Induction of Apoptosis in Human Leukemia Cell Line (HL60) by Animal's Venom Derived Peptides (ICD-85).
Our previous studies revealed an inhibitory effect of ICD-85 (Venom derived peptides) on breast cancer cell line MDA-MB231. ICD-85 was also confirmed by in-vivo studies to suppress the breast tumor in mice. However, the exact mechanism of ICD-85 was unknown. Hence, the present study was undertaken to assess the mechanism of ICD-85 effect as an anti-proliferative agent of cancer cells. The effect of ICD-85 on proliferation of HL-60 cancer cells was determined by using the MTT assay. The morphological changes of ICD-85 treated HL-60 cells were observed under transmission electron microscope (TEM). DNA fragmentation analysis was also carried out using gel electrophoresis. ICD-85 induced the marked inhibition of HL60 cell proliferation with an IC50-value of 0.04 μg/mL following 24 h of incubation. ICD-85 treated cells when compared with untreated cells, showed nuclear material condensation, endoplasmic reticulum dilation, mitochondria swelling or degradation, increased cytoplasmic vacuoles, reduction or disappearance in cytoplasmic process and decreased nuclear/cytoplasmic ratio was observed. The characteristic DNA ladder formation of ICD-85-treated cells in agarose gel electrophoresis confirmed the results obtained through the electron microscopy. The results of the present study indicated that ICD-85 inhibited the cancer cell proliferation by inducing cell apoptosis.


A Single-Cell Atlas of In Vivo Mammalian Chromatin Accessibility.
We applied a combinatorial indexing assay, sci-ATAC-seq, to profile genome-wide chromatin accessibility in ∼100,000 single cells from 13 adult mouse tissues. We identify 85 distinct patterns of chromatin accessibility, most of which can be assigned to cell types, and ∼400,000 differentially accessible elements. We use these data to link regulatory elements to their target genes, to define the transcription factor grammar specifying each cell type, and to discover in vivo correlates of heterogeneity in accessibility within cell types. We develop a technique for mapping single cell gene expression data to single-cell chromatin accessibility data, facilitating the comparison of atlases. By intersecting mouse chromatin accessibility with human genome-wide association summary statistics, we identify cell-type-specific enrichments of the heritability signal for hundreds of complex traits. These data define the in vivo landscape of the regulatory genome for common mammalian cell types at single-cell resolution.


Anxious attachment style and hopelessness as predictors of burden in caregivers of patients with disorders of consciousness: a pilot study.
Previous studies on caregivers of patients with disorders of consciousness (DOCs) have highlighted that their overall burden is not related to disease duration or diagnosis, but mainly to their personal characteristics. The aim of this study was to investigate the impact of attachment style and hopelessness on overall burden in caregivers of patients in both vegetative state and minimally conscious state. Nineteen caregivers of patients with DOCs, hosted in a long-term care facility, were assessed using the Caregiver Burden Inventory, the Attachment Style Questionnaire, and the Beck Hopelessness Scale. Socio-demographic information was also collected. Data were analysed through descriptive statistics, correlations, one sample t-test and a multiple regression analysis using SPSS. Burden was not associated with duration of caregiving and gender had no effect on overall burden. Multiple regression analysis indicated that preoccupied attachment style and hopelessness together predicted 49% of the total variability of burden (R(2 )= 0.489; adjusted R = 0.43). These data suggest that caregivers need psychological assessment and support in order to keep under control the level of burden and to help themselves be a better resource for their relatives.


Where less may be more: how the rare biosphere pulls ecosystems strings.
Rare species are increasingly recognized as crucial, yet vulnerable components of Earth's ecosystems. This is also true for microbial communities, which are typically composed of a high number of relatively rare species. Recent studies have demonstrated that rare species can have an over-proportional role in biogeochemical cycles and may be a hidden driver of microbiome function. In this review, we provide an ecological overview of the rare microbial biosphere, including causes of rarity and the impacts of rare species on ecosystem functioning. We discuss how rare species can have a preponderant role for local biodiversity and species turnover with rarity potentially bound to phylogenetically conserved features. Rare microbes may therefore be overlooked keystone species regulating the functioning of host-associated, terrestrial and aquatic environments. We conclude this review with recommendations to guide scientists interested in investigating this rapidly emerging research area.


Heavy metal risk management: case analysis.
To prepare measures for practical policy utilization and the control of heavy metals, hazard control related institutions by country, present states of control by country, and present states of control by heavy metals were examined. Hazard control cases by heavy metals in various countries were compared and analyzed. In certain countries (e.g., the U.S., the U.K., and Japan), hazardous substances found in foods (e.g., arsenic, lead, cadmium, and mercury) are controlled. In addition, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) recommends calculating the provisional tolerable weekly intake (PTWI) of individual heavy metals instead of the acceptable daily intake (ADI) to compare their pollution levels considering their toxicity accumulated in the human body. In Korea, exposure assessments have been conducted, and in other countries, hazardous substances are controlled by various governing bodies. As such, in Korea and other countries, diverse food heavy metal monitoring and human body exposure assessments are conducted, and reducing measures are prepared accordingly. To reduce the danger of hazardous substances, many countries provide leaflets and guidelines, develop hazardous heavy metal intake recommendations, and take necessary actions. Hazard control case analyses can assist in securing consumer safety by establishing systematic and reliable hazard control methods.


Modification of vitronectin by advanced glycation alters functional properties in vitro and in the diabetic retina.
Early diabetic retinopathy is characterized by areas of acellular capillaries and the accumulation of advanced glycation end products (AGE). Endothelial cell maintenance, growth, and migration is regulated by a complex system involving the partitioning of growth factors between extracellular matrix-bound proteoglycans and cells, as well as by the activation and control of pericellular proteolysis. Using specific antibodies, we compared the immunolocalization of the vascular heparan sulfate proteoglycan (HSPG)-binding protein vitronectin (VN), HSPG, basic fibroblast growth factor, and collagen type 1 in retinae prepared from 11-month-old diabetic and nondiabetic Wistar rats. In normal rats, VN immunostaining was prominent in vascularized parts of the inner retina and colocalized with HSPG, which itself showed costaining with basic fibroblast growth factor in the extracellular matrix, vascular walls, and the inner limiting membrane. In contrast, the recognition of VN, HSPG, and basic fibroblast growth factor in diabetic retinae was greatly reduced in the inner limiting membrane and the extracellular matrix, where increased immunoreactive AGE colocalizing with VN were detectable. Capillary labeling of retinal vessel walls for plasminogen activator inhibitor-1 was moderate in both normal and diabetic retinae. AGE-VN was demonstrated in tissue extracts from retina by immunoprecipitation and Western blotting and presented a similar increase of AGE-related immunoreactivity compared with AGE-VN generated in vitro. AGE-VN in vitro had lost its native conformation, yielded high Mr SDS-resistant products, and was resistant to proteolysis because of modification of about 30% of lysines. Because binding of glycosaminoglycans, as well as interaction of type I collagen and the morphoregulatory proteins osteonectin and tenascin with AGE-VN, were reduced to at least 50% of control, alteration of basic residues in the heparin-binding domain of VN is plausible. In comparison to nonmodified VN, AGE-VN exhibited reduced cell attachment-promoting activity. Together, these in vitro results suggest that AGE-VN found in vivo is related to morphologic and functional changes in the diabetic retina and may contribute to the genesis of acellular capillaries in early diabetic retinopathy.


The Surgical Apgar Score in esophagectomy.
The Surgical Apgar Score is a validated prognostic tool that is based on select intraoperative variables (heart rate, mean arterial pressure, and blood loss). It has been shown to be a strong predictor of morbidity and mortality in a variety of surgical populations. Esophagectomy for malignancy represents a unique subset of patients at high risk for postoperative complications. This study assessed the ability of a modified esophagectomy Surgical Apgar Score (eSAS) to predict 30-day major morbidity. A retrospective review included 168 patients who underwent elective esophagectomy for malignant disease at the University of Wisconsin from January 2009 through July 2013. Preoperative patient characteristics, intraoperative details, and short-term outcomes were recorded. Primary outcome was 30-day major morbidity. Univariate and multivariate analyses were performed to determine associations between predictive variables, eSAS, and major morbidity. Major morbidity occurred in 35% of cases. Univariate analysis showed that eSAS of 6 or less was strongly associated with major morbidity (unadjusted odds ratio, 2.55; 95% confidence interval, 1.32-4.91; P = .005). Other risk factors included transhiatal technique, body mass index less than 20 or greater than 35 kg/m(2), and history of diabetes mellitus. In multivariate analysis, eSAS of 6 or less remained a strong predictor of postoperative complications (adjusted odds ratio, 3.75; 95% confidence interval, 1.70-8.26; P = .001). The eSAS was strongly associated with 30-day major morbidity after esophagectomy. Prospective studies are needed to determine whether improved outcomes can be achieved with the eSAS for risk-stratified triage and postoperative care modification.


Central nervous system ischemia after varicella infection and desmopressin therapy for enuresis.
A 7-year-old boy had a left-sided cerebrovascular accident 48 hours after beginning intranasal desmopressin acetate (DDAVP) therapy for persistent secondary nocturnal enuresis and approximately 2 weeks after varicella infection. A possible connection between desmopressin therapy or varicella infection (or both) and the patients neurologic symptoms is discussed, as is the relationship of desmopressin with hypercoagulability, Suggestions for patient/parent education, medical history taking, and patient surveillance are offered to prescribing physicians.


Detection of human tumor cells by amplicon fusion site polymerase chain reaction (AFS-PCR).
Reliable diagnostic strategies for individuals with cancer demand practical methods for highly sensitive and specific detection of tumor cells. Amplification of genomic regions that include putative oncogenes is common in tumor cells of various types. Genomic array platforms offer the opportunity to identify and precisely map amplified genomic regions (ampGRs). The stable existence of these tumor cell–specific genomic aberrations during and after therapy, in theory, make ampGRs optimal targets for cancer diagnostics. In this study, we mapped ampGRs around the proto-oncogene MYCN of human neuroblastomas using a high-resolution tiling array (HR-TA). Based on the HR-TA data, we were able to precisely describe the telomeric and centromeric borders of the ampGRs and deduce virtual fusion sites of the joined ampGRs (amplicon fusion sites [AFSs]). These AFSs served as blueprints for the subsequent design of AFS bridging PCR assays (AFS-PCRs). Strikingly, these assays were absolutely tumor cell specific and capable of detecting 1 tumor cell in 1 × 10(6) to 8 × 10(6) control cells. We successfully proved the in vivo practicability of AFS-PCR by detecting and quantifying the specific AFS DNA of human MYCN-amplified neuroblastomas in the patients' corresponding peripheral blood and bone marrow samples. Thus, we believe AFS-PCR could become a powerful and nevertheless feasible personalized diagnostic tool applicable to a large number of cancer patients, including children with MYCN-amplified neuroblastomas.


Survivin Monoclonal Antibodies Detect Survivin Cell Surface Expression and Inhibit Tumor Growth In Vivo.
Purpose: Survivin is an inhibitor of apoptosis protein (IAP) that is highly expressed in many cancers and represents an attractive molecule for targeted cancer therapy. Although primarily regarded as an intracellular protein with diverse actions, survivin has also been identified in association with circulating tumor exosomes.Experimental Design: We have reported that active, specific vaccination with a long peptide survivin immunogen leads to the development of survivin-specific CD8-mediated tumor cell lysis and prolongation of survival in tumor-bearing mice. In addition to cellular antitumor responses, circulating anti-survivin antibodies are detected in the serum of mice and human glioblastoma patients following vaccination with the survivin immunogen.Results: Here we demonstrate that survivin is present on the outer cell membrane of a wide variety of cancer cell types, including both murine and human glioma cells. In addition, antibodies to survivin that are derived from the immunogen display antitumor activity against murine GL261 gliomas in both flank and intracranial tumor models and against B16 melanoma as well.Conclusions: In addition to immunogen-induced, CD8-mediated tumor cell lysis, antibodies to the survivin immunogen have antitumor activity in vivo Cell-surface survivin could provide a specific target for antibody-mediated tumor immunotherapeutic approaches. Clin Cancer Res; 24(11); 2642-52. ©2018 AACR.


FASCICLIN-LIKE 18 Is a New Player Regulating Root Elongation in Arabidopsis thaliana.
The plasticity of root development represents a key trait that enables plants to adapt to diverse environmental cues. The pattern of cell wall deposition, alongside other parameters, affects the extent, and direction of root growth. In this study, we report that FASCICLIN-LIKE ARABINOGALACTAN PROTEIN 18 (FLA18) plays a role during root elongation in Arabidopsis thaliana. Using root-specific co-expression analysis, we identified FLA18 to be co-expressed with a sub-set of genes required for root elongation. FLA18 encodes for a putative extra-cellular arabinogalactan protein from the FLA-gene family. Two independent T-DNA insertion lines, named fla18-1 and fla18-2, display short and swollen lateral roots (LRs) when grown on sensitizing condition of high-sucrose containing medium. Unlike fla4/salt overly sensitive 5 (sos5), previously shown to display short and swollen primary root (PR) and LRs under these conditions, the PR of the fla18 mutants is slightly longer compared to the wild-type. Overexpression of the FLA18 CDS complemented the fla18 root phenotype. Genetic interaction between either of the fla18 alleles and sos5 reveals a more severe perturbation of anisotropic growth in both PR and LRs, as compared to the single mutants and the wild-type under restrictive conditions of high sucrose or high-salt containing medium. Additionally, under salt-stress conditions, fla18sos5 had a small, chlorotic shoot phenotype, that was not observed in any of the single mutants or the wild type. As previously shown for sos5, the fla18-1 and fla18-1sos5 root-elongation phenotype is suppressed by abscisic acid (ABA) and display hypersensitivity to the ABA synthesis inhibitor, Fluridon. Last, similar to other cell wall mutants, fla18 root elongation is hypersensitive to the cellulose synthase inhibitor, Isoxaben. Altogether, the presented data assign a new role for FLA18 in the regulation of root elongation. Future studies of the unique vs. redundant roles of FLA proteins during root elongation is anticipated to shed a new light on the regulation of root architecture during plant adaptation to different growth conditions.


Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells.
DNA mismatch repair enzymes (for example, MSH2) maintain genomic integrity, and their deficiency predisposes to several human cancers and to drug resistance. We found that leukemia cells from a substantial proportion of children (∼11%) with newly diagnosed acute lymphoblastic leukemia have low or undetectable MSH2 protein levels, despite abundant wild-type MSH2 mRNA. Leukemia cells with low levels of MSH2 contained partial or complete somatic deletions of one to four genes that regulate MSH2 degradation (FRAP1 (also known as MTOR), HERC1, PRKCZ and PIK3C2B); we also found these deletions in individuals with adult acute lymphoblastic leukemia (16%) and sporadic colorectal cancer (13.5%). Knockdown of these genes in human leukemia cells recapitulated the MSH2 protein deficiency by enhancing MSH2 degradation, leading to substantial reduction in DNA mismatch repair and increased resistance to thiopurines. These findings reveal a previously unrecognized mechanism whereby somatic deletions of genes regulating MSH2 degradation result in undetectable levels of MSH2 protein in leukemia cells, DNA mismatch repair deficiency and drug resistance.


Ensuring health equity of marginalized populations: experiences from mainstreaming the health of migrants.
Migrants around the world significantly contribute to the economies of countries of origin and destination alike. Despite the growing number of migrants in today's globalized world, the conditions in which migrants travel, live and work can carry exceptional risks to their physical and mental well-being. These risks are often linked to restrictive immigration and employment policies, economic and social factors and dominant anti-migrant sentiments in societies, and are often referred to as the social determinants of migrants' health. These social determinants need to be addressed in order for migrants to attain their development potential and to concurrently contribute to sustainable development, while reducing the health costs of migration for both migrants and societies of origin and destination. A multi-sectoral approach is required to effectively address the social determinants of migrants' health, as many of the solutions to improving migrants' health lie not only in the health sector but in other sectors, such as labour and immigration. This requires collaboration across the different sectors and integrating migrants' health issues in different sectoral policies to avoid marginalization and exclusion of migrants and ensure positive health outcomes for migrants and their families. The paper will discuss a 'Health in All Policies' (HiAP) approach to migrants' health as, to date, there has not been much discussion on framing migrants' health within an HiAP approach. The paper will also present some examples from countries who have addressed different aspects of migrants' health in line with the recommendations of the 61st World Health Assembly (WHA) Resolution 61.17 on the Health of Migrants (2008).


V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats.
To develop and validate a vasopressin (AVP) receptor knockdown strategy, we infused an antisense oligodeoxynucleotide to the V1 subtype mRNA into the septum of male rats with osmotic minipumps and measured behavioral, cellular and molecular parameters. Compared to vehicle and scrambled-sequence oligo controls, chronic antisense administration for up to 4 d diminished the ability of the animals to distinguish a previously exposed juvenile from a novel one and to respond to exogenous AVP (1 ng/5 microliters, intracerebroventricular) with an improved social memory. Furthermore, anxiety-related behavior was reduced. As measured in the behaviorally tested rats, antisense treatment resulted in a reduced binding of radiolabeled AVP in the septum, but not in other limbic brain areas (receptor autoradiography), and an increased amount of V1 receptor mRNA (reverse transcriptase PCR), indicating translational arrest and ongoing transcriptional activity. In sense oligo-treated rats, on the other hand, both the social and the anxiety-related behavior scores lay between levels obtained in control and antisense-treated animals. These sense-treated rats showed a slightly reduced V1 receptor density in the septum and reduced receptor mRNA levels, indicating hybridization of the sense oligo to the DNA. The data show the potential of antisense targeting to further reveal relationships between local gene expression, neuropeptide-receptor interactions in distinct brain areas, and behavioral performance.


Validation of the mortality prediction equation for damage control surgery in an independent severe trauma population.
A prediction model was developed in Cape Town which utilised age, preoperative lowest pH and lowest core body temperature to derive an equation for the purpose of predicting mortality in damage control surgery. It was shown to reliably predict death despite damage control surgery. The equation derivation dataset and the validation set showed the equation to have 100% positive predictive value (PPV) for both datasets and 24% sensitivity. The aim of the study was to validate the prediction model in an independent dataset from a prospective trauma registry. Retrospective analysis of an ethics-approved prospectively collected database and electronic medical records was performed on trauma patients undergoing damage control surgery at the Inkosi Albert Luthuli Central Hospital, Durban, between 2007 and 2013. Age, lowest preoperative core body temperature and the pH of the patients were analysed using the previously derived equation. The output from the equation was then classified as a prediction of death, based on the obtained values, and then compared to the actual outcome of whether the patients survived or died. A total of 48 patient records were analysed in the study. Twenty-nine patients in the cohort died. The equation predicted mortality in only four cases, of whom three died and one survived (75% PPV and 10% sensitivity). The unexpected survivor reduced the PPV to 75%, compared to 100% PPV achieved in the original study. The results of this study were inconsistent with those of the original study, and the 0.500 cut-off value used in the equation yielded PPV and sensitivity which were relatively non-clinically useful for the average patient in this cohort.


Variability of the Atmospheric PM10 Microbiome in Three Climatic Regions of France.
Primary Biogenic Organic Aerosols (PBOA) were recently shown to be produced by only a few types of microorganisms, emitted by the surrounding vegetation in the case of a regionally homogeneous field site. This study presents the first comprehensive description of the structure and main sources of airborne microbial communities associated with temporal trends in Sugar Compounds (SC) concentrations of PM10 in 3 sites under a climatic gradient in France. By combining sugar chemistry and DNA Metabarcoding approaches, we intended to identify PM10-associated microbial communities and their main sources at three sampling-sites in France, under different climates, during the summer of 2018. This study accounted also for the interannual variability in summer airborne microbial community structure (bacteria and fungi only) associated with PM10-SC concentrations during a 2 consecutive years' survey at one site. Our results showed that temporal changes in PM10-SC in the three sites are associated with the abundance of only a few specific taxa of airborne fungi and bacterial. These taxa differ significantly between the 3 climatic regions studied. The microbial communities structure associated with SC concentrations of PM10 during a consecutive 2-year study remained stable in the rural area. Atmospheric concentration levels of PM10-SC species varied significantly between the 3 study sites, but with no clear difference according to site typology (rural vs. urban), suggesting that SC emissions are related to regional rather than local climatic characteristics. The overall microbial beta diversity in PM10 samples is significantly different from that of the main vegetation around the urban sites studied. This indicates that the airborne microorganisms at these urban sites are not solely from the immediate surrounding vegetation, which contrasts with observations at the scale of a regionally homogeneous rural site in 2017. These results improve our understanding of the spatial behavior of tracers of PBOA emission sources, which need to be better characterized to further implement this important mass fraction of Organic Matter (OM) in Chemical Transport models (CTM).


Detection of Helicobacter pylori infection of the gastric mucosa by measurement of gastric aspirate ammonium and urea concentrations.
Helicobacter pylori possesses unusually high urease activity that lowers the urea concentration and raises the ammonium concentration of the gastric juice in infected people. The value of measuring urea and ammonium concentrations in gastric juice obtained during upper gastrointestinal endoscopy as a means of diagnosing the presence and eradication of the infection was assessed. Twenty four subjects with the infection and 14 in whom it had been eradicated were examined. Their H pylori status was confirmed by antral biopsy and 14C urea breath test. The median (range) gastric juice urea concentration in infected subjects was 0.8 mmol/l (0.5-2.9 mmol/l), which was lower than that in the uninfected subjects (2.1 mmol/l (1.0-3.7 mmol/l)) (p less than 0.001). The median gastric juice ammonium concentration in infected subjects was 3.4 mmol/l (1.0-13.0 mmol/l), which was higher than that in the uninfected subjects (0.64 mmol/l (0.02-1.4 mmol/l)) (p less than 0.001). Though the two groups overlapped in respect of their urea and ammonium concentrations, they were completely different when the urea: ammonium ratios were calculated--the ratios ranged from 0.04-0.7 (median 0.26) and from 1.1-113 (median 3.4) in infected and uninfected subjects respectively (p less than 0.001). Treatment with H2 antagonists did not change the concentrations of urea and ammonium or their ratio in gastric juice. Measurement of the urea: ammonium ratio in aspirated gastric juice obtained during routine upper gastrointestinal endoscopy may provide a rapid method of detecting H pylori infection and of confirming its eradication.


Epidermal growth factor-mediated activation of the map kinase cascade results in altered expression and function of ABCG2 (BCRP).
Epidermal growth factor (EGF) is a multifunctional growth factor known to play a major role in proliferation and differentiation processes. EGF-induced differentiation is a prerequisite for function of various cell types, among them cytotrophoblasts, a functionally important cellular fraction in human placenta. Stimulation of cytotrophoblasts with EGF results in formation of a multinuclear syncytium representing the feto-maternal interface, which protects the fetus against exogenous substances. It is well established that part of this protection system is based on ATP-binding cassette (ABC) transporters such as ABCG2 (breast cancer resistance protein, BCRP). However, little is known about regulation of transport proteins in the framework of EGF-mediated cellular differentiation. In the present work we show a significant increase of ABCG2 expression by EGF in cytotrophoblasts, BeWo, and MCF-7 cells on both mRNA and protein levels. This increase resulted in decreased sensitivity to the ABCG2 substrates mitoxantrone and topotecan. In each cell type, EGF increases expression of ABCG2 by activation of mitogen-activated protein kinase cascade via phosphorylation of extracellular regulated kinase (ERK)1/2 and c-jun NH-terminal kinase/stress-activated protein kinase (JNK/SAPK). Consequently, the increase of ABCG2 by EGF was abolished by pretreatment of cells with the tyrosine kinase inhibitor 4-(3-chloroanillino)-6,7-dimethoxyquinazoline (AG1478) or the mitogen-activated protein kinase kinase inhibitor 2'-amino-3'methoxyflavone (PD 98059), thereby reestablishing sensitivity toward mitoxantrone. Moreover, analysis of ABCG2 expression during placental development revealed a significant increase in preterm versus term placenta. Taken together, our data show regulation of ABCG2 expression by EGF. In view of EGF signal transduction as a target for drugs (e.g., gefitinib), which are in turn substrates and/or inhibitors of ABCG2, this regulation has therapeutic consequences.


The relationship between sex hormones and high-density lipoprotein cholesterol levels in healthy adult men.
The objective of this study was to clarify the complex and uncertain relationship between endogenous sex hormones and high-density lipoprotein (HDL) cholesterol levels in healthy men. Fifty-five healthy adult men were consecutively recruited from an ongoing cross-sectional study of cardiovascular disease risk factors from a lipid research clinic at the University of Washington, Seattle. Subjects receiving medication were excluded. Multiple linear regression analysis identified several factors that correlated highly significantly with HDL cholesterol levels, including alcohol intake; frequency of strenuous exercise; age; levels of total cholesterol, low-density lipoprotein cholesterol, and triglyceride; and carbohydrate intake. Nearly 80% of the heterogeneity in HDL cholesterol levels could be accounted for by these factors. Despite finding significant correlations with factors known to influence HDL cholesterol levels, no correlation with estradiol level, testosterone level, or the ratio of estradiol to testosterone levels was apparent. In conclusion, endogenous sex hormones do not appear to influence HDL cholesterol levels in healthy adult men. Alternatively, a large proportion of the heterogeneity in HDL levels in this group of men can be accounted for by environmental factors. The disparity between this conclusion and others may be partially due to differences in accounting for these confounding variables.


Transitional versus surgical menopause in a rodent model: etiology of ovarian hormone loss impacts memory and the acetylcholine system.
Clinical research suggests that type of ovarian hormone loss at menopause influences cognition. Until recently ovariectomy (OVX) has been the primary rodent model to examine effects of ovarian hormone loss on cognition. This model limits evaluations to abrupt and complete ovarian hormone loss, modeling less than 13% of women who receive surgical menopause. The majority of women do not have their ovaries surgically removed and undergo transitional hormone loss via ovarian follicular depletion. 4-Vinylcyclohexene-diepoxide (VCD) produces gradual ovarian follicular depletion in the rodent, with hormone profiles more similar to naturally menopausal women vs. OVX. We directly compared VCD and OVX models to examine whether type of hormone loss (transitional vs. surgical) impacted cognition as assessed on a maze battery as well as the cholinergic system tested via scopolamine mnemonic challenge and brain acetylcholinesterase activity. Middle-aged rats received either sham surgery, OVX surgery, VCD, or VCD then OVX to assess effects of removal of residual ovarian output after transitional menopause and follicular depletion. VCD-induced transitional menopause impaired learning of a spatial recent memory task; surgical removal of residual ovarian hormones by OVX abolished this negative effect of transitional menopause. Furthermore, transitional menopause before OVX was better for memory than an abrupt loss of hormones via OVX only. Surgical ovarian hormone loss, regardless of menopause history, increased hippocampal acetylcholinesterase activity. Circulating gonadotropin and androstenedione levels were related to cognitive competence. Collectively, findings suggest that in the rat, initiation of transitional menopause before surgical ovary removal can benefit mnemonic function and could obviate some negative cognitive consequences of surgical menopause alone.


Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis.
While a number of studies have documented the importance of microglia in central nervous system (CNS) response to injury, infection and disease, little is known regarding its role in viral encephalitis. We therefore, exploited an experimental model of Japanese Encephalitis, to better understand the role played by microglia in Japanese Encephalitis Virus (JEV) infection. Lectin staining performed to assess microglial activation indicated a robust increase in reactive microglia following infection. A difference in the topographic distribution of activated, resting, and phagocytic microglia was also observed. The levels of various proinflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (Cox-2), IL-6, IL-1beta, TNF-alpha, and MCP-1 that have been implicated in microglial response to an activational state was significantly elevated following infection. These cytokines exhibited region selective expression in the brains of infected animals, with the highest expression observed in the hippocampus. Moreover, the expression of neuronal specific nuclear protein NeuN was markedly downregulated during progressive infection indicating neuronal loss. In vitro studies further confirmed that microglial activation and subsequent release of various proinflammatory mediators induces neuronal death following JEV infection. Although initiation of immune responses by microglial cells is an important protective mechanism in the CNS, unrestrained inflammatory responses may result in irreparable brain damage. Our findings suggest that the increased microglial activation following JEV infection influences the outcome of viral pathogenesis. It is likely that the increased microglial activation triggers bystander damage, as the animals eventually succumb to infection.


Impact of emotional and motivational regulation on putting performance: a frontal alpha asymmetry study.
The efficacy of emotional and motivational regulation can determine athletic performance. Giving the short duration and fast changing nature of emotions experienced by athletes in competition, it is important to examine the temporal dynamics of emotional and motivational regulation. The aim of this study was to investigate emotional and motivational regulation as measured by frontal alpha asymmetry in skilled golfers during putting performance after a performance failure. Twenty skilled university golfers were recruited and requested to perform 40 putts at an individualized difficulty level of 40-60% successful putting rate. Trials immediately after a failed putt were selected for analysis. Successful performances were those trials where a hole was and unsuccessful performances were those that failed. The frontal alpha asymmetry index of LnF4-LnF3 was derived for statistical analysis. (1) Successful performance was preceded by a larger frontal alpha asymmetry index at T2 than that of T1, and (2) a larger frontal alpha asymmetry index was observed for unsuccessful performance than for successful performance at T1. The results suggest that successful emotional and motivational regulation was characterized by a progressive increase of frontal alpha asymmetry, which led to subsequent putting success when facing an emotionally provocative putting failure. These findings shed light on the application of frontal alpha asymmetry for the understanding and enhancement of emotional and motivational regulation during sport performance.


User fee policies to promote health service access for the poor: a wolf in sheep's clothing?
An international survey of health service user fee and exemption policies in 26 low- and middle-income countries assessed whether user fee policies were supported by measures that protect the poor. In particular, it explored whether governments were introducing a package of supportive measures to promote service improvements that benefit disadvantaged groups and tackle differential ability to pay through an effective series of exemptions. The results show that many countries lack policies that promote access for disadvantaged groups within user fee systems and quality improvements such as revenue retention at the health care facility and expenditure guidelines for local managers. More significant policy failures were identified for exemptions: 27 percent of countries had no policy to exempt the poor; in contrast, health workers were exempted in 50 percent of countries. Even when an official policy to exempt the poor existed, there were numerous informational, administrative, economic, and political constraints to effective implementation of these exemptions. The authors argue that user fee policy should be developed more cautiously and in a more informed environment. Fees are likely to exacerbate existing inequities in health care financing unless exemptions policy can effectively reach those unable to pay.


Stress-induced birefringence in microstructured optical fibers.
We present a numerical study of stress-induced birefringence in microstructured optical fibers (MOFs), using a finite-element method. MOFs under lateral forces and twists are considered separately. Compared with that in standard single-mode optical fibers, stress-induced linear birefringence in MOFs under a lateral force is reduced with increasing air-hole size, whereas twist-induced circular birefringence in MOFs is enhanced when the air-hole size is small.


Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial.
The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. ClinicalTrials.gov, NCT02216279.


Group size effects in social evolution.
How the size of social groups affects the evolution of cooperative behaviors is a classic question in evolutionary biology. Here we investigate group size effects in the evolutionary dynamics of games in which individuals choose whether to cooperate or defect and payoffs do not depend directly on the size of the group. We find that increasing the group size decreases the proportion of cooperators at both stable and unstable rest points of the replicator dynamics. This implies that larger group sizes can have negative effects (by reducing the amount of cooperation at stable polymorphisms) and positive effects (by enlarging the basin of attraction of more cooperative outcomes) on the evolution of cooperation. These two effects can be simultaneously present in games whose evolutionary dynamics feature both stable and unstable rest points, such as public goods games with participation thresholds. Our theory recovers and generalizes previous results and is applicable to a broad variety of social interactions that have been studied in the literature.


Haplotypes in the complement factor H (CFH) gene: associations with drusen and advanced age-related macular degeneration.
Age-related macular degeneration (AMD), the leading cause of blindness in the Western world, is a complex disease that affects people over 50 years old. The complement factor H (CFH) gene has been repeatedly shown to be a major factor in determining susceptibility to the advanced form of the condition. We aimed to better understand the functional role of this gene in the AMD disease process and assess whether it is associated with earlier forms of the disease. WE genotyped SNPS at the cfh gene locus in three independent populations with AMD: (a) extended families where at least 3 family members had AMD; (b) sporadic cases of advanced AMD and (c) cases from the Age-Related Eye Disease Study (AREDS). We investigated polymorphisms and haplotypes in and around the CFH gene to assess their role in AMD. CFH is associated with early/intermediate and advanced AMD in both familial and sporadic cases. In our populations, the CFH SNP, rs2274700, is most strongly associated with AMD and when incorporated into a haplotype with the Y402H SNP and rs1061147, the strongest association is observed (p<10(-9)). Our results, reproduced in three populations that represent the spectrum of AMD cases, provide evidence that the CFH gene is associated with drusen as well as with advanced AMD. We also identified novel susceptibility and protective haplotypes in the AMD populations.


Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.
The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker-initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.


P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating.
Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions.


Mechanisms of Insertion of dCTP and dTTP Opposite the DNA Lesion O6-Methyl-2'-deoxyguanosine by Human DNA Polymerase η.
O6-Methyl-2'-deoxyguanosine (O6-MeG) is a ubiquitous DNA lesion, formed not only by xenobiotic carcinogens but also by the endogenous methylating agent S-adenosylmethionine. It can introduce mutations during DNA replication, with different DNA polymerases displaying different ratios of correct or incorrect incorporation opposite this nucleoside. Of the "translesion" Y-family human DNA polymerases (hpols), hpol η is most efficient in incorporating equal numbers of correct and incorrect C and T bases. However, the mechanistic basis for this specific yet indiscriminate activity is not known. To explore this question, we report biochemical and structural analysis of the catalytic core of hpol η. Activity assays showed the truncated form displayed similar misincorporation properties as the full-length enzyme, incorporating C and T equally and extending from both. X-ray crystal structures of both dC and dT paired with O6-MeG were solved in both insertion and extension modes. The structures revealed a Watson-Crick-like pairing between O6-MeG and 2"-deoxythymidine-5"-[(α, β)-imido]triphosphate (approximating dT) at both the insertion and extension stages with formation of two H-bonds. Conversely, both the structures with O6- MeG opposite dCTP and dC display sheared configuration of base pairs but to different degrees, with formation of two bifurcated H-bonds and two single H-bonds in the structures trapped in the insertion and extension states, respectively. The structural data are consistent with the observed tendency of hpol η to insert both dC and dT opposite the O6-MeG lesion with similar efficiencies. Comparison of the hpol η active site configurations with either O6-MeG:dC or O6-MeG:dT bound compared with the corresponding situations in structures of complexes of Sulfolobus solfataricus Dpo4, a bypass pol that favors C relative to T by a factor of ∼4, helps rationalize the more error-prone synthesis opposite the lesion by hpol η.


Commonality of processes underlying visual and verbal recognition memory.
Memory for visual and verbal material engages widely distributed systems, to a large degree focussed in different hemispheres. It might thus be expected that these disparate neuronal populations should display significantly different characteristics in regard to mnemonic performance. Visual memory, fundamental to all human beings, and whose characteristics are largely shared with macaques, was assayed using unique non-objective, colored images lacking ready verbal description and was contrasted with memory for four-letter non-offensive English words. The effects of memory loading, stimulus duration and long-term test intervals (1-2 weeks) were studied in regard to accuracy and reaction times for recognizing initial versus re-exposure to these two types of items. No effects of memory loading were apparent despite the incrementing memory load in the 240-item, running recognition sessions. Words were better remembered than images, both in the long and short term, but the detailed characteristics of reaction times and accuracy in relation to number of intervening items, and in long-term memory were strikingly similar. Given the wide and well-established disparity in cerebral loci participating in linguistic versus image analysis, these multiple similarities in the pattern of mnemonic performance indicate that the underlying neuronal processes must be comparable for remembering either images or words. Furthermore, the strong link manifested between individual items across a varying number of intervening intervals and added items suggests that a phenomenon highly similar to the "stimulus specific adaptation" (SSA), displayed by units in macaque inferotemporal cortex, occurs for each item to be recognized. Finally, the significant augmentation in accuracy both in short- and long-term memory for images when viewing time permits saccades is explained if each saccade and fixational pause recruits additional neurons into the pool displaying SSA, or its equivalent, for the item being viewed.


Pharmacy education in India.
Pharmacy education in India traditionally has been industry and product oriented. In contrast to the situation in developed nations, graduate pharmacists prefer placements in the pharmaceutical industry. To practice as a pharmacist in India, one needs at least a diploma in pharmacy, which is awarded after only 2 years and 3 months of pharmacy studies. These diploma-trained pharmacists are the mainstay of pharmacy practice. The pharmacy practice curriculum has not received much attention. In India, there has been a surge in the number of institutions offering pharmacy degrees at various levels and a practice-based doctor of pharmacy (PharmD) degree program was started in some private institutions in 2008. However, relatively little information has been published describing the current status of complex pharmacy education of India. In this paper we describe pharmacy education in India and highlight major issues in pharmacy practice including deficiencies in curriculum. The changing face of the profession is discussed, including the establishment of the PharmD program. The information presented in this paper may stimulate discussion and critical analysis and planning, and will be of value in further adaptation of the pharmacy education to desired educational outcomes.


Discriminative Properties of Hippocampal Hypoperfusion in Marijuana Users Compared to Healthy Controls: Implications for Marijuana Administration in Alzheimer's Dementia.
Few studies have evaluated the impact of marijuana use on regional cerebral blood flow. To determine whether perfusion in specific brain regions on functional neuroimaging, including those affected by Alzheimer's disease pathology, are abnormal in marijuana users compared to controls. Persons with a diagnosis of cannabis use disorder by DSM-IV and DSM-V criteria (n = 982) were compared to controls (n = 92) with perfusion neuroimaging with SPECT at rest and at a concentration task. Perfusion estimates were quantified using a standard atlas. Cerebral perfusion differences were calculated using one-way ANOVA. Diagnostic separation was determined with discriminant analysis of all subjects. Feature selection with a minimum redundancy maximum relevancy (mRMR) identified predictive regions in a subset of marijuana users (n = 436) with reduced psychiatric co-morbidities. Marijuana users showed lower cerebral perfusion on average (p < 0.05). Discriminant analysis distinguished marijuana users from controls with correct classification of 96% and leave one out cross-validation of 92%. With concentration SPECT regions, there was correct classification of 95% with a leave-one-out cross validation of 90%. AUC analysis for concentration SPECT regions showed 95% accuracy, 90% sensitivity, and 83% specificity. The mRMR analysis showed right hippocampal hypoperfusion on concentration SPECT imaging was the most predictive in separating marijuana subjects from controls. Multiple brain regions show low perfusion on SPECT in marijuana users. The most predictive region distinguishing marijuana users from healthy controls, the hippocampus, is a key target of Alzheimer's disease pathology. This study raises the possibility of deleterious brain effects of marijuana use.


The homeostatic chemokine CCL21 predicts mortality and may play a pathogenic role in heart failure.
CCL19 and CCL21, acting through CCR7, are termed homeostatic chemokines. Based on their role in concerting immunological responses and their proposed involvement in tissue remodeling, we hypothesized that these chemokines could play a pathogenic role in heart failure (HF). Our main findings were: (i) Serum levels of CCL19 and particularly CCL21 were markedly raised in patients with chronic HF (n = 150) as compared with healthy controls (n = 20). A CCL21 level above median was independently associated with all-cause mortality. (ii) In patients with HF following acute myocardial infarction (MI; n = 232), high versus low CCL21 levels 1 month post-MI were associated with cardiovascular mortality, even after adjustment for established risk factors. (iii). Explanted failing human LV tissue (n = 29) had markedly increased expression of CCL21 as compared with non-failing myocardium (n = 5). (iv) Our studies in CCR7(-/-) mice showed improved survival and attenuated increase in markers of myocardial dysfunction and wall stress in post-MI HF after 1 week, accompanied by increased myocardial expression of markers of regulatory T cells. (v) Six weeks post-MI, there was an increase in markers of myocardial dysfunction and wall stress in CCR7 deficient mice. High serum levels of CCL21 are independently associated with mortality in chronic and acute post-MI HF. Our findings in CCR7 deficient mice may suggest that CCL21 is not only a marker, but also a mediator of myocardial failure. However, while short term inhibition of CCR7 may be beneficial following MI, a total lack of CCR7 during long-term follow-up could be harmful.


High performance communication by people with paralysis using an intracortical brain-computer interface.
Brain-computer interfaces (BCIs) have the potential to restore communication for people with tetraplegia and anarthria by translating neural activity into control signals for assistive communication devices. While previous pre-clinical and clinical studies have demonstrated promising proofs-of-concept (Serruya et al., 2002; Simeral et al., 2011; Bacher et al., 2015; Nuyujukian et al., 2015; Aflalo et al., 2015; Gilja et al., 2015; Jarosiewicz et al., 2015; Wolpaw et al., 1998; Hwang et al., 2012; Spüler et al., 2012; Leuthardt et al., 2004; Taylor et al., 2002; Schalk et al., 2008; Moran, 2010; Brunner et al., 2011; Wang et al., 2013; Townsend and Platsko, 2016; Vansteensel et al., 2016; Nuyujukian et al., 2016; Carmena et al., 2003; Musallam et al., 2004; Santhanam et al., 2006; Hochberg et al., 2006; Ganguly et al., 2011; O'Doherty et al., 2011; Gilja et al., 2012), the performance of human clinical BCI systems is not yet high enough to support widespread adoption by people with physical limitations of speech. Here we report a high-performance intracortical BCI (iBCI) for communication, which was tested by three clinical trial participants with paralysis. The system leveraged advances in decoder design developed in prior pre-clinical and clinical studies (Gilja et al., 2015; Kao et al., 2016; Gilja et al., 2012). For all three participants, performance exceeded previous iBCIs (Bacher et al., 2015; Jarosiewicz et al., 2015) as measured by typing rate (by a factor of 1.4-4.2) and information throughput (by a factor of 2.2-4.0). This high level of performance demonstrates the potential utility of iBCIs as powerful assistive communication devices for people with limited motor function.Clinical Trial No: NCT00912041.


Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease.
Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss. To examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival;(2) nutritional status; (3) quality of life;(4) minor and major complications of percutaneous endoscopic gastrostomy. We searched the Cochrane Neuromuscular Disease Group Trials Register (24 November 2009), MEDLINE (from January 1966 to September 2009), and EMBASE (from January 1980 to September 2009) for all papers on enteral tube feeding in amyotrophic lateral sclerosis/motor neuron disease. The results were screened to identify randomised controlled trials and to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles and enlisted personal communications to identify any additional references. A priori selection criteria included randomised and quasi-randomized controlled trials evaluating the efficacy of percutaneous endoscopic gastrostomy or other feeding tube placement. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review. We independently assessed study design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, (3) self-perceived quality of life and (4) safety of the procedure as indicated by minor and major complications of surgical or radiological guided PEG tube insertion. We found no randomised controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective studies in the 'Discussion' section. There are no randomised controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for any of the outcome measures. The 'best' evidence to date suggests a survival advantage for some people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable. Quality of life has been addressed in studies and needs more attention. Based on a number of recent non-randomized studies comparing surgical and radiographic approaches to feeding tube insertion these two procedures for PEG tube insertion appear to be equivalent.


Rifampin phosphotransferase is an unusual antibiotic resistance kinase.
Rifampin (RIF) phosphotransferase (RPH) confers antibiotic resistance by conversion of RIF and ATP, to inactive phospho-RIF, AMP and Pi. Here we present the crystal structure of RPH from Listeria monocytogenes (RPH-Lm), which reveals that the enzyme is comprised of three domains: two substrate-binding domains (ATP-grasp and RIF-binding domains); and a smaller phosphate-carrying His swivel domain. Using solution small-angle X-ray scattering and mutagenesis, we reveal a mechanism where the swivel domain transits between the spatially distinct substrate-binding sites during catalysis. RPHs are previously uncharacterized dikinases that are widespread in environmental and pathogenic bacteria. These enzymes are members of a large unexplored group of bacterial enzymes with substrate affinities that have yet to be fully explored. Such an enzymatically complex mechanism of antibiotic resistance augments the spectrum of strategies used by bacteria to evade antimicrobial compounds.


Young men have equivalent biochemical outcomes compared with older men after treatment with brachytherapy for prostate cancer.
To evaluate retrospectively the biochemical outcomes of young men treated with low-dose-rate brachytherapy for prostate cancer. From 1990 to 2005, 1,665 men with clinically localized prostate cancer were treated with low-dose-rate brachytherapy +/- hormone therapy (HT) +/- external beam radiotherapy and underwent > or = 2 years of follow-up. Patients were stratified on the basis of age: < or = 60 (n = 378) and >60 years (n = 1,287). Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/mL. Univariate and multivariate analyses were used to determine the association of variables with freedom from biochemical failure (FFbF). Median follow-up was 68 months (range, 24-180) for men < or = 60 years and 66 months (range, 24-200) for men >60. For the entire group, the actuarial 5- and 8-year FFbF rates were 94% and 88%, respectively. Men < or = 60 demonstrated similar 5- and 8-year FFbF (95% and 92%) compared with men >60 (93% and 87%; p = 0.071). A larger percent of young patients presented with low-risk disease; lower clinical stage, Gleason score (GS), and pretreatment PSA values; were treated after 1997; did not receive any HT; and had a high biologic effective dose (BED) of radiation (all ps <0.001). On multivariate analysis, PSA (p = 0.001), GS (p = 0.005), and BED (p < 0.001) were significantly associated with FFbF, but age was not (p = 0.665). Young men achieve excellent 5- and 8-year biochemical control rates that are comparable to those of older men after prostate brachytherapy. Young age should not be a deterrent when considering brachytherapy as a primary treatment option for clinically localized prostate cancer.


Clinical trial of sequential treatments of moderately severe and severe malaria with dihydroartemisinin suppository followed by mefloquine in Thailand.
One hundred and fifty patients with severe falciparum malaria were administered sequential combination of dihydroartemisinin suppository followed by an oral mefloquine tablet. Dihydroartemisinin suppositories (80 mg/capsule) were given rectally once daily for 3 days with a total dose of 8-10 mg/kg. Two doses of mefloquine, 15 mg/kg/dose and 10 mg/kg/dose, were given at 72 hr and 84 hr, respectively. The mean [SD] parasite clearance time and fever clearance time were 46.1 [15.7] hr and 82.5 [59.6] hr, respectively. No death or major adverse drug effects occurred. The cure rate at 28 days of inpatient follow-up was 95% (113 of 119 patients). In severe malaria, dihydroartemisinin suppository followed by oral mefloquine is a suitable alternative treatment to parenteral drugs.


The discovery of structural form.
Algorithms for finding structure in data have become increasingly important both as tools for scientific data analysis and as models of human learning, yet they suffer from a critical limitation. Scientists discover qualitatively new forms of structure in observed data: For instance, Linnaeus recognized the hierarchical organization of biological species, and Mendeleev recognized the periodic structure of the chemical elements. Analogous insights play a pivotal role in cognitive development: Children discover that object category labels can be organized into hierarchies, friendship networks are organized into cliques, and comparative relations (e.g., "bigger than" or "better than") respect a transitive order. Standard algorithms, however, can only learn structures of a single form that must be specified in advance: For instance, algorithms for hierarchical clustering create tree structures, whereas algorithms for dimensionality-reduction create low-dimensional spaces. Here, we present a computational model that learns structures of many different forms and that discovers which form is best for a given dataset. The model makes probabilistic inferences over a space of graph grammars representing trees, linear orders, multidimensional spaces, rings, dominance hierarchies, cliques, and other forms and successfully discovers the underlying structure of a variety of physical, biological, and social domains. Our approach brings structure learning methods closer to human abilities and may lead to a deeper computational understanding of cognitive development.


Suicide Risk Management Protocol in Post-Cardiac Arrest Survivors: Development, Feasibility, and Outcomes.
Suicidal ideation is an important part of the spectrum of depression, but studies of outcomes after cardiac events often avoid asking about suicide as part of their assessment due to perceived resource constraints and the complexity of managing this finding. To describe the development, feasibility, and outcomes of a suicide risk management protocol implemented by research assistants administering the Patient Health Questionnaire Depression Scale (PHQ-9). Patients surviving in-hospital cardiac arrest at any Veterans Affairs hospital during 2014 to 2015 received PHQ-9 screening as a part of longitudinal telephone or mail interviews administered at 3, 6, 9, and 12 months after hospital discharge. Those who screened positive for suicidal ideation were administered a telephone risk assessment protocol. Fifty-five of 366 (15%) interviewed Veterans endorsed suicidal ideation according to the PHQ-9 on 82 of their completed interviews. Of those who endorsed suicidal ideation during their interview, 81% of interviews included passive suicidal ideation without intent or plan. Five (9%) patients were recommended to receive expedited follow-up with a mental health provider or suicide prevention coordinator located within their Veterans Affairs healthcare facility. In 50 (63%) interviews, the patient already had reliable resources, such as a mental health provider or the number to the Veterans Crisis Line. Suicidal ideation is common after in-hospital cardiac arrest, although most patients are at low risk. Addressing suicidal ideation in an observational research study is feasible, with a detailed protocol and research staff who can respond to incidents of high-risk suicidal ideation in collaboration with study clinicians.


Organizational characteristics and cancer care for nursing home residents.
We evaluate whether organization, market, policy, and resident characteristics are related to cancer care processes and outcomes for dually eligible residents of Michigan nursing homes who entered facilities without a cancer diagnosis but subsequently developed the disease. DATA SOURCES/STUDY DESIGN/DATA COLLECTION: Using data from the Michigan Tumor Registry (1997-2000), Medicare claims, Medicaid cost reports, and the Area Resource File, we estimate logistic regression models of diagnosis at or during the month of death and receipt of pain medication during the month of or month after diagnosis. Approximately 25 percent of the residents were diagnosed at or near death. Only 61 percent of residents diagnosed with late or unstaged cancer received pain medication during the diagnosis month or the following month. Residents in nursing homes with lower staffing and in counties with fewer hospital beds were more likely to be diagnosed at death. After the Balanced Budget Act (BBA), residents were more likely to be diagnosed at death. Nursing home characteristics and community resources are significantly related to the cancer care residents receive. The BBA was associated with an increased likelihood of later diagnosis of cancer.


Acute recurrent pericarditis: from pathophysiology towards new treatment strategy.
Acute idiopathic or so-called viral pericarditis is a frequent and usually benign disease, although recurrences are frequent. Data strongly suggest the presence of underlying autoinflammatory and/or autoimmune disorders. It has been reported that there is an inflammatory response of the innate immune system typical of 'autoinflammatory diseases', predominantly mediated by interleukin-1 (IL-1). This may result from the activation of the inflammasome by a cardiotropic virus or a non-specific agent. The inflammatory response of the adaptive immune system, typical of 'autoimmune diseases'-mainly mediated by autoantibodies or autoreactive T lymphocytes-seems also involved as anti-heart or anti-intercalated disk autoantibodies were associated with a higher number of recurrences and hospitalisations. Current guidelines recommend that aspirin/non-steroidal anti-inflammatory drugs for a few weeks should be associated to colchicine for 6 months in recurrent pericarditis. In refractory cases, low-dose corticosteroids or immunosuppressive drugs have been proposed with limited efficacy. Growing evidences suggest a place of IL-1 receptor antagonists in the treatment of recurrent pericarditis. Many retrospective studies, one recent randomised placebo-controlled study and data of a real-life large international registry showed the good efficacy of anakinra with a good safety profile. Other IL-1 receptor antagonists showed promising results (canakinumab, rilonacept). However, IL-1 receptor antagonists' position in the treatment algorithm of recurrent pericarditis needs further evaluation in larger prospective clinical trials to replicate initial findings as well as to assess safety, cost-effectiveness and long-term efficacy.


Balloon-expandable stent placement in patients with immediate reocclusion after initial successful thrombolysis of acute middle cerebral arterial obstruction.
We present the results of our approach for treating 12 consecutive cases of acute middle cerebral artery (MCA) stroke by performing balloon-expandable stent (BES) placement after immediate reocclusion due to the underlying stenosis after intra-arterial thrombolysis (IAT). We retrospectively reviewed the clinical outcomes of 12 patients with acute MCA stroke who underwent recanalization by BES placement in an underlying stenosis after IAT. The time to treatment, urokinase dose, duration of the procedure, recanalization rates and symptomatic hemorrhage were analyzed. Clinical outcome measures were assessed on admission and at discharge (the National Institutes of Health stroke scores [NIHSS]) as well as three months after treatment (modified Rankin scales [mRS]). The median NIHSS score on admission was 8.6. Four patients received IV rtPA. The median time from symptom onset to IAT was 236 minutes and the median duration of IAT was 62 minutes. The median dose of urokinase was 140,000 units. Initial recanalization after stent deployment (thrombolysis in cerebral ischemia attack grade of II or III) was achieved in all patients. Two patients died in the hospital due to aspiration pneumonia during medical management. In two patients, in-stent reocclusion occurred within 48 hours after stent deployment. At discharge, the median NIHSS score in ten patients (including the patients with reobstruction) was 2.4. The three-month outcome was excellent (mRS, 0-1) in eight patients. In this study, BES deployment was safe and effective in patients with an immediately reoccluded MCA after successful IAT.


Challenges and guidelines for clinical trial of herbal drugs.
World Health Organization (WHO) has defined herbal medicines as finished labeled medicinal product that contain an active ingredient, aerial, or underground parts of the plant or other plant material or combinations. According to a report of WHO, about 80% of the world population is reported to rely on traditional medicine for their primary health care needs. Even in the developed countries, complementary or alternative medicine is gaining popularity. A report of a global survey on national policy on traditional medicine and regulation of herbal medicines indicated that about 50 countries including China, Japan, and Germany already have their national policy and laws on regulations of traditional medicines. Herbal drugs possess a long history of its use and better patient tolerance. These are cheaper and easily available in countries like India due to rich agro culture conditions. However, reckless utilization of resources threatens the sustainability of several plant species. Traditional medicines are governed by the Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945. In 1959, the Government of India amended the Drugs and Cosmetics Act to include drugs that are derived from traditional Indian medicine. In 1993, the guidelines for the safety and efficacy of herbal medicines developed by an expert committee directed that the procedures laid down by the office of the Drug Controller General of India for allopathic drugs should be followed for all traditional and herbal products to enter into clinical trials for any therapeutic condition. However, there are certain loop holes in the clinical trials of herbal drugs as the lack of stringent bylaws and regulations. Hence, a deep insight of important challenges and major regulatory guidelines for clinical trial of herbal drugs and botanicals is discussed in the present communication. There is lack of scientific evidence to evaluate safety and efficacy of herbal drugs. The quality of the trial drug has to be tested for batch-to-batch uniformity of the active constituents. It is very difficult to have active and control groups with identical color, smell and taste of the herbal drug, which cannot be imitated while manufacturing a placebo. These challenges can be reduced or overcome by applying most recent methodologies and guidelines for clinical trials. Since the quality control of herbal medicines is complicated and difficult, relevant and appropriate requirements should be established for the assessment of safety and efficacy for different categorized herbal medicines to reduce cost and expenditure. And, efforts should be made for the integration of traditional medicine into national healthcare systems. Different challenges and regulatory guidelines discussed for the clinical trial of herbal drugs will be useful for various industries for considering it before going ahead for clinical trial of their product.


Characterization of bacteriocins produced by two strains of Lactobacillus plantarum isolated from Beloura and Chouriço, traditional pork products from Portugal.
Bacteriocins bacST202Ch and bacST216Ch, produced by Lactobacillus plantarum strains isolated from Beloura and Chouriço, respectively, inhibited the growth of a number of Gram-positive and Gram-negative meat spoilage bacteria. According to trycine-SDS-PAGE, bacST202Ch and bacST216Ch are approximately 3.5 and 10.0 kDa in size, respectively. Maximal activity of bacST202Ch (25,600 AU/ml) was recorded after 27 h of and bacST216Ch (102,400 AU/ml) after 22 h of growth. The mode of activity, as determined against Enterococcus faecium HKLHS, is bactericidal. Both peptides adsorb to the surface of the producer cells, but at very low concentrations. Both peptides remained active after 120 min at 100 degrees C and after 2 h of incubation at pH 2.0-12.0. Treatment for 120 min at 121 degrees C did not affect bacST216Ch activity. Activity of bacST202Ch and bacST216Ch was not affected by 1% Triton X-100, Tween 80, Tween 20, SDS, NaCl, urea and EDTA. Bacteriocin ST216Ch was deactivated in the presence of 1% Triton X-114. The nucleotide sequence of a 1044 bp DNA fragment amplified from L. plantarum ST202Ch is identical to the structural gene encoding pediocin PA-1, suggesting that the two bacteriocins are identical. Based on the broad spectrum of antibacterial activity, strains ST202Ch and ST216Ch may be used as starter cultures in the fermentation of meat products.


A Ten-Year Study of Prostate Cancer: A Southern Iranian Experience.
Prostate cancer is the most common malignancy among the male population in the United States and the 3rd most common non-skin cancer among men in Iran. Its prevalence has shown a rising trend in recent decades. The aim of this study was to report the epidemiological features of prostate cancer in patients referred for prostate biopsy in the south of Iran and to evaluate the accuracy of the levels of the prostate-specific antigen (PSA) and the PSA-density (PSAD) as well as the extension of the disease in the prediction of the biological behavior of prostate cancer. This is a retrospective study on the medical records of 1982 consecutive patients who underwent transrectal ultrasound-guided biopsy due to an abnormal digital rectal examination and/or an elevated PSA level following referral from the Urology Ward to the Radiology Department of Shahid Faghihi Hospital in Shiraz, southern Iran, between December 2003 and July 2014. The overall cancer detection rate was 33.1%. Although the cancer was more prevalent among the elderly patients, a significant fraction (7%) of the patients were aged < 55 years. The sensitivity and specificity of the PSA were 97.4% and 8.7% and those of the PSAD were 82.9% and 52%, respectively. Of the 637 patients with prostate cancer, 250 (39.2%) had unilateral disease, 378 (59.4%) had bilateral disease, and 9 (1.4%) had inner-gland involvement. Most of the patients with bilateral involvement had high-grade Gleason scores. Our study underlines the relationship between age and the frequency of cancer; the levels of the PSA and the PSAD and the Gleason score; and the extent of tumor involvement and the grade of prostate cancer and also highlights the significance of screening, especially in younger patients.


Neural population coding of sound level adapts to stimulus statistics.
Mammals can hear sounds extending over a vast range of sound levels with remarkable accuracy. How auditory neurons code sound level over such a range is unclear; firing rates of individual neurons increase with sound level over only a very limited portion of the full range of hearing. We show that neurons in the auditory midbrain of the guinea pig adjust their responses to the mean, variance and more complex statistics of sound level distributions. We demonstrate that these adjustments improve the accuracy of the neural population code close to the region of most commonly occurring sound levels. This extends the range of sound levels that can be accurately encoded, fine-tuning hearing to the local acoustic environment.


Neurosteroids enhance spontaneous glutamate release in hippocampal neurons. Possible role of metabotropic sigma1-like receptors.
Pregnenolone sulfate (PREGS), one of the most abundantly produced neurosteroids in the mammalian brain, improves cognitive performance in rodents. The mechanism of this effect has been attributed to its allosteric modulatory actions on glutamate- and gamma-aminobutyric acid-gated ion channels. Here we report a novel effect of PREGS that could also mediate some of its actions in the nervous system. We found that PREGS induces a robust potentiation of the frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors in cultured hippocampal neurons. PREGS also decreased paired pulse facilitation of autaptic EPSCs evoked by depolarization, indicating that it modulates glutamate release probability presynaptically. PREGS potentiation of mEPSCs was mimicked by dehydroepiandrosterone sulfate and (+)-pentazocine but not by (-)-pentazocine, the synthetic (-)-enantiomer of PREGS or the inactive steroid isopregnanolone. The sigma receptor antagonists, haloperidol and BD-1063, blocked the effect of PREGS on mEPSCs, as did pertussis toxin and the membrane-permeable Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl) ester. These results suggest that PREGS increases spontaneous glutamate release via activation of a presynaptic G(i/o)-coupled sigma receptor and an elevation in intracellular Ca2+ levels. We postulate that presynaptic actions of neurosteroids have a role in the maturation and/or maintenance of synaptic networks and the processing of information in the central nervous system.


Spontaneous reversal of stenosis in tissue-engineered vascular grafts.
We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)-approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.


Results of a 2011 national questionnaire for investigation of mean glandular dose from mammography in Japan.
Diagnostic reference levels (DRLs) for mammography have yet to be created in Japan. A national questionnaire investigation into radiographic conditions in Japan was carried out for the purpose of creating DRLs. Items investigated included the following: tube voltage; tube current; current-time product; source-image distance; craniocaudal view; automatic exposure control (AEC) settings; name of mammography unit; image receptor system (computed radiography (CR), flat panel detector (FPD), or film/screen (F/S)); and supported or unsupported monitor diagnosis (including monitor resolution). Estimation of the mean glandular dose (MGD) for mammography was performed and compared with previous investigations. The MGD was 1.58(0.48) mGy, which did not significantly differ from a 2007 investigation. In relation to image receptors, although no difference in average MGD values was observed between CR and FPD systems, F/S systems had a significantly decreased value compared to both CR and FPDs. Concerning digital systems (FPDs), the MGD value of the direct conversion system was significantly higher than the indirect conversion system. No significant difference in MGD value was evident concerning type of monitor diagnosis for either the CR or the FPD digital systems; however, hard copies were used more often in CR. No significant difference in the MGD value was found in relation to monitor resolution. This report suggests ways to lower the doses patients undergoing mammography receive in Japan, and serves as reference data for 4.2 cm compressed breast tissue of 50% composition DRLs. Furthermore, our findings suggest that further optimisation of FPD settings can promote a reduction in the MGD value.


Cytogenetic and molecular findings in patients with Turner's syndrome stigmata.
Cytogenetic and DNA analysis in 12 people with stigmata of Turner's syndrome was carried out. Cytogenetic analysis of these patients showed two subjects with 46,X, i(Xq) karyotypes, one with 45,X/46,X, i(Xq), one with 46,X,t(X;Y), and eight with 45,X/46,X,mar. Molecular analysis of DNA samples was performed in nine out of 12 patients with marker chromosomes. PCR analysis with oligoprimers specific for SRY, DYZ1, or DYZ3 loci identified Y chromosome material in five patients in the latter group. The X chromosome origin of the marker chromosome was proved by FISH technique with biotin labelled pericentromeric X chromosome specific probe in four other patients. These results show that patients with a number of Turner's syndrome stigmata usually do not have a typical XO karyotype but have some structural chromosomal aberrations involving the X or Y chromosomes. Combined application of cytogenetic, molecular cytogenetic (FISH), and PCR techniques significantly improves the precision of marker chromosome identification and thus might be of practical importance for the proper management and treatment of affected patients. Peculiarities of pathological manifestations of different karyotypes bearing structural abnormalities of the X or Y chromosomes in patients with Turner's syndrome stigmata, as well as feasible genetic mechanisms of sex determination and differentiation abnormalities in these subjects, are briefly discussed.


First Report of Taro (Colocasia esculenta) Leaf Blight Caused by Phytophthora colocasiae in Nigeria.
In November 2009, many farmers in Abia State were alarmed by complete destruction of their taro (Colocasia esculenta (L.) Schott.) crop. Symptoms, suggestive of leaf blight caused by Phytophthora colocasiae Raciborski (2), began as small, brown, water-soaked lesions that rapidly enlarged to form large, dark brown, coalescing lesions, sometimes with orange host exudations. White sporulation was evident on the lesion surface under wet conditions. The pathogen caused rapid defoliation and killed plants. The epidemic was widespread in 2010 during the rainy season (April to November) in all taro-growing areas of Nigeria. Diseased leaves were collected from taro in Iwo Village near Ibadan, cut into 4-cm2 pieces, washed in several changes of sterile water, and incubated in petri dishes lined with wet filter paper at 22°C. Newly produced sporangia were collected from the incubated leaves and plated on a selective medium (1). Sporangia were hyaline, papillate, and measured 25 to 55 × 15 to 30 μm. Zoospores encysted within 30 min after release; cysts were 9.7 to 19.5 μm in diameter. Sporangia and zoospore formation were induced in water and by chilling, respectively (1). Two leaves each of three 1-month-old taro and three Xanthosoma plants (both unknown clones) and six detached leaves of taro were inoculated with a 1 × 105/ml zoospore suspension of isolates PC01 and PC02. Detached leaves were incubated in moist chambers at 22°C. Plants were covered with polyethylene bags for 12 h after inoculation and maintained in a screenhouse. Water-soaked lesions appeared on detached leaves within 24 h postinoculation and the leaves were completely rotted 48 h later. All inoculated attached leaves of taro, but not Xanthosoma, showed typical leaf blight symptoms including abundant sporangial production. Noninoculated control detached leaves and plants were disease free. Sporangia from detached and attached inoculated leaves, when plated on selective medium, produced typical P. colocasiae colonies. The internal transcribed spacer (ITS) region of rDNA was amplified using the ITS1 and ITS4 primers (3). Amplicons (786 bp) were sequenced in both directions and submitted to GenBank (Accession Nos. HQ602756, HQ602757, HQ602758, and HQ602759). A BLASTn search revealed 99% similarity to a P. colocasiae strain of the Pacific Region (Accession No. GU111604), but only 94% similarity to a P. colocasiae strain from India (Accession No. GQ202149). The sequence analysis, morphological characteristics, and pathogenicity test confirmed the taro leaf blight pathogen as P. colocasiae. There are previous reports of occurrence of taro blight-like disease attributed to P. colocasiae in Ethiopia, Equatorial Guinea (1), and more recently in Cameroon, but comprehensive details on pathogen or disease are not available. To our knowledge, this is the first confirmed record in Nigeria of P. colocasiae causing taro blight. This disease poses a serious threat to the production and biodiversity of this important food crop. Urgent interventions are necessary to halt this emerging epidemic in West and Central Africa. References: (1) Phytophthora colocasiae, In: CABI-Crop Protection Compendium. CAB International, Wallingford, UK, 2005. (2) P. S. Tsao. Page 219 in: Phytophthora: Its Biology, Taxonomy, Ecology and Pathology. The American Phytopathological Society. St. Paul, MN, 1983. (3) T. J. White et al. Page 315 in: PCR Protocol: A Guide to Methods and Applications. Academic Press, London. 1990.


Aluminium-mediated aromatic C-F bond activation: regioswitchable construction of benzene-fused triphenylene frameworks.
Selective synthesis of benzo[f]tetraphenes or benzo[g]chrysenes was achieved via aromatic C-F bond cleavage and unprecedented regioselective C-C bond formation depending upon the choice of aluminium reagents. On treatment with AlCl3, 2-(biphenyl-2-yl)-1-fluoronaphthalenes afforded exclusively benzo[f]tetraphenes via C-C bond formation on the carbon atom γ to the original position of the fluorine substituent. In contrast, α-selective C-C bond formation was promoted by treatment with γ-Al2O3 to give benzo[g]chrysenes.


Baseline Morphine Consumption May Explain Between-Study Heterogeneity in Meta-analyses of Adjuvant Analgesics and Improve Precision and Accuracy of Effect Estimates.
Statistical heterogeneity can increase the uncertainty of results and reduce the quality of evidence derived from systematic reviews. At present, it is uncertain what the major factors are that account for heterogeneity in meta-analyses of analgesic adjuncts. Therefore, the aim of this review was to identify whether various covariates could explain statistical heterogeneity and use this to improve accuracy when reporting the efficacy of analgesics. We searched for reviews using MEDLINE, EMBASE, CINAHL, AMED, and the Cochrane Database of Systematic Reviews. First, we identified the existence of considerable statistical heterogeneity (I > 75%). Second, we conducted meta-regression analysis for the outcome of 24-hour morphine consumption using baseline risk (control group morphine consumption) and other clinical and methodological covariates. Finally, we constructed a league table of adjuvant analgesics using a novel method of reporting effect estimates assuming a fixed consumption of 50 mg postoperative morphine. We included 344 randomized controlled trials with 28,130 participants. Ninety-one percent of analyses showed considerable statistical heterogeneity. Baseline risk was a significant cause of between-study heterogeneity for acetaminophen, nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, tramadol, ketamine, α2-agonists, gabapentin, pregabalin, lidocaine, magnesium, and dexamethasone (R = 21%-100%; P < .05). There was some evidence that the methodological limitations of the trials explained some of the residual heterogeneity. Type of surgery was not independently associated with analgesic efficacy. Assuming a fixed baseline risk of 50 mg (in order of efficacy), gabapentin, acetaminophen, α2-agonists, nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, pregabalin, tramadol, magnesium, and lidocaine demonstrated moderate clinically significant reductions (>10 mg). We could not exclude a moderate clinically significant effect with ketamine. Dexamethasone demonstrated a small clinical benefit (>5 mg). We empirically identified baseline morphine consumption as the major source of heterogeneity in meta-analyses of adjuvant analgesics across all surgical interventions. Controlling for baseline morphine consumption, clinicians can use audit data to estimate the morphine-reducing effect of adding any adjuvant for their local population, regardless which surgery they undergo. Moreover, we have utilized these findings to present a novel method of reporting and an amended method of graphically displaying effect estimates, which both reduces confounding from variable baseline risk in included trials and is able to adjust for other clinical and methodological confounding variables. We recommend use of these methods in clinical practice and future reviews of analgesics for postoperative pain.


Secukinumab Immunogenicity over 52 Weeks in Patients with Psoriatic Arthritis and Ankylosing Spondylitis.
Secukinumab, a fully human antiinterleukin 17A monoclonal antibody, is efficacious for the treatment of psoriatic arthritis (PsA) and ankylosing spondylitis (AS). This study examined the immunogenicity of secukinumab in patients with PsA and AS exposed to secukinumab for up to 52 weeks. Antibody bridging assays were used to assess the immunogenicity of secukinumab in patients with PsA [FUTURE 1-3 studies, and AS (MEASURE 1-4 studies)]. Evaluations were at baseline and at weeks 16 (AS only), 24, and 52. Treatment-emergent antidrug antibodies (TE-ADA) were defined as a positive ADA signal in ≥ 1 posttreatment sample in patients negative at baseline. Positive samples were analyzed for drug-neutralizing potential, and effect of TE-ADA on secukinumab pharmacokinetics, immunogenicity-related adverse events (AE), and efficacy through Week 52 were assessed. Of 1414 treated PsA and 1164 treated AS patients with samples available for immunogenicity evaluation, 5 (0.35%) and 8 (0.69%), respectively, developed TE-ADA. All but 1 PsA patient were biologic-naive; two of the 5 PsA and one of the 8 AS patients received concomitant methotrexate, and two of the 8 AS patients received concomitant sulfasalazine. Associations between TE-ADA and secukinumab dose, frequency, or administration mode were not observed. Other than one PsA patient, all TE-ADA were non-neutralizing. No TE-ADA were associated with any AE. All TE-ADA were associated with normal secukinumab pharmacokinetics and none were associated with loss of secukinumab efficacy. Secukinumab treatment was associated with a low (< 1%) incidence of immunogenicity in patients with PsA or AS. (clinicaltrials.gov: NCT01392326; NCT01752634; NCT01989468; NCT01358175; NCT01649375; NCT02008916; NCT02159053).


Vertical transmission of a phylogenetically complex microbial consortium in the viviparous sponge Ircinia felix.
Many marine demosponges contain large amounts of phylogenetically complex yet highly sponge-specific microbial consortia within the mesohyl matrix, but little is known about how these microorganisms are acquired by their hosts. Settlement experiments were performed with the viviparous Caribbean demosponge Ircinia felix to investigate the role of larvae in the vertical transmission of the sponge-associated microbial community. Inspections by electron microscopy revealed large amounts of morphologically diverse microorganisms in the center of I. felix larvae, while the outer rim appeared to be devoid of microorganisms. In juveniles, microorganisms were found between densely packed sponge cells. Denaturing gradient gel electrophoresis (DGGE) was performed to compare the bacterial community profiles of adults, larvae, and juvenile sponges. Adults and larvae were highly similar in DGGE band numbers and banding patterns. Larvae released by the same adult individual contained highly similar DGGE banding patterns, whereas larvae released by different adult individuals showed slightly different DGGE banding patterns. Over 200 bands were excised, sequenced, and phylogenetically analyzed. The bacterial diversity of adult I. felix and its larvae was comparably high, while juveniles showed reduced diversity. In total, 13 vertically transmitted sequence clusters, hereafter termed "IF clusters," that contained sequences from both the adult sponge and offspring (larvae and/or juveniles) were found. The IF clusters belonged to at least four different eubacterial phyla and one possibly novel eubacterial lineage. In summary, it could be shown that in I. felix, vertical transmission of microorganisms through the larvae is an important mechanism for the establishment of the sponge-microbe association.


Erythropoietin-- measurement and clinical applications.
Erythropoietin (EPO) is an endogenous hormone produced primarily by the kidney which controls the production of erythrocytes. The main stimulus to production is low tissue oxygen (hypoxia) and EPO triggers the formation of red blood cells by binding to a receptor on erythroid progenitor target cells. Alteration in the EPO regulatory system produces a change in circulating EPO in a variety of disease states, such as renal anaemia and polycythaemia. The availability of recombinant EPO in the 1980s transformed the treatment of anaemia, particularly anaemia of end stage renal disease, and led to the development of more sensitive and specific assays for the measurement of EPO. There are more widespread uses for EPO and preliminary studies indicate that EPO may be useful as a neuroprotective agent by reducing inflammation near the site of injury. The use of EPO to boost endurance in athletes has attracted unwanted publicity, although analytical techniques are now available that can differentiate between endogenous and recombinant EPO. Different types of erythropoietic agents have been developed with a longer plasma half-life and the ability to maintain haemoglobin levels for longer periods and reduce the need for frequent dosing with EPO.