Knowledge and attitudes towards antiretroviral therapy among factory workers participating in a cohort on HIV and AIDS, Addis Ababa, Ethiopia.
This study investigates barriers that may pose a threat to a successful implementation of an antiretroviral treatment (ART) program in Ethiopia. As prelude to the provision of ART among factory workers participating in a cohort study on HIV and AIDS in Ethiopia, we measured knowledge and attitudes towards several aspects of ART and provided an educational intervention. The proportion of participants having good knowledge on issues concerning adherence was found reasonably good (67.7%), concerning the benefit of ART was intermediate (37.7%) and concerning eligibility was very low (16.8%). Knowledge concerning eligibility improved somewhat after the provision of the educational intervention. Only one third of HIV infected persons discloses their HIV status to their partner. Several aspects that could impact adherence to ART will be discussed, such as ART knowledge, social support, willingness to take ART, and disclosure of serostatus, taking the cohort study site into account. Results indicate a tremendous need to educate cohort participants before and during introduction of ART. Efforts to increase knowledge of ART, and especially knowledge of eligibility criteria to start ART, seem warranted, as well as encouragement to identify social support and disclose HIV serostatus, as these factors directly impact the success of an ART program.


Tracking the global dispersal of a cosmopolitan insect pest, the peach potato aphid.
Global commerce and human transportation are responsible for the range expansion of various insect pests such as the plant sucking aphids. High resolution DNA markers provide the opportunity to examine the genetic structure of aphid populations, identify aphid genotypes and infer their evolutionary history and routes of expansion which is of value in developing management strategies. One of the most widespread aphid species is the peach-potato aphid Myzus persicae, which is considered as a serious pest on various crops in many parts of the world. The present study examined the genetic variation of this aphid at a world scale and then related this to distribution patterns. In particular, 197 aphid parthenogenetic lineages from around the world were analysed with six microsatellite loci. Bayesian clustering and admixture analysis split the aphid genotypes into three genetic clusters: European M. persicae persicae, New Zealand M. persicae persicae and Global M. persicae nicotianae. This partition was supported by FST and genetic distance analyses. The results showed two further points, a possible connection between genotypes found in the UK and New Zealand and globalization of nicotianae associated with colonisation of regions where tobacco is not cultivated. In addition, we report the presence of geographically widespread clones and for the first time the presence of a nicotianae genotype in the Old and New World. Lastly, heterozygote deficiency was detected in some sexual and asexual populations. The study revealed important genetic variation among the aphid populations we examined and this was partitioned according to region and host-plant. Clonal selection and gene flow between sexual and asexual lineages are important factors shaping the genetic structure of the aphid populations. In addition, the results reflected the globalization of two subspecies of M. persicae with successful clones being spread at various scales throughout the world. A subspecies appears to result from direct selection on tobacco plants. This information highlights the ultimate ability of a polyphagous aphid species to generate and maintain ecologically successful gene combinations through clonal propagation and the role of human transportation and global commerce for expanding their range.


Systematic review and meta-analysis of surgical outcomes comparing mechanical valve replacement and bioprosthetic valve replacement in infective endocarditis.
Infective endocarditis (IE) is an infection involving either native or prosthetic heart valves, the endocardial surface of the heart or any implanted intracardiac devices. IE is a rare condition affecting 3-15 patients per 100,000 population. In-hospital mortality rates in patients with IE remain high at around 20% despite treatment advances. There is no consensus recommendation favoring either bioprosthetic valve or mechanical valve implantation in the setting of IE; patient age, co-morbidities and preferences should be considered selecting the replacement prosthesis. A systematic review and meta-analysis of studies reporting the outcomes of patients undergoing bioprosthetic or mechanical valve replacement for infective endocarditis with data extracted for overall survival, valve reinfection rates and valve reoperation. Eleven relevant studies were identified, with 2,336 patients receiving a mechanical valve replacement and 2,057 patients receiving a bioprosthetic valve replacement. There was no significant difference for overall survival between patients treated with mechanical valves and those treated with bioprosthetic valves [hazard ratio (HR) 0.94, 95% confidence interval (CI): 0.73-1.21, P=0.62]. There was no significant difference in reoperation rates between patients treated with a bioprosthetic valve and those treated with a mechanical valve (HR 0.82, 95% CI: 0.34-1.98, P=0.66) and there was no significant difference in the rate of valve reinfection rates (HR 0.95, 95% CI: 0.48-1.89, P=0.89). The presence of infective endocarditis alone should not influence the decision of which type of valve prosthesis that should be implanted. This decision should be based on patient age, co-morbidities and preferences.


Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity.
Modulation of endogenous cellular defense mechanisms represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. This paper introduces the emerging role of exogenous molecules in hormetic-based neuroprotection and the mitochondrial redox signaling concept of hormesis and its applications to the field of neuroprotection and longevity. Maintenance of optimal long-term health conditions is accomplished by a complex network of longevity assurance processes that are controlled by vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as polyphenols and L-carnitine/acetyl-L-carnitine, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. Hormesis provides the central underpinning of neuroprotective responses, providing a framework for explaining the common quantitative features of their dose response relationships, their mechanistic foundations, their relationship to the concept of biological plasticity as well as providing a key insight for improving the accuracy of the therapeutic dose of pharmaceutical agents within the highly heterogeneous human population. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways including sirtuin, Nrfs and related pathways that integrate adaptive stress responses in the prevention of neurodegenerative diseases. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.


Cardiac Magnetic Resonance Imaging Features in Hypertrophic Cardiomyopathy Diagnosed at <21 Years of Age.
Hypertrophic cardiomyopathy (HC) is the most common inherited cardiomyopathy, with varied timing of phenotypic and clinical presentation. Literature describing cardiac magnetic resonance (CMR) imaging and late gadolinium enhancement (LGE) in young patients with HC is limited. This study included patients diagnosed with HC at young age (<21 years) between January 1990 and January 2015 who underwent transthoracic echocardiography and CMR with assessment of LGE at a single tertiary referral center. LGE was quantified via a method of 6 standard deviations and patients were grouped based upon presence or absence of LGE (≤1% and >1% LGE, respectively). Sudden cardiac death (SCD) risk was assessed in patients >16 years of age using the European SCD risk score. A composite outcome of New York Heart Association class III-IV symptoms, aborted SCD, heart transplantation, and all-cause mortality was assessed via Kaplan-Meier curves with log-rank analysis. Overall, 126 patients were included (78 male; 62%). Median age of diagnosis was 15 (12 to 18) years. LGE was present in 81 (64%) patients, although only 4 (3%) patients had LGE >15%. Median age at CMR imaging was 19 (15 to 23) years. Patients with LGE had greater wall thickness (25 ± 8 mm vs 22 ± 7 mm, p = 0.01). Median European SCD risk score was 4.7 (2.9 to 6.5). Median follow-up was 6.5 (2.5 to 13) years with 26 patients (21%) meeting the composite outcome. There were no significant differences in composite outcome since age of diagnosis when stratified by presence/absence of LGE (p = 1.0). The presence of LGE in young HC patients was not an independent risk factor for cardiovascular morbidity and mortality. Wall thickness was greater in patients with LGE. There remains a need for further evaluation of this unique HC cohort.


Recurrent Neural Network Approach Based on the Integral Representation of the Drazin Inverse.
In this letter, we present the dynamical equation and corresponding artificial recurrent neural network for computing the Drazin inverse for arbitrary square real matrix, without any restriction on its eigenvalues. Conditions that ensure the stability of the defined recurrent neural network as well as its convergence toward the Drazin inverse are considered. Several illustrative examples present the results of computer simulations.


Bone marrow aspirate injection for treatment of critical limb ischemia with comparison to patients undergoing high-risk bypass grafts.
Bone marrow cell therapy (BMCT) for patients with critical limb ischemia (CLI) is a potential treatment in candidates with poor options for standard revascularization procedures. Whereas clinical trials are ongoing, there are few comparative data to assess its efficacy compared with bypass. Patients with poor revascularization options underwent BMCT between 2011 and 2013. Outcomes were compared with those of a cohort of CLI patients undergoing infrainguinal bypass thought to be at high risk for graft failure (tissue loss, a tibial target, and a previous endovascular treatment or bypass). BMCT patients underwent harvest of bone marrow that was then concentrated and injected intramuscularly into the ischemic limb. There were 20 BMCT patients and 35 high-risk bypass patients. All BMCT patients had either rest pain (80%) or tissue loss (80%). The majority (65%) had a prior intervention (bypass, 30%; endovascular, 58%) compared with high-risk bypass patients, all of whom had previous revascularization attempts (bypass, 43% [P = .35]; endovascular, 77% [P = .14]). Mean follow-up was 773 days after BMCT and 972 days after high-risk bypass. All patients tolerated BMCT without issues or complications. A second BMCT treatment was performed in 21% because of clinical deterioration. Wound healing occurred in 75% at 1.5 years, including patients receiving second injections, all of which resolved. Rest pain improved in 87.5% of patients. Pain completely resolved in 58% at 1.5 years. Ankle-brachial index improvement was 0.23 (±0.25). Three BMCT patients went on to amputation. One-year freedom from major amputation or death was 78% for BMCT vs 69% for high-risk bypass (P = .60). BMCT is a potential option in CLI patients who are not candidates for bypass or endovascular intervention. Limb salvage is unexpectedly high in this population with few other options.


Randomized controlled trial testing an internet physical activity intervention for sedentary adults.
Internet-based physical activity (PA) interventions have shown promise, although findings remain equivocal. We used formative research to enhance a previously demonstrated program (Step into Motion) with the goal of developing an Internet program poised for dissemination. We conducted focus groups to identify Internet features targeted to theoretical constructs (social cognitive theory) predictive of PA behavior and rated as "useful for increasing PA." We identified 5 theory-targeted Internet features as useful for increasing PA: (1) a PA tracking/logging calendar targeting self-monitoring and goal setting; (2) geographic mapping tools targeting perceived environment; (3) a discussion forum targeting social support; (4) exercise videos targeting observational learning; and (5) regular updates of peer PA progress targeting situation. We then tested the efficacy of the enhanced program (enhanced Internet, EI; N = 25) in relation to publicly available PA Websites (standard Internet, SI; N = 28) among 53 participants in a randomized controlled trial. The EI arm increased PA in relation to the SI arm at 3 months (18.4 to 186.0 min/wk vs. 20.9 to 57.3 min/wk; p = .03) but between-groups differences were not observed at 6 months (176.8 vs. 133.5 min/wk; p = .44). EI participants maintained PA from 3 to 6 months (186.0 to 176.8 min/wk), and the SI group increased PA (57.3 to 133.5 min/wk). The EI program was efficacious at improving PA levels in relation to publicly available Websites initially, but differences in PA levels were not maintained at 6 months. Future research should identify Internet features that promote long-term maintenance.


Repeated social stress leads to contrasting patterns of structural plasticity in the amygdala and hippocampus.
Previous studies have demonstrated that repeated immobilization and restraint stress cause contrasting patterns of dendritic reorganization as well as alterations in spine density in amygdalar and hippocampal neurons. Whether social and ethologically relevant stressors can induce similar patterns of morphological plasticity remains largely unexplored. Hence, we assessed the effects of repeated social defeat stress on neuronal morphology in basolateral amygdala (BLA), hippocampal CA1 and infralimbic medial prefrontal cortex (mPFC). Male Wistar rats experienced social defeat stress on 5 consecutive days during confrontation in the resident-intruder paradigm with larger and aggressive Wild-type Groningen rats. This resulted in clear social avoidance behavior one day after the last confrontation. To assess the morphological consequences of repeated social defeat, 2 weeks after the last defeat, animals were sacrificed and brains were stained using a Golgi-Cox procedure. Morphometric analyses revealed that, compared to controls, defeated Wistar rats showed apical dendritic decrease in spine density on CA1 but not BLA. Sholl analysis demonstrated a significant dendritic atrophy of CA1 basal dendrites in defeated animals. In contrast, basal dendrites of BLA pyramidal neurons exhibited enhanced dendritic arborization in defeated animals. Social stress failed to induce lasting structural changes in mPFC neurons. Our findings demonstrate for the first time that social defeat stress elicits divergent patterns of structural plasticity in the hippocampus versus amygdala, similar to what has previously been reported with repeated physical stressors. Therefore, brain region specific variations may be a universal feature of stress-induced plasticity that is shared by both physical and social stressors.


Tumor enzymes and prognosis in transitional cell carcinoma of the bladder: prediction of risk of progression in patients with superficial disease.
The activities of 6 enzymes of carbohydrate metabolism were estimated in superficial transitional cell carcinomas from 103 patients undergoing transurethral resection of the bladder for the first time. The patients were followed by quarterly endoscopic examinations for a maximum of 81 months (median 33 months). During followup 24 patients had progressive disease. The activities of phosphofructokinase and phosphohexose isomerase were significantly lower in tumors from patients whose disease had superficially invaded the lamina propria (stage pT1) than in others in whom it was confined to the bladder mucosa (stage pTa). Similarly the activities of the 2 enzymes were significantly higher in well differentiated (grade 1) than in moderately well differentiated (grade 2) carcinomas. Univariate analyses using the log rank test showed that neither pathological stage nor malignancy grade of the carcinoma was a significant factor in predicting the risk of progression. Of the 6 enzymes, below median activities of phosphofructokinase, lactate dehydrogenase and phosphohexose isomerase were associated with a significantly increased risk of progression in these patients. Multivariate analyses using Cox's proportional hazards model showed that the activity of lactic dehydrogenase in superficial transitional cell carcinoma is an independent prognostic factor in predicting the risk of progression. It is postulated that the measurements of the activities of the 3 enzymes in tumors from patients with superficial transitional cell carcinoma might help to select individual patients with a high risk of progression for adjuvant intravesical treatments.


A polymorphism of the 5 alpha-reductase gene and its association with prostate cancer: a case-control analysis.
Prostate cancer (CaP) is the most commonly diagnosed, nondermatological cancer in the United States. The development and progression of CaP is influenced by androgens. 5 alpha-Reductase, type II, converts testosterone to dihydrotestosterone and is critical to the development of the prostate. A TA dinucleotide repeat polymorphism exists in the 3' untranslated region of the 5 alpha-reductase type II gene. 5 alpha-Reductase alleles with longer TA repeats are more common in African-Americans, the group with the highest incidence of CaP. It has been hypothesized that the longer TA repeat alleles might be associated with increased risk of CaP. We studied this potential association within the Physician's Health Study, a predominantly Caucasian cohort study. Using PCR we identified the TA genotype in 590 men with CaP and 802 age-matched controls. The frequency of each allele in the controls was TA(0), 0.87, TA(9), 0.13, and TA(18), 0.01. Homozygotes for the longer TA alleles, TA(9) and TA(18), were underrepresented among cases with an odds ratio of 0.47 (confidence interval, 0.20-1.12), but this was not statistically significant (P = 0.08, two tailed). Our analysis does not support the prior hypothesis that longer TA alleles confer an increased risk of CaP in a predominantly Caucasian population; in fact, longer TA alleles are more prevalent in men without CaP.


The food environment and adult obesity in US metropolitan areas.
This research examines the larger-scale associations between obesity and food environments in metropolitan areas in the United States (US). The US Census County Business Patterns dataset for 2011 was used to construct various indices of food environments for selected metropolitan areas. The numbers of employees engaged in supermarkets, convenience stores, full service restaurants, fast food restaurants, and snack/coffee shops were standardised using the location quotients, and factor analysis was used to produce two uncorrelated factors measuring food environments. Data on obesity were obtained from the 2011 Behavioral Risk Factor Surveillance System. Individual level obesity measures were linked to the metropolitan area level food environment factors. Models were fitted using generalised estimating equations to control for metropolitan area level intra-correlation and individual level sociodemographic characteristics. It was found that adults residing in cities with a large share of supermarket and full-service restaurant workers were less likely to be obese, while adults residing in cities with a large share of convenience store and fast food restaurant workers were more likely to be obese. Supermarkets and full-service restaurant workers are concentrated in the Northeast and West of the US, where obesity prevalence is relatively lower, while convenience stores and fast-food restaurant workers are concentrated in the South and Midwest, where obesity prevalence is relatively higher. The food environment landscapes measured at the metropolitan area level explain the continental-scale patterns of obesity prevalence. The types of food that are readily available and widely served may translate into obesity disparities across metropolitan areas.


Effects of external qi-therapy on emotions, electroencephalograms, and plasma cortisol.
The authors investigated the effect of external Qi-therapy (EQT) on changes in encephalograms (EEGs) and circulating cortisol concentrations. Ten college students participated in crossover sessions, receiving EQT or placebo treatment with their eyes open. Subjects reported improved emotions of satisfaction, relaxation, and calmness during EQT as compared to levels reported during placebo treatments. There were significant differences in the proportions of alpha and beta EEG waves between the two sessions, and the relative strengths of alpha waves were higher during EQT than during control sessions (p < .05). Plasma cortisol concentrations during EQT were significantly lower than during control sessions p < .05). Thus, Qi-therapy was more effective in inducing relaxation than placebo treatment.


Refining animal experiments: the first Brazilian regulation on animal experimentation.
The very first law on animal experimentation has been approved recently in Brazil, and now is part of a set of the legal instruments that profile the Brazilian government's attitude toward the use of animals in experiments. Law 11794/08 establishes a new legal instrument that will guide new methods of conduct for ethics committees, researchers and representatives of animal protection societies. This comment aims to analyse critically the implications that this law brings to Brazilian reality. The link between it and the Russell and Burch's Three Rs concept is defined, and certain problems are identified. The conclusion is that the body of the law emphasises the refinement of animal experiments, but gives little importance to the principles of reduction and replacement.


Translational Molecular Ecology in practice: Linking DNA-based methods to actionable marine environmental management.
Molecular-based approaches can provide timely biodiversity assessments, showing an immense potential to facilitate decision-making in marine environmental management. However, the uptake of molecular data into environmental policy remains minimal. Here, we showcase a selection of local to global scale studies applying molecular-based methodologies for environmental management at various stages of implementation. Drawing upon lessons learned from these case-studies, we provide a roadmap to facilitate applications of DNA-based methods to marine policies and to overcome the existing challenges. The main impediment identified is the need for standardized protocols to guarantee data comparison across spatial and temporal scales. Adoption of Translational Molecular Ecology - the sustained collaboration between molecular ecologists and stakeholders, will enhance consensus with regards to the objectives, methods, and outcomes of environmental management projects. Establishing a sustained dialogue among stakeholders is key to accelerating the adoption of molecular-based approaches for marine monitoring and assessment.


A genetic approach to the biosynthesis of the rifamycin-chromophore in Nocardia mediterranei. II. Isolation and characterization of a shikimate excreting auxotrophic mutant of Nocardia mediterranei with normal rifamycin-production.
The mutant under study, designated A10, is derived from a Nocardia mediterranei strain, N813, which is a high rifamycin B producer. A10 is auxotrophic for aromatic amino acids but unlike A8 (see preceding paper) produces the same amount of rifamycin B as the parent. Shikimic acid and 3-dehydroshikimic acid are accumulated in the fermentation broth of this mutant. It was shown to be blocked in one of the enzymes leading from shikimate to chorismate. No formation of shikimate-3-phosphate from shikimate and ATP could be detected in vitro using crude extracts of this mutant and of the parent. As mutant A10 is only defective in the biosynthesis of aromatic amino acids and not in the biosynthesis of rifamycins it would appear that the seven-carbon amino unit of the rifamycin-chromophore must be derived from an intermediate of the shikimate pathway not behind shikimate. By referring to the results of the preceding paper it can be seen that the origin of this moiety can definitely be localized between 3-deoxy-D-arabinoheptulosonic acid-7-phosphate and shikimate.


Retrospective Comparison of Open versus Endovascular Procedures for Takayasu Arteritis.
To compare the outcomes between vascular surgery and endovascular procedures in a cohort of patients with Takayasu arteritis (TA). A retrospective cohort study was conducted of patients with TA who underwent vascular interventions at a tertiary center between 1984 and 2009. The American College of Rheumatology criteria for TA were used to select patients. Disease activity was assessed according to the Kerr criteria. Data are reported using descriptive statistics and Kaplan-Meier methods for complication rates. The cohort included 66 patients with TA who underwent 119 vascular procedures (surgery 93; endovascular repair 26). The most frequent indication for vascular surgery and endovascular procedure was arm claudication (surgical group 43%, endovascular repair group 31%). In 59% of the vascular surgical procedures and in 38% of endovascular procedures, the disease was active within 1 month of intervention. The most frequent arterial lesion requiring intervention was the aorta (28%) in the vascular surgery group and the subclavian (35%) in the endovascular repair group. Early complications occurred after 15 surgeries and 4 endovascular repair procedures (p = 0.93). Late complications occurred after 34 surgical procedures and 10 endovascular repair procedures (44% vs 66%, respectively; p = 0.33). The majority of complications in both groups were restenosis. Hypertension, dyslipidemia, and higher doses of corticosteroids were associated with an increased risk of postprocedural complications and restenosis. In patients with TA, both open surgical and endovascular revascularization procedures are associated with high failure rates and frequent operative complications. Traditional cardiovascular risk factors, corticosteroid dose, and active disease are risk factors for restenosis after revascularization procedures.


Function of the nucleotide exchange activity of vav1 in T cell development and activation.
The guanine nucleotide exchange factor (GEF) Vav1 is essential for transducing T cell antigen receptor (TCR) signals and therefore plays a critical role in the development and activation of T cells. It has been presumed that the GEF activity of Vav1 is important for its function; however, there has been no direct demonstration of this. Here, we generated mice expressing enzymatically inactive, but normally folded, Vav1 protein. Analysis of these mice showed that the GEF activity of Vav1 was necessary for the selection of thymocytes and for the optimal activation of T cells, including signal transduction to Rac1, Akt, and integrins. In contrast, the GEF activity of Vav1 was not required for TCR-induced calcium flux, activation of extracellular signal-regulated kinase and protein kinase D1, and cell polarization. Thus, in T cells, the GEF activity of Vav1 is essential for some, but not all, of its functions.


Toward an understanding of the molecular mechanisms of barnacle larval settlement: a comparative transcriptomic approach.
The barnacle Balanus amphitrite is a globally distributed biofouler and a model species in intertidal ecology and larval settlement studies. However, a lack of genomic information has hindered the comprehensive elucidation of the molecular mechanisms coordinating its larval settlement. The pyrosequencing-based transcriptomic approach is thought to be useful to identify key molecular changes during larval settlement. Using 454 pyrosequencing, we collected totally 630,845 reads including 215,308 from the larval stages and 415,537 from the adults; 23,451 contigs were generated while 77,785 remained as singletons. We annotated 31,720 of the 92,322 predicted open reading frames, which matched hits in the NCBI NR database, and identified 7,954 putative genes that were differentially expressed between the larval and adult stages. Of these, several genes were further characterized with quantitative real-time PCR and in situ hybridization, revealing some key findings: 1) vitellogenin was uniquely expressed in late nauplius stage, suggesting it may be an energy source for the subsequent non-feeding cyprid stage; 2) the locations of mannose receptors suggested they may be involved in the sensory system of cyprids; 3) 20 kDa-cement protein homologues were expressed in the cyprid cement gland and probably function during attachment; and 4) receptor tyrosine kinases were expressed higher in cyprid stage and may be involved in signal perception during larval settlement. Our results provide not only the basis of several new hypotheses about gene functions during larval settlement, but also the availability of this large transcriptome dataset in B. amphitrite for further exploration of larval settlement and developmental pathways in this important marine species.


The second-to-fourth digit ratio correlates with the rate of academic performance in medical school students.
Prenatal androgens have important organizing effects on the development and future behavior of the brain. The second-to-fourth digit length ratio (2D:4D) has been proposed as a marker of these prenatal androgen effects, with a relatively longer fourth finger indicating higher prenatal androgen exposure. 2D:4D has been shown to predict the success of men who play sports and of financial traders. However, to date little is known regarding the effects of prenatal androgens on academic performance, for example, admission to and success in a highly competitive university system such as the state-run Italian medical schools. Here, we report the findings of a study conducted at the University of Catania Medical School, Italy, in which the 2D:4D ratio was sampled in a group of 48 male students. The 2D:4D ratios were found to be correlated with the performance of the students on the admission test to the medical school, their salivary testosterone levels and their aggressiveness; however, no correlation was observed with the mean score on exams during the course of study. Our results suggest that pre and/or postnatal androgens increase performance in situations that require prompt decision-making and the ability to take risks, but do not influence performance when a more analytical and planned approach is called for.


Pulse compression in adiabatically tapered silicon photonic wires.
We present a comprehensive analysis of pulse compression in adiabatically tapered silicon photonic wire waveguides (Si-PhWWGs), both at telecom (λ ∼ 1.55 μm) and mid-IR (λ ≳ 2.1 μm) wavelengths. Our theoretical and computational study is based on a rigorous model that describes the coupled dynamics of the optical field and photogenerated free carriers, as well as the influence of the physical and geometrical parameters of the Si-PhWWGs on these dynamics. We consider both the soliton and non-soliton pulse propagation regimes, rendering the conclusions of this study relevant to a broad range of experimental settings and practical applications. In particular, we show that by engineering the linear and nonlinear optical properties of Si-PhWWGs through adiabatically varying their width, one can achieve more than 10× pulse compression in millimeter-long waveguides. The inter-dependence between the pulse characteristics and compression efficiency is also discussed.


ChIP-sequencing analysis of E2F transcription factor 2 reveals its role in various biological processes of rheumatoid arthritis synovial fibroblasts.
The development and progression of rheumatoid arthritis (RA) are complex and the pathogenesis of this disease is not fully understood. E2F transcription factor 2 (E2F2) affects the development and progression of many diseases. To identify the mechanisms underlying the role of E2F2 in RA, chromatin immunoprecipitation was performed followed by sequencing (ChIP-seq) using the E2F2 antibody. Gene Ontology (GO) analysis of differentially expressed genes (DEGs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of captured downstream target genes and Metascape analysis of 22 protein molecules partly elucidated the mechanism by which E2F2 affects the progression of RA. Results indicated that E2F2 affects the metabolism of RASFs and the development of ribosome synthesis as well as the stress response. Results indicated that E2F2 can affect multiple biological processes involving RASFs and indicate a unique possibility of targeting E2F2 in the treatment of RA.


Environmental correlates of species rank - abundance distributions in global drylands.
Theoretical models predict lognormal species abundance distributions (SADs) in stable and productive environments, with log-series SADs in less stable, dispersal driven communities. We studied patterns of relative species abundances of perennial vascular plants in global dryland communities to: i) assess the influence of climatic and soil characteristics on the observed SADs, ii) infer how environmental variability influences relative abundances, and iii) evaluate how colonisation dynamics and environmental filters shape abundance distributions. We fitted lognormal and log-series SADs to 91 sites containing at least 15 species of perennial vascular plants. The dependence of species relative abundances on soil and climate variables was assessed using general linear models. Irrespective of habitat type and latitude, the majority of the SADs (70.3%) were best described by a lognormal distribution. Lognormal SADs were associated with low annual precipitation, higher aridity, high soil carbon content, and higher variability of climate variables and soil nitrate. Our results do not corroborate models predicting the prevalence of log-series SADs in dryland communities. As lognormal SADs were particularly associated with sites with drier conditions and a higher environmental variability, we reject models linking lognormality to environmental stability and high productivity conditions. Instead our results point to the prevalence of lognormal SADs in heterogeneous environments, allowing for more evenly distributed plant communities, or in stressful ecosystems, which are generally shaped by strong habitat filters and limited colonisation. This suggests that drylands may be resilient to environmental changes because the many species with intermediate relative abundances could take over ecosystem functioning if the environment becomes suboptimal for dominant species.


Two types of Cassie-to-Wenzel wetting transitions on superhydrophobic surfaces during drop impact.
Despite the fact that superhydrophobic surfaces possess useful and unique properties, their practical application has remained limited by durability issues. Among those, the wetting transition, whereby a surface gets impregnated by the liquid and permanently loses its superhydrophobicity, certainly constitutes the most limiting aspect under many realistic conditions. In this study, we revisit this so-called Cassie-to-Wenzel transition (CWT) under the broadly encountered situation of liquid drop impact. Using model hydrophobic micropillar surfaces of various geometrical characteristics and high speed imaging, we identify that CWT can occur through different mechanisms, and at different impact stages. At early impact stages, right after contact, CWT occurs through the well established dynamic pressure scenario of which we provide here a fully quantitative description. Comparing the critical wetting pressure of surfaces and the theoretical pressure distribution inside the liquid drop, we provide not only the CWT threshold but also the hardly reported wetted area which directly affects the surface spoiling. At a later stage, we report for the first time to our knowledge, a new CWT which occurs during the drop recoil toward bouncing. With the help of numerical simulations, we discuss the mechanism underlying this new transition and provide a simple model based on impulse conservation which successfully captures the transition threshold. By shedding light on the complex interaction between impacting water drops and surface structures, the present study will facilitate designing superhydrophobic surfaces with a desirable wetting state during drop impact.


Decreasing prevalence of oral cleft live births in the Netherlands, 1997-2006.
The number of new oral cleft patients has fallen in the Netherlands. This may be explained by two hypotheses: (1) greater prenatal detection of congenital anomalies has led to more pregnancy terminations and (2) increased folic acid use has reduced the oral cleft risk. Both hypotheses would mainly apply to the category cleft lip/alveolus ± cleft palate (CL±P), since, unlike cleft palate only (CP), CL±P can be detected prenatally by two-dimensional (2D) ultrasound and develops during the period recommended for folic acid use. The authors aimed to determine trends in prevalence over 1997-2006 and to evaluate the hypotheses by stratifying trends by cleft category. This study was a time-trend analysis of infants born alive with oral clefts in the Netherlands during 1997-2006 and registered in the national oral cleft registry. The authors calculated prevalence rates and the estimated annual percentage change (EAPC) for all oral clefts and the two categories. In 1997-2006, 3308 infants out of 1 970 872 live births had oral clefts, an overall prevalence per 10 000 live births of 16.8 (CL±P: 11.3; CP: 5.5). Time-trend analysis showed that the prevalence of all oral clefts decreased (EAPC -1.8%; 95% CI: -3.0% to -0.6%), as did the CL±P prevalence (EAPC -2.3%; 95% CI: -3.8% to -0.9%). No significant trends were found for the CP prevalence. Because the live-birth prevalence of CL±P decreased, that of all oral clefts decreased. These findings are in line with both hypotheses and may therefore have implications for prenatal counselling and folic acid policy.


Designation of Streptomycete 16S and 23S rRNA-based target regions for oligonucleotide probes.
The 16S and 23S rRNA of various Streptomyces species were partially sequenced and screened for the presence of stretches that could define all members of the genus, groups of species, or individual species. Nucleotide 929 (Streptomyces ambofaciens nomenclature [J.L. Pernodet, M.T. Alegre, F. Boccard, and M. Guerineau, Gene 79:33-46, 1989]) is a nucleotide highly unique to Streptomyces species which, in combination with flanking regions, allowed the designation of a genus-specific probe. Regions 158 through 203 of the 16S rRNA and 1518 through 1645 of the 23S rRNA (helix 54 [Pernodet et al., Gene 79:33-46, 1989]) have a high potential to define species, whereas the degree of variation in regions 982 through 998 and 1102 through 1122 of the 16S rRNA is less pronounced but characteristic for at least certain species. Alone or in combination with each other, these regions may serve as target sites for synthetic oligonucleotide probes and primers to be used in the determination of pure cultures and in the characterization of community structures. The specificity of several probes is demonstrated by dot blot hybridization.


Identifying gene pathways associated with cancer characteristics via sparse statistical methods.
We propose a statistical method for uncovering gene pathways that characterize cancer heterogeneity. To incorporate knowledge of the pathways into the model, we define a set of activities of pathways from microarray gene expression data based on the Sparse Probabilistic Principal Component Analysis (SPPCA). A pathway activity logistic regression model is then formulated for cancer phenotype. To select pathway activities related to binary cancer phenotypes, we use the elastic net for the parameter estimation and derive a model selection criterion for selecting tuning parameters included in the model estimation. Our proposed method can also reverse-engineer gene networks based on the identified multiple pathways that enables us to discover novel gene-gene associations relating with the cancer phenotypes. We illustrate the whole process of the proposed method through the analysis of breast cancer gene expression data.


microRNAs in the Lymphatic Endothelium: Master Regulators of Lineage Plasticity and Inflammation.
microRNAs (miRNAs) are highly conserved, small non-coding RNAs that regulate gene expression at the posttranscriptional level. They have crucial roles in organismal development, homeostasis, and cellular responses to pathological stress. The lymphatic system is a large vascular network that actively regulates the immune response through antigen trafficking, cytokine secretion, and inducing peripheral tolerance. Here, we review the role of miRNAs in the lymphatic endothelium with a particular focus on their role in lymphatic endothelial cell (LEC) plasticity, inflammation, and regulatory function. We highlight the lineage plasticity of LECs during inflammation and the importance of understanding the regulatory role of miRNAs in these processes. We propose that targeting miRNA expression in lymphatic endothelium can be a novel strategy in treating human pathologies associated with lymphatic dysfunction.


Use of a Fully Automated Internet-Based Cognitive Behavior Therapy Intervention in a Community Population of Adults With Depression Symptoms: Randomized Controlled Trial.
Although internet-based cognitive behavior therapy (iCBT) interventions can reduce depression symptoms, large differences in their effectiveness exist. The aim of this study was to evaluate the effectiveness of an iCBT intervention called Thrive, which was designed to enhance engagement when delivered as a fully automated, stand-alone intervention to a rural community population of adults with depression symptoms. Using no diagnostic or treatment exclusions, 343 adults with depression symptoms were recruited from communities using an open-access website and randomized 1:1 to the Thrive intervention group or the control group. Using self-reports, participants were evaluated at baseline and 4 and 8 weeks for the primary outcome of depression symptom severity and secondary outcome measures of anxiety symptoms, work and social adjustment, psychological resilience, and suicidal ideation. Over the 8-week follow-up period, the intervention group (n=181) had significantly lower depression symptom severity than the control group (n=162; P<.001), with a moderate treatment effect size (d=0.63). Moderate to near-moderate effect sizes favoring the intervention group were observed for anxiety symptoms (P<.001; d=0.47), work/social functioning (P<.001; d=0.39), and resilience (P<.001; d=0.55). Although not significant, the intervention group was 45% less likely than the control group to experience increased suicidal ideation (odds ratio 0.55). These findings suggest that the Thrive intervention was effective in reducing depression and anxiety symptom severity and improving functioning and resilience among a mostly rural community population of US adults. The effect sizes associated with Thrive were generally larger than those of other iCBT interventions delivered as a fully automated, stand-alone intervention. ClinicalTrials.gov NCT03244878; https://clinicaltrials.gov/ct2/show/NCT03244878.


Design of glycolysis.
The design of the glycolytic pathway resulting from the continuous refinement of evolution is discussed with regard to three aspects. 1. Functional and structural properties of individual enzymes. The catalytic constants of the glycolytic enzymes are remarkably optimized; the turnover numbers are within one order of magnitude. The same is true for the molarities of catalytic centres in the cytosol, as is noted for yeast. Functional properties of the enzymes are reflected in their tertiary and quaternary structures. 2. Regulatory mechanisms of single enzymes. A classification of the various types of enzymic control mechanisms operating in the glycolytic pathway is given. In addition to the usual Michaelis-Menten saturation kinetics and the various types of inhibition there is control by positive and negative effectors based on oligomeric structures (fast acting, fine control) as well as regulation by chemical interconversion structures (fast acting, fine control) as well as regulation by chemical based on enzymes cascades (slow acting, very effective). 3. Functional and regulatory mechanisms of the whole glycolytic reaction pathway. A prominent feature is the high enzyme:substrate ratio, which guarantees fast response times. However, a quantitative treatment of the overall kinetics is limited by an incomplete knowledge of the enzymes' dynamic and chemical compartmentation as well as some of their control properties. From an analysis of the oscillatory state, certain control points in the glycolytic chain can be located that coincide with major branching points to other metabolic pathways. These points are controlled by fast-acting cooperative enzymes that operate in a flip-flop mechanism together with the respective antagonistic enzymes, preventing futile cycles. The gating enzymes leading to the glycogen store and the citric acid cycle are of the slow-acting but very effective interconvertible type. The combination of all the complex and intricate features of design yields a glycolytic network that enables the cell to respond to its various metabolic needs quickly, effectively and economically.


Multiple cerebral infarction and paradoxical air embolism during hepatectomy using the Cavitron Ultrasonic Surgical Aspirator -A case report-.
A venous air embolism and paradoxical air embolism (PAE) are serious complications in patients undergoing a hepatectomy. We report a case of PAE and cerebral infarctions in a patient undergoing a hepatic resection using a Cavitron Ultrasonic Surgical Aspirator (CUSA®). A 65-year-old woman underwent a left lobe hepatectomy. During the middle phase of the liver resection with CUSA®, there was a sudden decrease in arterial blood pressure, end-tidal carbon dioxide and SpO(2). With resuscitation, intraoperative ultrasonography revealed massive air emboli in both her left and right heart, which lasted for 40 min. The hepatectomy was completed after the disappearance of the air emboli from her heart. After surgery, her mental status was stuporous. The brain CT and MRI revealed multiple acute cerebral infarctions. Finally, she died from septic shock. This case highlights the need for anesthetists and surgeons to be aware of the potential for CUSA®-related massive PAE.


Fermentative production of Vitamin E tocotrienols in Saccharomyces cerevisiae under cold-shock-triggered temperature control.
The diverse physiological functions of tocotrienols have listed them as valuable supplementations to α-tocopherol-dominated Vitamin E products. To make tocotrienols more readily available, tocotrienols-producing S. cerevisiae has been constructed by combining the heterologous genes from photosynthetic organisms with the endogenous shikimate pathway and mevalonate pathway. After identification and elimination of metabolic bottlenecks and enhancement of precursors supply, the engineered yeast can produce tocotrienols at yield of up to 7.6 mg/g dry cell weight (DCW). In particular, proper truncation of the N-terminal transit peptide from the plant-sourced enzymes is crucial. To further solve the conflict between cell growth and tocotrienols accumulation so as to enable high-density fermentation, a cold-shock-triggered temperature control system is designed for efficient control of two-stage fermentation, leading to production of 320 mg/L tocotrienols. The success in high-density fermentation of tocotrienols by engineered yeast sheds light on the potential of fermentative production of vitamin E tocochromanols.


Instilling fear makes good business sense: unwarranted hysterectomies in Karnataka.
This paper uses data from two fact-finding exercises in two districts of Karnataka to trace how government and private doctors alike pushed women to undergo hysterectomies. The doctors provided grossly unscientific information to poor Dalit women to instil a fear of "cancer" in their minds to wilfully mislead them to undergo hysterectomies, following which many suffered complications and died. The paper examines a review, made by two separate panels of experts, of women's medical records from private hospitals to illustrate that a large proportion of the hysterectomies performed were medically unwarranted; that private doctors were using highly suspect diagnostic criteria, based on a single ultrasound scan, to perform the hysterectomies and had not sent even a single sample for histopathology; and that the medical records were incomplete, erroneous and, in several instances, manipulated. The paper describes how a combination of patriarchal bias, professional unscrupulousness and pro-private healthcare policies posed a serious threat to the survival and well-being of women in Karnataka.


Animal movements in the Kenya Rift and evidence for the earliest ambush hunting by hominins.
Animal movements in the Kenya Rift Valley today are influenced by a combination of topography and trace nutrient distribution. These patterns would have been the same in the past when hominins inhabited the area. We use this approach to create a landscape reconstruction of Olorgesailie, a key site in the East African Rift with abundant evidence of large-mammal butchery between ~1.2 and ~0.5 Ma BP. The site location in relation to limited animal routes through the area show that hominins were aware of animal movements and used the location for ambush hunting during the Lower to Middle Pleistocene. These features explain the importance of Olorgesailie as a preferred location of repeated hominin activity through multiple changes in climate and local environmental conditions, and provide insights into the cognitive and hunting abilities of Homo erectus while indicating that their activities at the site were aimed at hunting, rather than scavenging.


Viability analysis and apoptosis induction of breast cancer cells in a microfluidic device: effect of cytostatic drugs.
Breast cancer is the leading cause of cancer deaths among non-smoking women worldwide. At the moment the treatment regime is such that patients receive different chemotherapeutic and/or hormonal treatments dependent on the hormone receptor status, the menopausal status and age. However, in vitro sensitivity testing of tumor biopsies could rationalize and improve the choice of chemo- and hormone therapy. Lab-on-a-Chip devices, using microfluidic techniques, make detailed cellular analysis possible using fewer cells, enabling working with a patients' own cells and performing chemo- and hormone sensitivity testing in an ex vivo setting. This article describes the development of two microfluidic devices made in poly(dimethylsiloxane) (PDMS) to validate the cell culture properties and analyze the chemosensitivity of MCF-7 cells (estrogen receptor positive human breast cancer cells) in response to the drug staurosporine (SSP). In both cases, cell viability was assessed using the life-stain Calcein-AM (CAAM) and the death dye propidium iodide (PI). MCF-7 cells could be statically cultured for up to 7 days in the microfluidic chip. A 30 min flow with SSP and a subsequent 24 h static incubation in the incubator induced apoptosis in MCF-7 cells, as shown by a disappearance of the aggregate-like morphology, a decrease in CAAM staining and an increase in PI staining. This work provides valuable leads to develop a microfluidic chip to test the chemosensitivity of tumor cells in response to therapeutics and in this way improve cancer treatment towards personalized medicine.


New Pharmacotherapy Targeting Cognitive Dysfunction of Schizophrenia via Modulation of GABA Neuronal Function.
Schizophrenia is considered a neurodevelopmental and neurodegenerative disorder. Cognitive impairment is a core symptom in patients with the illness, and has been suggested a major predictor of functional outcomes. Reduction of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) interneurons has been associated with the pathophysiology of schizophrenia, in view of the link between the abnormality of GABA neurons and cognitive impairments of the disease. It is assumed that an imbalance of excitatory and inhibitory (E-I) activity induced by low activity of glutamatergic projections and PV-positive GABA interneurons in the prefrontal cortex resulted in sustained neural firing and gamma oscillation, leading to impaired cognitive function. Therefore, it is important to develop novel pharmacotherapy targeting GABA neurons and their activities. Clinical evidence suggests serotonin (5-HT) 1A receptor agonist improves cognitive disturbances of schizophrenia, consistent with results from preclinical studies, through mechanism that corrects E-I imbalance via the suppression of GABA neural function. On the other hand, T-817MA, a novel neurotrophic agent, ameliorated loss of PV-positive GABA neurons in the medial prefrontal cortex and reduction of gamma-band activity, as well as cognitive dysfunction in animal model of schizophrenia. In conclusion, a pharmacotherapy to alleviate abnormalities in GABA neurons through 5-HT1A agonists and T-817MA is expected to prevent the onset and/or progression of schizophrenia.


Primary hemiarthroplasty versus conservative treatment for comminuted fractures of the proximal humerus in the elderly (ProCon): a multicenter randomized controlled trial.
Fractures of the proximal humerus are associated with a profound temporary and sometimes permanent, impairment of function and quality of life. The treatment of comminuted fractures of the proximal humerus like selected three-or four-part fractures and split fractures of the humeral head is a demanding and unresolved problem, especially in the elderly. Locking plates appear to offer improved fixation; however, screw cut-out rates ranges due to fracture collapse are high. As this may lead to higher rates of revision surgery, it may be preferable to treat comminuted fractures in the elderly primarily with a prosthesis or non-operatively. Results from case series and a small-sample randomized controlled trial (RCT) suggest improved function and less pain after primary hemiarthroplasty (HA); however these studies had some limitations and a RCT is needed. The primary aim of this study is to compare the Constant scores (reflecting functional outcome and pain) at one year after primary HA versus non-operative treatment in elderly patients who sustained a comminuted proximal humeral fracture. Secondary aims include effects on functional outcome, pain, complications, quality of life, and cost-effectiveness. A prospective, multi-center RCT will be conducted in nine centers in the Netherlands and Belgium. Eighty patients over 65 years of age, who have sustained a three-or four part, or split head proximal humeral fracture will be randomized between primary hemiarthroplasty and conservative treatment. The primary outcome is the Constant score, which indicates pain and function. Secondary outcomes include the Disability of the Arm and Shoulder (DASH) score, Visual Analogue Scale (VAS) for pain, radiographic healing, health-related quality of life (Short-form-36, EuroQol-5D) and healthcare consumption. Cost-effectiveness ratios will be determined for both trial arms. Outcome will be monitored at regular intervals over the subsequent 24 months (1, 3 and 6 weeks, and 3, 6, 12, 18, and 24 months). Data will be analyzed on an intention to treat basis, using univariate and multivariable analyses. This trial will provide level-1 evidence on the effectiveness of the two mostly applied treatment options for three-or four part and split head proximal humeral fractures in the elderly. These data may support the development of a clinical guideline for treatment of these traumatic injuries. Netherlands Trial Register (NTR2040).


Nasal rinsing with hypertonic solution: an adjunctive treatment for pediatric seasonal allergic rhinoconjunctivitis.
Recent but limited evidence suggests that nasal lavage with hypertonic saline may be useful as an adjunctive treatment modality in the management of pediatric allergic rhinitis. The aim of this study was to clarify whether nasal irrigation with hypertonic solution should be routinely recommended to children with seasonal grass pollen rhinoconjunctivitis. Fourty-four children with seasonal grass pollen rhinoconjunctivitis were recruited. Twenty-two patients were randomized to receive three-times daily nasal rinsing with hypertonic saline during the pollen season, which lasted 7 weeks. Twenty-two patients were allocated to receive no nasal irrigation and were used as controls. Twenty patients per group completed the study. A mean daily rhinoconjunctivitis score based on the presence of nasal discharge and obstruction as well as ocular symptoms as reddening and itching were calculated for each week of the pollen season. Patients were allowed to use oral antihistamines when required and the mean number of drugs taken per week was also calculated. The mean weekly rhinoconjunctivitis score in the active group was reduced during the whole pollen period. This difference was statistically significant in week 6 and 7 of therapy. A markedly reduced intake of oral antihistamines was also observed in patients allocated to nasal rinsing, being statistically significant in 5 of the 7 weeks. No adverse effect was reported in the active group. This study supports the use of nasal rinsing with hypertonic saline in the pediatric patient with seasonal allergic rhinoconjunctivitis. This treatment proved to be tolerable, inexpensive and effective.


Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules.
Granulomatous syndromes, such as Wegener's granulomatosis, are defined according to complex criteria, but the underlying cause is rarely identified. We present evidence for a new aetiology for chronic granulomatous lesions associated with a recessive genetic defect, which is linked to the human leucocyte antigen (HLA) locus. Five adults with necrotising granulomatous lesions in the upper respiratory tract and skin, associated with recurrent bacterial respiratory infections and skin vasculitis, were identified. A diagnosis of Wegener's granulomatosis was considered in all of them, but abandoned because of an incompatible disease course and resistance to immunosuppressive treatments. Peripheral-blood samples were taken and analysed by immunohistochemistry and fluorescent-activated-cell-sorter analysis. Since all five patients were homozygous for the HLA locus, we looked for genetic defects located within the HLA-locus with PCR and restriction fragment length polymorphism. A severe decrease in cell-surface expression of HLA class-I molecule was seen in all patients. Defective expression of the transporter associated with antigen presentation (TAP) genes was responsible for the HLA class-I down-regulation, and in two patients we identified a mutation in the TAP2 gene responsible for the defective expression of the TAP complex. We showed the presence of autoreactive natural killer (NK) cells and gammadelta T lymphocytes in the peripheral blood cells of two patients. Correction of the genetic defect in vitro restored normal expression of HLA class-I molecules and prevented self-reactivity in the patients' cells. Histology of granulomatous lesions showed the presence of a large proportion of activated NK cells. Our findings define the cause and pathogenesis of a new syndrome that affects patients with a defective surface expression of HLA class-I molecules. The syndrome resembles Wegener's granulomatosis both clinically and histologically. Patients have chronic necrotising granulomatous lesions in the upper respiratory tract and skin, recurrent infections of the respiratory tract, and skin vasculitis. A predominant NK population within the granulomatous lesions suggests that the pathophysiology of the skin lesions may relate to the inability of HLA class-I molecules to turn off NK cell responses. Accurate genetic analysis of a defined syndrome can provide a better understanding of the cause and pathogenesis of a disease.


Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus.
Febrile seizures are a common childhood seizure disorder and a defining feature of genetic epilepsy with febrile seizures plus (GEFS+), a syndrome frequently associated with Na+ channel mutations. Here, we describe the creation of a knockin mouse heterozygous for the C121W mutation of the beta1 Na+ channel accessory subunit seen in patients with GEFS+. Heterozygous mice with increased core temperature displayed behavioral arrest and were more susceptible to thermal challenge than wild-type mice. Wild-type beta1 was most concentrated in the membrane of axon initial segments (AIS) of pyramidal neurons, while the beta1(C121W) mutant subunit was excluded from AIS membranes. In addition, AIS function, an indicator of neuronal excitability, was substantially enhanced in hippocampal pyramidal neurons of the heterozygous mouse specifically at higher temperatures. Computational modeling predicted that this enhanced excitability was caused by hyperpolarized voltage activation of AIS Na+ channels. This heat-sensitive increased neuronal excitability presumably contributed to the heightened thermal seizure susceptibility and epileptiform discharges seen in patients and mice with beta1(C121W) subunits. We therefore conclude that Na+ channel beta1 subunits modulate AIS excitability and that epilepsy can arise if this modulation is impaired.


Polymorphisms in the dopamine transporter gene (SLC6A3/DAT1) and alcohol dependence in humans: a systematic review.
Dopamine neurotransmission has been a key player in attempts to identify genetic factors involved in alcohol dependence. The dopamine transporter terminates dopaminergic neurotransmission, making the gene encoding the transporter (SLC6A3/DAT1) an attractive candidate in clinical studies on alcohol dependence. We conducted a systematic review of 18 studies examining associations between polymorphisms in DAT1 and alcohol dependence. The DAT1 variable number tandem repeat, the most frequent studied polymorphism in DAT1, did not show a direct association with alcohol dependence in general. Several, but not all, studies found that the DAT1 variable number tandem repeat (9-repeat allele) was associated with alcohol-withdrawal symptoms, such as seizures and delirium tremens. We discuss shortcomings, such as lack of power and disregarding moderating variables, as well as future challenges of gene association studies.


Patient and Family Engagement in the ICU. Untapped Opportunities and Underrecognized Challenges.
The call for meaningful patient and family engagement in health care and research is gaining impetus. Healthcare institutions and research funding agencies increasingly encourage clinicians and researchers to work actively with patients and their families to advance clinical care and research. Engagement is increasingly mandated by healthcare organizations and is becoming a prerequisite for research funding. In this article, we review the rationale and the current state of patient and family engagement in patient care and research in the ICU. We identify opportunities to strengthen engagement in patient care by promoting greater patient and family involvement in care delivery and supporting their participation in shared decision-making. We also identify challenges related to patient willingness to engage, barriers to participation, participant risks, and participant expectations. To advance engagement, clinicians and researchers can develop the science behind engagement in the ICU context and demonstrate its impact on patient- and process-related outcomes. In addition, we provide practical guidance on how to engage, highlight features of successful engagement strategies, and identify areas for future research. At present, enormous opportunities remain to enhance engagement across the continuum of ICU care and research.


Ki-67 predicts disease recurrence and poor prognosis in pancreatic neuroendocrine neoplasms.
Pancreatic neuroendocrine neoplasms are rare malignancies for which the ideal staging method remains controversial. Ki-67 is a cell proliferation marker that has been shown to have some utility in predicting prognosis in neuroendocrine neoplasms. We sought to test the predictive ability of Ki-67 staining for disease recurrence and overall survival (OS) in pancreatic neuroendocrine neoplasms. The medical records of patients who underwent pancreatic resection for pancreatic neuroendocrine neoplasms at a tertiary referral hospital from 1994 to 2009 were reviewed. The pathologic specimens of all were stained for Ki-67 and recorded as percentage of cells staining positive per high-powered field. The 10-year disease-free and OSs were analyzed. We identified 140 patients. Gender and age were not associated with increased risk of disease recurrence. Patients with tumors >4 cm or with Ki-67 staining >9% were more likely to have disease recurrence (P = .0454 and .047) and have decreased OS (P < .0001 and .0007). Increasing tumor size and increasing Ki-67 staining both correlate with increased risk of disease recurrence and decreased OS. Designing a staging system that incorporates both of these clinical variables will enable better identification of patients at risk for recurrent pancreatic neuroendocrine neoplasms.


Role of the left atrial function on the pseudonormalization of the transmitral flow velocity pattern evaluated by two-dimensional tissue tracking technique.
Mechanisms of the pseudonormalization (PN) of the transmitral flow (TMF) velocity pattern have been mainly attributed to left ventricular diastolic function. To assess the influence of left atrial (LA) function on the PN with two-dimensional tissue tracking technique. The subjects consisted of 21 healthy volunteers and 70 patients with various cardiac diseases. Images of one cardiac cycle in the apical four-chamber view were stored by the HIVISION 900 (Hitachi Medico, Chiba, Japan). The LA volume (LAV) loop was created using two-dimensional tissue tracking technique and LAV index (LAVI) at a given cardiac phase was calculated. A preload of 90mmHg was applied using a customized lower body positive pressure (LBPP) system. Patients were divided into the PN group (n=18) with their early diastolic TMF velocity (E) increased and late diastolic TMF velocity (A) decreased, and the non-(N)-PN group (n=52) with both E and A wave velocities increased by LBPP. (1) During LBPP, the LAVImax in both the groups increased significantly. (2) In the N-PN group, the LAVIpass (p<0.001), LAVIact (p<0.01), and LAVItotal (p<0.0001) increased significantly. The dV/dts (p<0.0001) and dV/dtE (p<0.0001) increased significantly with an increase in the dV/dtA. On the other hand, there was no change in those parameters except LAVIpass (p<0.05) and dV/dtE (p<0.05) significantly increased in the PN group. (3) As a result, the LAVImin was significantly greater in the PN group than in the N-PN group (p<0.0001) during LBPP. The ratio of E velocity to early diastolic mitral annular velocity (E/E') during LBPP was significantly greater in the PN group than in the N-PN group (p<0.0001). The lack of an increase in active LA emptying volume in response to an increase of preload leads to elevated LA pressure and the pseudonormalization of the TMF velocity pattern in patients with various cardiac diseases.


Identification of proteins adducted by lipid peroxidation products in plasma and modifications of apolipoprotein A1 with a novel biotinylated phospholipid probe.
Reactive electrophiles generated by lipid peroxidation are thought to contribute to cardiovascular disease and other oxidative stress-related pathologies by covalently modifying proteins and affecting critical protein functions. The difficulty of capturing and analyzing the relatively small fraction of modified proteins complicates identification of the protein targets of lipid electrophiles. We recently synthesized a biotin-modified linoleoylglycerylphosphatidylcholine probe called PLPBSO ( Tallman et al. Chem. Res. Toxicol. 2007, 20, 227-234 ), which forms typical linoleate oxidation products and covalent adducts with model peptides and proteins. Supplementation of human plasma with PLPBSO followed by free radical oxidation resulted in covalent adduction of PLPBSO to plasma proteins, which were isolated with streptavidin and identified by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Among the most highly modified proteins was apolipoprotein A1 (ApoA1), which is the core component of high density lipoprotein (HDL). ApoA1 phospholipid adduct sites were mapped by LC-MS-MS of tryptic peptides following mild base hydrolysis to release esterified phospholipid adducts. Several carboxylated adducts formed from phospholipid-esterified 9,12-dioxo-10( E)-dodecenoic acid (KODA), 9-hydroxy, 12-oxo-10( E)-dodecenoic acid (HODA), 7-oxoheptanoic acid, 8-oxooctanoic acid, and 9-oxononanoic acid were identified. Free radical oxidations of isolated HDL also generated adducts with 4-hydroxynonenal (HNE) and other noncarboxylated electrophiles, but these were only sporadically identified in the PLPBSO-adducted ApoA1, suggesting a low stoichiometry of modification in the phospholipid-adducted protein. Both phospholipid electrophiles and HNE adducted His162, which resides in an ApoA1 domain involved in the activation of Lecithin-cholesterol acyltransferase and maturation of the HDL particle. ApoA1 lipid electrophile adducts may affect protein functions and provide useful biomarkers for oxidative stress.


Dynamic RNA profiling in Plasmodium falciparum synchronized blood stages exposed to lethal doses of artesunate.
Translation of the genome sequence of Plasmodium sp. into biologically relevant information relies on high through-put genomics technology which includes transcriptome analysis. However, few studies to date have used this powerful approach to explore transcriptome alterations of P. falciparum parasites exposed to antimalarial drugs. The rapid action of artesunate allowed us to study dynamic changes of the parasite transcriptome in synchronous parasite cultures exposed to the drug for 90 minutes and 3 hours. Developmentally regulated genes were filtered out, leaving 398 genes which presented altered transcript levels reflecting drug-exposure. Few genes related to metabolic pathways, most encoded chaperones, transporters, kinases, Zn-finger proteins, transcription activating proteins, proteins involved in proteasome degradation, in oxidative stress and in cell cycle regulation. A positive bias was observed for over-expressed genes presenting a subtelomeric location, allelic polymorphism and encoding proteins with potential export sequences, which often belonged to subtelomeric multi-gene families. This pointed to the mobilization of processes shaping the interface between the parasite and its environment. In parallel, pathways were engaged which could lead to parasite death, such as interference with purine/pyrimidine metabolism, the mitochondrial electron transport chain, proteasome-dependent protein degradation or the integrity of the food vacuole. The high proportion of over-expressed genes encoding proteins exported from the parasite highlight the importance of extra-parasitic compartments as fields for exploration in drug research which, to date, has mostly focused on the parasite itself rather than on its intra and extra erythrocytic environment. Further work is needed to clarify which transcriptome alterations observed reflect a specific response to overcome artesunate toxicity or more general perturbations on the path to cellular death.


The H3-H4 N-terminal tail domains are the primary mediators of transcription factor IIIA access to 5S DNA within a nucleosome.
Reconstitution of a DNA fragment containing a Xenopus borealis somatic type 5S rRNA gene into a nucleosome greatly restricts the binding of transcription factor IIIA (TFIIIA) to its cognate DNA sequence within the internal promoter of the gene. Removal of all core histone tail domains by limited trypsin proteolysis or acetylation of the core histone tails significantly relieves this inhibition and allows TFIIIA to exhibit high-affinity binding to nucleosomal DNA. Since only a single tail or a subset of tails may be primarily responsible for this effect, we determined whether removal of the individual tail domains of the H2A-H2B dimer or the H3-H4 tetramer affects TFIIIA binding to its cognate DNA site within the 5S nucleosome in vitro. The results show that the tail domains of H3 and H4, but not those of H2A and/or H2B, directly modulate the ability of TFIIIA to bind nucleosomal DNA. In vitro transcription assays carried out with nucleosomal templates lacking individual tail domains show that transcription efficiency parallels the binding of TFIIIA. In addition, we show that the stoichiometry of core histones within the 5S DNA-core histone-TFIIIA triple complex is not changed upon TFIIIA association. Thus, TFIIIA binding occurs by displacement of H2A-H2B-DNA contacts but without complete loss of the dimer from the nucleoprotein complex. These data, coupled with previous reports (M. Vettese-Dadey, P. A. Grant, T. R. Hebbes, C. Crane-Robinson, C. D. Allis, and J. L. Workman, EMBO J. 15:2508-2518, 1996; L. Howe, T. A. Ranalli, C. D. Allis, and J. Ausio, J. Biol. Chem. 273:20693-20696, 1998), suggest that the H3/H4 tails are the primary arbiters of transcription factor access to intranucleosomal DNA.


Application of a Novel Force-Field to Manipulate the Relationship Between Pelvis Motion and Step Width in Human Walking.
Motion of the pelvis throughout a step predicts step width during human walking. This behavior is often considered an important component of ensuring bipedal stability, but can be disrupted in populations with neurological injuries. The purpose of this study was to determine whether a novel force-field that exerts mediolateral forces on the legs can manipulate the relationship between pelvis motion and step width, providing proof-of-concept for a future clinical intervention. We designed a force-field able to: 1) minimize the delivered mediolateral forces (Transparent mode); 2) apply mediolateral forces to assist the leg toward mechanically-appropriate step widths (Assistive mode); and 3) apply mediolateral forces to perturb the leg away from mechanically-appropriate step widths (Perturbing mode). Neurologically-intact participants were randomly assigned to either the Assistive group (n = 12) or Perturbing group (n = 12), and performed a series of walking trials in which they interfaced with the force-field. We quantified the step-by-step relationship between mediolateral pelvis displacement and step width using partial correlations. Walking in the Transparent force-field had a minimal effect on this relationship. However, force-field assistance directly strengthened the relationship between pelvis displacement and step width, whereas force-field perturbations weakened this relationship. Both assistance and perturbations were followed by short-lived effects during a wash-out period, in which the relationship between pelvis displacement and step width differed from the baseline value. The present results demonstrate that the link between pelvis motion and step width can be manipulated through mechanical means, which may be useful for retraining gait balance in clinical populations.


A didactic and hands-on module enhances resident microsurgical knowledge and technical skill.
Simulation has been adopted as a powerful training tool in many areas of health care. However, it has not yet been systematically embraced in neurosurgery because of the absence of validated tools, assessment scales, and curricula. To use our validated microanastomosis module and scale to evaluate the effects of an educational intervention on the performance of neurosurgery residents at the 2012 Congress of Neurological Surgeons Annual Meeting. The module consisted of an end-to-end microanastomosis of a 3-mm vessel and was divided into 3 phases: (1) a cognitive and microsuture prelecture testing phase, (2) a didactic lecture, and (3) a cognitive and microsuture postlecture testing phase. We compared resident knowledge and technical proficiency from the pretesting and posttesting phases. One neurosurgeon and 7 neurosurgery residents participated in the study. None had previous experience in microsurgery. The average score on the microsuture prelecture and postlecture tests, as measured by our assessment scale, was 32.50 and 39.75, respectively (P = .001). The number of completed sutures at the end of each procedure was higher for 75% of participants in the postlecture testing phase (P = .03). The average score on the cognitive postlecture test (12.75) was significantly better than that of the cognitive prelecture test (8.38; P = .001). Simulation has the potential to enhance resident education and to elevate proficiency levels. Our data suggest that a focused microsurgical module that incorporates a didactic component and a technical component can enhance resident knowledge and technical proficiency in microsurgical anastomosis.


Caenorhabditis elegans aristaless/Arx gene alr-1 restricts variable gene expression.
Variable expressivity of mutant phenotypes in genetically identical individuals is a phenomenon widely reported but poorly understood. For example, mutations in the gene encoding the transcription factor ALR-1 in Caenorhabditis elegans result in variable touch receptor neuron (TRN) function. Using single-molecule in situ hybridization, we demonstrate that this phenotypic variability reflects enhanced variability in the expression of the selector gene mec-3, which is needed, together with unc-86, for the differentiation of the TRNs. In a yeast expression system, ALR-1 enhances MEC-3/UNC-86-dependent transcription from the mec-3 promoter, showing that ALR-1 can enhance bulk mec-3 expression. We show that, due to stochastic fluctuations, autoregulation of mec-3 is not sufficient for TRN differentiation; ALR-1 provides a second positive feedback loop that increases mec-3 expression, by restricting variability, and thus ensures TRN differentiation. Our results link fluctuations in gene expression to phenotypic variability, which is seen in many mutant strains, and provide an explicit demonstration of how variable gene expression can be curtailed in developing cells to ensure their differentiation. Because ALR-1 and similar proteins (Drosophila Aristaless and human ARX) are needed for the expression of other transcription factors, we propose that proteins in this family may act to ensure differentiation more generally.


Characterization of prolactin binding by membrane preparations from rat liver.
Binding sites for prolactin were identified in a plasma-membrane-enriched fraction isolated from livers of mature female rats. 125I-labelled sheep prolactin prepared by the lactoperoxidase procedure retained the same molecular integrity and binding affinity as the native hormone at physiological pH. The receptors bound prolactin from different species, whereas non-lactogenic hormones were not bound. The binding of 125I-labelled sheep prolactin was activated equally by bivalent and univalent cations, bivalent cations exerting their maximal effect at much lower concentrations. The association of 125I-labelled sheep prolactin with the receptor was a time- and temperature-dependent process. Partial dissociation was detected. The binding of 125I-labelled sheep prolactin was strongly influenced by pH, with an optimum observed at pH 6.5. Receptor activity was destroyed by Pronase and phospholipase C, whereas neuraminidase increased binding. Treatment of the membranes by ribonuclease and deoxyribonuclease did not affect the binding. Binding of 125I-labelled sheep prolactin was inhibited by p-chloromercuribenzoic acid, dithiothreitol and by brief exposure to high temperatures. Scatchard analysis of the binding of 125I-labelled sheep prolactin to receptors indicated that prolactin has a high affinity for its receptor. Binding of prolactin to liver membranes showed some properties different from those observed with mammary cells. Binding by these tissues differed in pH optimum, in effects of ions, and in response to neuraminidase.


Sprouty2 downregulates angiogenesis during mouse skin wound healing.
Angiogenesis is regulated by signals received by receptor tyrosine kinases such as vascular endothelial growth factor receptors. Mammalian Sprouty (Spry) proteins are known to function by specifically antagonizing the activation of the mitogen-activated protein kinase signaling pathway by receptor tyrosine kinases, a pathway known to promote angiogenesis. To examine the role of Spry2 in the regulation of angiogenesis during wound repair, we used a model of murine dermal wound healing. Full-thickness excisional wounds (3 mm) were made on the dorsum of anesthetized adult female FVB mice. Samples were harvested at multiple time points postwounding and analyzed using real-time RT-PCR, Western blot analysis, and immunofluorescent histochemistry. Spry2 mRNA and protein levels in the wound bed increased significantly during the resolving phases of healing, coincident with the onset of vascular regression in this wound model. In another experiment, intracellular levels of Spry2 or its dominant-negative mutant (Y55F) were elevated by a topical application to the wounds of controlled-release gel containing cell permeable, transactivator of transcription-tagged Spry2, Spry2Y55F, or green fluorescent protein (as control). Wound samples were analyzed for vascularity using CD31 immunofluorescent histochemistry as well as for total and phospho-Erk1/2 protein content. The treatment of wounds with Spry2 resulted in a significant decrease in vascularity and a reduced abundance of phospho-Erk1/2 compared with wounds treated with the green fluorescent protein control. In contrast, the wounds treated with the dominant-negative Spry2Y55F exhibited a moderate increase in vascularity and elevated phospho-Erk1/2 content. These results indicate that endogenous Spry2 functions to downregulate angiogenesis in the healing murine skin wound, potentially by inhibiting the mitogen-activated protein kinase signaling pathway.


Characterisation of peripheral bone mineral density in youth at risk of secondary osteoporosis - a preliminary insight.
To describe peripheral long bone material and structural differences in youth at risk of secondary osteoporosis across disease-specific profiles. Upper- and lower limbs of children and adolescents were scanned at 4% distal and 66% mid-shaft sites using peripheral Quantitative Computed Tomography sub-categorised as (1) increased risk of secondary osteoporosis (neuromuscular disorders; chronic diseases; endocrine diseases; inborn errors of metabolism; iatrogenic conditions), (2) low motor competence and (3) non-affected controls. Children with disease-specific profiles showed a range of bone deficits compared to the control group with these predominantly indicated for neuromuscular disorders, chronic diseases and low motor competence. Deficits between upper arm and lower leg long bone parameters were different for disease-specific profiles compared to the control group. Endocortical radius, muscle area, and mid-cortical ring density were not significantly different for any disease-specific profile compared to the control group for any bone sites. Neuromuscular disorders, chronic diseases and low motor competence have a strong correlation to bone health for appendicular bone parameters in youth, suggesting a critical mechanical loading influence which may differ specific to disease profile. As mechanical loading effects are observed in regional bone analyses, targeted exercise interventions to improve bone strength should be implemented to examine if this is effective in reducing the risk of secondary osteoporosis in youth.


A Clinical Perspective of Sleep and Andrological Health: Assessment, Treatment Considerations, and Future Research.
Sleep that is insufficient, misaligned, or disrupted causes hypersomnolence and neuropsychological deficits, adversely affects cardiometabolic health, and is increasingly recognized to impair other biological processes that lead to conditions important to men, such as hypogonadism, erectile dysfunction, and infertility. Literature review from 1970 to December 2018. High-quality and complementary epidemiological and interventional studies establish that abnormal sleep is associated with increased mortality, hypertension, and other cardiometabolic disorders (insufficient, disrupted, and misaligned sleep), as well as reduced fecundity and total sperm count (insufficient sleep), erectile dysfunction (disrupted sleep), and low testosterone (both). Circadian misalignment shifts the peak of testosterone's diurnal rhythm to occur soon after waking up, irrespective of the biological clock time, but it does not change the mean concentration. Preliminary studies show that extending sleep in individuals who are chronically sleep deprived may become a strategy to reduce insulin resistance and hypertension. Continuous positive airway pressure therapy can improve erectile function, and possibly systemic testosterone exposure, but only when used adherently by men with obstructive sleep apnea. Both high-dose and replacement-dose testosterone therapies modestly worsen sleep-disordered breathing, but they also improve cardiometabolic function and sexual desire. Persistence of either the adverse or beneficial outcomes over the longer term requires further investigation. Sleep is increasingly recognized to be essential for healthy living. Establishing the effect of abnormal sleep, and of improving sleep, on andrological issues of prime interest to men will promote prioritization of sleep, and may thereby improve overall long-term health outcomes.


Molecular Determinants of Enterotoxigenic Escherichia coli Heat-Stable Toxin Secretion and Delivery.
Enterotoxigenic Escherichia coli (ETEC), a heterogeneous diarrheal pathovar defined by production of heat-labile (LT) and/or heat-stable (ST) toxins, causes substantial morbidity among young children in the developing world. Studies demonstrating a major burden of ST-producing ETEC have focused interest on ST toxoids for ETEC vaccines. We examined fundamental aspects of ST biology using ETEC strain H10407, which carries estH and estP genes encoding STh and STp, respectively, in addition to eltAB genes responsible for LT. Here, we found that deletion of estH significantly diminished cyclic GMP (cGMP) activation in target epithelia, while deletion of estP had a surprisingly modest impact, and a dual estH estP mutant was not appreciably different from the estH mutant. However, we noted that either STh or STp recombinant peptides stimulated cGMP production and that the loss of estP was compensated by enhanced estH transcription. We also found that the TolC efflux protein was essential for toxin secretion and delivery, providing a potential avenue for efflux inhibitors in treatment of acute diarrheal illness. In addition, we demonstrated that the EtpA adhesin is required for optimal delivery of ST and that antibodies against either the adhesin or STh significantly impaired toxin delivery and cGMP activation in target T84 cells. Finally, we used FLAG epitope fusions to demonstrate that the STh propeptide sequence is secreted by ETEC, potentially providing additional epitopes for antibody neutralization. These studies collectively extend our understanding of ETEC pathogenesis and potentially inform additional avenues to mitigate disease by these common diarrheal pathogens.


Variations of DNA polymerase-alpha and -beta during prolonged stimulation of human lymphocytes.
Stimulation of human lymphocytes with phytohemagglutinin is known to induce an increase in overall DNA polymerase activity (DNA nucleotidyltransferase; deoxynucleosidetriphosphate:DNA deoxynucleotidyltransferase, EC 184.108.40.206). Previous work [Pedrali Noy, G., Dalprà, L. Pedrini, A. M., Ciarrocchi, G., Giulotto, E., Nuzzo, F. & Falaschi, A. (1974) Nucleic Acids Res. 1, 1183] has shown that two subsequent waves of induction of DNA polymerase can be observed in this system; a first wave occurs in parallel with the increase in DNA replication rate; a second one occurs when the DNA synthesis rate is returned to minimal levels; the second peak is parallel to a maximum in DNA ligase and DNase levels. In the present work we have measured the levels of the DNA polymerases-alpha and -beta in phytohemagglutinin-stimulated lymphocytes during a 12-day period; both enzymes are present at detectable levels at time zero; in correspondence to the peak of DNA synthesis rate (between the fourth and fifth day) a peak of DNA polymerase-alpha is observed, increasing by a factor of approximately 20-fold over the zero time value; subsequently, the level of DNA polymerase-alpha decreases in parallel with DNA synthesis rate. The DNA polymerase-beta is also increased in correspondence to the peak in DNA synthesis rate, but reaches its maximum at later times, between the eighth and tenth day of incubation. The capacity of stimulated lymphocytes to perform repair synthesis following UV damage was measured in the same cells used for the enzyme activity determinations; this capacity also shows two maxima: a first one correlated with the peak in DNA replication rate, and a second one correlated with the peak of DNA polymerase-beta. These data suggest a certain tendency to the specialization of functions in human cell DNA polymerases; the alpha-enzyme seems mainly correlated with DNA replication, whereas the beta-enzyme seems more correlated with the ability of the cell to perform repair type synthesis.


Effect of improved TLD dosimetry on the determination of dose rate constants for (125)I and (103)Pd brachytherapy seeds.
To more accurately account for the relative intrinsic energy dependence and relative absorbed-dose energy dependence of TLDs when used to measure dose rate constants (DRCs) for (125)I and (103)Pd brachytherapy seeds, to thereby establish revised "measured values" for all seeds and compare the revised values with Monte Carlo and consensus values. The relative absorbed-dose energy dependence, f(rel), for TLDs and the phantom correction, Pphant, are calculated for (125)I and (103)Pd seeds using the EGSnrc BrachyDose and DOSXYZnrc codes. The original energy dependence and phantom corrections applied to DRC measurements are replaced by calculated (f(rel))(-1) and Pphant values for 24 different seed models. By comparing the modified measured DRCs to the MC values, an appropriate relative intrinsic energy dependence, kbq (rel), is determined. The new Pphant values and relative absorbed-dose sensitivities, SAD (rel), calculated as the product of (f(rel))(-1) and (kbq (rel))(-1), are used to individually revise the measured DRCs for comparison with Monte Carlo calculated values and TG-43U1 or TG-43U1S1 consensus values. In general, f(rel) is sensitive to the energy spectra and models of the brachytherapy seeds. Values may vary up to 8.4% among (125)I and (103)Pd seed models and common TLD shapes. Pphant values depend primarily on the isotope used. Deduced (kbq (rel))(-1) values are 1.074 ± 0.015 and 1.084 ± 0.026 for (125)I and (103)Pd seeds, respectively. For (1 mm)(3) chips, this implies an overall absorbed-dose sensitivity relative to (60)Co or 6 MV calibrations of 1.51 ± 1% and 1.47 ± 2% for (125)I and (103)Pd seeds, respectively, as opposed to the widely used value of 1.41. Values of Pphant calculated here have much lower statistical uncertainties than literature values, but systematic uncertainties from density and composition uncertainties are significant. Using these revised values with the literature's DRC measurements, the average discrepancies between revised measured values and Monte Carlo values are 1.2% and 0.2% for (125)I and (103)Pd seeds, respectively, compared to average discrepancies for the original measured values of 4.8%. On average, the revised measured values are 4.3% and 5.9% lower than the original measured values for (103)Pd and (125)I seeds, respectively. The average of revised DRCs and Monte Carlo values is 3.8% and 2.8% lower for (125)I and (103)Pd seeds, respectively, than the consensus values in TG-43U1 or TG-43U1S1. This work shows that f(rel) is TLD shape and seed model dependent suggesting a need to update the generalized energy response dependence, i.e., relative absorbed-dose sensitivity, measured 25 years ago and applied often to DRC measurements of (125)I and (103)Pd brachytherapy seeds. The intrinsic energy dependence for LiF TLDs deduced here is consistent with previous dosimetry studies and emphasizes the need to revise the DRC consensus values reported by TG-43U1 or TG-43U1S1.


Anaphase inactivation of the spindle checkpoint.
The spindle checkpoint delays cell cycle progression until microtubules attach each pair of sister chromosomes to opposite poles of the mitotic spindle. Following sister chromatid separation, however, the checkpoint ignores chromosomes whose kinetochores are attached to only one spindle pole, a state that activates the checkpoint prior to metaphase. We demonstrate that, in budding yeast, mutual inhibition between the anaphase-promoting complex (APC) and Mps1, an essential component of the checkpoint, leads to sustained inactivation of the spindle checkpoint. Mps1 protein abundance decreases in anaphase, and Mps1 is a target of the APC. Furthermore, expression of Mps1 in anaphase, or repression of the APC in anaphase, reactivates the spindle checkpoint. This APC-Mps1 feedback circuit allows cells to irreversibly inactivate the checkpoint during anaphase.


Sikhism, spirituality and psychiatry.
Sikhism has millions of followers in India and among the Indian diaspora. As a religion it is relatively young but carries with it unique perspectives which are often not well known. The holy book of Sikhism, Guru Granth Sahib, is not only the last Guru, but also remained a key text for this religion. Using descriptions of the religion and its followers we attempt to understand the context of spirituality within this religion and attempt to apply it to clinical settings. We explored various texts to understand the notions of spirituality and ethics and directions for living one's life. We studied both the Gurumukhi version as well as the English translation of the Sikh holy text. In the context of history of the Sikhs, various descriptions related to mental well being were identified. In this paper we describe the history, development and the core values of the religion and we also review their role on psychiatric and mental health settings for managing Sikh patients. Guru Granth Sahib offers a very useful insight into what is understood by the term equivalent to depression and its phenomenology. The notions of dukh (loosely translated as pain, but can also mean sadness or suffering) and maya (illusion) and their role in daily living are also discussed. In this paper these descriptions are explored further and their importance explained.


Update: Characteristics of Patients in a National Outbreak of E-cigarette, or Vaping, Product Use-Associated Lung Injuries - United States, October 2019.
CDC, the Food and Drug Administration, state and local health departments, and other public health and clinical stakeholders are investigating a national outbreak of electronic-cigarette (e-cigarette), or vaping, product use-associated lung injury (EVALI) (1). As of October 22, 2019, 49 states, the District of Columbia (DC), and the U.S. Virgin Islands have reported 1,604 cases of EVALI to CDC, including 34 (2.1%) EVALI-associated deaths in 24 states. Based on data collected as of October 15, 2019, this report updates data on patient characteristics and substances used in e-cigarette, or vaping, products (2) and describes characteristics of EVALI-associated deaths. The median age of EVALI patients who survived was 23 years, and the median age of EVALI patients who died was 45 years. Among 867 (54%) EVALI patients with available data on use of specific e-cigarette, or vaping, products in the 3 months preceding symptom onset, 86% reported any use of tetrahydrocannabinol (THC)-containing products, 64% reported any use of nicotine-containing products, and 52% reported use of both. Exclusive use of THC-containing products was reported by 34% of patients and exclusive use of nicotine-containing products by 11%, and for 2% of patients, no use of either THC- or nicotine-containing products was reported. Among 19 EVALI patients who died and for whom substance use data were available, 84% reported any use of THC-containing products, including 63% who reported exclusive use of THC-containing products; 37% reported any use of nicotine-containing products, including 16% who reported exclusive use of nicotine-containing products. To date, no single compound or ingredient used in e-cigarette, or vaping, products has emerged as the cause of EVALI, and there might be more than one cause. Because most patients reported using THC-containing products before symptom onset, CDC recommends that persons should not use e-cigarette, or vaping, products that contain THC. In addition, because the specific compound or ingredient causing lung injury is not yet known, and while the investigation continues, persons should consider refraining from the use of all e-cigarette, or vaping, products.