Hemi body irradiation: An economical way of palliation of pain in bone metastasis in advanced cancer.
The primary aim of this prospective non-randomized study was to evaluate the effect of hemi-body irradiation (HBI) on pain and quality of life in cancer patients with extensive bone metastases. The secondary aim was to evaluate side-effects and cost-effectiveness of the treatment. Between March 2008 and December 2010, a total of 23 (male = 14, female = 9, median age = 60 years) diagnosed cases of metastatic cancer patients (prostate = 11, breast = 6, and lung = 6) received HBI, which was delivered as lower (n = 7) (dose = 8 Gy), upper (n = 8) (dose = 6 Gy), or sequential HBI (n = 8) with a Telecobalt unit (Theratron 780C). Among them, one lung cancer patient died at 2 months and one prostate cancer patient defaulted after the second follow-up. Thus, 21 patients (male = 13, female = 8, median age = 65 years) (prostatic cancer = 10, breast cancer = 6, and lung cancer = 5) were followed up for a minimum of 6 months. Evaluations were performed before and at 2, 4, 8, 16, and 24 weeks after treatment. Pain evaluation was done by Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), Percentage of Pain Relief (PRR), and Global Pain Score (GPS). Toxicity was assessed by CTC v-3 toxicity scores in the medical record. Assessment of oral morphine consumption was done before and after radiation using paired t-test, and correlation analysis was also done with decrease of morphine consumption and reduction of pain score using statistical analysis. Response (control of pain) was partial (PR) in 67% and complete (CR) in 22% of patients. For most patients, the pain control lasted throughout the follow-up period (6 months). From 66.66% patients requiring 13 or more Morphine (10 mg) tablets per day prior to HBI, none of the patients required to consume 13 or more Morphine (10 mg) tablets per day following HBI, which was correlated with significant reduction in various pain scores (P < 0.05). One way ANOVA with Dunnett's Multiple Comparison Test (P < 0.05) was significant in VAS score changes, VRS score changes, PPR score changes, and GPS score changes. Along with the decrease in morphine tablets, the Linear Correlation of various scales for pain reduction like VAS, VRS, PPR, and GPS were significant. As such, the quality of life was better due to decreased pain and also, a decrease in the dose of analgesics. Grade 1 and 2 hematological toxicity and grade 1 diarrhea were observed as common side-effects. The average total cost of treatment including hospital stay, medicines, and radiation charges was around INR 400.00. This study shows that hemibody irradiation is not only an effective modality for palliation of severe bone pain in advanced cancer cases but also economical, involves short hospital stay, with acceptable side-effects, utilizes the simple Telecobalt machine, and is less cumbersome in comparison to other currently available pain palliation methods like oral morphine and radiopharmaceuticals.


Athletes who train on unstable compared to stable surfaces exhibit unique postural control strategies in response to balance perturbations.
Athletes have been shown to exhibit better balance compared to non-athletes (NON). However, few studies have investigated how the surface on which athletes train affects the strategies adopted to maintain balance. Two distinct athlete groups who experience different types of sport-specific balance training are stable surface athletes (SSA) such as basketball players and those who train on unstable surfaces (USA) such as surfers. The purpose of this study was to investigate the effects of training surface on dynamic balance in athletes compared to NON. Eight NON, eight SSA, and eight USA performed five 20-s trials in each of five experimental conditions including a static condition and four dynamic conditions in which the support surface translated in the anteroposterior (AP) or mediolateral (ML) planes using positive or negative feedback paradigms. Approximate entropy (ApEn) and root mean square distance (RMS) of the center of pressure (CoP) were calculated for the AP and ML directions. Four 3 × 5 (group × condition) repeated measures ANOVAs were used to determine significant effects of group and condition on variables of interest. USA exhibited smaller ApEn values than SSA in the AP signals while no significant differences were observed in the ML CoP signals. Generally, the negative feedback conditions were associated with significantly greater RMS values than the positive feedback conditions. USA exhibit unique postural strategies compared to SSA. These unique strategies seemingly exhibit a direction-specific attribute and may be associated with divergent motor control strategies.


STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection.
Chronic infections induce a complex immune response that controls pathogen replication, but also causes pathology due to sustained inflammation. Ca2+ influx mediates T cell function and immunity to infection, and patients with inherited mutations in the gene encoding the Ca2+ channel ORAI1 or its activator stromal interaction molecule 1 (STIM1) are immunodeficient and prone to chronic infection by various pathogens, including Mycobacterium tuberculosis (Mtb). Here, we demonstrate that STIM1 is required for T cell-mediated immune regulation during chronic Mtb infection. Compared with WT animals, mice with T cell-specific Stim1 deletion died prematurely during the chronic phase of infection and had increased bacterial burdens and severe pulmonary inflammation, with increased myeloid and lymphoid cell infiltration. Although STIM1-deficient T cells exhibited markedly reduced IFN-γ production during the early phase of Mtb infection, bacterial growth was not immediately exacerbated. During the chronic phase, however, STIM1-deficient T cells displayed enhanced IFN-γ production in response to elevated levels of IL-12 and IL-18. The lack of STIM1 in T cells was associated with impaired activation-induced cell death upon repeated TCR engagement and pulmonary lymphocytosis and hyperinflammation in Mtb-infected mice. Chronically Mtb-infected, STIM1-deficient mice had reduced levels of inducible regulatory T cells (iTregs) due to a T cell-intrinsic requirement for STIM1 in iTreg differentiation and excessive production of IFN-γ and IL-12, which suppress iTreg differentiation and maintenance. Thus, STIM1 controls multiple aspects of T cell-mediated immune regulation to limit injurious inflammation during chronic infection.


Interface chemistry and molecular interactions of phosphonic acid self-assembled monolayers on oxyhydroxide-covered aluminum in humid environments.
Barrier properties of self-assembled octadecylphosphonic acid (ODPA) monolayers on plasma-modified oxyhydroxide-covered aluminum surfaces were analyzed by means of in situ photoelastic modulated infrared reflection absorption spectroscopy (PM-IRRAS). The surface hydroxyl density prior to ODPA adsorption was increased by means of a low-temperature H(2)O-plasma treatment. Adsorption isotherms of H(2)O on ODPA self-assembled monolayer (SAM) modified surfaces in comparison to bare oxide covered aluminum surfaces showed that the ODPA SAM leads to a strongly reduced amount of adsorbed water based on the inability of water to form hydrogen bonds to the low-energy aliphatic surface. However, the ODPA SAM covered surfaces did not show a significant inhibition of the H(2)O/D(2)O isotope exchange reaction between the D(2)O gas phase and the hydroxyl groups of the aluminum oxyhydroxide film, as the interfacial layer between the ODPA SAM and the metal substrate, while the interfacial phosphonate group as well as the orientation of the SAM is not affected by the adsorption of water. It can be followed that the strong adhesion promoting and high corrosion resistances of organophosphonate monolayers on oxyhydroxide-covered aluminum is a result of the strong acid-base interaction of the phosphonate headgroup with the Al ions in the oxyhydroxide film, even in the presence of high interfacial water activity and the molecular interactions of the aliphatic chains. However, the barrier effect of such monolayers on the transport of water is negligible.


Paraxial ray analysis of a cat's-eye retroreflector.
The cat's-eye retroreflector is a passive optical system consisting of a secondary mirror placed at the focal point of a primary lens. We analyze the cat's eye using the paraxial ray matrix approach. The position of the equivalent reflecting surface and the angular field of view of a realizable cat's eye are functions of the radius of curvature of the secondary mirror. The field of view is maximum for a secondary mirror with a concave radius of curvature equal to the focal length of the primary lens. We further derive the general dependence of retroreflection errors on misadjustment of the secondary mirror.


Exogenous determinants of early-life conditions, and mortality later in life.
We analyze causal effects of conditions early in life on the individual mortality rate later in life. Conditions early in life are captured by transitory features of the macro-environment around birth, notably the state of the business cycle around birth, but also food price deviations, weather indicators, and demographic indicators. We argue that these features can only affect high-age mortality by way of the individual early-life conditions. Moreover, they are exogenous from the individual point of view, which is a methodological advantage compared to the use of unique characteristics of the newborn individual or his or her family or household as early-life indicators. We collected national annual time-series data on the above-mentioned indicators, and we combine these to the individual data records from the Danish Twin Registry covering births in 1873-1906. The empirical analyses (mostly based on the estimation of duration models) indicate a significant negative causal effect of economic conditions early in life on individual mortality rates at higher ages. If the national economic performance in the year of birth exceeds its trend value (i.e., if the business cycle is favorable) then the mortality rate later in life is lower. The implied effect on the median lifetime of those who survive until age 35 is about 10 months. A systematic empirical exploration of all macro-indicators reveals that economic conditions in the first years after birth also affect mortality rates later in life.


Why not common morality?
This paper challenges the leading common morality accounts of medical ethics which hold that medical ethics is nothing but the ethics of everyday life applied to today's high-tech medicine. Using illustrative examples, the paper shows that neither the Beauchamp and Childress four-principle account of medical ethics nor the Gert et al 10-rule version is an adequate and appropriate guide for physicians' actions. By demonstrating that medical ethics is distinctly different from the ethics of everyday life and cannot be derived from it, the paper argues that medical professionals need a touchstone other than common morality for guiding their professional decisions. That conclusion implies that a new theory of medical ethics is needed to replace common morality as the standard for understanding how medical professionals should behave and what medical professionalism entails. En route to making this argument, the paper addresses fundamental issues that require clarification: what is a profession? how is a profession different from a role? how is medical ethics related to medical professionalism? The paper concludes with a preliminary sketch for a theory of medical ethics.


Pulsed radiofrequency attenuates diabetic neuropathic pain and suppresses formalin-evoked spinal glutamate release in rats.
Pulsed radiofrequency (PRF) has been used to treat chronic pain for years, but its effectiveness and mechanism in treating diabetic neuropathic pain are still unexplored. The aim of this study was to elucidate the modulation of diabetic neuropathic pain induced by streptozotocin and the release of spinal excitatory amino acids by PRF. Diabetes was induced by intraperitoneal administration of streptozotocin. Pulsed radiofrequency was applied to L5 and L6 dorsal roots at 42 °C for 2 min. The responses of all of the groups to thermal, mechanical and cold stimuli were measured for a period of 6 d after this process. Seven days after PRF treatment, intrathecal microdialysis was used to examine the effect of pulsed radiofrequency on the formalin-evoked spinal release of excitatory amino acids and concurrent behaviour responses from diabetic rats. Three weeks after intraperitoneal streptozotocin treatment and before PRF application, mechanical, thermal and cold hypersensitivity occurred. Application of PRF significantly alleviated hyperglycaemia-induced mechanical, thermal and cold hypersensitivity and also attenuated the increase in formalin-evoked CSF glutamate concentration, compared with sham treated diabetic rats. It may be concluded that PRF has an analgesic effect on neuropathic pain by suppressing the nociception-induced release of excitatory neurotransmitters. PRF may provide a novel promising therapeutic approach for managing diabetic neuropathic pain.


Raised circulating tenascin-C in rheumatoid arthritis.
The aim of this study was to examine whether circulating levels of the pro-inflammatory glycoprotein tenascin-C (TNC) are elevated in musculoskeletal disorders including rheumatoid arthritis (RA) and to assess in RA whether levels are related to clinical disease status and/or patient response to treatment. TNC in serum or plasma was quantified by ELISA. Samples from 4 cohorts of RA patients were examined and compared to normal human subjects and to patients with other inflammatory diseases. Circulating TNC levels were significantly raised in patients with RA, as well as patients with systemic lupus erythematosus, idiopathic inflammatory myositis, psoriatic arthritis and ankylosing spondylitis, whilst patients with Sjogren's syndrome displayed levels similar to healthy controls. The highest levels of TNC were observed in RA patients with late stage disease. In early disease TNC levels correlated positively with ultrasound determined erosion scores. Treatment of early RA patients with infliximab plus methotrexate (MTX) resulted in a transient decrease in circulating TNC over the first year of therapy. In contrast, TNC levels increased over time in RA patients receiving MTX alone. In patients treated with infliximab plus MTX, baseline TNC levels significantly correlated with tender joint counts (TJC) at 18 and 54 weeks after initiation of infliximab therapy. Raised circulating TNC levels are detected in specific inflammatory diseases. Levels are especially high in RA where they may act as a biomarker of bone erosion and a predictor of the effect of infliximab on RA patient joint pain.


Randomised trial of chloroquine/sulphadoxine-pyrimethamine in Gambian children with malaria: impact against multidrug-resistant P. falciparum.
In the Gambia, the combination of chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) has replaced CQ monotherapy for treatment of malaria caused by Plasmodium falciparum. We measured the efficacy of the combination CQ/SP, and the prevalence of parasites carrying alleles associated with resistance to CQ or SP. We conducted a single-blind, randomised, controlled trial to compare the efficacy of CQ/SP to that of SP or CQ alone. The study took place in the town of Farafenni and surrounding villages in the Gambia. Participants were children aged 12 mo to 10 y presenting as outpatients with uncomplicated P. falciparum malaria. 500 children were randomised to receive CQ, SP, or CQ/SP as supervised treatment and actively followed over 28 d. Primary outcome was parasitaemia at any time during follow-up. Secondary outcomes were PCR-confirmed recrudescent infections among treatment failures, and clinical failure requiring rescue medication by day 28. Pretreatment parasite isolates from 161 patients were tested for the presence of resistance-associated genetic markers. The prevalence of parasitological failure by day 28 for the CQ group was 60.3%, compared to 17.6% for SP (odds ratio [OR], 0.106; 95% confidence interval [CI], 0.057-0.194; p < 0.001) and 13.9% for CQ/SP (OR versus CQ, 0.140; 95% CI, 0.078-0.250; p < 0.001). There was no difference between the SP and CQ/SP groups (OR, 1.324; 95% CI, 0.705-2.50). The projected prevalence of PCR-corrected treatment failure was 30.2, 6.06, and 3.94% in the CQ, SP, and CQ/SP groups, respectively. The pfdhfr-triple mutant and pfdhps-437G mutation were common, with prevalences of 67.4 and 51.2%, respectively. Pretreatment carriage of pfdhps-437G and of multidrug-resistant parasite genotypes was associated with treatment failure in the SP group, but not in the CQ or CQ/SP groups. The combination of CQ/SP was an efficacious treatment for uncomplicated malaria in Gambian children in this study, but the frequent occurrence of multidrug-resistant parasites suggests that this observed efficacy is not sustainable.


Comparative Analysis of EO-1 ALI and Hyperion, and Landsat ETM+ Data for Mapping Forest Crown Closure and Leaf Area Index.
In this study, a comparative analysis of capabilities of three sensors for mapping forest crown closure (CC) and leaf area index (LAI) was conducted. The three sensors are Hyperspectral Imager (Hyperion) and Advanced Land Imager (ALI) onboard EO-1 satellite and Landsat-7 Enhanced Thematic Mapper Plus (ETM+). A total of 38 mixed coniferous forest CC and 38 LAI measurements were collected at Blodgett Forest Research Station, University of California at Berkeley, USA. The analysis method consists of (1) extracting spectral vegetation indices (VIs), spectral texture information and maximum noise fractions (MNFs), (2) establishing multivariate prediction models, (3) predicting and mapping pixel-based CC and LAI values, and (4) validating the mapped CC and LAI results with field validated photo-interpreted CC and LAI values. The experimental results indicate that the Hyperion data are the most effective for mapping forest CC and LAI (CC mapped accuracy (MA) = 76.0%, LAI MA = 74.7%), followed by ALI data (CC MA = 74.5%, LAI MA = 70.7%), with ETM+ data results being least effective (CC MA = 71.1%, LAI MA = 63.4%). This analysis demonstrates that the Hyperion sensor outperforms the other two sensors: ALI and ETM+. This is because of its high spectral resolution with rich subtle spectral information, of its short-wave infrared data for constructing optimal VIs that are slightly affected by the atmosphere, and of its more available MNFs than the other two sensors to be selected for establishing prediction models. Compared to ETM+ data, ALI data are better for mapping forest CC and LAI due to ALI data with more bands and higher signal-to-noise ratios than those of ETM+ data.


Chronic obstructive pulmonary disease exacerbation: A single-center perspective on hospital readmissions.
Chronic obstructive pulmonary disease (COPD) is the third most common cause in the United States of hospital readmission within 30 days of discharge. Readmissions, which are attributed to poor quality of care, are costly. We examined the factors associated with 30-day readmission in patients hospitalized with acute exacerbation of COPD. Our hypothesis was that early readmissions among patients with COPD are related to patient factors rather than system or provider factors. We performed a retrospective chart review of all patients discharged from our facility from June 2010 to May 2011 with a primary discharge diagnosis of COPD. Detailed patient characteristics were obtained from the electronic medical record. Patients were followed for 30 days post-discharge date. We examined the differences in baseline characteristics of patients readmitted within 30 days and those not readmitted. A total of 160 patients were admitted for 192 hospitalizations during the study period; 31 patients (19.4%) were readmitted within 30 days. Patients who were readmitted did not differ from those who were not readmitted of the following factors: baseline medication use, length of stay, and outpatient follow-up postdischarge. Readmitted patients were more likely to be black, to have coronary artery disease, to have a history of alcohol abuse, and to be on supplemental oxygen. Multivariate analysis showed a 2.17 odds of 30-day readmission (95% CI, 1.16-4.09) in patients with alcohol abuse, and 2.52 (95% CI, 1.18-5.38) in those on supplemental oxygen. In our study population, 19.4% of acute exacerbation COPD patients were readmitted within 30 days. Patient factors (such as alcohol abuse and advanced disease) were associated with 30-day readmission.


Atypical energy eigenstates in the Hubbard chain and quantum disentangled liquids.
We investigate the implications of integrability for the existence of quantum disentangled liquid (QDL) states in the half-filled one-dimensional Hubbard model. We argue that there exist finite energy-density eigenstates that exhibit QDL behaviour in the sense of Grover & Fisher (2014 J. Stat. Mech.2014, P10010. (doi:10.1088/1742-5468/2014/10/P10010)). These states are atypical in the sense that their entropy density is smaller than that of thermal states at the same energy density. Furthermore, we show that thermal states in a particular temperature window exhibit a weaker form of the QDL property, in agreement with recent results obtained by strong-coupling expansion methods in Veness et al. (2016 (http://arxiv.org/abs/1611.02075)).This article is part of the themed issue 'Breakdown of ergodicity in quantum systems: from solids to synthetic matter'.


Levodopa with carbidopa diminishes glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in rat skeletal muscle.
We hypothesized that levodopa with carbidopa, a common therapy for patients with Parkinson's disease, might contribute to the high prevalence of insulin resistance reported in patients with Parkinson's disease. We examined the effects of levodopa-carbidopa on glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in skeletal muscle, the predominant insulin-responsive tissue. In isolated muscle, levodopa-carbidopa completely prevented insulin-stimulated glycogen accumulation and glucose transport. The levodopa-carbidopa effects were blocked by propranolol, a beta-adrenergic antagonist. Levodopa-carbidopa also inhibited the insulin-stimulated increase in glycogen synthase activity, whereas propranolol attenuated this effect. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was reduced by levodopa-carbidopa, although Akt phosphorylation was unaffected by levodopa-carbidopa. A single in vivo dose of levodopa-carbidopa increased skeletal muscle cAMP concentrations, diminished glycogen synthase activity, and reduced tyrosine phosphorylation of IRS-1. A separate set of rats was treated intragastrically twice daily for 4 wk with levodopa-carbidopa. After 4 wk of treatment, oral glucose tolerance was reduced in rats treated with drugs compared with control animals. Muscles from drug-treated rats contained at least 15% less glycogen and approximately 50% lower glycogen synthase activity compared with muscles from control rats. The data demonstrate beta-adrenergic-dependent inhibition of insulin action by levodopa-carbidopa and suggest that unrecognized insulin resistance may exist in chronically treated patients with Parkinson's disease.


Effect of load on the bone around bone-anchored amputation prostheses.
Osseointegrated transfemoral amputation prostheses have proven successful as an alternative method to the conventional socket-type prostheses. The method improves prosthetic use and thus increases the demands imposed on the bone-implant system. The hypothesis of the present study was that the loads applied to the bone-anchored implant system of amputees would result in locations of high stress and strain transfer to the bone tissue and thus contribute to complications such as unfavourable bone remodeling and/or elevated inflammatory response and/or compromised sealing function at the tissue-abutment interface. In the study, site-specific loading measurements were made on amputees and used as input data in finite element analyses to predict the stress and strain distribution in the bone tissue. Furthermore, a tissue sample retrieved from a patient undergoing implant revision was characterized in order to evaluate the long-term tissue response around the abutment. Within the limit of the evaluated bone properties in the present experiments, it is concluded that the loads applied to the implant system may compromise the sealing function between the bone and the abutment, contributing to resorption of the bone in direct contact with the abutment at the most distal end. This was supported by observations in the retrieved clinical sample of bone resorption and the formation of a soft tissue lining along the abutment interface. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1113-1122, 2017.


[Lung Volume Reduction Surgery].
Lung volume reduction surgery (LVRS) offers improvement in lung function, quality of life and even survival in well selected patients with severe emphysema. Patients with all types of emphysema morphology can profit from LVRS when certain selection criteria are present. Hyperinflation plays a key role in qualifying for the procedure. Candidate selection should be performed at high volume centers with a multidisciplinary emphysema board. Qualified thoracic surgeons together with pulmonologists and radiologists identify the suitable patient considering emphysema morphology with its target areas for resection, lung function parameters and cardiac comorbidities. This review outlines candidate selection, technique and results of LVRS to inform referring physicians how to screen und inform their patients.


Definition of a RACK1 Interaction Network in Drosophila melanogaster Using SWATH-MS.
Receptor for Activated protein C kinase 1 (RACK1) is a scaffold protein that has been found in association with several signaling complexes, and with the 40S subunit of the ribosome. Using the model organism Drosophila melanogaster, we recently showed that RACK1 is required at the ribosome for internal ribosome entry site (IRES)-mediated translation of viruses. Here, we report a proteomic characterization of the interactome of RACK1 in Drosophila S2 cells. We carried out Label-Free quantitation using both Data-Dependent and Data-Independent Acquisition (DDA and DIA, respectively) and observed a significant advantage for the Sequential Window Acquisition of all THeoretical fragment-ion spectra (SWATH) method, both in terms of identification of interactants and quantification of low abundance proteins. These data represent the first SWATH spectral library available for Drosophila and will be a useful resource for the community. A total of 52 interacting proteins were identified, including several molecules involved in translation such as structural components of the ribosome, factors regulating translation initiation or elongation, and RNA binding proteins. Among these 52 proteins, 15 were identified as partners by the SWATH strategy only. Interestingly, these 15 proteins are significantly enriched for the functions translation and nucleic acid binding. This enrichment reflects the engagement of RACK1 at the ribosome and highlights the added value of SWATH analysis. A functional screen did not reveal any protein sharing the interesting properties of RACK1, which is required for IRES-dependent translation and not essential for cell viability. Intriguingly however, 10 of the RACK1 partners identified restrict replication of Cricket paralysis virus (CrPV), an IRES-containing virus.


Assessment of a clinical score for screening suspected pulmonary tuberculosis cases.
To assess the accuracy (sensitivity) of a clinical score for presumptive pulmonary tuberculosis cases during screening. Descriptive cross-sectional study comprising 1,365 patients attending the department of lung diseases at a secondary care outpatient clinic in the city of Rio de Janeiro, Southeastern Brazil, during 2006 and 2007. All respondents answered a standardized questionnaire administered by the clinic's nursing staff. Information on age, weight and clinical symptoms were collected. The presumptive diagnosis of pulmonary tuberculosis was made by summing up the scores of the data collected. The diagnosis of active tuberculosis was based on bacteriological findings and medical criteria. There were estimated sensitivity, specificity, positive predictive value and negative predictive value for a set prevalence, and 95% confidence intervals for different score cutoffs. The score performance was assessed using the receiver operating characteristic (ROC) curve. For the diagnosis of tuberculosis, cough for more than one week and cough for more than three weeks showed a sensitivity of 88.2% (86.2, 90.2) and 61.1% (57.93, 64.3), specificity 19.2% (16.6, 21.8) and 51.3% (48.1, 54.5), respectively. The clinical score of 8 had a sensitivity of 83.13% (77.8, 87.6), specificity of 51.8% (48.5, 55.1), positive predictive value of 91.6% (90.0, 83.2) and negative predictive value of 32.9% (30.1, 35.7). Cough for more than three weeks showed low sensitivity and specificity. A highly sensitive clinical score can be an alternative tool for screening pulmonary tuberculosis as it allows early care of suspected cases and standard nursing care approach.


Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.
Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.


Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use.
Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine.


Candida albicans quorum-sensing molecule farnesol modulates staphyloxanthin production and activates the thiol-based oxidative-stress response in Staphylococcus aureus.
Microbial species utilize secreted-signaling molecules to coordinate their behavior. Our previous investigations demonstrated a key role for the Candida albicans-secreted quorum-sensing molecule farnesol in modulating Staphylococcus aureus response to antimicrobials in mixed biofilms. In this study, we aimed to provide mechanistic insights into the impact of farnesol on S. aureus within the context of inter-species interactions. To mimic biofilm dynamics, farnesol-sensitized S. aureus cells were generated via sequential farnesol exposure. The sensitized phenotype exhibited dramatic loss of the typical pigment, which we identified as staphyloxanthin, an important virulence factor synthesized by the Crt operon in S. aureus. Additionally, farnesol exposure exerted oxidative-stress as indicated by transcriptional analysis demonstrating alterations in redox-sensors and major virulence regulators. Paradoxically, the activated stress-response conferred S. aureus with enhanced tolerance to H2O2 and phagocytic killing. Since expression of enzymes in the staphyloxanthin biosynthesis pathway was not impacted by farnesol, we generated a theoretical-binding model which indicated that farnesol may block staphyloxanthin biosynthesis via competitive-binding to the CrtM enzyme crucial for staphyloxanthin synthesis, due to high structural similarity to the CrtM substrate. Finally, mixed growth with C. albicans was found to similarly induce S. aureus depigmentation, but not during growth with a farnesol-deficient C. albicans strain. Collectively, the findings demonstrate that a fungal molecule acts as a redox-cycler eliciting a bacterial stress response via activation of the thiol-based redox system under the control of global regulators. Therefore, farnesol-induced transcriptional modulations of key regulatory networks in S. aureus may modulate the pathogenesis of C. albicans-S. aureus co-infections.


Methyl DNA adducts, DNA repair, and hypoxanthine-guanine phosphoribosyl transferase mutations in peripheral white blood cells from patients with malignant melanoma treated with dacarbazine and hydroxyurea.
Dacarbazine (DTIC) is a DNA-methylating drug used in the treatment of malignant melanoma. Among the DNA dducts induced by DTIC are N7-methylguanine (N7-meG) and O6-methylguanine (O6-meG). The latter adduct, in particular, may be important in the mutagenic as well as the cytotoxic activity of DTIC. Repair of O6-meG is carried out by the enzyme O6-alkylguanine-DNA-alkyltransferase (AGT) by a process which results in its autoinactivation. N7-meG is lost from DNA partly spontaneously and partly by enzymatic depurination followed by excision repair of the resulting apurinic site. The purpose of this study was to determine the in vivo kinetics of formation and repair of O6-meG and N7-meG and the changes in AGT in peripheral WBCs with repeated doses of DTIC, and to determine the effects on these processes of concomitant administration of hydroxyurea. In addition, we examined the induction of mutations at the HPRT gene locus. Thirty-four patients with malignant melanoma received 1.0 g/m2 DTIC i.v. every 3 weeks. Hydroxyurea was added to the second and subsequent doses of DTIC in 19 patients. The concentrations of O6-meG, N7-meG, and AGT in peripheral blood lymphocytes were determined up to 24 h after each of the first two doses of DTIC. Mutations at the HPRT gene locus were determined using the T-cell clonal assay. Peak O6-meG levels were detected 1 and 4 h after the first and second dose of DTIC, respectively. AGT concentrations declined to 56.7% (range, 40.3-76.9%) and 55.0% (range, 45.4-58.9%) of pretreatment levels 24 h after the first and second doses of DTIC, respectively, and were still approximately 25%below their initial levels just prior to administration of the second dose of DTIC. An increase in formation of O6-meG was observed at all time points after the second dose of DTIC (P = 0.0001), which was not affected by cotreatment with hydroxyurea (P > 0.5). There was a negative correlation between pretreatment AGT levels and the O6-meG concentration at 24 h after therapy (r = -0.554, P = 0.014). N7-meG levels peaked at 6 h after DTIC therapy and were not significantly influenced by the cycle number. Cotreatment with hydroxyurea tended to be associated with lower levels of N7-meG (P = 0.08). There was no correlation between either O6-meG or N7-meG levels and the grade of neutropenia. On the basis of a limited series of blood samples analyzed, there was no firm evidence that chemotherapy with DTIC resulted in induction of HPRT mutations in lymphocytes. In conclusion, repeated administrations of DTIC resulted in higher concentrations of O6-meG, probably due to reduction in cellular AGT. Hydroxyurea did not significantly influence the kinetics of O6-meG, and N7-meG adduct formation. There was no significant induction of HPRT gene mutations with DTIC. This study suggests that sequencing of DTIC doses should be evaluated using the time course of cellular AGT depletion and DNA adduct formation to achieve higher cytotoxic efficiency.


Europium Cyclooctatetraene Nanowire Carpets: A Low-Dimensional, Organometallic, and Ferromagnetic Insulator.
We investigate the magnetic and electronic properties of europium cyclooctatetraene (EuCot) nanowires by means of low-temperature X-ray magnetic circular dichroism (XMCD) and scanning tunneling microscopy (STM) and spectroscopy (STS). The EuCot nanowires are prepared in situ on a graphene surface. STS measurements identify EuCot as an insulator with a minority band gap of 2.3 eV. By means of Eu M5,4 edge XMCD, orbital and spin magnetic moments of (-0.1 ± 0.3)μB and (+7.0 ± 0.6)μB, respectively, were determined. Field-dependent measurements of the XMCD signal at the Eu M5 edge show hysteresis for grazing X-ray incidence at 5 K, thus confirming EuCot as a ferromagnetic material. Our density functional theory calculations reproduce the experimentally observed minority band gap. Modeling the experimental results theoretically, we find that the effective interatomic exchange interaction between Eu atoms is on the order of millielectronvolts, that magnetocrystalline anisotropy energy is roughly half as big, and that dipolar energy is approximately ten times lower.


Anti-platelet and anti-thrombotic effect of a traditional herbal medicine Kyung-Ok-Ko.
Kyung-Ok-Ko (KOK), a traditional herbal prescription, contains six main ingredients; Rehmannia glutinosa var. purpurae, Lycium chinense, Aquillaria agallocha, Poria cocos, Panax ginseng, and honey. KOK has been widely taken as a traditional oriental medicine for improving blood circulation or age-related symptoms, such as dementia and stroke. However, the effect of KOK on platelet activity has not been clarified. To evaluate the effect of KOK on platelet function, we evaluated its effect on functional markers of platelet activation such as aggregation and shape change. As a mechanism study for the effect of KOK, we examined its effect on granule secretion, intracellular Ca(2+) increase, and PLCγ and Akt activation. To investigate the effect of orally administered KOK (0.5, 1, 2 g/kg), we examined its ex vivo effect on platelet aggregation in rat, and its in vivo anti-thrombotic effect in mice thromboembolism model. Furthermore, the effect of KOK on bleeding time was examined to estimate its potential side effect. KOK (0.3, 1, 3, 10 mg/ml) inhibited collagen-induced platelet aggregation and shape change in rat platelets in a concentration-dependent manner. The mechanism for the anti-platelet effect of KOK seems to involve the inhibition of ATP release, intracellular Ca(2+) elevation, and the phosphorylation of PLCγ and Akt. In rat ex vivo study, KOK (2 g/kg, p.o. for 1 day, and 0.5, 1, 2 g/kg, p.o. for 7 days) also had significant inhibitory effects on collagen-induced platelet aggregation. In addition, KOK showed a significant protective effect against thrombosis attack in mice. The prolongation of bleeding time by KOK was much less than that by ASA, suggesting a beneficial potential of KOK than ASA in view of side effect. These findings suggest that KOK elicits remarkable anti-platelet and anti-thrombotic effects with less side effect of bleeding, and therefore, it may have a therapeutic potential for the prevention of platelet-associated cardiovascular diseases.


Reasons for resubmission of research projects to the research ethics committee of a university hospital in São Paulo, Brazil.
It is important to know the reasons for resubmitting research projects to the Research Ethics Committee in order to help researchers to prepare their research projects, informed consent forms and needed research documentation. To verify the reasons for resubmitting projects that were previously rejected by the Ethics Committee. This is a cross-sectional study that evaluated research projects involving human beings. Research projects were submitted in 2007 to the Research Ethics Committee of the Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo. One thousand two hundred and fifty six research projects were submitted to the ethics committee and the average time for evaluating the research projects and related documents until a final decision was reached was 49.95 days. From the total, 399 projects were reviewed in 2 or more meetings until a final decision was reached. Of these, 392 research projects were included in the study; 35 projects were subsequently excluded for involving animals. Among the research projects included, 42.5% concerned research with new drugs, vaccines and diagnostic tests, 48.5% consisted of undergraduate students' research projects, 68.9% of the research had no sponsorship, and 97.5% were eventually approved. The main reasons for returning the projects to the researchers were the use of inadequate language and/or difficulty of understanding the informed consent form (32.2%), lack of information about the protocol at the informed consent form (25.8%), as well as doubts regarding methodological and statistical issues of the protocol (77.1%). Other reasons for returning the research projects involved lack of, inaccuracy on or incomplete documentation, need of clarification or approval for participation of external entities on the research, lack of information on financial support. Among the research projects that were returned to the researchers for additional clarification, the main reasons were inadequacies or doubts about the terms used in the informed consent form as well as lack of information regarding the research at the informed consent form and methodological and statistical issues regarding the protocol.


Antibiotics for mastitis in breastfeeding women.
Mastitis can be caused by ineffective positioning of the baby at the breast or restricted feeding. Infective mastitis is commonly caused by Staphylococcus Aureus. Incidence of mastitis in breastfeeding women may reach 33%. Effective milk removal, pain medication and antibiotic therapy have been the mainstays of treatment. This review aims to examine the effectiveness of antibiotic therapies in relieving symptoms for breastfeeding women with mastitis with or without laboratory investigation. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (December 2007), the Cochrane Central Register of Clinical Trials (The Cochrane Library 2007, Issue 4), MEDLINE (1996 to 2007) and EMBASE (January 1985 to 2007). We contacted investigators and other content experts known to us for unpublished trials and scanned the reference lists of retrieved articles Randomized and quasi-randomized clinical trials comparing the effectiveness of various types of antibiotic therapies or antibiotic therapy versus alternative therapies for the treatment of mastitis were selected. Two authors independently assessed trial quality and extracted data. When in dispute, we consulted a third author. Two trials met the inclusion criteria. One small trial (n = 25) compared amoxicillin with cephradine and found no significant difference between the two antibiotics in terms of symptom relief and abscess formation. Another, older study compared breast emptying alone as "supportive therapy" versus antibiotic therapy plus supportive therapy, and no therapy. The findings of the latter study suggested faster clearance of symptoms for women using antibiotics, although the study design was problematic. There is insufficient evidence to confirm or refute the effectiveness of antibiotic therapy for the treatment of lactational mastitis. There is an urgent need to conduct high-quality, double-blinded randomized clinical trials to determine whether antibiotics should be used in this common postpartum condition.


In vivo skeletal imaging of 18F-fluoride with positron emission tomography reveals damage- and time-dependent responses to fatigue loading in the rat ulna.
The skeletal response to damaging fatigue loading is not fully understood. We used (18)F-fluoride PET to describe the time course of the skeletal response following the creation of increasing levels of in vivo, fatigue-induced damage. The right forelimbs of 40 adult rats were loaded in vivo in cyclic compression to four levels of subfracture, fatigue displacement: 30, 45, 65, or 85% of fracture displacement. Rats were injected with a bone-seeking radionuclide ((18)F-fluoride) on days 0 (4 h), 2, 4, 7, 9, 11, 18, 24, and 30, and imaged using a small animal positron emission tomography (PET) scanner. We quantified fluoride uptake in the central 50% of the right (loaded) and left (control) forelimbs. There were significant increases in fluoride uptake in loaded forelimbs compared to control on day 0 for all displacement groups. Normalized uptake (loaded/control) reached peak levels 4 to 9 days after loading. Normalized uptake depended significantly on the level of fatigue displacement. Normalized uptake increased progressively from the 30 to the 45% displacement level (P < 0.001), and from the 45 to the 65% level (P < 0.001) but did not differ between 65 and 85% (P = 0.41). Histologically, we observed a rapid periosteal response with increased vascularity as early as day 1 and abundant woven bone formation between days 3 and 7. Periosteal and woven bone thicknesses were greater in bones subjected to more fatigue displacement. We conclude that a single bout of fatigue loading leads to a transient increase in the uptake of (18)F-fluoride, that the uptake is in proportion to the level of initial damage and is associated with increased vascularity and woven bone formation in the first week after loading.


Vitamin D supplementation and serum neurofilament light chain in interferon-beta-1b-treated MS patients.
Serum neurofilament light chain (sNfL) is a promising biomarker of MS activity, progression, and treatment response. The aim of the present study was to address whether sNfL concentrations are affected by supplementation of vitamin D and correlate with disease activity in interferon-beta-1b (IFNb-1b)-treated Finnish MS. Serum samples were available of 32 participants of the Finnish vitamin D randomized controlled trial (17 vitamin D/15 placebo). Serum 25 hydroxyvitamin D was measured using radioimmunoassay and sNfL using single-molecule array (Simoa). Correlation of sNfL with brain magnetic resonance imaging (MRI) activity, burden of disease (BOD, mm3 ), and disability was assessed at the study baseline and at 52 weeks. Serum NfL concentrations were similar in the patients randomized to high-dose vitamin D and placebo at the study baseline and at month 12 follow-up (p-value). Concentrations of sNfL were higher in patients with Gadolinium-enhancing lesions in brain MRI: median (95% CI) sNfL was 14.84 (9.9-42.5) pg/ml and 11.39 (8.9-13.2) pg/ml in patients without Gd+ lesions (p = .0144) and correlated with enhancing lesion volume (Pearson r = .36, p = .037) at the study baseline but not at week 52. Serum NfL did not correlate with the MRI BOD or disability measured by expanded disability status scale and 25-foot walk test. In this small cohort of clinically stable IFN-treated Finnish MS patients, sNfL levels were similarly low in patients supplemented with high-dose vitamin D or placebo. Subclinical disease activity in MRI was associated with higher sNfL levels.


Unexpected maintenance of hepatitis C viral diversity following liver transplantation.
Chronic hepatitis C virus (HCV) infection can lead to liver cirrhosis in up to 20% of individuals, often requiring liver transplantation. Although the new liver is known to be rapidly reinfected, the dynamics and source of the reinfecting virus(es) are unclear, resulting in some confusion concerning the relationship between clinical outcome and viral characteristics. To clarify the dynamics of liver reinfection, longitudinal serum viral samples from 10 transplant patients were studied. Part of the E1/E2 region was sequenced, and advanced phylogenetic analysis methods were used in a multiparameter analysis to determine the history and ancestry of reinfecting lineages. Our results demonstrated the complexity of HCV evolutionary dynamics after liver transplantation, in which a large diverse population of viruses is transmitted and maintained for months to years. As many as 30 independent lineages in a single patient were found to reinfect the new liver. Several later posttransplant lineages were more closely related to older pretransplant viruses than to viruses detected immediately after transplantation. Although our data are consistent with a number of interpretations, the persistence of high viral genetic variation over long periods of time requires an active mechanism. We discuss possible scenarios, including frequency-dependent selection or variation in selective pressure among viral subpopulations, i.e., the population structure. The latter hypothesis, if correct, could have relevance to the success of newer direct-acting antiviral therapies.


Practice changing mature results of RTOG study 9802: another positive PCV trial makes adjuvant chemotherapy part of standard of care in low-grade glioma.
The long-term follow-up of the RTOG 9802 trial that compared 54 Gy of radiotherapy (RT) with the same RT followed by adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy in high-risk low-grade glioma shows a major increase in survival after adjuvant PCV chemotherapy. Median overall survival increased from 7.8 years to 13.3 years, with a hazard ratio of death of 0.59 (log rank: P = .002). This increase in survival was observed despite the fact that 77% of patients who progressed after RT alone received salvage chemotherapy. With this outcome, RT + PCV is now to be considered standard of care for low-grade glioma requiring postsurgical adjuvant treatment. Unfortunately, studies on molecular correlates associated with response are still lacking. This is now the third trial showing benefit from the addition of PCV to RT in grade II or III diffuse glioma. The optimal parameter for selecting patients for adjuvant PCV has not yet been fully elucidated, but several candidate markers have so far emerged. It is still unclear whether temozolomide can replace PCV and whether initial management with chemotherapy only is a safe initial treatment. Potentially, that may adversely affect overall survival, but concerns for delayed RT-induced neurotoxicity may limit acceptance of early RT in patients with expected long term survival. The current evidence supports that in future trials, grades II and III tumors with similar molecular backgrounds should be combined, and trials should focus on molecular glial subtype regardless of grade.


Inhibition of HCV translation by disrupting the structure and interactions of the viral CRE and 3' X-tail.
A phylogenetically conserved RNA structure within the NS5B coding region of hepatitis C virus functions as a cis-replicating element (CRE). Integrity of this CRE, designated SL9266 (alternatively 5BSL3.2), is critical for genome replication. SL9266 forms the core of an extended pseudoknot, designated SL9266/PK, involving long distance RNA-RNA interactions between unpaired loops of SL9266 and distal regions of the genome. Previous studies demonstrated that SL9266/PK is dynamic, with 'open' and 'closed' conformations predicted to have distinct functions during virus replication. Using a combination of site-directed mutagenesis and locked nucleic acids (LNA) complementary to defined domains of SL9266 and its interacting regions, we have explored the influence of this structure on genome translation and replication. We demonstrate that LNAs which block formation of the closed conformation inhibit genome translation. Inhibition was at least partly independent of the initiation mechanism, whether driven by homologous or heterologous internal ribosome entry sites or from a capped message. Provision of SL9266/PK in trans relieved translational inhibition, and mutational analysis implied a mechanism in which the closed conformation recruits a cellular factor that would otherwise suppresses translation. We propose that SL9266/PK functions as a temporal switch, modulating the mutually incompatible processes of translation and replication.


WITHDRAWN: Interventions for treating wrist fractures in children.
Approximately a third of all fractures in children occur at the wrist, usually from falling onto an outstretched hand. We aimed to evaluate removable splintage versus plaster casts (requiring removal by a specialist) for undisplaced compression (buckle) fractures; cast length and position; and the role of surgical fixation for displaced wrist fractures in children. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (October 2007), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2007, Issue 4), MEDLINE (from 1966), EMBASE (from 1988), CINAHL (from 1982) and reference lists of articles. Date of last search October 2007. Any randomised or quasi-randomised controlled trials comparing types and position of casts and the use of surgical fixation for distal radius fractures in children. Two authors performed trial selection. All three authors independently assessed methodological quality and extracted data. The 10 included trials, involving 827 children, were of variable quality.Four trials compared removable splintage versus the traditional below-elbow cast in children with buckle fractures. There was no short-term deformity recorded in all four trials and, in one trial, no refracture at six months. The Futura splint was cheaper to use; a removable plaster splint was less restrictive to wear enabling more children to bathe and participate in other activities, and the option preferred by children and parents; the soft bandage was more comfortable, convenient and less painful to wear; home-removable plaster casts removed by parents did not result in significant differences in outcome but were strongly favoured by parents.Two trials found below-elbow versus above-elbow casts did not increase redisplacement of reduced fractures or cast-related complications, were less restrictive during use and avoided elbow stiffness.One trial evaluating the effect of arm position in above-elbow casts found no effect on deformity.Three trials found that percutaneous wiring significantly reduced redisplacement and remanipulation but one of these found no advantage in function at three months. Limited evidence supports the use of removable splintage for buckle fractures and challenges the traditional use of above-elbow casts after reduction of displaced fractures. Although percutaneous wire fixation prevents redisplacement, the effects on longer term outcomes including function are not established.Further research is warranted on the optimum approach, including splintage, for buckle fractures; and on the use of below-elbow casts and indications for surgery for displaced wrist fractures in children.


Quasi-phase-matched second harmonic generation in silicon nitride ring resonators controlled by static electric field.
Actively-controlled second harmonic generation in a silicon nitride ring resonator is proposed and simulated. The ring was designed to resonate at both pump and second harmonic wavelengths and quasi-phase-matched frequency conversion is induced by a periodic static electric field generated by voltage applied to electrodes arranged along the ring. Nonlinear propagation simulations were undertaken and an efficiency of -21.67 dB was calculated for 60 mW of pump power at 1550 nm and for a 30V applied voltage, which compares favorably with demonstrated all-optical second harmonic generation in integrated microresonators. Transient effects were also evaluated. The proposed design can be exploited for the construction of electro-optical devices based on nonlinear effects in CMOS compatible circuits.


Longevity, genes, and aging.
Until recently, biogerontology was a backwater of biology, but progress in the qualitative and quantitative genetic analysis of longevity has led to a revolution in aging research. This research has revealed that extended longevity is frequently associated with enhanced metabolic capacity and response to stress. Moreover, it suggests that there are multiple mechanisms of aging. Because of its complexity, the aging process takes us into the realm of integrative biology, and thus, biogerontology should prove instrumental in deciphering the functional and regulatory circuitry of the sequenced genome.


Ten years of health workforce planning in the Netherlands: a tentative evaluation of GP planning as an example.
In many countries, health-care labour markets are constantly being challenged by an alternation of shortage and oversupply. Avoiding these cyclic variations is a major challenge. In the Netherlands, a workforce planning model has been used in health care for ten years. Since 1970, the Dutch government has explored different approaches to determine the inflow in medical schools. In 2000, a simulation model for health workforce planning was developed to estimate the required and available capacity of health professionals in the Netherlands. In this paper, this model is explained, using the Dutch general practitioners as an example. After the different steps in the model are clarified, it is shown how elements can be added to arrive at different versions of the model, or 'scenarios'. A comparison is made of the results of different scenarios for different years. In addition, the subsequent stakeholder decision-making process is considered. Discussion of this paper shows that workforce planning in the Netherlands is a complex modelling task, which is sensitive to different developments influencing the balance between supply and demand. It seems plausible that workforce planning has resulted in a balance between supply and demand of general practitioners. Still, it remains important that the modelling process is accepted by the different stakeholders. Besides calculating the balance between supply and demand, there needs to be an agreement between the stakeholders to implement the advised training inflow.The Dutch simulation model was evaluated using six criteria to be met by models suitable for policy objectives. This model meets these criteria, as it is a comprehensive and parsimonious model that can include all relevant factors. Over the last decade, health workforce planning in the Netherlands has become an accepted instrument for calculating the required supply of health professionals on a regular basis. One of the strengths of the Dutch model is that it can be used for different types of medical and allied health professionals. A weakness is that the model is not yet fully capable of including substitutions between different medical professions to plan from a skill-mix perspective. Several improvements remain possible.


Making colourful sense of Raman images of single cells.
In order to understand biological systems it is important to gain pertinent information on the spatial localisation of chemicals within cells. With the relatively recent advent of high-resolution chemical imaging this is being realised and one rapidly developing area of research is the Raman mapping of single cells, an approach whose success has vast potential for numerous areas of biomedical research. However, there is a danger of undermining the potential routine use of Raman mapping due to a lack of consistency and transparency in the way false-shaded Raman images are constructed. In this study we demonstrate, through the use of simulated data and real Raman maps of single human keratinocyte (HaCaT) cells, how changes in the application of colour shading can dramatically alter the final Raman images. In order to avoid ambiguity and potential subjectivity in image interpretation we suggest that data distribution plots are used to aid shading approaches and that extreme care is taken to use the most appropriate false-shading for the biomedical question under investigation.


Trophic diversity in the evolution and community assembly of loricariid catfishes.
The Neotropical catfish family Loricariidae contains over 830 species that display extraordinary variation in jaw morphologies but nonetheless reveal little interspecific variation from a generalized diet of detritus and algae. To investigate this paradox, we collected δ13C and δ15N stable isotope signatures from 649 specimens representing 32 loricariid genera and 82 species from 19 local assemblages distributed across South America. We calculated vectors representing the distance and direction of each specimen relative to the δ15N/δ13C centroid for its local assemblage, and then examined the evolutionary diversification of loricariids across assemblage isotope niche space by regressing the mean vector for each genus in each assemblage onto a phylogeny reconstructed from osteological characters. Loricariids displayed a total range of δ15N assemblage centroid deviation spanning 4.9‰, which is within the tissue-diet discrimination range known for Loricariidae, indicating that they feed at a similar trophic level and that δ15N largely reflects differences in their dietary protein content. Total range of δ13C deviation spanned 7.4‰, which is less than the minimum range reported for neotropical river fish communities, suggesting that loricariids selectively assimilate a restricted subset of the full basal resource spectrum available to fishes. Phylogenetic regression of assemblage centroid-standardized vectors for δ15N and δ13C revealed that loricariid genera with allopatric distributions in disjunct river basins partition basal resources in an evolutionarily conserved manner concordant with patterns of jaw morphological specialization and with evolutionary diversification via ecological radiation. Trophic partitioning along elemental/nutritional gradients may provide an important mechanism of dietary segregation and evolutionary diversification among loricariids and perhaps other taxonomic groups of apparently generalist detritivores and herbivores. Evolutionary patterns among the Loricariidae show a high degree of trophic niche conservatism, indicating that evolutionary lineage affiliation can be a strong predictor of how basal consumers segregate trophic niche space.


Physiological ligands ADP and Pi modulate the degree of intrinsic coupling in the ATP synthase of the photosynthetic bacterium Rhodobacter capsulatus.
The proton-pumping and the ATP hydrolysis activities of the ATP synthase of Rhodobacter capsulatus have been compared as a function of the ADP and P(i) concentrations. The proton pumping was measured either with the transmembrane pH difference probe, 9-amino-6-chloro-2-methoxyacridine, or with the transmembrane electric potential difference probe, bis(3-propyl-5-oxoisoxazol-4-yl)pentamethine oxonol, obtaining consistent results. The comparison indicates that an intrinsic uncoupling of ATP synthase is induced when the concentration of either ligand is decreased. The half-maximal effect was found in the submicromolar range for ADP and at about 70 microM for P(i). It is proposed that a switch from a partially uncoupled state of ATP synthase to the coupled state is induced by the simultaneous binding of ADP and P(i).


Overexpression of the mitochondrial T3 receptor p43 induces a shift in skeletal muscle fiber types.
In previous studies, we have characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor and consequently stimulating mitochondrial activity and mitochondrial biogenesis. We have established the involvement of this T3 pathway in the regulation of in vitro myoblast differentiation. We have generated mice overexpressing p43 under control of the human alpha-skeletal actin promoter. In agreement with the previous characterization of this promoter, northern-blot and western-blot experiments confirmed that after birth p43 was specifically overexpressed in skeletal muscle. As expected from in vitro studies, in 2-month old mice, p43 overexpression increased mitochondrial genes expression and mitochondrial biogenesis as attested by the increase of mitochondrial mass and mt-DNA copy number. In addition, transgenic mice had a body temperature 0.8 degrees C higher than control ones and displayed lower plasma triiodothyronine levels. Skeletal muscles of transgenic mice were redder than wild-type animals suggesting an increased oxidative metabolism. In line with this observation, in gastrocnemius, we recorded a strong increase in cytochrome oxidase activity and in mitochondrial respiration. Moreover, we observed that p43 drives the formation of oxidative fibers: in soleus muscle, where MyHC IIa fibers were partly replaced by type I fibers; in gastrocnemius muscle, we found an increase in MyHC IIa and IIx expression associated with a reduction in the number of glycolytic fibers type IIb. In addition, we found that PGC-1alpha and PPARdelta, two major regulators of muscle phenotype were up regulated in p43 transgenic mice suggesting that these proteins could be downstream targets of mitochondrial activity. These data indicate that the direct mitochondrial T3 pathway is deeply involved in the acquisition of contractile and metabolic features of muscle fibers in particular by regulating PGC-1alpha and PPARdelta.


Size-assortative choice and mate availability influences hybridization between red wolves (Canis rufus) and coyotes (Canis latrans).
Anthropogenic hybridization of historically isolated taxa has become a primary conservation challenge for many imperiled species. Indeed, hybridization between red wolves (Canis rufus) and coyotes (Canis latrans) poses a significant challenge to red wolf recovery. We considered seven hypotheses to assess factors influencing hybridization between red wolves and coyotes via pair-bonding between the two species. Because long-term monogamy and defense of all-purpose territories are core characteristics of both species, mate choice has long-term consequences. Therefore, red wolves may choose similar-sized mates to acquire partners that behave similarly to themselves in the use of space and diet. We observed multiple factors influencing breeding pair formation by red wolves and found that most wolves paired with similar-sized conspecifics and wolves that formed congeneric pairs with nonwolves (coyotes and hybrids) were mostly female wolves, the smaller of the two sexes. Additionally, we observed that lower red wolf abundance relative to nonwolves and the absence of helpers increased the probability that wolves consorted with nonwolves. However, successful pairings between red wolves and nonwolves were associated with wolves that maintained small home ranges. Behaviors associated with territoriality are energetically demanding and behaviors (e.g., aggressive interactions, foraging, and space use) involved in maintaining territories are influenced by body size. Consequently, we propose the hypothesis that size disparities between consorting red wolves and coyotes influence positive assortative mating and may represent a reproductive barrier between the two species. We offer that it may be possible to maintain wild populations of red wolves in the presence of coyotes if management strategies increase red wolf abundance on the landscape by mitigating key threats, such as human-caused mortality and hybridization with coyotes. Increasing red wolf abundance would likely restore selection pressures that increase mean body and home-range sizes of red wolves and decrease hybridization rates via reduced occurrence of congeneric pairs.


Pharmacologic characterization of a nicotine-discriminative stimulus in rhesus monkeys.
This study examined mechanisms by which nicotine (1.78 mg/kg base s.c.) produces discriminative stimulus effects in rhesus monkeys. In addition to nicotine, various test compounds were studied including other nicotinic acetylcholine receptor agonists (varenicline and cytisine), antagonists [mecamylamine and the α4β2 receptor-selective antagonist dihydro-β-erythroidine (DHβE)], a nicotinic acetylcholine receptor antagonist/indirect-acting catecholamine agonist (bupropion), and non-nicotinics (cocaine and midazolam). Nicotine, varenicline, and cytisine dose-dependently increased drug-lever responding; the ED(50) values were 0.47, 0.53, and 39 mg/kg, respectively. Bupropion and cocaine produced 100% nicotine-lever responding in a subset of monkeys, whereas mecamylamine, DHβE, and midazolam produced predominantly vehicle-lever responding. The training dose of nicotine resulted in 1128 ng/ml cotinine in saliva. Mecamylamine antagonized the discriminative stimulus effects of nicotine and varenicline, whereas DHβE was much less effective. Nicotine and varenicline had synergistic discriminative stimulus effects. In monkeys responding predominantly on the vehicle lever after a test compound (bupropion, cocaine, and midazolam), that test compound blocked the nicotine-discriminative stimulus, perhaps reflecting a perceptual-masking phenomenon. These results show that nicotine, varenicline, and cytisine produce discriminative stimulus effects through mecamylamine-sensitive receptors (i.e., nicotinic acetylcholine) in primates, whereas the involvement of DHβE-sensitive receptors (i.e., α4β2) is unclear. The current nicotine-discrimination assay did not detect a difference in agonist efficacy between nicotine, varenicline, and cytisine, but did show evidence of involvement of dopamine. The control that nicotine has over choice behavior can be disrupted by non-nicotinic compounds, suggesting that non-nicotinics could be exploited to decrease the control that tobacco has over behavior.


Acute effects of exercise and calorie restriction on triglyceride metabolism in women.
The mechanisms by which exercise reduces fasting plasma triglyceride (TG) concentrations in women and the effect of negative energy balance independent of muscular contraction are not known.The aim of this study was to evaluate the effects of equivalent energy deficits induced by exercise or calorie restriction on basal VLDL-TG metabolism in women. Eleven healthy women (age = 23.5 ± 2.7 yr, body mass index = 21.6 ± 1.4 kg·m-2; mean ± SD) underwent a stable isotopically labeled tracer infusion study to determine basal VLDL-TG kinetics after performing, in random order, three experimental trials on the previous day: (i) a single exercise bout (brisk walking at 60% of peak oxygen consumption for 123 ± 18 min, with a net energy expenditure of 2.06 ± 0.39 MJ, ∼500 kcal), (ii) dietary energy restriction of 2.10 ± 0.41 MJ, and (iii) a control day of isocaloric feeding and rest (zero energy balance). Fasting plasma VLDL-TG concentration was approximately 30% lower after the exercise trial compared with the control trial (P < 0.001), whereas no significant change was detected after the calorie restriction trial (P = 0.297 vs control). Relative to the control condition, exercise increased the plasma clearance rate of VLDL-TG by 22% (P = 0.001) and reduced hepatic VLDL-TG secretion rate by approximately 17% (P = 0.042), whereas hypocaloric diet had no effect on VLDL-TG kinetics (P > 0.2). (i) Exercise-induced hypotriglyceridemia in women manifests through a different mechanism (increased clearance and decreased secretion of VLDL-TG) than that previously described in men (increased clearance of VLDL-TG only), and (ii) exercise affects TG homeostasis by eliciting changes in VLDL-TG kinetics that cannot be reproduced by an equivalent diet-induced energy deficit, indicating that these changes are independent of the exercise-induced negative energy balance but instead are specific to muscular contraction.


Palladium-Catalyzed Fluorination of Cyclic Vinyl Triflates: Effect of TESCF3 as an Additive.
A method for the palladium-catalyzed fluorination of cyclic vinyl triflates has been developed. As with several previous palladium-catalyzed fluorination reactions using fluoride salts, controlling the regioselectivity presented a challenge in developing a practical synthetic procedure. The addition of triethyl(trifluoromethyl)silane (TESCF3 ) was found to effectively address this problem and resulted in drastically improved regioselectivities in this palladium-catalyzed fluorination reaction. This discovery, along with the use of a new biarylphosphine ligand, allowed for the development of an efficient and highly regioselective protocol for the fluorination of vinyl triflates. This method is compatible with a range of sensitive functional groups and provides access to five-, six-, and seven-membered cyclic vinyl fluorides.


The stress-buffering effects of a brief dyadic interaction before an acute stressor.
Although previous studies have confirmed that affectionate interaction can reduce the effects of stress, whether or not this effect is due more to habituation or the accumulation of affection remains an area of debate. The goal of the present study was to determine how specific acts of affection mitigate the effects of stress. Sixty mixed-sex dyads (half platonic friends and half dating partners) were randomly assigned to one of three conditions, affectionate interaction, quiet rest with the friend/romantic partner present, or separation from the friend/romantic partner, before one of the partners experienced a series of stressful activities. Results revealed that participants in the affection condition experienced the smallest increase in cardiovascular arousal regardless of relationship status. Participants' endocrine responses were more nuanced and depended on both their biological sex and the nature of the relationship with the companion. Given that these systems did not act in concert with one another, results provide mixed evidence for both an accumulation and habituation effect.


Nucleotide sequence of the transposable element IS15.
We have determined the complete nucleotide sequence of the right (R) copy of the insertion sequence IS15 which flanks, in direct orientation, the composite transposon Tn1525. IS15-R, which is capable of independent transposition, is 1648 bp long and has short (14 bp) perfect inverted repeats at its termini. Analysis of the nucleotide sequence indicates that IS15-R results from the transposition, in direct orientation, of a smaller (820 bp long) IS, designated IS15-delta, into itself. This integration event is accompanied by the duplication of 8 bp in the target DNA. IS15-delta possesses two large overlapping open reading frames (ORF) located on opposite strands. Because of this particular structure, IS15 possesses four large ORFs which, due to the integration event, exhibit some differences with those of the parental IS15-delta.


HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging.
We investigated the interactions between human immunodeficiency virus (HIV) infection and aging and their effects on brain function demands by means of functional magnetic resonance imaging (fMRI). A multiple-regression model was used to study the association and interaction between fMRI measures, HIV serostatus, and age for 26 HIV-infected subjects and 25 seronegative subjects. Although HIV serostatus and age independently affected fMRI measures, no interaction occurred. Functional brain demands in HIV-positive subjects were equivalent to those of HIV-negative subjects who were 15-20 years older. Frailty parallels between HIV infection and aging could result from continued immunological challenges depleting resources and triggering increased metabolic demands. In the future, fMRI could be a noninvasive biomarker to assess HIV infection in the brain.


Safety, Tolerability and Immunogenicity of Pentavalent Rotavirus Vaccine Manufactured by a Modified Process.
Rotavirus is the leading cause of severe diarrhea in infants and young children. The current formulation of pentavalent rotavirus vaccine (RV5) must be stored refrigerated at 2-8°C. A modified formulation of RV5 (RV5mp) has been developed with stability at 37°C for 7 days and an expiry extended to 36 months when stored at 2-8°C. This study (ClinicalTrials.gov identifier: NCT01600092; EudraCT number: 2012-001611-23) evaluated the safety, tolerability and immunogenicity of RV5mp versus the currently marketed RV5 in infants. To maintain blinding, both vaccine formulations were stored refrigerated at 2-8°C for the duration of the study. Immunogenicity endpoints were (1) serum neutralizing antibody titers to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and (2) proportion of subjects with a ≥3-fold rise from baseline for serum neutralizing antibody to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and serum antirotavirus immunoglobulin A. The RV5mp group (n = 505) and RV5 group (n = 509) had comparable safety profiles. There were no deaths and no vaccine-related serious adverse events in this study. With respect to immunogenicity, RV5mp was noninferior compared with RV5. Serum neutralizing antibody responses by country and breast-feeding status were generally consistent with the overall results. RV5mp enhances storage requirements while maintaining the immunogenicity and safety profile of the currently licensed RV5. A vaccine that is stable at room temperature may be more convenient for vaccinators, particularly in places where the cold chain is unreliable, and ultimately will permit more widespread use.


The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis.
Parathyroid hormone increases bone strength primarily by stimulating bone formation, whereas antiresorptive drugs reduce bone resorption. We conducted a randomized, double-blind clinical study of parathyroid hormone and alendronate to test the hypothesis that the concurrent administration of the two agents would increase bone density more than the use of either one alone. A total of 238 postmenopausal women (who were not using bisphosphonates) with low bone mineral density at the hip or spine (a T score of less than -2.5, or a T score of less than -2.0 with an additional risk factor for osteoporosis) were randomly assigned to daily treatment with parathyroid hormone (1-84) (100 microg; 119 women), alendronate (10 mg; 60 women), or both (59 women) and were followed for 12 months. Bone mineral density at the spine and hip was assessed by dual-energy x-ray absorptiometry and quantitative computed tomography. Markers of bone turnover were measured in fasting blood samples. The bone mineral density at the spine increased in all the treatment groups, and there was no significant difference in the increase between the parathyroid hormone group and the combination-therapy group. The volumetric density of the trabecular bone at the spine increased substantially in all groups, but the increase in the parathyroid hormone group was about twice that found in either of the other groups. Bone formation increased markedly in the parathyroid hormone group but not in the combination-therapy group. Bone resorption decreased in the combination-therapy group and the alendronate group. There was no evidence of synergy between parathyroid hormone and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of parathyroid hormone. Longer-term studies of fractures are needed to determine whether and how antiresorptive drugs can be optimally used in conjunction with parathyroid hormone therapy.


The eNutrition Academy: Supporting a New Generation of Nutritional Scientists around the World.
Nutrition training and building capacity to provide a competent workforce to support national and regional efforts to combat malnutrition remain a major challenge in Africa and other developing regions of the world. The capacity to provide the necessary intellectual drive for nutrition research, policy, and practice in countries lacking in readiness for nutrition actions is imperative to improve the health of their people. To help address this need, the eNutrition Academy (eNA) was formed as a global partnership organization by the African Nutrition Society, the Federation of African Nutrition Societies, the Nutrition Society of the United Kingdom and Ireland, the ASN, and the International Union of Nutritional Sciences, supported by Cambridge University Press. The primary objective of this partnership is to provide an online learning platform that is free to access, enabling users to benefit from a wide range of learning materials from basic tools to more-advanced learning materials for teachers and researchers in developing countries. The goal of this article was to summarize the findings of a symposium held at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2015, which explored the themes of international capacity development, with a particular focus on the African continent, online learning, and the eNA e-learning platform. Given the vast human capacity present in Africa that is poised to create new solutions to address the public health needs of the continent, now is an opportune time to establish South-North and South-South partnerships to develop the next generation of African nutritional scientists.


The effects of regular yoga practice on pulmonary function in healthy individuals: a literature review.
Yoga is a popular form of exercise in the Western world, and yoga's effects on pulmonary function have been investigated previously. The purpose of this article is to review this research systematically and determine if regular yoga training improves pulmonary function in apparently healthy individuals. Using the Alternative Health Watch, the Physical Education Index, Medline,(®) and the SPORTdiscus databases; and the keywords yoga, respiration, and pulmonary function, a comprehensive search was conducted that yielded 57 studies. Of these studies selections were made to include only experimental studies written in English, published in peer-reviewed journals after 1980, and investigating the effects of regular yoga practice on pulmonary function in healthy individuals participating in the studies. Yoga improved pulmonary function, as measured by maximum inspiratory pressure, maximum expiratory pressure, maximum voluntary ventilation, forced vital capacity, forced expiratory volume in 1 second, and peak expiratory flow rate, in all (N=9), but 1, study. Overall, pulmonary function appears to improve with a minimum of 10 weeks of regular yoga practice, and the magnitude of this improvement is related to fitness level and/or the length of time the subjects spend practicing pranayama (i.e., breathing exercises). In other words, greater improvements in pulmonary function are more likely to be seen in less-fit individuals and/or those that engage in longer periods of pranayama. Additional studies examining various yoga practices are warranted to gain a more comprehensive understanding of the effects of yoga techniques on pulmonary functions.


Phosphorylation network rewiring by gene duplication.
Elucidating how complex regulatory networks have assembled during evolution requires a detailed understanding of the evolutionary dynamics that follow gene duplication events, including changes in post-translational modifications. We compared the phosphorylation profiles of paralogous proteins in the budding yeast Saccharomyces cerevisiae to that of a species that diverged from the budding yeast before the duplication of those genes. We found that 100 million years of post-duplication divergence are sufficient for the majority of phosphorylation sites to be lost or gained in one paralog or the other, with a strong bias toward losses. However, some losses may be partly compensated for by the evolution of other phosphosites, as paralogous proteins tend to preserve similar numbers of phosphosites over time. We also found that up to 50% of kinase-substrate relationships may have been rewired during this period. Our results suggest that after gene duplication, proteins tend to subfunctionalize at the level of post-translational regulation and that even when phosphosites are preserved, there is a turnover of the kinases that phosphorylate them.


The flgK motility operon of Borrelia burgdorferi is initiated by a sigma 70-like promoter.
A cluster of flagellar genes of Borrelia burgdorferi was identified and sequenced. This cluster comprises an operon, designated the flgK operon, which is initiated by a sigma 70-like promoter. The flgK operon consists of flbF (function unknown), flgK (encoding HAP1), flgL (encoding HAP3) and orfX (function unknown), and maps at 185 kb on the chromosome. In other bacteria, the hook-associated proteins HAP1 and HAP3 connect the flagellar filament to the hook and are required for the last stage of flagellar assembly. Reverse transcriptase-PCR analysis indicated that flbF through to orfX are transcribed as a single mRNA, and primer extension analysis revealed that transcription of the flgK operon is initiated by a sigma 70-like promoter upstream of flbF. Subcloning the flgK promoter element into a promoter probe cat vector revealed that the flgK promoter element had strong activity in both Escherichia coli and Salmonella typhimurium. In addition, when this construct was transformed into a fliA mutant of S. typhimurium which lacked a functional flagellar-specific sigma 28 factor, the flgK promoter was still functional. Based on these results, the promoter element of the flagellin gene (fla, hereafter referred to as flaB) was re-examined. flaB encodes the flagellar filament protein, and a sigma gp33-34-like promoter has been reported to be involved in the transcription of this gene. A transcriptional start point was found 1 bp downstream of the reported start site. The sequence around -10 and -35 are consistent with the presence of a sigma 70-like promoter in addition to the putative sigma gp33-34-like promoter for flaB. In contrast to the flgK promoter element, no activity was detected after subcloning a flaB promoter element into the promoter probe cat vector. Because a sigma 70-like promoter rather than a unique flagellar sigma factor is involved in the later stage of flagellar assembly, the regulation of B. burgdorferi flagellar genes is evidently different from that of other bacteria.


Anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility.
Limited observational evidence suggests potential benefit for subfertile women undergoing operative hysteroscopy with several anti-adhesion therapies (e.g. insertion of an intrauterine device (IUD) or balloon, hormonal treatment, barrier gels or human amniotic membrane grafting) to decrease intrauterine adhesions (IUAs). To assess the effectiveness of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility. We searched the following databases from inception to March 2015: the Cochrane Menstrual Disorders and Subfertility Specialised Register, the Cochrane Central Register of Controlled Trials (2015, Issue 2), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and other electronic sources of trials, including trial registers, sources of unpublished literature and reference lists. We handsearched The Journal of Minimally Invasive Gynecology, and we contacted experts in the field. Randomised comparisons of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy following operative hysteroscopy in subfertile women. The primary outcome was live birth or ongoing pregnancy. Secondary outcomes were clinical pregnancy, miscarriage and IUAs present at second look, along with their mean adhesion scores or severity. Two review authors independently selected studies, assessed risk of bias, extracted data and evaluated quality of the evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) method. We included 11 randomised studies on use of an inserted device versus no treatment (two studies; 84 women) or another inserted device (one study; 162 women), hormonal treatment versus no treatment or placebo (two studies; 131 women), gel versus no treatment (five studies; 383 women) and graft versus no graft (one study; 43 women). The total number of women randomly assigned was 924, but data on only 803 participants were available for analysis. The proportion of subfertile women varied from 0% (one study; 41 women), to less than 50% (six studies; 487 women), to 100% (one study; 43 women); the proportion was unknown in three studies (232 women). Most studies (9/11) were at high risk of bias with respect to one or more methodological criteria.We found no evidence of differences between anti-adhesion therapy and no treatment or placebo with respect to live birth rates (odds ratio (OR) 0.99, 95% confidence interval (CI) 0.46 to 2.13, P value = 0.98, three studies, 150 women; low-quality evidence) and no statistical heterogeneity (Chi(2) = 0.14, df = 2 (P value = 0.93), I(2) = 0%).Anti-adhesion therapy was associated with fewer IUAs at any second-look hysteroscopy when compared with no treatment or placebo (OR 0.36, 95% CI 0.20 to 0.64, P value = 0.0005, seven studies, 528 women; very low-quality evidence). We found no statistical heterogeneity (Chi(2) = 2.65, df = 5 (P value = 0.75), I(2) = 0%). The number needed to treat for an additional beneficial outcome (NNTB) was 9 (95% CI 6 to 20).No evidence suggested differences between an IUD and an intrauterine balloon with respect to IUAs at second-look hysteroscopy (OR 1.23, 95% CI 0.64 to 2.37, P value = 0.54, one study, 162 women; very low-quality evidence). Implications for clinical practiceThe quality of the evidence retrieved was low or very low for all outcomes. Clinical effectiveness of anti-adhesion treatment for improving key reproductive outcomes or for decreasing IUAs following operative hysteroscopy in subfertile women remains uncertain. Implications for researchAdditional studies are needed to assess the effectiveness of different anti-adhesion therapies for improving reproductive outcomes in subfertile women treated by operative hysteroscopy.


Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury.
WNT/β-catenin signalling is crucial for intestinal homoeostasis. The intestinal epithelium and stroma are the major source of WNT ligands but their origin and role in intestinal stem cell (ISC) and epithelial repair remains unknown. Macrophages are a major constituent of the intestinal stroma. Here, we analyse the role of macrophage-derived WNT in intestinal repair in mice by inhibiting their release using a macrophage-restricted ablation of Porcupine, a gene essential for WNT synthesis. Such Porcn-depleted mice have normal intestinal morphology but are hypersensitive to radiation injury in the intestine compared with wild-type (WT) littermates. Porcn-null mice are rescued from radiation lethality by treatment with WT but not Porcn-null bone marrow macrophage-conditioned medium (CM). Depletion of extracellular vesicles (EV) from the macrophage CM removes WNT function and its ability to rescue ISCs from radiation lethality. Therefore macrophage-derived EV-packaged WNTs are essential for regenerative response of intestine against radiation.


Life-Threatening Serotonin Syndrome Precipitated by Discontinuation of Serotonin-Dopamine Antagonist in the Presence of Serotonergic Agents: A Case Report.
Serotonin syndrome is caused by excessive activation of serotonin (5-hydroxytryptamine [5-HT]) neurotransmission. Although the discontinuation of antipsychotics with 5-HT2 receptor antagonistic characteristics could theoretically result in serotonin syndrome, there have been very few reports on the syndrome thus far. A 75-year-old woman with somatoform disorder was transferred to our emergency room because of pyrexia, unconsciousness, and myoclonus with hyperreflexia. She had been taking milnacipran and perospirone for 10 years and had started taking duloxetine 2 months before the event. Thereafter, she suffered diaphoresis, gait disturbance, and tremor. Her psychiatrist advised her to stop taking perospirone, because of suspicion of extrapyramidal symptoms, a day before admission. The clinical diagnosis of serotonin syndrome was made based on her symptoms while using serotonergic agents. Her symptoms were so severe that she was transferred to the intensive care unit, where supportive care was successful. Discontinuation of antipsychotics that are 5-HT2 receptor antagonists may lead to serotonin syndrome in patients who take serotonergic agents. As extrapyramidal symptoms and serotonin toxicity share some clinical features, detailed drug history and physical examination are necessary for successful treatment.


A correlation between the severity of lung lesions on radiographs and clinical findings in patients with severe acute respiratory syndrome.
The purpose of this study was to quantify lesions on chest radiographs in patients with severe acute respiratory syndrome (SARS) and analyze the severity of the lesions with clinical parameters. Two experienced radiologists reviewed chest radiographs of 28 patients with SARS. Each lung was divided into upper, middle, and lower zones. A SARS-related lesion in each zone was scored using a four-point scale: zero to three. The mean and maximal radiographic scores were analyzed statistically to determine if the scorings were related to the laboratory data and clinical course. Forward stepwise multiple linear regression showed that the mean radiographic score correlated most significantly with the number of hospitalized days (p < 0.001). The second most significant factor was the absolute lymphocyte count (p < 0.001) and the third most significant factor was the number of days of intubation (p = 0.025). The maximal radiographic score correlated best with the percentage of lymphocytes in a leukocyte count (p < 0.001), while the second most significant factor was the number of hospitalized days (p < 0.001) and the third most significant factor was the absolute lymphocyte count (p = 0.013). The mean radiographic scores of the patients who died, with comorbidities and without a comorbidity were 11.1, 6.3 and 2.9, respectively (p = 0.032). The corresponding value for maximal radiographic scores were 17.7, 9.7 and 6.0, respectively (p = 0.033). The severity of abnormalities quantified on chest radiographs in patients with SARS correlates with the clinical parameters.


Realizing a High ZT of 1.6 in N-Type Mg3Sb2-Based Zintl Compounds through Mn and Se Codoping.
Mg3Sb2-based compounds by virtue of nontoxicity and low-cost have become a promising class of candidates for midtemperature thermoelectric power generation. Here, we successfully fabricated n-type Mg3Sb2-based materials using an inexpensive and efficient approach of one-step ball milling and spark plasma sintering, and demonstrate that a complementary and favorable effect of multiple elements coalloying/-doping leads to an excellent thermoelectric performance. The intrinsic p-type conducting behavior for Mg3Sb2 could be changed to n-type through Bi and Se coalloying on Sb sublattices with excess Mg, resulting from the suppression of Mg vacancies and the formation of Mg interstitial. Furthermore, Mn doping on Mg sublattices could soften the chemical bonds, leading to the increase of carrier mobility and concentration simultaneously. Additionally, multielement coalloying/-doping could significantly increase the lattice disorder, which undoubtedly strengthens the phonon scattering and readily results in a suppressed lattice thermal conductivity. As a result, a highest ZT value of 1.6 at 723 K and an average ZT value up to 1.1 were obtained in the temperature range of 323-723 K in the Mg3.18Mn0.02Sb1.5Bi0.49Se0.01 sample, which is one of the highest values among the Te free Mg3Sb2. This work could give guidance for improving the thermoelectric performance of Zintl phase materials or even others using the multielement codoping/-alloying strategy.