A review of the major threats and challenges to global bat conservation.
Bats are an ecologically and taxonomically diverse group accounting for roughly a fifth of mammalian diversity worldwide. Many of the threats bats face (e.g., habitat loss, bushmeat hunting, and climate change) reflect the conservation challenges of our era. However, compared to other mammals and birds, we know significantly less about the population status of most bat species, which makes prioritizing and planning conservation actions challenging. Over a third of bat species assessed by the International Union for Conservation of Nature (IUCN) are considered threatened or data deficient, and well over half of the species have unknown or decreasing population trends. That equals 988 species, or 80% of bats assessed by IUCN, needing conservation or research attention. Delivering conservation to bat species will require sustained efforts to assess population status and trends and address data deficiencies. Successful bat conservation must integrate research and conservation to identify stressors and their solutions and to test the efficacy of actions to stabilize or increase populations. Global and regional networks that connect researchers, conservation practitioners, and local stakeholders to share knowledge, build capacity, and prioritize and coordinate research and conservation efforts, are vital to ensuring sustainable bat populations worldwide.


Bruton's Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells in Nonobese Diabetic Mice.
Expansion of autoimmune-prone marginal zone (MZ) B cells has been implicated in type 1 diabetes. To test disease contributions of MZ B cells in NOD mice, Notch2 haploinsufficiency (Notch2(+/-)) was introduced but failed to eliminate the MZ, as it does in C57BL/6 mice. Notch2(+/-)/NOD have MZ B cell numbers similar to those of wild-type C57BL/6, yet still develop diabetes. To test whether BCR signaling supports Notch2(+/-)/NOD MZ B cells, Bruton's tyrosine kinase (Btk) deficiency was introduced. Surprisingly, MZ B cells failed to develop in Btk-deficient Notch2(+/-)/NOD mice. Expression of Notch2 and its transcriptional target, Hes5, was increased in NOD MZ B cells compared with C57BL/6 MZ B cells. Btk deficiency reduced Notch2(+/-) signaling exclusively in NOD B cells, suggesting that BCR signaling enhances Notch2 signaling in this autoimmune model. The role of BCR signaling was further investigated using an anti-insulin transgenic (Tg) BCR (125Tg). Anti-insulin B cells in 125Tg/Notch2(+/-)/NOD mice populate an enlarged MZ, suggesting that low-level BCR signaling overcomes reliance on Notch2. Tracking clonotypes of anti-insulin B cells in H chain-only VH125Tg/NOD mice showed that BTK-dependent selection into the MZ depends on strength of antigenic binding, whereas Notch2-mediated selection does not. Importantly, anti-insulin B cell numbers were reduced by Btk deficiency, but not Notch2 haploinsufficiency. These studies show that 1) Notch2 haploinsufficiency limits NOD MZ B cell expansion without preventing type 1 diabetes, 2) BTK supports the Notch2 pathway in NOD MZ B cells, and 3) autoreactive NOD B cell survival relies on BTK more than Notch2, regardless of MZ location, which may have important implications for disease-intervention strategies.


Visceral Leishmaniasis in Benishangul-Gumuz Regional State, Western Ethiopia: Reemerging or Emerging?
Kala-azar is a growing public health problem in Ethiopia. Benishangul-Gumuz regional state was previously not known to be endemic for the disease. In response to a case report from the region, we conducted a rapid assessment survey. A pretested questionnaire was used to capture sociodemographic and clinical histories pertinent to kala-azar. Study participants with complaints of fever and headache for 2 weeks or more were tested for kala-azar and malaria. All participants were screened with the leishmanin skin test and the direct agglutination test for exposure to Leishmania, defined as a positive result with either or both tests. Of 275 participants, 20 were exposed giving an overall leishmaniasis seroprevalence rate of 7.3%. Among the 20 positive individuals, 19 were farmers and nine of them reported no travel history outside their district. It appears that kala-azar is emerging in Dangur and Guba districts of Benishangul-Gumuz regional state, probably in connection with human encroachment into one or several previously out-of-reach zoonotic foci. We recommend integrated epidemiological surveys for confirmation and early containment of disease transmission in the area.


Regional and seasonal variation in airborne grass pollen levels between cities of Australia and New Zealand.
Although grass pollen is widely regarded as the major outdoor aeroallergen source in Australia and New Zealand (NZ), no assemblage of airborne pollen data for the region has been previously compiled. Grass pollen count data collected at 14 urban sites in Australia and NZ over periods ranging from 1 to 17 years were acquired, assembled and compared, revealing considerable spatiotemporal variability. Although direct comparison between these data is problematic due to methodological differences between monitoring sites, the following patterns are apparent. Grass pollen seasons tended to have more than one peak from tropics to latitudes of 37°S and single peaks at sites south of this latitude. A longer grass pollen season was therefore found at sites below 37°S, driven by later seasonal end dates for grass growth and flowering. Daily pollen counts increased with latitude; subtropical regions had seasons of both high intensity and long duration. At higher latitude sites, the single springtime grass pollen peak is potentially due to a cooler growing season and a predominance of pollen from C3 grasses. The multiple peaks at lower latitude sites may be due to a warmer season and the predominance of pollen from C4 grasses. Prevalence and duration of seasonal allergies may reflect the differing pollen seasons across Australia and NZ. It must be emphasized that these findings are tentative due to limitations in the available data, reinforcing the need to implement standardized pollen-monitoring methods across Australasia. Furthermore, spatiotemporal differences in grass pollen counts indicate that local, current, standardized pollen monitoring would assist with the management of pollen allergen exposure for patients at risk of allergic rhinitis and asthma.


The 2008 Declaration of Helsinki - first among equals in research ethics?
The World Medical Association's (WMA) Declaration of Helsinki is one of the most important and influential international research ethics documents. Its most recent 2008 version declares unprecedented universal primacy over all existing national or international ethical, legal, or regulatory requirements. This self-proclaimed status as a set of minimal ethical standards raises important questions about the Declaration's appropriate normative status. The present paper argues that the new claim of ethical primacy is problematic and makes the Declaration unnecessarily vulnerable to criticism. Future revisions of the Declaration should therefore remove this claim and strengthen the document, first, by clarifying its normative status as a set of strong default recommendations, to be followed unless there is compelling ethical reason to do otherwise; and second, by improving the substance of the Declaration through further precision, specification, and argument.


Functional interaction between the coactivator Drosophila CREB-binding protein and ASH1, a member of the trithorax group of chromatin modifiers.
CREB-binding protein (CBP) is a coactivator for multiple transcription factors that transduce a variety of signaling pathways. Current models propose that CBP enhances gene expression by bridging the signal-responsive transcription factors with components of the basal transcriptional machinery and by augmenting the access of transcription factors to DNA through the acetylation of histones. To define the pathways and proteins that require CBP function in a living organism, we have begun a genetic analysis of CBP in flies. We have overproduced Drosophila melanogaster CBP (dCBP) in a variety of cell types and obtained distinct adult phenotypes. We used an uninflated-wing phenotype, caused by the overexpression of dCBP in specific central nervous system cells, to screen for suppressors of dCBP overactivity. Two genes with mutant versions that act as dominant suppressors of the wing phenotype were identified: the PKA-C1/DCO gene, encoding the catalytic subunit of cyclic AMP protein kinase, and ash1, a member of the trithorax group (trxG) of chromatin modifiers. Using immunocolocalization, we showed that the ASH1 protein is specifically expressed in the majority of the dCBP-overexpressing cells, suggesting that these proteins have the potential to interact biochemically. This model was confirmed by the findings that the proteins interact strongly in vitro and colocalize at specific sites on polytene chromosomes. The trxG proteins are thought to maintain gene expression during development by creating domains of open chromatin structure. Our results thus implicate a second class of chromatin-associated proteins in mediating dCBP function and imply that dCBP might be involved in the regulation of higher-order chromatin structure.


Predictors, spatial distribution, and occurrence of woody invasive plants in subtropical urban ecosystems.
We examined the spatial distribution, occurrence, and socioecological predictors of woody invasive plants (WIP) in two subtropical, coastal urban ecosystems: San Juan, Puerto Rico and Miami-Dade, United States. These two cities have similar climates and ecosystems typical of subtropical regions but differ in socioeconomics, topography, and urbanization processes. Using permanent plot data, available forest inventory protocols and statistical analyses of geographic and socioeconomic spatial predictors, we found that landscape level distribution and occurrence of WIPs was not clustered. We also characterized WIP composition and occurrence using logistic models, and found they were strongly related to the proportional area of residential land uses. However, the magnitude and trend of increase depended on median household income and grass cover. In San Juan, WIP occurrence was higher in areas of high residential cover when incomes were low or grass cover was low, whereas the opposite was true in Miami-Dade. Although Miami-Dade had greater invasive shrub cover and numbers of WIP species, San Juan had far greater invasive tree density, basal area and crown cover. This study provides an approach for incorporating field and available census data in geospatial distribution models of WIPs in cities throughout the globe. Findings indicate that identifying spatial predictors of WIPs depends on site-specific factors and the ecological scale of the predictor. Thus, mapping protocols and policies to eradicate urban WIPs should target indicators of a relevant scale specific to the area of interest for their improved and proactive management.


Treg Depletion-enhanced IL-2 Treatment Facilitates Therapy of Established Tumors Using Systemically Delivered Oncolytic Virus.
There are several roadblocks that hinder systemic delivery of oncolytic viruses to the sites of metastatic disease. These include the tumor vasculature, which provides a physical barrier to tumor-specific virus extravasation. Although interleukin-2 (IL-2) has been used in antitumor therapy, it is associated with endothelial cell injury, leading to vascular leak syndrome (VLS). Here, we demonstrate that IL-2-mediated VLS, accentuated by depletion of regulatory T cells (Treg), facilitates localization of intravenously (IV) delivered oncolytic virus into established tumors in immune-competent mice. IL-2, in association with Treg depletion, generates "hyperactivated" natural killer (NK) cells, possessing antitumor activity and secreting factors that facilitate virus spread/replication throughout the tumor by disrupting the tumor architecture. As a result, the combination of Treg depletion/IL-2 and systemic oncolytic virotherapy was found to be significantly more therapeutic against established disease than either treatment alone. These data demonstrate that it is possible to combine biological therapy with oncolytic virotherapy to generate systemic therapy against established tumors.


Oral ondansetron versus domperidone for symptomatic treatment of vomiting during acute gastroenteritis in children: multicentre randomized controlled trial.
Vomiting in children with acute gastroenteritis (AG) is not only a direct cause of fluid loss but it is also a major factor of failure of oral rehydration therapy (ORT). Physicians who provide care to paediatric patients in the emergency department (ED) usually prescribe intravenous fluid therapy (IVT) for mild or moderate dehydration when vomiting is the major symptom. Thus, effective symptomatic treatment of vomiting would lead to an important reduction in the use of IVT and, consequently, of the duration of hospital stay and of frequency of hospital admission. Available evidence on symptomatic treatment of vomiting shows the efficacy of the most recently registered molecule (ondansetron) but a proper evaluation of antiemetics drugs largely used in clinical practice, such as domperidone, is lacking. To compare the efficacy of ondansetron and domperidone for the symptomatic treatment of vomiting in children with AG who have failed ORT. Multicentre, double-blind randomized controlled trial conducted in paediatric EDs. Children aged from 1 to 6 years who vomiting, with a presumptive clinical diagnosis of AG, and without severe dehydration will be included. After the failure of a initial ORS administration in ED, eligible children will be randomized to receive: 1) ondansetron syrup (0,15 mg/Kg of body weight); 2) domperidone syrup (0,5 mg/Kg of body weight); 3) placebo. The main study outcome will be the percentage of patients needing nasogastric or IVT after symptomatic oral treatment failure, defined as vomiting or fluid refusal after a second attempt of ORT. Data relative to study outcomes will be collected at 30 minute intervals for a minimum of 6 hours. A telephone follow up call will be made 48 hours after discharge. A total number of 540 children (i.e. 180 patients in each arm) will be enrolled. The trial results would provide evidence on the efficacy of domperidone, which is largely used in clinical practice despite the lack of proper evaluation and a controversial safety profile, as compared to ondansetron, which is not yet authorized in Italy despite evidence supporting its efficacy in treating vomiting. The trial results would contribute to a reduction in the use of IVT and, consequently, in hospital admissions in children with AG. The design of this RCT, which closely reflect current clinical practice in EDs, will allow immediate transferability of results. ClinicalTrials.gov: NCT01257672.


Reductive metabolism of the important atmospheric gas isoprene by homoacetogens.
Isoprene is the most abundant biogenic volatile organic compound (BVOC) in the Earth's atmosphere and plays important roles in atmospheric chemistry. Despite this, little is known about microbiological processes serving as a terrestrial sink for isoprene. While aerobic isoprene degrading bacteria have been identified, there are no known anaerobic, isoprene-metabolizing organisms. In this study an H2-consuming homoacetogenic enrichment was shown to utilize 1.6 μmoles isoprene h-1 as an electron acceptor in addition to HCO3-. The isoprene-reducing community was dominated by Acetobacterium spp. and isoprene was shown to be stoichiometrically reduced to three methylbutene isomers (2-methyl-1-butene (>97%), 3-methyl-1-butene (≤2%), 2-methyl-2-butene (≤1%). In the presence of isoprene, 40% less acetate was formed suggesting that isoprene reduction is coupled to energy conservation in Acetobacterium spp. This study improves our understanding of linkages and feedbacks between biogeochemistry and terrestrial microbial activity.


ARF-GAP-mediated interaction between the ER-Golgi v-SNAREs and the COPI coat.
In eukaryotic cells, secretion is achieved by vesicular transport. Fusion of such vesicles with the correct target compartment relies on SNARE proteins on both vesicle (v-SNARE) and the target membranes (t-SNARE). At present it is not clear how v-SNAREs are incorporated into transport vesicles. Here, we show that binding of ADP-ribosylation factor (ARF)-GTPase-activating protein (GAP) to ER-Golgi v-SNAREs is an essential step for recruitment of Arf1p and coatomer, proteins that together form the COPI coat. ARF-GAP acts catalytically to recruit COPI components. Inclusion of v-SNAREs into COPI vesicles could be mediated by direct interaction with the coat. The mechanisms by which v-SNAREs interact with COPI and COPII coat proteins seem to be different and may play a key role in determining specificity in vesicle budding.


Spectrum of disease in the male breast.
The purpose of this article is to review the anatomy of the male breast and to describe the imaging findings of a variety of diseases that affect the male breast to better understand and recognize the imaging findings and underlying pathophysiology of diseases and conditions affecting this emerging subset of patients. Understanding the anatomy of the male breast is central to developing a differential diagnosis and delivering optimal care in male patients presenting with breast complaints. Diseases in the male breast can affect the skin and subcutaneous tissues, stroma and glandular elements, and neurovascular and lymphatic structures. Although the most commonly encountered disease entity is gynecomastia, men can develop many other benign and neoplastic diseases, including primary breast cancer. By incorporating clinical presentation with imaging findings on mammography and ultrasound, the breast imager can more effectively establish the correct diagnosis in males.


Access to oral health care - an Australian perspective.
The objectives of this paper are to give a brief description of the Australian context for its dental care services and to discuss some of the nationally recognized issues in access to dental care with special reference to the situation in the most populous state, New South Wales. Australia is the size of continental USA but with only around 21 million people, 85% of whom reside within 50 km of the coastline. Thus, access to health care has a strong urban-rural dimension. The universal healthcare coverage excludes dental care, 80-90% of which is delivered through traditional fee-for-service private dental care. A public dental care system exists with varying eligibility criteria from state to state, mostly directed at children, low-income individuals, pensioners, and defined disadvantaged groups. Thus, access to dental care also has a strong socioeconomic dimension with disadvantaged people having serious access problems and extensive waiting times. Government and other reports have documented considerable polarization issues both in oral health and in access to dental care. Suggested change strategies have ranged from broad political changes in the dental care system to local oral health promotion initiatives, but overall, dental care remains a pawn in state-commonwealth political squabbles. In response to strong public reactions documented shortcomings of the public dental care system the government of New South Wales has recently initiated a political inquiry into dental care. Unless new resources are injected and policy adjustments made, serious changes are unlikely.


Prevalence of mental retardation and developmental disabilities: estimates from the 1994/1995 national health interview survey disability supplements.
In 1994 and 1995, the National Health Interview Survey included a Disability Supplement (NHIS-D) to collect extensive information about disabilities among individuals sampled as part of annual census-based household interview surveys. Here we describe the development and application of operational definitions of mental retardation and developmental disabilities to items in the NHIS-D to estimate prevalence. In our analyses, we estimate the prevalence of mental retardation in the noninstitutionalized population of the United States to be 7.8 people per thousand (.78%); of developmental disabilities, 11.3 people per thousand (1.13%); and the combined prevalence of mental retardation and/or developmental disabilities to be 14.9 per thousand (1.49%). Differences in prevalence estimates for mental retardation and developmental disabilities and among people of various ages are explored.


Control of cross-presentation during dendritic cell maturation.
The initiation of most cytotoxic immune responses requires MHC class I-restricted presentation of internalized antigens to CD8(+) T lymphocytes, a process called cross-presentation. In dendritic cells (DC), the only antigen-presenting cells that activate naive T cells, cross-presentation is particularly efficient after internalization of opsonized antigens or immune complexes, which are cross-presented through a proteasome- and transporter associated with antigen processing (TAP)-dependent MHC class I antigen presentation pathway. We now show that FcgammaR-mediated cross-presentation is tightly regulated during DC maturation. Cross-presentation increases soon after activation by lipopolysaccharides, and it is then inhibited in fully mature cells. The initial induction of cross-presentation results from an increase of both antigen internalization and delivery to the cytosol, and from a slight rise in the activity of the proteasome and TAP. The subsequent block of cross-presentation in mature DC is a consequence of the selective down-modulation of antigen internalization and cytosolic delivery, while proteasome and TAP activities continue to rise. Therefore, FcgammaR-mediated cross-presentation is regulated during DC maturation by the selective control of antigen internalization and transport to the cytosol.


Export-deficient monoubiquitinated PEX5 triggers peroxisome removal in SV40 large T antigen-transformed mouse embryonic fibroblasts.
Peroxisomes are ubiquitous cell organelles essential for human health. To maintain a healthy cellular environment, dysfunctional and superfluous peroxisomes need to be selectively removed. Although emerging evidence suggests that peroxisomes are mainly degraded by pexophagy, little is known about the triggers and molecular mechanisms underlying this process in mammalian cells. In this study, we show that PEX5 proteins fused to a bulky C-terminal tag trigger peroxisome degradation in SV40 large T antigen-transformed mouse embryonic fibroblasts. In addition, we provide evidence that this process is autophagy-dependent and requires monoubiquitination of the N-terminal cysteine residue that marks PEX5 for recycling. As our findings also demonstrate that the addition of a bulky tag to the C terminus of PEX5 does not interfere with PEX5 monoubiquitination but strongly inhibits its export from the peroxisomal membrane, we hypothesize that such a tag mimics a cargo protein that cannot be released from PEX5, thus keeping monoubiquitinated PEX5 at the membrane for a sufficiently long time to be recognized by the autophagic machinery. This in turn suggests that monoubiquitination of the N-terminal cysteine of peroxisome-associated PEX5 not only functions to recycle the peroxin back to the cytosol, but also serves as a quality control mechanism to eliminate peroxisomes with a defective protein import machinery.


MultiNotch MS3 enables accurate, sensitive, and multiplexed detection of differential expression across cancer cell line proteomes.
Multiplexed quantitation via isobaric chemical tags (e.g., tandem mass tags (TMT) and isobaric tags for relative and absolute quantitation (iTRAQ)) has the potential to revolutionize quantitative proteomics. However, until recently the utility of these tags was questionable due to reporter ion ratio distortion resulting from fragmentation of coisolated interfering species. These interfering signals can be negated through additional gas-phase manipulations (e.g., MS/MS/MS (MS3) and proton-transfer reactions (PTR)). These methods, however, have a significant sensitivity penalty. Using isolation waveforms with multiple frequency notches (i.e., synchronous precursor selection, SPS), we coisolated and cofragmented multiple MS2 fragment ions, thereby increasing the number of reporter ions in the MS3 spectrum 10-fold over the standard MS3 method (i.e., MultiNotch MS3). By increasing the reporter ion signals, this method improves the dynamic range of reporter ion quantitation, reduces reporter ion signal variance, and ultimately produces more high-quality quantitative measurements. To demonstrate utility, we analyzed biological triplicates of eight colon cancer cell lines using the MultiNotch MS3 method. Across all the replicates we quantified 8,378 proteins in union and 6,168 proteins in common. Taking into account that each of these quantified proteins contains eight distinct cell-line measurements, this data set encompasses 174,704 quantitative ratios each measured in triplicate across the biological replicates. Herein, we demonstrate that the MultiNotch MS3 method uniquely combines multiplexing capacity with quantitative sensitivity and accuracy, drastically increasing the informational value obtainable from proteomic experiments.


[Definition of priority medicines for monitoring laboratory quality in Brazil: the interface between health surveillance and the National Drug Policy].
A key objective of the Brazilian National Drug Policy is the quality of medicines supplied to the population. This study aimed to set priorities for the analysis of the National Program for Quality Control of Medicines. The main criterion was the drug's presence in at least three Pharmaceutical Care Programs under the Ministry of Health. Additional criteria were presence on the National List of Essential Drugs (RENAME) in 2002 and its indication for the 20 main causes of disability-adjusted life years (DALY). The sources were data from the Ministry of Health and related legislation. The drugs were classified according to the Anatomical Therapeutic Chemical Classification System (ATC) of the WHO. The 13 pharmaceutical care programs included 893 products classified in 449 different ATC codes. Twenty-eight drugs were considered priorities, 26 of which were listed on the RENAME and 12 indicated as causes of DALY. It is recommended that the National Health Surveillance Agency and Secretariat of Science, Technology, and Strategic Inputs establish an integrated strategy to guarantee comprehensive quality of these drugs, including laboratory quality, registration, good manufacturing practices, and information for health professionals and the general population.


Hyperpolarized 13C NMR studies of glucose metabolism in living breast cancer cell cultures.
The recent development of dissolution dynamic nuclear polarization (DNP) gives NMR the sensitivity to follow metabolic processes in living systems with high temporal resolution. In this article, we apply dissolution DNP to study the metabolism of hyperpolarized U-(13)C,(2)H7-glucose in living, perfused human breast cancer cells. Spectrally selective pulses were used to maximize the signal of the main product, lactate, whilst preserving the glucose polarization; in this way, both C1-lactate and C3-lactate could be observed with high temporal resolution. The production of lactate by T47D breast cancer cells can be characterized by Michaelis-Menten-like kinetics, with K(m) = 3.5 ± 1.5 mM and V(max) = 34 ± 4 fmol/cell/min. The high sensitivity of this method also allowed us to observe and quantify the glycolytic intermediates dihydroxyacetone phosphate and 3-phosphoglycerate. Even with the enhanced DNP signal, many other glycolytic intermediates could not be detected directly. Nevertheless, by applying saturation transfer methods, the glycolytic intermediates glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate, glyceraldehyde-3-phosphate, phosphoenolpyruvate and pyruvate could be observed indirectly. This method shows great promise for the elucidation of the distinctive metabolism and metabolic control of cancer cells, suggesting multiple ways whereby hyperpolarized U-(13)C,(2)H7-glucose NMR could aid in the diagnosis and characterization of cancer in vivo.


Mortality in people diagnosed with type 2 diabetes at an older age: a systematic review.
To review all published observational studies reporting on all-cause mortality in patients with type 2 diabetes to determine the degree of increased mortality when diagnosed at an older age. Systematic literature search. The review included studies carried out in populations from Germany, United Kingdom, United States, Japan, Italy, Western Australia, Netherlands and Sweden. Medline, CINAHL, EMBASE, National Research Register and Cochrane Reviews were systematically searched from 1975 to 2004. We identified observational studies that reported overall mortality for people diagnosed with type 2 diabetes when they were over the age of 60, compared with a non-diabetic population. Outcome measures were expressed as risk ratios or relative risks. Among 14 eligible studies, one study reported reduced mortality for patients diagnosed with type 2 diabetes over the age of 60, whereas another found virtually no increased risk of mortality. However, 7 of the 14 studies reported increased mortality in all patients diagnosed when older, and 5 studies for certain subgroups only. A meta-analysis showed the combined relative risks (with 95% CI) of increased mortality for men diagnosed between the ages of 60 and 70 to be 1.38 (1.08-1.76) and 1.13 (0.88-1.45) for men diagnosed aged 70 years or older. A similar pattern was found for the same age groups for women, with combined relative risks of 1.40 (1.10-1.79) and 1.19 (0.93-1.52) respectively. Increased mortality associated with a diagnosis of type 2 diabetes at an older age is lower than that reported for the general older diabetic population.


Effects of lithium carbonate administration to healthy cats.
Lithium carbonate administration to healthy cats was evaluated in 2 controlled studies (a dose-response study and a bone marrow evaluation study) to determine the effectiveness of lithium as a bone marrow stimulant. Lithium carbonate was administrated at dosage ranging from 300 to 1,050 mg/m2 of body surface/d. Complete blood count, serum lithium concentration determination, serum biochemical analysis, urinalysis, and bone marrow aspiration and biopsy were periodically performed. Serum lithium concentration greater than 2 mEq/L was associated with significant decrease in numbers of circulating segmented neutrophils (less than 1,200 cells/microliter; P less than 0.01) and lymphocytes (less than 1,300 cells/microliter; P less than 0.0001), as well as significant (P less than 0.05) decrease in urine specific gravity. Bone marrow evaluation revealed apparent maturation arrest of the neutrophil cell line. Coincident with the changes in laboratory values, the lithium-treated cats became ill. Changes in behavior and vocalization were seen, followed by anorexia, vomiting, and diarrhea. In later stages of intoxication, cats became hyperexcitable and manifested coarse muscular tremors. It was concluded that lithium carbonate does not have potential value as a bone marrow stimulant and is toxic to cats at serum concentration greater than 2 mEq/L.


Interaction of 2'-deoxyguanosine triphosphate analogue inhibitors of HIV reverse transcriptase with human mitochondrial DNA polymerase gamma.
Mitochondrial toxicity is a limiting factor in the use of some nucleoside reverse transcriptase inhibitors of HIV. To further understand the impact of structural features on the incorporation and exonuclease removal of nucleoside monophosphate (MP) analogues by human mitochondrial DNA polymerase (pol gamma), transient kinetic studies were done with analogues of 2'-deoxyguanosine triphosphate. The kinetic parameters for the incorporation and removal of carbovir (CBV)-MP, dioxolane guanosine (DXG)-MP and 2',3'-dideoxy-2',3'-didehydroguanosine (d4G)-MP were studied with pol gamma holoenzyme. The importance of the ribose oxygen in incorporation by pol gamma was illustrated by an approximate 3,000-fold decrease in the incorporation efficiency of an analogue lacking the ribose oxygen (CBV-TP) relative to those containing a ribose oxygen (DXG-TP and d4G-TP). As a result, a comparison with previous data for the incorporation by HIV reverse transcriptase showed CBV-TP to be approximately 800-8,000-fold more selective for its antiviral target over pol gamma relative to the other guanosine analogues. However, DXG-TP and d4G-TP were found to be much more selective than previously reported values for mitochondrial toxic nucleoside analogues. Structural modelling based on sequence homology with other polymerase A family members suggests that an interaction between the ribose oxygen and arginine 853 in pol gamma may play a critical role in causing this differential incorporation. Exonuclease removal of a chain-terminating CBV-MP was also found to be more efficient by pol gamma. These results help to further elucidate the structure activity relationships for pol gamma and should aid in the design of more selective antiviral agents.


A Comparison between Indoor and Outdoor Rape Suspects in Sweden.
As the number of rapes is increasing in Sweden, and the number of individuals convicted of these crimes is decreasing, it is of importance to study offender characteristics of those committing these crimes and the circumstances in which these crimes are conducted, such as indoors or outdoors. Data from Swedish population-based registers were used to identify individuals suspected of rape, aggravated rape, attempted rape or attempted aggravated rape (in short: rape+) against females ≥18 years old between 2007-2017. Latent Class Analysis was then used to identify classes of rape+ suspects with respect to the location of the rape+ and then compare the two groups. A total of 19,723 individuals were included of which the majority (n = 17,520; 88.8%) were suspected of indoor rape+. In both groups, we identified a low offenders' class and a high offenders' class. In addition, first-generation immigrants had a higher odds of being suspected of outdoor rape+ than Swedish-born suspects, and a previous conviction of violent crime was a risk factor for committing outdoor rape+.


Efficacy and Safety of Levosulpiride Versus Haloperidol Injection in Patients With Acute Psychosis: A Randomized Double-Blind Study.
Injectable antipsychotics are frequently required for controlling agitation and aggression in acute psychosis. No study has examined the use of injectable levosulpiride for this indication. To compare the efficacy and safety of injectable levosulpiride and haloperidol in patients with acute psychosis. This was a randomized, double-blind, parallel-group study in which 60 drug-naive patients having acute psychosis were randomly assigned to receive either intramuscular haloperidol (10-20 mg/d) or levosulpiride (25-50 mg/d) for 5 days. All patients were rated on Brief Psychiatric Rating Scale (BPRS), Overt Agitation Severity Scale (OASS), Overt Aggression Scale-Modified (OAS-M) scores, Simpson Angus Scale (SAS), and Barnes Akathisia Rating Scale (BARS). Repeated-measures ANOVA for BPRS scores showed significant effect of time (P < 0.001) and a trend toward greater reduction in scores in haloperidol group as shown by group × time interaction (P = 0.076). Repeated-measures ANOVA for OASS showed significant effect of time (P < 0.001) but no group × time interaction. Repeated-measures ANOVA for OAS-M scores showed significant effect of time (P < 0.001) and greater reduction in scores in haloperidol group as shown by group × time interaction (P = 0.032). Lorazepam requirement was much lower in haloperidol group as compared with those receiving levosulpiride (P = 0.022). Higher rates of akathisia and extrapyramidal symptoms were noted in the haloperidol group. Haloperidol was more effective than levosulpiride injection for psychotic symptoms, aggression, and severity of agitation in acute psychosis, but extrapyramidal adverse effects were less frequent with levosulpiride as compared with those receiving haloperidol.


Exercise recommendations for individuals with spinal cord injury.
Persons with spinal cord injury (SCI) exhibit deficits in volitional motor control and sensation that limit not only the performance of daily tasks but also the overall activity level of these persons. This population has been characterised as extremely sedentary with an increased incidence of secondary complications including diabetes mellitus, hypertension and atherogenic lipid profiles. As the daily lifestyle of the average person with SCI is without adequate stress for conditioning purposes, structured exercise activities must be added to the regular schedule if the individual is to reduce the likelihood of secondary complications and/or to enhance their physical capacity. The acute exercise responses and the capacity for exercise conditioning are directly related to the level and completeness of the spinal lesion. Appropriate exercise testing and training of persons with SCI should be based on the individual's exercise capacity as determined by accurate assessment of the spinal lesion. The standard means of classification of SCI is by application of the International Standards for Classification of Spinal Cord Injury, written by the Neurological Standards Committee of the American Spinal Injury Association. Individuals with complete spinal injuries at or above the fourth thoracic level generally exhibit dramatically diminished cardiac acceleration with maximal heart rates less than 130 beats/min. The work capacity of these persons will be limited by reductions in cardiac output and circulation to the exercising musculature. Persons with complete spinal lesions below the T(10) level will generally display injuries to the lower motor neurons within the lower extremities and, therefore, will not retain the capacity for neuromuscular activation by means of electrical stimulation. Persons with paraplegia also exhibit reduced exercise capacity and increased heart rate responses (compared with the non-disabled), which have been associated with circulatory limitations within the paralysed tissues. The recommendations for endurance and strength training in persons with SCI do not vary dramatically from the advice offered to the general population. Systems of functional electrical stimulation activate muscular contractions within the paralysed muscles of some persons with SCI. Coordinated patterns of stimulation allows purposeful exercise movements including recumbent cycling, rowing and upright ambulation. Exercise activity in persons with SCI is not without risks, with increased risks related to systemic dysfunction following the spinal injury. These individuals may exhibit an autonomic dysreflexia, significantly reduced bone density below the spinal lesion, joint contractures and/or thermal dysregulation. Persons with SCI can benefit greatly by participation in exercise activities, but those benefits can be enhanced and the relative risks may be reduced with accurate classification of the spinal injury.


Defensive production of quinoline by a phasmid insect (Oreophoetes peruana).
Adults and nymphs of the Peruvian stick insect Oreophoetes peruana (order Phasmatodea) have a pair of thoracic glands from which they discharge a malodorous fluid when disturbed. The secretion contains a single volatile component, quinoline. Quinoline has not been reported previously from an animal source. The compound proved repellent or topically irritant in assays with ants, spiders, cockroaches and frogs. O. peruana nymphs, at molting, do not extricate the shed cuticular lining of the glands, thereby managing not to lose their secretory supply when they cast their skin. They are able, as a consequence, to discharge secretion even while still teneral after molting.


Chapter 4. Susceptibility of sharks, rays and chimaeras to global extinction.
Marine biodiversity worldwide is under increasing threat, primarily as a result of over-harvesting, pollution and climate change. Chondrichthyan fishes (sharks, rays and chimaeras) have a perceived higher intrinsic risk of extinction compared to other fish. Direct fishing mortality has driven many declines, even though some smaller fisheries persist without associated declines. Mixed-species fisheries are of particular concern, as is illegal, unreported and unregulated (IUU) fishing. The lack of specific management and reporting mechanisms for the latter means that many chondrichthyans might already be susceptible to extinction from stochastic processes entirely unrelated to fishing pressure itself. Chondrichthyans might also suffer relatively more than other marine taxa from the effects of fishing and habitat loss and degradation given coastal habitat use for specific life stages. The effects of invasive species and pollution are as yet too poorly understood to predict their long-term role in affecting chondrichthyan population sizes. The spatial distribution of threatened chondrichthyan species under World Conservation Union (IUCN) Red List criteria are clustered mainly in (1) south-eastern South America; (2) western Europe and the Mediterranean; (3) western Africa; (4) South China Sea and Southeast Asia and (5) south-eastern Australia. To determine which ecological and life history traits predispose chondrichthyans to being IUCN Red-Listed, and to examine the role of particular human activities in exacerbating threat risk, we correlated extant marine species' Red List categorisation with available ecological (habitat type, temperature preference), life history (body length, range size) and human-relationship (whether commercially or game-fished, considered dangerous to humans) variables. Threat risk correlations were constructed using generalised linear mixed-effect models to account for phylogenetic relatedness. We also contrasted results for chondrichthyans to marine teleosts to test explicitly whether the former group is intrinsically more susceptible to extinction than fishes in general. Around 52% of chondrichthyans have been Red-Listed compared to only 8% of all marine teleosts; however, listed teleosts were in general placed more frequently into the higher-risk categories relative to chondrichthyans. IUCN threat risk in both taxa was positively correlated with body size and negatively correlated albeit weakly, with geographic range size. Even after accounting for the positive influence of size, Red-Listed teleosts were still more likely than chondrichthyans to be classified as threatened. We suggest that while sharks might not have necessarily experienced the same magnitude of deterministic decline as Red-Listed teleosts, their larger size and lower fecundity (not included in the analysis) predispose chondrichthyans to a higher risk of extinction overall. Removal of these large predators can elicit trophic cascades and destabilise the relative abundance of smaller species. Predator depletions can lead to permanent shifts in marine communities and alternate equilibrium states. Climate change might influence the phenology and physiology of some species, with the most probable response being changes in the timing of migrations and shifts in distribution. The synergistic effects among harvesting, habitat changes and climate-induced forcings are greatest for coastal chondrichthyans with specific habitat requirements and these are currently the most likely candidates for extinction. Management of shark populations must take into account the rate at which drivers of decline affect specific species. Only through the detailed collection of data describing demographic rates, habitat affinities, trophic linkages and geographic ranges, and how environmental stressors modify these, can extinction risk be more precisely estimated and reduced. The estimation of minimum viable population sizes, below which rapid extinction is more likely due to stochastic processes, is an important component of this endeavour and should accompany many of the current approaches used in shark management worldwide.


A randomized controlled trial of intensive sleep retraining (ISR): a brief conditioning treatment for chronic insomnia.
To investigate the effectiveness of intensive sleep retraining in comparison and combination with traditional behavioral intervention for chronic primary insomnia. Seventy-nine volunteers with chronic sleep-onset insomnia (with or without sleep maintenance difficulties) were randomly assigned either to intensive sleep retraining (ISR), stimulus control therapy (SCT), ISR plus SCT, or the control (sleep hygiene) treatment condition. ISR treatment consisted of 50 sleep onset trials over a 25-h sleep deprivation period. Treatment response was assessed with sleep diary, activity monitoring, and questionnaire measures. The active treatment groups (ISR, SCT, ISR+SCT) all resulted in significant improvements in sleep onset latency and sleep efficiency, with moderate to large effect sizes from pre- to post-treatment. Wake time after sleep onset decreased significantly in the SCT and ISR+SCT groups. Total sleep time increased significantly in the ISR and ISR+SCT treatment groups. Participants receiving ISR (ISR, ISR+SCT) experienced rapidly improved SOL and TST during treatment, suggesting an advantage of rapid improvements in sleep in response to ISR. Although there were few statistically significant differences between groups on individual variables, ISR+SCT resulted in consistently larger effect sizes of change than other treatments, including questionnaire measures of sleep quality, sleep self-efficacy, and daytime functioning. The combination treatment group (ISR+SCT) showed trends to outperform other active treatment groups with fewer treatment dropouts, and a greater proportion of treatment responders with 61% reaching "good sleeper" status. Treatment gains achieved at post-treatment in the active treatment groups were largely maintained throughout follow-up periods to 6 months. This 25-hour intensive conditioning treatment for chronic insomnia can produce rapid improvements in sleep, daytime functioning, and psychological variables. Adding ISR to traditional interventions seems to result in a superior treatment response.


Controlled trial of nebulized albuterol in children younger than 2 years of age with acute asthma.
To determine the response to nebulized beta 2 agonist, 28 children younger than 2 years of age who visited the emergency department during an episode of acute asthma were studied. Each subject had a previous history of recurrent wheezing episodes. They were randomly assigned to receive two administrations of either nebulized albuterol (0.15 mg/kg per dose) or placebo (normal saline) with oxygen, 1 hour apart. After two nebulizations, the albuterol-treated patients had a greater improvement in clinical status (respiratory rate, degree of wheezing and accessory muscle use, total clinical score, and arterial oxygen saturation) than the placebo group. None of the patients in the albuterol group experienced a decrease of arterial oxygen saturation of greater than or equal to 2%. It is concluded that a trial of nebulized beta 2 agonists is warranted in the treatment of acute asthma in infants and young children.


What do self-efficacy items measure? Examining the discriminant content validity of self-efficacy items.
Self-efficacy - an individual's judgement of their ability to successfully perform a behaviour - is commonly used to explain and predict behaviour. It is measured through self-report questionnaires. These scales require good content validity, that is must measure the full scope and content of the construct without contamination from similar constructs. This study uses a systematic, transparent quantitative method (discriminant content validation, DCV) to assess the content validity of a variety of self-efficacy items and qualitatively explores participant interpretations of these items. A quantitative DCV and qualitative think-aloud study of self-efficacy item interpretation. Participants (n = 21) were presented with items designed to measure self-efficacy and related constructs following standard DCV methodology. Items were rated against construct definitions to determine whether they measured a particular construct (yes/no). Judges' confidence in each assessment was also assessed (%) and used to establish quantitative estimates of content validity for each item. A qualitative think-aloud study explored the judgements made in a subset of participants. 8/8 self-efficacy items were found to measure self-efficacy; however, 2/8 of these also measured motivation. 6/8 items displayed discriminant content validity and thus can be considered 'pure' measures of self-efficacy. The think-aloud study indicated that item wording is a likely cause of item misinterpretation. Self-efficacy items vary in terms of their content validity with only some of the items assessed providing 'pure' measures of the self-efficacy construct. Item wording should be considered during study design to avoid misinterpretation. Statement of contribution What is already known on this subject? For decades, questions have been raised relating to the content validity of self-efficacy scales, with suggestions of possible construct contamination. Previous studies have shown that manipulation of the wording of self-efficacy scale items results in varied participant interpretations. While self-efficacy items have been found to be distinguishable from other similar constructs, it is equally important to ensure that they are uncontaminated by different constructs within the same theory. Otherwise, when the theory is used to investigate behaviour, variance attributable to self-efficacy may be attributed to a different construct or vice versa. The present study uses discriminant content validation to test this and a think-aloud study to explore participants' interpretation of classic self-efficacy items. What does this study add? The study uses discriminant content validity methodology to assess the content validity of self-efficacy scales. Self-efficacy items which are contaminated with content from other constructs are identified. Information is presented on 'pure' self-efficacy items which can be used to guide item selection in future studies.


Separate valuation subsystems for delay and effort decision costs.
Decision making consists of choosing among available options on the basis of a valuation of their potential costs and benefits. Most theoretical models of decision making in behavioral economics, psychology, and computer science propose that the desirability of outcomes expected from alternative options can be quantified by utility functions. These utility functions allow a decision maker to assign subjective values to each option under consideration by weighting the likely benefits and costs resulting from an action and to select the one with the highest subjective value. Here, we used model-based neuroimaging to test whether the human brain uses separate valuation systems for rewards (erotic stimuli) associated with different types of costs, namely, delay and effort. We show that humans devalue rewards associated with physical effort in a strikingly similar fashion to those they devalue that are associated with delays, and that a single computational model derived from economics theory can account for the behavior observed in both delay discounting and effort discounting. However, our neuroimaging data reveal that the human brain uses distinct valuation subsystems for different types of costs, reflecting in opposite fashion delayed reward and future energetic expenses. The ventral striatum and the ventromedial prefrontal cortex represent the increasing subjective value of delayed rewards, whereas a distinct network, composed of the anterior cingulate cortex and the anterior insula, represent the decreasing value of the effortful option, coding the expected expense of energy. Together, these data demonstrate that the valuation processes underlying different types of costs can be fractionated at the cerebral level.


Structural and chemical analysis of gadolinium halides encapsulated within WS2 nanotubes.
The hollow cavities of nanotubes serve as templates for the growth of size- and shape-confined functional nanostructures, giving rise to novel materials and properties. In this work, considering their potential application as MRI contrast agents, gadolinium halides are encapsulated within the hollow cavities of WS2 nanotubes by capillary filling to obtain GdX3@WS2 nanotubes (where X = Cl, Br or I and @ means encapsulated in). Aberration corrected scanning/transmission electron microscopy (S/TEM) and spectroscopy is employed to understand the morphology and composition of the GdI3@WS2 nanotubes. The three dimensional morphology is studied with STEM tomography but understanding the compositional information is non-trivial due to the presence of multiple high atomic number elements. Therefore, energy dispersive X-ray spectroscopy (EDS) tomography was employed revealing the three dimensional chemical composition. Molecular dynamics simulations of the filling procedure shed light into the mechanics behind the formation of the confined gadolinium halide crystals. The quasi-1D system employed here serves as an example of a TEM-based chemical nanotomography method that could be extended to other materials, including beam-sensitive soft materials.


European Psychiatric Association Guidance on psychotherapy in chronic depression across Europe.
Patients with chronic depression (CD) by definition respond less well to standard forms of psychotherapy and are more likely to be high utilizers of psychiatric resources. Therefore, the aim of this guidance paper is to provide a comprehensive overview of current psychotherapy for CD. The evidence of efficacy is critically reviewed and recommendations for clinical applications and research are given. We performed a systematic literature search to identify studies on psychotherapy in CD, evaluated the retrieved documents and developed evidence tables and recommendations through a consensus process among experts and stakeholders. We developed 5 recommendations which may help providers to select psychotherapeutic treatment options for this patient group. The EPA considers both psychotherapy and pharmacotherapy to be effective in CD and recommends both approaches. The best effect is achieved by combined treatment with psychotherapy and pharmacotherapy, which should therefore be the treatment of choice. The EPA recommends psychotherapy with an interpersonal focus (e.g. the Cognitive Behavioural Analysis System of Psychotherapy [CBASP]) for the treatment of CD and a personalized approach based on the patient's preferences. The DSM-5 nomenclature of persistent depressive disorder (PDD), which includes CD subtypes, has been an important step towards a more differentiated treatment and understanding of these complex affective disorders. Apart from dysthymia, ICD-10 still does not provide a separate entity for a chronic course of depression. The differences between patients with acute episodic depression and those with CD need to be considered in the planning of treatment. Specific psychotherapeutic treatment options are recommended for patients with CD. Patients with chronic forms of depression should be offered tailored psychotherapeutic treatments that address their specific needs and deficits. Combination treatment with psychotherapy and pharmacotherapy is the first-line treatment recommended for CD. More research is needed to develop more effective treatments for CD, especially in the longer term, and to identify which patients benefit from which treatment algorithm.


Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro.
Prolyl hydroxylation of hypoxible-inducible factor alpha (HIF-alpha) proteins is essential for their recognition by pVHL containing ubiquitin ligase complexes and subsequent degradation in oxygen (O(2))-replete cells. Therefore, HIF prolyl hydroxylase (PHD) enzymatic activity is critical for the regulation of cellular responses to O(2) deprivation (hypoxia). Using a fusion protein containing the human HIF-1alpha O(2)-dependent degradation domain (ODD), we monitored PHD activity both in vivo and in cell-free systems. This novel assay allows the simultaneous detection of both hydroxylated and nonhydroxylated PHD substrates in cells and during in vitro reactions. Importantly, the ODD fusion protein is regulated with kinetics identical to endogenous HIF-1alpha during cellular hypoxia and reoxygenation. Using in vitro assays, we demonstrated that the levels of iron (Fe), ascorbate, and various tricarboxylic acid (TCA) cycle intermediates affect PHD activity. The intracellular levels of these factors also modulate PHD function and HIF-1alpha accumulation in vivo. Furthermore, cells treated with mitochondrial inhibitors, such as rotenone and myxothiazol, provided direct evidence that PHDs remain active in hypoxic cells lacking functional mitochondria. Our results suggest that multiple mitochondrial products, including TCA cycle intermediates and reactive oxygen species, can coordinate PHD activity, HIF stabilization, and cellular responses to O(2) depletion.


Drivers of High-cost Medical Complexity in a Medicaid Population.
Efforts to improve outcomes for the 10% of patients using two thirds of health care expenditures increasingly include addressing social determinants. Empiric evidence is needed to identify the highest impact nonmedical drivers of medical complexity and cost. This study examines whether complex, highest cost patients have different patterns of critical life adversity than those with better health and lower utilization. Using a validated algorithm we constructed a complexity/cost risk patient profile. We developed and fielded a life experience survey (Supplemental Digital Content 1, http://links.lww.com/MLR/B920) to a representative sample, then examined how the prevalence of specific adversities varied between complex, high-cost individuals, and others. Surveys were sent to 9176 adult Medicaid members in Portland, Oregon. Our primary variable was high medical complexity health cost risk; an alternative specification combined health cost risk and actual utilization/cost. Our survey instrument measured exposure to early and later-life adversities. Compared with healthy individuals in our population, medically complex individuals had significantly higher rates of adversity. The greatest risk of medical complexity and cost was associated with substance use [odds ratio (OR), 4.1], homelessness (OR, 3.0), childhood maltreatment (OR, 2.8), and incarceration (OR 2.4). Those with the highest prior year acute care utilization and cost had the highest rates of these same factors: substance use (62.5%), homelessness (61.7%), childhood maltreatment (55.5%), and incarceration (52.1%). Clinical and policy strategies that mitigate high-impact social drivers of poor outcomes are likely critical for improving both health and costs for complex, high-needs patients.


Internal dose escalation associated with increased local control for melanoma brain metastases treated with stereotactic radiosurgery.
The internal high-dose volume varies widely for a given prescribed dose during stereotactic radiosurgery (SRS) to treat brain metastases (BMs). This may be altered during treatment planning, and the authors have previously shown that this improves local control (LC) for non-small cell lung cancer BMs without increasing toxicity. Here, they seek to identify potentially actionable dosimetric predictors of LC after SRS for melanoma BM. The records of patients with unresected melanoma BM treated with single-fraction Gamma Knife RS between 2006 and 2017 were reviewed. LC was assessed on a per-lesion basis, defined as stability or a decrease in lesion size. Outcome-oriented approaches were utilized to determine optimal dichotomization for dosimetric variables relative to LC. Univariable and multivariable Cox regression analysis was implemented to evaluate the impact of collected parameters on LC. Two hundred eighty-seven melanoma BMs in 79 patients were identified. The median age was 56 years (range 31-86 years). The median follow-up was 7.6 months (range 0.5-81.6 months), and the median survival was 9.3 months (range 1.3-81.6 months). Lesions were optimally stratified by volume receiving at least 30 Gy (V30) greater than or equal to versus less than 25%. V30 was ≥ and < 25% in 147 and 140 lesions, respectively. For all patients, 1-year LC was 83% versus 66% for V30 ≥ and < 25%, respectively (p = 0.001). Stratifying by volume, lesions 2 cm or less (n = 215) had 1-year LC of 82% versus 70% (p = 0.013) for V30 ≥ and < 25%, respectively. Lesions > 2 to 3 cm (n = 32) had 1-year LC of 100% versus 43% (p = 0.214) for V30 ≥ and < 25%, respectively. V30 was still predictive of LC even after controlling for the use of immunotherapy and targeted therapy. Radionecrosis occurred in 2.8% of lesions and was not significantly associated with V30. For a given prescription dose, an increased internal high-dose volume, as indicated by measures such as V30 ≥ 25%, is associated with improved LC but not increased toxicity in single-fraction SRS for melanoma BM. Internal dose escalation is an independent predictor of improved LC even in patients receiving immunotherapy and/or targeted therapy. This represents a dosimetric parameter that is actionable at the time of treatment planning and warrants further evaluation.


Assembly of the draft genome of buckwheat and its applications in identifying agronomically useful genes.
Buckwheat (Fagopyrum esculentum Moench; 2n = 2x = 16) is a nutritionally dense annual crop widely grown in temperate zones. To accelerate molecular breeding programmes of this important crop, we generated a draft assembly of the buckwheat genome using short reads obtained by next-generation sequencing (NGS), and constructed the Buckwheat Genome DataBase. After assembling short reads, we determined 387,594 scaffolds as the draft genome sequence (FES_r1.0). The total length of FES_r1.0 was 1,177,687,305 bp, and the N50 of the scaffolds was 25,109 bp. Gene prediction analysis revealed 286,768 coding sequences (CDSs; FES_r1.0_cds) including those related to transposable elements. The total length of FES_r1.0_cds was 212,917,911 bp, and the N50 was 1,101 bp. Of these, the functions of 35,816 CDSs excluding those for transposable elements were annotated by BLAST analysis. To demonstrate the utility of the database, we conducted several test analyses using BLAST and keyword searches. Furthermore, we used the draft genome as a reference sequence for NGS-based markers, and successfully identified novel candidate genes controlling heteromorphic self-incompatibility of buckwheat. The database and draft genome sequence provide a valuable resource that can be used in efforts to develop buckwheat cultivars with superior agronomic traits.


The modified 'Jo'burg' technique for securing intercostal chest drains.
Insertion of an intercostal chest drain (ICD) is a common intervention in the management of either blunt or penetrating thoracic trauma. It is frequently performed by junior medical personnel as an emergency procedure during the initial resuscitation period and often within a stressful environment. Approximately one-fifth of all ICD insertions are associated with complications. In a retrospective review of over 1000 ICD insertions, 7% of the complications observed were due to inadequate fixation, resulting in dislodgement. The risk of dislodgement is greatest during transit or transfer of a casualty. In a military setting, this may involve movement of a casualty in a non-permissive environment and includes transfer on and off rotary wing, fixed wing, road vehicle and maritime transport platforms as well as between stretchers and hospital beds. While ICD insertion follows a standard technique in accordance with the Advanced Trauma Life Support guidelines, the method of securing ICDs has not been standardised across the Defence Medical Services (DMS). The aim of this paper is to first propose a modified version of a tried and tested technique of securing ICDs with alternative steps described for medical staff unfamiliar with surgical knot tying by hand. Second, we present the results from a pilot validation study of this technique when introduced to candidates on a trauma surgical skills course. We describe and demonstrate a robust, easily teachable and reproducible technique for securing ICDs. We would advocate the use of this technique among both surgically and non-surgically trained medical personnel and suggest that this should become the standardised technique for securing ICDs across the DMS. This could be easily implemented by introducing this technique into the various military trauma courses, for example the Military Operational Surgical Training, Medical Emergency Response Team and Critical Care Air Support Team courses.


Clear Cell Carcinoma of the Endometrium: Evaluation of Prognostic Parameters in a Multi-institutional Cohort of 165 Cases.
Clear cell carcinoma (CCC) comprises a rare yet an aggressive subtype, accounting for less than 5% of all uterine carcinomas. Several clinicopathologic features have been predictive of poor prognosis; however, data remain controversial. The aim of this study was to evaluate the clinicopathologic features of a multi-institutional cohort of endometrial CCC in order to identify which, if any, have prognostic significance. Retrospective review of endometrial CCC diagnosed between 1995 and 2012 at 3 institutions was conducted to evaluate clinicopathologic parameters: age, race, tumor size, stage, myometrial invasion (MI), lymphovascular invasion, lymph node and adnexal involvement, adjuvant therapy, and outcomes. Data were analyzed using Fisher exact, Cox regression, and Kaplan-Meier analyses. Patients' ages ranged from 36 to 90 years (median, 67 years). The median tumor size was 3.6 cm. Inner-half MI was present in 44%, lymphovascular invasion in 34%, adnexal involvement in 16%, and lymph node metastasis in 30% of cases. Fifty-eight percent of the patients presented with early-stage disease. The 5-year overall survival (OS) was 58%. Shorter disease-free interval (DFI) was significantly associated with older age at diagnosis (>70 years), advanced-stage disease, adnexal involvement, and deep MI (P = 0.005, P = 0.001, P = 0.001, and P = 0.003, respectively). Patients who received adjuvant chemotherapy had a significantly worse DFI and 5-year OS (P = 0.001 and P = 0.001, respectively). A significantly shorter 5-year OS was noted with advanced stage (III-IV) and presence of adnexal involvement (P = 0.001 and P = 0.021, respectively). On Cox regression analysis, advanced-stage disease, older age, and adnexal involvement were significant independent predictors of worse DFI (P = 0.001, P = 0.005, and P = 0.019, respectively), whereas inner-half MI was a significant independent predictor of longer DFI (P = 0.004). Adjuvant radiotherapy alone was a significant independent predictor of better 5-year OS (P = 0.012). In our series of endometrial CCC, older age at diagnosis, advanced stage, deep MI, and adnexal involvement were independent poor prognostic factors. Adjuvant radiotherapy had a significant positive impact on 5-year OS.


The safety and efficacy of minimally invasive discectomy: a meta-analysis of prospective randomised controlled trials.
The objective of this study was to compare the safety and efficacy of minimally invasive discectomy (MID) with standard discectomy (SD) and determine whether the use of the MID technique could decrease the recurrence of lumbar disc herniation (LDH) after the surgery. In February 2014, a comprehensive search was performed in PubMed, EMBASE, Web of Science, Cochrane Library and the Chinese Biological Medicine Database. Only randomised controlled trials (RCT) that compared MID with SD for the surgical management of LDH were included. These trials were carefully picked out following the inclusion and exclusion criteria. Using the Cochrane Collaboration guidelines, two authors independently extracted data and assessed these trials' quality. The age of the patients, size of incision, surgical time, blood loss, visual analogue scale (VAS) score after the surgery, hospital stay, disc herniation recurrence, X-ray exposure and surgical costs in these studies were abstracted and synthesised by a meta-analysis with RevMan 5.2.0 software, and the main results (VAS score after the surgery and disc herniation recurrence) of publication bias were examined by Stata 12.0. Overall, 16 trials involving 2,139 patients meeting our criteria were included and analysed. Comparing MID and SD, the former was more likely to increase disc herniation recurrence [relative risk (RR) = 1.95, 95 % confidence interval (CI) 1.19-3.19, p = 0.008], and it involved a smaller size of incision [mean difference (MD) = -1.91, 95 % CI -3.33 to -0.50, p = 0.008], shorter hospital stay, longer operating time (MD = 11.03, 95 %C I 6.62-15.44, p < 0.00001) and less blood loss (MD = -13.56, 95 % CI -22.26 to -4.87, p = 0.002), while no statistical difference appeared with regard to the age of the patients, VAS score after the surgery, X-ray exposure, hospital stay and surgical costs. Based on available evidence, MID results in less suffering for patients during the hospital course with a similar clinical efficacy compared to SD. This makes MID a promising procedure for patients with LDH; however, to popularise it greater effort is required to reduce disc herniation recurrence.


Characterization of ligand binding to mitochondrial benzodiazepine receptors.
We have evaluated the affinity and density of binding sites for [3H]Ro5-4864 and [3H]PK11195 in intact and fragmented rat kidney mitochondria. These sites are known as peripheral-type or mitochondrial benzodiazepine receptors (MBR) and the preceding paper provided evidence that they function in vitro as modulators of mitochondrial respiratory control (1). In this report, MBR density, localization, and ligand specificity were investigated. In intact mitochondria, there were approximately the same number of binding sites for [3H]PK11195 as for [3H]Ro5-4864, and their apparent Kd values were identical. However, in mitochondrial fragments, there were 80% more binding sites for [3H]Ro5-4864 than for [3H]PK01195. Rat kidney mitochondria were fractionated by decompression and digitonin-based methods into outer and inner membrane-containing fractions before and after incorporation of the MBR-specific photoaffinity ligand [3H]PK14105. Assays of selective mitochondrial membrane markers and [3H]Ro5-4864 binding or specifically bound [3H]PK14105 revealed that the receptors were found in the mitochondrial outer membrane. We also evaluated the binding of a large number of structurally and pharmacologically diverse compounds to MBR by studying their ability to inhibit the binding of both 3H-ligands. These compounds had affinities ranging from 0.015 to 100 microM and, with a few exceptions, were similar in their abilities to bind to MBR in intact and fragmented mitochondria. However, there was considerable variation in the ratios between drug potencies at displacing [3H]Ro5-4864 and [3H]PK11195. This represents a new form of evidence that these two radioligands do not label identical sites on the receptor. Thirteen of the drugs, including [3H]Ro5-4864 and [3H]PK11195, were analyzed as to the nature of the inhibition and, with only two exceptions, were competitive inhibitors. One drug, Konig's polyanion, was uncompetitive whereas the other, cyclosporin A, was a noncompetitive inhibitor. These studies revealed several new classes of MBR ligands and suggest that the relationship between ligand structure and binding affinity is highly complex.


The T309G MDM2 gene polymorphism is a novel risk factor for proliferative vitreoretinopathy.
Proliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism (rs2279744) in PVR. Distribution of T309G MDM2 genotypes among European subjects undergoing RD surgery was evaluated. Proportions of genotypes between subsamples from different countries were analyzed. Also, a genetic interaction between rs2279744 in MDM2 and rs1042522 in p53 gene was analyzed. Significant differences were observed comparing MDM2 genotype frequencies at position 309 of intron 1 between cases (GG: 21.6%, TG: 54.5%, TT: 23.8%) and controls (GG: 7.3%, TG: 43.9%, TT: 48.7%). The proportions of genotypes between sub-samples from different countries showed a significant difference. Distribution of GG genotype revealed differences in Spain (35.1-53.0)/(22.6-32.9), Portugal (39.0-74.4)/(21.4-38.9), Netherlands (40.6-66.3)/(25.3-38.8) and UK (37.5-62.4)/(23.3-34.2). The OR of G carriers in the global sample was 5.9 (95% CI: 3.2 to 11.2). The OR of G carriers from Spain and Portugal was 5.4 (95% CI: 2.2-12.7), whereas in the UK and the Netherlands was 7.3 (95% CI: 2.8-19.1). Results indicate that the G allele of rs2279744 is associated with a higher risk of developing PVR in patients undergoing a RD surgery. Further studies are necessary to understand the role of this SNP in the development of PVR.


Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity.
Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes.


Sudarshan kriya yoga: Breathing for health.
Breathing techniques are regularly recommended for relaxation, stress management, control of psychophysiological states, and to improve organ function. Yogic breathing, defined as a manipulation of breath movement, has been shown to positively affect immune function, autonomic nervous system imbalances, and psychological or stress-related disorders. The aim of this study was to assess and provide a comprehensive review of the physiological mechanisms, the mind-body connection, and the benefits of Sudarshan Kriya Yoga (SKY) in a wide range of clinical conditions. Various online databases searched were Medline, Psychinfo, EMBASE, and Google Scholar. All the results were carefully screened and articles on SKY were selected. The references from these articles were checked to find any other potentially relevant articles. SKY, a unique yogic breathing practice, involves several types of cyclical breathing patterns, ranging from slow and calming to rapid and stimulating. There is mounting evidence to suggest that SKY can be a beneficial, low-risk, low-cost adjunct to the treatment of stress, anxiety, post-traumatic stress disorder, depression, stress-related medical illnesses, substance abuse, and rehabilitation of criminal offenders.


Single-particle trajectories reveal two-state diffusion-kinetics of hOGG1 proteins on DNA.
We reanalyze trajectories of hOGG1 repair proteins diffusing on DNA. A previous analysis of these trajectories with the popular mean-squared-displacement approach revealed only simple diffusion. Here, a new optimal estimator of diffusion coefficients reveals two-state kinetics of the protein. A simple, solvable model, in which the protein randomly switches between a loosely bound, highly mobile state and a tightly bound, less mobile state is the simplest possible dynamic model consistent with the data. It yields accurate estimates of hOGG1's (i) diffusivity in each state, uncorrupted by experimental errors arising from shot noise, motion blur and thermal fluctuations of the DNA; (ii) rates of switching between states and (iii) rate of detachment from the DNA. The protein spends roughly equal time in each state. It detaches only from the loosely bound state, with a rate that depends on pH and the salt concentration in solution, while its rates for switching between states are insensitive to both. The diffusivity in the loosely bound state depends primarily on pH and is three to ten times higher than in the tightly bound state. We propose and discuss some new experiments that take full advantage of the new tools of analysis presented here.


Excited-state dynamics of nitroperylene in solution: solvent and excitation wavelength dependence.
The photophysics and excited-state dynamics of nitroperylene (NPe) in solvents of various polarities and viscosities, including a room-temperature ionic liquid, have been investigated by femtosecond-resolved transient absorption spectroscopy. The excited-state absorption spectrum was found to depend substantially on solvent polarity. In the most polar solvents, it is very similar to that of the NPe radical cation generated upon bimolecular quenching by an electron acceptor, denoting a substantial charge-transfer character of the S1 state. Contrary to smaller nitroaromatic compounds, NPe in the S1 state does not undergo ultrafast intersystem crossing (ISC) but decays mainly by internal conversion (IC). In nonprotic solvents, IC involves low-frequency modes with large amplitude motion associated with the nitro group and depends on both the solvent viscosity and polarity. It takes place on a 100 ps time scale in acetonitrile, while in cyclohexane, it is slow enough for ISC to become competitive. Moreover, both the fluorescence quantum yield and the excited-state dynamics were found to differ, depending on which side of the S0-S1 absorption band excitation was performed. This dependence is explained by the inhomogeneous nature of the absorption spectrum arising from a distribution of twist angles of the nitro group relative to the aromatic plane. On the other hand, such excitation wavelength effects were not observed in protic solvents, where the excited-state lifetime was found to be substantially shorter than that in nonprotic solvents. This behavior is rationalized in terms of a H-bonding interaction, which limits the torsional disorder of NPe and favors ultrafast nonradiative deactivation of the excited state. Transient absorption measurements performed for comparative purpose with nitropyrene in acetonitrile confirm the occurrence of ultrafast ISC in smaller nitroaromatic compounds.


Inter- and intrajudge reliability for videofluoroscopic swallowing evaluation measures.
Interjudge reliability for videofluoroscopic (VFS) swallowing evaluations has been investigated, and results have, for the most part, indicated that reliability is poor. While previous studies are well-designed investigations of interjudge reliability, few reports of intrajudge reliability are available for VFS measures derived from frame-by-frame analysis that clinicians typically employ. The purpose of this study was to examine the inter- and intrajudge reliability of VFS examination measures commonly used to assess swallowing functions. No training to criteria occurred. VFS examinations were conducted on 20 patients who had suffered a stroke within six weeks and had no structural abnormalities or tracheostomies. Three clinical judges served as subjects and rated the VFS examinations from videotape using frame-by-frame analysis. A clinician's repeated review of measures employed in the 20 examinations indicated high intrajudge reliability for a number of measures, suggesting that an experienced clinician may employ consistent standards for rating certain VFS measures across patients and time. These standards appear to vary among clinicians and yield unacceptable interjudge reliability. The need to train clinicians to criteria to improve interjudge reliability is discussed.


Minimizing AED adverse effects: improving quality of life in the interictal state in epilepsy care.
The goals of epilepsy therapy are to achieve seizure freedom while minimizing adverse effects of treatment. However, producing seizure-freedom is often overemphasized, at the expense of inducing adverse effects of treatment. All antiepileptic drugs (AEDs) have the potential to cause dose-related, "neurotoxic" adverse effects (i.e., drowsiness, fatigue, dizziness, blurry vision, and incoordination). Such adverse effects are common, especially when initiating AED therapy and with polytherapy. Dose-related adverse effects may be obviated in most patients by dose reduction of monotherapy, reduction or elimination of polytherapy, or substituting for a better tolerated AED. Additionally, all older and several newer AEDs have idiosyncratic adverse effects which usually require withdrawal in an affected patient, including serious rash (i.e., Stevens-Johnson Syndrome, toxic epidermal necrolysis), hematologic dyscrasias, hepatotoxicity, teratogenesis in women of child bearing potential, bone density loss, neuropathy, and severe gingival hyperplasia. Unfortunately, occurrence of idiosyncratic AED adverse effects cannot be predicted or, in most cases, prevented in susceptible patients. This article reviews a practical approach for the definition and identification of adverse effects of epilepsy therapies, and reviews the literature demonstrating that adverse effects result in detrimental quality of life in epilepsy patients. Strategies for minimizing AED adverse effects by reduction or elimination of AED polytherapy, appropriately employing drug-sparing therapies, and optimally administering AEDs are outlined, including tenets of AED selection, titration, therapeutic AED laboratory monitoring, and avoidance of chronic idiosyncratic adverse effects.


Role of telomeres in vascular senescence.
Telomeres are DNA regions composed of TTAGGG repeats that are located at the ends of chromosomes. Specific proteins associate with the telomeres and form non-nucleosomal DNA-protein complexes that serve as protective caps for the chromosome ends. There is accumulating evidence that progressive telomere shortening is closely related to cardiovascular disease. For example, vascular cell senescence has been reported to occur in human atherosclerotic lesions and this change is associated with telomere shortening. Impairment of telomere integrity causes vascular dysfunction, which is prevented by the activation of telomerase. Mice with short telomeres develop hypertension and exhibit impaired neovascularization. Short telomeres have also been reported in the leukocytes of patients with cardiovascular disease or various cardiovascular risk factors. Although it remains unclear whether short telomeres directly cause cardiovascular disease, manipulation of telomere function is potentially an attractive strategy for the treatment of vascular senescence.


Positive interactions between nitrogen-fixing legumes and four different neighbouring species in a biodiversity experiment.
The importance of facilitative processes due to the presence of nitrogen-fixing legumes in temperate grasslands is a contentious issue in biodiversity experiments. Despite a multitude of studies of fertilization effects of legumes on associated nonfixers in agricultural systems, we know little about the dynamics in more diverse systems. We hypothesised that the identity of target plant species (phytometers) and the diversity of neighbouring plant species would affect the magnitude of such positive species interactions. We therefore sampled aboveground tissues of phytometers planted into all plots of a grassland biodiversity-ecosystem functioning experiment and analysed their N concentrations, delta15N values and biomasses. The four phytometer species (Festuca pratensis, Plantago lanceolata, Knautia arvensis and Trifolium pratensis) each belonged to one of the four plant functional groups used in the experiment and allowed the effects of diversity on N dynamics in individual species to be assessed. We found significantly lower delta15N values and higher N concentrations and N contents (amount of N per plant) in phytometer species growing with legumes, indicating a facilitative role for legumes in these grassland ecosystems. Our data suggest that the main driving force behind these facilitative interactions in plots containing legumes was reduced competition for soil nitrate ("nitrate sparing"), with apparent N transfer playing a secondary role. Interestingly, species richness (and to a lesser extent functional group number) significantly decreased delta15N values, N concentrations and N content irrespective of any legume effect. Possible mechanisms behind this effect, such as increased N mineralisation and nitrate uptake in more diverse plots, now need further investigation. The magnitude of the positive interactions depended on the identity of the phytometer species. Evidence for increased N uptake in communities containing legumes was found in all three nonlegume phytometer species, with a subsequent strong increase in biomass in the grass F. pratensis across all diversity levels, and a lesser biomass gain in P. lanceolata and K. arvensis. In contrast, the legume phytometer species T. pratense was negatively affected when other legumes were present in their host communities across all diversity levels.


Epigenetic modifications of the renin-angiotensin system in cardiometabolic diseases.
Cardiometabolic diseases (CMDs) are among the most prevalent and the highest mortality diseases. Single disease etiology such as gene mutation, polymorphisms, or environmental exposure has failed to explain the origin of CMD. This can be evident in the discrepancies in disease susceptibility among individuals exposed to the same environmental insult or who acquire the same genetic variation. Epigenetics is the intertwining of genetic and environmental factors that results in diversity in the disease course, severity, and prognosis among individuals. Environmental exposures modify the epigenome and thus provide a link for translating environmental impact on changes in gene expression and precipitation to pathological conditions. Renin-angiotensin system (RAS) is comprising genes responsible for the regulation of cardiovascular, metabolic, and glycemic functions. Epigenetic modifications of RAS genes can lead to overactivity of the system, increased sympathetic activity and autonomic dysfunction ultimately contributing to the development of CMD. In this review, we describe the three common epigenetic modulations targeting RAS components and their impact on the susceptibility to cardiometabolic dysfunction. Additionally, we highlight the therapeutic efforts of targeting these epigenetic imprints to the RAS and its effects.


Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading, see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: For patients in whom the risk of HIT is considered to be > 0.1%, we recommend platelet count monitoring (Grade 1C). For patients who are receiving therapeutic-dose unfractionated heparin (UFH), we suggest at least every-other-day platelet count monitoring until day 14, or until UFH is stopped, whichever occurs first (Grade 2C). For patients who are receiving postoperative antithrombotic prophylaxis with UFH (HIT risk > 1%), we suggest at least every-other-day platelet count monitoring between postoperative days 4 to 14 (or until UFH is stopped, whichever occurs first) [Grade 2C]. For medical/obstetric patients who are receiving prophylactic-dose UFH, postoperative patients receiving prophylactic-dose low molecular weight heparin (LMWH), postoperative patients receiving intravascular catheter UFH "flushes," or medical/obstetrical patients receiving LMWH after first receiving UFH (risk, 0.1 to 1%), we suggest platelet count monitoring every 2 days or 3 days from day 4 to day 14, or until heparin is stopped, whichever occurs first (Grade 2C). For medical/obstetrical patients who are only receiving LMWH, or medical patients who are receiving only intravascular catheter UFH flushes (risk < 0.1%), we suggest clinicians do not use routine platelet count monitoring (Grade 2C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative anticoagulant, such as lepirudin (Grade 1C+), argatroban (Grade 1C), bivalirudin (Grade 2C), or danaparoid (Grade 1B). For patients with strongly suspected (or confirmed) HIT, we recommend routine ultrasonography of the lower-limb veins for investigation of deep venous thrombosis (Grade 1C); against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered; that the VKA antagonist be administered only during overlapping alternative anticoagulation (minimum 5-day overlap); and begun with low, maintenance doses (all Grade 2C). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (Grade 2C) [corrected] For patients with a history of HIT who are HIT antibody negative and require cardiac surgery, we recommend use of UFH (Grade 1C).


Susceptibility loci for intracranial aneurysm in European and Japanese populations.
Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects approximately 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.


Fish consumption, low-level mercury, lipids, and inflammatory markers in children.
There is considerable evidence that consuming fish has numerous health benefits, including a reduced risk of cardiovascular disease. However, fish is also the primary source of human exposure to mercury (Hg). In a cross-sectional study of 9-11 year old children (N=100), we measured fish consumption, blood lipids, total blood Hg, diurnal salivary cortisol (4 samples collected throughout the day), and performed a proteomic analysis of serum proteins using spectral count shotgun proteomics. Children who consumed fish had a significantly more atheroprotective lipid profile but higher levels of blood Hg relative to children that did not consume fish. Although the levels of blood Hg were very low in these children (M=0.77 μg/L; all but 1 participant had levels below 3.27 μg/L), increasing blood Hg was significantly associated with blunted diurnal cortisol levels. Blood Hg was also significantly associated with acute-phase proteins suggesting systemic inflammation, and several of these proteins were found to significantly reduce the association between Hg and diminished cortisol when included in the model. This study of a pediatric population is the first to document an association between blood Hg, systemic inflammation, and endocrine disruption in humans. Without a better understanding of the long-term consequences of an atheroprotective lipid profile relative to blunted diurnal cortisol and systemic inflammation, a determination of the risk-benefit ratio for fish consumption by children is not possible.


Mosaic structure of native ant supercolonies.
According to the inclusive fitness theory, some degree of positive relatedness is required for the evolution and maintenance of altruism. However, ant colonies are sometimes large interconnected networks of nests, which are genetically homogenous entities, causing a putative problem for the theory. We studied spatial structure and genetic relatedness in two supercolonies of the ant Formica exsecta, using nuclear and mitochondrial markers. We show that there may be multiple pathways to supercolonial social organization leading to different spatial genetic structures. One supercolony formed a genetically homogenous population dominated by a single mtDNA haplotype, as expected if founded by a small number of colonizers, followed by nest propagation by budding and domination of the habitat patch. The other supercolony had several haplotypes, and the spatial genetic structure was a mosaic of nuclear and mitochondrial clusters. Genetic diversity probably originated from long-range dispersal, and the mosaic population structure is likely a result of stochastic short-range dispersal of individuals. Such a mosaic spatial structure is apparently discordant with the current knowledge about the integrity of ant colonies. Relatedness was low in both populations when estimated among nestmates, but increased significantly when estimated among individuals sharing the same genetic cluster or haplogroup. The latter association indicates the important historical role of queen dispersal in the determination of the spatial genetic structure.


Multiview Alignment and Generation in CCA via Consistent Latent Encoding.
Multiview alignment, achieving one-to-one correspondence of multiview inputs, is critical in many real-world multiview applications, especially for cross-view data analysis problems. An increasing amount of work has studied this alignment problem with canonical correlation analysis (CCA). However, existing CCA models are prone to misalign the multiple views due to either the neglect of uncertainty or the inconsistent encoding of the multiple views. To tackle these two issues, this letter studies multiview alignment from a Bayesian perspective. Delving into the impairments of inconsistent encodings, we propose to recover correspondence of the multiview inputs by matching the marginalization of the joint distribution of multiview random variables under different forms of factorization. To realize our design, we present adversarial CCA (ACCA), which achieves consistent latent encodings by matching the marginalized latent encodings through the adversarial training paradigm. Our analysis, based on conditional mutual information, reveals that ACCA is flexible for handling implicit distributions. Extensive experiments on correlation analysis and cross-view generation under noisy input settings demonstrate the superiority of our model.


Genomic and functional analysis of Vibrio phage SIO-2 reveals novel insights into ecology and evolution of marine siphoviruses.
We report on a genomic and functional analysis of a novel marine siphovirus, the Vibrio phage SIO-2. This phage is lytic for related Vibrio species of great ecological interest including the broadly antagonistic bacterium Vibrio sp. SWAT3 as well as notable members of the Harveyi clade (V.harveyi ATTC BAA-1116 and V.campbellii ATCC 25920). Vibrio phage SIO-2 has a circularly permuted genome of 80598 bp, which displays unusual features. This genome is larger than that of most known siphoviruses and only 38 of the 116 predicted proteins had homologues in databases. Another divergence is manifest by the origin of core genes, most of which share robust similarities with unrelated viruses and bacteria spanning a wide range of phyla. These core genes are arranged in the same order as in most bacteriophages but they are unusually interspaced at two places with insertions of DNA comprising a high density of uncharacterized genes. The acquisition of these DNA inserts is associated with morphological variation of SIO-2 capsid, which assembles as a large (80 nm) shell with a novel T=12 symmetry. These atypical structural features confer on SIO-2 a remarkable stability to a variety of physical, chemical and environmental factors. Given this high level of functional and genomic novelty, SIO-2 emerges as a model of considerable interest in ecological and evolutionary studies.