and their efflux from the cell. FTY720-mediated LN homing events further downstream are dependent on CCL19, CCL21, VLA-4alpha, and CD44. Use of T cells deficient in 5-lipoxygenase, Abcb1, and Abcc1, and comparison of the effects of FTY720 with those of S1P, suggest a model of sequential engagement of Abcb1, SP1 receptors, 5-lipoxygenase, and Abcc1 to enhance T cell migration and homing.


Structure and function of the Escherichia coli Tol-Pal stator protein TolR.
TolR is a 15-kDa inner membrane protein subunit of the Tol-Pal complex in Gram-negative bacteria, and its function is poorly understood. Tol-Pal is recruited to cell division sites where it is involved in maintaining the integrity of the outer membrane. TolR is related to MotB, the peptidoglycan (PG)-binding stator protein from the flagellum, suggesting it might serve a similar role in Tol-Pal. The only structure thus far reported for TolR is of the periplasmic domain from Haemophilus influenzae in which N- and C-terminal residues had been deleted (TolR(62-133), Escherichia coli numbering). H. influenzae TolR(62-133) is a symmetrical dimer with a large deep cleft at the dimer interface. Here, we present the 1.7-Å crystal structure of the intact periplasmic domain of E. coli TolR (TolR(36-142)). E. coli TolR(36-142) is also dimeric, but the architecture of the dimer is radically different from that of TolR(62-133) due to the intertwining of its N and C termini. TolR monomers are rotated ∼180° relative to each other as a result of this strand swapping, obliterating the putative PG-binding groove seen in TolR(62-133). We found that removal of the strand-swapped regions (TolR(60-133)) exposes cryptic PG binding activity that is absent in the full-length domain. We conclude that to function as a stator in the Tol-Pal complex dimeric TolR must undergo large scale structural remodeling reminiscent of that proposed for MotB, where the N- and C-terminal sequences unfold in order for the protein to both reach and bind the PG layer ∼90 Å away from the inner membrane.


Three-photon-excited upconversion luminescence of niobium ions doped silicate glass by a femtosecond laser irradiation.
We report on the bluish green upconversion luminescence of niobium ions doped silicate glass by a femtosecond laser irradiation. The dependence of the fluorescence intensity on the pump power density of laser indicates that the conversion of infrared irradiation to visible emission is dominated by three-photon excitation process. We suggest that the charge transfer from O(2-) to Nb(5+) can efficiently contribute to the bluish green emission. The results indicate that transition metal ions without d electrons play an important role in fields of optics when embedded into silicate glass matrix.


The manifold actions of endocannabinoids on female and male reproductive events.
Epidemiological studies have highlighted the ever growing use of illegal drugs among teenagers. The negative effects of marijuana (a Cannabis sativa extract) on reproductive health are poorly known among young people, although chronic exposure to delta-9-tetrahydrocannabinol, the main psychoactive constituent of marijuana, impairs human reproductive potential by disrupting menstrual cycle, suppressing oogenesis and impairing embryo implantation and development, in women, and by increasing ejaculation problems, reducing sperm count and motility, and generating loss of libido and impotence, in men. Endocannabinoids, their metabolic enzymes and target receptors form the so called "endocannabinoid system" and they have been demonstrated to respond to fertility signals. In addition, they interfere with hormones, cytokines and other signalling molecules in both female and male reproductive events. In this review, we shall summarize the current knowledge on the endocannabinoid system, and on the multifaceted roles played by endocannabinoids in reproduction along the evolutionary axis from invertebrates to mammals. Furthermore, we shall discuss the potential use of distinct elements of the endocannabinoid system for the diagnosis and/or treatment of human infertility.


Global Trends and Prostate Cancer: A Review of Incidence, Detection, and Mortality as Influenced by Race, Ethnicity, and Geographic Location.
Although research has reported that prostate cancer (PCa) incidence and mortality rates are among the highest for African Americans, the data is inconclusive regarding PCa rates in native African men, Black men residing in other countries, and men in Asia, Europe, and the Americas. Data reveals that prostate-specific antigen (PSA) testing and disease incidence have risen significantly in developing and Asian countries, and PCa has become one of the leading male cancers in many of those nations. The objective of this study was to review published peer-reviewed studies that address PCa in different regions of the world to get a better understanding of how PCa incidence, prevalence, detection, and mortality are influenced by race, ethnicity, and geography. A secondary goal was to compare PCa data from various world regions to contextualize how disproportionate the incidence and mortality rates are among men from the African diaspora versus men of European, Hispanic, and Asian descent, as well as to highlight the need for more robust screening and treatment guidelines in developing countries. There are differences in incidence and mortality rates between men of African, Asian, Hispanic, and European ancestry, confirming the involvement of genetic factors. However, differences between men of the same race and ethnicity who live in different countries suggest that environmental factors may also be implicated. Availability and access to diagnostic and health-care services as well as recommendations regarding PCa testing vary from country to country and contribute to the variability in incidence and mortality rates.


Antiretroviral drug supply challenges in the era of scaling up ART in Malawi.
The number of people receiving antiretroviral treatment (ART) has increased considerably in recent years and is expected to continue to grow in the coming years. A major challenge is to maintain uninterrupted supplies of antiretroviral (ARV) drugs and prevent stock outs. This article discusses issues around the management of ARVs and prevention of stock outs in Malawi, a low-income country with a high HIV/AIDS burden, and a weak procurement and supply chain management system. This system for ARVs, paid for by the Global Fund to Fight AIDS, Tuberculosis and Malaria, and bypassing the government Central Medical Stores, is in place, using the United Nations Children's Fund's (UNICEF's) procurement services. The system, managed by a handful of people who spend limited time on supply management, is characterized by a centrally coordinated quantification based on verified data from all national ART clinics, parallel procurement through UNICEF, and direct distribution to ART clinics. The model worked well in the first years of the ART programme with a single first-line ARV regimen, but with more regimens becoming available (e.g., alternative first-line, second-line and paediatric regimens), it has become more difficult to administer. Managing supplies through a parallel system has the advantage that weaknesses in the national system have limited influence on the ARV procurement and supply chain management system. However, as the current system operates without a central warehouse and national buffer stock capacity, it diminishes the ability to prevent ARV stock outs. The process of ordering ARVs, from the time that estimates are made to the arrival of supplies in health facilities, takes approximately one year. Addressing the challenges involved in maintaining ARVs through an efficient procurement and supply chain management system that prevents ARV stock outs through the establishment of a dedicated procurement team, a central warehouse and/or national buffer stock is a priority.


Infections in Moderate to Severe Psoriasis Patients Treated with Biological Drugs Compared to Classic Systemic Drugs: Findings from the BIOBADADERM Registry.
Information regarding the safety of biological drugs prescribed to psoriasis patients on daily and long-term bases is insufficient. We used data from the BIOBADADERM registry (Spanish Registry of Adverse Events for Biological Therapy in Dermatological Diseases) to generate crude rates of infection during therapy with systemic drugs, including biological drugs (infliximab, etanercept, adalimumab, and ustekinumab) and nonbiological drugs (acitretin, cyclosporine, and methotrexate). We also calculated unadjusted and adjusted risk ratios (RRs) (with propensity score adjustment) of infection, serious infections, and recurrent infections of systemic therapies compared with methotrexate, using Poisson regression. Our study included records of 2,153 patients (7,867.5 person-years). The adjusted RR of overall infection was significantly increased in the groups treated with adalimumab with methotrexate (adjusted RR = 2.13, 95% confidence interval [CI] = 1.2-3.7), infliximab (adjusted RR = 1.71, 95% CI = 1.1-2.65), cyclosporine (adjusted RR = 1.58, 95% CI = 1.17-2.15), ustekinumab with methotrexate (adjusted RR = 1.56, 95% CI = 1.08-2.25), and etanercept (adjusted RR = 1.34, 95% CI: 1.02-1.76) compared with methotrexate alone. Cyclosporine had a significant risk of serious infection (adjusted RR = 3.12, 95% CI = 1.1-8.8), followed by adalimumab combined with methotrexate (adjusted RR = 3.28, 95% CI = 0.8-13.5). Adalimumab in combination with methotrexate had the highest risk of infection recurrence (adjusted RR = 4.33, 95% CI = 2.27-8.24).


Structural Validity of the World Assumption Scale.
The World Assumption Scale (WAS) is a frequently used measure in trauma research. The 32 items of the WAS are intended to represent eight assumptions about the benevolence of the world, the meaningfulness of events, and the worthiness of the self. Debate about the validity of the WAS is ongoing, particularly in terms of its empirical factor structure; some studies have confirmed a model of eight correlated factors whereas several other studies have not. The WAS items were administered to a clinical sample of patients who sought professional help because of posttraumatic complaints (n = 1,791) as well as a sample of healthcare professionals (n = 236). We split the clinical sample into three subsamples, then performed exploratory factor analysis using data from one subsample and tested the factor structure with confirmatory factor analysis using the other two subsamples. A consistent model of eight correlated factors was demonstrated, with almost all factors showing acceptable reliability, Cronbach's αs = .68-.84. We tested this factor model against data from the sample of healthcare professionals with increasingly stringent levels of invariance and found it to be scalar invariant (same structure, loadings, and thresholds). In a regression analysis, five factors showed significant associations with posttraumatic stress disorder (PTSD) symptoms, and two factors had unique associations with PTSD symptoms after we controlled for traumatic events: Self-Worth, β = -.31; and Luck, β = -.15. Future research should aim to distinguish between different assumptions and their individual influences on posttraumatic complaints.


Genomic Characterization of Candidate Division LCP-89 Reveals an Atypical Cell Wall Structure, Microcompartment Production, and Dual Respiratory and Fermentative Capacities.
Recent experimental and bioinformatic advances enable the recovery of genomes belonging to yet-uncultured microbial lineages directly from environmental samples. Here, we report on the recovery and characterization of single amplified genomes (SAGs) and metagenome-assembled genomes (MAGs) representing candidate phylum LCP-89, previously defined based on 16S rRNA gene sequences. Analysis of LCP-89 genomes recovered from Zodletone Spring, an anoxic spring in Oklahoma, predicts slow-growing, rod-shaped organisms. LCP-89 genomes contain genes for cell wall lipopolysaccharide (LPS) production but lack the entire machinery for peptidoglycan biosynthesis, suggesting an atypical cell wall structure. The genomes, however, encode S-layer homology domain-containing proteins, as well as machinery for the biosynthesis of CMP-legionaminate, inferring the possession of an S-layer glycoprotein. A nearly complete chemotaxis machinery coupled to the absence of flagellar synthesis and assembly genes argues for the utilization of alternative types of motility. A strict anaerobic lifestyle is predicted, with dual respiratory (nitrite ammonification) and fermentative capacities. Predicted substrates include a wide range of sugars and sugar alcohols and a few amino acids. The capability of rhamnose metabolism is confirmed by the identification of bacterial microcompartment genes to sequester the toxic intermediates generated. Comparative genomic analysis identified differences in oxygen sensitivities, respiratory capabilities, substrate utilization preferences, and fermentation end products between LCP-89 genomes and those belonging to its four sister phyla (Calditrichota, SM32-31, AABM5-125-24, and KSB1) within the broader FCB (Fibrobacteres-Chlorobi-Bacteroidetes) superphylum. Our results provide a detailed characterization of members of the candidate division LCP-89 and highlight the importance of reconciling 16S rRNA-based and genome-based phylogenies.IMPORTANCE Our understanding of the metabolic capacities, physiological preferences, and ecological roles of yet-uncultured microbial phyla is expanding rapidly. Two distinct approaches are currently being utilized for characterizing microbial communities in nature: amplicon-based 16S rRNA gene surveys for community characterization and metagenomics/single-cell genomics for detailed metabolic reconstruction. The occurrence of multiple yet-uncultured bacterial phyla has been documented using 16S rRNA surveys, and obtaining genome representatives of these yet-uncultured lineages is critical to our understanding of the role of yet-uncultured organisms in nature. This study provides a genomics-based analysis highlighting the structural features and metabolic capacities of a yet-uncultured bacterial phylum (LCP-89) previously identified in 16S rRNA surveys for which no prior genomes have been described. Our analysis identifies several interesting structural features for members of this phylum, e.g., lack of peptidoglycan biosynthetic machinery and the ability to form bacterial microcompartments. Predicted metabolic capabilities include degradation of a wide range of sugars, anaerobic respiratory capacity, and fermentative capacities. In addition to the detailed structural and metabolic analysis provided for candidate division LCP-89, this effort represents an additional step toward a unified scheme for microbial taxonomy by reconciling 16S rRNA gene-based and genomics-based taxonomic outlines.


Eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio as an associated factor of high risk plaque on coronary computed tomography in patients without coronary artery disease.
Coronary computed tomography angiography (CCTA)-verified high risk plaque (HRP) characteristics including positive remodeling and low attenuation plaque have been associated with acute coronary syndromes. Several studies reported that the n-3 polyunsaturated fatty acids have been associated with cardiovascular events. However, the relationship between serum eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio and CCTA-verified HRP in patients without known coronary artery disease (CAD) is unclear. We aimed at investigating the relation between EPA/AA and CCTA-verified HRP in patients without known CAD. We included 193 patients undergoing CCTA without known CAD (65.5 ± 12.0 years, 55.0% male). No patient has been treated with EPA. The relation of coronary risk factors, lipid profile, high-sensitivity C-reactive protein, coronary artery calcification score (CACS), number of vessel disease, plaque burden, and EPA/AA with the presence of HRP was evaluated by logistic regression analysis. Incremental value of EPA/AA to predict HRP was also analyzed by C-index, NRI, and IDI. A Cox proportional hazards model was used to estimate the time to cardiovascular event. HRP was observed in 37 (19%) patients. Multivariable logistic regression analysis revealed that current smoking (OR 2.58; p=0.046), number of vessel disease (OR 1.87; p=0.031), and EPA/AA ratio (OR 0.65; p=0.0006) were independent associated factors of HRP on CCTA. Although the addition of EPA/AA to the baseline model did not significantly improve C-index, both NRI (0.60, p=0.0049) and IDI (0.054, p=0.0072) were significantly improved. Patients with HRP had significantly higher rate of events compared with patients without HRP (14% vs. 3%, Logrank p=0.0004). On multivariable Cox hazard analysis, baseline EPA/AA ratio was an independent predictor (HR 0.57, p=0.047). Low EPA/AA was an associated factor of HRP on CCTA in patients without CAD. In addition to conventional coronary risk factors and CACS, EPA/AA and CCTA might be useful for risk stratification of CAD.


The Role of Attitudes, Social Norms, and Perceived Behavioral Control as Factors Influencing Urban and Suburban Residential Adoption of Stormwater Best Management Practices.
Nonpoint source pollution conveyed by stormwater in urban areas poses a significant threat to quality of waterbodies in the US. In the absence of systematic regulations on household stormwater management, municipalities rely largely on educational programs to encourage voluntary adoption of lawncare best management practices (BMPs) by residents who slow down and temporarily capture excess stormwater and filter out pollutants entering waterways. The current literature on factors influencing urban dwellers' adoption of lawncare BMPs mostly focuses on demographics, barriers to adoption, and effectiveness of education and outreach programs. This study applies the reasoned action approach (RAA) behavioral theory to investigate how the combination of individuals' attitudes, social norms, and perceived behavioral control may affect their decision to adopt three lawncare BMPs, including mulching and fertilizer/pesticide avoidance, and support a municipal ban on lawncare chemicals. We use survey data (n = 235) from residents in two neighboring cities in central Maine, USA. We found that perceived behavioral control predicted fertilizer/pesticide avoidance and mulching, and that beliefs and attitudes toward the outcomes of adopting lawncare BMPS were positively associated with mulching and support for a municipal ban on lawncare chemicals. We observed statistically significant but inconsistent associations between several independent variables-including descriptive and injunctive social norms, gender, level of education, age, and home ownership status-and our dependent variables of interest. The findings provide insights into an underexplored set of factors and confirmatory evidence for previously tested factors influencing urban residents' BMP adoption, and suggest new strategies and communication frames for environmental managers and researchers.


Understanding the recovery phase of breast reconstructions: Patient-reported outcomes correlated to the type and timing of reconstruction.
During preoperative discussions with breast reconstruction patients, questions often arise about what to expect during the recovery period. However, there is a paucity of data elucidating post-breast reconstruction pain, fatigue, and physical morbidity. This information is important to patient and physician understanding of reconstructive choices and the postoperative recovery process. We sought to evaluate how recovery may vary for patients based on the timing and type of reconstruction. Patients were recruited as part of the Mastectomy Reconstruction Outcomes Consortium (MROC) study, which is a prospective, multicentered National Institute of Health (NIH)-funded study (1RO1CA152192). Here, patients completed the Numerical Pain Rating Scale (NPRS), McGill Pain Questionnaire, and Breast-Q preoperatively, at 1 week, and 3 months postoperatively. Pain, fatigue, and upper body morbidity were evaluated by the type and timing of reconstruction. A total of 2013 MROC study participants had completed a 3-month follow-up, and therefore they were included for the analysis. A total of 1583 (78.6%) and 1517 patients (75.3%) completed surveys at 1 week and 3 months, respectively, post reconstruction. Across all procedure groups, fatigue and physical well-being scores did not return to preoperative levels by 3 months. At 3 months, pain measured by the NPRS differed across procedure types (P = 0.01), with tissue expander/implant (TE/I) having more pain than direct to implant (P < 0.01). Similarly, at 3 months, chest and upper body physical morbidity, as measured by BREAST-Q, differed by procedure types (P < 0.001), with generally less morbidity for autologous reconstruction as compared with TE/Is. For all reconstructive procedure groups, patients did not fully recover at 3 months post surgery. In addition, postoperative pain and upper body physical morbidity vary significantly by reconstructive procedure with patients undergoing TE/I reporting the most distress.


MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis.
Two eukaryotic pathways for processing double-strand breaks (DSBs) as crossovers have been described, one dependent on the MutL homologs Mlh1 and Mlh3, and the other on the structure-specific endonuclease Mus81. Mammalian MUS81 has been implicated in maintenance of genomic stability in somatic cells; however, little is known about its role during meiosis. Mus81-deficient mice were originally reported as being viable and fertile, with normal meiotic progression; however, a more detailed examination of meiotic progression in Mus81-null animals and WT controls reveals significant meiotic defects in the mutants. These include smaller testis size, a depletion of mature epididymal sperm, significantly upregulated accumulation of MLH1 on chromosomes from pachytene meiocytes in an interference-independent fashion, and a subset of meiotic DSBs that fail to be repaired. Interestingly, chiasmata numbers in spermatocytes from Mus81-/- animals are normal, suggesting additional integrated mechanisms controlling the two distinct crossover pathways. This study is the first in-depth analysis of meiotic progression in Mus81-nullizygous mice, and our results implicate the MUS81 pathway as a regulator of crossover frequency and placement in mammals.


Determinants of social participation--with friends and others who are not family members--for youths with cerebral palsy.
Social participation provides youths with opportunities to develop their self-concept, friendships, and meaning in life. Youths with cerebral palsy (CP) have been reported to participate more in home-based leisure activities and to have fewer social experiences with friends and others than youths without disabilities. The objective of this study was to identify youth, family, and service determinants of the participation of youths with CP in leisure activities with friends and others who are not family members. The study design was a cross-sectional analysis. The participants were 209 youths who were 13 to 21 years old (52% male), had CP, and were classified in Gross Motor Function Classification System (GMFCS) levels I to V as well as their parents. The participants were recruited from 7 children's hospitals in 6 different states. Youths completed the Children's Assessment of Participation and Enjoyment in structured interviews. Parents completed the Coping Inventory, Pediatric Outcomes Data Collection Instrument, Family Environment Scale, Measure of Processes of Care, and demographic and service questionnaires. Researchers determined GMFCS levels. A sequential multiple regression analysis was used to determine the youth, family, and service variables that predicted participation with friends and with others who were not family members. Sports and physical function, communication or speech problems, educational program, and the extent to which the desired community recreational activities were obtained explained 45.8% of the variance in the number of activities engaged in with friends. A higher level of parental education explained 6.3% of the variance in the number of activities engaged in with others who were not family members. Limitations The youths' activity preferences and intensity of participation were not examined. /b> Youth and service characteristics were determinants of participation with friends but not others who were not family members. The findings have implications for the role of physical therapists in promoting sports and physical and communication abilities and enhancing community opportunities to optimize the social participation of youths with CP.


Tai chi exercise for patients with cardiovascular conditions and risk factors: A SYSTEMATIC REVIEW.
To conduct a systematic review of the literature evaluating tai chi exercise as an intervention for patients with cardiovascular disease (CVD) or with CVD risk factors (CVDRF). We searched (1) MEDLINE, CAB Alt HealthWatch, BIOSIS previews, Science Citation Index, EMBASE, and Social Science Citation Index from inception through October 2007; (2) Chinese Medical Database, China Hospital Knowledge, China National Knowledge Infrastructure, and China Traditional Chinese Medicine Database from inception through June 2005; and (3) the medical libraries of Beijing and Nanjing Universities. Clinical studies published in English and Chinese including participants with established CVD or CVDRF were included. Data were extracted in a standardized manner; 2 independent investigators assessed methodological quality, including the Jadad score for randomized controlled trials (RCTs). Twenty-nine studies met inclusion criteria: 9 RCTs, 14 nonrandomized studies, and 6 observational trials. Three studies examined subjects with coronary heart disease, 5 in subjects with heart failure, and 10 in heterogeneous populations that included those with CVD. Eleven studies examined subjects with CVDRF (hypertension, dyslipidemia, impaired glucose metabolism). Study duration ranged from 8 weeks to 3 years. Most studies included fewer than 100 subjects (range, 5-207). Six of 9 RCTs were of adequate quality (Jadad >or= 3). Most studies reported improvements with tai chi, including blood pressure reductions and increases in exercise capacity. No adverse effects were reported. Preliminary evidence suggests that tai chi exercise may be a beneficial adjunctive therapy for some patients with CVD and CVDRF. Further research is needed.


The return of the frequency sweep: designing adiabatic pulses for contemporary NMR.
Frequency-modulated (FM) pulses that function according to adiabatic principles are becoming increasingly popular in many areas of NMR. Often adiabatic pulses can extend experimental capabilities and minimize annoying experimental imperfections. Here, adiabatic principles and some of the current methods used to create these pulses are considered. The classical adiabatic rapid passage, which is a fundamental element upon which all adiabatic pulses and sequences are based, is analyzed using vector models in different rotating frames of reference. Two methods to optimize adiabaticity are described, and ways to tailor modulation functions to best satisfy specific experimental needs are demonstrated. Finally, adiabatic plane rotation pulses and frequency-selective multiple spin-echo sequences are considered.


Marriage and Masculinity: Male-Breadwinner Culture, Unemployment, and Separation Risk in 29 Countries.
Scholars argue that gender culture, understood as a set of beliefs, norms, and social expectations defining masculinities and femininities, plays an important role in shaping when romantic relationships end. However, the relevance of gender culture is often underappreciated, in part because its empirical identification remains elusive. This study leverages cross-country variation in gender norms to test the hypothesis that gender culture conditions which heterosexual romantic relationships end and when. We analyze the extent to which male-breadwinning norms determine the association between men's unemployment and couple separation. Using harmonized household panel data for married and cohabiting heterosexual couples in 29 countries from 2004 to 2014, our results provide robust evidence that male-breadwinner norms are a key driver of the association between men's unemployment and the risk of separation. The magnitude of this mechanism is sizeable; an increase of one standard deviation in male-breadwinner norms increases the odds of separation associated with men's unemployment by 32 percent. Analyses also show that the importance of male-breadwinner norms is strongest among couples for whom the male-breadwinner identity is most salient, namely married couples. By directly measuring and leveraging variation in the key explanatory of interest, gender culture, our study offers novel and robust evidence reinforcing the importance of gender norms to understand when romantic relationships end.


Reactome: a database of reactions, pathways and biological processes.
Reactome (http://www.reactome.org) is a collaboration among groups at the Ontario Institute for Cancer Research, Cold Spring Harbor Laboratory, New York University School of Medicine and The European Bioinformatics Institute, to develop an open source curated bioinformatics database of human pathways and reactions. Recently, we developed a new web site with improved tools for pathway browsing and data analysis. The Pathway Browser is an Systems Biology Graphical Notation (SBGN)-based visualization system that supports zooming, scrolling and event highlighting. It exploits PSIQUIC web services to overlay our curated pathways with molecular interaction data from the Reactome Functional Interaction Network and external interaction databases such as IntAct, BioGRID, ChEMBL, iRefIndex, MINT and STRING. Our Pathway and Expression Analysis tools enable ID mapping, pathway assignment and overrepresentation analysis of user-supplied data sets. To support pathway annotation and analysis in other species, we continue to make orthology-based inferences of pathways in non-human species, applying Ensembl Compara to identify orthologs of curated human proteins in each of 20 other species. The resulting inferred pathway sets can be browsed and analyzed with our Species Comparison tool. Collaborations are also underway to create manually curated data sets on the Reactome framework for chicken, Drosophila and rice.


Forecasting ocean acidification impacts on kelp forest ecosystems.
Ocean acidification is one the biggest threats to marine ecosystems worldwide, but its ecosystem wide responses are still poorly understood. This study integrates field and experimental data into a mass balance food web model of a temperate coastal ecosystem to determine the impacts of specific OA forcing mechanisms as well as how they interact with one another. Specifically, we forced a food web model of a kelp forest ecosystem near its southern distribution limit in the California large marine ecosystem to a 0.5 pH drop over the course of 50 years. This study utilizes a modeling approach to determine the impacts of specific OA forcing mechanisms as well as how they interact. Isolating OA impacts on growth (Production), mortality (Other Mortality), and predation interactions (Vulnerability) or combining all three mechanisms together leads to a variety of ecosystem responses, with some taxa increasing in abundance and other decreasing. Results suggest that carbonate mineralizing groups such as coralline algae, abalone, snails, and lobsters display the largest decreases in biomass while macroalgae, urchins, and some larger fish species display the largest increases. Low trophic level groups such as giant kelp and brown algae increase in biomass by 16% and 71%, respectively. Due to the diverse way in which OA stress manifests at both individual and population levels, ecosystem-level effects can vary and display nonlinear patterns. Combined OA forcing leads to initial increases in ecosystem and commercial biomasses followed by a decrease in commercial biomass below initial values over time, while ecosystem biomass remains high. Both biodiversity and average trophic level decrease over time. These projections indicate that the kelp forest community would maintain high productivity with a 0.5 drop in pH, but with a substantially different community structure characterized by lower biodiversity and relatively greater dominance by lower trophic level organisms.


Cesium Toxicity Alters MicroRNA Processing and AGO1 Expressions in Arabidopsis thaliana.
MicroRNAs (miRNAs) are short RNA fragments that play important roles in controlled gene silencing, thus regulating many biological processes in plants. Recent studies have indicated that plants modulate miRNAs to sustain their survival in response to a variety of environmental stimuli, such as biotic stresses, cold, drought, nutritional starvation, and toxic heavy metals. Cesium and radio-cesium contaminations have arisen as serious problems that both impede plant growth and enter the food chain through contaminated plants. Many studies have been performed to define plant responses against cesium intoxication. However, the complete profile of miRNAs in plants during cesium intoxication has not been established. Here we show the differential expression of the miRNAs that are mostly down-regulated during cesium intoxication. Furthermore, we found that cesium toxicity disrupts both the processing of pri-miRNAs and AGONOUTE 1 (AGO1)-mediated gene silencing. AGO 1 seems to be especially destabilized by cesium toxicity, possibly through a proteolytic regulatory pathway. Our study presents a comprehensive profile of cesium-responsive miRNAs, which is distinct from that of potassium, and suggests two possible mechanisms underlying the cesium toxicity on miRNA metabolism.


Aggregation of biological particles under radial directional guidance.
Many biological environments display an almost radially-symmetric structure, allowing proteins, cells or animals to move in an oriented fashion. Motivated by specific examples of cell movement in tissues, pigment protein movement in pigment cells and animal movement near watering holes, we consider a class of radially-symmetric anisotropic diffusion problems, which we call the star problem. The corresponding diffusion tensor D(x) is radially symmetric with isotropic diffusion at the origin. We show that the anisotropic geometry of the environment can lead to strong aggregations and blow-up at the origin. We classify the nature of aggregation and blow-up solutions and provide corresponding numerical simulations. A surprising element of this strong aggregation mechanism is that it is entirely based on geometry and does not derive from chemotaxis, adhesion or other well known aggregating mechanisms. We use these aggregate solutions to discuss the process of pigmentation changes in animals, cancer invasion in an oriented fibrous habitat (such as collagen fibres), and sheep distributions around watering holes.


Understanding How Policy and Culture Create Oppressive Conditions for LGBTQ2S Youth in the Shelter System.
This study examined the experiences that lesbian, gay, bisexual, transgender, queer, questioning, and two-spirit (LGBTQ2S) homeless youth have in shelters and the disjunctures that occur for this population in Toronto's shelter system. The attitudes and behaviors of shelter workers and management toward LGBTQ2S youth were also explored. A critical action research approach, informed by critical ethnography and institutional ethnography was employed. Thirty-three people participated in this study in the Greater Toronto Area. The study triangulated data from interviews, focus groups, observations, and document analysis. The systemic enactment of homophobia, transphobia, and hegemonic masculinity are often normalized in shelters and create significant barriers to safe, accessible, and supportive services for LGBTQ2S youth. Excessive bureaucratic regulation and the lack of necessary bureaucratic regulation in highly significant areas play a key role in creating the disjunctures that occur for LGBTQ2S youth in shelters.


Coping with TB immune reconstitution inflammatory syndrome.
The TB immune reconstitution inflammatory syndrome (IRIS) is a relatively frequent complication in HIV-TB-coinfected patients after they start highly active antiretroviral therapy (HAART). There are two forms of TB IRIS: the 'paradoxical' type (clinical worsening of a patient on TB treatment) and the 'unmasking' type (undiagnosed TB becoming apparent after starting HAART). Their pathogeneses are not fully understood, although, as the name suggests, IRIS following initiation of HAART is accompanied by an increase in immune responses to Mycobacterium tuberculosis. The diagnosis of TB IRIS is mainly clinical; so far there are no laboratory tests able to diagnose or predict TB IRIS. Risk factors for TB IRIS include a low CD4(+) lymphocyte count, disseminated TB infection at HAART initiation and a short interval between TB treatment and HAART initiation. TB IRIS complicates the treatment and care for HIV-TB-coinfected patients. In this paper, we discuss some aspects of pathogenesis and options for the treatment and prevention of TB IRIS.


Comparing the effects of white coat hypertension and sustained hypertension on mortality in a UK primary care setting.
We examined all-cause mortality within a primary care setting in patients with white coat hypertension or sustained hypertension in whom blood pressure (BP) monitoring was indicated. This prospective multicenter study of ambulatory BP monitoring included 48 family practices in the county of Oxfordshire, United Kingdom. Mortality was compared for patients having white coat hypertension (mean of 3 clinic BP readings >140/90 mm Hg and daytime ambulatory readings< or =135/85 mm Hg) and patients having sustained hypertension (mean of 3 clinic readings >140/90 mm Hg and daytime ambulatory readings >135/85 mm Hg). A routine primary care cohort consisting of 5,182 patients chosen to undergo ambulatory BP monitoring by their family physician was followed up for a median of 7.3 years (interquartile range, 5.8-8.9). There were 335 deaths (6.5%), corresponding to a mortality rate of 8.9 deaths (95% confidence interval [CI], 8.0-9.9) per 1,000 years of follow-up. Patients with white coat hypertension (n = 1,117) were more likely to be female and were on average younger than patients with sustained hypertension (n = 4,065). The unadjusted rate of all-cause mortality in patients with white coat hypertension was lower, at 4.4 deaths per 1,000 years of follow-up (95% CI, 3.1-6.0) than that in patients with sustained hypertension, at 10.2 deaths per 1,000 years of follow-up (95% CI, 9.1-11.4). This reduction in all-cause mortality was still clinically significant after adjustment for age, sex, smoking, use of antihypertensive medication, and practice-clustering effects (hazard ratio = 0.64; 95% CI, 0.42-0.97; P=.04). White coat hypertension (elevation of clinic BP only) confers significantly less risk of death than sustained hypertension (elevation of both clinic and ambulatory BPs). Trials are now needed to evaluate the risk reduction achievable in patients who have white coat hypertension and are receiving BP-lowering therapy.


Surveillance of patients with inflammatory bowel disease.
Patients with inflammatory bowel disease involving the colon are at increased risk for developing colorectal cancer. Colonoscopy surveillance is important to identify and treat IBD associated dysplasia. The SCENIC consensus provides evidence-based recommendations for optimal surveillance and management of dysplasia in IBD. Chromoendoscopy, with the surface application of dyes to enhance mucosal visualization, is the superior endoscopic surveillance strategy to detect dysplasia. Most dysplasia is visible, and can be endoscopically resected. Future studies should determine the effect of new surveillance strategies on the incidence of CRC and mortality in patients with IBD.


Evidence that random and imprinted Xist expression is controlled by preemptive methylation.
The mouse Xist gene is expressed exclusively from the inactive X chromosome and may control the initiation of X inactivation. We show that in somatic tissues the 5' end of the silent Xist allele on the active X chromosome is fully methylated, while the expressed allele on the inactive X is completely unmethylated. In tissues that undergo imprinted paternal Xist expression and imprinted X inactivation, the paternal Xist allele is unmethylated, and the silent maternal allele is fully methylated. In the male germline, a developmentally regulated demethylation of Xist occurs at the onset of meiosis and is retained in mature spermatozoa. This may be the cause of imprinted expression of the paternal Xist allele. A role for methylation in the control of Xist expression is further supported by the finding that in differentiating embryonic stem cells during the initiation of X inactivation, differential methylation of Xist alleles precedes the onset of Xist expression.


A randomized controlled trial of the effects of a combination of static and dynamic magnetic fields on carpal tunnel syndrome.
To determine if a physics-based combination of simultaneous static and time-varying dynamic magnetic field stimulation to the wrist 4 hours/day for 2 months can reduce subjective neuropathic pain and influence objective electrophysiologic parameters of patients with carpal tunnel syndrome (CTS). Randomized, double-blinded, placebo-controlled trial of 36 symptomatic hands. Primary endpoints were visual analog scale (VAS) and neuropathic pain scale (NPS) scores at baseline and 2 months and a Patient's Global Impression of Change (PGIC) questionnaire at the end of 2 months. Secondary endpoints were neurologic examination, median nerve distal latencies (compound muscle action potential [CMAP]/sensory nerve action potential [SNAP]), dynamometry, pinch gauge readings, and current perception threshold (CPT) scores. An "active" device was provided gratis at the end of the study, with 15 subjects voluntarily remaining within the open protocol an additional 2-10 months and using the preselected primary and secondary parameters. (two months). Of the 31 hands, 25 (13 magnet, 12 sham) had moderate to severe pain (VAS > 4). The VAS and PGIC revealed a nonsignificant pain reduction. NPS analyses (anova) demonstrated a statistically significant reduction of "deep" pain (35% downward arrow vs 12% upward arrow, P = 0.018), NPS Total Composite (decreases of 42% vs 24%, P = 0.042), NPS Total Descriptor Score (NPS 8; 43% vs 24%), and NPS 4 (42% vs 11%). Motor strength, CMAP/SNAP, and CPT scores were not significantly changed. Of the 15 hands with up to 10 months of active PEMF (pulsed electromagnetic fields) exposure, there was objective improvement in nerve conduction (CMAP = 53%, SNAP = 40%, >1 SD), and subjective improvement on examination (40%), pain scores (50%), and PGIC (70%). No detectable changes in motor strength and CPT. PEMF exposure in refractory CTS provides statistically significant short- and longterm pain reduction and mild improvement in objective neuronal functions. Neuromodulation appears to influence nociceptive-C and large A-fiber functions, probably through ion/ligand binding.


Synthesis, characterization and application of novel MnO and CuO impregnated biochar composites to sequester arsenic (As) from water: Modeling, thermodynamics and reusability.
The present study aimed at enhancing the adsorption potential of novel nanocomposites of Sesbania bispinosa biochar (SBC) with copper oxide (SBC/CuO) and manganese oxide nanoparticles (SBC/MnO) for the efficient and inexpensive removal of environmentally concerned contaminant arsenic (As) from contaminated water at batch scale. The scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, energy dispersive X-ray (EDX), X-ray diffraction (XRD) and point of zero charge (PZC) analyses proved successful impregnation of the metallic nanoparticles on SBC surface. The results revealed the maximum As removal (96 %) and adsorption (12.47 mg/g) by SBC/CuO composite at 10 mg As/L, optimum pH-4, dose 1.0 g/L and ambient temperature (25 ± 1.5 °C) as compared with SBC (7.33 mg/g) and SBC/MnO (7.34 mg/g). Among four types of adsorption isotherms, Freundlich isotherm demonstrated best fit with R2 > 0.997. While pseudo second-order kinetic model revealed better agreement with kinetic experimental data as matched with other kinetic models. The thermodynamic results depicted that As adsorption on the as-synthesized adsorbents was endothermic and spontaneous in nature with increased randomness. The SBC/CuO displayed excellent reusability and stability over four adsorption/desorption cycles and proved that the as-synthesized SBC/CuO composite may be the efficient adsorbent for practical removal of As from contaminated water.


Clinical, Radiographic, and Surgical Presentation of Subscapularis Tendon Tears: A Retrospective Analysis of 139 Patients.
To analyze and correlate the clinical, radiographic, and surgical presentation of subscapularis (SSc) tears treated with arthroscopic repair. We retrospectively identified 455 patients who underwent rotator cuff tear repairs at our institution from 2010 to 2014. Of these patients, 139 underwent an SSc repair either in isolation or concurrently with other rotator cuff procedures. Tear size was classified arthroscopically by whether tears involved the superior one-third of the SSc tendon, superior two-thirds of the SSc tendon, or complete SSc tendon. Patient demographic characteristics, assessments of belly-press weakness and the lift-off test, magnetic resonance imaging (MRI) findings, and data on concurrent supraspinatus and biceps tendon pathology were collected and analyzed according to tear size. Our cohort had a mean age of 61.8 ± 12.5 years, with a male-female gender ratio of 1.7:1. There were 22 tears of the superior one-third of the SSc (16%), 96 tears of the superior two-thirds of the SSc (69%), and 21 complete SSc tears (15%). Overall, MRI diagnosis of SSc tears had a sensitivity of 83% and specificity of 70%. MRI sensitivity was associated with tear severity (P = .02), with complete tears having an MRI sensitivity of 100%; superior two-thirds, 82%; and superior one-third, 67%. Physical examination sensitivity for belly-press weakness and the lift-off test was 61% and 63%, respectively, and did not correspond with tear size. Increased SSc tear size corresponded with a history of trauma (P = .04) and the presence of concurrent supraspinatus tears (P = .03) and biceps pathology (P = .003). The diagnosis of SSc tears remains challenging because of the limited sensitivity of MRI and physical examination. The diagnostic sensitivity of MRI is associated with SSc tear size, whereas physical examination is independent of tear size. Additional associations identified in this study include increased SSc tear size corresponding with a history of trauma, presence of concurrent supraspinatus tears, and presence of concurrent biceps tendon pathology. Level III, retrospective comparative study.


Judging whether a patient is actually improving: more pitfalls from the science of human perception.
Fallible human judgment may lead clinicians to make mistakes when assessing whether a patient is improving following treatment. This article provides a narrative review of selected studies in psychology that describe errors that potentially apply when a physician assesses a patient's response to treatment. Comprehension may be distorted by subjective preconceptions (lack of double blinding). Recall may fail through memory lapses (unwanted forgetfulness) and tacit assumptions (automatic imputation). Evaluations may be further compromised due to the effects of random chance (regression to the mean). Expression may be swayed by unjustified overconfidence following conformist groupthink (group polarization). An awareness of these five pitfalls may help clinicians avoid some errors in medical care when determining whether a patient is improving.


The impact of depression and anxiety on quality of life in Chinese cancer patient-family caregiver dyads, a cross-sectional study.
Cancer and its treatment can result in psychological distress in both adults with cancer and in their family caregivers. This psychological distress acts as a significant adverse factor in patient-caregiver dyads. The study purposes included: (i) to assess anxiety and depression in adults with cancer and their family caregivers, and examine the dyadic relationship of anxiety and depression in patient-caregiver dyads; (ii) to investigate factors that may modify these relationships; and (iii) to explore the impact of anxiety and depression on patient-caregiver dyad quality of life (QOL). This was a secondary analysis of a cross-sectional study. Participants consisted of 641 patient-caregiver dyads. Participants completed a survey assessing adults with cancer-related, family caregiver-related, and family-related variables using a demographic/clinical information sheet. In addition, anxiety/depression and QOL were assessed by using the Chinese version of the Hospital Anxiety and Depression Scale and SF-12 respectively. Data were analyzed by using descriptive statistics, Pearson correlations, subgroup analysis, and the Actor-Partner Interdependence Model. Nearly one-third of participants had experienced anxiety and depression. Adults with cancer and family caregivers experienced a similar degree of anxiety and depression. Correlations (r) of anxiety and depression between patient-caregiver dyads ranged from 0.25 to 0.32. Various factors influencing the anxiety and depression relationship between patient-caregiver dyads were identified, including adults with cancer-related (e.g., age, gender, marital status, level of being informed about the disease, different types of cancer and treatment), family caregiver-related (e.g., being the spouse of a patient, duration in their role as a family caregiver, and amount of time spent on caregiving each day), and family-related (family relationship pre- and post-cancer, financial burden on the family due to cancer treatment) variables. To some extent, both actor and partner effects were identified for anxiety and depression on the QOL of patient-caregiver dyads. Study findings call attention to anxiety and depression, as well as related factors, in patient-caregiver dyads. The underlined essential components and focus of intervention, which will be developed to decrease psychological distress and improve QOL in patient-caregiver dyads, included individual characteristics of patient-caregiver dyads, family relationship, and anxiety and depression in their counterparts.


Asymmetric activation of the hsp90 dimer by its cochaperone aha1.
The chaperone Hsp90 is an ATP-dependent, dimeric molecular machine regulated by several cochaperones, including inhibitors and the unique ATPase activator Aha1. Here, we analyzed the mechanism of the Aha1-mediated acceleration of Hsp90 ATPase activity and identified the interaction surfaces of both proteins using multidimensional NMR techniques. For maximum activation of Hsp90, the two domains of Aha1 bind to sites in the middle and N-terminal domains of Hsp90 in a sequential manner. This binding induces the kinetically unfavored N terminally dimerized state of Hsp90, which primes for the hydrolysis-competent conformation. Surprisingly, this activation mechanism is asymmetric. The presence of one Aha1 molecule per Hsp90 dimer is sufficient to bridge the two subunits and to fully stimulate Hsp90 ATPase activity. This seems to functionalize the two subunits of the Hsp90 dimer in different ways, in that one subunit can be used for conformational ATPase regulation and the other for substrate protein processing.


The biotrophic, non-appressorium-forming grass pathogen Claviceps purpurea needs a Fus3/Pmk1 homologous mitogen-activated protein kinase for colonization of rye ovarian tissue.
Claviceps purpurea is a common pathogen of a wide range of grasses and cereals that is able to establish a stable, balanced interaction with its host plant and is considered a biotroph. It does not form special penetration structures such as appressoria. To study the signaling processes involved in this special host-pathogen interaction, we have cloned a gene, cpmk1, encoding a mitogen-activated protein (MAP) kinase that shows significant homology to Fus3 of Saccharomyces cerevisiae and to pmk1 of Magnaporthe grisea. Using a gene-replacement approach, we isolated a Acpmk1 mutant and characterized it in detail. Loss of CPMK1 has no obvious effect on vegetative properties (such as growth rate, morphology, and conidia formation); however, infection tests on rye show that the mutant is unable to colonize rye tissue, i.e., it appears to be completely nonpathogenic. Complementation of the mutant with a wild-type copy of cpmk1 fully restores its pathogenicity, confirming that this MAP kinase is essential for infection of rye by C. purpurea. Transformation of the delta pmk1 mutant of M. grisea with a complete copy of cpmk1 (including the C. purpurea promoter) fully restored its ability to form appressoria and its pathogenicity on barley. Although both fungi drastically differ in their pathogenic strategies, this result indicates that the signal pathway involving CPMK1 is highly conserved.


Sexual conflict and correlated evolution between male persistence and female resistance traits in the seed beetle Callosobruchus maculatus.
Traumatic mating (or copulatory wounding) is an extreme form of sexual conflict whereby male genitalia physically harm females during mating. In such species females are expected to evolve counter-adaptations to reduce male-induced harm. Importantly, female counter-adaptations may include both genital and non-genital traits. In this study, we examine evolutionary associations between harmful male genital morphology and female reproductive tract morphology and immune function across 13 populations of the seed beetle Callosobruchus maculatus We detected positive correlated evolution between the injuriousness of male genitalia and putative female resistance adaptations across populations. Moreover, we found evidence for a negative relationship between female immunity and population productivity, which suggests that investment in female resistance may be costly due to the resource trade-offs that are predicted between immunity and reproduction. Finally, the degree of female tract scarring (harm to females) was greater in those populations with both longer aedeagal spines and a thinner female tract lining. Our results are thus consistent with a sexual arms race, which is only apparent when both male and female traits are taken into account. Importantly, our study provides rare evidence for sexually antagonistic coevolution of male and female traits at the within-species level.


Codon usage bias and effective population sizes on the X chromosome versus the autosomes in Drosophila melanogaster.
Codon usage bias (CUB) in Drosophila is higher for X-linked genes than for autosomal genes. One possible explanation is that the higher effective recombination rate for genes on the X chromosome compared with the autosomes reduces their susceptibility to Hill-Robertson effects, and thus enhances the efficacy of selection on codon usage. The genome sequence of D. melanogaster was used to test this hypothesis. Contrary to expectation, it was found that, after correcting for the effective recombination rate, CUB remained higher on the X than on the autosomes. In contrast, an analysis of polymorphism data from a Rwandan population showed that mean nucleotide site diversity at 4-fold degenerate sites for genes on the X is approximately three-quarters of the autosomal value after correcting for the effective recombination rate, compared with approximate equality before correction. In addition, these data show that selection for preferred versus unpreferred synonymous variants is stronger on the X than the autosomes, which accounts for the higher CUB of genes on the X chromosome. This difference in the strength of selection does not appear to reflect the effects of dominance of mutations affecting codon usage, differences in gene expression levels between X and autosomes, or differences in mutational bias. Its cause therefore remains unexplained. The stronger selection on CUB on the X chromosome leads to a lower rate of synonymous site divergence compared with the autosomes; this will cause a stronger upward bias for X than A in estimates of the proportion of nonsynonymous mutations fixed by positive selection, for methods based on the McDonald-Kreitman test.


Orientation discrimination in 5-year-olds and adults tested with luminance-modulated and contrast-modulated gratings.
We compared thresholds for discriminating orientation by 5-year-olds and adults for first-order (luminance-modulated) and second-order (contrast-modulated) gratings. To achieve equal visibility, we set the contrast for each age and condition at a fixed multiple of the contrast threshold for discriminating horizontal from vertical gratings. The minimum tilt that could be discriminated from vertical was four to five times larger in 5-year-olds than in adults, even when the noise was removed from the first-order stimuli and amplitude modulation increased to 0.90. Thresholds at both ages were significantly worse (1.2-1.5 times worse) for second-order modulation than for equally visible first-order modulation, and 5-year-olds were equally immature for both types of pattern. Together, the findings suggest that orientation discrimination is slow to develop and worse for second-order than first-order patterns in both children and adults.


Development of a fall-risk checklist using the Delphi technique.
This study developed a checklist of both intrinsic and extrinsic risk factors for falls among older people based on consensus among a panel of experts and obtained expert content validity. The developed checklist is intended to help nurses better understand risk factors and take effective measures to prevent falls. Ageing involves changes in musculoskeletal and neuromuscular systems that make older people more prone to balance problems and falling. While it is believed that both environmental factors and personal habits play important roles in predisposing older people to falls, few broad-based approach checklists to identify both intrinsic and extrinsic risk factors have been published. Even fewer checklists addressing psychosocial problems currently exist. The authors developed a preliminary checklist through literature review. This study was designed using the Delphi technique, which is widely accepted as an effective method to secure consensus from experts of different backgrounds and perspectives. The Delphi technique was used to consolidate and compare the opinions of qualified experts from six different fields over three review rounds. Experts' content validity index was used to confirm validity. Authors developed a preliminary checklist covering nine domains, which, after using the Delphi technique, was expanded to the 10 domains of demographics, illness, medicine, balance measurement, footwear, nutrition, cognitive function, social support, environment and fear of falling. Changes based on panel member suggestions made in the first review round included clarification of definitions for 'dim light', 'slippery', 'doormat' and 'clutter' and revisions to definitions of cigarette and alcohol consumption and types of exercise. Changes made following the second round review included clarification of the meaning and function of social support and the replacement of SPMSQ with MMSE. In the final round, the term 'physical mental disturbance' was changed to 'fear of falling'. The scores of CVI were very high. The Delphi technique was used successfully to refine the author-developed checklist based on experts' input. To ensure expert input reliability, concepts were defined by the authors and supported with photographs and videos, as needed. The checklist helps assess risk factors and identify older people at higher risk of falls and may help reduce fall risk.


Calcaneum broadband ultrasound attenuation relates to vegetarian and omnivorous diets differently in men and women: an observation from the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study.
Vegetarian diets have been suggested to be beneficial for bone health due to increased consumption of plant foods, including soya, or reduced consumption of meat. However, meat may also be beneficial for bone health. The evidence relating diet to bone health is based largely on studies of women, often in those at high risk of osteoporosis. Few studies have investigated dietary inter-relationships in men as well as women from general populations. We examined broadband ultrasound attenuation (BUA) of the calcaneum, using a CUBA clinical instrument, in 6,369 men and 5,379 postmenopausal women. The population was divided into four groups according to vegetarian status and frequency of soya consumption, which was defined by response to a food frequency questionnaire that estimates frequency of consumption of food types over the year prior to completion. Regular soya consumers were defined as those who ate soya products with a frequency of between once a day and once a week. Calcaneum BUA in vegetarian men was significantly lower than omnivores by approximately 6% (5 dB/MHz) and was 15% (13.6 dB/MHz) lower in those who were also regular soya consumers. This difference remained after adjustment for age, height, weight, smoking habit, physical activity, selected foods and nutrients and exclusion of those with a prior history of osteoporosis, fractures or cancer. Calcaneum BUA in omnivorous men with regular soya consumption was not lower than the remaining population. In women, there were no significant differences by usual dietary pattern. This surprising finding indicates that regular soya intake is not associated with better bone indices in vegetarian men. The difference in BUA was not explained by the known common covariates; however, it is possible that other aspects of lifestyle associated with these eating behaviors might explain this observation. Plausible mechanisms exist for our findings; soya contains phytoestrogens, likened to naturally occurring estrogens, and meat has been shown to influence levels of IGF-1 and sex hormone binding globulin, which may be related to bone health. Our findings emphasize the need for further research and investigation into dietary inter-relationships and bone health and the effects of vegetarian status, including consumption of soya-based foods, in men as well as women.


A Simulated Level Loading of Supply and Demand for Beds in a Tertiary Care Children's Hospital Reduces Overall Bed Requirements.
Anticipating throughput and allocating resources effectively in children's hospitals have unique challenges relative to adult inpatient centers. The seasonal and daily variation can be difficult to anticipate in terms of impact and creating plans for adequate preparation. Discrete event simulation methodology can be helpful in determining appropriate allocation of resources and has been increasingly appropriated in health care from industry. A representative sample set was abstracted from the Cohen Children's Medical Center census tracking system to describe the present state. A larger data set was used to determine the appropriate level load. The total work performed each hour from 8 AM to 8 PM was evaluated against the level load plan of 11.5%. During the initial hours of the working period when the total work was low, more discharges were added. For each discharge added, an equal quantity of discharges was subtracted from the later hours of the day to bring the total work below 11.5% for each hour. Once the simulated state discharges were determined, a new aggregate bed supply line was created. These values were then added to the original visualization to show improvement. Our analysis suggests that a large part of the discharge/transfer activity and bed demand activity occurs in the pediatric intensive care unit in a roughly 4- to 5-hour window. Our simulation analysis suggests that level loading of this resource-intensive activity period has a potential to reduce bed occupancy, increase bed availability in peak bed demand times, and improve efficiency and throughput throughout the hospital. Discrete event simulation can be an effective tool for pediatric inpatient centers to determine appropriate allocation of resources to enhance patient safety and throughput without significant, costly expansion of bed capacity.


A Novel Cosegregating DCTN1 Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology.
A novel cosegregating splice site variant in the Dynactin-1 (DCTN1) gene was discovered by Next Generation Sequencing (NGS) in a family with a history of bipolar disorder (BD) and major depressive diagnosis (MDD). Psychiatric illness in this family follows an autosomal dominant pattern. DCTN1 codes for the largest dynactin subunit, namely p150Glued, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT→TT transversion in the DCTN1 gene, uncovered in the present work, is predicted to disrupt the invariant canonical splice donor site IVS22 + 1G > T and result in intron retention and a premature termination codon (PTC). Thus, this splice site variant is predicted to trigger RNA nonsense-mediated decay (NMD) and/or result in a C-terminal truncated p150Glued protein (ct-p150Glued), thereby negatively impacting retrograde axonal transport and neuronal autophagy. BD prophylactic medications, and most antipsychotics and antidepressants, are known to enhance neuronal autophagy. This variant is analogous to the dominant-negative GLUED Gl1 mutation in Drosophila, which is responsible for a neurodegenerative phenotype. The newly identified variant may reflect an autosomal dominant cause of psychiatric pathology in this affected family. Factors that affect alternative splicing of the DCTN1 gene, leading to NMD and/or ct-p150Glued, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD.


Integrated endoscopy system for simultaneous imaging and spectroscopy for early lung cancer detection.
An integrated endoscopy system for simultaneous imaging and spectroscopy was developed to facilitate more accurate and convenient detection of early lung cancers. A specially designed three-CCD camera in combination with a dedicated light source permits capture of both white-light color images and tissue autofluorescence images without the need to switch between two different cameras. A mirror with an optical fiber at its center, placed at an interim imaging plane inside the camera unit, facilitates simultaneous imaging and spectroscopy measurements in either white-light reflectance mode or fluorescence mode. The system has been successfully tested in a clinic, demonstrating a practical approach to improve both diagnostic sensitivity and specificity at the same time.


Telomere length attrition and chronic periodontitis: an ARIC Study nested case-control study.
This nested case-control study sought to determine whether an accelerated rate of leukocyte telomere length (LTL) shortening over 6 years was associated with chronic periodontitis. We sampled cases (n = 178) with severe chronic periodontitis and controls (n = 178) with no/mild chronic periodontitis from the Atherosclerosis Risk in Communities study. Controls were frequency-matched to cases by study site, age, sex and race. Age ranged from 53 to 73 years. Severe chronic periodontitis was defined using the CDC-AAP case classification. LTL was measured from DNA collected at two time points, 6 years apart, with quantitative polymerase chain reaction relative to a single-copy control gene. Multiple linear regression evaluated associations between LTL measured at baseline, follow-up and change scores with severe chronic periodontitis, adjusting for potential confounders. Cases had shorter LTL than controls at baseline (p = 0.03) and follow-up (p = 0.04) after adjusting for confounding. Overall there was a net reduction in LTL over time (p = 0.02). The rate of LTL did not differ between cases and controls (p = 0.80). Leukocyte telomere length shortening occurred at the same rate among adults with and without severe chronic periodontitis. This suggests that LTL shortening may have occurred earlier in the life course.


Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7 and Escape Variants.
Inhibitors of the hepatitis C virus (HCV) NS5A protein are a key component of effective treatment regimens, but the genetic heterogeneity of HCV has limited the efficacy of these agents and mutations lead to resistance. We directly compared the efficacy of all clinically relevant NS5A inhibitors against HCV genotype 1-7 prototype isolates and resistant escape variants, and investigated the effects of pre-existing resistance-associated substitutions (RAS) on HCV escape from treatment. We measured the efficacy of different concentrations of daclatasvir, ledipasvir, ombitasvir, elbasvir, ruzasvir, velpatasvir, and pibrentasvir in cultured cells infected with HCV recombinants expressing genotype 1-7 NS5A proteins with or without RAS. We engineered HCV variants that included RAS identified in escape experiments, using recombinants with or without T/Y93H and daclatasvir, or that contained RAS previously reported from patients. NS5A inhibitors had varying levels of efficacy against original and resistant viruses. Only velpatasvir and pibrentasvir had uniform high activity against all HCV genotypes tested. RAS hotspots in NS5A were found at amino acids 28, 30, 31, and 93. Engineered escape variants had high levels of fitness. Pibrentasvir had the highest level of efficacy against variants; viruses with RAS at amino acids 28, 30, or 31 had no apparent resistance to pibrentasvir, and HCV with RAS at amino acid 93 had a low level of resistance to this drug. However, specific combinations of RAS and deletion of amino acid 32 led to significant resistance to pibrentasvir. For the remaining NS5A inhibitors tested, RAS at amino acids 28 and 93 led to high levels of resistance. Among these inhibitors, velpatasvir was more effective against variants with RAS at amino acid 30 and some variants with RAS at amino acid 31 than the other agents. Variants with the pre-existing RAS T/Y93H acquired additional NS5A changes during escape experiments, resulting in HCV variants with specific combinations of RAS, showing high fitness and high resistance. We performed a comprehensive comparison of the efficacy of the 7 clinically relevant inhibitors of HCV NS5A and identified variants associated with resistance to each agent. These findings could improve treatment of patients with HCV infection.


The susceptibility of pure tubulin to high magnetic fields: a magnetic birefringence and x-ray fiber diffraction study.
The orientational behavior of microtubules assembled in strong magnetic fields has been studied. It is shown that when microtubules are assembled in a magnetic field, they align with their long axis parallel to the magnetic field. The effect of several parameters known to affect the microtubule assembly are investigated with respect to their effect on the final degree of alignment. Aligned samples of hydrated microtubules suitable for low-resolution x-ray fiber diffraction experiments have been produced, and the results obtained from the fiber diffraction experiments have been compared with the magnetic birefringence experiments. Comparisons with earlier fiber diffraction work and small-angle x-ray solution scattering experiments have been made.


The Neuroprotective Effect of Hemin and the Related Mechanism in Sevoflurane Exposed Neonatal Rats.
Many studies have reported that sevoflurane can increase neuronal apoptosis and result in cognitive deficits in rodents. Although neurotoxicity may be associated with mitochondrial dysfunction and oxidative stress, the exact mechanism remains unclear. In order to evaluate potential treatment therapies, we studied the effects of hemin on neurotoxicity of neonatal rat sevoflurane exposure. Postnatal day (P) seven rats were assigned randomly to four groups; (1) group C: non-anesthesia, (2) group H: intraperitoneal hemin (50 mg kg-1) treatment on days 5 and 6, (3) group S: 3% sevoflurane exposure for 4 h, and (4) group SH: hemin treatment + sevoflurane exposure. The expression of neuroglobin in neonatal hippocampus was determined by western blot and immunohistochemistry. Neuroglobin was localized by immunofluorescence. Western blot for the expression of cleaved caspase-3 and TUNEL were used to detect neonatal hippocampal apoptosis, and cytochrome c was used to evaluate mitochondrial function. Drp-1 and Mfn-2 immunoblotting were used to assess mitochondrial dynamics. The Morris water maze test was performed to detect cognitive function in the rats on P30. Exposure to sevoflurane increased the expression of cleaved caspase-3, cytochrome c, and Drp1 in the neonatal hippocampus and resulted in cognitive deficiency but decreased expression of Mfn2. Hemin reduced apoptosis, improved mitochondrial dynamics and ameliorated the cognitive impairment caused by sevoflurane exposure. Hemin reduced neuronal apoptosis, improved mitochondrial dynamics and protected against cognitive deficits induced by sevoflurane in neonatal rats. This neuroprotective effect may be achieved by increasing the expression of neuroglobin.


TMEM2 Is a SOX4-Regulated Gene That Mediates Metastatic Migration and Invasion in Breast Cancer.
The developmental transcription factor SOX4 contributes to the metastatic spread of multiple solid cancer types, but its direct target genes that mediate cancer progression are not well defined. Using a systematic molecular and genomic approach, we identified the TMEM2 transmembrane protein gene as a direct transcriptional target of SOX4. TMEM2 was transcriptionally activated by SOX4 in breast cancer cells where, like SOX4, TMEM2 was found to mediate proinvasive and promigratory effects. Similarly, TMEM2 was sufficient to promote metastatic colonization of breast cancer cells and its expression in primary breast tumors associated with a higher likelihood of metastatic relapse. Given earlier evidence that genetic inactivation of SOX4 or TMEM2 yield similar defects in cardiac development, our findings lead us to propose that TMEM2 may not only mediate the pathologic effects of SOX4 on cancer progression but also potentially its contributions to embryonic development. Cancer Res; 76(17); 4994-5005. ©2016 AACR.


Endoscopic biliary drainage before pancreaticoduodenectomy for periampullary malignancies.
Despite decreased operative mortality, pancreaticoduodenectomy (PD) remains a formidable operation with substantial morbidity. We have evaluated the influence of preoperative endoscopic biliary drainage (EBD) on morbidity after PD for malignant biliary obstruction by retrospectively reviewing the medical records of 182 patients undergoing PD between April 1985 and August 1996. Of 52 study patients with malignant obstructive jaundice, 22 underwent preoperative EBD, and 30 were not drained. Eighty-three patients were excluded for bilirubin levels less than 5 mg/dl, 43 had other biliary drainage, and 4 had jaundice with benign pathology. Preoperative, intraoperative, and postoperative factors were compared. The two groups were well matched for clinical presentation and operative characteristics except for lower preoperative values of liver chemistries in patients undergoing EBD. Length of postoperative hospitalization for patients undergoing EBD was 13.5 days, compared with 19 days for patients who were not drained (p = 0.02). Patients who were not drained tended to have more overall complications (p = 0.054). Multivariate analysis revealed time to regular diet (p < 0.0001) and no preoperative drainage (p = 0.04) to be independent factors significantly increasing the length of hospitalization. Endoscopic biliary drainage before PD significantly reduced the length of postoperative hospitalization and was associated with less postoperative morbidity. Further studies, including cost analysis, are warranted.


A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen.
The objective was to investigate the stimulating and normalizing effect of the adaptogen Rhodiola rosea extract SHR-5 in foreign students during a stressful examination period. The study was performed as a double-blind, randomized and placebo-controlled with low repeated dose regime. The study drug and the placebo were taken for 20 days by the students during an examination period. The physical and mental performance were assessed before and after the period, based on objective as well as on subjective evaluation. The most significant improvement in the SHR-5 group was seen in physical fitness, mental fatigue and neuro-motoric tests (p <0.01). The self-assessment of the general well-being was also significantly (p < 0.05) better in the verum group. No significance was seen in the correction of text tests or a neuro-muscular tapping test. The overall conclusion is that the study drug gave significant results compared to the placebo group but that the dose level probably was suboptimal.


Statistical significance of hair analysis of clenbuterol to discriminate therapeutic use from contamination.
Clenbuterol is a well-established β2-agonist, which is prohibited in sports and strictly regulated for use in the livestock industry. During the last few years clenbuterol-positive results in doping controls and in samples from residents or travellers from a high-risk country were suspected to be related the illegal use of clenbuterol for fattening. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to detect low clenbuterol residues in hair with a detection limit of 0.02 pg/mg. A sub-therapeutic application study and a field study with volunteers, who have a high risk of contamination, were performed. For the application study, a total dosage of 30 µg clenbuterol was applied to 20 healthy volunteers on 5 subsequent days. One month after the beginning of the application, clenbuterol was detected in the proximal hair segment (0-1 cm) in concentrations between 0.43 and 4.76 pg/mg. For the second part, samples of 66 Mexican soccer players were analyzed. In 89% of these volunteers, clenbuterol was detectable in their hair at concentrations between 0.02 and 1.90 pg/mg. A comparison of both parts showed no statistical difference between sub-therapeutic application and contamination. In contrast, discrimination to a typical abuse of clenbuterol is apparently possible. Due to these findings results of real doping control samples can be evaluated.


Compound I of heme oxygenase cannot hydroxylate its heme meso-carbon.
Heme oxygenase (HO) catalyzes heme catabolism through three successive oxygenation steps where the substrate heme itself activates O2. It has been thought that the reactive species responsible for the first heme oxygenation, meso-hydroxylation, is the hydroperoxy-ferric heme intermediate (Fe-OOH) rather than an oxo ferryl porphyrin cation radical, so-called compound I. A recent theoretical study (Kamachi, T.; Yoshizawa, K. J. Am. Chem. Soc. 2005, 127, 10686), however, proposed that compound I can oxidize its meso-carbon atom with the assistance of a bridging water molecule. In this communication, we report the first direct observation of compound I of a heme-HO-1 complex, generated by reaction of ferric-HO-1 with m-chloroperbenzoic acid. HO compound I slowly decays to compound II without producing any meso-hydroxylated products. It does react with guaiacol and thioanisole, however. Our findings unambiguously rule out involvement of compound I in the HO catalysis.


The application of near-infrared oximetry to cerebral monitoring during aneurysm embolization: a comparison with intraprocedural angiography.
Near-infrared spectroscopy (NIRS) has been used to monitor regional cerebral oxygen saturation (rSO2) in patients at risk of cerebral desaturation during surgical and neurointerventional procedures. However, the quantitative capabilities of the method have been questioned, as has its validation compared with jugular bulb oximetry. Here, we compare NIRS data acquired during coil embolization procedures with incidence of vasospasm as detected from angiography. Thirty-two subarachnoid hemorrhage patients underwent embolization. Bilateral SomaSensor strips (Invos 4100, Somanetics) were affixed to the forehead at constant anatomic positions, avoiding frontal sinuses and scalp hair. Mean arterial pressure, SaO2, end-tidal pCO2, temperature and Hb were held within a narrow range during the procedure. Ipsilateral angiography was performed every 10 to 15 minutes. An independent neuroradiologist classified any vasospasm in the parent vessel as mild (25% baseline), moderate (50%), severe (75%), or total (100%). Of all, 15/32 (46.9%) patients developed spasm; in 2 it was severe or total. There was no significant association between World Federation of Neurological Surgeons grade and baseline rSO2 signal (either ipsilateral or contralateral to the side of the aneurysm) (P=0.598). There was no significant association between side of aneurysm and baseline rSO2 signal (P=0.243). However, episodes of angiographic spasm were strongly associated with reduction in trend ipsilateral NIRS signal (P<0.001); furthermore, the degree of spasm (especially more than 75% vessel diameter reduction) was associated with a greater reduction in same-side NIRS signal (P<0.001) (2-level random effects regression model, Stata 8.2, Stata Corp, TX). NIRS may have a useful role to play in the detection of cerebral desaturation secondary to vasospasm during neuroendovascular procedures.


Active vitamin D potentiates the anti-neoplastic effects of calcium in the colon: A cross talk through the calcium-sensing receptor.
Epidemiological studies suggest an inverse correlation between dietary calcium (Ca(2+)) and vitamin D intake and the risk of colorectal cancer (CRC). It has been shown in vitro that the active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25-D3) can upregulate expression of the calcium-sensing receptor (CaSR). In the colon, CaSR has been suggested to regulate proliferation of colonocytes. However, during tumorigenesis colonic CaSR expression is downregulated and we hypothesized that the loss of CaSR could influence the anti-tumorigenic effects of Ca(2+) and vitamin D. Our aim was to assess the impact of CaSR expression and function on the anti-neoplastic effects of 1,25-D3 in colon cancer cell lines. We demonstrated that in the healthy colon of mice, high vitamin D diet (2500 IU/kg diet) increased expression of differentiation and apoptosis markers, decreased expression of proliferation markers and significantly upregulated CaSR mRNA expression, compared with low vitamin D diet (100 IU/kg diet). To determine the role of CaSR in this process, we transfected Caco2-15 and HT29 CRC cells with wild type CaSR (CaSR-WT) or a dominant negative CaSR mutant (CaSR-DN) and treated them with 1,25-D3 alone, or in combination with CaSR activators (Ca(2+) and NPS R-568). 1,25-D3 enhanced the anti-proliferative effects of Ca(2+) and induced differentiation and apoptosis only in cells with a functional CaSR, which were further enhanced in the presence of NPS R-568, a positive allosteric modulator of CaSR. The mutant CaSR inhibited the anti-tumorigenic effects of 1,25-D3 suggesting that the anti-neoplastic effects of 1,25-D3 are, at least in part, mediated by the CaSR. Taken together, our data provides molecular evidence to support the epidemiological observation that both, vitamin D and calcium are needed for protection against malignant transformation of the colon and that their effect is modulated by the presence of a functional CaSR. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.