Investigation on the interaction between endocrine disruptor triphenyltin with human serum albumin.
The interaction between triphenyltin (TPT) and human serum albumin (HSA) in physiological buffer (pH=7.4) was investigated by the fluorescence quenching technique. The results of fluorescence titration revealed that TPT could strongly quench the intrinsic fluorescence of HSA through a static quenching procedure. The apparent binding constants K and number of binding sites n of TPT with HSA were 2.51×10(3) and 0.96 at 298 K which were obtained by the fluorescence quenching method. The thermodynamic parameters enthalpy change (ΔH), entropy change (ΔS) were positive, which indicated that the interaction of TPT with HSA was driven mainly by hydrophobic forces. The process of binding was a spontaneous process in which Gibbs free energy change was negative. The distance r between donor (HSA) and acceptor (TPT) was calculated to be 3.13 nm based on Forster's non-radiative energy transfer theory. The results of synchronous fluorescence, three-dimensional fluorescence and circular dichroism (CD) spectra showed that the triphenyltin induced conformational changes of HSA.


What do we currently know from in vivo bone strain measurements in humans?
Bone strains are the most important factors for osteogenic adaptive responses. During the past decades, scientists have been trying to describe the relationship between bone strain and bone osteogenic responses quantitatively. However, only a few studies have examined bone strains under physiological condition in humans, owing to technical difficulty and ethical restrictions. The present paper reviews previous work on in vivo bone strain measurements in humans, and the various methodologies adopted in these measurements are discussed. Several proposals are made for future work to improve our understanding of the human musculoskeletal system. Literature suggests that strains and strain patterns vary systematically in response to different locomotive activities, foot wear, and even different venues. The principal compressive, tension and engineering shear strain, compressive strain rate and shear strain rate in the tibia during running seem to be higher than those during walking. The high impact exercises, such as zig-zag hopping and basketball rebounding induced greater principal strains and strain rates in the tibia than normal activities. Also, evidence suggests an increase of tibia strain and strain rate after muscle fatigue, which strongly supports the opinion that muscle contractions play a role on the alteration of bone strain patterns.


Modeling Brain Dynamics in Brain Tumor Patients Using the Virtual Brain.
Presurgical planning for brain tumor resection aims at delineating eloquent tissue in the vicinity of the lesion to spare during surgery. To this end, noninvasive neuroimaging techniques such as functional MRI and diffusion-weighted imaging fiber tracking are currently employed. However, taking into account this information is often still insufficient, as the complex nonlinear dynamics of the brain impede straightforward prediction of functional outcome after surgical intervention. Large-scale brain network modeling carries the potential to bridge this gap by integrating neuroimaging data with biophysically based models to predict collective brain dynamics. As a first step in this direction, an appropriate computational model has to be selected, after which suitable model parameter values have to be determined. To this end, we simulated large-scale brain dynamics in 25 human brain tumor patients and 11 human control participants using The Virtual Brain, an open-source neuroinformatics platform. Local and global model parameters of the Reduced Wong-Wang model were individually optimized and compared between brain tumor patients and control subjects. In addition, the relationship between model parameters and structural network topology and cognitive performance was assessed. Results showed (1) significantly improved prediction accuracy of individual functional connectivity when using individually optimized model parameters; (2) local model parameters that can differentiate between regions directly affected by a tumor, regions distant from a tumor, and regions in a healthy brain; and (3) interesting associations between individually optimized model parameters and structural network topology and cognitive performance.


Linear growth patterns in prepubertal children following liver transplantation.
Factors impacting linear growth following pediatric liver transplantation (LT) are not well understood. This longitudinal analysis examines predictors of linear growth impairment in prepubertal children included in Studies of Pediatric Liver Transplantation. In 1143 children with serial measurements, mean height scores increased from -1.55 at LT to -0.87 and -0.68 at 24 and 36 months post LT with minimal subsequent catch up growth observed until 60 months. Subgroup analysis of height measurements at 24 months (n = 696), 33.8% were below 10th percentile at 24 months post LT. Multivariate analysis revealed linear growth impairment more likely in patients with metabolic disease (OR 4.4, CI: 1.83-10.59) and >18 months of steroids exposure (OR 3.02, CI: 1.39-6.55). Higher percentiles for weight (OR 0.80, CI: 0.65-0.99) and height (OR 0.62, CI: 0.51-0.77) at LT decreased risk. Less linear catch up was observed in patients with metabolic disease, non-Biliary atresia cholestatic diseases and lower weight and higher height percentiles prior to LT. Prolonged steroid exposure and elevated calculated glomerular filtration rate and gamma-Glutamyltransferase following LT were associated with less catch up growth. Linear growth impairment and incomplete linear catch up growth are common following LT and may improve by avoiding advanced growth failure before LT and steroid exposure minimization.


A randomised controlled trial of triple antiplatelet therapy (aspirin, clopidogrel and dipyridamole) in the secondary prevention of stroke: safety, tolerability and feasibility.
Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke. A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01). Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy. Controlled-Trials.com ISRCTN83673558.


A study on alcohol use and its related health and social problems in rural Puducherry, India.
Harmful use of alcohol was the cause for 5.9% of all deaths and 5.1% of the global burden of disease and injury. India is the third largest market for alcoholic beverages in the world with estimated 62.5 million alcohol user in 2005. The objective of this study was to know the prevalence of alcohol consumption, pattern of drinking, and its effect on people's health and social consequences. This cross-sectional study was conducted in 850 households selected from 19 villages of two Primary Health Centers. A total of 30 clusters were selected, and from each cluster, 28 houses were surveyed by random walk method. Information was collected on predesigned and pretested questionnaire forms and analyzed using Epi Info 3.4.3. Chi-square test was used for statistical significance. The overall prevalence of alcohol use among ≥18 years of age was 9.7% and exclusively among males was 17.1%. The highest prevalence (17.1%) was among 46-55 years age groups and the residents of joint families (37.0%). One-third of the users began drinking before 20 years of age and half of them consumed for getting relief from pain/strain/tiredness. About half of the users had strained relations with their family members and neighbors both. The majority had alcohol dependence problems and about one-fifth had chronic health problems, diabetes mellitus, and hypertension. The prevalence of alcohol use in Puducherry was low and restricted to males only. The prevalence was high among low uneducated farmers and labors. About one-third of users had alcohol dependence problems and one-fifth had chronic health problems.


Protease-activated receptor 2 (PAR-2) antagonist AZ3451 as a novel therapeutic agent for osteoarthritis.
Osteoarthritis (OA) is a highly prevalent joint disorder blamed for pain and disability in older individuals. It's commonly accepted that inflammation, apoptosis, autophagy and cellular senescence participate in the progress of OA. Protease activated receptor 2 (PAR2), a member of the G-protein coupled receptors, is involved in the regulation of various inflammation diseases. Previous studies have identified PAR2 as a potential therapeutic target for the treatment of OA. Here, we investigated the role of PAR2 antagonist AZ3451 in inflammation response, apoptosis, autophagy and cellular senescence during OA. We confirmed that PAR2 expression was significantly up-regulated in OA articular cartilage tissues as well as in interleukin 1β (IL-1β) stimulated chondrocytes. We demonstrated AZ3451 could prevent the IL-1β-induced inflammation response, cartilage degradation and premature senescence in chondrocytes. Further study showed that AZ3451 attenuated chondrocytes apoptosis by activating autophagy in vitro. The P38/MAPK, NF-κB and PI3K/AKT/mTOR pathways were involved in the protective effect of AZ3451. In vivo, we found that intra-articular injection of AZ3451 could ameliorate the surgery induced cartilage degradation in rat OA model. Our work provided a better understanding of the mechanism of PAR2 in OA, and indicated that PAR2 antagonist AZ3451 might serve as a promising strategy for OA treatment.


Cardio-renal cachexia syndromes (CRCS): pathophysiological foundations of a vicious pathological circle.
Cardio-renal syndromes (CRS) are defined as disorders of the heart and kidney whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. CRS have been classified into five categories, where types 2 and 4 represent respectively chronic cardio-renal and chronic reno-cardiac syndromes. In these conditions, the chronic disorder of either the heart or kidney has been shown to induce some degree of cachexia. At the same time, cachexia has been proposed as a possible mechanism contributing to the worsening of such pathological organ cross talk. Common pathogenetic mechanisms underlie body wasting in cachectic states of different chronic heart and kidney diseases. In these circumstances, a vicious circle could arise, in which cachexia associated with either heart failure or chronic kidney disease may contribute to further damage of the other organ. In chronic CRS, activation of the immune and neuroendocrine systems contributes to the genesis of cachexia, which in turn can negatively affect the heart and kidney function. In patients with cardiac sustained activation of the immune and neuroendocrine systems and oxidative stress, renal vascular resistance can increase and therefore impair renal perfusion, leading to worsening kidney function. Similarly, in renal cachexia, increased levels of pro-inflammatory cytokines can cause progressive left ventricular systolic dysfunction, myocardial cell death, endothelial dysfunction and increased myocardial fibrosis, with consequent impairment of the chronic reno-cardiac syndrome type 4. Thus, we speculate that the occurrence of different types of chronic CRS could represent a fundamental step in the genesis of cachexia, being renal and cardiac dysfunction closely related to the occurrence of systemic disorders leading to a final common pathway. Therefore, the heart and kidney and cachexia represent a triad causing a vicious circle that increases mortality and morbidity: In such circumstances, we may plausibly talk about cardio-renal cachexia syndrome. Complex interrelations may explain the transition from CRS to cachexia and from cachexia to CRS. Identification of the exact mechanisms occurring in these conditions could potentially help in preventing and treating this deadly combination.


Employment opportunities of persons with disabilities and the special subsidiary company scheme in Japan.
This paper intends to review the historical development and related issues involved in the employment of persons with disabilities under the Law on Employment Promotion of Persons with Disabilities in Japan in light of the UN Convention on the Rights of Persons with Disabilities (CRPD). The actual situations of the special subsidiary company system, which was established by the Law to assist large-sized enterprises in achieving their legally mandated quota, were analyzed, based on the relevant data and materials published by the government and other sources. The targeted enterprises could achieve the highest employment rates of persons with disabilities through the establishment of special subsidiary companies. However, various studies on these companies have revealed that more effort is needed to improve the quality of employment of their workers with disabilities in light of the UN Convention on the Rights of Persons with Disabilities (CRPD).


Can variable practice habits and injection port dead-volume put patients at risk?
Injection ports used to administer medications and draw blood samples have inherent dead-volume. This volume can potentially lead to inadvertent drug administration, contribute to erroneous laboratory values by dilution of blood samples, and increase the risk of vascular air embolism. We sought to characterize provider practice in management of intravenous (IV) and arterial lines and measure dead-volumes of various injection ports. A survey was circulated to anesthesiology physicians and nurses to determine practice habits when administering medications and drawing blood samples. Dead-volume of one and four-way injection ports was determined by injecting methylene blue to simulate medication administration or blood sample aspiration and using absorption spectroscopy to measure sample concentration. Among the 65 survey respondents, most (64.52%) increase mainstream flow rate to flush medication given by a 1-way injection port. When using 4-way stopcocks, 56.45% flush through the same injection site. To obtain a sample from an arterial line, 67.74% draw back blood and collect the sample from the same 4-way stopcock; 32.26% use a different stopcock. Mean (SD) dead-volume in microliters ranged from 0.1 (0.0) to 5.6 (1.0) in 1-way injection ports and from 54.1 (2.8) to 126.5 (8.3) in 4-way injection ports. The practices of our providers when giving medications and drawing blood samples are variable. The dead-volume associated with injection ports used at our institution may be clinically significant, increasing errors in medication delivery and laboratory analysis.


A conserved family of elav-like genes in vertebrates.
A large family of genes encodes proteins with RNA recognition motifs that are presumed to bind RNA and to function in posttranscriptional regulation. Neural-specific members of this family include elav, a gene required for correct differentiation and maintenance of neurons in Drosophila melanogaster, and a related gene, HuD, which is expressed in human neuronal cells. I have identified genes related to elav and HuD in Xenopus laevis, zebrafish, and mouse that define a family of four closely related vertebrate elav-like genes (elrA, elrB, elrC, and elrD) in fish, frogs, and mammals. In addition to protein sequence conservation, a segment of the 3'-untranslated sequence of elrD is also conserved, implying a functional role in elrD expression. In adult frogs, elrC and elrD are exclusively expressed in the brain, whereas elrB is expressed in brain, testis, and ovary. During Xenopus development, elrC and elrD RNAs are detected by late gastrula and late neurula stages, respectively, whereas a nervous system-specific elrB RNA species is expressed by early tadpole stage. Additional elrB transcripts are detected in the ovary and early embryo, demonstrating a maternal supply of mRNA and possibly of protein. These expression patterns suggest a role for different elav-like genes in early development and neuronal differentiation. Surprisingly, elrA is expressed in all adult tissues tested and at all times during development. Thus, the widely expressed elrA is expected to have a related function in all cells.


Human papillomavirus (HPV) vaccine implementation in low and middle-income countries (LMICs): health system experiences and prospects.
Prophylactic vaccines for human papillomavirus (HPV) are being introduced in many countries for the prevention of cervical cancer, the second most important cause of cancer-related death in women globally. This is likely to have a significant impact on the future burden of cervical cancer, particularly where screening is non-existent or limited in scale. Previous research on the challenges of vaccinating girls with the HPV vaccine has focused on evidence from developed countries. We conducted a systematic search of the literature in order to describe the barriers and challenges to implementation of HPV vaccine in low- and middle-income countries. We identified literature published post-2006 to September 2012 from five major databases. We validated the findings of the literature review with evidence from qualitative key informant interviews. Three key barriers to HPV vaccine implementation were identified: sociocultural, health systems and political. A linked theme, the sustainability of HPV vaccines programmes in low- and middle-income countries, cuts across these three barriers. Delivering HPV vaccine successfully will require multiple barriers to be addressed. Earlier research in developed countries emphasised sociocultural issues as the most significant barriers for vaccine roll-out. Our evidence suggests that the range of challenges for poorer countries is significantly greater, not least the challenge of reaching girls for three doses in settings where school attendance is low and/or irregular. Financial and political barriers to HPV vaccine roll-out continue to be significant for many poorer countries. Several demonstration and pilot projects have achieved high rates of acceptability and coverage and lessons learned should be documented and shared.


Time and intensity cues are processed independently in the auditory system of the owl.
Space-specific neurons, found in the barn owl's inferior colliculus, respond selectively to a narrow range of interaural time and intensity differences. We show that injecting a local anesthetic into one cochlear nucleus, nucleus magnocellularis, alters the space-specific cell's selectivity for interaural time difference, leaving its selectivity for interaural intensity difference intact. Anesthetizing the other cochlear nucleus, nucleus angularis, has the converse effects. We show also that the space-specific neuron's selectivity for one interaural cue is the same for all effective values of the other cue. We conclude that time and intensity cues are processed in separate neural channels of the barn owl's auditory system and that the two cues operate independently.


The regulation by iron of the synthesis of adhesins and cytoadherence levels in the protozoan Trichomonas vaginalis.
Levels of adherence of Trichomonas vaginalis to epithelial cells was found to be modulated by iron. Cytoadherence values were greater than or equal to twofold higher for trichomonads grown in a complex cultivation medium supplemented with iron. This increase in adherence levels was specifically mediated by iron; parasites cultured in a low-iron medium in the presence of salts other than iron were unresponsive to changes in adherence levels. Expression of the higher adherence property, by parasites grown first in low-iron medium followed by supplementation with iron, was a function of time, and the extent of cytoadherence was proportional to the concentration of iron added to the medium. Lactoferrin, an important iron source for trichomonads at the site of infection, elevated adherence of the parasite to epithelial cells, demonstrating the likely in vivo modulation of adherence by iron. The alteration of levels of adherence caused by iron was determined to be a reflection of gene expression of previously characterized trichomonad adhesins. Parasites grown under iron-replete conditions had higher quantities of surface-exposed adhesins, and this was a result of increased synthesis of adhesins. Actinomycin D and alpha-amanitin prevented expression of adhesin molecules, which resulted in decreased cytoadherence, showing that adhesin synthesis was dependent on gene transcription. Data indicated that genes encoding the four trichomonad adhesins are coordinately regulated by iron.


Whole-Exome Sequencing in Age-Related Macular Degeneration Identifies Rare Variants in COL8A1, a Component of Bruch's Membrane.
Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare coding variants across all genes of the genome and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts remains scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD cause, we performed the largest WES study in AMD to date in a large European cohort consisting of 1125 AMD patients and 1361 control participants. Genome-wide case-control association study of WES data. One thousand one hundred twenty-five AMD patients and 1361 control participants. A single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative effect of multiple rare variants with 1 gene was analyzed using a gene-based CMC burden test. Immunohistochemistry was performed to determine the localization of the Col8a1 protein in mouse eyes. Genetic variants associated with AMD. We detected significantly more rare protein-altering variants in the COL8A1 gene in patients (22/2250 alleles [1.0%]) than in control participants (11/2722 alleles [0.4%]; P = 7.07×10-5). The association of rare variants in the COL8A1 gene is independent of the common intergenic variant (rs140647181) near the COL8A1 gene previously associated with AMD. We demonstrated that the Col8a1 protein localizes at Bruch's membrane. This study supported a role for protein-altering variants in the COL8A1 gene in AMD pathogenesis. We demonstrated the presence of Col8a1 in Bruch's membrane, further supporting the role of COL8A1 variants in AMD pathogenesis. Protein-altering variants in COL8A1 may alter the integrity of Bruch's membrane, contributing to the accumulation of drusen and the development of AMD.


Charging for nature: marine park fees and management from a user perspective.
User fees can contribute to the financial sustainability of marine protected areas (MPAs), yet they must be acceptable to users. We explore changes in the fee system and management of Bonaire National Marine Park (BNMP) from the perspective of users. Responses from 393 tourists indicated that 90% were satisfied with park conditions and considered current user fees reasonable. However, only 47% of divers and 40% of non-divers were prepared to pay more. Diver willingness-to-pay (WTP) appears to have decreased since 1991, but this difference could be due in part to methodological differences between studies. Although current fees are close to diver maximum stated WTP, revenues could potentially be increased by improving the current fee system in ways that users deem acceptable. This potential surplus highlights the value of understanding user perceptions toward MPA fees and management.


Changes in fish communities on a small spatial scale, an effect of increased habitat complexity by an offshore wind farm.
The number of offshore wind farms (OWF) is increasing to meet the demands for renewable energy. The piles and hard substrate surrounding these piles creates new habitat for species with preference to hard substrates. We studied the impact of this hard substrate on the fish community in a Dutch OWF in the sandy southern North Sea, which had been in operation for five years. Multi-mesh gillnets were placed near the OWF structures on the hard substrate protection revetments and on the sandy bottom in the middle of the farm. The catches indicated attraction of cod, pouting, bullrout and edible and velvet crab, while attraction to the sandy habitat was shown for flatfish and whiting. Further, two species previously not caught in this area, goldsinny wrasse and grey trigger fish, were caught on the hard substrate. In addition a Dual-Frequency Identification Sonar (DIDSON) was used to record transects through the farm to observe individual fish in the water column throughout the farm and very near the OWF structures. High abundances of fish near the structure were observed during some days, while during other days equal distribution of fish in the area was observed. The area around the structures is thus only used temporarily for shelter or feeding. The DIDSON also allowed looking at the aggregation level of the fish. Seasonally the aggregation level differed most likely due to different species occurring in the area. In April, most fish were aggregated in schools, while in summer most observations were individual fish or loose aggregations. The wind farm structures had limited effect on the aggregation level compared to season or weather conditions.


Genetic modification of stem cells for improved therapy of the infarcted myocardium.
The conventional treatment modalities for ischemic heart disease only provide symptomatic relief to the patient without repairing and regenerating the damaged myocardium. Stem cell transplantation has emerged as a promising alternative therapeutic approach for cardiovascular diseases. Stem cells possess the potential of differentiation to adopt morphofunctional cardiac and vasculogenic phenotypes to repopulate the scar tissue and restore regional blood flow in the ischemic myocardium. These beneficial therapeutic effects make stem cell transplantation the method of choice for the treatment of ischemic heart disease. The efficacy of stem cell transplantation may be augmented by genetic manipulation of the cells prior to transplantation. Not only will insertion of therapeutic transgene(s) into the stem cells support the survival and differentiation of cells in the unfavorable microenvironment of the ischemic myocardium, but also the genetically manipulated stem cells will serve as a source of the transgene expression product in the heart for therapeutic benefits. We provide an overview of the extensively studied stem cell types for cardiac regeneration, the various methods in which these cells have been genetically manipulated and rationale of genetic modification of stem cells for use in regenerative cardiovascular therapeutics.


Mechanistic Pathways of Mindfulness Meditation in Combat Veterans With Posttraumatic Stress Disorder.
This study's objective was to evaluate the effect of two common components of meditation (mindfulness and slow breathing) on potential mechanistic pathways. A total of 102 combat veterans with posttraumatic stress disorder (PTSD) were randomized to (a) the body scan mindfulness meditation (MM), (b) slow breathing (SB) with a biofeedback device, (c) mindful awareness of the breath with an intention to slow the breath (MM+SB), or (d) sitting quietly (SQ). Participants had 6 weekly one-on-one sessions with 20 minutes of daily home practice. The mechanistic pathways and measures were as follows: (a) autonomic nervous system (hyperarousal symptoms, heart rate [HR], and heart rate variability [HRV]); (b) frontal cortex activity (attentional network task [ANT] conflict effect and event-related negativity and intrusive thoughts); and (c) hypothalamic-pituitary-adrenal axis (awakening cortisol). PTSD measures were also evaluated. Meditation participants had significant but modest within-group improvement in PTSD and related symptoms, although there were no effects between groups. Perceived impression of PTSD symptom improvement was greater in the meditation arms compared with controls. Resting respiration decreased in the meditation arms compared with SQ. For the mechanistic pathways, (a) subjective hyperarousal symptoms improved within-group (but not between groups) for MM, MM+SB, and SQ, while HR and HRV did not; (b) intrusive thoughts decreased in MM compared with MM+SB and SB, while the ANT measures did not change; and (c) MM had lower awakening cortisol within-group (but not between groups). Treatment effects were mostly specific to self-report rather than physiological measures. Continued research is needed to further evaluate mindfulness meditation's mechanism in people with PTSD.


Sites of Anesthetic Inhibitory Action on a Cationic Ligand-Gated Ion Channel.
Pentameric ligand-gated ion channels have been identified as the principal target of general anesthetics (GA), whose molecular mechanism of action remains poorly understood. Bacterial homologs, such as the Gloeobacter violaceus receptor (GLIC), have been shown to be valid functional models of GA action. The GA bromoform inhibits GLIC at submillimolar concentration. We characterize bromoform binding by crystallography and molecular dynamics (MD) simulations. GLIC's open form structure identified three intra-subunit binding sites. We crystallized the locally closed form with an additional bromoform molecule in the channel pore. We systematically compare binding with the multiple potential sites of allosteric channel regulation in the open, locally closed, and resting forms. MD simulations reveal differential exchange pathways between sites from one form to the other. GAs predominantly access the receptor from the lipid bilayer in all cases. Differential binding affinity among the channel forms is observed; the pore site markedly stabilizes the inactive versus active state.


The Efficacy and Safety of Rapid Cycling Vagus Nerve Stimulation in Children With Intractable Epilepsy.
Vagus nerve stimulation (VNS) is an effective adjunctive therapy for drug-resistant epilepsy. Nevertheless, information is lacking regarding optimization of stimulation parameters to improve efficacy. Our study examines the safety and efficacy of rapid duty cycle VNS (OFF time ≤1.1 minute keeping duty cycle less than 50%) in pediatric cohort with intractable epilepsy. Retrospective chart review of 50 patients (one to 17 years) with drug-resistant epilepsy treated with VNS between 2010 and 2015 at a single pediatric epilepsy center. Safety and tolerability data were aggregated across all patient visits to determine frequency of adverse events between differing duty cycles. We also compared seizure reduction rates for each patient at (1) last regular duty cycle visit, (2) first rapid duty cycle visit, and (3) last recorded rapid duty cycle visit. Rapid duty cycle was well tolerated, with no adverse events reported in 96.6% patient encounters. At the last visit before switching to rapid duty cycle 45.5% patients were showing response to VNS (seizure reduction rates ≥50%). This rate increased to 77.3% after switching to rapid duty cycle and remained at 77.4% at the last rapid duty cycle visit. Fifteen patients (34.1%) became responders to VNS after switching to rapid cycling; another 19 (43.2%) maintained their response with mostly improved seizure reduction rates. In only a few instances, responders became nonresponders after switching to rapid duty cycle. Rapid duty cycle VNS is probably safe and well tolerated; it may also be more efficacious than regular cycling VNS in some patients. This study highlights the necessity of prospective, long-term, double-blinded studies for understanding the advantages of this VNS modality.


Activity of a novel Hec1-targeted anticancer compound against breast cancer cell lines in vitro and in vivo.
Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI(50) = 14.29-73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI(50) > 10 μmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of in vivo tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers.


Proportion of US adults potentially affected by the 2014 hypertension guideline.
The new 2014 blood pressure (BP) guideline released by the panel members appointed to the Eighth Joint National Committee (JNC 8; 2014 BP guideline) proposed less restrictive BP targets for adults aged 60 years or older and for those with diabetes and chronic kidney disease. To estimate the proportion of US adults potentially affected by recent changes in recommendations for management of hypertension. Cross-sectional, nationally representative survey. Using data from the National Health and Nutrition Examination Survey between 2005 and 2010 (n = 16,372), we evaluated hypertension control and treatment recommendations for US adults. Proportion of adults estimated to meet guideline-based BP targets under the 2014 BP guideline and under the previous seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guideline. The proportion of younger adults (18-59 years) with treatment-eligible hypertension under the JNC 7 guideline was 20.3% (95% CI, 19.1%-21.4%) and decreased to 19.2% (95% CI, 18.1%-20.4%) under the 2014 BP guideline. Larger declines were observed among older adults (≥60 years), decreasing from 68.9% (95% CI, 66.9%-70.8%) under JNC 7 to 61.2% (95% CI, 59.3%-63.0%) under the 2014 BP guideline. The proportion of adults with treatment-eligible hypertension who met BP goals increased slightly for younger adults, from 41.2% (95% CI, 38.1%-44.3%) under JNC 7 to 47.5% (95% CI, 44.4%-50.6%) under the 2014 BP guideline, and more substantially for older adults, from 40.0% (95% CI, 37.8%-42.3%) under JNC 7 to 65.8% (95% CI, 63.7%-67.9%) under the 2014 BP guideline. Overall, 1.6% (95% CI, 1.3%-1.9%) of US adults aged 18-59 years and 27.6% (95% CI, 25.9%-29.3%) of adults aged 60 years or older were receiving BP-lowering medication and meeting more stringent JNC 7 targets. These patients may be eligible for less stringent or no BP therapy with the 2014 BP guideline. Compared with the JNC 7 guideline, the 2014 BP guideline from the panel members appointed to the JNC 8 was associated with a reduction in the proportion of US adults recommended for hypertension treatment and a substantial increase in the proportion of adults considered to have achieved goal BP, primarily in older adults.


Quality of life in active surveillance and the associations with decision-making-a literature review.
Several studies have been conducted on the quality of life (QoL) in men with low risk prostate cancer (PCa) who choose active surveillance (AS). While recent reviews have shown a lack of consistency among the available QoL-studies, a few key points have been identified, including decision-making (DM)-related issues and their potential effect on QoL. The importance of this theme has also been recently highlighted by the international task force of the European School of Oncology. However, to our knowledge, there are no studies that have specifically marshalled scientific knowledge on the association between DM and QoL among men with low-risk PCa undergoing AS. We performed a literature review to fill this gap, taking a systematic approach to retrieving and selecting articles that included both DM and QoL measures. Among the 272 articles retrieved, we selected nine observational, quantitative articles with both DM and QoL measures. The most considered DM aspects within these studies were decisional conflict and preference for the patient's role in the DM process, as well as health-related QoL aspects. The studies included 42 assessments of the relationship between an empirical measure of DM and an empirical measure of QoL. Among these assessments, 23 (55%) were both positive and significant. They mostly concerned the relationship between patient-related (decisional self-efficacy, decisional control and knowledge) and external (presence of social support, collaborative role within the DM process, and influence of different physicians) DM aspects, as well as the QoL after choice. The findings of these studies revealed key challenges to research and clinical practice related to DM and QoL in AS. These include adopting a person-centred perspective where clinicians, caregivers and their interactions are also included in evaluations and where the psychosocial existential experience of individuals within the DM and AS journey is considered. Much more attention needs to be paid to the DM process after diagnosis, as well as to all the other moments where patients may have to or want to review their decision. Healthcare professionals play a key role in enabling men to make informed decisions and to take care of their health and well-being during AS. There is still work that needs to be done in training healthcare professionals from different disciplines to work together in a model of shared DM and AS tailored to the needs of low-risk PCa patients and their family members.


Vitamin K supplementation for cystic fibrosis.
Cystic fibrosis is a genetic disorder which can lead to multiorgan dysfunction. Malabsorption of fat and fat-soluble vitamins (A, D, E, K) may occur and can cause subclinical deficiencies of some of these vitamins. Vitamin K is known to play an important role in both blood coagulation and bone formation. Supplementation with vitamin K appears to be one way of addressing the deficiency, but there is very limited agreement on the appropriate dose and frequency of use of these supplements. To assess the effects of vitamin K supplementation in people with cystic fibrosis and to determine the optimal dose and route of administration of vitamin K for both routine and therapeutic use. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 08 October 2014. Randomised and quasi-randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in children or adults diagnosed with cystic fibrosis (by sweat test or genetic testing). Two authors independently screened papers, extracted trial details and assessed their risk of bias. Two trials (total of 32 participants) each lasting one month were included in the review and were assessed as having a moderate risk of bias. One was a dose-ranging parallel group trial in children (aged 8 to 18 years); and the other (with an older cohort) had a cross-over design comparing supplements to no treatment, but no separate data were reported for the first intervention period. Neither of the trials addressed any of the primary outcomes (coagulation, bone formation and quality of life). Both trials reported the restoration of serum vitamin K and undercarboxylated osteocalcin levels to the normal range after one month of daily supplementation with 1 mg of vitamin K. Evidence from randomised controlled trials on the benefits of routine vitamin K supplementation for people with CF is currently weak and limited to two small trials of short duration. However, no harm was found and until further evidence is available, the present recommendations should be adhered to.


A systematic meta-thematic synthesis to examine the views and experiences of women following water immersion during labour and waterbirth.
To gather, quality assess, synthesize and interpret the views, feeling, and experiences of women who used water immersion during labour and/or birth. A systematic meta-thematic synthesis and GRADE-CERQual. We searched MEDLINE, CINHAL, PsychINFO, AMED, EMBASE (MIDIRS only), LILACS, AJOL. Additional searches were carried out using Ethos (thesis database), cross-referencing against Google Scholar and citation chasing. Searches were carried out in August 2019, updated February 2020. Studies that met the selection criteria were appraised for quality. Data were extracted from the studies using meta-thematic analytical techniques; coding, descriptive findings, and analytical findings. The descriptive findings were subjected to confidence assessments using GRADE-CERQual. Seven studies met the inclusion criteria. Nine key statements of findings were generated - one had high confidence, three moderate, three low and one very low confidence in the findings. The analytical findings generated three main themes: Liberation and Self-Emancipation, Synergy, transcendence and demarcation and Transformative birth and beyond. Overall, women experienced warm water immersion during labour and/or birth positively. Both the water and pool itself, facilitated women's physical and psychological needs during labour and/or birth, including offering effective analgesia. Our findings indicated that birthing pools are versatile tools that provide for a space that women can adapt and influence to best suit their individual needs. Women who used warm water immersion for labour and/or birth describe liberating and transformative experiences of welcoming their babies into the world. They were empowered, liberated, and satisfied. We recommend maternity professionals and services offer water immersion as a standard method of pain relief during labour/birth. Understanding women's experiences of labour and birth will inform future clinical practice. Midwives are optimally positioned to enhance women's access to water immersion. These findings have implications for education, guideline, and policy development as well as clinical practice.


Borrelia burgdorferi sensu lato in Ixodes ricinus ticks collected from migratory birds in Southern Norway.
Borrelia burgdorferi sensu lato (s.l.) are the causative agent for Lyme borreliosis (LB), the most common tick-borne disease in the northern hemisphere. Birds are considered important in the global dispersal of ticks and tick-borne pathogens through their migration. The present study is the first description of B. burgdorferi prevalence and genotypes in Ixodes ricinus ticks feeding on birds during spring and autumn migration in Norway. 6538 migratory birds were captured and examined for ticks at Lista Bird Observatory during the spring and the autumn migration in 2008. 822 immature I. ricinus ticks were collected from 215 infested birds. Ticks were investigated for infection with B. burgdorferi s.l. by real-time PCR amplification of the 16S rRNA gene, and B. burgdorferi s.l. were thereafter genotyped by melting curve analysis after real-time PCR amplification of the hbb gene, or by direct sequencing of the PCR amplicon generated from the rrs (16S)-rrl (23S) intergenetic spacer. B. burgdorferi s.l. were detected in 4.4% of the ticks. The most prevalent B. burgdorferi genospecies identified were B. garinii (77.8%), followed by B.valaisiana (11.1%), B. afzelii (8.3%) and B. burgdorferi sensu stricto (2.8%). Infection rate in ticks and genospecies composition were similar in spring and autumn migration, however, the prevalence of ticks on birds was higher during spring migration. The study supports the notion that birds are important in the dispersal of ticks, and that they may be partly responsible for the heterogeneous distribution of B. burgdorferi s.l. in Europe.


Histoplasmosis-associated immune reconstitution inflammatory syndrome.
A 27-year-old HIV-positive male patient with disseminated cutaneous histoplasmosis was treated with both HAART and amphotericin B (total accumulated dose of 0.5 g). Amphotericin B was later replaced with itraconazole (200mg/day). Two months after therapy had been started and the cutaneous lesions had healed, the patient interrupted both treatments voluntarily and his health deteriorated. HAART was then re-introduced and CD4+ cell count increased sharply at the same time as lymph node histoplasmosis was diagnosed. This paradoxical response? the relapse of histoplasmosis and concomitant increase in CD4+ cell count and undetectable viral load after resumption of HAART ? suggests that this was a case of immune reconstitution inflammatory syndrome (IRIS).


Functional annotation of proteome encoded by human chromosome 22.
As part of the chromosome-centric human proteome project (C-HPP) initiative, we report our progress on the annotation of chromosome 22. Chromosome 22, spanning 51 million base pairs, was the first chromosome to be sequenced. Gene dosage alterations on this chromosome have been shown to be associated with a number of congenital anomalies. In addition, several rare but aggressive tumors have been associated with this chromosome. A number of important gene families including immunoglobulin lambda locus, Crystallin beta family, and APOBEC gene family are located on this chromosome. On the basis of proteomic profiling of 30 histologically normal tissues and cells using high-resolution mass spectrometry, we show protein evidence of 367 genes on chromosome 22. Importantly, this includes 47 proteins, which are currently annotated as "missing" proteins. We also confirmed the translation start sites of 120 chromosome 22-encoded proteins. Employing a comprehensive proteogenomics analysis pipeline, we provide evidence of novel coding regions on this chromosome which include upstream ORFs and novel exons in addition to correcting existing gene structures. We describe tissue-wise expression of the proteins and the distribution of gene families on this chromosome. These data have been deposited to ProteomeXchange with the identifier PXD000561.


Phototaxis and polarotaxis hand in hand: night dispersal flight of aquatic insects distracted synergistically by light intensity and reflection polarization.
Based on an earlier observation in the field, we hypothesized that light intensity and horizontally polarized reflected light may strongly influence the flight behaviour of night-active aquatic insects. We assumed that phototaxis and polarotaxis together have a more harmful effect on the dispersal flight of these insects than they would have separately. We tested this hypothesis in a multiple-choice field experiment using horizontal test surfaces laid on the ground. We offered simultaneously the following visual stimuli for aerial aquatic insects: (1) lamplit matte black canvas inducing phototaxis alone, (2) unlit shiny black plastic sheet eliciting polarotaxis alone, (3) lamplit shiny black plastic sheet inducing simultaneously phototaxis and polarotaxis, and (4) unlit matte black canvas as a visually unattractive control. The unlit matte black canvas trapped only a negligible number (13) of water insects. The sum (16,432) of the total numbers of water beetles and bugs captured on the lamplit matte black canvas (7,922) and the unlit shiny black plastic sheet (8,510) was much smaller than the total catch (29,682) caught on the lamplit shiny black plastic sheet. This provides experimental evidence for the synergistic interaction of phototaxis (elicited by the unpolarized direct lamplight) and polarotaxis (induced by the strongly and horizontally polarized plastic-reflected light) in the investigated aquatic insects. Thus, horizontally polarizing artificial lamplit surfaces can function as an effective ecological trap due to this synergism of optical cues, especially in the urban environment.


Artificial sweeteners, caffeine, and alcohol intoxication in bar patrons.
Previous laboratory research on alcohol absorption has found that substitution of artificially sweetened alcohol mixers for sucrose-based mixers has a marked effect on the rate of gastric emptying, resulting in elevated blood alcohol concentrations. Studies conducted in natural drinking settings, such as bars, have indicated that caffeine ingestion while drinking is associated with higher levels of intoxication. To our knowledge, research has not examined the effects of alcohol mixers that contain both an artificial sweetener and caffeine, that is, diet cola. Therefore, we assessed the event-specific association between diet cola consumption and alcohol intoxication in bar patrons. We sought to determine whether putative increases in blood alcohol, produced by accelerated gastric emptying following diet cola consumption, as identified in the laboratory, also appear in a natural setting associated with impaired driving. We conducted a secondary analysis of data from 2 nighttime field studies that collected anonymous information from 413 randomly selected bar patrons in 2008 and 2010. Data sets were merged and recoded to distinguish between energy drink, regular cola, diet cola, and noncaffeinated alcohol mixers. Caffeinated alcohol mixers were consumed by 33.9% of the patrons. Cola-caffeinated mixed drinks were much more popular than those mixed with energy drinks. A large majority of regular cola-caffeinated mixed drink consumers were men (75%), whereas diet cola-caffeinated mixed drink consumers were more likely to be women (57%). After adjusting for the number of drinks consumed and other potential confounders, number of diet cola mixed drinks had a significant association with patron intoxication (β = 0.233, p < 0.0001). Number of drinks mixed with regular (sucrose-sweetened) cola and energy drinks did not have significant associations with intoxication (p > 0.05). Caffeine's effect on intoxication may be most pronounced when mixers are artificially sweetened, that is, lack sucrose which slows the rate of gastric emptying of alcohol. Risks associated with on-premise drinking may be reduced by greater attention given to types of mixers, particularly diet colas.


Numerical detection of the Gardner transition in a mean-field glass former.
Recent theoretical advances predict the existence, deep into the glass phase, of a novel phase transition, the so-called Gardner transition. This transition is associated with the emergence of a complex free energy landscape composed of many marginally stable sub-basins within a glass metabasin. In this study, we explore several methods to detect numerically the Gardner transition in a simple structural glass former, the infinite-range Mari-Kurchan model. The transition point is robustly located from three independent approaches: (i) the divergence of the characteristic relaxation time, (ii) the divergence of the caging susceptibility, and (iii) the abnormal tail in the probability distribution function of cage order parameters. We show that the numerical results are fully consistent with the theoretical expectation. The methods we propose may also be generalized to more realistic numerical models as well as to experimental systems.


Young people's moral attitudes and motivations towards direct-to-consumer genetic testing for inherited risk of Alzheimer disease.
Since the U.S. Food and Drug Administration approved sales of genetic tests for late-onset Alzheimer's disease (LOAD) risk, a heated debate has arisen over whether these tests should indeed be offered online and direct-to-consumer (DTC). As this debate progresses, it is important to understand the ethical perspectives and motivations of young people, who are a key target group for DTC services. Thirty-one grandchildren of people with LOAD, aged 16-26, were interviewed about their moral attitudes and motivations with regards to DTC genetic testing for LOAD. Even though most participants claimed that people should have the right to access these services, they also expressed concerns about potential distress in response to learning about risk, particularly for minors. About a third were interested in testing, primarily to gain self-knowledge regarding one's health; however, face-to-face services were vastly preferred over the online option. While DTC genetic companies often market their services as a "fun consumer product", DTC testing for LOAD was largely understood as a serious health screening procedure and a vulnerable moment in the lives of young people in Alzheimer's families. This points to the importance of appropriate standards of information and support to young people pre- and post-testing.


A double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression.
Previous reports have suggested that lamotrigine is effective as an antidepressant augmentation agent in patients with treatment-resistant unipolar depression. This study is the largest double-blind placebo-controlled study conducted to date of lamotrigine in this role. In this multicenter trial, conducted at 19 sites, patients aged 18-65 years with a DSM-IV/ICD-10 diagnosis of unipolar, nonpsychotic major depressive disorder (confirmed by the Mini-International Neuropsychiatric Interview) who had failed at least 1 adequate trial of an antidepressant (N = 183) were first treated for 8 weeks with open-label paroxetine or paroxetine controlled-release in dosages up to 50 mg/d or 62.5 mg/d, respectively. Individuals with a 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 15 (n = 96) were then randomized on a double-blind basis to receive either placebo or lamotrigine in dosages titrated upward to a maximum of 400 mg/d for 10 weeks. Sixty-five patients completed the study. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS), and the main secondary outcome measures were the HDRS-17 and Clinical Global Impressions-Severity of Illness (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) ratings. Data were collected from 2003 to 2006. Results of the primary efficacy analysis of the randomized patients using the MADRS, HDRS-17, CGI-S, and CGI-I did not demonstrate a statistically significant difference between lamotrigine and placebo groups, although some secondary analyses were suggestive of efficacy, particularly in those patients who completed the study (completer analysis) and in more severely ill patients (HDRS-17 ≥ 25). This add-on study of patients with treatment-resistant depression failed to detect a statistically significant difference between lamotrigine and placebo given for 10 weeks. However, post hoc analyses suggest that future studies of lamotrigine's efficacy might focus on specific subgroups with depression. clinicaltrials.gov Identifier: NCT00901407.


Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism.
Intrauterine growth restriction (IUGR) is a major risk factor for both perinatal and long-term morbidity. Bovine lactoferrin (bLf) is a major milk glycoprotein considered as a pleiotropic functional nutrient. The impact of maternal supplementation with bLf on IUGR-induced sequelae, including inadequate growth and altered cerebral development, remains unknown. IUGR was induced through maternal dexamethasone infusion (100 μg/kg during last gestational week) in rats. Maternal supplementation with bLf (0.85% in food pellet) was provided during both gestation and lactation. Pup growth was monitored, and Pup brain metabolism and gene expression were studied using in vivo (1)H NMR spectroscopy, quantitative PCR, and microarray in the hippocampus at postnatal day (PND)7. Maternal bLf supplementation did not change gestational weight but increased the birth body weight of control pups (4%) with no effect on the IUGR pups. Maternal bLf supplementation allowed IUGR pups to recover a normalized weight at PND21 (weaning) improving catch-up growth. Significantly altered levels of brain metabolites (γ-aminobutyric acid, glutamate, N-acetylaspartate, and N-acetylaspartylglutamate) and transcripts (brain-derived neurotrophic factor (BDNF), divalent metal transporter 1 (DMT-1), and glutamate receptors) in IUGR pups were normalized with maternal bLf supplementation. Our data suggest that maternal bLf supplementation is a beneficial nutritional intervention able to revert some of the IUGR-induced sequelae, including brain hippocampal changes.


Quantification of effective attenuation coefficients using continuous wavelet transform of photoacoustic signals.
A method for quantifying the effective attenuation coefficients of optical absorbers by using the continuous wavelet transform (CWT) to calculate the time-resolved frequency spectra of photoacoustic signals is proposed. Because the coefficients can be quantified according to the relative intensity of the frequency content of the signals, it is unnecessary to determine the fluences. A computational simulation reveals that the time-resolved frequency spectra exhibit better correlation with the coefficients than do power spectra calculated using a Fourier transformation. The CWT-based method was experimentally verified, and the coefficients were quantified with mean square error of 2.0 cm(-1).


Cytochrome P450IA1 induction and localization in endothelium of vertebrate (teleost) heart.
Previous studies have shown that high levels of cytochrome P450 can occur in cardiac microsomes of vertebrates [Mol. Pharmacol. 21:517-526, (1982)]. Here we identify the dominant cardiac P450 in the marine fish scup as P450E, a teleost representative of P450IA1, and we describe its restricted cellular localization in the heart. Treatment of scup with beta-naphthoflavone produced an unusually strong (10-fold) induction of spectrally measured P450 in cardiac microsomes, with specific content reaching levels (0.5 nmol/mg) similar to those induced in scup liver. Microsomal ethoxyresorufin O-deethylase and aryl hydrocarbon hydroxylase activities, catalytic functions of scup P450E, were induced in parallel with P450 content. Similar induction was seen in both atrium and ventricle. Immunoblot analysis with monoclonal antibody 1-12-3, specific to scup P450E and other vertebrate P450IA1 proteins, showed that this hydrocarbon-inducible P450 is the dominant and possibly sole P450 form in heart microsomes of experimentally induced animals. Immunohistochemical analysis of scup heart sections (2-4-microns) with monoclonal antibody 1-12-3 revealed that P450E was detectable only in endothelial cells of the endocardium and of the coronary vasculature. A similar endothelial cell localization of the monoclonal antibody 1-12-3 epitope was observed in heart of rainbow trout, induced with beta-naphthoflavone, indicating a general nature for the endothelial localization of induced cardiac P450. Morphometric analysis showed that endothelium could constitute 8-9% of the volume of teleost heart, from which we calculate that P450IA1 could account for as much as 25% of the endothelial cell microsomal protein. Heart microsomes of untreated animals from contaminated environments also contained high levels of P450E, indicating that induction like that caused by beta-naphthoflavone could occur with chemicals in the environment. Strongly induced P450E (P450IA1) in endothelium could play a critical role in chemical-biological interactions involving xenobiotics affecting the vasculature of the heart or other organs.


A simplified, 96-well-adapted, ATP luminescence-based motility assay.
Directional motility assays make use of Boyden chambers or Transwell culture inserts with porous membranes that separate cells seeded in the upper chamber from a chemoattractant supplied in a lower chamber. These assays are often time-consuming and are associated with several limitations due to manual counting and inconsistent results; low signal-to-noise ratio and fluorescence interference; and high cost and the need for specific equipment. Here, we describe a simple, direct, and easy ATP luminescence-based motility assay (ALMA), which can be used for 96-well plate quantification.


A Role for the Twins Protein Phosphatase (PP2A-B55) in the Maintenance of Drosophila Genome Integrity.
The protein phosphatase 2A (PP2A) is a conserved heterotrimeric enzyme that regulates several cellular processes including the DNA damage response and mitosis. Consistent with these functions, PP2A is mutated in many types of cancer and acts as a tumor suppressor. In mammalian cells, PP2A inhibition results in DNA double strand breaks (DSBs) and chromosome aberrations (CABs). However, the mechanisms through which PP2A prevents DNA damage are still unclear. Here, we focus on the role of the Drosophila twins (tws) gene in the maintenance of chromosome integrity; tws encodes the B regulatory subunit (B/B55) of PP2A. Mutations in tws cause high frequencies of CABs (0.5 CABs/cell) in Drosophila larval brain cells and lead to an abnormal persistence of γ-H2Av repair foci. However, mutations that disrupt the PP4 phosphatase activity impair foci dissolution but do not cause CABs, suggesting that a delayed foci regression is not clastogenic. We also show that Tws is required for activation of the G2/M DNA damage checkpoint while PP4 is required for checkpoint recovery, a result that points to a conserved function of these phosphatases from flies to humans. Mutations in the ATM-coding gene tefu are strictly epistatic to tws mutations for the CAB phenotype, suggesting that failure to dephosphorylate an ATM substrate(s) impairs DNA DSBs repair. In addition, mutations in the Ku70 gene, which do not cause CABs, completely suppress CAB formation in tws Ku70 double mutants. These results suggest the hypothesis that an improperly phosphorylated Ku70 protein can lead to DNA damage and CABs.


Preoperative embolization versus no embolization for WHO grade I intracranial meningioma: a retrospective matched cohort study.
The controversy continues over the clinical utility of preoperative embolization for reducing tumor vascularity of intracranial meningiomas prior to resection. Previous studies comparing embolization and nonembolization patients have not controlled for detailed tumor parameters before assessing outcomes. The authors reviewed the cases of all patients who underwent resection of a WHO grade I intracranial meningioma at their institution from 2008 to 2016. Propensity score matching was used to generate embolization and nonembolization cohorts of 52 patients each, and a retrospective review of clinical and radiological outcomes was performed. In total, 52 consecutive patients who underwent embolization (mean follow-up 34.8 ± 31.5 months) were compared to 52 patients who did not undergo embolization (mean follow-up 32.8 ± 28.7 months; p = 0.63). Variables controlled for included patient age (p = 0.82), tumor laterality (p > 0.99), tumor location (p > 0.99), tumor diameter (p = 0.07), tumor invasion into a major dural sinus (p > 0.99), and tumor encasement around the internal carotid artery or middle cerebral artery (p > 0.99). The embolization and nonembolization cohorts did not differ in terms of estimated blood loss during surgery (660.4 ± 637.1 ml vs 509.2 ± 422.0 ml; p = 0.17), Simpson grade IV resection (32.7% vs 25.0%; p = 0.39), perioperative procedural complications (26.9% vs 19.2%; p = 0.35), development of permanent new neurological deficits (5.8% vs 7.7%; p = 0.70), or favorable modified Rankin Scale (mRS) score (a score of 0-2) at last follow-up (96.0% vs 92.3%; p = 0.43), respectively. When comparing the final mRS score to the preoperative mRS score, patients in the embolization group were more likely than patients in the nonembolization group to have an improvement in mRS score (50.0% vs 28.8%; p = 0.03). After controlling for patient age, tumor size, tumor laterality, tumor location, tumor invasion into a major dural sinus, and tumor encasement of the internal carotid artery or middle cerebral artery, preoperative meningioma embolization intended to decrease tumor vascularity did not improve the surgical outcomes of patients with WHO grade I intracranial meningiomas, but it did lead to a greater chance of clinical improvement compared to patients not treated with embolization.


Development of a self-assessment instrument to determine daily intake and variability of dietary vitamin K.
To develop and validate a brief, self-assessment instrument (K-Card) to determine daily variations in dietary vitamin K1 (phylloquinone) intake for use in patients receiving oral warfarin anticoagulant therapy. The K-Card was designed to include a checklist of selected common foods and beverages providing > or = 5 microg vitamin K per serving in American diets and items with lower vitamin K content typically consumed in quantities which contribute significantly to total vitamin K intake. The K-Card was validated against records of weighed food intake from thirty-six healthy volunteers, 20 to 40 and 60 to 80 years of age, whose phylloquinone intakes and plasma concentrations had been previously measured by the Metabolic Research Unit, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA USA. Future use of the K-Card by patients was simulated by a single investigator using 108 one-day weighed food records to estimate phylloquinone intakes. Dietary phylloquinone calculated from the K-Card was compared to the values of phylloquinone intake from the diet records collected on the same days, and to fasting plasma phylloquinone concentrations obtained from the same individuals on the following day. The mean dietary phylloquinone intake (+/- SEM) was 138.8 +/- 15.7 microg for the K-Cards compared to 136.0 +/- 15.8 microg for the diet records (p = 0.067). Bland-Altman limits of agreement between quantities of dietary phylloquinone calculated from the K-Card and values obtained from the weighed food records were +/- 38 microg. In this simulation, the K-Card provided an accurate estimate of dietary phylloquinone intake and therefore deserves further testing for use by patients receiving coumarin-based anticoagulant therapy to determine whether variability in dietary patterns contributes to disruptions in anticoagulant drug efficacy and safety.


Amylin blunts hyperphagia and reduces weight and fat gain during recovery in socially stressed rats.
During recovery from social stress in a visible burrow system (VBS), during which a dominance hierarchy is formed among the males, rats display hyperphagia and gain weight preferentially as visceral adipose tissue. By proportionally increasing visceral adiposity, social stress may contribute to the establishment of metabolic disorder. Amylin was administered to rats fed ad libitum during recovery from VBS stress in an attempt to prevent hyperphagia and the resultant gain in body weight and fat mass. Amylin treatment reduced food intake, weight gain, and accumulation of fat mass in male burrow rats, but not in male controls that spent time housed with a single female rather than in the VBS. Amylin did not alter neuropeptide Y (NPY), agouti-related peptide (AgRP), or proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus of the hypothalamus as measured at the end of the recovery period, nor did it affect plasma corticosterone or leptin. Amylin exerted most of its effect on food intake during the first few days of recovery, possibly through antagonism of NPY and/or increasing leptin sensitivity. The potential for chronic social stress to contribute to metabolic disorder is diminished by amylin treatment, though the neuroendocrine mechanisms behind this effect remain elusive.


Enkephalin downregulation in the nucleus accumbens underlies chronic stress-induced anhedonia.
Restraint and immobilization have been extensively used to study habituation of the neuroendocrine response to a repeated stressor, but behavioral consequences of this stress regimen remain largely uncharacterized. In this study, we used sucrose preference and the elevated-plus maze to probe behavioral alterations resulting from 14 days of restraint in rats. We observed a decrease in sucrose preference in stressed animals, particularly in a subgroup of individuals, but no alteration in anxiety behaviors (as measured in the elevated-plus maze) four days following the last restraint. In these low-sucrose preference animals, we observed a downregulation of the expression of preproenkephalin mRNA in the nucleus accumbens. Furthermore, we observed a strong correlation between enkephalin expression and sucrose preference in the shell part of the nucleus accumbens, with a lower level of enkephalin expression being associated with lower sucrose preference. Interestingly, quantification of the corticosterone response revealed a delayed habituation to restraint in the low-sucrose preference population, which suggests that vulnerability to stress-induced deficits might be associated with prolonged exposure to glucocorticoids. The induction of ΔFosB is also reduced in the nucleus accumbens shell of the low-sucrose preference population and this transcription factor is expressed in enkephalin neurons. Taken together, these results suggest that a ΔFosB-mediated downregulation of enkephalin in the nucleus accumbens might underlie the susceptibility to chronic stress. Further experiments will be needed to determine causality between these two phenomena.


MicroRNAs: modulators of cell identity, and their applications in tissue engineering.
MicroRNAs post-transcriptionally regulate the expression of approximately 60% of the mammalian genes, and have an important role in maintaining the differentiated state of somatic cells through the expression of unique tissuespecific microRNA sets. Likewise, the stemness of pluripotent cells is also sustained by embryonic stem cell-enriched microRNAs, which regulate genes involved in cell cycle, cell signaling and epigenetics, among others. Thus, microRNAs work as modulator molecules that ensure the appropriate expression profile of each cell type. Manipulation of microRNA expression might determine the cell fate. Indeed, microRNA-mediated reprogramming can change the differentiated status of somatic cells towards stemness or, conversely, microRNAs can also transform stem- into differentiated-cells both in vitro and in vivo. In this Review, we outline what is currently known in this field, focusing on the applications of microRNA in tissue engineering.


The search for noise-induced cochlear synaptopathy in humans: Mission impossible?
Animal studies demonstrate that noise exposure can permanently damage the synapses between inner hair cells and auditory nerve fibers, even when outer hair cells are intact and there is no clinically relevant permanent threshold shift. Synaptopathy disrupts the afferent connection between the cochlea and the central auditory system and is predicted to impair speech understanding in noisy environments and potentially result in tinnitus and/or hyperacusis. While cochlear synaptopathy has been demonstrated in numerous experimental animal models, synaptopathy can only be confirmed through post-mortem temporal bone analysis, making it difficult to study in living humans. A variety of non-invasive measures have been used to determine whether noise-induced synaptopathy occurs in humans, but the results are conflicting. The overall objective of this article is to synthesize the existing data on the functional impact of noise-induced synaptopathy in the human auditory system. The first section of the article summarizes the studies that provide evidence for and against noise-induced synaptopathy in humans. The second section offers potential explanations for the differing results between studies. The final section outlines suggested methodologies for diagnosing synaptopathy in humans with the aim of improving consistency across studies.


Deformability based cell margination--a simple microfluidic design for malaria-infected erythrocyte separation.
In blood vessels with luminal diameter less than 300 µm, red blood cells (RBCs) which are smaller in size and more deformable than leukocytes, migrate to the axial centre of the vessel due to flow velocity gradient within the vessels. This phenomenon displaces the leukocytes to the vessel wall and is aptly termed as margination. Here, we demonstrate using microfluidics that stiffer malaria-infected RBCs (iRBCs) behave similar to leukocytes and undergo margination towards the sidewalls. This provides better understanding of the hemodynamic effects of iRBCs in microcirculation and its contribution to pathophysiological outcome relating to cytoadherence to endothelium. In this work, cell margination is mimicked for the separation of iRBCs from whole blood based on their reduced deformability. The malaria infected sample was tested in a simple long straight channel microfluidic device fabricated in polydimethylsiloxane. In this microchannel, cell margination was directed along the channel width with the iRBCs aligning near each sidewall and then subsequently removed using a 3-outlet system, thus achieving separation. Tests were conducted using ring stage and late trophozoite/schizont stage iRBCs. Device performance was quantified by analyzing the distribution of these iRBCs across the microchannel width at the outlet and also conducting flow cytometry analysis. Results indicate recovery of approximately 75% for early stage iRBCs and >90% for late stage iRBCs at the side outlets. The simple and passive system operation makes this technique ideal for on-site iRBCs enrichment in resource-limited settings, and can be applied to other blood cell diseases, e.g. sickle cell anemia and leukemia, characterized by changes in cell stiffness.


Validation of Walk Score for estimating access to walkable amenities.
Proximity to walkable destinations or amenities is thought to influence physical activity behaviour. Previous efforts attempting to calculate neighbourhood walkability have relied on self-report or time-intensive and costly measures. Walk Score is a novel and publicly available website that estimates neighbourhood walkability based on proximity to 13 amenity categories (eg, grocery stores, coffee shops, restaurants, bars, movie theatres, schools, parks, libraries, book stores, fitness centres, drug stores, hardware stores, clothing/music stores). The purpose of this study is to test the validity and reliability of Walk Score for estimating access to objectively measured walkable amenities. Walk Scores of 379 residential/non-residential addresses in Rhode Island were manually calculated. Geographic information systems (GIS) was used to objectively measure 4194 walkable amenities in the 13 Walk Score categories. GIS data were aggregated from publicly available data sources. Sums of amenities within each category were matched to address data, and Pearson correlations were calculated between the category sums and address Walk Scores. Significant correlations were identified between Walk Score and all categories of aggregated walkable destinations within a 1-mile buffer of the 379 residential and non-residential addresses. Test-retest reliability correlation coefficients for a subsample of 100 addresses were 1.0. These results support Walk Score as a reliable and valid measure of estimating access to walkable amenities. Walk Score may be a convenient and inexpensive option for researchers interested in exploring the relationship between access to walkable amenities and health behaviours such as physical activity.


Dietary patterns and associated risk factors among school age children in urban Ghana.
Understanding dietary patterns in the study of diet-disease relationships is crucial for designing dietary behaviour interventions. This study aimed to determine associations between dietary patterns and background characteristics among school age children (9-15 years) in Ghana. A cross-sectional sample of 487 urban-dwelling children age 9-15 years was recruited using simple random sampling from 24 schools (12 private and 12 public) in the Ga-East Municipality in Southern Ghana. A 7-day food frequency questionnaire was used to record children's consumption of over 100 unique food items. Principal component analyses based on 14 food groups was used to describe emerging dietary patterns (DP). BMI-for-age z-scores segregated by sex were derived using WHO Anthro plus software. Linear regression was used to test associations between 'diet factor' scores, and weight status controlling for age. Four DPs were identified that explained 53.2% of variation in the diets of children: (1) energy dense; (2) starchy root staple and vegetables; (3) cereal-grain staples and poultry; and (4) fish & seafoods. Energy dense DP characterised by processed meat, fried foods, and sugary foods was associated with child overweight/obese status after controlling for age, sex, SES and school type [F(5, 484) = 6.868, p < 0.001]. Starchy root with vegetable DP was negatively associated with overweight/obese status, private school attendance and higher SES after controlling for age at bivariate level. However, relationship between 'starchy root staples and vegetables' DP and overweight/obese status lost significance after controlling for other covariates. Our data identified energy-dense dietary pattern to be significantly associated with childhood overweight and obesity. Targeted dietary messages are required to address energy-dense dietary patterns among school-age children.


Awareness and perceptions of electroconvulsive therapy among psychiatric patients: a cross-sectional survey from teaching hospitals in Karachi, Pakistan.
Electroconvulsive therapy (ECT) is shown to be effective in many psychiatric illnesses, but its distorted projection by the Pakistani media and its unregulated use by many physicians across the country have adversely affected its acceptability. Given this situation we aimed to assess the awareness and perceptions regarding ECT as a treatment modality among the psychiatric patients. This was a questionnaire based cross-sectional study carried out at 2 tertiary care hospitals in Karachi, Pakistan. We interviewed 190 patients of which 140 were aware of ECT. The study showed that the level of education had a significant impact on the awareness of ECT (p = 0.009). The most common source of awareness was electronic and print media (38%), followed by relatives (24%) and doctors (23%). Physical injuries (42%) and neurological (12%) and cognitive disturbances (11%) were the commonly feared side effects. The most popular belief about ECT was that it was a treatment of last resort (56%). Thirty-nine percent thought that ECT could lead to severe mental and physical illness and 37% considered it inhumane. Patients' willingness to receive ECT was dependant on whether or not they were convinced of its safety (p = 0.001) and efficacy (p = 0.0001). We identified a serious lack of dissemination of information regarding ECT by the psychiatrists and the mental health care providers. This may be the result of an inadequate postgraduate training in Pakistan or just a lack of concern about the mentally ill patients. The media seemed to be the major source of information for our patients. We also saw the prevalence of a variety of myths regarding ECT in our society, which we feel may be responsible for the patients' adverse attitudes. Given the widespread applicability of ECT there is a dire need to dispel these misconceptions and improve its acceptability.


Primate translational vestibuloocular reflexes. I. High-frequency dynamics and three-dimensional properties during lateral motion.
The dynamics and three-dimensional (3-D) properties of the primate translational vestibuloocular reflex (trVOR) for high-frequency (4-12 Hz, +/-0.3-0.4 g) lateral motion were investigated during near-target viewing at center and eccentric targets. Horizontal response gains increased with frequency and depended on target eccentricity. The larger the horizontal and vertical target eccentricity, the steeper the dependence of horizontal response gain on frequency. In addition to horizontal eye movements, robust torsional response components also were present at all frequencies. During center-target fixation, torsional response phase was opposite (anticompensatory) to that expected for an "apparent" tilt response. Instead torsional response components depended systematically on vertical-target eccentricity, increasing in amplitude when looking down and reversing phase when looking up. As a result the trVOR eye velocity vector systematically tilted away from a purely horizontal direction, through an angle that increased with vertical eccentricity with a slope of approximately 0.7. This systematic dependence of torsional eye velocity tilt on vertical eye position suggests that the trVOR might follow the 3-D kinematic requirements that have been shown to govern visually guided eye movements and near-target fixation.


Multimodality therapy: radiation and continuous concomitant cis-platinum and PKC inhibition in a cervical carcinoma model.
The addition of chemotherapy to radiation therapy has the potential to sterilize micrometastases and tumor foci adjacent and peripheral to the treatment field, so as to enhance local control of malignancy and improve primary and salvage therapy. Studies were done to investigate the effects of combining cisplatin (CP), the most active single agent in squamous-cell cancer of the cervix, with irradiation and the addition of a protein kinase C (PKC) inhibitor. This initial report of these studies describes our experience in exposing human cervical carcinoma (HeLa-S3) cells grown in culture as multicellular tumor spheroids to continuous CP combined with radiation in an attempt to mimic both clinically achievable serum concentrations of CP and a weekly fractionated-dose environment. Radiation-dose-dependent delays of spheroid growth were not significantly increased in the presence of the PKC inhibitor 7-OH-staurosporine (UCN-01) at 1.0 nM and 10.0 nM concentrations. When dose comparisons at 8 Gy alone (2 Gy x 4 fractions) were made for combined therapy with either CP alone (1.0 microgram/ml) or UCN-01 alone, absolute delays in spheroid growth at the highest concentrations used were comparable (range: 37-41 days). Although these data alone would not support minimal chemotherapeutic interaction, it appears that the overall effects observed for combination therapy were predominately radiation-dose dependent. The combination of UCN-01 plus CP (0.5 and 1.0 mu/ml, respectively) was effective in increasing the cytostatic and cytotoxic effects of irradiation at 4 Gy (2 Gy x 2 fractions). Observations made as early as day 4 and day 7 posttreatment were indicative of > or = 40% and 60%, respectively, of morphological damage. Spheroid growth was essentially static at these doses over the evaluation time of 60 days. Intracellular junctions were disorganized, and spheroid swelling was evident and contributed to the modest dimensional changes observed after treatment. No surviving fractions could be generated from spheroids that were mechanically disrupted, trypsinized, and plated at day 7 after the initiation of treatment. At 2 months, 88% (14/16) and 94% (15/16) of the multimodality treatment groups (4 Gy + UCN-01 + CP [0.5 and 1.0 mu/ml], respectively) had sterilized spheroids, indicating that the CP concentration dependence may not be a sole determinant of efficacy. Our therapeutic strategy for combining irradiation with CP was based on the contemporary use of CP as the most successful agent in producing high survival rates in gynecological malignancy. The combination of UCN-01 with CP and irradiation may, however, represent a more effective strategy for enhancing future cisplatin-based chemotherapy regimens.


The effect of load magnitude on three-dimensional patellar kinematics in vivo.
Studies of three-dimensional patellar kinematics done with little or no applied load may not accurately reflect kinematics at physiological load levels, and may provide different results to those acquired with greater applied loads or in physiologic weightbearing. We report the effect of load magnitude on three-dimensional patellar kinematics (flexion, spin and tilt; proximal, lateral and anterior translation) using a validated, sequential static, MRI-based method. Ten healthy subjects loaded their study knee to 0% (no load), 15% and 30% bodyweight (BW) using a custom designed loading rig. Differences between loading levels were determined as a function of knee flexion for each kinematic parameter using linear hierarchical random-effects models. Quadratic and random slope terms were included in the models when significant. We found that the patellae flexed less with knee flexion at 30% BW load compared to 0% BW load (p<0.001) and 15% BW (p=0.004) load. The patellae showed a slight medial tilt with knee flexion at 30% BW load which was significantly less than the medial tilt seen at 0% BW load (p=0.017) and 15% BW load (p=0.043) with knee flexion. Small but statistically significant differences were also observed for proximal and anterior translation; the patellae were in a more proximal and posterior position at 30% BW load than at 0% BW load (p=0.010 and p=0.005, respectively) and 15% BW load (p<0.001 and p=0.029, respectively). Since differences in three-dimensional patellar kinematics were observed between loading levels, magnitudes of prescribed loads must be considered when designing studies and comparing results between studies.


Search for chargino-neutralino production in pp collisions at sq rt[s] = 1.96 TeV.
We present a search for associated production of the chargino and neutralino supersymmetric particles using up to 1.1 fb{-1} of integrated luminosity collected by the CDF II experiment at the Tevatron pp collider at sq rt[s]=1.96 TeV. We analyze events with a large transverse momentum imbalance and either three charged leptons or two charged leptons of the same electric charge. The numbers of observed events are consistent with standard model expectations. Upper limits on the production cross section are derived in different theoretical models.


Use of anti-aging herbal medicine, Lycium barbarum, against aging-associated diseases. What do we know so far?
Lycium barbarum (Gouqizi, Fructus Lycii, Wolfberry) is well known for nourishing the liver, and in turn, improving the eyesight. However, many people have forgotten its anti-aging properties. Valuable components of L. barbarum are not limited to its colored components containing zeaxanthin and carotene, but include the polysaccharides and small molecules such as betaine, cerebroside, beta-sitosterol, p-coumaric, and various vitamins. Despite the fact that L. barbarum has been used for centuries, its beneficial effects to our bodies have not been comprehensively studied with modern technology to unravel its therapeutic effects at the biochemical level. Recently, our laboratory has demonstrated its neuroprotective effects to counter neuronal loss in neurodegenerative diseases. Polysaccharides extracted from L. barbarum can protect neurons against beta-amyloid peptide toxicity in neuronal cell cultures, and retinal ganglion cells in an experimental model of glaucoma. We have even isolated the active component of polysaccharide which can attenuate stress kinases and pro-apoptotic signaling pathways. We have accumulated scientific evidence for its anti-aging effects that should be highlighted for modern preventive medicine. This review is to provide background information and a new direction of study for the anti-aging properties of L. barbarum. We hope that new findings for L. barbarum will pave a new avenue for the use of Chinese medicine in modern evidence-based medicine.


Dynamic Causal Modeling applied to fMRI data shows high reliability.
Sensitivity, specificity, and reproducibility are vital to interpret neuroscientific results from functional magnetic resonance imaging (fMRI) experiments. Here we examine the scan-rescan reliability of the percent signal change (PSC) and parameters estimated using Dynamic Causal Modeling (DCM) in scans taken in the same scan session, less than 5 min apart. We find fair to good reliability of PSC in regions that are involved with the task, and fair to excellent reliability with DCM. Also, the DCM analysis uncovers group differences that were not present in the analysis of PSC, which implies that DCM may be more sensitive to the nuances of signal changes in fMRI data.


Robust social categorization emerges from learning the identities of very few faces.
Viewers are highly accurate at recognizing sex and race from faces-though it remains unclear how this is achieved. Recognition of familiar faces is also highly accurate across a very large range of viewing conditions, despite the difficulty of the problem. Here we show that computation of sex and race can emerge incidentally from a system designed to compute identity. We emphasize the role of multiple encounters with a small number of people, which we take to underlie human face learning. We use highly variable everyday 'ambient' images of a few people to train a Linear Discriminant Analysis (LDA) model on identity. The resulting model has human-like properties, including a facility to cohere previously unseen ambient images of familiar (trained) people-an ability which breaks down for the faces of unknown (untrained) people. The first dimension created by the identity-trained LDA classifies both familiar and unfamiliar faces by sex, and the second dimension classifies faces by race-even though neither of these categories was explicitly coded at learning. By varying the numbers and types of face identities on which a further series of LDA models were trained, we show that this incidental learning of sex and race reflects covariation between these social categories and face identity, and that a remarkably small number of identities need be learnt before such incidental dimensions emerge. The task of learning to recognize familiar faces is sufficient to create certain salient social categories. (PsycINFO Database Record


Bevacizumab in combination with paclitaxel for HER-2 negative metastatic breast cancer: an economic evaluation.
The addition of bevacizumab to weekly paclitaxel as primary chemotherapy for HER-2 negative metastatic breast cancer (MBC) prolongs progression-free survival without a substantial increase of toxicity. A Markov cohort simulation was used to follow the clinical course of typical patients with MBC. Information on response rates and major adverse effects was derived, and transition probabilities were estimated, based on the results of the E2100 clinical trial. Direct costs were assessed from the perspective of the Swiss health system. The addition of bevacizumab to weekly paclitaxel is estimated to cost an additional 40,369euro and to yield a gain of 0.22 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of 189,427euro/QALY gained. Probabilistic sensitivity analysis showed that the willingness-to-pay threshold of 60,000euro was never reached. The addition of bevacizumab to paclitaxel in MBC patients is expensive given the clinical benefit in terms of QALYs gained.


Trends and oscillations in the Indian summer monsoon rainfall over the last two millennia.
Observations show that summer rainfall over large parts of South Asia has declined over the past five to six decades. It remains unclear, however, whether this trend is due to natural variability or increased anthropogenic aerosol loading over South Asia. Here we use stable oxygen isotopes in speleothems from northern India to reconstruct variations in Indian monsoon rainfall over the last two millennia. We find that within the long-term context of our record, the current drying trend is not outside the envelope of monsoon's oscillatory variability, albeit at the lower edge of this variance. Furthermore, the magnitude of multi-decadal oscillatory variability in monsoon rainfall inferred from our proxy record is comparable to model estimates of anthropogenic-forced trends of mean monsoon rainfall in the 21st century under various emission scenarios. Our results suggest that anthropogenic-forced changes in monsoon rainfall will remain difficult to detect against a backdrop of large natural variability.


Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether and tertiary-butyl alcohol in rats: Contribution of binding to α2u-globulin in male rats and high-exposure nonlinear kinetics to toxicity and cancer outcomes.
In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary-butyl ether (ETBE), caused liver tumors in male rats, while tertiary-butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary-butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat-specific protein α2u-globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0-∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male-rat-specific mode of action for TBA-induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0-∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd.


Six-month quality-of-life and functional status of acute respiratory distress syndrome survivors compared to patients at risk: a population-based study.
The long-term attributable burden related to acute respiratory distress syndrome (ARDS) is not fully investigated. The aim of this study is to evaluate the quality of life (QOL) and functional status at 6 months after hospitalization in patients at risk for ARDS who did and did not develop the syndrome. This is a population-based prospective cohort study of adult patients from Olmsted County, Minnesota, with or at risk for ARDS hospitalized from October 2008 to July 2011. The primary outcomes were changes in QOL and functional status, measured through 12-Item Short Form Survey (SF-12) and Barthel Index (BI) respectively, from baseline to 6 months, compared between survivors who did and did not develop ARDS. Of 410 patients with or at risk for ARDS, 98 had baseline surveys collected and 67 responded to a 6-month survey (26 ARDS, 41 non-ARDS). Both ARDS and non-ARDS groups had lower physical component of SF-12 at baseline compared to general population (P < 0.001 for both). ARDS patients had poorer baseline functional status compared to non-ARDS (mean BI 80 ± 25 vs. 88 ± 22, P = 0.03). No significant differences were observed for the change between 6 months and baseline BI (delta 2.3 for ARDS vs. 2.0 for non-ARDS, P = 0.5), or mental (delta 2.7 vs. 2.4, P = 0.9) or physical (delta -3 vs. -3.3, P = 0.9) component of SF-12 between survivors with and without ARDS. In this population-based study, decreased QOL and functional status 6 months after hospitalization were largely explained by baseline condition, with similar recovery in survivors who did and did not develop ARDS.