Nurse-led primary health care for homeless men: a multimethods descriptive study.
To explore the primary healthcare needs and health service use of homeless men in inner Sydney. People experiencing homelessness have greater health needs than the general population and place high demands on tertiary care, which is expensive and may not be the optimum service for their needs. Accessible, approachable and affordable primary healthcare services could improve the health of homeless persons and potentially decrease costs to the healthcare system. A multimethod design using a cross-sectional survey (n = 40) and administrative data (n = 2 707 daily summaries) collected from a nurse-led primary healthcare clinic for homeless men in Sydney. Survey respondents were aged 27-76 years. Health problems reflected multimorbidity, with mental health issues present in almost all respondents. The majority had attended the clinic more than 20 times in the past year and said the services, treatments and referrals helped them avoid the emergency department. Administrative data indicated that medication administration was the most frequent service provided. Referrals to other health services doubled over the 7-year period. Multiple morbidities, particularly mental health issues, are associated with homelessness. A proactive approach by nurses including preventative services appeared to overcome barriers to health service use. This nurse-led primary healthcare clinic highlights the importance of providing services to homeless men with multiple comorbidities. Respect and trust in addition to easy access to health services appear to be important facilitators of health service use. A greater number of primary health services that collaborate with specialist services, including nurse-led clinics, may facilitate health care for persons who are homeless, reducing the burden on acute services.


Role of vaccine therapy in cancer: biology and practice.
Vaccines constitute a potential new therapeutic approach for a range of human cancers. Unlike other therapeutics, vaccines initiate a dynamic process in the host immune system that can be exploited with subsequent therapies. Indeed, recent preclinical and clinical studies with cancer vaccines have provided evidence that this unique therapeutic modality should lead to consideration of new paradigms in both clinical trial design and endpoints and in combination therapies. The present article reviews and sets out a rationale for these new paradigms, with a focus on prostate cancer.


Risk factors for neck and upper extremity disorders among computers users and the effect of interventions: an overview of systematic reviews.
To summarize systematic reviews that 1) assessed the evidence for causal relationships between computer work and the occurrence of carpal tunnel syndrome (CTS) or upper extremity musculoskeletal disorders (UEMSDs), or 2) reported on intervention studies among computer users/or office workers. PubMed, Embase, CINAHL and Web of Science were searched for reviews published between 1999 and 2010. Additional publications were provided by content area experts. The primary author extracted all data using a purpose-built form, while two of the authors evaluated the quality of the reviews using recommended standard criteria from AMSTAR; disagreements were resolved by discussion. The quality of evidence syntheses in the included reviews was assessed qualitatively for each outcome and for the interventions. Altogether, 1,349 review titles were identified, 47 reviews were retrieved for full text relevance assessment, and 17 reviews were finally included as being relevant and of sufficient quality. The degrees of focus and rigorousness of these 17 reviews were highly variable. Three reviews on risk factors for carpal tunnel syndrome were rated moderate to high quality, 8 reviews on risk factors for UEMSDs ranged from low to moderate/high quality, and 6 reviews on intervention studies were of moderate to high quality. The quality of the evidence for computer use as a risk factor for CTS was insufficient, while the evidence for computer use and UEMSDs was moderate regarding pain complaints and limited for specific musculoskeletal disorders. From the reviews on intervention studies no strong evidence based recommendations could be given. Computer use is associated with pain complaints, but it is still not very clear if this association is causal. The evidence for specific disorders or diseases is limited. No effective interventions have yet been documented.


Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance.
Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance.


A non-radical mechanism for methane hydroxylation at the diiron active site of soluble methane monooxygenase.
We propose a non-radical mechanism for the conversion of methane into methanol by soluble methane monooxygenase (sMMO), the active site of which involves a diiron active center. We assume the active site of the MMOH(Q) intermediate, exhibiting direct reactivity with the methane substrate, to be a bis(mu-oxo)diiron(IV) complex in which one of the iron atoms is coordinatively unsaturated (five-coordinate). Is it reasonable for such a diiron complex to be formed in the catalytic reaction of sMMO? The answer to this important question is positive from the viewpoint of energetics in density functional theory (DFT) calculations. Our model thus has a vacant coordination site for substrate methane. If MMOH(Q) involves a coordinatively unsaturated iron atom at the active center, methane is effectively converted into methanol in the broken-symmetry singlet state by a non-radical mechanism; in the first step a methane C-H bond is dissociated via a four-centered transition state (TS1) resulting in an important intermediate involving a hydroxo ligand and a methyl ligand, and in the second step the binding of the methyl ligand and the hydroxo ligand through a three-centered transition state (TS2) results in the formation of a methanol complex. This mechanism is essentially identical to that of the methane-methanol conversion by the bare FeO(+) complex and relevant transition metal-oxo complexes in the gas phase. Neither radical species nor ionic species are involved in this mechanism. We look in detail at kinetic isotope effects (KIEs) for H atom abstraction from methane on the basis of transition state theory with Wigner tunneling corrections.


Effect of nitrate, acetate, and hydrogen on native perchlorate-reducing microbial communities and their activity in vadose soil.
The effect of nitrate, acetate, and hydrogen on native perchlorate-reducing bacteria (PRB) was examined by conducting microcosm tests using vadose soil collected from a perchlorate-contaminated site. The rate of perchlorate reduction was enhanced by hydrogen amendment and inhibited by acetate amendment, compared with unamendment. Nitrate was reduced before perchlorate in all amendments. In hydrogen-amended and unamended soils, nitrate delayed perchlorate reduction, suggesting that the PRB preferentially use nitrate as an electron acceptor. In contrast, nitrate eliminated the inhibitory effect of acetate amendment on perchlorate reduction and increased the rate and the extent, possibly because the preceding nitrate reduction/denitrification decreased the acetate concentration that was inhibitory to the native PRB. In hydrogen-amended and unamended soils, perchlorate reductase gene (pcrA) copies, representing PRB densities, increased with either perchlorate or nitrate reduction, suggesting that either perchlorate or nitrate stimulates the growth of the PRB. In contrast, in acetate-amended soil pcrA increased only when perchlorate was depleted: a large portion of the PRB may have not utilized nitrate in this amendment. Nitrate addition did not alter the distribution of the dominant pcrA clones in hydrogen-amended soil, likely because of the functional redundancy of PRB as nitrate-reducers/denitrifiers, whereas acetate selected different pcrA clones from those with hydrogen amendment.


Putting different price tags on the same health condition: re-evaluating the well-being valuation approach.
Many recent writings in health policy have proposed that health be valued directly and in monetary terms using the new well-being valuation method. Yet there is no clear consensus on what the best measure of individual's experience may be for the evaluation process. To shed light on this issue, monetary values for a number of health problems are compared across different well-being measures within the same UK data set. We find that, whilst there is strong internal consistency of health impacts within each well-being measure, hugely different monetary valuations are obtained for the same health problem across different well-being measures. Our results, although should only viewed as illustrative, call for economists to rethink about which measure of well-being or experienced utility to be used in the well-being valuation method, should the approach ever be implemented in real policy contexts.


Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease.
The long non-coding RNA CDKN2B-AS1, commonly referred to as the A ntisense N on-coding R NA in the I NK4 L ocus (ANRIL), is a 3.8-kb-long RNA transcribed from the short arm of human chromosome 9 on p21.3 that overlaps a critical region encompassing three major tumor suppressor loci juxtaposed to the INK4b-ARF-INK4a gene cluster and the methyl-thioadenosine phosphorylase (MTAP) gene. Genome-wide association studies have identified this region with a remarkable and growing number of disease-associated DNA alterations and single nucleotide polymorphisms, which corresponds to increased susceptibility to human disease. Recent attention has been devoted on whether these alterations in the ANRIL sequence affect its expression levels and/or its splicing transcript variation, and in consequence, global cellular homeostasis. Moreover, recent evidence postulates that ANRIL not only can regulate their immediate genomic neighbors in cis, but also has the capacity to regulate additional loci in trans. This action would further increase the complexity for mechanisms imposed through ANRIL and furthering the scope of this lncRNA in disease pathogenesis. In this chapter, we summarize the most recent findings on the investigation of ANRIL and provide a perspective on the biological and clinical significance of ANRIL as a putative biomarker, specifically, its potential role in directing cellular fates leading to cancer and cardiovascular disease.


Assessing the Goodness of Fit of Phylogenetic Comparative Methods: A Meta-Analysis and Simulation Study.
Phylogenetic comparative methods (PCMs) have been applied widely in analyzing data from related species but their fit to data is rarely assessed. Can one determine whether any particular comparative method is typically more appropriate than others by examining comparative data sets? I conducted a meta-analysis of 122 phylogenetic data sets found by searching all papers in JEB, Blackwell Synergy and JSTOR published in 2002-2005 for the purpose of assessing the fit of PCMs. The number of species in these data sets ranged from 9 to 117. I used the Akaike information criterion to compare PCMs, and then fit PCMs to bivariate data sets through REML analysis. Correlation estimates between two traits and bootstrapped confidence intervals of correlations from each model were also compared. For phylogenies of less than one hundred taxa, the Independent Contrast method and the independent, non-phylogenetic models provide the best fit.For bivariate analysis, correlations from different PCMs are qualitatively similar so that actual correlations from real data seem to be robust to the PCM chosen for the analysis. Therefore, researchers might apply the PCM they believe best describes the evolutionary mechanisms underlying their data.


Antigen processing defects in cervical carcinomas limit the presentation of a CTL epitope from human papillomavirus 16 E6.
Human papillomavirus (HPV) infection, particularly type 16, is causally associated with the development of cervical cancer. The E6 and E7 proteins of HPV are constitutively expressed in cervical carcinoma cells making them attractive targets for CTL-based immunotherapy. However, few studies have addressed whether cervical carcinomas can process and present HPV E6/E7-derived Ags for recognition by CTL. We generated HLA-A*0201-restricted CTL clones against HPV16 E6(29-38) that recognized HPV16 E6 Ags transfected into B lymphoblastoid cells. These CTL were unable to recognize HLA-A*0201(+) HPV16 E6(+) cervical carcinoma cell lines even when the level of endogenous HPV16 E6 in these cells was increased by transfection. This defect in presentation of HPV16 E6(29-38) correlated with low level expression of HLA class I, proteasome subunits low molecular mass protein 2 and 7, and the transporter proteins TAP1 and TAP2 in the cervical carcinoma cell lines. The expression of all of these proteins could be up-regulated by IFN-gamma, but this was insufficient for CTL recognition unless the level of HPV16 E6 Ag was also increased by transfection. CTL recognition of the HPV16 E6(29-38) epitope in 721.174 B cells was dependent on TAP expression but independent of immunoproteasome expression. Collectively, these findings suggest that presentation of the HPV16 E6(29-38) epitope in cervical carcinoma cell lines is limited both by the level of TAP expression and by the low level or availability of the source HPV E6 oncoprotein. These observations place constraints on the use of this, and potentially other, HPV-derived CTL epitopes for the immunotherapy of cervical cancer.


Obesity.
Excessive fat deposition in obesity has a multifactorial aetiology, but is widely considered the result of disequilibrium between energy intake and expenditure. Despite specific public health policies and individual treatment efforts to combat the obesity epidemic, >2 billion people worldwide are overweight or obese. The central nervous system circuitry, fuel turnover and metabolism as well as adipose tissue homeostasis are important to comprehend excessive weight gain and associated comorbidities. Obesity has a profound impact on quality of life, even in seemingly healthy individuals. Diet, physical activity or exercise and lifestyle changes are the cornerstones of obesity treatment, but medical treatment and bariatric surgery are becoming important. Family history, food environment, cultural preferences, adverse reactions to food, perinatal nutrition, previous or current diseases and physical activity patterns are relevant aspects for the health care professional to consider when treating the individual with obesity. Clinicians and other health care professionals are often ill-equipped to address the important environmental and socioeconomic drivers of the current obesity epidemic. Finally, understanding the epigenetic and genetic factors as well as metabolic pathways that take advantage of 'omics' technologies could play a very relevant part in combating obesity within a precision approach.


Suicidal ideation in a European Huntington's disease population.
Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0), anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood (OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines.


A comprehensive hybridization model allows whole HERV transcriptome profiling using high density microarray.
Human endogenous retroviruses (HERVs) have received much attention for their implications in the etiology of many human diseases and their profound effect on evolution. Notably, recent studies have highlighted associations between HERVs expression and cancers (Yu et al., Int J Mol Med 32, 2013), autoimmunity (Balada et al., Int Rev Immunol 29:351-370, 2010) and neurological (Christensen, J Neuroimmune Pharmacol 5:326-335, 2010) conditions. Their repetitive nature makes their study particularly challenging, where expression studies have largely focused on individual loci (De Parseval et al., J Virol 77:10414-10422, 2003) or general trends within families (Forsman et al., J Virol Methods 129:16-30, 2005; Seifarth et al., J Virol 79:341-352, 2005; Pichon et al., Nucleic Acids Res 34:e46, 2006). To refine our understanding of HERVs activity, we introduce here a new microarray, HERV-V3. This work was made possible by the careful detection and annotation of genomic HERV/MaLR sequences as well as the development of a new hybridization model, allowing the optimization of probe performances and the control of cross-reactions. RESULTS: HERV-V3 offers an almost complete coverage of HERVs and their ancestors (mammalian apparent LTR-retrotransposons, MaLRs) at the locus level along with four other repertoires (active LINE-1 elements, lncRNA, a selection of 1559 human genes and common infectious viruses). We demonstrate that HERV-V3 analytical performances are comparable with commercial Affymetrix arrays, and that for a selection of tissue/pathological specific loci, the patterns of expression measured on HERV-V3 is consistent with those reported in the literature. Given its large HERVs/MaLRs coverage and additional repertoires, HERV-V3 opens the door to multiple applications such as enhancers and alternative promoters identification, biomarkers identification as well as the characterization of genes and HERVs/MaLRs modulation caused by viral infection.


Spatial analysis of the etiology of amyotrophic lateral sclerosis among 1991 Gulf War veterans.
Veterans of the 1991 Gulf War have an increased risk of amyotrophic lateral sclerosis (ALS), but the etiology is unknown. This study sought to identify geographic areas with elevated risk for the later development of ALS among military personnel who served in the first Gulf War. A unified geographic information system (GIS) was constructed to allow analysis of secondary data on troop movements in the 1991 Gulf War theatre in the Persian Gulf region including Iraq, northern Saudi Arabia, and Kuwait. We fit Bayesian Poisson regression models to adjust for potential risk factors, including one relatively discrete environmental exposure, and to identify areas associated with elevated risk of ALS. We found that service in particular locations of the Gulf was associated with an elevated risk for later developing ALS, both before and after adjustment for branch of service and potential of exposure to chemical warfare agents in and around Khamisiyah, Iraq. Specific geographic locations of troop units within the 1991 Gulf War theatre are associated with an increased risk for the subsequent development of ALS among members of those units. The identified spatial locations represent the logical starting points in the search for potential etiologic factors of ALS among Gulf War veterans. Of note, for locations where the relative odds of subsequently developing ALS are among the highest, specific risk factors, whether environmental or occupationally related, have not been identified. The results of spatial models can be used to subsequently look for risk factors that follow the spatial pattern of elevated risk.


Regulation of encephalitogenic T cells with recombinant TCR ligands.
We have previously described recombinant MHC class II beta1 and alpha1 domains loaded with free antigenic peptides with potent inhibitory activity on encephalitogenic T cells. We have now produced single-chain constructs in which the peptide Ag is genetically encoded within the same exon as the linked beta1 and alpha1 domains, overcoming the problem of displacement of peptide Ag from the peptide binding cleft. We here describe clinical effects of recombinant TCR ligands (RTLs) comprised of the rat RT1.B beta1alpha1 domains covalently linked to the 72-89 peptide of guinea pig myelin basic protein (RTL-201), to the corresponding 72-89 peptide from rat myelin basic protein (RTL-200), or to cardiac myosin peptide CM-2 (RTL-203). Only RTL-201 possessed the ability to prevent and treat active or passive experimental autoimmune encephalomyelitis. Amelioration of experimental autoimmune encephalomyelitis was associated with a selective inhibition of proliferation response and cytokine production by Ag-stimulated lymph node T cells and a drastic reduction in the number of encephalitogenic and recruited inflammatory cells infiltrating the CNS. The exquisitely selective inhibition could be observed between molecules that differ by a single methyl group (the single amino acid residue difference between RTL-200 (threonine) and RTL-201 (serine) at position 80 of the myelin basic protein peptide). These novel RTLs provide a platform for developing potent and selective human diagnostic and therapeutic agents for treatment of autoimmune disease.


Carcinosarcoma of the biliary system in a cat.
A 12-year-old, mixed-breed domestic cat was diagnosed with a multicystic hepatic mass via ultrasonographic examination and computer tomography scan. The tumor associated with the left medial liver lobe, and connected by a thin stalk to the hilar region, was surgically removed. The mass was firm, encapsulated, mottled white to red black, multinodular, and cystic. Histologic diagnosis was carcinosarcoma supported by positive immunohistochemistry for cytokeratins and vimentin of atypical neoplastic cell populations. On the basis of morphology, the origin was considered to be in the biliary tract. Biliary carcinosarcoma is a rare neoplasm that occurs in people. The epidemiology and risk factors have not yet been determined, and the prognosis is poor except for cases in which curative resection is performed.


STRONTIUM AND CALCIUM UPTAKE BY THE GREEN ALGA, OOCYSTIS EREMOSPHAERIA.
The uptake of calcium and strontium by a green unicellular alga cultured in media containing these elements in concentrations found in nature is directly proportional to the concentration in the media. Variation in the concentration of either element has a slight inverse influence on the uptake of the other. The increase of strontium uptake when the calcium concentration is very low indicates that strontium is substituted for calcium when calcium is limited and suggests that the alga requires either element.


Pure agnosia for mirror stimuli after right inferior parietal lesion.
This study reports the experimental investigation of G.R., a patient suffering from a highly specific disorder in discriminating mirror stimuli following a right temporoparietal cerebrovascular accident. G.R. showed intact perceptual, attentional, mnestic, linguistic and executive abilities. Object recognition was accurate even under unusual viewing conditions. He was highly accurate in defining the canonical orientation of common objects and in discriminating misoriented objects among identical distracters. However, he was severely impaired in tasks requiring mirror-stimulus discrimination, a deficit that persisted even when the object's coordinates were systematically misaligned with respect to his body. The disorder was also dependent upon the frame of reference (allocentric versus egocentric) activated on the basis of task demands. These results demonstrate the existence of a highly specific disorder in discriminating mirror stimuli defined in object-based coordinates, suggesting a failure in processing the directionality of an object's intrinsic x-axis.


Estrone sulfonates as inhibitors of estrone sulfatase.
In our continuing quest to design efficient inhibitors of estrone sulfatase activity and to assess the recognition of estrone sulfate surrogates by estrone sulfatase, we synthesized and evaluated several sulfonate derivatives of 5,6,7,8-tetrahydronaphth-2-ol and estrone. 5,6,7,8-Tetrahydronaphth-2-methanesulfonate (11), and 5,6,7,8-tetrahydronaphth-2-(p-toluene)sulfonate (12) were found not to inhibit estrone sulfatase activity; estrone-3-methane-sulfonate (5), estrone-3-ethanesulfonate (6), estrone-3-butanesulfonate (7), and estrone-3-[(+)10-camphor]sulfonate (8) all weakly inhibited estrone sulfatase, and the best inhibitor, from this class of compounds, was estrone-3-(p-toluene)sulfonate (9). At 10 microM, it inhibited estrone sulfatase activity by 91%. These results emphasize some of the requirements needed for high-affinity binding to the enzyme.


Medico-legal aspects of mesothelioma.
The Authors, reviewing the Literature on asbestos-related Malignant Mesothelioma (MM), found that because of its very peculiar characteristics, the causal link between professional asbestos exposure and the development of this tumour is very difficult to define in respect to: diagnosis, causal link and individuation of possible culpable conducts. The evaluation of causal link in different medico-legal areas is studied by different criteria. In civil law the criterion of weak causality is followed to allow compensation for damages. For institutional purposes in INAIL, the definition of causal link is particularly facilitated by the legal presumption of origin. In fact it is sufficient, that asbestos-related lesions are ascertained in individuals who are or were exposed at any time of their professional life to the risk of inhaling asbestos fibres. In criminal law, the current approach of the Supreme Court is to demand evidence of strong causality, with a high logical probability and rational credibility, and beyond reasonable doubt, because criminal liability is personal as established in article 27 of the Italian Constitution. It is worth pointing out that all the levels of evidence indicated above must pass the test of scientific suitability or possibility.


Macrophage infection via selective capture of HIV-1-infected CD4+ T cells.
Macrophages contribute to HIV-1 pathogenesis by forming a viral reservoir and mediating neurological disorders. Cell-free HIV-1 infection of macrophages is inefficient, in part due to low plasma membrane expression of viral entry receptors. We find that macrophages selectively capture and engulf HIV-1-infected CD4+ T cells leading to efficient macrophage infection. Infected T cells, both healthy and dead or dying, were taken up through viral envelope glycoprotein-receptor-independent interactions, implying a mechanism distinct from conventional virological synapse formation. Macrophages infected by this cell-to-cell route were highly permissive for both CCR5-using macrophage-tropic and otherwise weakly macrophage-tropic transmitted/founder viruses but restrictive for nonmacrophage-tropic CXCR4-using virus. These results have implications for establishment of the macrophage reservoir and HIV-1 dissemination in vivo.


Health effects of hot weather: from awareness of risk factors to effective health protection.
Because of the increasing concerns about climate change and deadly heatwaves in the past, the health effects of hot weather are fast becoming a global public health challenge for the 21st century. Some cities across the world have introduced public health protection measures, with the timely provision of appropriate home-based prevention advice to the general public being the most crucial point of intervention. In this Review, we report current epidemiological and physiological evidence about the range of health effects associated with hot weather, and draw attention to the interplay between climate factors, human susceptibility, and adaptation measures that contribute to heat burdens. We focus on the evidence base for the most commonly provided heat-protection advice, and make recommendations about the optimum clinical and public health practice that are expected to reduce health problems associated with current and future hot weather.


Relation of polymorphism of arsenic metabolism genes to arsenic methylation capacity and developmental delay in preschool children in Taiwan.
Inefficient arsenic methylation capacity has been associated with developmental delay in children. The present study was designed to explore whether polymorphisms and haplotypes of arsenic methyltransferase (AS3MT), glutathione-S-transferase omegas (GSTOs), and purine nucleoside phosphorylase (PNP) affect arsenic methylation capacity and developmental delay. A case-control study was conducted from August 2010 to March 2014. All participants were recruited from the Shin Kong Wu Ho-Su Memorial Teaching Hospital. In total, 179 children with developmental delay and 88 children without delay were recruited. Urinary arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) were measured using a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphisms of AS3MT, GSTO, and PNP were performed using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Polymorphisms of AS3MT genes were found to affect susceptibility to developmental delay in children, but GSTO and PNP polymorphisms were not. Participants with AS3MT rs3740392 A/G+G/G genotype, compared with AS3MT rs3740392 A/A genotype, had a significantly lower secondary methylation index. This may result in an increased OR for developmental delay. Participants with the AS3MT high-risk haplotype had a significantly higher OR than those with AS3MT low-risk haplotypes [OR and 95% CI, 1.59 (1.08-2.34)]. This is the first study to show a joint dose-response effect of this AS3MT high-risk haplotype and inefficient arsenic methylation capacity on developmental delay. Our data provide evidence that AS3MT genes are related to developmental delay and may partially influence arsenic methylation capacity.


Rauwolfia serpentina improves altered glucose and lipid homeostasis in fructose-induced type 2 diabetic mice.
Rauwolfia serpentina is well-reported in traditional medicines for the treatment of hypertensive and neurological disorders. However, its antidiabetic potential has been currently described in both alloxan-treated and normoglycemic mice. Present effort was carried out to investigate the effect of methanol root extract (MREt) of R.serpentina in fructose-induced type 2 diabetic mice. Experimental mice were grouped into normal control (distilled water 1ml/kg) and fructose-induced type 2 diabetic groups (10% fructose 1 ml/kg).The second group sub-divided into negative (0.05% DMSO 1ml/kg) control, positive (pioglitazone 15mg/kg) control and three test groups (MREt 10, 30 & 60 mg/kg). Each treatment was given orally for 14 days consecutively then mice were sacrificed in order to collect serum and liver samples to analyze physical, biochemical as well as hematological markers. MREt significantly improved percent body weight and glycemic change along with serum insulin, total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL-c), very low-density lipoprotein (VLDL-c), high-density lipoprotein-cholesterols (HDL-c), total hemoglobin, glycosylated hemoglobin, hepatic glycogen, coronary risk and fasting insulin resistance indices while suppressed down the activity of 3-hydroxy-3-methylglutaryl Coenzyme A reductase enzyme in test groups when compared with diabetic controls. The present findings conclude that MREt of R. serpentina can effectively betters the carbohydrate and lipid homeostasis by either inhibiting fructose absorption in intestine or decreasing insulin resistance in fructose-induced type 2 diabetic mice.


Quantifying the Heat Dissipation from a Molecular Motor's Transport Properties in Nonequilibrium Steady States.
Theoretical analysis, which maps single-molecule time trajectories of a molecular motor onto unicyclic Markov processes, allows us to evaluate the heat dissipated from the motor and to elucidate its dependence on the mean velocity and diffusivity. Unlike passive Brownian particles in equilibrium, the velocity and diffusion constant of molecular motors are closely inter-related. In particular, our study makes it clear that the increase of diffusivity with the heat production is a natural outcome of active particles, which is reminiscent of the recent experimental premise that the diffusion of an exothermic enzyme is enhanced by the heat released from its own catalytic turnover. Compared with freely diffusing exothermic enzymes, kinesin-1, whose dynamics is confined on one-dimensional tracks, is highly efficient in transforming conformational fluctuations into a locally directed motion, thus displaying a significantly higher enhancement in diffusivity with its turnover rate. Putting molecular motors and freely diffusing enzymes on an equal footing, our study offers a thermodynamic basis to understand the heat-enhanced self-diffusion of exothermic enzymes.


SSTAR, a Stand-Alone Easy-To-Use Antimicrobial Resistance Gene Predictor.
We present the easy-to-use Sequence Search Tool for Antimicrobial Resistance, SSTAR. It combines a locally executed BLASTN search against a customizable database with an intuitive graphical user interface for identifying antimicrobial resistance (AR) genes from genomic data. Although the database is initially populated from a public repository of acquired resistance determinants (i.e., ARG-ANNOT), it can be customized for particular pathogen groups and resistance mechanisms. For instance, outer membrane porin sequences associated with carbapenem resistance phenotypes can be added, and known intrinsic mechanisms can be included. Unique about this tool is the ability to easily detect putative new alleles and truncated versions of existing AR genes. Variants and potential new alleles are brought to the attention of the user for further investigation. For instance, SSTAR is able to identify modified or truncated versions of porins, which may be of great importance in carbapenemase-negative carbapenem-resistant Enterobacteriaceae. SSTAR is written in Java and is therefore platform independent and compatible with both Windows and Unix operating systems. SSTAR and its manual, which includes a simple installation guide, are freely available from https://github.com/tomdeman-bio/Sequence-Search-Tool-for-Antimicrobial-Resistance-SSTAR-. IMPORTANCE Whole-genome sequencing (WGS) is quickly becoming a routine method for identifying genes associated with antimicrobial resistance (AR). However, for many microbiologists, the use and analysis of WGS data present a substantial challenge. We developed SSTAR, software with a graphical user interface that enables the identification of known AR genes from WGS and has the unique capacity to easily detect new variants of known AR genes, including truncated protein variants. Current software solutions do not notify the user when genes are truncated and, therefore, likely nonfunctional, which makes phenotype predictions less accurate. SSTAR users can apply any AR database of interest as a reference comparator and can manually add genes that impact resistance, even if such genes are not resistance determinants per se (e.g., porins and efflux pumps).


Unspecific elevation of plasma troponin-T and CK-MB after coronary surgery.
Biochemical markers of myocardial injury are frequently elevated after cardiac surgery. It is generally accepted that release unrelated to permanent myocardial damage explains a proportion of these elevations. However, little is known about the magnitude and temporal characteristics of this diagnostic noise. One way to address this issue would be to study a group without permanent myocardial injury. The unique release kinetics of troponin-T (permanent myocardial injury causes a sustained release of structurally bound troponin) were used to identify patients with no or minimal permanent myocardial injury. Blood was sampled from patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) before surgery, 3 and 8 h after unclamping the aorta, and each morning until postoperative day 4, for analysis of enzymes and troponin-T. From 302 consecutive patients a subgroup was identified that fulfilled the following criteria: (a) normalized troponin-T levels < or = postoperative day 4; (b) no ECG changes indicating myocardial injury. Seventy-seven patients fulfilled the criteria above and in this subgroup troponin-T (2.08 +/- 1.42 microg/l; range 0.35-8.99 microg/l) peaked at the 3 h recording and creatine kinase monobasic (CK-MB) (28.6 +/- 11.3 microg/l; range 11.9-86.0 microg/l) peaked at the 8 h recording after unclamping the aorta. Substantial early elevations of plasma CK-MB and troponin-T occurred in patients with no or minimal permanent myocardial injury after CABG. Unspecific release was most pronounced during the timeframe that is usually studied to evaluate myocardial protective strategies or to compare revascularization procedures.


Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer.
We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin. No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST). Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment. Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.


Elastic light-scattering measurements of single biological cells in an optical trap.
We have developed an instrument for determination of the angular light scattering of beads and biological cells. The instrument uses radiation pressure for levitation of particles inside a cuvette. The setup consists of two 780-nm diode lasers in a vertical double-beam trapping configuration. In the horizontal direction a weakly focused 633-nm probe beam is used to illuminate the trapped particle. One can detect scattered light over the range of from - 150 to 150 deg with an angular resolution of 0.9 deg using an avalanche photodiode. With this setup light scattering from polystyrene beads was measured, and the obtained scattering patterns were compared with theoretical scattering patterns from Lorenz-Mie theory. The results show that the setup is stable, gives reproducible patterns, and qualitatively agrees with the calculations. Trapping of biological cells is more difficult than trapping of beads, because smaller forces result from smaller refractive indices. We present an angular scattering pattern measured from a human lymphocyte measured from 20 to 60 deg.


Human genes with CpG island promoters have a distinct transcription-associated chromatin organization.
More than 50% of human genes initiate transcription from CpG dinucleotide-rich regions referred to as CpG islands. These genes show differences in their patterns of transcription initiation, and have been reported to have higher levels of some activation-associated chromatin modifications. Here we report that genes with CpG island promoters have a characteristic transcription-associated chromatin organization. This signature includes high levels of the transcription elongation-associated histone modifications H4K20me1, H2BK5me1 and H3K79me1/2/3 in the 5' end of the gene, depletion of the activation marks H2AK5ac, H3K14ac and H3K23ac immediately downstream of the transcription start site (TSS), and characteristic epigenetic asymmetries around the TSS. The chromosome organization factor CTCF may be bound upstream of RNA polymerase in most active CpG island promoters, and an unstable nucleosome at the TSS may be specifically marked by H4K20me3, the first example of such a modification. H3K36 monomethylation is only detected as enriched in the bodies of active genes that have CpG island promoters. Finally, as expression levels increase, peak modification levels of the histone methylations H3K9me1, H3K4me1, H3K4me2 and H3K27me1 shift further away from the TSS into the gene body. These results suggest that active genes with CpG island promoters have a distinct step-like series of modified nucleosomes after the TSS. The identity, positioning, shape and relative ordering of transcription-associated histone modifications differ between genes with and without CpG island promoters. This supports a model where chromatin organization reflects not only transcription activity but also the type of promoter in which transcription initiates.


Cross-Sectional Associations Between Sitting Time and Several Aspects of Mental Health in Belgian Adults.
Sedentary behavior (including sitting) is negatively associated with physical health, independent from physical activity (PA). Knowledge on the associations with mental health is less elaborated. Therefore this study aims to investigate the relationship between sitting and 5 indices of mental health in adults (psychological distress, depression, anxiety, somatization, and sleeping problems), and between sitting interactions (sitting×gender, sitting×age, sitting×education, and sitting×PA) and these mental health indices. A cohort of Belgian adults (25-64 years; n = 4344) provided self-reported data on sitting and PA and on 5 mental health indices. Cross-sectional associations were examined using multiple linear regression analyses. Analyses adjusted for gender, age, education, and PA showed significant positive associations between sitting and the 5 mental health indices (P < .05). All associations were true for both men and women, and for low and high educated individuals, while some were only found in older individuals (somatization, P < .001) and those being insufficiently active (psychological distress, P = .007; depression, P = .002; and anxiety, P = .014). More sitting seems to be associated with poorer mental health, independently of gender, age, education, and PA. Moderation analyses showed that these associations may differ according to age and PA levels.


[Development of a Japanese version of the Modified Questionnaire on the Pulmonary Functional Status and Dyspnea].
A Japanese version of the Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ-M) was made through a translation-backtranslation procedure under agreement with the original author, Dr. Lareau, SC. Three components of the Japanese version, dyspnea with activities (DA), fatigue with activities (FA), and change experienced by patients with activities (CA), were tested using 63 chronic respiratory disease (CRD) patients. Cronbach's alpha was the same, 0.93, for DA, FA and CA. Average values for DA, FA, and CA were significantly associated with the MRC and BDI scores in 63 patients. In 43 Chronic Obstructive Pulmonary Disease (COPD) patients, average values for DA, FA, and CA were significantly associated with the % predicted FEV1.0. After 26 patients were randomly selected, the same protocol was repeated with a 10- to 14-day interval to validate the reproducibility of the PFSDQ-M. Correlation coefficients were 0.94, 0.88, and 0.91 for DA, FA, and CA, respectively. Then, 52 patients were randomly selected and the same protocol was repeated with a 6- to 12-month interval to evaluate the sensitivity of PFQD-M. The changes in DA, FA and CA with the 6- to 12-month interval were significantly associated with changes in MRC and TDI. In 37 COPD patients, changes in DA, FA, and CA with the 6- to 12-month interval were significantly associated with the changes in the % predicted FEV1.0. These results show that the Japanese version of PFSDQ-M is valid in its reproducibility and internal consistency, and may also have construct validity and sensitivity for evaluating the functional status and dyspnea of patients with chronic respiratory illness.


Sam68 RNA binding protein is an in vivo substrate for protein arginine N-methyltransferase 1.
RNA binding proteins often contain multiple arginine glycine repeats, a sequence that is frequently methylated by protein arginine methyltransferases. The role of this posttranslational modification in the life cycle of RNA binding proteins is not well understood. Herein, we report that Sam68, a heteronuclear ribonucleoprotein K homology domain containing RNA binding protein, associates with and is methylated in vivo by the protein arginine N-methyltransferase 1 (PRMT1). Sam68 contains asymmetrical dimethylarginines near its proline motif P3 as assessed by using a novel asymmetrical dimethylarginine-specific antibody and mass spectrometry. Deletion of the methylation sites and the use of methylase inhibitors resulted in Sam68 accumulation in the cytoplasm. Sam68 was also detected in the cytoplasm of PRMT1-deficient embryonic stem cells. Although the cellular function of Sam68 is unknown, it has been shown to export unspliced human immunodeficiency virus RNAs. Cells treated with methylase inhibitors prevented the ability of Sam68 to export unspliced human immunodeficiency virus RNAs. Other K homology domain RNA binding proteins, including SLM-1, SLM-2, QKI-5, GRP33, and heteronuclear ribonucleoprotein K were also methylated in vivo. These findings demonstrate that RNA binding proteins are in vivo substrates for PRMT1, and their methylation is essential for their proper localization and function.


Comparison of psychosocial adaptation of advanced stage Hodgkin's disease and acute leukemia survivors. Cancer and Leukemia Group B.
The purpose of this study was to compare the long-term psychosocial adaptation of Hodgkin's disease and adult acute leukemia survivors. Two hundred seventy-three Hodgkin's disease (HD) and 206 adult acute leukemia (AL) survivors were interviewed by telephone concerning their psychosocial adjustment and problems they attributed to having been treated for cancer, using identical research procedures and a common set of instruments. The following measures were used: Psychosocial Adjustment to Illness Scale (PAIS); Brief Symptom Inventory (BSI); current Conditioned Nausea and Vomiting triggered by treatment-related stimuli (CNVI); Indices of Employment, Insurance and Sexual Problems Attributed to Cancer; Negative Socioeconomic Impact of Cancer Index (NSI). All participants had been treated on one of nine Hodgkin's disease or 13 acute leukemia Cancer and Leukemia Group B (CALGB) clinical trials from 1966-1988, and had been off treatment for one year or more (mean years: HD = 5.9; AL = 5.6). HD survivors' risk of having a high distress score on the BSI was almost twice that found for AL survivors (odds ratio = 1.90), with 21% of HD vs. 14% of AL survivors (P < 0.05) having scores that were 1.5 standard deviations above the norm, suggestive of a possible psychiatric disorder. HD survivors reported greater fatigue (POMS Fatigue, P = 0.01; Vigor Subscales, P = 0.001), greater conditioned nausea (CNVI, P < 0.05), greater impact of cancer on their family life (PAIS Domestic Environment, P = 0.004) and poorer sexual functioning (PAIS Sexual Relationships, P = 0.0001), than AL survivors. Treatment-related issues may have placed HD survivors at a greater risk for problems in long-term adaptation than AL survivors.


[Advances in therapy for ascites and hepatorenal syndrome].
Sequential diuretic treatment of ascites with spironolactone and furosemide is equivalent to initial combination therapy. Orally applicable vasopressin-V2-receptor antagonists are an interesting novel therapeutic approach for the elimination of free water. The therapeutic efficacy for patients with cirrhosis and ascites is currently being investigated in phase II trials. Following paracentesis of up to 6 liters volume, infusion of 3.5 % saline is as effective as 20 % albumin. Another trial confirms the superiority of TIPS for the treatment of massive ascites, also demonstrating survival benefit. Determination of leukocyte esterase activity with a simple stix method may be helpful for the rapid and easy diagnosis of spontaneous bacterial peritonitis. Patients with hepatorenal syndrome seem to benefit from a combination of terlipressin and albumin whereas the effect of albumin dialysis on survival remains to be proven.


Daily Activities Related to Mobile Cognitive Performance in Middle-Aged and Older Adults: An Ecological Momentary Cognitive Assessment Study.
Daily activities have been associated with neurocognitive performance. However, much of this research has used in-person neuropsychological testing that requires participants to travel to a laboratory or clinic, which may not always be feasible and does not allow for the examination of real-time relationships between cognition and behavior. Thus, there is a need to understand the real-time relationship between activities in the real world and neurocognitive functioning to improve tracking of symptoms or disease states and aid in the early identification of neurocognitive deficits among at-risk individuals. We used a smartphone-based ecological momentary cognitive assessment (EMCA) platform to examine real-time relationships between daily activities and neurocognitive performance (executive functioning and verbal learning) in the everyday environment of middle-aged and older adults with and without HIV. A total of 103 adults aged 50-74 years (67 persons with HIV; mean age 59 years, SD 6.4) were recruited from the University of California, San Diego HIV Neurobehavioral Research Program and the San Diego community. Participants completed our EMCA protocol for 14 days. Participants reported their current daily activities 4 times per day; following 2 of the 4 daily ecological momentary assessment (EMA) surveys, participants were administered the mobile Color-Word Interference Test (mCWIT) and mobile Verbal Learning Test (mVLT), each once per day. Activities were categorized into cognitively stimulating activities, passive leisure activities, and instrumental activities of daily living (IADLs). We used multilevel modeling to examine the same-survey and lagged within-person and between-person effects of each activity type on mobile cognitive performance. On average, participants completed 91% of the EMA surveys, 85% of the mCWIT trials, and 80% of the mVLT trials, and they reported engaging in cognitively stimulating activities on 17% of surveys, passive leisure activities on 33% of surveys, and IADLs on 20% of surveys. Adherence and activity percentages did not differ by HIV status. Within-persons, engagement in cognitively stimulating activities was associated with better mCWIT performance (β=-1.12; P=.007), whereas engagement in passive leisure activities was associated with worse mCWIT performance (β=.94; P=.005). There were no lagged associations. At the aggregate between-person level, a greater percentage of time spent in cognitively stimulating activities was associated with better mean mVLT performance (β=.07; P=.02), whereas a greater percentage of time spent in passive leisure activities was associated with worse mean mVLT performance (β=-.07; P=.01). IADLs were not associated with mCWIT or mVLT performance. Smartphones present unique opportunities for assessing neurocognitive performance and behavior in middle-aged and older adults' own environment. Measurement of cognition and daily functioning outside of clinical settings may generate novel insights on the dynamic association of daily behaviors and neurocognitive performance and may add new dimensions to understanding the complexity of human behavior.


In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors.
Matrix metalloproteinases (MMPs) secreted by cervical and ovarian cancer, especially MMP-2 and MMP-9, play crucial roles in tumor invasion and metastasis. We examined the effect of cytokines, mitogens, inducers and inhibitors on MMP-2 and MMP-9 expression in cervical and ovarian cancer cell lines. Human cervical (HeLa and DoTc2-4510) and ovarian (SK-OV-3) cell lines were cultured in appropriate media. At near confluence, the cells were washed with PBS and incubated in serum-free medium with various concentrations of several cytokines, mitogens and inhibitors. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by gelatinase zymography and quantitated by densitometry. HeLa and SK-OV-3 cell lines expressed MMP-2 whereas DoTc2-4510 cells expressed MMP-9. Treatment of cervical cancer cell lines (HeLa and DoTc2-4510) with PMA had no effect on MMP-2 expression and a moderate stimulatory effect in ovarian cancer cell line SK-OV-3. MMP-9 was stimulated by phorbol 12-myristate 13-acetate in HeLa cells and enhanced in DoTc2-4510. Tumor necrosis factor-alpha and interleukin-1beta, had slight inhibitory effect on HeLa cell expression of MMP-2 while lipopolysaccharide stimulated MMP-2 in HeLa cells. Doxycycline, epigallocatechin gallate, a nutrient mixture, actinomycin-D, cyclohexamide, retinoic acid and dexamethasone inhibited MMP-2 in HeLa and SK-OV-3 cell lines and inhibited MMP-9 in DoTc2-4510. Our results show that cytokines, mitogens, inducers and inhibitors have an up or down regulatory effect on MMP-2 and MMP-9 expression in ovarian and cervical cancer cell lines, suggesting these agents may be effective strategies to treat these cancers.


Technical determinants of tackle and ruck performance in International rugby union.
The most frequently occurring contact events in rugby union are the tackle and ruck. The ability repeatedly to engage and win the tackle and ruck has been associated with team success. To win the tackle and ruck, players have to perform specific techniques. These techniques have not been studied at the highest level of rugby union. Therefore, the purpose of this study was to identify technical determinants of tackle and ruck performance at the highest level of rugby union. A total of 4479 tackle and 2914 ruck events were coded for the Six Nations and Championship competitions. Relative risk ratio (RR), the ratio of the probability of an outcome occurring when a characteristic was observed (versus the non-observed characteristic), was determined using multinomial logistic regression. Executing front-on tackles reduced the likelihood of offloads and tackle breaks in both competitions (Six Nations RR 3.0 Behind tackle, 95% confidence interval [95% CI]: 1.9-4.6, effect size [ES] = large, P < 0.001); Championship RR 2.9 Jersey tackle, 95% CI: 1.3-6.4, ES = moderate, P = 0.01). Fending during contact increased the chances of offloading and breaking the tackle in both competitions (Six Nations RR 4.5 Strong, 95% CI: 2.2-9.2, ES = large, P = P < 0.001; Championship RR 5.1 Moderate, 95% CI: 3.5-7.4, ES = large, P < 0.001). For the ruck, actively placing the ball increased the probability of maintaining possession (Six Nations RR 2.2, 95% CI: 1.1-4.3, ES = moderate, P = 0.03); Championship RR 4.0, 95% CI: 1.3-11.8, ES = large, P = 0.01). The techniques identified in this study should be incorporated and emphasised during training to prepare players for competition. Furthermore, these techniques need to be added to coaching manuals for the tackle and ruck.


[Recognition and diagnosis in the intellectually impaired in mental health care].
Recognition of intellectual abilities of a patient is essential for good treatment. However, this may be hard to achieve, even by experienced professionals.
 AIM: To educate professionals how to detect and diagnose intellectual impairment accompanied by an approximate knowledge on methods and pitfalls in establishing psychiatric diagnoses.
 METHOD: Several valid instruments for the screening of intellectual impairment in the Netherlands are described in conjunction with adjoining steps in the diagnostic process.
 RESULTS: To determine mild intellectual disability or borderline intellectual functioning by screening and testing intelligence and adaptive functioning, and by establishing an integrative diagnosis by including emotional as well as social level of functioning. Some pitfalls in the diagnostic process are discussed.
 CONCLUSION: Clinicians must be aware which tools to use to determine broad functioning of the patient and which further steps are necessary for a good diagnosis.


A novel GC-MS method in urinary estrogen analysis from postmenopausal women with osteoporosis.
Estrogen metabolites play important roles in the development of female-related disorders and homeostasis of the bone. To improve detectability, a validated gas chromatography-mass spectrometry (GC-MS) method was conducted with two-phase extractive ethoxycarbonlyation (EOC) and subsequent pentafluoropropionyl (PFP) derivatization was introduced. The resulting samples were separated through a high-temperature MXT-1 column within an 8 min run and were detected in the selected ion monitoring (SIM) mode. The optimized analytical conditions led to good separation with a symmetric peak shape for 19 estrogens as their EOC-PFP derivatives. The limit of quantification (LOQ) was from 0.02 to ∼0.1 ng/ml for most estrogens analyzed, except for 2-hydroxyestriol (0.5 ng/ml). The devised method was found to be linear (r² > 0.995) in the range from the LOQ to 40 ng/ml, whereas the precision (% CV) and accuracy (% bias) ranged from 1.4 to 10.5% and from 91.4 to 108.5%, respectively. The good sensitivity and selectivity of this method even allowed quantification of the estrogen metabolites in urine samples obtained from the postmenopausal female patients with osteoporosis. The present technique can be useful for clinical diagnosis as well as to better understand the pathogenesis of estrogen-related disorders in low-level quantification.


On being "in recovery": A national study of prevalence and correlates of adopting or not adopting a recovery identity among individuals resolving drug and alcohol problems.
The concept of recovery has become an organizing paradigm in the addiction field globally. Although a convenient label to describe the broad phenomena of change when individuals resolve significant alcohol or other drug (AOD) problems, little is known regarding the prevalence and correlates of adopting such an identity. Greater knowledge would inform clinical, public health, and policy communication efforts. We conducted a cross-sectional nationally representative survey (N = 39,809) of individuals resolving a significant AOD problem (n = 1,995). Weighted analyses estimated prevalence and tested correlates of label adoption. Qualitative analyses summarized reasons for prior recovery identity adoption/nonadoption. The proportion of individuals currently identifying as being in recovery was 45.1%, never in recovery 39.5%, and no longer in recovery 15.4%. Predictors of identifying as being in recovery included formal treatment and mutual-help participation, and history of being diagnosed with AOD or other psychiatric disorders. Qualitative analyses regarding reasons for no/prior recovery identity found themes related to low AOD problem severity, viewing the problem as resolved, or having little difficulty of stopping. Despite increasing use of the recovery label and concept, many resolving AOD problems do not identify in this manner. These appear to be individuals who have not engaged with the formal or informal treatment systems. To attract, engage, and accommodate this large number of individuals who add considerably to the AOD-related global burden of disease, AOD public health communication efforts may need to consider additional concepts and terminology beyond recovery (e.g., "problem resolution") to meet a broader range of preferences, perspectives and experiences. (PsycINFO Database Record


Expression and localization of GPR109A (PUMA-G/HM74A) mRNA and protein in mammalian retinal pigment epithelium.
GPR109A has been identified as a G-protein-coupled receptor for niacin. beta-hydroxybutyrate (beta-HB) is a physiologic ligand for the receptor. beta-HB, the predominate ketone body in circulation, is an important energy source for neurons, including retinal neurons, under various physiologic and pathologic conditions. The identification of GPR109A as the receptor for beta-HB suggests additional, hitherto unknown, functions for this metabolite. The circulating levels of beta-HB increase in diabetes. Since retinopathy is a serious complication associated with diabetes, we investigated GPR109A expression in retina and in different retinal cell types to determine if the receptor may have a role in the pathophysiology of diabetic retinopathy. RT-PCR, fluorescent in situ hybridization, and immunofluorescent techniques were used to analyze GPR109A expression in mouse retina and in three transformed retinal cell lines: ARPE-19 (RPE), RGC-5 (ganglion), and rMC-1 (Müller). Activation of GPR109A by niacin and beta-HB was demonstrated in ARPE-19 cells by cAMP assay. Studies conducted using mouse retinal tissues demonstrated that GPR109A is expressed in retina with its expression restricted to RPE, where it differentially polarizes to the basolateral membrane. These results were confirmed with cell lines, which demonstrated GPR109A expression in ARPE-19, but not in rMC-1 and RGC-5 cells. Primary cultures of mouse RPE also showed robust expression of GPR109A. cAMP assay demonstrated that GPR109A expressed in RPE is functional. These data represent the first report on GPR109A expression in retina. The exclusive expression of GPR109A in RPE basolateral membrane, which has access to beta-HB in blood, may have biologic importance in diabetic retinopathy.


Femtosecond Sagnac interferometer for phase spectroscopy.
We developed a novel femtosecond Sagnac interferometer that enables us to take single-shot measurements of both the difference transmission and the difference phase spectra. Owing to the excellent stability of the Sagnac interferometer, a difference phase spectrum was obtained with a high phase change sensitivity of ~lambda/100 after a 1000-shot accumulation. The spectral range, wavelength, and time resolution were 530-650 nm, 1 nm, and 200 fs, respectively.


Benign macrocystic serous cystadenoma of the pancreas.
Serous cystadenoma is a rare benign cystic lesion of pancreas. They are mostly known as benign cystic tumors of pancreas but malign transformation as serous cystadenocarcinoma is also reported. It is more commonly observed in women with the mean age of onset is 62 years. The majority of patients present nonspecific symptoms such as abdominal pain, weight loss, nausea, vomiting, fever, and melena. One-third of the patients are asymptomatic. A 60-year-old woman presents with abdominal pain and nausea for 1 month was admitted. Physical and laboratory findings were normal. Abdomen computed tomography scan confirmed a large number of millimetric cysts of 45 × 47 × 50 mm in size at the head of the pancreas. Due to patient's symptoms and mass effect, Whipple procedure was performed. In the gross examination, a nodular area of 5 × 5 × 4 cm was observed in the head of the pancreas. The microscopic examination of the material revealed cystic structures with fibrous stroma dotted with single layered cuboidal epithelium in the pancreatic tissue. The pathology report confirmed benign macrocystic serous cystadenoma. Serous cystadenomas are rare benign cystic lesions of the pancreas. Although they are benign lesions, it is crucial to differentiate them from other cystic lesions of the pancreas and malignant serous cystadenocarcinomas.


Semantic Relations between Visual Objects Can Be Unconsciously Processed but Not Reported under Change Blindness.
Change blindness-the failure to detect changes in visual scenes-has often been interpreted as a result of impoverished visual information encoding or as a failure to compare the prechange and postchange scene. In the present electroencephalography study, we investigated whether semantic features of prechange and postchange information are processed unconsciously, even when observers are unaware that a change has occurred. We presented scenes composed of natural objects in which one object changed from one presentation to the next. Object changes were either semantically related (e.g., rail car changed to rail) or unrelated (e.g., rail car changed to sausage). Observers were first asked to detect whether any change had occurred and then to judge the semantic relation of the two objects involved in the change. We found a semantic mismatch ERP effect, that is, a more negative-going ERP for semantically unrelated compared to related changes, originating from a cortical network including the left middle temporal gyrus and occipital cortex and resembling the N400 effect, albeit at longer latencies. Importantly, this semantic mismatch effect persisted even when observers were unaware of the change and the semantic relationship of prechange and postchange object. This finding implies that change blindness does not preclude the encoding of the prechange and postchange objects' identities and possibly even the comparison of their semantic content. Thus, change blindness cannot be interpreted as resulting from impoverished or volatile visual representations or as a failure to process the prechange and postchange object. Instead, change detection appears to be limited at a later, postperceptual stage.


Self-Selected Versus Standardised Warm-Ups; Physiological Response on 500 m Sprint Kayak Performance.
This study investigated the effectiveness of a self-selected (SS) warm-up on 500 m sprint kayak performance (K500) compared to continuous (CON) and intermittent high intensity (INT)-type warm-ups. Twelve nationally ranked sprint kayakers (age 17.7 ± 2.3 years, mass 69.2 ± 10.8 kg) performed CON (15 min at the power at 2 m·mol-1), INT (10 min at 2 m·mol-1, followed by 5 × 10 s sprints at 200% power at VO2max with 50 s recovery at 55% power at VO2max), and SS (athlete's normal competition warm-up) warm-ups in a randomised order. After a five-minute passive recovery, K500 performance was determined on a kayak ergometer. Heart rate and blood lactate (BLa) were recorded before and immediately after each warm-up and K500 performance. Ratings of perceived exertion (RPE) were recorded at the end of the warm-up and K500. BLa, heart rate, and RPE were generally higher after the INT than CON and SS warm-ups (p < 0.05). No differences in these parameters were found between the conditions for the time trial (p > 0.05). RPE and changes in BLa and heart rate after the K500 were comparable. There were no differences in K500 performance after the CON, SS, or INT warm-ups. Applied practitioners can, therefore, attain similar performance independent of warm-up type.


An empowerment framework for nursing leadership development: supporting evidence.
This article is a report on a descriptive study of nurse leaders' perspectives of the outcomes of a formal leadership programme. Effective nurse leaders are necessary to address complex issues associated with healthcare systems reforms. Little is known about the types of leadership development programmes that most effectively prepare nurse leaders for healthcare challenges. When nurse leaders use structural and psychological empowerment strategies, the results are safer work environments and better nurse outcomes. The leadership development programme associated with this study is based on a unifying theoretical empowerment framework to empower nurse leaders and enable them to empower others. Twenty seven front-line and mid-level nurse leaders with variable years of experience were interviewed for 1 year after participating in a formal leadership development programme. Data were gathered in 2008-2009 from four programme cohorts. Four researchers independently developed code categories and themes using qualitative content analysis. Evidence of leadership development programme empowerment included nurse leader reports of increased self-confidence with respect to carrying out their roles and responsibilities; positive changes in their leadership styles; and perceptions of staff recognition of positive stylistic changes. Regardless of years of experience, mid-level leaders had a broader appreciation of practice environment issues than front-line leaders. Time for reflection was valuable to all participants, and front-line leaders, in particular, appreciated the time to discuss nurse-specific issues with their colleagues. This study provides evidence that a theoretical empowerment framework and strategies can empower nurse leaders, potentially resulting in staff empowerment.


Maternal food consumption during pregnancy and asthma, respiratory and atopic symptoms in 5-year-old children.
Associations between maternal vitamin E, vitamin D and zinc intakes during pregnancy and asthma, wheeze and eczema in 5-year-old children have previously been reported. A study was undertaken to investigate whether maternal intake of specific foods during pregnancy is associated with asthma and allergic outcomes in the same children. A longitudinal birth cohort study was conducted in 1,924 children born to women recruited during pregnancy. Maternal diet during pregnancy was assessed by food frequency questionnaire (FFQ). Cohort children were followed up at 5 years by symptom questionnaire and FFQ. Food groups of interest were fruit, vegetables, fruit juice, whole grain products, fish, dairy products and fat spreads. Trends across outcome groups defined by level of food intake are presented. 1,253 children participated at 5 years and maternal FFQ data were available for 1,212. No consistent associations were found between childhood outcomes and maternal intake of the analysed foods except for apples and fish. Maternal apple intake was beneficially associated with ever wheeze (OR highest vs lowest tertile 0.63, 95% CI 0.42 to 0.95), ever asthma (OR 0.54, 95% CI 0.32 to 0.92) and doctor-confirmed asthma (OR 0.47, 95% CI 0.27 to 0.82) in the children. Maternal fish consumption was beneficially associated with doctor-confirmed eczema (OR >or=1/week vs never 0.57, 95% CI 0.35 to 0.92). There was no evidence for associations between maternal intake of most foods during pregnancy and asthma, respiratory and allergic outcomes in 5-year-old children, except for apples and fish. Consumption of apples and fish during pregnancy may have a protective effect against the development of childhood asthma and allergic disease.


Transcription-coupled deposition of histone modifications during MHC class II gene activation.
Posttranslational histone modifications associated with actively expressed genes are generally believed to be introduced primarily by histone-modifying enzymes that are recruited by transcription factors or their associated co-activators. We have performed a comprehensive spatial and temporal analyses of the histone modifications that are deposited upon activation of the MHC class II gene HLA-DRA by the co-activator CIITA. We find that transcription-associated histone modifications are introduced during two sequential phases. The first phase precedes transcription initiation and is characterized exclusively by a rapid increase in histone H4 acetylation over a large upstream domain. All other modifications examined, including the acetylation and methylation of several residues in histone H3, are restricted to short regions situated at or within the 5' end of the gene and are established during a second phase that is concomitant with ongoing transcription. This second phase is completely abrogated when elongation by RNA polymerase II is blocked. These results provide strong evidence that transcription elongation can play a decisive role in the deposition of histone modification patterns associated with inducible gene activation.


Assessment of a new undergraduate module in musculoskeletal medicine.
Despite the high prevalence of musculoskeletal disorders seen by primary care physicians, numerous studies have demonstrated deficiencies in the adequacy of musculoskeletal education at multiple stages of medical education. The aim of this study was to assess a newly developed module in musculoskeletal medicine for use at European undergraduate level (i.e., the medical-school level). A two-week module in musculoskeletal medicine was designed to cover common musculoskeletal disorders that are typically seen in primary care. The module incorporated an integrated approach, including core lectures, bedside clinical examination, and demonstration of basic practical procedures. A previously validated examination in musculoskeletal medicine was used to assess the cognitive knowledge of ninety-two students on completion of the module. A historical control group (seventy-two students) from a prior course was used for comparison. The new module group (2009) performed significantly better than the historical (2006) control group in terms of score (62.3% versus 54.3%, respectively; p < 0.001) and pass rate (38.4% versus 12.5%, respectively; p = 0.0002). In a subgroup analysis of the new module group, students who enrolled in the graduate entry program (an accelerated four-year curriculum consisting of students who have already completed an undergraduate university degree) were more likely to perform better in terms of average score (72.2% versus 57%, respectively; p < 0.001) and pass rates (70.9% versus 21.4%, respectively; p < 0.001) compared with students who had enrolled via the traditional undergraduate route. In terms of satisfaction rates, the new module group reported a significantly higher satisfaction rate than that reported by the historical control group (63% versus 15%, respectively; p < 0.001). In conclusion, the musculoskeletal module described in this paper represents an educational advance at undergraduate (i.e., medical-school) level as demonstrated by the improvement in scores in a validated examination. As pressure on medical curricula grows to accommodate advancing medical knowledge, it is important to continue to improve, assess, and consolidate the position of musculoskeletal medicine in contemporary medical education.


Online information seeking by patients with bipolar disorder: results from an international multisite survey.
Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information. A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data. 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor. Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.


Small molecules, big players: the National Cancer Institute's Initiative for Chemical Genetics.
In 2002, the National Cancer Institute created the Initiative for Chemical Genetics (ICG), to enable public research using small molecules to accelerate the discovery of cancer-relevant small-molecule probes. The ICG is a public-access research facility consisting of a tightly integrated team of synthetic and analytical chemists, assay developers, high-throughput screening and automation engineers, computational scientists, and software developers. The ICG seeks to facilitate the cross-fertilization of synthetic chemistry and cancer biology by creating a research environment in which new scientific collaborations are possible. To date, the ICG has interacted with 76 biology laboratories from 39 institutions and more than a dozen organic synthetic chemistry laboratories around the country and in Canada. All chemistry and screening data are deposited into the ChemBank web site (http://chembank.broad.harvard.edu/) and are available to the entire research community within a year of generation. ChemBank is both a data repository and a data analysis environment, facilitating the exploration of chemical and biological information across many different assays and small molecules. This report outlines how the ICG functions, how researchers can take advantage of its screening, chemistry and informatic capabilities, and provides a brief summary of some of the many important research findings.


Terazosin for benign prostatic hyperplasia.
Lower urinary tract symptoms associated with benign prostatic obstruction (BPO) occur in up to 70% of men over the age of 60 years. To relieve these bothersome symptoms, treatment options include alpha-antagonists, also know as alpha-blockers. We conducted a systematic review to evaluate the effectiveness and adverse effects of the alpha-blocker, terazosin, for treatment of urinary symptoms associated with BPO. Trials were searched in computerized general and specialized databases (MEDLINE, Cochrane Library), by checking bibliographies, and by contacting manufacturers and researchers. Studies were included if they (1) were randomized trials of at least 1 month duration, and (2) included men with symptomatic BPO and compared terazosin with placebo or active controls. Study, patient characteristics and outcomes data were extracted in duplicate onto standardized forms utilizing a prospectively developed protocol. The main outcome measure for comparing the effectiveness of terazosin with placebo or other BPO medications was change in urological symptoms as measured by validated symptom scores. Secondary outcomes included urodynamic measures. The main outcome measure for adverse effects was the number of men reporting side effects. We also evaluated the number of men withdrawing from treatment and the number withdrawing due to adverse effects. 17 studies involving 5,151 subjects met inclusion criteria (placebo-controlled (10); alpha-blockers (7); finasteride alone or in combination with terazosin as well as placebo (1); microwave therapy (TUMT) (1). Study duration ranged from 4-52 weeks. Mean age was 65 years and 82% of men were white. Baseline urologic symptom scale scores and flow rates demonstrated that men had moderate BPO. Efficacy outcomes were rarely reported in a fashion that allowed for data pooling but indicated that terazosin improved symptom scores and flow rates more than placebo or finasteride and similarly to other alpha antagonists. The pooled mean percentage improvements for the Boyarsky symptom score was 37% for terazosin versus 15% for placebo (n=4 studies). The mean percentage improvement for the American Urological Association symptom score (AUA) was 38% compared to 17% and 20% for placebo and finasteride, respectively (n = 2 studies). The pooled mean improvement in the International Prostate Symptom Score (IPSS) (40%) was similar to tamsulosin (43%). Peak urine flow rates improved greater with terazosin (22%), than placebo (11%) and finasteride (15%) but did not differ significantly from the other alpha-blockers. The percentage of men discontinuing terazosin was comparable to men receiving placebo and finasteride but was greater then with other alpha-antagonists. Adverse effects were greater than placebo and included dizziness, asthenia, headache and postural hypotension. The available evidence suggests that terazosin improves urinary symptoms and flow measures associated with BPO. Effectiveness is superior to placebo or finasteride, similar to other alpha-blockers but less than TUMT. Adverse effects were generally mild but more frequent than other alpha-blockers and associated with between a two-four fold increase in treatment discontinuation.


Methodologies for the Analysis of HCV-Specific CD4(+) T Cells.
Virus-specific CD4(+) T cells play a major role in viral infections, such as hepatitis C virus (HCV). Viral clearance is associated with vigorous and multi-specific CD4(+) T-cell responses, while chronic infection has been shown to be associated with weak or absent T-cell responses. Most of these studies have used functional assays to analyze virus-specific CD4(+) T-cell responses; however, these and other detection methods have various limitations. Therefore, the important question of whether virus-specific CD4(+) T cells are completely absent or primarily impaired in specific effector functions during chronic infection, has yet to be analyzed in detail. A novel assay, in which virus-specific CD4(+) T-cell frequencies can be determined by de novo CD154 (CD40 ligand) expression in response to viral antigens, can help to overcome some of the limitations of functional assays and restrictions of multimer-based methods. This and other current established methods for the detection of HCV-specific CD4(+) T cells will be discussed in this review.


An integrated port camera and display system for laparoscopy.
In this paper, we built and tested the port camera, a novel, inexpensive, portable, and battery-powered laparoscopic tool that integrates the components of a vision system with a cannula port. This new device 1) minimizes the invasiveness of laparoscopic surgery by combining a camera port and tool port; 2) reduces the cost of laparoscopic vision systems by integrating an inexpensive CMOS sensor and LED light source; and 3) enhances laparoscopic surgical procedures by mechanically coupling the camera, tool port, and liquid crystal display (LCD) screen to provide an on-patient visual display. The port camera video system was compared to two laparoscopic video systems: a standard resolution unit from Karl Storz (model 22220130) and a high definition unit from Stryker (model 1188HD). Brightness, contrast, hue, colorfulness, and sharpness were compared. The port camera video is superior to the Storz scope and approximately equivalent to the Stryker scope. An ex vivo study was conducted to measure the operative performance of the port camera. The results suggest that simulated tissue identification and biopsy acquisition with the port camera is as efficient as with a traditional laparoscopic system. The port camera was successfully used by a laparoscopic surgeon for exploratory surgery and liver biopsy during a porcine surgery, demonstrating initial surgical feasibility.


Landscape of current and emerging cell therapy clinical trials in the UK: current status, comparison to global trends and future perspectives.
Cell Therapy Clinical Trial and Preclinical Research databases have been established by the Cell Therapy Catapult to document current and future cell therapy clinical trials in the UK. We identified 41 ongoing trials in April 2014, an increase of seven trials from April 2013. In addition, we identified 45 late-stage preclinical research projects. The majority of the clinical trials are early phase, primarily led by academic groups. The leading therapeutic areas are cancer, cardiology and neurology. The trends in the UK are also seen globally. As the field matures, more later phase and commercial studies will emerge and the challenges will likely evolve into how to manufacture sufficient cell quantities, manage complex logistics for multi-center trials and control cost.


Optical spectral reflectance of human articular cartilage - relationships with tissue structure, composition and mechanical properties.
The information from spectral reflectance of articular cartilage has been related to the integrity of the tissue. This study explores more in detail the interrelations between the cartilage composition, structure and mechanical properties, and optical spectral reflectance. Using human osteochondral samples the reflectance spectral images of articular cartilage were captured and analyzed by using CIELAB color space as well as principal component analysis. With both analysis methods statistically significant correlations were observed between the reflectance and histological integrity, as assessed by Mankin scoring, tissue proteoglycan content and dynamic modulus. In thick human cartilage, the reflectance was found to be independent of the cartilage thickness, suggesting negligible influence of the underlying subchondral bone. Based on the present results diagnostically relevant information on cartilage quality can be extracted using optical spectral reflectance measurements. These measurements could be feasible during arthroscopic surgery when more in-depth information of the properties of articular cartilage is needed.


Occipital Nerve Stimulation for Refractory Chronic Migraine: Results of a Long-Term Prospective Study.
Refractory chronic migraine affects approximately 4% of the population worldwide and results in severe pain, lifestyle limitations, and decreased quality of life. Occipital nerve stimulation (ONS) refers to the electric stimulation of the distal branches of greater and lesser occipital nerves; the surgical technique has previously been described and has demonstrated efficacy in the treatment of a wide variety of headache disorders. The aim of this study is to evaluate the long-term efficacy and tolerability of ONS for medically intractable chronic migraine. Prospective, long-term, open-label, uncontrolled observational study. Single public university hospital. Patients who met the International Headache Society criteria for chronic migraine, all of them having been previously treated with other therapeutic alternatives, and who met all inclusion and exclusion criteria for neurostimulation, received the implantation of an ONS system after a positive psychological evaluation and a positive response to a preliminary occipital nerve blockage. The implantation was performed in 2 phases: a 10 day trial with implanted occipital leads connected to an external stimulator and, if more than 50% pain relief was obtained, permanent pulse generator implantation and connection to the previously implanted leads. After the surgery, the patients were thoroughly evaluated annually using different scales: pain Visual Analogue Scale (VAS), number of migraine attacks per month, sleep quality, functionality in social and labor activities, reduction in pain medication, patient satisfaction, tolerability, and reasons for termination. The average follow-up time was 9.4 ± 6.1 years, and 31 patients completed a 7-year follow-up period. Thirty-seven patients were enrolled and classified according to the location and quality of their pain, accompanying symptoms, work status, and psychological effects. Substantial pain reduction was obtained in most patients, and the VAS decreased by 4.9 ± 2.0 points. These results remained stable over the follow-up period. Five of the 35 permanently implanted patients with migraine attacks at baseline were free from these attacks at their last visits, whereas the pain severity decreased 3.8 ± 2.5 (according to the VAS) in the remaining patients. Seven of the 35 permanent implanted devices were definitively removed: 2 devices because of treatment inefficacy, and 5 devices because the patients were asymptomatic and considered to be cured from their pain, even with the stimulation off. Systemic side effects were not observed. Limitations of the current study include its uncontrolled and open-label design. Additionally, not all patients completed the 7-year follow-up period. We consider that the trigemino-cervical autonomous and cervical connection may explain why ONS might relieve chronic migraine pain, but this is just a theoretical explanation which should be demonstrated in future studies. The results achieved in this study suggest that ONS may provide long-term benefits for patients with medically intractable chronic migraine. These outcomes are slightly better than previous reports and were maintained over the 7-year follow-up. We believe that an accurate selection of patients, realization of diagnostic occipital nerve blocks, psychological evaluations, rigorous surgical technique, and appropriate parameter programming helped us achieve these outcomes. Key words: Refractory chronic migraine, headache, occipital nerve stimulatino, peripheral nerve stimulation, occipital nerve block.


Activation of TRPML1 clears intraneuronal Aβ in preclinical models of HIV infection.
Antiretroviral therapy extends the lifespan of human immunodeficiency virus (HIV)-infected patients, but many survivors develop premature impairments in cognition. These residual cognitive impairments may involve aberrant deposition of amyloid β-peptides (Aβ). By unknown mechanisms, Aβ accumulates in the lysosomal and autophagic compartments of neurons in the HIV-infected brain. Here we identify the molecular events evoked by the HIV coat protein gp120 that facilitate the intraneuronal accumulation of Aβ. We created a triple transgenic gp120/APP/PS1 mouse that recapitulates intraneuronal deposition of Aβ in a manner reminiscent of the HIV-infected brain. In cultured neurons, we found that the HIV coat protein gp120 increased the transcriptional expression of BACE1 through repression of PPARγ, and increased APP expression by promoting interaction of the translation-activating RBP heterogeneous nuclear ribonucleoprotein C with APP mRNA. APP and BACE1 were colocalized into stabilized membrane microdomains, where the β-cleavage of APP and Aβ formation were enhanced. Aβ-peptides became localized to lysosomes that were engorged with sphingomyelin and calcium. Stimulating calcium efflux from lysosomes with a TRPM1 agonist promoted calcium efflux, luminal acidification, and cleared both sphingomyelin and Aβ from lysosomes. These findings suggest that therapeutics targeted to reduce lysosomal pH in neurodegenerative conditions may protect neurons by facilitating the clearance of accumulated sphingolipids and Aβ-peptides.


Implementation of the chronic care model in small medical practices improves cardiovascular risk but not glycemic control.
OBJECTIVE To test whether the implementation of elements of the Chronic Care Model (CCM) via a specially trained practice nurse leads to an improved cardiovascular risk profile among type 2 diabetes patients. RESEARCH DESIGN AND METHODS This cluster randomized controlled trial with primary care physicians as the unit of randomization was conducted in the German part of Switzerland. Three hundred twenty-six type 2 diabetes patients (age >18 years; at least one glycosylated hemoglobin [HbA1c] level of ≥7.0% [53 mmol/mol] in the preceding year) from 30 primary care practices participated. The intervention included implementation of CCM elements and involvement of practice nurses in the care of type 2 diabetes patients. Primary outcome was HbA1c levels. The secondary outcomes were blood pressure (BP), LDL cholesterol, accordance with CCM (assessed by Patient Assessment of Chronic Illness Care [PACIC] questionnaire), and quality of life (assessed by the 36-item short-form health survey [SF-36]). RESULTS After 1 year, HbA1c levels decreased significantly in both groups with no significant difference between groups (-0.05% [-0.60 mmol/mol]; P = 0.708). Among intervention group patients, systolic BP (-3.63; P = 0.050), diastolic BP (-4.01; P < 0.001), LDL cholesterol (-0.21; P = 0.033), and PACIC subscores (P < 0.001 to 0.048) significantly improved compared with control group patients. No differences between groups were shown in the SF-36 subscales. CONCLUSIONS A chronic care approach according to the CCM and involving practice nurses in diabetes care improved the cardiovascular risk profile and is experienced by patients as a better structured care. Our study showed that care according to the CCM can be implemented even in small primary care practices, which still represent the usual structure in most European health care systems.


Mutation of melanosome protein RAB38 in chocolate mice.
Mutations of genes needed for melanocyte function can result in oculocutaneous albinism. Examination of similarities in human gene expression patterns by using microarray analysis reveals that RAB38, a small GTP binding protein, demonstrates a similar expression profile to melanocytic genes. Comparative genomic analysis localizes human RAB38 to the mouse chocolate (cht) locus. A G146T mutation occurs in the conserved GTP binding domain of RAB38 in cht mice. Rab38(cht)/Rab38(cht) mice exhibit a brown coat similar in color to mice with a mutation in tyrosinase-related protein 1 (Tyrp1), a mouse model for oculocutaneous albinism. The targeting of TYRP1 protein to the melanosome is impaired in Rab38(cht)/Rab38(cht) melanocytes. These observations, and the fact that green fluorescent protein-tagged RAB38 colocalizes with end-stage melanosomes in wild-type melanocytes, suggest that RAB38 plays a role in the sorting of TYRP1. This study demonstrates the utility of expression profile analysis to identify mammalian disease genes.


Reconfigurable array interconnection by photorefractive correlation.
Electronic parallel processors might communicate more effectively by photons sent through glass or air than by electrons sent through wires, but quickly routing thousands of optical signals remains a problem. Previous photorefractive interconnection networks have dedicated one hologram to each input channel. Instead, we compute a control image from the entire network configuration and store it as a single color-keyedvolume hologram. This lets us use hologram superposition for fast switchingbetween multiple prestored patterns. During operation, data signals from the input modulator array, powered by a shared wavelength-tunable laser, are correlated optically with one color-matched connection hologram to produce the output array. This decouples both data rate and interconnect switching speeds from the slow photorefractive response. We can display arbitrary connection weights using simple binary-phase spatial light modulators and gracefully accommodate modulator limitations by trading off control-image bandwidth for output signal-to-noise ratio. Experimental results with color-multiplexed reflection holograms in z-cut LiNbO(3) confirmed our theoretical predictions that this approach works best for densely connected networks with high fan-in to each output. We obtained an average aggregate signal-to-noise ratio of more than 200:1 for 1024 inputs and outputs.