Extended-spectrum beta-lactamase-producing Enterobacteriaceae strains in community-acquired bacteremia in Southern Israel.
In recent years, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae have emerged in many hospitals worldwide. The increasing dissemination and long-term carriage of these organisms within the community carry tremendous implications on the empirical therapy of community-acquired infection. To evaluate the prevalence and clinical features of community-acquired bacteremia involving ESBL-producing Enterobacteriaceae in southern Israel (ESBL-P) we retrospectively studied all Enterobacteriaceae bacteremias during an 8-month period in the Negev region using medical and laboratory records. Antibiotic susceptibility was determined using the disk-diffusion method. ESBL production was determined using an E-test ESBL strip. Cases involving ESBL-P were compared to those involving non-producing strains (ESBL-NP) using the chi-square test. In all, 187 Enterobacteriaceae bacteremias were detected, of which 119 were community-acquired (63.6%). ESBL-P were found in six cases (5%) which are described herein in greater detail. Patients with ESBL-P bacteremia were older, and were more likely to stay in the intensive-care unit. Urinary catheterization and bed-ridden conditions were significant risk factors for ESBL-P. ESBL-P strains were significantly resistant to nearly all antibiotic agents except for imipienem and piperacillin-tazobactam as opposing to ESBL-NP. Patients with ESBL-P bacteremia were more likely to suffer from complications and had a higher mortality. This paper is the first to describe community-acquired Enterobacteriaceae bacteremia involving ESBL-P strains in Israel. Although the exact prevalence of these organisms in Israel is currently unknown, our findings suggest that ESBL-producers have already begun to disseminate in our community.


Meteorological aspects of the el nino/southern oscillation.
The single most prominent signal in year-to-year climate variability is the Southern Oscillation, which is associated with fluctuations in atmospheric pressure at sea level in the tropics, monsoon rainfall, and wintertime circulation over North America and other parts of the extratropics. Although meteorologists have known about the Southern Oscillation for more than a half-century, its relation to the oceanic El Niño phenomenon was not recognized until the late 1960's, and a theoretical understanding of these relations has begun to emerge only during the past few years. The past 18 months have been characterized by what is probably the most pronounced and certainly the best-documented El Niño/Southern Oscillation episode of the past century. In this review meteorological aspects of the time history of the 1982-1983 episode are described and compared with a composite based on six previous events between 1950 and 1975, and the impact of these new observations on theoretical interpretations of the event is discussed.


Calcification of differentiating skeletal mesenchyme in vitro.
Embryonic limb-bud mesenchyme was induced to calcify in culture by the addition of 3 mM inorganic phosphate to the medium. Phosphate enhanced calcification of the matrix produced by mesenchymal or fibroblast-like cells, whereas no calcification was evident in areas where cartilage had developed. However, calcification was induced throughout the cell layer by altering the cartilage matrix properties with certain enzymes or by changing the phenotypic expression of the cells with vitamin A.


Towards complete and accurate reporting of studies of diagnostic accuracy: The STARD Initiative.
To comprehend the results of diagnostic accuracy studies, readers must understand the design, conduct, analysis, and results of such studies. That goal can be achieved only through complete transparency from authors. To improve the accuracy and completeness of reporting of studies of diagnostic accuracy in order to allow readers to assess the potential for bias in the study and to evaluate its generalizability. The Standards for Reporting of Diagnostic Accuracy (STARD) steering committee searched the literature to identify publications on the appropriate conduct and reporting of diagnostic studies and extracted potential items into an extensive list. Researchers, editors, methodologists and statisticians, and members of professional organizations shortened this list during a 2-day consensus meeting with the goal of developing a checklist and a generic flow diagram for studies of diagnostic accuracy. The search for published guidelines on diagnostic research yielded 33 previously published checklists, from which we extracted a list of 75 potential items. The consensus meeting shortened the list to 25 items, using evidence on bias whenever available. A prototypical flow diagram provides information about the method of patient recruitment, the order of test execution, and the numbers of patients undergoing the test under evaluation, the reference standard, or both. Evaluation of research depends on complete and accurate reporting. If medical journals adopt the checklist and the flow diagram, the quality of reporting of studies of diagnostic accuracy should improve to the advantage of the clinicians, researchers, reviewers, journals, and the public.


Analysis on Population Level Reveals Trappability of Wild Rodents Is Determined by Previous Trap Occupant.
Live trapping is central to the study of small mammals. Thus, any bias needs to be understood and accounted for in subsequent analyses to ensure accurate population estimates. One rarely considered bias is the behavioural response of individuals to the trap, in particular the olfactory cues left behind by previous occupants (PO). We used a data set of 8,115 trap nights spanning 17 separate trapping sessions between August 2002 and November 2013 in Wytham Woods, Oxfordshire, UK to examine if the decision to enter a trap was affected by the PO, if this was detectable in traditional Capture-Mark-Recapture trapping data (i.e., individuals not uniquely marked), and if it was possible for this effect to bias the population estimates obtained. Data were collected on Apodemus sylvaticus, Myodes glareolus, and Microtus agrestis. Three Generalised Linear Models revealed a significant tendency for the three species to enter traps with same-species PO. With, for example, A. sylvaticus 9.1 times more likely to enter a same species PO trap compared to one that contained a M. agrestis in the grassland during the nocturnal period. Simulation highlighted that, when all other factors are equal, the species with the highest PO effect will have the highest capture rate and therefore return more accurate population estimates. Despite the large dataset, certain species-, sex-, and/ or age-combinations were under-represented, and thus no effects of any additional individual-specific characteristics could be evaluated. Uniquely marking individuals would allow for the PO effect to be disentangled from other biases such as trap-shyness and spatial heterogeneity, but may not be possible in all cases and will depend on the aims of the study and the resources available.


Training of leadership skills in medical education.
Effective team performance is essential in the delivery of high-quality health-care. Leadership skills therefore are an important part of physicians' everyday clinical life. To date, the development of leadership skills are underrepresented in medical curricula. Appropriate training methods for equipping doctors with these leadership skills are highly desirable. The review aims to summarize the findings in the current literature regarding training in leadership skills in medicine and tries to integrate the findings to guide future research and training development. The PubMED, ERIC, and PsycArticles, PsycINFO, PSYNDEX and Academic search complete of EBSCOhost were searched for training of leadership skills in medicine in German and English. Relevant articles were identified and findings were integrated and consolidated regarding the leadership principles, target group of training and number of participants, temporal resources of the training, training content and methods, the evaluation design and trainings effects. Eight studies met all inclusion criteria and no exclusion criteria. The range of training programs is very broad and leadership skill components are diverse. Training designs implied theoretical reflections of leadership phenomena as well as discussions of case studies from practice. The duration of training ranged from several hours to years. Reactions of participants to trainings were positive, yet no behavioral changes through training were examined. More research is needed to understand the factors critical to success in the development of leadership skills in medical education and to adapt goal-oriented training methods. Requirements analysis might help to gain knowledge about the nature of leadership skills in medicine. The authors propose a stronger focus on behavioral training methods like simulation-based training for leadership skills in medical education.


Novel action of quinolones on osteoclast-like cells.
Quinolones have a broad antibacterial spectrum against Gram-negative and Gram-positive bacteria. The compounds, however, have a few adverse effects, such as convulsion and toxicity to articular cartilage. We observed that some quinolones such as Naldixic acid, Ofloxacin, and Norfloxacin have osteoclast-inducing effects. All quinolones we tested produced tumor necrosis factor-alpha and prostaglandin E2, and have potency as osteoclast inducers to cultured cells. These results suggest that some quinolones affect osteoclast induction or activation, and this may be related to the production of tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2).


Repeated withdrawal from ethanol spares contextual fear conditioning and spatial learning but impairs negative patterning and induces over-responding: evidence for effect on frontal cortical but not hippocampal function?
Repeated exposure of rats to withdrawal from chronic ethanol reduces hippocampal long-term potentiation and gives rise to epileptiform-like activity in hippocampus. We investigated whether such withdrawal experience also affects learning in tasks thought to be sensitive to hippocampal damage. Rats fed an ethanol-containing diet for 24 days with two intermediate 3-day withdrawal episodes, resulting in intakes of 13-14 g/kg ethanol per day, showed impaired negative patterning discrimination compared with controls and animals that had continuous 24-day ethanol treatment, but did not differ from these animals in the degree of contextual freezing 24 h after training or in spatial learning in the Barnes maze. Repeatedly withdrawn animals also showed increased numbers of responses in the period immediately before reinforcement became available in an operant task employing a fixed-interval schedule although overall temporal organization of responding was unimpaired. Thus, in our model of repeated withdrawal from ethanol, previously observed changes in hippocampal function did not manifest at the behavioural level in the tests employed. The deficit seen after repeated withdrawal in the negative patterning discrimination and over-responding in the fixed-interval paradigm might be related to the changes in the functioning of the cortex after withdrawal.


Implementation Science Research Examining the Integration of Evidence-Based Practices Into HIV Prevention and Clinical Care: Protocol for a Mixed-Methods Study Using the Exploration, Preparation, Implementation, and Sustainment (EPIS) Model.
The Exploration, Preparation, Implementation, and Sustainment (EPIS) model is an implementation framework for studying the integration of evidence-based practices (EBPs) into real-world settings. The EPIS model conceptualizes implementation as a process starting with the earliest stages of problem recognition (Exploration) through the continued use of an EBP in a given clinical context (Sustainment). This is the first implementation science (IS) study of the integration of EBPs into adolescent HIV prevention and care settings. This protocol (ATN 153 EPIS) is part of the Scale It Up program, a research program administered by the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN), described in this issue by Naar et al. The EPIS study is a descriptive study of the uptake of 4 EBPs within the Scale It Up program. The goal of EPIS is to understand the barriers and facilitators associated with the Preparation, Implementation, and Sustainment of EBPs into HIV prevention and clinical care settings. The EPIS study is a convergent parallel mixed-methods IS study. Key implementation stakeholders, that is, clinical care providers and leaders, located within 13 ATN sites across the United States will complete a qualitative interview conducted by telephone and Web-based surveys at 3 key implementation stages. The Preparation assessment occurs before EBP implementation, Implementation occurs immediately after sites finish implementation activities and prepare for sustainment, and Sustainment occurs 1 year postimplementation. Assessments will examine stakeholders' perceptions of the barriers and facilitators to EBP implementation within their clinical site as outlined by the EPIS framework. The EPIS baseline period began in June 2017 and concluded in May 2018; analysis of the baseline data is underway. To date, 153 stakeholders have completed qualitative interviews, and 91.5% (140/153) completed the quantitative survey. The knowledge gained from the EPIS study will strengthen the implementation and sustainment of EBPs in adolescent prevention and clinical care contexts by offering insights into the barriers and facilitators of successful EBP implementation and sustainment in real-world clinical contexts. DERR1-10.2196/11202.


Cyanobacteria as photosynthetic biocatalysts: a systems biology perspective.
The increasing need to replace oil-based products and to address global climate change concerns has triggered considerable interest in photosynthetic microorganisms. Cyanobacteria, in particular, have great potential as biocatalysts for fuels and fine-chemicals. During the last few years the biotechnological applications of cyanobacteria have experienced an unprecedented increase and the use of these photosynthetic organisms for chemical production is becoming a tangible reality. However, the field is still immature and many concerns about the economic feasibility of the biotechnological potential of cyanobacteria remain. In this review we describe recent successes in biofuel and fine-chemical production using cyanobacteria. We discuss the role of the photosynthetic metabolism and highlight the need for systems-level metabolic optimization in order to achieve the true potential of cyanobacterial biocatalysts.


Building Capacity for Productive Indigenous Community-University Partnerships.
This paper describes capacity development as a key aspect of community-based research with indigenous communities. University research engagement with indigenous communities includes extensive, and often negative, historical antecedents. We discuss strategies for developing effective, egalitarian, and balanced indigenous community-university relationships to build research capacity of these communities, and to create sustainable partnerships to improve health and wellness, and to reduce health disparities. We draw on the experience of eight investigators conducting research with indigenous communities to assess effective strategies for building and enhancing partnerships, including (1) supporting indigenous investigator development; (2) developing university policies and practices sensitive and responsive to Indigenous community settings and resources, and training for research; (3) developing community and scientifically acceptable research designs and practices; (4) aligning indigenous community and university review boards to enhance community as well as individual protection (e.g., new human subjects training for Indigenous research, joint research oversight, adaptation of shorter consent forms, appropriate incentives, etc.); (5) determining appropriate forms of dissemination (i.e., Indian Health Services provider presentation, community reports, digital stories, etc.); (6) best practices for sharing credit; and (7) reducing systematic discrimination in promotion and tenure of indigenous investigators and allies working in indigenous communities.


The wide-angle point spread function of the human eye reconstructed by a new optical method.
The point spread function (PSF) of the human eye spans over a wide angular distribution where the central part is associated mostly to optical aberrations while the peripheral zones are associated to light scattering. There is a plethora of optical methods for the direct and indirect measurements of the central part of the PSF as a result of monochromatic and polychromatic aberrations. The impact of the spatial characteristics of this central part of the PSF on the retinal image quality and visual function has been extensively analyzed and documented both by optical and psychophysical methods. However, the more peripheral areas of the PSF in the living human eye, ranging from about 1 to 10 degrees of eccentricity, have been investigated only psychophysically. We report here a new optical method for the accurate reconstruction of the wide-angle PSF in the living human eye up to 8 degrees. The methodology consists of projecting disks of uniform radiance on the retina, recording the images after reflection and double pass through the eye's optics and performing a proper analysis of the images. Examples of application of the technique in real eyes with different amount of scatter artificially induced are presented. This procedure allows the direct, accurate, and in vivo measurement of the effect of intraocular scattering and may be a step toward the comprehensive optical evaluation of the optics of the living human eye.


The leader of the HIV-1 RNA genome forms a compactly folded tertiary structure.
The untranslated leader of the RNA genome of the human immunodeficiency virus type 1 (HIV-1) encodes multiple signals that regulate distinct steps of the viral replication cycle. The RNA secondary structure of several replicative signals in the HIV-1 leader is critical for function. Well-known examples include the TAR hairpin that forms the binding site for the viral Tat trans-activator protein and the DIS hairpin that is important for dimerization and subsequent packaging of the viral RNA into virion particles. In this study, we present evidence for the formation of a tertiary structure by the complete HIV-1 leader RNA. This conformer was recognized as a fast-migrating band on nondenaturing polyacrylamide gels, and such a migration effect is generally attributed to differences in compactness. Both the 5' and 3' domains of the 335-nt HIV-1 leader RNA are required for the formation of the compact RNA structure, and the presence of several putative interaction domains was revealed by an extensive analysis of the denaturing effect of antisense DNA oligonucleotides. The buffer conditions and sequence requirements for conformer formation are strikingly different from that of the RNA-dimerization reaction. In particular, the conformer was destabilized in the presence of Mg2+ ions and by the viral nucleocapsid (NC) protein. The presence of a stable RNA structure in the HIV-1 leader was also apparent when this RNA was used as template for reverse transcription, which yielded massive stops ahead of the structured leader domain. Formation of the conformer is a reversible event, suggesting that the HIV-1 leader is a dynamic molecule. The putative biological function of this conformational polymorphism as molecular RNA switch in the HIV-1 replication cycle is discussed.


Dieting decreases plasma tryptophan and increases the prolactin response to d-fenfluramine in women but not men.
We studied the effect of 3 weeks of moderate calorie restriction on 5-HT-mediated prolactin (PRL) release in healthy volunteers using the 5-HT-releasing agent d-fenfluramine. In women, dieting significantly lowered plasma total and free tryptophan (TRP) and increased the PRL response to d-fenfluramine. None of these measures were altered in men who dieted. These findings add to the data indicating that dieting alters brain 5-HT function in women, perhaps as a consequence of reducing the availability of plasma TRP.


Mortality risk in splenectomised patients: a Danish population-based cohort study.
The extent and magnitude of mortality risk among patients splenectomised for a variety of indications is not well-described in the literature. We assessed mortality risk among splenectomised patients compared to the general population and to un-splenectomised patients with similar underlying medical conditions. We conducted a historical population-based cohort study in Denmark between January 1, 1996 and December 31, 2005. Mortality risk was evaluated within 90 days, 91-365 days, and >365 days post-splenectomy, controlling for age, sex, and comorbid conditions using Cox proportional hazards models for a splenectomised cohort compared to the general Danish population and a matched indication cohort. We identified a total of 3812 splenectomised patients, 38,120 population comparisons, and 8310 matched indication comparisons. Within 90 days post-splenectomy, the adjusted relative risk (RR) for death, regardless of indication, was highly elevated compared to the general population: RR 33.6 [95% confidence interval (CI): 6.9, 35.0]. This risk declined substantially after 90 days post-splenectomy but remained higher 365 days post-splenectomy for all indications compared to the general population. When compared to the matched indication cohort, short- and long-term mortality risk with splenectomy was not increased. Regardless of indication, the adjusted short- and long-term risk of death for splenectomised patients was higher than the general population. Most of this risk seems to be due to the underlying splenectomy indication and not to splenectomy alone.


Temporary abolition of pain in man.
In eight patients with intense chronic cutaneous pain, sensory nerves or roots. supplying the painful area were stimulated. Square-wave 0.1-millisecond pulses at 100 cycles per second were applied, and the voltage was raised until the patient reported tingling in the area. During this stimulation, pressure on previously sensitive areas failed to evoke pain. Four patients, who had diseases of their peripheral nerves, experienced relief of their pain for more than half an hour after stimulation for 2 minutes.


Toxicological effects of bioactive peptide fractions obtained from Bothrops jararaca snake venom on the structure and function of mouse seminiferous epithelium.
Pathogenesis of Bothrops envenomations is complex and despite numerous studies on the effects of this snake venom on various biological systems, relatively little is known about such effects on the male reproductive system. In the present study, the toxicological outcomes of the low molecular weight fraction (LMWF) of B. jararaca snake venom - containing a range of bioactive peptides - were investigated on the dynamics and structure of the seminiferous epithelium and 15P-1 Sertoli cells viability. LMWF (5 µg/dose per testis) venom was administered in male Swiss mice by intratesticular (i.t.) injection. Seven days after this procedure, the testes were collected for morphological and morphometric evaluation, distribution of claudin-1 in the seminiferous epithelium by immunohistochemical analyses of testes, and the nitric oxide (NO) levels were evaluated in the total extract of the testis protein. In addition, the toxicological effects of LMWF and crude venom (CV) were analyzed on the 15P-1 Sertoli cell culture. LMWF induced changes in the structure and function of the seminiferous epithelium without altering claudin-1 distribution. LMWF effects were characterized especially by lost cells in the adluminal compartment of epithelium (spermatocytes in pachytene, preleptotene spermatocytes, zygotene spermatocytes, and round spermatid) and different stages of the seminiferous epithelium cycle. LMWF also increased the NO levels in the total extract of the testis protein and was not cytotoxic in concentrations and time tested in the present study. However, CV showed cytotoxicity at 10 μg/mL from 6 to 48 h of treatment. The major finding of the present study was that the LMWF inhibited spermatozoa production; principally in the spermiogenesis stage without altering claudin-1 distribution in the basal compartment. Moreover, NO increased by LMWF induce open of complexes junctions and release the germ cells of the adluminal compartment to the seminiferous tubule.


The potential of composite cognitive scores for tracking progression in Huntington's disease.
Composite scores derived from joint statistical modelling of individual risk factors are widely used to identify individuals who are at increased risk of developing disease or of faster disease progression. We investigated the ability of composite measures developed using statistical models to differentiate progressive cognitive deterioration in Huntington's disease (HD) from natural decline in healthy controls. Using longitudinal data from TRACK-HD, the optimal combinations of quantitative cognitive measures to differentiate premanifest and early stage HD individuals respectively from controls was determined using logistic regression. Composite scores were calculated from the parameters of each statistical model. Linear regression models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change over 24 months between premanifest and early stage HD groups respectively and controls. ES for the composites were compared with ES for individual cognitive outcomes and other measures used in HD research. The 0.632 bootstrap was used to eliminate biases which result from developing and testing models in the same sample. In early HD, the composite score from the HD change prediction model produced an ES for difference in rate of 24-month change relative to controls of 1.14 (95% CI: 0.90 to 1.39), larger than the ES for any individual cognitive outcome and UHDRS Total Motor Score and Total Functional Capacity. In addition, this composite gave a statistically significant difference in rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI: 0.04 to 0.44), even though none of the individual cognitive outcomes produced statistically significant ES over this period. Composite scores developed using appropriate statistical modelling techniques have the potential to materially reduce required sample sizes for randomised controlled trials.


The production of hemicellulases by Thermomyces lanuginosus strain SSBP: influence of agitation and dissolved oxygen tension.
Shake-flask cultivation of T. lanuginosus strain SSBP on coarse corn cobs yielded beta-xylanase levels of 56,500 nkat/ml at 50 degrees C, whereas other hemicellulases (beta-xylosidase, beta-glucosidase, and alpha-L-arabinofuranosidase) were produced at levels less than 7 nkat/ml. Cultivation on D-xylose yielded much lower levels of xylanase (350 nkat/ml), although other hemicellulase levels were similar to those produced on corn cobs. The influence of agitation rate and dissolved oxygen tension (DOT) on hemicellulase production was studied further in a bioreactor. On xylose, xylanase activities of 4,330 nkat/ml and 4,900 nkat/ml were obtained at stirrer speeds up to 1,400 rpm to control DOT. At a constant stirrer speed of 400 rpm, xylanase activities of 10,930 nkat/ml and 15,630 nkat/ml were obtained when cultivated on xylose and beechwood xylan respectively, despite DOT levels below 5% for the duration of fermentation. The results indicate that there is an interaction between agitation rate and DOT, impacting on xylanase and accessory enzyme production. Higher agitation rates favoured the production of xylosidase, arabinofuranosidase and glucosidase by T. lanuginosus strain SSBP, whereas the lower agitation rates favoured xylanase production. Rheological difficulties precluded cultivation on corn cobs in the bioreactor. Volumetric xylanase productivities of 1,060,000 nkat/l x h and 589,000 nkat/l x h obtained on beechwood xylan and xylose indicate that T. lanuginosus strain SSBP is a hyperxylanase producer with considerable industrial potential.


Frequency of CYP3A5 Genetic Polymorphisms and Tacrolimus Pharmacokinetics in Pediatric Liver Transplantation.
The evidence available in the pediatric population is limited for making clinical decisions regarding the optimization of tacrolimus (TAC) in pharmacotherapy. The objective of this study was to estimate the frequency of CYP3A5 genetic polymorphisms and their relationship with tacrolimus requirements in the pediatric population. This was a longitudinal cohort study with a two-year follow-up of 77 patients under 18 years old who underwent a liver transplant during the period 2009-2012 at the J.P. Garrahan Pediatric Hospital. Tacrolimus levels from day five up to two years after the transplant were obtained from hospital records of routine therapeutic drug monitoring. The genotyping of CYP3A5 (CYP3A5*1/*3 or *3/*3) was performed in liver biopsies from both the donor and the recipient. The frequency of CYP3A5*1 expression for recipients was 37.1% and 32.2% for donors. Patients who received an expresser organ showed lower Co/dose, especially following 90 days after the surgery. The role of each polymorphism is different according to the number of days after the transplant, and it must be taken into account to optimize the benefits of TAC therapy during the post-transplant induction and maintenance phases.


Quality of life and resource utilization-Swedish data from the Care of Late-Stage Parkinsonism (CLaSP) study.
Few studies have investigated the health-related quality of life (HRQoL), resource use and costs in patients with late-stage Parkinson's disease (PD), and data from the Swedish setting are scarce. First, we analyse the HRQoL in late-stage PD in Sweden. Second, we analyse the resource use and costs per severity level. Third, we analyse the relationship between costs and physician- and patient reported-outcome measures. The study was based on Swedish data from the Care of Late-Stage Parkinsonism (CLaSP) study. The costs of healthcare contacts, drugs, formal and informal care, and productivity loss were collected over three months. Assessments at baseline were used for outcomes (EQ-5D, Hoehn and Yahr (H&Y), Schwab and England Scale, Unified Parkinson's Disease Rating Scale subscales (UPDRS) and Non-Motor Symptoms Scale (NMSS)). Costs were estimated in € 2016. In total, 106 patients were included. The mean EQ-5D score in the total group was 0.24 (±0.33). The mean total cost excluding informal care per patient in the three-month period was approximately €14,097 (BCa 95% CI €12,007 and €16,039). Professional care accounted for the largest share (75 percent) of the total costs. The EQ-5D, H&Y, Schwab and England Scale, and NMSS were statistically significant predicting factors for total costs. Patients with late-stage PD are a vulnerable patient group that is costly to society and the impairment in patients' HRQoL is immense. Thus, healthcare decision-makers should optimize the organization and provision of healthcare for these patients.


Promoter and neck region length variation of DC-SIGN is not associated with susceptibility to tuberculosis in Tunisian patients.
The C-type lectin DC-SIGN (CD209) is an important pathogen recognition receptor of the innate immune system. Recent studies showed that DC-SIGN is the major receptor of Mycobacterium tuberculosis on human dendritic cells and that polymorphisms in the DC-SIGN promoter region are associated with susceptibility to tuberculosis. In this light, we aimed to study the potential implication of DC-SIGN genetic variation in the predisposition to tuberculosis in a group of Tunisian patients. We thus performed an association study comprising 138 tuberculosis patients and 140 healthy controls. Sequencing of the DC-SIGN promoter region detected four polymorphisms (-939, -871, -601, and -336), but no differences in their allelic distribution were observed between the two groups. In addition, the analysis of length variation in the DC-SIGN neck region indicated extremely low levels of polymorphisms and, again, no differences between patients and controls. Our data showed therefore that neither promoter variants nor length variation in the neck region of DC-SIGN is associated with susceptibility to tuberculosis in Tunisian patients.


Characterization of the beta-ketoadipate pathway in Sinorhizobium meliloti.
Aromatic compounds represent an important source of energy for soil-dwelling organisms. The beta-ketoadipate pathway is a key metabolic pathway involved in the catabolism of the aromatic compounds protocatechuate and catechol, and here we show through enzymatic analysis and mutant analysis that genes required for growth and catabolism of protocatechuate in the soil-dwelling bacterium Sinorhizobium meliloti are organized on the pSymB megaplasmid in two transcriptional units designated pcaDCHGB and pcaIJF. The pcaD promoter was mapped by primer extension, and expression from this promoter is demonstrated to be regulated by the LysR-type protein PcaQ. Beta-ketoadipate succinyl-coenzyme A (CoA) transferase activity in S. meliloti was shown to be encoded by SMb20587 and SMb20588, and these genes have been renamed pcaI and pcaJ, respectively. These genes are organized in an operon with a putative beta-ketoadipyl-CoA thiolase gene (pcaF), and expression of the pcaIJF operon is shown to be regulated by an IclR-type transcriptional regulator, SMb20586, which we have named pcaR. We show that pcaR transcription is negatively autoregulated and that PcaR is a positive regulator of pcaIJF expression and is required for growth of S. meliloti on protocatechuate as the carbon source. The characterization of the protocatechuate catabolic pathway in S. meliloti offers an opportunity for comparison with related species, including Agrobacterium tumefaciens. Differences observed between S. meliloti and A. tumefaciens pcaIJ offer the first evidence of pca genes that may have been acquired after speciation in these closely related species.


Signaling to transcription networks in the neuronal retrograde injury response.
Retrograde signaling from axon to soma activates intrinsic regeneration mechanisms in lesioned peripheral sensory neurons; however, the links between axonal injury signaling and the cell body response are not well understood. Here, we used phosphoproteomics and microarrays to implicate approximately 900 phosphoproteins in retrograde injury signaling in rat sciatic nerve axons in vivo and approximately 4500 transcripts in the in vivo response to injury in the dorsal root ganglia. Computational analyses of these data sets identified approximately 400 redundant axonal signaling networks connected to 39 transcription factors implicated in the sensory neuron response to axonal injury. Experimental perturbation of individual overrepresented signaling hub proteins, including Abl, AKT, p38, and protein kinase C, affected neurite outgrowth in sensory neurons. Paradoxically, however, combined perturbation of Abl together with other hub proteins had a reduced effect relative to perturbation of individual proteins. Our data indicate that nerve injury responses are controlled by multiple regulatory components, and suggest that network redundancies provide robustness to the injury response.


ISAAC - InterSpecies Analysing Application using Containers.
Information about genes, transcripts and proteins is spread over a wide variety of databases. Different tools have been developed using these databases to identify biological signals in gene lists from large scale analysis. Mostly, they search for enrichments of specific features. But, these tools do not allow an explorative walk through different views and to change the gene lists according to newly upcoming stories. To fill this niche, we have developed ISAAC, the InterSpecies Analysing Application using Containers. The central idea of this web based tool is to enable the analysis of sets of genes, transcripts and proteins under different biological viewpoints and to interactively modify these sets at any point of the analysis. Detailed history and snapshot information allows tracing each action. Furthermore, one can easily switch back to previous states and perform new analyses. Currently, sets can be viewed in the context of genomes, protein functions, protein interactions, pathways, regulation, diseases and drugs. Additionally, users can switch between species with an automatic, orthology based translation of existing gene sets. As todays research usually is performed in larger teams and consortia, ISAAC provides group based functionalities. Here, sets as well as results of analyses can be exchanged between members of groups. ISAAC fills the gap between primary databases and tools for the analysis of large gene lists. With its highly modular, JavaEE based design, the implementation of new modules is straight forward. Furthermore, ISAAC comes with an extensive web-based administration interface including tools for the integration of third party data. Thus, a local installation is easily feasible. In summary, ISAAC is tailor made for highly explorative interactive analyses of gene, transcript and protein sets in a collaborative environment.


Regression-based identification of behavior-encoding neurons during large-scale optical imaging of neural activity at cellular resolution.
The advent of methods for optical imaging of large-scale neural activity at cellular resolution in behaving animals presents the problem of identifying behavior-encoding cells within the resulting image time series. Rapid and precise identification of cells with particular neural encoding would facilitate targeted activity measurements and perturbations useful in characterizing the operating principles of neural circuits. Here we report a regression-based approach to semiautomatically identify neurons that is based on the correlation of fluorescence time series with quantitative measurements of behavior. The approach is illustrated with a novel preparation allowing synchronous eye tracking and two-photon laser scanning fluorescence imaging of calcium changes in populations of hindbrain neurons during spontaneous eye movement in the larval zebrafish. Putative velocity-to-position oculomotor integrator neurons were identified that showed a broad spatial distribution and diversity of encoding. Optical identification of integrator neurons was confirmed with targeted loose-patch electrical recording and laser ablation. The general regression-based approach we demonstrate should be widely applicable to calcium imaging time series in behaving animals.


Conformational dynamics of DNA polymerase probed with a novel fluorescent DNA base analogue.
DNA polymerases discriminate between correct and incorrect nucleotide substrates during a "nonchemical" step that precedes phosphodiester bond formation in the enzymatic cycle of nucleotide incorporation. Despite the importance of this process in polymerase fidelity, the precise nature of the molecular events involved remains unknown. Here we report a fluorescence resonance energy transfer (FRET) system that monitors conformational changes of a polymerase-DNA complex during selection and binding of nucleotide substrates. This system utilizes the fluorescent base analogue 1,3-diaza-2-oxophenothiazine (tC) as the FRET donor and Alexa-555 (A555) as the acceptor. The tC donor was incorporated within a model DNA primer/template in place of a normal base, adjacent to the primer 3' terminus, while the A555 acceptor was attached to an engineered cysteine residue (C751) located in the fingers subdomain of the Klenow fragment (KF) polymerase. The FRET efficiency increased significantly following binding of a correct nucleotide substrate to the KF-DNA complex, showing that the fingers had closed over the active site. Fluorescence anisotropy titrations utilizing tC as a reporter indicated that the DNA was more tightly bound by the polymerase under these conditions, consistent with the formation of a closed ternary complex. The rate of the nucleotide-induced conformational transition, measured in stopped-flow FRET experiments, closely matched the rate of correct nucleotide incorporation, measured in rapid quench-flow experiments, indicating that the conformational change was the rate-limiting step in the overall cycle of nucleotide incorporation for the labeled KF-DNA system. Taken together, these results indicate that the FRET system can be used to probe enzyme conformational changes that are linked to the biochemical function of DNA polymerase.


Spatiotemporal neural characterization of prediction error valence and surprise during reward learning in humans.
Reward learning depends on accurate reward associations with potential choices. These associations can be attained with reinforcement learning mechanisms using a reward prediction error (RPE) signal (the difference between actual and expected rewards) for updating future reward expectations. Despite an extensive body of literature on the influence of RPE on learning, little has been done to investigate the potentially separate contributions of RPE valence (positive or negative) and surprise (absolute degree of deviation from expectations). Here, we coupled single-trial electroencephalography with simultaneously acquired fMRI, during a probabilistic reversal-learning task, to offer evidence of temporally overlapping but largely distinct spatial representations of RPE valence and surprise. Electrophysiological variability in RPE valence correlated with activity in regions of the human reward network promoting approach or avoidance learning. Electrophysiological variability in RPE surprise correlated primarily with activity in regions of the human attentional network controlling the speed of learning. Crucially, despite the largely separate spatial extend of these representations our EEG-informed fMRI approach uniquely revealed a linear superposition of the two RPE components in a smaller network encompassing visuo-mnemonic and reward areas. Activity in this network was further predictive of stimulus value updating indicating a comparable contribution of both signals to reward learning.


Characterization of severe fever with thrombocytopenia syndrome in rural regions of Zhejiang, China.
Severe fever with thrombocytopenia syndrome virus (SFTSV) infections have recently been found in rural regions of Zhejiang. A severe fever with thrombocytopenia syndrome (SFTS) surveillance and sero-epidemiological investigation was conducted in the districts with outbreaks. During the study period of 2011-2014, a total of 51 SFTSV infection cases were identified and the case fatality rate was 12% (6/51). Ninety two percent of the patients (47/51) were over 50 years of age, and 63% (32/51) of laboratory confirmed cases occurred from May to July. Nine percent (11/120) of the serum samples from local healthy people without symptoms were found to be positive for antibodies to the SFTS virus. SFTSV strains were isolated by culture using Vero, and the whole genomic sequences of two SFTSV strains (01 and Zhao) were sequenced and submitted to the GenBank. Homology analysis showed that the similarity of the target nucleocapsid gene from the SFTSV strains from different geographic areas was 94.2-100%. From the constructed phylogenetic tree, it was found that all the SFTSV strains diverged into two main clusters. Only the SFTSV strains from the Zhejiang (Daishan) region of China and the Yamaguchi, Miyazakj regions of Japan, were clustered into lineage II, consistent with both of these regions being isolated areas with similar geographic features. Two out of eight predicted linear B cell epitopes from the nucleocapsid protein showed mutations between the SFTSV strains of different clusters, but did not contribute to the binding ability of the specific SFTSV antibodies. This study confirmed that SFTSV has been circulating naturally and can cause a seasonal prevalence in Daishan, China. The results also suggest that the molecular characteristics of SFTSV are associated with the geographic region and all SFTSV strains can be divided into two genotypes.


Developmental transcript profiling of cyst nematode feeding cells in soybean roots.
Cyst nematodes of the genus Heterodera are obligate, sedentary endoparasites that have developed highly evolved relationships with specific host plant species. Successful parasitism involves significant physiological and morphological changes to plant root cells for the formation of specialized feeding cells called syncytia. To better understand the molecular mechanisms that lead to the development of nematode feeding cells, transcript profiling was conducted on developing syncytia induced by the soybean cyst nematode Heterodera glycines in soybean roots by coupling laser capture microdissection with high-density oligonucleotide microarray analysis. This approach has identified pathways that may play intrinsic roles in syncytium induction, formation, and function. Our data suggest interplay among phytohormones that likely regulates synchronized changes in the expression of genes encoding cell-wall-modifying proteins. This process appears to be tightly controlled and coordinately regulated with cell wall rigidification processes that may involve lignification of feeding cell walls. Our data also show local downregulation of jasmonic acid biosynthesis and responses in developing syncytia, which suggest a local suppression of plant defense mechanisms. Moreover, we identified genes encoding putative transcription factors and components of signal transduction pathways that may be important in the regulatory processes governing syncytium formation and function. Our analysis provides a broad mechanistic picture that forms the basis for future hypothesis-driven research to understand cyst nematode parasitism and to develop effective management tools against these pathogens.


Perspectives of Young Adults on Receiving Telepsychiatry Services in an Urban Early Intervention Program for First-Episode Psychosis: A Cross-Sectional, Descriptive Survey Study.
Limited knowledge exists on telepsychiatry in specialized services for first-episode psychosis (FEP), despite its potential for improving service access and engagement. To explore access and use of technology, obstacles to attending clinic appointments, and perspectives of young adults with FEP on using telepsychiatry as part of outpatient services. A cross-sectional, descriptive survey study was conducted between July and October 2017 with young adults between the ages of 18 and 38 recruited from a specialized program for FEP in an urban Canadian setting. Data were analysed using descriptive statistics and content analysis. Among 51 participants (mean age = 26.1, SD = 4.2; 59% male; 20% experiencing housing instability), more than half (59%, n = 30) rarely or never used mainstream video chat (e.g., Facetime). The majority (78%, n = 40) reported obstacles to attending appointments, with several (37%, n = 19) identifying two or more. Almost half (49%, n = 25) were very favorable towards telepsychiatry and a quarter (25%, n = 13) were somewhat favorable. Participants expressed several concerns about telepsychiatry, including loss of human contact and confidentiality. To our knowledge, this is a first study on the perspectives of individuals with FEP about telepsychiatry. Despite experiencing obstacles to attending appointments and expressing receptivity towards telepsychiatry, participants did not have access to these services. It is important to provide education to clinicians on the potential of telepsychiatry to improve service access. Also, more research is needed on when, where, and how telepsychiatry can be integrated into existing care while addressing patient and clinician concerns.


Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy.
Epilepsy is defined as the tendency to spontaneous, excessive neuronal discharge, manifesting as seizures. It is a common disorder with an incidence of 50 per 100,000 per year and a prevalence of 0.5% to 1% (Hauser 1993) in the developed world.Carbamazepine is a commonly used antiepileptic drug that is associated with a number of troublesome adverse events including dizziness, double vision and unsteadiness. These often occur during peaks in plasma concentration. The occurrence of such adverse events may limit the daily dose that can be tolerated and reduce the chances of seizure control for patients requiring higher doses (Vojvodic 2002). A controlled-release formulation of carbamazepine delivers the same dose over a longer period of time when compared to a standard formulation, thereby reducing post-dose peaks and potentially reducing adverse events associated with peak plasma levels. To determine the efficacy of immediate-release carbamazepine (IR CBZ) versus controlled-release carbamazepine (CR CBZ) in patients with newly diagnosed epilepsy.To determine the efficacy of switching to CR CBZ in patients treated with IR CBZ but experiencing unacceptable adverse events. We searched the Cochrane Epilepsy Group Specialised Register (25 September 2009), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 4), and MEDLINE (1950 to September week 3, 2009). Randomised controlled trials comparing IR CBZ to CR CBZ in patients commencing monotherapy and patients presently treated with IR CBZ but experiencing unacceptable adverse events.Primary outcome measures include seizure frequency, incidence of adverse events, proportions with treatment failure and quality of life measures. The methodological quality of each study was assessed with respect to study design, type of control, method and concealment of allocation, blinding and completeness of follow up, and the presence of blinding for assessment of non-fatal outcomes. We did not make use of an overall quality score.Two review authors (GP, MS) independently extracted the data and recorded relevant information on a standardised data extraction form. Results were assessed for inclusion.The heterogeneity of the included trials resulted in only a narrative, descriptive analysis being possible for both categorical and time-to-event data. Ten trials fulfilled the criteria for inclusion in this review. One trial included patients with newly diagnosed epilepsy and nine included patients on treatment with IR CBZ.Eight trials reported heterogeneous measures of seizure frequency with conflicting results. A statistically significant difference was observed in only one trial, with patients prescribed CR CBZ experiencing fewer seizures than patients prescribed IR CBZ.Nine trials reported measures of adverse events. There was a trend in favour of CR CBZ with four trials reporting a statistically significant reduction in adverse events compared to IR CBZ. A further two trials reported fewer adverse events with CR CBZ, not statistically significant. One trial found no difference, with a further trial reporting increased adverse events in the CR CBZ although not statistically significant. At present, data from trials do not confirm or refute an advantage for CR CBZ over IR CBZ for seizure frequency or adverse events in patients with newly diagnosed epilepsy.For trials involving epilepsy patients already prescribed IR CBZ, no conclusions can be drawn concerning superiority of CR CBZ with respect to seizure frequency.There is a trend for CR CBZ to be associated with fewer adverse events when compared to IR CBZ. A change to CR CBZ may therefore be a worthwhile strategy in patients with acceptable seizure control on IR CBZ but experiencing unacceptable adverse events. The included trials were of small size, poor methodological quality and possessed a high risk of bias, limiting the validity of this conclusion.Randomised controlled trials comparing CR CBZ to IR CBZ and using clinically relevant outcomes are required to inform the choice of CBZ preparation for patients with newly diagnosed epilepsy.


Pathways to mental well-being for graduates of mindfulness-based cognitive therapy (MBCT) and mindfulness-based stress reduction (MBSR): A mediation analysis of an RCT.
To explore mediated effects of Mindfulness-Based Cognitive Therapy-"Taking it Further" (MBCT-TiF) on mental well-being through changes in mindfulness, self-compassion, and decentering. A secondary analysis of an RCT using simple mediation, with 164 graduates of MBCT and mindfulness-based stress reduction (MBSR), was implemented whereby MBCT-TiF (vs ongoing mindfulness practice; OMP) was the independent variable; changes in mindfulness, self-compassion, and decentering during the intervention were the mediators; and mental well-being at post-intervention, whilst controlling for baseline, was the dependent variable. Secondary outcomes included psychological quality of life, depression, and anxiety. Compared to OMP, MBCT-TiF experienced significant improvements in mental well-being through changes in all three mediators (mindfulness: ab = 0.11 [0.03, 0.25]; decentering: ab = 0.16 [0.05, 0.33]; self-compassion: ab = 0.07 [0.01, 0.18]). A similar pattern was demonstrated for depression, but only mindfulness and decentering mediated effects on psychological quality of life and anxiety. The findings provide preliminary support for all three mediators in driving change in mental well-being in a sample of MBCT/MBSR graduates. Future work must be theory-driven and powered to test all mediators in parallel and alongside other potential mediators (e.g., equanimity) to further understand independent contributions and interacting effects.Trial registration: ClinicalTrials.gov identifier: NCT05154266.


The politics of medical inflation.
This paper discusses the politics of anti-inflationary policy in the medical care sector. We first clarify the issue by distinguishing between four different conceptions commonly used when discussing medical inflation. We then present some of the standard solutions to these problems suggested by economists. In the main part of the paper, we analyze the response of the government. We show that the underlying causes for failure in the economic market are likely to exist in the political market as well. In particular, the public good aspect of anti-inflationary policy fails to provide a strong incentive for the consumers of medical care. In contrast, the providers have very powerful incentives in the political market because the benefits of governmental action in this sector greatly affect them. Providers exert great pressure to prevent government policies aimed at reducing medical care expenditures. We present evidence and theory to explicate which sets of circumstances are most conducive to governmental action. We show that the most effective anti-inflationary programs in medical financing are least likely to be implemented and that a dispersed, pluralistic financing structure reduces the government's incentive to curb inflation.


A compositionally heterogeneous martian mantle due to late accretion.
The approximately chondritic estimated relative abundances of highly siderophile elements (HSE) in the bulk martian mantle suggest that these elements were added after Mars' core formed. The shergottite-nakhlite-chassigny (SNC) meteorites imply an average mantle Pt abundance of ≈3 to 5 parts per billion, which requires the addition of 1.6 × 1021 kilograms of chondritic material, or 0.25% martian masses, to the silicate Mars. Here, we present smoothed particle hydro-dynamics impact simulations that show that Mars' HSE abundances imply one to three late collisions by large differentiated projectiles. We show that these collisions would produce a compositionally heterogeneous martian mantle. Based mainly on W isotopes, it has been argued that Mars grew rapidly in only about 2 to 4 million years (Ma). However, we find that impact generation of mantle domains with variably fractionated Hf/W and diverse 182W could imply a Mars formation time scale up to 15 Ma.


Past, present and future of spike sorting techniques.
Spike sorting is a crucial step to extract information from extracellular recordings. With new recording opportunities provided by the development of new electrodes that allow monitoring hundreds of neurons simultaneously, the scenario for the new generation of algorithms is both exciting and challenging. However, this will require a new approach to the problem and the development of a common reference framework to quickly assess the performance of new algorithms. In this work, we review the basic concepts of spike sorting, including the requirements for different applications, together with the problems faced by presently available algorithms. We conclude by proposing a roadmap stressing the crucial points to be addressed to support the neuroscientific research of the near future.


Anti-TNF therapy: past, present and future.
While for a century therapeutics has been dominated by small molecules, i.e. organic chemicals of ~400Da absorbable via the gut, this is no longer the case. There are now a plethora of important medicines which are proteins and injectable, which have dramatically improved the therapy of many inflammatory diseases and of cancer. Most of these are monoclonal antibodies, some are receptor Ig Fc fusion proteins, others are cytokines or enzymes. The key to this new aspect of therapeutics has been the filling of unmet needs, and the consequent commercial success, which promoted further research and development. The first 'biologic' for a common disease, rheumatoid arthritis (RA), was a monoclonal antibody, infliximab, to human tumour necrosis factor (TNF). This was based on our work, which is described in this review, summarizing how TNF was defined as a good target in RA, how it was developed is described here, as well as future indications for anti-TNF and related agents. Biologics are now the fastest growing sector of therapeutics.


The direct cooling of the preoptic-hypothalamic area elicits the release of thyroid stimulating hormone during wakefulness but not during REM sleep.
Thermoregulatory responses to temperature changes are not operant during REM sleep (REMS), but fully operant in non-REM sleep and wakefulness. The specificity of the relationship between REMS and the impairment of thermoregulation was tested by eliciting the reflex release of Thyrotropin Releasing Hormone (TRH), which is integrated at hypothalamic level. By inducing the sequential secretion of Thyroid Stimulating Hormone (TSH) and Thyroid Hormone, TRH intervenes in the regulation of obligatory and non-shivering thermogenesis. Experiments were performed on male albino rats implanted with epidural electrodes for EEG recording and 2 silver-copper wire thermodes, bilaterally placed in the preoptic-hypothalamic area (POA) and connected to small thermoelectric heat pumps driven by a low-voltage high current DC power supply. In preliminary experiments, a thermistor was added in order to measure hypothalamic temperature. The activation of TRH hypophysiotropic neurons by the thermode cooling of POA was indirectly assessed, in conditions in which thermoregulation was either fully operant (wakefulness) or not operant (REMS), by a radioimmunoassay determination of plasmatic levels of TSH. Different POA cooling were performed for 120 s or 40 s at current intensities of 80 mA and 125 mA, respectively. At both current intensities, POA cooling elicited, with respect to control values (no cooling current), a significant increase in plasmatic TSH levels in wakefulness, but not during REMS. These results confirm the inactivation of POA thermal sensitivity during REMS and show, for the first time, that this inactivation concerns also the fundamental endocrine control of non-shivering thermogenesis.


Cytochrome c Biogenesis.
Escherichia coli employs several c-type cytochromes, which are found in the periplasm or on the periplasmic side of the cytoplasmic membrane; they are used for respiration under different growth conditions. All E. colic-type cytochromes are multiheme cytochromes; E. coli does not have a monoheme cytochrome c of the kind found in mitochondria. The attachment of heme to cytochromes c occurs in the periplasm, and so the apoprotein must be transported across the cytoplasmic membrane; this step is mediated by the Sec system, which transports unfolded proteins across the membrane. The protein CcmE has been found to bind heme covalently via a single bond and then transfer the heme to apocytochromes. It should be mentioned that far less complex systems for cytochrome c biogenesis exist in other organisms and that enterobacteria do not function as a representative model system for the process in general, although plant mitochondria use the Ccm system found in E. coli. The variety and distribution of cytochromes and their biogenesis systems reflect their significance and centrality in cellular bioenergetics, though the necessity for and origin of the diverse biogenesis systems are enigmatic.


The role of transient spectral 'bursts' in functional connectivity: A magnetoencephalography study.
Neural oscillations dominate electrophysiological measures of macroscopic brain activity and fluctuations in these rhythms offer an insightful window on cortical excitation, inhibition, and connectivity. However, in recent years the 'classical' picture of smoothly varying oscillations has been challenged by the idea that many 'oscillations' may actually be formed from the recurrence of punctate high-amplitude bursts in activity, whose spectral composition intersects the traditionally defined frequency ranges (e.g. alpha/beta band). This finding offers a new interpretation of measurable brain activity, however neither the methodological means to detect bursts, nor their link to other findings (e.g. connectivity) have been settled. Here, we use a new approach to detect bursts in magnetoencephalography (MEG) data. We show that a time-delay embedded Hidden Markov Model (HMM) can be used to delineate single-region bursts which are in agreement with existing techniques. However, unlike existing techniques, the HMM looks for specific spectral patterns in timecourse data. We characterise the distribution of burst duration, frequency of occurrence and amplitude across the cortex in resting state MEG data. During a motor task we show how the movement related beta decrease and post movement beta rebound are driven by changes in burst occurrence. Finally, we show that the beta band functional connectome can be derived using a simple measure of burst overlap, and that coincident bursts in separate regions correspond to a period of heightened coherence. In summary, this paper offers a new methodology for burst identification and connectivity analysis which will be important for future investigations of neural oscillations.


An Application-Directed, Versatile DNA FISH Platform for Research and Diagnostics.
DNA fluorescence in situ hybridization (DNA FISH) has emerged as a powerful microscopy technique that allows a unique view into the composition and arrangement of the genetic material in its natural context-be it the cell nucleus in interphase, or chromosomes in metaphase spreads. The core principle of DNA FISH is the ability of fluorescently labeled DNA probes (either double- or single-stranded DNA fragments) to bind to their complementary sequences in situ in cells or tissues, revealing the location of their target as fluorescence signals detectable with a fluorescence microscope. Numerous variants and improvements of the original DNA FISH method as well as a vast repertoire of applications have been described since its inception more than 4 decades ago. In recent years, the development of many new fluorescent dyes together with drastic advancements in methods for probe generation (Boyle et al., Chromosome Res 19:901-909, 2011; Beliveau et al., Proc Natl Acad Sci U S A 109:21301-21306, 2012; Bienko et al., Nat Methods 10:122-124, 2012), as well as improvements in the resolution of microscopy technologies, have boosted the number of DNA FISH applications, particularly in the field of genome architecture (Markaki et al., Bioessays 34:412-426, 2012; Beliveau et al., Nat Commun 6:7147, 2015). However, despite these remarkable steps forward, choosing which type of DNA FISH sample preparation protocol, probe design, hybridization procedure, and detection method is best suited for a given application remains still challenging for many research labs, preventing a more widespread use of this powerful technology. Here, we present a comprehensive platform to help researchers choose which DNA FISH protocol is most suitable for their particular application. In addition, we describe computational pipelines that can be implemented for efficient DNA FISH probe design and for signal quantification. Our goal is to make DNA FISH a versatile and streamlined technique that can be easily implemented by both research and diagnostic labs.


Gradually Disengaging: Parent-Health care Provider Relationships After a Child's Death in the Pediatric Intensive Care Unit.
When a child dies in the intensive care unit, many bereaved parents want relationships with their child's health care staff to continue in the form of follow-up care. However, the nature of these relationships and how they change across the parents' bereavement journey is currently unknown. This article explores early and ongoing relationships between parents and health care staff when a child dies in intensive care. Constructivist grounded theory methods were used to recruit 26 bereaved parents from four Australian pediatric intensive care units into the study. Data were collected via audio-recorded, semistructured interviews and analyzed using the constant comparative methods and theoretical memoing. Findings show that these relationships focus on Gradually disengaging, commonly moving through three phases after the child dies: Saying goodbye, Going home, and Seeking supports. These findings provide guidance to health care staff on what families need as they leave the intensive care unit and move through bereavement.


Evaluation of the feasibility and performance of early warning scores to identify patients at risk of adverse outcomes in a low-middle income country setting.
This study describes the availability of core parameters for Early Warning Scores (EWS), evaluates the ability of selected EWS to identify patients at risk of death or other adverse outcome and describes the burden of triggering that front-line staff would experience if implemented. Longitudinal observational cohort study. District General Hospital Monaragala. All adult (age >17 years) admitted patients. Existing physiological parameters, adverse outcomes and survival status at hospital discharge were extracted daily from existing paper records for all patients over an 8-month period. Discrimination for selected aggregate weighted track and trigger systems (AWTTS) was assessed by the area under the receiver operating characteristic (AUROC) curve.Performance of EWS are further evaluated at time points during admission and across diagnostic groups. The burden of trigger to correctly identify patients who died was evaluated using positive predictive value (PPV). Of the 16 386 patients included, 502 (3.06%) had one or more adverse outcomes (cardiac arrests, unplanned intensive care unit admissions and transfers). Availability of physiological parameters on admission ranged from 90.97% (95% CI 90.52% to 91.40%) for heart rate to 23.94% (95% CI 23.29% to 24.60%) for oxygen saturation. Ability to discriminate death on admission was less than 0.81 (AUROC) for all selected EWS. Performance of the best performing of the EWS varied depending on admission diagnosis, and was diminished at 24 hours prior to event. PPV was low (10.44%). There is limited observation reporting in this setting. Indiscriminate application of EWS to all patients admitted to wards in this setting may result in an unnecessary burden of monitoring and may detract from clinician care of sicker patients. Physiological parameters in combination with diagnosis may have a place when applied on admission to help identify patients for whom increased vital sign monitoring may not be beneficial. Further research is required to understand the priorities and cues that influence monitoring of ward patients. NCT02523456.


Decomposing unpleasantness: differential exogenous attention to disgusting and fearful stimuli.
Negative stimuli have consistently been shown to efficiently attract exogenous attention. Two different types of unpleasant stimuli, disgusting and fearful, sharing similar arousal and valence, are usually employed as a single category. However, since they diverge in several important aspects (biological functionality, associated feelings, and central and peripheral physiological correlates), it may be expected that their potential to capture attention differs. Event-related potentials and behavioral indices were recorded while participants were engaged in a digit categorization task in response to three types of irrelevant, distracting pictures: disgusting, fearful and neutral. Disgusting trials were associated with worse performance than fearful trials in the digit categorization task as revealed by reaction times and number of errors. Moreover, P2-associated cuneus activation and scalp anterior P2 amplitude were greater for disgusting than for fearful distracters. All these indices reveal that, under the experimental conditions employed in the present study, disgusting distracters are more efficient at attracting exogenous attention than are fearful distracters.


Transformation of 2D Planes into 3D Soft and Flexible Structures with Embedded Electrical Functionality.
Three-dimensional (3D) structures composed of flexible and soft materials have been in demand for implantable biomedical devices. However, the fabrication of 3D structures using microelectromechanical system (MEMS) techniques has limitations in terms of the materials and the scale of the structures. Here, a technique to selectively bond polydimethylsiloxane (PDMS) and parylene-C by plasma treatment is reported, with which two-dimensional structures that are fabricated using MEMS techniques are turned into 3D structures by the inflation of selectively non-bonded patterns. The bonding strength and the bonding mechanism were analyzed by mechanical tests and chemical analyses, respectively. We fabricated soft and flexible 3D structures with various patterns and dimensions, even with embedded electrical functions, including light emitting diodes and electrocorticogram electrodes. Based on these results, the flexible, soft, and MEMS-capable 3D structures that are obtained by the developed selective bonding technique are promising for applications in a wide range of biomedical applications.


Ataxia-telangiectasia gene (ATM) mutation heterozygosity in breast cancer: a narrative review.
Despite the fact that heterozygosity for a pathogenic ATM variant is present in 1%-2% of the adult population, clinical guidelines to inform physicians and genetic counsellors about optimal management in that population are lacking. In this narrative review, we describe the challenges and controversies in the management of women who are heterozygous for a pathogenic ATM variant with respect to screening for breast and other malignancies, to choices for systemic therapy, and to decisions about radiation therapy. Given that the lifetime risk for breast cancer in women who are heterozygous for a pathogenic ATM variant is likely greater than 25%, those women should undergo annual mammographic screening starting at least by 40 years of age. For women in this group who have a strong family history of breast cancer, earlier screening with both magnetic resonance imaging and mammography should be considered. High-quality data to inform the management of established breast cancer in carriers of pathogenic ATM variants are lacking. Although deficiency in the ATM gene product might confer sensitivity to dna-damaging pharmaceuticals such as inhibitors of poly (adp-ribose) polymerase or platinum agents, prospective clinical trials have not been conducted in the relevant patient population. Furthermore, the evidence with respect to radiation therapy is mixed; some data suggest increased toxicity, and other data suggest improved clinical benefit from radiation in women who are carriers of a pathogenic ATM variant. As in the 2017 U.S. National Comprehensive Cancer Network guidelines, we recommend high-risk imaging for women in Ontario who are heterozygous for a pathogenic ATM variant. Currently, ATM carrier status should not influence decisions about systemic or radiation therapy in the setting of an established breast cancer diagnosis.


FAT1 mutations cause a glomerulotubular nephropathy.
Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.


Circulating tocopherols and risk of coronary artery disease: A systematic review and meta-analysis.
Circulating level of tocopherols was supposed to be associated with risk of coronary artery disease. However, the results from previous studies remain controversial. Therefore, we conducted a meta-analysis based on observational studies to evaluate the association between circulating tocopherols and coronary artery disease risk for the first time. Meta-analysis. PubMed, Embase and Cochrane databases were searched to retrieve articles published during January 1995 and May 2015. Articles were included if they provided sufficient information to calculate the weighted mean difference and its corresponding 95% confidence interval. Circulating level of total tocopherols was significantly lower in coronary artery disease patients than that in controls (weighted mean difference -4.33 μmol/l, 95% confidence interval -6.74 to -1.91, P < 0.01). However, circulating α-tocopherol alone was not significantly associated with coronary artery disease risk. Results from subgroup analyses showed that a lower level of circulating total tocopherols was merely associated with higher coronary artery disease risk in studies with higher sex ratio in cases (<2, weighted mean difference -0.07 μmol/l, 95% confidence interval -1.15 to 1.00, P = 0.90; ≥ 2, weighted mean difference -6.00 μmol/l, 95% confidence interval -9.76 to -2.22, P < 0.01). Similarly, a lower level of circulating total tocopherols was associated with early onset coronary artery disease rather than late onset coronary artery disease (<60 years, weighted mean difference -5.40 μmol/l, 95% confidence interval -9.22 to -1.57, P < 0.01; ≥ 60 years, weighted mean difference -1.37 μmol/l, 95% confidence interval -3.48 to 0.74, P = 0.20). We also found some discrepancies in circulating total tocopherols when the studies were stratified by matching status and assay methods. Our findings suggest that a deficiency in circulating total tocopherols might be associated with higher coronary artery disease risk. Whereas circulating α-tocopherol alone could not protect us from developing coronary artery disease. Further prospective studies were warranted to confirm our findings.


Will buffer zones around schools in agricultural areas be adequate to protect children from the potential adverse effects of pesticide exposure?
California has proposed limiting agricultural pesticide use within 0.4 km of schools and childcare facilities. However, the 0.4-km buffer may not be appropriate for all pesticides because of differing toxicities, fate, and application methods. Living near pesticide use has been associated with poorer birth outcomes, neurodevelopment, and respiratory function in children. More research about exposures in schools, childcare facilities, and homes is needed. Despite incomplete science, this regulation is an important step to reduce potential exposures to children. The most vulnerable exposure period may be in utero, and future regulations should also aim to reduce exposures to pregnant women.


The effect of including a conventional snack (cereal bar) and a nonconventional snack (almonds) on hunger, eating frequency, dietary intake and body weight.
With the increasing prevalence of being overweight and obesity, dietary strategies to curb hunger levels and increase satiety at lower energy intakes are sought. The frequency of eating and type of snack may influence total energy intake. The present study aimed to assess the impact of providing either a conventional snack (cereal bar) or a nonconventional snack (almonds) on eating frequency, hunger rating, dietary intake, body weight and blood lipids. Forty-five healthy men (aged 25-50 years, body mass index = 25-35 kg m(-2)) were recruited and allocated to a control, cereal bar or almond snack group. Two packets of cereal bars and almonds were introduced for 12 weeks to the cereal bar group and the almond snack group, respectively. Dietary intakes and eating frequency were assessed by 4-day unweighed diet diaries; visual analogue scales were used to assess hunger ratings; and fasting blood parameters (i.e. glucose, insulin, total cholesterol, triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol) were measured at baseline, 6 and 12 weeks. In addition, anthropometric measures (height, weight, skinfold thickness, waist and hip circumference) were measured at baseline, 6 and 12 weeks. The present study found no significant change in the eating frequency within groups at 12 weeks. However, the almond snack group had a significantly higher eating frequency than the control group (P < or = 0.05) and cereal bar group (P < or = 0.01). This did not result in higher energy intake, body weight or percentage body fat in the almond snack group. The present study demonstrated that snacking on almonds, in comparison to cereal bars, promoted a higher eating frequency, but not a higher energy intake. Advice to snack on either almonds or cereal bars did not result in weight gain, suggesting that energy compensation took place.


Characterization using FLIPR of rat vanilloid receptor (rVR1) pharmacology.
The vanilloid receptor (VR1) is a ligand-gated ion channel, which plays an important role in nociceptive processing. Therefore, a pharmacological characterization of the recently cloned rat VR1 (rVR1) was undertaken. HEK293 cells stable expressing rVR1 (rVR1-HEK293) were loaded with Fluo-3AM and then incubated at 25 degrees C for 30 min with or without various antagonists or signal transduction modifying agents. Then intracellular calcium concentrations ([Ca(2+)](i)) were monitored using FLIPR, before and after the addition of various agonists. The rank order of potency of agonists (resiniferatoxin (RTX)>capsaicin>olvanil>PPAHV) was as expected, and all were full agonists. The potencies of capsaicin and olvanil, but not RTX or PPAHV, were enhanced at pH 6.4 (pEC(50) values of 7.47+/-0.06, 7.16+/-0.06, 8.19+/-0.06 and 6.02+/-0.03 respectively at pH 7.4 vs 7.71+/-0.05, 7.58+/-0.14, 8.10+/-0.05 and 6.04+/-0.08 at pH 6.4). Capsazepine, isovelleral and ruthenium red all inhibited the capsaicin (100 nM)-induced Ca(2+) response in rVR1-HEK293 cells, with pK(B) values of 7.52+/-0.08, 6.92+/-0.11 and 8.09+/-0.12 respectively (n=6 each). The response to RTX and olvanil were also inhibited by these compounds. None displayed any agonist-like activity. The removal of extracellular Ca(2+) abolished, whilst inhibition of protein kinase C with chelerythrine chloride (10 microM) partially (approximately 20%) inhibited, the capsaicin (10 microM)-induced Ca(2+) response. However, tetrodotoxin (3 microM), nimodipine (10 microM), omega-GVIA conotoxin (1 microM), thapsigargin (1 microM), U73122 (3 microM) or H-89 (3 microM) had no effect on the capsaicin (100 nM)-induced response. In conclusion, the recombinant rVR1 stably expressed in HEK293 cells acts as a ligand-gated Ca(2+) channel with the appropriate agonist and antagonist pharmacology, and therefore is a suitable model for studying the effects of drugs at this receptor.


Basic principles of drug--excipients interactions.
Excipients are generally considered inert additives included in drug formulation to help in the manufacturing, administration or absorption. Other reasons for inclusion concern product differentiation, appearance enhancement or retention of quality. Excipients can initiate, propagate or participate in chemical or physical interactions with an active substance, possibly leading to compromised quality or performance of the medication. Understanding the chemical and physical nature of excipients, the impurities or residues associated with them and how they may interact with other materials, or with each other, forewarns the pharmaceutical technologist of possibilities for undesirable developments.


ZIF-8@ZIF-67-Derived Nitrogen-Doped Porous Carbon Confined CoP Polyhedron Targeting Superior Potassium-Ion Storage.
Potassium ion batteries (KIB) have become a compelling energy-storage system owing to their cost effectiveness and the high abundance of potassium in comparison with lithium. However, its practical applications have been thwarted by a series of challenges, including marked volume expansion and sluggish reaction kinetics caused by the large radius of potassium ions. In line with this, the exploration of reliable anode materials affording high electrical conductivity, sufficient active sites, and structural robustness is the key. The synthesis of ZIF-8@ZIF-67 derived nitrogen-doped porous carbon confined CoP polyhedron architectures (NC@CoP/NC) to function as innovative KIB anode materials is reported. Such composites enable an outstanding rate performance to harvest a capacity of ≈200 mAh g-1 at 2000 mA g-1 . Additionally, a high cycling stability can be gained by maintaining a high capacity retention of 93% after 100 cycles at 100 mA g-1 . Furthermore, the potassium ion storage mechanism of the NC@CoP/NC anode is systematically probed through theoretical simulations and experimental characterization. This contribution may offer an innovative and feasible route of emerging anode design toward high performance KIBs.


Iron deficiency from the standpoint of cardiac rehabilitation: novel therapeutic opportunities.
Anemia is one of the most frequent comorbidities found in patients with coronary artery disease and chronic heart failure (CHF) who are being followed in cardiac rehabilitation facilities. The more frequent type of anemia is caused by iron deficiency (IDA, iron-deficiency anemia): this review summarizes the state of the art of this topic. First of all, the mechanisms of IDA will be analyzed. Subsequently, a description of the main conditions where IDA can unfavorably affect the clinical course, and of its more frequent complications, will be presented (percutaneous interventions, heart surgery, CHF). Special attention will be paid in the description of anemia in the setting of CHF. To this regard, in recent years a relevant amount of research has been carried out, to determine whether treating anemia (either by directly stimulating erythropoiesis or by correcting iron deficiency by oral or intravenous route) is of any clinical and prognostic relevance in patients with CHF. The results of this research will, therefore, be summarized and critically discussed. Finally, we will outline the promising role of cardiac rehabilitation facilities and of its network of experts in the diagnosis, prognostic stratification, and treatment of anemia and iron deficiency.


The Economics of Taxes on Sugar-Sweetened Beverages: A Review of the Effects on Prices, Sales, Cross-Border Shopping, and Consumption.
During the past decade, dozens of countries, regions, and cities have enacted taxes on sugar-sweetened beverages (SSBs). They have been primarily motivated by a desire to raise prices, reduce sales and consumption, improve population health, and raise revenue. This review outlines the economic rationale for SSB taxes and illustrates their predicted effects. It reviews the research on the effects of these taxes on retail prices, sales, cross-border shopping, consumption, and product availability. The evidence indicates that the amount by which taxes increase retail prices (also called the pass-through of the tax) varies by jurisdiction, ranging from less than 50% to 100% of the tax. Sales tend to decrease significantly in the taxing jurisdiction, although this seems to be partly offset by residents increasingly shopping outside of the taxing jurisdiction (i.e., engaging in cross-border shopping).Overall, taxes lower consumption of the taxed beverages by adults, although not for all types of beverages or all groups of consumers. We conclude with suggestions for improving the design of such taxes and directions for future research.


Ancestral sequence alignment under optimal conditions.
Multiple genome alignment is an important problem in bioinformatics. An important subproblem used by many multiple alignment approaches is that of aligning two multiple alignments. Many popular alignment algorithms for DNA use the sum-of-pairs heuristic, where the score of a multiple alignment is the sum of its induced pairwise alignment scores. However, the biological meaning of the sum-of-pairs of pairs heuristic is not obvious. Additionally, many algorithms based on the sum-of-pairs heuristic are complicated and slow, compared to pairwise alignment algorithms. An alternative approach to aligning alignments is to first infer ancestral sequences for each alignment, and then align the two ancestral sequences. In addition to being fast, this method has a clear biological basis that takes into account the evolution implied by an underlying phylogenetic tree. In this study we explore the accuracy of aligning alignments by ancestral sequence alignment. We examine the use of both maximum likelihood and parsimony to infer ancestral sequences. Additionally, we investigate the effect on accuracy of allowing ambiguity in our ancestral sequences. We use synthetic sequence data that we generate by simulating evolution on a phylogenetic tree. We use two different types of phylogenetic trees: trees with a period of rapid growth followed by a period of slow growth, and trees with a period of slow growth followed by a period of rapid growth. We examine the alignment accuracy of four ancestral sequence reconstruction and alignment methods: parsimony, maximum likelihood, ambiguous parsimony, and ambiguous maximum likelihood. Additionally, we compare against the alignment accuracy of two sum-of-pairs algorithms: ClustalW and the heuristic of Ma, Zhang, and Wang. We find that allowing ambiguity in ancestral sequences does not lead to better multiple alignments. Regardless of whether we use parsimony or maximum likelihood, the success of aligning ancestral sequences containing ambiguity is very sensitive to the choice of gap open cost. Surprisingly, we find that using maximum likelihood to infer ancestral sequences results in less accurate alignments than when using parsimony to infer ancestral sequences. Finally, we find that the sum-of-pairs methods produce better alignments than all of the ancestral alignment methods.


Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector.
The identification of monogenic and complex genes responsible for neurological disorders requires new approaches for delivering therapeutic protein genes to significant numbers of cells in the central nervous system. A lentivirus-based vector capable of infecting dividing and quiescent cells was investigated in vivo by injecting highly concentrated viral vector stock into the striatum and hippocampus of adult rats. Control brains were injected with a Moloney murine leukemia virus, adenovirus, or adeno-associated virus vector. The volumes of the areas containing transduced cells and the transduced-cell densities were stereologically determined to provide a basis for comparison among different viral vectors and variants of the viral vector stocks. The efficiency of infection by the lentivirus vector was improved by deoxynucleoside triphosphate pretreatment of the vector and was reduced following mutation of integrase and the Vpr-matrix protein complex involved in the nuclear translocation of the preintegration complex. The lentivirus vector system was able to efficiently and stably infect quiescent cells in the primary injection site with transgene expression for over 6 months. Triple labeling showed that 88.7% of striatal cells transduced by the lentivirus vector were terminally differentiated neurons.


Explaining temporal trends in annualised relapse rates in placebo groups of randomised controlled trials in relapsing multiple sclerosis: systematic review and meta-regression.
Recent studies have shown a decrease in annualised relapse rates (ARRs) in placebo groups of randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS). We conducted a systematic literature search of RCTs in RMS. Data on eligibility criteria and baseline characteristics were extracted and tested for significant trends over time. A meta-regression was conducted to estimate their contribution to the decrease of trial ARRs over time. We identified 56 studies. Patient age at baseline (p < 0.001), mean duration of multiple sclerosis (MS) at baseline (p = 0.048), size of treatment groups (p = 0.003), Oxford Quality Scale scores (p = 0.021), and the number of eligibility criteria (p<0.001) increased significantly, whereas pre-trial ARR (p = 0.001), the time span over which pre-trial ARR was calculated (p < 0.001), and the duration of placebo-controlled follow-up (p = 0.006) decreased significantly over time. In meta-regression of trial placebo ARR, the temporal trend was found to be insignificant, with major factors explaining the variation: pre-trial ARR, the number of years used to calculate pre-trial ARR and study duration. The observed decline in trial ARRs may result from decreasing pre-trial ARRs and a shorter time period over which pre-trial ARRs were calculated. Increasing patient age and duration of illness may also contribute.


The use of stem cells for pancreatic regeneration in diabetes mellitus.
The endocrine pancreas represents an interesting arena for regenerative medicine and cell therapeutics. One of the major pancreatic diseases, diabetes mellitus is a metabolic disorder caused by having an insufficient number of insulin-producing β cells. Replenishment of β cells by cell transplantation can restore normal metabolic control. The shortage in donor pancreata has meant that the demand for transplantable β cells has outstripped the supply, which could be met by using alternative sources of stem cells. This situation has opened up new areas of research, such as cellular reprogramming and in vivo β-cell regeneration. Pluripotent stem cells seem to be the best option for clinical applications of β-cell regeneration in the near future, as these cells have been demonstrated to represent an unlimited source of functional β cells. Although compelling evidence shows that the adult pancreas retains regenerative capacity, it remains unclear whether this organ contains stem cells. Alternatively, specialized cell types within or outside the pancreas retain plasticity in proliferation and differentiation. Cellular reprogramming or transdifferentiation of exocrine cells or other types of endocrine cells in the pancreas could provide a long-term solution.


Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT).
To evaluate the efficacy of ginkgo biloba, acetazolamide, and their combination as prophylaxis against acute mountain sickness. Prospective, double blind, randomised, placebo controlled trial. Approach to Mount Everest base camp in the Nepal Himalayas at 4280 m or 4358 m and study end point at 4928 m during October and November 2002. 614 healthy western trekkers (487 completed the trial) assigned to receive ginkgo, acetazolamide, combined acetazolamide and ginkgo, or placebo, initially taking at least three or four doses before continued ascent. Incidence measured by Lake Louise acute mountain sickness score > or = 3 with headache and one other symptom. Secondary outcome measures included blood oxygen content, severity of syndrome (Lake Louise scores > or = 5), incidence of headache, and severity of headache. Ginkgo was not significantly different from placebo for any outcome; however participants in the acetazolamide group showed significant levels of protection. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide (odds ratio 3.76, 95% confidence interval 1.91 to 7.39, number needed to treat 4), 35% for ginkgo (0.95, 0.56 to 1.62), and 14% for combined ginkgo and acetazolamide (3.04, 1.62 to 5.69). The proportion of patients with increased severity of acute mountain sickness was 18% for placebo, 3% for acetazoalmide (6.46, 2.15 to 19.40, number needed to treat 7), 18% for ginkgo (1, 0.52 to 1.90), and 7% for combined ginkgo and acetazolamide (2.95, 1.30 to 6.70). When compared with placebo, ginkgo is not effective at preventing acute mountain sickness. Acetazolamide 250 mg twice daily afforded robust protection against symptoms of acute mountain sickness.


Free-energy relationships for the interactions of tryptophan with phosphocholines.
In membrane proteins and peptides, tryptophan exhibits a marked tendency to occur in locations that correspond to the interfacial region of the lipid bilayer. The relative contributions of electrostatic, dipolar, hydrophobic and conformational effects on the interactions of tryptophan with lipids have been the subject of much speculation. In order to elucidate the fundamental properties of tryptophan-phosphocholine interactions in the absence of competing factors such as protein conformation and membrane perturbation, we have determined the binding characteristics of a homologous series of tryptophan analogues to 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) in deuterochloroform using NMR titrimetric approaches. The data are analysed using a binding model that includes lipid aggregation and the explicit association of water with the lipid. For a series of substituents (OMe, Me, H, F, Cl, Br, I, NO(2)) at the 5-position of the indole ring, the trends in the free energy of association for the formation of 1 : 1 and 1 : 2 lipid-tryptophan adducts both follow an inverted- relationship as a function of the corresponding para-Hammett parameter, with tryptophan (R = H) exhibiting the weakest binding. These trends are shown to be consistent with participation of the indole side chain in both hydrogen bonds and cation-pi interactions. Molecular dynamics simulations of tryptophan and DMPC in an explicit chloroform solvent model demonstrate that for the formation of lipid-tryptophan adducts, binding is driven predominantly by carbonyl-cation and cation-pi interactions with the choline ammonium group, alongside hydrogen bonding interactions with the lipid phosphate. Some of these interactions operate co-operatively, which may account for the observed trends in free energy.


Network resonance can be generated independently at distinct levels of neuronal organization.
Resonance is defined as maximal response of a system to periodic inputs in a limited frequency band. Resonance may serve to optimize inter-neuronal communication, and has been observed at multiple levels of neuronal organization. However, it is unknown how neuronal resonance observed at the network level is generated and how network resonance depends on the properties of the network building blocks. Here, we first develop a metric for quantifying spike timing resonance in the presence of background noise, extending the notion of spiking resonance for in vivo experiments. Using conductance-based models, we find that network resonance can be inherited from resonances at other levels of organization, or be intrinsically generated by combining mechanisms across distinct levels. Resonance of membrane potential fluctuations, postsynaptic potentials, and single neuron spiking can each be generated independently of resonance at any other level and be propagated to the network level. At all levels of organization, interactions between processes that give rise to low- and high-pass filters generate the observed resonance. Intrinsic network resonance can be generated by the combination of filters belonging to different levels of organization. Inhibition-induced network resonance can emerge by inheritance from resonance of membrane potential fluctuations, and be sharpened by presynaptic high-pass filtering. Our results demonstrate a multiplicity of qualitatively different mechanisms that can generate resonance in neuronal systems, and provide analysis tools and a conceptual framework for the mechanistic investigation of network resonance in terms of circuit components, across levels of neuronal organization.