Bone histomorphometry of the clavicle in a forensic sample from Albania.
Forensic assessment of skeletal material includes age estimation of unknown individuals. When dealing with extremely fragmented human remains that lack macro-features used in age estimation, histological assessment of the skeletal elements can be employed. Historically, microscopic methods for age assessment used by forensic anthropologists have been available since 1965. Several skeletal elements have been used for this purpose. Among them, the clavicle has garnered very little attention. The purpose of this study is to explore the validity of clavicular histomorphometry as an age marker in a modern Balkan sample. This study examined a modern clavicular autopsy sample from Albania. The sample consisted of 33 individuals of known age and cause of death. Data were collected for micro-anatomical features including osteon population density (OPD) and cortical area. Intra- and inter-observer errors were assessed through technical error of measurement (TEM) and R coefficient. A validation study was performed in order to test the accuracy of existing histological formulae. Regression analysis was run to developed age prediction models with the best models tested through cross-validation and the comparison between OPD for the Albanian sample and a European-American sample examined. Intra- and inter-observer error TEM results demonstrated values falling within the limits of acceptance. The existing histological methods did not perform accurately on the sample under study. Regression equations for Albanians produced age estimations deviating 8 and 11 years from known age. Cross-validation on the most accurate regression formula which includes OPD as a single variable demonstrated similar mean errors. Statistically significant differences were observed between the Albanian and the European-American population when the two samples were compared. The research presented is the fifth article published and the fifth population explored on clavicular microstructure. The potential of histology to estimate age on the Albanian population is shown here; however, population effect, diet and health status might be considered. Further inclusion of individuals will corroborate our preliminary findings.


Treatment outcome in children with nontuberculous mycobacterial lymphadenitis: A retrospective follow-up study.
Information on the long-term treatment outcome following nontuberculous mycobacterial (NTM) lymphadenitis is very limited. We performed a study to (a) compare cure rates following different initial treatment courses, (b) describe subsequent treatment courses and their outcomes, and (c) determine the occurrence of late sequelae in immunocompetent children with NTM lymphadenitis. In 2011, we conducted a retrospective follow-up study in 71 parents whose children had been hospitalized with NTM disease 2002-2005. A telephone survey was performed using a standardized questionnaire to collect information on the therapeutic management and treatment outcome. Of 61 children with NTM lymphadenitis, 33 (54%) children were cured after the initial treatment. We found no significant difference in cure rates following surgical intervention only (45%, 13/29 children) and a combination of surgical intervention and chemotherapy (61%, 19/31 children). In 7 out of 11 children, the cure rate following complete lymph node excision was 64%. Subsequent courses of treatment including repeated surgical intervention, combination therapy, chemotherapy only, and wait-and-see strategy in children where initial therapy failed resulted in the cure of all 61 children. In four children (7%), recurrences were observed up to 5 years later. Our study showed that recurrent NTM lymphadenitis might be observed several years after initial resolution of disease. The cure rate following complete lymph node excision was lower than reported in other studies. Subsequent treatment courses were necessary in half of the children. Physicians and parents need to be aware that NTM lymphadenitis in children requires careful choice of intervention and active follow-up.


DprE1--from the discovery to the promising tuberculosis drug target.
Several groups working in the field of the development of new antituberculosis drugs have recently reported active compounds targeting mycobacterial enzyme DprE1. Along with its counterpart, DprE2, it catalyses a unique epimerization reaction resulting in the synthesis of decaprenylphosphoryl arabinose, the single donor of arabinosyl residues for the build-up of arabinans, fundamental components of the mycobacterial cell wall. This review presents the historical background leading to the discovery of DprE1, focusing on the biochemical and structural characterization of this important emerging target and introducing the molecules acting on DprE1 including the development of the most successful series--the benzothiazinones, currently in late pre-clinical development, which turned to be suicide inhibitors of DprE1.


ELISPOTs Produced by CD8 and CD4 Cells Follow Log Normal Size Distribution Permitting Objective Counting.
Each positive well in ELISPOT assays contains spots of variable sizes that can range from tens of micrometers up to a millimeter in diameter. Therefore, when it comes to counting these spots the decision on setting the lower and the upper spot size thresholds to discriminate between non-specific background noise, spots produced by individual T cells, and spots formed by T cell clusters is critical. If the spot sizes follow a known statistical distribution, precise predictions on minimal and maximal spot sizes, belonging to a given T cell population, can be made. We studied the size distributional properties of IFN-γ, IL-2, IL-4, IL-5 and IL-17 spots elicited in ELISPOT assays with PBMC from 172 healthy donors, upon stimulation with 32 individual viral peptides representing defined HLA Class I-restricted epitopes for CD8 cells, and with protein antigens of CMV and EBV activating CD4 cells. A total of 334 CD8 and 80 CD4 positive T cell responses were analyzed. In 99.7% of the test cases, spot size distributions followed Log Normal function. These data formally demonstrate that it is possible to establish objective, statistically validated parameters for counting T cell ELISPOTs.


Revision total hip arthroplasty in patients 80 years or older.
We evaluated all revisions performed from March 1996 to December 2008 and compared complications, mortality, and clinical outcomes between patients 80 years and older and patients younger than 80 years. Data were collected prospectively. There were 325 revisions, 84 (25.8%) in patients 80 years and older and 241 in patients younger than 80 years (62% revision for aseptic loosening in both groups). The mean follow-up was 4.3 years. The results, 80 years and older vs younger than 80 years, revealed the following: mortality, 5% vs 0% 3 months postoperatively; medical complications in 23.8% vs 6.2%; postoperative fractures, 9.5% vs 2.5%; and improved Merle d'Aubigné scores from 9.6 to 13.0 vs 10.4 to 14.3. Revision total hip arthroplasty in patients 80 years and older was associated with substantial clinical improvement and patient satisfaction. However, medical complications and 90-day mortality were higher, and postoperative fractures occurred more frequently.


The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers.
The association of germline mutations in the breast cancer susceptibility gene 1 (BRCA1) and the breast cancer susceptibility gene 2 (BRCA2) with the development of breast and ovarian cancers have been widely researched and recognised. It is known that these genes function at multiple sites in the body. Research has subsequently evolved into the connection of BRCA1/2 with cancers at other sites within the body. This review examines the association of BRCA1/2 germline gene mutations with prostate, pancreatic and stomach cancers. An extensive literature search revealed conflicting findings regarding the association of BRCA1/2 gene mutations with these cancers. Most studies suggest that there is an association between BRCA1/2 mutations and carcinoma of the prostate, pancreas and stomach, but some reports propose that such a correlation may be due to factors other than possessing a mutated BRCA1/2 gene, and other associations may be revealed as further epidemiological information becomes available. The review concludes that as more knowledge arises about the mechanisms of BRCA1/2 gene mutations, it should pave the way for future screening programmes to be applied effectively.


Which drugs cause preventable admissions to hospital? A systematic review.
Previous systematic reviews have found that drug-related morbidity accounts for 4.3% of preventable hospital admissions. None, however, has identified the drugs most commonly responsible for preventable hospital admissions. The aims of this study were to estimate the percentage of preventable drug-related hospital admissions, the most common drug causes of preventable hospital admissions and the most common underlying causes of preventable drug-related admissions. Bibliographic databases and reference lists from eligible articles and study authors were the sources for data. Seventeen prospective observational studies reporting the proportion of preventable drug-related hospital admissions, causative drugs and/or the underlying causes of hospital admissions were selected. Included studies used multiple reviewers and/or explicit criteria to assess causality and preventability of hospital admissions. Two investigators abstracted data from all included studies using a purpose-made data extraction form. From 13 papers the median percentage of preventable drug-related admissions to hospital was 3.7% (range 1.4-15.4). From nine papers the majority (51%) of preventable drug-related admissions involved either antiplatelets (16%), diuretics (16%), nonsteroidal anti-inflammatory drugs (11%) or anticoagulants (8%). From five studies the median proportion of preventable drug-related admissions associated with prescribing problems was 30.6% (range 11.1-41.8), with adherence problems 33.3% (range 20.9-41.7) and with monitoring problems 22.2% (range 0-31.3). Four groups of drugs account for more than 50% of the drug groups associated with preventable drug-related hospital admissions. Concentrating interventions on these drug groups could reduce appreciably the number of preventable drug-related admissions to hospital from primary care.


Advanced technologies for oral controlled release: cyclodextrins for oral controlled release.
Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability, and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug-drug or drug-additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water-soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g., as osmotic pumps) and/or hydrophobic CDs. New controlled delivery systems based on nanotechnology carriers (nanoparticles and conjugates) have also been reviewed.


Long noncoding RNAs in development and disease of the central nervous system.
The central nervous system (CNS) is a complex biological system composed of numerous cell types working in concert. The intricate development and functioning of this highly ordered structure depends upon exquisite spatial and temporal control of gene expression in the cells comprising the CNS. Thus, gene regulatory networks that control cell fates and functions play critical roles in the CNS. Failure to develop and maintain intricate regulatory networks properly leads to impaired development or neural dysfunction, which might manifest as neurological disorders. Long noncoding RNAs (lncRNAs) are emerging as important components of gene regulatory networks, working in concert with transcription factors and epigenetic regulators of gene expression. Interestingly, many lncRNAs are highly expressed in the adult and developing brain, often showing precise temporal and spatial patterns of expression. This specificity of expression and growing awareness of the importance of lncRNAs suggest that they play key roles in CNS development and function. In this review, we highlight the growing evidence for the importance of lncRNAs in the CNS and the indications that their dysregulation underlies some neurological disorders.


Gene expression in human alcoholism: microarray analysis of frontal cortex.
Changes in brain gene expression are thought to be responsible for the tolerance, dependence, and neurotoxicity produced by chronic alcohol abuse, but there has been no large scale study of gene expression in human alcoholism. RNA was extracted from postmortem samples of superior frontal cortex of alcoholics and nonalcoholics. Relative levels of RNA were determined by array techniques. We used both cDNA and oligonucleotide microarrays to provide coverage of a large number of genes and to allow cross-validation for those genes represented on both types of arrays. Expression levels were determined for over 4000 genes and 163 of these were found to differ by 40% or more between alcoholics and nonalcoholics. Analysis of these changes revealed a selective reprogramming of gene expression in this brain region, particularly for myelin-related genes which were down-regulated in the alcoholic samples. In addition, cell cycle genes and several neuronal genes were changed in expression. These gene expression changes suggest a mechanism for the loss of cerebral white matter in alcoholics as well as alterations that may lead to the neurotoxic actions of ethanol.


The 2015 Annual Meeting of SETAC German Language Branch in Zurich (7-10 September, 2015): Ecotoxicology and environmental chemistry-from research to application.
This report provides a brief review of the 20th annual meeting of the German Language Branch of the Society of Environmental Toxicology and Chemistry (SETAC GLB) held from September 7th to 10th 2015 at ETH (Swiss Technical University) in Zurich, Switzerland. The event was chaired by Inge Werner, Director of the Swiss Centre for Applied Ecotoxicology (Ecotox Centre) Eawag-EPFL, and organized by a team from Ecotox Centre, Eawag, Federal Office of the Environment, Federal Office of Agriculture, and Mesocosm GmbH (Germany). Over 200 delegates from academia, public agencies and private industry of Germany, Switzerland and Austria attended and discussed the current state of science and its application presented in 75 talks and 83 posters. In addition, three invited keynote speakers provided new insights into scientific knowledge 'brokering', and-as it was the International Year of Soil-the important role of healthy soil ecosystems. Awards were presented to young scientists for best oral and poster presentations, and for best 2014 master and doctoral theses. Program and abstracts of the meeting (mostly in German) are provided as Additional file 1.


Discussing prognosis with terminally ill cancer patients and relatives: a survey of physicians' intentions in seven countries.
To determine the extent to which physicians in different countries intend to inform terminal patients and relatives about prognosis, and to identify physician characteristics associated with an active approach to such discussions. In the context of a European research project, a study on disclosing prognosis was conducted in seven countries. A written questionnaire with questions regarding hypothetical cases and actual practices was sent to physicians from specialties involved in the care of dying patients. 10,139 questionnaires were studied. The response rate was greater than 50% in all countries except Italy (39%). The percentage of physicians who indicated that they would actively inform competent patients of their prognosis varied between countries from 52% in Italy to 99% in Sweden. For informing relatives of incompetent patients, rates were higher, ranging from 86% in Denmark to 98% in Australia. Younger physician age and training in palliative care were associated with an active intention to discuss prognosis. Physicians' intentions to discuss prognosis with patients and families vary largely across countries. Physician age and training in palliative care may also affect intentions. Continuing training should focus on improving physicians' ability to communicate responsibly about prognosis with patients and families.


The role of leukocyte-stromal interactions in chronic inflammatory joint disease.
Rheumatoid arthritis (RA) is a debilitating, chronic, persistent inflammatory disease that is characterised by painful and swollen joints. The aetiology of RA is unknown, however whereas past research has concentrated on the role of immune or inflammatory infiltrating cells in inflammation, it is becoming clear that stromal cells play a critical part in regulating the quality and duration of an inflammatory response. In this review we assess the role of fibroblasts within the inflamed synovium in modulating immune responses; in particular we examine the role of stromal cells in the switch from resolving to persistent inflammation as is found in the rheumatoid synovium.


The Role of Gastroesophageal Reflux and Other Factors during Progression to Esophageal Adenocarcinoma.
U.S. esophageal adenocarcinoma (EAC) incidence increased over 5-fold between 1975 and 2009. Symptomatic gastroesophageal reflux disease (sGERD) elevates the risk for EAC. However, a simple calculation suggests that changes in sGERD prevalence can explain at most approximately 16% of this trend. Importantly, a mechanistic understanding of the influence of sGERD and other factors (OF) on EAC is lacking. A multiscale model was developed to estimate temporal trends for sGERD and OF, and their mechanistic role during carcinogenesis. Model calibration was to Surveillance, Epidemiology, and End Results (SEER) incidence and age-dependent sGERD data using maximum likelihood and Markov chain Monte Carlo (MCMC) methods. Among men, 77.8% [95% credibility interval (CI), 64.9%-85.6%] of the incidence trend is attributable to OF, 13.4% (95% CI, 11.4%-17.3%) to sGERD, and 8.8% (95% CI, 4.2%-13.7%) to sGERD-OF interactions. Among women, 32.6% (95% CI, 27.0%-39.9%) of the trend is attributable to OF, 13.6% (95% CI, 12.5%-15.9%) to sGERD, and 47.4% (95% CI, 30.7%-64.6%) to interactions. The predicted trends were compared with historical trends for obesity, smoking, and proton pump inhibitor use. Interestingly, predicted OF cohort trends correlated most highly with median body mass index (BMI) at age 50 (r = 0.988 for men; r = 0.998 for women). sGERD and OF mechanistically increase premalignant cell promotion, which increases EAC risk exponentially with exposure duration. Surveillance should target individuals with long-duration sGERD and OF exposures.


Patient-related independent clinical risk factors for early complications following Nd: YAG laser resection of lung cancer.
Neodymium:yttrium aluminum garnet (Nd:YAG) laser resection is one of the most established interventional pulmonology techniques for immediate debulking of malignant central airway obstruction (CAO). The major aim of this study was to investigate the complication rate and identify clinical risk factors for complications in patients with advanced lung cancer. In the period from January 2006 to January 2011, data sufficient for analysis were identified in 464 patients. Nd:YAG laser resection due to malignant CAO was performed in all patients. The procedure was carried out in general anesthesia. Complications after laser resection were defined as severe hypoxemia, global respiratory failure, arrhythmia requiring treatment, hemoptysis, pneumothorax, pneumomediastinum, pulmonary edema, tracheoesophageal fistulae, and death. Risk factors were defined as acute myocardial infarction within 6 months before treatment, hypertension, chronic arrhythmia, chronic obstructive pulmonary disease (COPD), stabilized cardiomyopathy, previous external beam radiotherapy, previous chemotherapy, and previous interventional pulmonology treatment. There was 76.1% male and 23.9% female patients in the study, 76.5% were current smokers, 17.2% former smokers, and 6.3% of nonsmokers. The majority of patients had squamous cell lung cancer (70%), small cell lung cancer was identified in 18.3%, adenocarcinoma in 3.4%, and metastases from lung primary in 8.2%. The overall complication rate was 8.4%. Statistically significant risk factors were age (P = 0.001), current smoking status (P = 0.012), arterial hypertension (P < 0.0001), chronic arrhythmia (P = 0.034), COPD (P < 0.0001), and stabilized cardiomyopathy (P < 0.0001). Independent clinical risk factors were age over 60 years (P = 0.026), arterial hypertension (P < 0.0001), and COPD (P < 0.0001). Closer monitoring of patients with identified risk factors is advisable prior and immediately after laser resection. In order to avoid or minimize complications, special attention should be directed toward patients who are current smokers, over 60 years of age, with arterial hypertension or COPD.


T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients.
Lymphocytes contribute to ischemia/reperfusion (I/R) injury in several organ systems, but their relevance in ST elevation myocardial infarction (STEMI) is unknown. Our goal was to characterize lymphocyte dynamics in individuals after primary percutaneous coronary intervention (PPCI), assess the prognostic relevance of these cells, and explore mechanisms of lymphocyte-associated injury. Lymphocyte counts were retrospectively analyzed in 1,377 STEMI patients, and the prognostic relevance of post-PPCI lymphopenia was assessed by Cox proportional hazards regression. Blood from 59 prospectively recruited STEMI patients undergoing PPCI was sampled, and leukocyte subpopulations were quantified. Microvascular obstruction (MVO), a component of I/R injury, was assessed using MRI. In the retrospective cohort, lymphopenia was associated with a lower rate of survival at 3 years (82.8% vs. 96.3%, lowest vs. highest tertile; hazard ratio 2.42). In the prospective cohort, lymphocyte counts fell 90 minutes after reperfusion, primarily due to loss of T cells. CD8+ T cells decreased more than CD4+ T cells, and effector subsets exhibited the largest decline. The early decrease in effector T cell levels was greater in individuals that developed substantial MVO. The drop in T cell subsets correlated with expression of the fractalkine receptor CX3CR1 (r2 = 0.99, P = 0.006). Serum fractalkine concentration peaked at 90 minutes after reperfusion, coinciding with the T cell count nadir. Lymphopenia following PPCI is associated with poor prognosis. Our data suggest that fractalkine contributes to lymphocyte shifts, which may influence development of MVO through the action of effector T cells. Not applicable. British Heart Foundation (FS/12/31/29533) and National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre.


A pilot study of dentists' assessment of caries detection and staging systems applied to early caries: PEARL Network findings.
The International Caries Detection and Assessment System (ICDAS II) and the Caries Classification System (CCS) are caries stage description systems proposed for adoption into clinical practice. This pilot study investigated clinicians' training in and use of these systems for detection of early caries and recommendations for individual tooth treatment. Patient participants (N = 8) with a range of noncavitated lesions (CCS ranks 2 and 4 and ICDAS II ranks 2-4) identified by a team of calibrated examiners were recruited from the New York University College of Dentistry clinic. Eighteen dentists-8 from the Practitioners Engaged in Applied Research and Learning (PEARL) Network and 10 recruited from the Academy of General Dentistry-were randomly assigned to 1 of 3 groups: 5 dentists used only visual-tactile (VT) examination, 7 were trained in the ICDAS II, and 6 were trained in the CCS. Lesion stage for each tooth was determined by the ICDAS II and CCS groups, and recommended treatment was decided by all groups. Teeth were assessed both with and without radiographs. Caries was detected in 92.7% (95% CI, 88%-96%) of the teeth by dentists with CCS training, 88.8% (95% CI, 84%-92%) of the teeth by those with ICDAS II training, and 62.3% (95% CI, 55%-69%) of teeth by the VT group. Web-based training was acceptable to all dentists in the CCS group (6 of 6) but fewer of the dentists in the ICDAS II group (5 of 7). The modified CCS translated clinically to more accurate caries detection, particularly compared to detection by untrained dentists (VT group). Moreover, the CCS was more accepted than was the ICDAS II, but dentists in both groups were open to the application of these systems. Agreement on caries staging requires additional training prior to a larger validation study.


A simple ac photometric method for measuring complex Kerr Magnetooptic coefficients.
A method is described for measuring the amplitude and phase of the complex Kerr magnetooptic coefficients. A magnetic metal surface to be measured is switched between its magnetic states at an ac rate, thereby modulating a reflected light beam. By measuring the modulation depth with a synchronous detector and one angle, the two quantities above are determined. The method requires no precision optical equipment as is needed with polarimetric techniques.


Synaptic interactions between thalamic and cortical inputs onto cortical neurons in vivo.
To study the interactions between thalamic and cortical inputs onto neocortical neurons, we used paired-pulse stimulation (PPS) of thalamic and cortical inputs as well as PPS of two cortical or two thalamic inputs that converged, at different time intervals, onto intracellularly recorded cortical and thalamocortical neurons in anesthetized cats. PPS of homosynaptic cortico-cortical pathways produced facilitation, depression, or no significant effects in cortical pathways, whereas cortical responses to thalamocortical inputs were mostly facilitated at both short and long intervals. By contrast, heterosynaptic interactions between either cortical and thalamic, or thalamic and cortical, inputs generally produced decreases in the peak amplitudes and depolarization area of evoked excitatory postsynaptic potentials (EPSPs), with maximal effect at approximately 10 ms and lasting from 60 to 100 ms. All neurons tested with thalamic followed by cortical stimuli showed a decrease in the apparent input resistance (R(in)), the time course of which paralleled that of decreased responses, suggesting that shunting is the factor accounting for EPSP's decrease. Only half of neurons tested with cortical followed by thalamic stimuli displayed changes in R(in). Spike shunting in the thalamus may account for those cases in which decreased synaptic responsiveness of cortical neurons was not associated with decreased R(in) because thalamocortical neurons showed decreased firing probability during cortical stimulation. These results suggest a short-lasting but strong shunting between thalamocortical and cortical inputs onto cortical neurons.


Alcohol consumption and risky sexual behaviour in the fishing communities: evidence from two fish landing sites on Lake Victoria in Uganda.
The fishing communities are among population groups that are most at risk of HIV infection, with some studies putting the HIV prevalence at 5 to 10 times higher than in the general population. Alcohol consumption has been identified as one of the major drivers of the sexual risk behaviour in the fishing communities. This paper investigates the relationship between alcohol consumption patterns and risky behaviour in two fishing communities on Lake Victoria. Face-to-face interviews were conducted among 303 men and 172 women at the fish landing sites; categorised into fishermen, traders of fish or fish products and other merchandise, and service providers such as casual labourers and waitresses in bars and hotels, including 12 female sexual workers. Stratified random sampling methodology was used to select study units. Multivariable analysis was conducted to assess independent relationship between alcohol consumption and sexual risky behaviour. Measures of alcohol consumption included the alcohol use disorder test score (AUDIT), having gotten drunk in previous 30 days, drinking at least 2 times a week while measures for risky behaviour included engaging in transactional sex, inconsistent condom use, having sex with non-regular partner and having multiple sexual partners. The level of harmful use of alcohol in the two fishing communities was quite high as 62% of the male and 52% of the female drinkers had got drunk in previous 30 days. The level of risky sexual behaviour was equally high as 63% of the men and 59% of the women had unprotected sex at last sexual event. Of the 3 occupations fishermen had the highest levels of harmful use of alcohol and risky sexual behaviour followed by service providers judging from values of most indicators. The kind of alcohol consumption variables correlated with risky sexual behaviour variables, varied by occupation. Frequent alcohol consumption, higher AUDIT score, having got drunk, longer drinking hours and drinking any day of the week were strongly correlated with engaging in transactional sex among fishermen but fewer of the factors exhibited the same correlation among traders and service providers. Fishermen who drank 2 or more times a week were 7.9 times more likely to have had transactional sex (95% CI: 2.05-30.24) compared to those who never drank alcohol. A similar pattern was observed for traders and service providers at the landing sites. Inconsistent condom use or none use of condoms was not significantly correlated with any of the alcohol consumption indicator variables in multivariate analysis except for day of drinking among men. Alcohol consumption is strongly correlated with having multiple sexual partners, sex with non-regular partner and engagement in transactional sex but not with consistent condom use at fish landing sites. However, the pattern and strength of this correlation differs by occupation. HIV risk reduction programs targeting the fishing communities should address alcohol consumption, particularly alcohol consumption before sexual contact. Different occupations may need different interventions.


Neural mechanisms of rhythmic masking release in monkey primary auditory cortex: implications for models of auditory scene analysis.
The ability to detect and track relevant acoustic signals embedded in a background of other sounds is crucial for hearing in complex acoustic environments. This ability is exemplified by a perceptual phenomenon known as "rhythmic masking release" (RMR). To demonstrate RMR, a sequence of tones forming a target rhythm is intermingled with physically identical "Distracter" sounds that perceptually mask the rhythm. The rhythm can be "released from masking" by adding "Flanker" tones in adjacent frequency channels that are synchronous with the Distracters. RMR represents a special case of auditory stream segregation, whereby the target rhythm is perceptually segregated from the background of Distracters when they are accompanied by the synchronous Flankers. The neural basis of RMR is unknown. Previous studies suggest the involvement of primary auditory cortex (A1) in the perceptual organization of sound patterns. Here, we recorded neural responses to RMR sequences in A1 of awake monkeys in order to identify neural correlates and potential mechanisms of RMR. We also tested whether two current models of stream segregation, when applied to these responses, could account for the perceptual organization of RMR sequences. Results suggest a key role for suppression of Distracter-evoked responses by the simultaneous Flankers in the perceptual restoration of the target rhythm in RMR. Furthermore, predictions of stream segregation models paralleled the psychoacoustics of RMR in humans. These findings reinforce the view that preattentive or "primitive" aspects of auditory scene analysis may be explained by relatively basic neural mechanisms at the cortical level.


Creatine-dextrose and protein-dextrose induce similar strength gains during training.
Creatine supplementation during resistance exercise training has been reported to induce greater increases in fat-free mass (FFM), muscle fiber area, and strength when compared with a placebo. We have recently shown that timing of nutrient delivery in the postexercise period can have positive effects on whole body protein turnover (B. D. Roy et al., Med Sci Sports Exerc. 32(8):1412-1418, 2000). We tested the hypothesis that a postexercise protein-carbohydrate supplement would result in similar increases in FFM, muscle fiber area, and strength as compared with creatine monohydrate (CM), during a supervised 2-month resistance exercise training program in untrained men. Young healthy male subjects were randomized to receive either CM and glucose (N = 11; CM 10 g + glucose 75 g [CR-CHO] (CELL-Tech)) or protein and glucose (N = 8; casein 10 g + glucose 75 g [PRO+CHO]), using double-blinded allocation. Participants performed 8 wk of whole body split-routine straight set weight training, 1 h.d(-1), 6 d.wk(-1). Measurements, pre- and post-training were made of fat-free mass (FFM; DEXA), total body mass, muscle fiber area, isokinetic knee extension strength (45 and 240 degrees.s(-1)), and 1 repetition maximal (1RM) strength for 16 weight training exercises. Total body mass increased more for CR-CHO (+4.3 kg, 5.4%) as compared with PRO-CHO (+1.9 kg, 2.4%) (P < 0.05 for interaction) and FFM increased after training (P < 0.01) but was not significantly different between the groups (CR-CHO = +4.0 kg, 6.4%; PRO-CHO = +2.6 kg, 4.1%) (P = 0.11 for interaction). Muscle fiber area increased similarly after training for both groups (approximately 20%; P < 0.05). Training resulted in an increase in 1RM for each of the 16 activities (range = 14.2-39.9%) (P < 0.001), isokinetic knee extension torque (P < 0.01), with no treatment effects upon any of the variables. We concluded that postexercise supplementation with PRO-CHO resulted in similar increases in strength after a resistance exercise training program as compared with CR-CHO. However, the greater gains in total mass for the CR-CHO group may have implications for sport-specific performance.


Determination of ceftriaxone in human plasma using liquid chromatography-tandem mass spectrometry.
Ceftriaxone is a cephalosporin antibiotic drug used as first-line treatment for several bacterial diseases. Ceftriaxone belongs to the third generation of antibiotics and is available as an intramuscular or intravenous injection. Previously published pharmacokinetic studies have mainly used high-performance liquid chromatography coupled with ultraviolet detection (HPLC-UV) for the quantification of ceftriaxone. This study aimed to develop and validate a bioanalytical method for the quantification of ceftriaxone in human plasma using liquid chromatography followed by tandem mass spectrometry (LC-MS/MS). Sample preparation was performed by protein precipitation in combination with phospholipid-removal techniques for cleaning up matrix interferences. The chromatographic separation was performed on an Agilent Zorbax Eclipse Plus C18 column with 10 mM ammonium formate containing 2% formic acid: acetonitrile as mobile phase at a flow rate of 0.4 ml/min. Both the analyte and cefotaxime (internal standard) were quantified using the positive electrospray ionization (ESI) mode and selected reaction monitoring (SRM) for the precursor-product ion transitions m/z 555.0→396.1 for ceftriaxone and 456.0→324.0 for cefotaxime. The method was validated over the concentration range of 1.01-200 μg/ml. Calibration response showed good linearity (correlation coefficient > 0.99) and no significant matrix effects were observed. The intra-assay and inter-assay precision were less than 5% and 10%, respectively, and therefore well within standard regulatory acceptance criterion of ±15%.


A largely deformable surface type neural electrode array based on PDMS.
This paper describes a largely deformable surface type neural electrode array based on polydimethylsiloxane (PDMS) for cortical use. Noncracked and reliable metal patterns were fabricated successfully on PDMS substrate by employing an intermediate parylene layer. The mechanical and electrical stability of the fabricated electrode arrays was demonstrated by repeatable bending test using a custom-designed bending test module. Also the adhesion of the electrode structure consisting of PDMS, parylene and metal layers was proven by ASTM tape test. The electrode impedance was measured in phosphate buffered saline (PBS) solution at 37 (°) C over three months and analyzed using equivalent circuit models. Based on these results, it is concluded that the suggested electrode array provides a largely deformable structure with mechanical integrity and electrical stability, which can withstand mechanical stresses when inserted through a small trephination hole in the skull and expanded in the small room between the cortex and the skull without damage to the electrode array.


Role of TRIM5α RING domain E3 ubiquitin ligase activity in capsid disassembly, reverse transcription blockade, and restriction of simian immunodeficiency virus.
The mammalian tripartite motif protein, TRIM5α, recognizes retroviral capsids entering the cytoplasm and blocks virus infection. Depending on the particular TRIM5α protein and retrovirus, complete disruption of the TRIM5α RING domain decreases virus-restricting activity to various degrees. TRIM5α exhibits RING domain-dependent E3 ubiquitin ligase activity, but the specific role of this activity in viral restriction is unknown. We created a panel of African green monkey TRIM5α (TRIM5α(AGM)) mutants, many of which are specifically altered in RING domain E3 ubiquitin ligase function, and characterized the phenotypes of these mutants with respect to restriction of simian and human immunodeficiency viruses (SIV(mac) and HIV-1, respectively). TRIM5α(AGM) ubiquitin ligase activity was essential for both the accelerated disassembly of SIV(mac) capsids and the disruption of reverse transcription. The levels of SIV(mac) particulate capsids in the cytosol of target cells expressing the TRIM5α variants strongly correlated with the levels of viral late reverse transcripts. RING-mediated ubiquitylation and B30.2(SPRY) domain-determined capsid binding independently contributed to the potency of SIV(mac) restriction by TRIM5α(AGM). In contrast, TRIM5α proteins attenuated in RING ubiquitin ligase function still accelerated HIV-1 capsid disassembly, inhibited reverse transcription, and blocked infection. Replacement of the helix-4/5 loop in the SIV(mac) capsid with the corresponding region of the HIV-1 capsid diminished the dependence of restriction on TRIM5α RING function. Thus, ubiquitylation mediated by the RING domain of TRIM5α(AGM) is essential for blocking SIV(mac) infection at the stage of capsid uncoating.


Deciphering the role of the chitin synthase families 1 and 2 in the in vivo and in vitro growth of Aspergillus fumigatus by multiple gene targeting deletion.
Although chitin is an essential component of the fungal cell wall (CW), its biosynthesis and role in virulence is poorly understood. In Aspergillus fumigatus, there are eight chitin synthase (CHS) genes belonging to two families CHSA-C, CHSG in family 1 and CHSF, CHSD, CSMA, CSMB in family 2). To understand the function of these CHS genes, their single and multiple deletions were performed using β-rec/six system to be able to delete all genes within each family (up to a quadruple ΔchsA/C/B/G mutant in family 1 and a quadruple ΔcsmA/csmB/F/D mutant in family 2). Radial growth, conidiation, mycelial/conidial morphology, CW polysaccharide content, Chs-activity, susceptibility to antifungal molecules and pathogenicity in experimental animal aspergillosis were analysed for all the mutants. Among the family 1 CHS, ΔchsA, ΔchsB and ΔchsC mutants showed limited impact on chitin synthesis. In contrast, there was reduced conidiation, altered mycelial morphotype and reduced growth and Chs-activity in the ΔchsG and ΔchsA/C/B/G mutants. In spite of this altered phenotype, these two mutants were as virulent as the parental strain in the experimental aspergillosis models. Among family 2 CHS, phenotypic defects mainly resulted from the CSMA deletion. Despite significant morphological mycelial and conidial growth phenotypes in the quadruple ΔcsmA/csmB/F/D mutant, the chitin content was poorly affected by gene deletions in this family. However, the entire mycelial cell wall structure was disorganized in the family 2 mutants that may be related to the reduced pathogenicity of the quadruple ΔcsmA/csmB/F/D mutant strain compared to the parental strain, in vivo. Deletion of the genes encompassing the two families (ΔcsmA/csmB/F/G) showed that in spite of being originated from an ancient divergence of fungi, these two families work cooperatively to synthesize chitin in A. fumigatus and demonstrate the essentiality of chitin biosynthesis for vegetative growth, resistance to antifungal drugs, and virulence of this filamentous fungus.


Charge transport in films of Geobacter sulfurreducens on graphite electrodes as a function of film thickness.
Harnessing, and understanding the mechanisms of growth and activity of, biofilms of electroactive bacteria (EAB) on solid electrodes is of increasing interest, for application to microbial fuel and electrolysis cells. Microbial electrochemical cell technology can be used to generate electricity, or higher value chemicals, from organic waste. The capability of biofilms of electroactive bacteria to transfer electrons to solid anodes is a key feature of this emerging technology, yet the electron transfer mechanism is not fully characterized as yet. Acetate oxidation current generated from biofilms of an EAB, Geobacter sulfurreducens, on graphite electrodes as a function of time does not correlate with film thickness. Values of film thickness, and the number and local concentration of electrically connected redox sites within Geobacter sulfurreducens biofilms as well as a charge transport diffusion co-efficient for the biofilm can be estimated from non-turnover voltammetry. The thicker biofilms, of 50 ± 9 μm, display higher charge transport diffusion co-efficient than that in thinner films, as increased film porosity of these films improves ion transport, required to maintain electro-neutrality upon electrolysis.


Watching polymers grow: real time monitoring of polymerizations via an on-line ESI-MS/microreactor coupling.
A technique for the continuous on-line monitoring of polymerization processes by electrospray ionization mass spectrometry (ESI-MS) is presented via coupling with a commercial microreactor system. The potential is demonstrated by monitoring polymerizations in real time under synthesis conditions. Furthermore, a single acrylate monomer insertion into a oligo-RAFT agent, as used in the synthesis of monodisperse sequence controlled materials, was optimized by on-line screening of reaction conditions.


Comparison of epinephrine vs lipid rescue to treat severe local anesthetic toxicity - an experimental study in piglets.
Local anesthetic (LA) intoxication with severe hemodynamic compromise is a potential catastrophic event. Lipid resuscitation has been recommended for the treatment of LA-induced cardiac arrest. However, there are no data about effectiveness of Intralipid for the treatment of severe cardiovascular compromise prior to cardiac arrest. Aim of this study was to compare effectiveness of epinephrine and Intralipid for the treatment of severe hemodynamic compromise owing to bupivacaine intoxication. Piglets were anesthetized with sevoflurane, intubated, and ventilated. Bupivacaine was infused with a syringe driver via a central venous catheter at a rate of 1 mg·kg(-1) ·min(-1) until invasively measured mean arterial pressure (MAP) dropped to 50% of the initial value. Bupivacaine infusion was then stopped, and epinephrine 3 μg·kg(-1) (group 1), Intralipid(®) 20% 2 ml·kg(-1) (group 2), or Intralipid 20% 4 ml·kg(-1) (group 3) was immediately administered. Survival, hemodynamic course, and ET(CO2) were recorded. Twenty-one piglets (3 × 7), with median age of 26 days (19-43) and weighing 4.9 kg (4.3-5.8), were investigated. All animals in group 1 (100%) but only four of seven (57%) piglets in group 2 and group 3, respectively, survived. Normalization of hemodynamic parameters (HR, MAP) and ET(CO2) was fastest in group 1 with all piglets achieving HR and MAP values at or above baseline within 1 min. For the treatment of severe hemodynamic compromise owing to bupivacaine intoxication in piglets, first-line rescue with epinephrine was more effective than Intralipid with regard to survival as well as normalization of hemodynamic parameters and ET(CO2) .


Low abundant soil bacteria can be metabolically versatile and fast growing.
The abundance of species is assumed to depend on their life history traits, such as growth rate and resource specialization. However, this assumption has not been tested for bacteria. Here we investigate how abundance of soil bacteria relates to slow growth and substrate specialization (oligotrophy) vs. fast growth and substrate generalization (copiotrophy). We collected 47 saprotrophic soil bacterial isolates of differing abundances and measured their growth rate and the ability to use a variety of single carbon sources. Opposite to our expectation, there was no relationship between abundance in soil and the measured growth rate or substrate utilization profile (SUP). However, isolates with lower growth rates used fewer substrates than faster growing ones supporting the assumption that growth rate may relate to substrate specialization. Interestingly, growth rate and SUP were correlated with phylogeny, rather than with abundance in soil. Most markedly, Gammaproteobacteria on average grew significantly faster and were able to use more substrates than other bacterial classes, whereas Alphaproteobacteria were growing relatively slowly and used fewer substrates. This finding suggests that growth and substrate utilization are phylogenetically deeply conserved. We conclude that growth rate and substrate utilization of soil bacteria are not general determinants of their abundance. Future studies on explaining bacterial abundance need to determine how other factors, such as competition, predation and abiotic factors may contribute to rarity or abundance in soil bacteria.


De novo telomere addition at chromosome breaks: Dangerous Liaisons.
Telomerase counteracts the loss of terminal DNA sequences from chromosome ends; however, it may erroneously add telomeric repeats to DNA double-strand breaks. In this issue, Ouenzar et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201610071) uncover cell cycle-dependent sequestration of the telomerase RNA in nucleoli, a process that excludes telomerase from DNA repair sites.


Dietary practices and beliefs of patients with chronic liver disease.
To study of the dietary practices and beliefs of patients suffering from chronic liver disease. Two private tertcary care hospitals. Fifty patients presenting to the Gastroenterology Clinics at the Aga Khan University Hospital and Baqai Hospital, with compensated liver disease and no other co-morbid condition which required dietary modifications, were enrolled in the study. Patients were interviewed regarding their current dietary practices using an open-ended questionnaire. The mean age of the patients was 48 years and the majority were in relatively poor nutritional status. Four had BMI's < 18; 58% had Hb < 12 g/dl and 36% had albumin levels < 3 gm/dl. The percentage of patients avoiding various foods is as follows: meats 72%, fats and oils 64%, salt 42%, spices 34%, milk and milk products 28%, rice 20%. The most commonly cited reason for avoiding a given food was the advice of the family doctor, followed by advice by gastroenterologists, family and friends. Concepts from alternative medicine and continuation of dietary restrictions imposed during a decompensated phase also influenced intake. Compromised nutritional status is a poor predictor of clinical outcome in liver disease therefore it is important that gastroenterologists be proactive regarding nutritional counseling and both patients and their primary care physicians understand the importance of not imposing unnecessary restrictions on dietary intake.


Pelagic harmful algal blooms and climate change: Lessons from nature's experiments with extremes.
Time series now have sufficient duration to determine harmful algal bloom (HAB) responses to changing climate conditions, including warming, stratification intensity, freshwater inputs and natural patterns of climate variability, such as the El Niño Southern Oscillation and Pacific Decadal Oscillation. Against the context of time series, such as those available from phytoplankton monitoring, dinoflagellate cyst records, the Continuous Plankton Recorder surveys, and shellfish toxin records, it is possible to identify extreme events that are significant departures from long-term means. Extreme weather events can mimic future climate conditions and provide a "dress rehearsal" for understanding future frequency, intensity and geographic extent of HABs. Three case studies of extreme HAB events are described in detail to explore the drivers and impacts of these oceanic outliers that may become more common in the future. One example is the chain-forming diatom of the genus Pseudo-nitzschia in the U.S. Pacific Northwest and its response to the 2014-16 northeast Pacific marine heat wave. The other two case studies are pelagic flagellates. Highly potent Alexandrium catenella group 1 dinoflagellate blooms (up to 150 mg/kg PST in mussels; 4 human poisonings) during 2012-17 created havoc for the seafood industry in Tasmania, south-eastern Australia, in a poorly monitored area where such problems were previously unknown. Early evidence suggests that changes in water column stratification during the cold winter-spring season are driving new blooms caused by a previously cryptic species. An expansion of Pseudochattonella cf. verruculosa to the south and A. catenella to the north over the past several years resulted in the convergence of both species to cause the most catastrophic event in the history of the Chilean aquaculture in the austral summer of 2016. Together, these two massive blooms were colloquially known as the "Godzilla-Red tide event", resulting in the largest fish farm mortality ever recorded worldwide, equivalent to an export loss of USD$800 million which when combined with shellfish toxicity, resulted in major social unrest and rioting. Both blooms were linked to the strong El Niño event and the positive phase of the Southern Annular Mode, the latter an indicator of anthropogenic climate change in the southeastern Pacific region. For each of these three examples, representing recent catastrophic events in geographically distinct regions, additional targeted monitoring was employed to improve the understanding of the climate drivers and mechanisms that gave rise to the event and to document the societal response. Scientists must be poised to study future extreme HAB events as these natural experiments provide unique opportunities to define and test multifactorial drivers of blooms.


Analysis of self-determined motivation in basketball players through goal orientations.
The purpose of this study was twofold. Firstly to examine the relations between the different constructs that defines Nicholls' Achievement Goal Theory and Deci and Ryan's self-determination theory. Secondly to analyse the differences that exist between them with respect to the socio-demographic variables gender and age. A sample of 292 federated basketball players from the Region of Murcia (Spain) with ages between 14 and 18 years old was used. In addition, Castilian versions of The Perception of Success Questionnaire (POSQ) and the Sports Motivational Scale (SMS) were administered. Three statistical analyses were employed, a descriptive analysis, a correlation analysis and a regression analysis. The results showed a positive relation between ego orientation, extrinsic motivation and amotivation. The motivational relations between both theories and the differences with respect to gender and age are discussed. We have found out that mainly gender and also age differences are strong predictors of ego orientation, extrinsic motivation of external regulation and amotivation. We can also confirm that extrinsic motivation of external regulation positively predicts ego orientation and a decrease of task orientation. The results ratify the use of the Spanish version of the SMS to measure different types of motivation within the sports context.


Patient-provider communication about pregnancy and HIV among female sex workers living with HIV in Santo Domingo, Dominican Republic.
Health providers can play an important role in communication about pregnancy, particularly for women at increased risk for pregnancy complications, including female sex workers (FSWs) living with HIV. This study explored factors related to patient-provider communication about pregnancy among 253 FSWs living with HIV of reproductive age in Santo Domingo, Dominican Republic. A cross-sectional design was employed including structured socio-behavioral surveys. Data were analyzed utilizing bivariate and multivariate logistic regression. Of the 253 FSWs living with HIV in this study, 95.7% had been pregnant at least once (median: 4; IQR: 3,6), 28.0% wanted more children and 36% reported a pregnancy after HIV diagnosis. Over half of participants (58.0%) reported having ever spoken to a health provider about pregnancy while living with HIV. Multivariate logistic regression found significant associations between having spoken to a health provider about HIV in pregnancy and a more positive perception of their provider (AOR: 2.0; 95% CI: 1.0, 2.5) and years since HIV diagnosis (AOR: 1.1; 95% CI: 1.0, 1.1). Participants were less likely to speak with a provider if they had a history of drug use (AOR: 0.4; 95% CI: 0.2, 0.9) or current alcohol use (AOR: 0.5; 95% CI: 0.3, 0.9). Findings highlight the importance of non-judgmental and tailored provider-initiated conversations surrounding pregnancy. Future research is needed to better understand how and when pregnancy communication is initiated, as well as the content of clinical care conversations, to address the reproductive health of FSWs living with HIV.


Transcatheter closure of perimembranous ventricular septal defects using the new Amplatzer membranous VSD occluder: results of the U.S. phase I trial.
This phase I study attempted to report the initial safety and efficacy results of transcatheter closure of perimembranous ventricular septal defects (PmVSDs) using the new Amplatzer Membranous VSD Occluder (AGA Medical Corp., Golden Valley, Minnesota) in the U.S. The most common congenital heart disease is PmVSD. Surgical repair is widely accepted, but still carries a small but definite risk of morbidity and mortality. Between October 2003 and August 2004, a total of 35 patients with PmVSD underwent an attempt of transcatheter closure under transesophageal and/or intracardiac echocardiographic guidance. The median age was 7.7 years (range, 1.2 to 54.4 years) and median weight was 25 kg (range, 8.3 to 110 kg). The median Qp/Qs ratio was 1.8 (range, 1 to 4), and the median VSD size as assessed by echocardiography was 7 mm (range, 4 to 15 mm). The attempt to place a device was successful in 32 patients (91%). The median device size used was 10 mm (range, 6 to 16 mm). The complete closure rates by echocardiography at 10 min (transesophageal/intracardiac), 24 h, 1 month, and 6 months (transthoracic) were 47% (15/32), 63% (20/32), 78% (25/32), and 96% (27/28), respectively. The median fluoroscopy time was 36 min (range, 14 to 191 min), and the median total procedure time was 121 min (range, 67 to 276 min). Three patients (8.6%) had serious adverse events of complete heart block, peri-hepatic bleeding, and rupture of tricuspid valve chordae tendineae. No other patient encountered serious adverse events during the follow-up. Transcatheter closure of a PmVSD is technically feasible and seems safe enough in children over 8 kg in weight to warrant continuation of clinical trials to assess the long-term safety and efficacy.


Altered neural signatures of interoception in multiple sclerosis.
Multiple sclerosis (MS) patients present several alterations related to sensing of bodily signals. However, no specific neurocognitive impairment has yet been proposed as a core deficit underlying such symptoms. We aimed to determine whether MS patients present changes in interoception-that is, the monitoring of autonomic bodily information-a process that might be related to various bodily dysfunctions. We performed two studies in 34 relapsing-remitting, early-stage MS patients and 46 controls matched for gender, age, and education. In Study 1, we evaluated the heartbeat-evoked potential (HEP), a cortical signature of interoception, via a 128-channel EEG system during a heartbeat detection task including an exteroceptive and an interoceptive condition. Then, we obtained whole-brain MRI recordings. In Study 2, participants underwent fMRI recordings during two resting-state conditions: mind wandering and interoception. In Study 1, controls exhibited greater HEP modulation during the interoceptive condition than the exteroceptive one, but no systematic differences between conditions emerged in MS patients. Patients presented atrophy in the left insula, the posterior part of the right insula, and the right anterior cingulate cortex, with abnormal associations between neurophysiological and neuroanatomical patterns. In Study 2, controls showed higher functional connectivity and degree for the interoceptive state compared with mind wandering; however, this pattern was absent in patients, who nonetheless presented greater connectivity and degree than controls during mind wandering. MS patients were characterized by atypical multimodal brain signatures of interoception. This finding opens a new agenda to examine the role of inner-signal monitoring in the body symptomatology of MS.


Isolation of the thrombospondin membrane receptor.
Thrombospondin (TSP), a 450-kD multifunctional glycoprotein with a broad tissue distribution, is secreted upon platelet stimulation, binds to the activated platelet surface, and supports platelet aggregation. We have identified and isolated an 88-kd membrane glycoprotein present in platelets, endothelial cells, monocytes, and a variety of human tumor cell lines that is the membrane binding site for TSP. Endogenous platelet TSP binding to thrombin- and ionophore-stimulated human platelets was inhibited in the presence of the monoclonal antibody OKM5. TSP binding to C32 melanoma cells and HT1080 fibrosarcoma cells was specific and also inhibitable with OKM5 Mab. Cell labeling followed by specific immunoprecipitation demonstrated biosynthesis of a single 88-kD glycoprotein. Binding of TSP to the isolated membrane protein was specific and saturable. These studies identify an 88-kD membrane glycoprotein that reacts with the monoclonal antibody, OKM5, and may function as the cellular TSP receptor.


Patient-reported outcome measures for the identification of supportive care needs in people with lung cancer: are we there yet?
The use of patient-reported outcome measures is a method of identifying and addressing supportive care needs (SCN) of people with lung cancer, which are often overlooked. The objectives of this study were to identify and evaluate existing SCN tools previously used in studies with patients with lung cancer and to establish their suitability for use in research and clinical practice. A systematic search was carried out in the MEDLINE, CINAHL, EMBASE, PsychINFO, and British Nursing Index databases to locate studies conducted between January 2000 and November 2010 that made use of validated self-report SCN tools with patients with lung cancer. Twelve articles introducing 8 instruments met prespecified selection criteria. All tools were appraised for their content, comprehensiveness, appropriateness, psychometric properties, and feasibility and acceptability. Only 1 lung cancer-specific SCN tool was identified. Whereas the majority of tools had acceptable psychometric properties, only 1 tool had gone through a systematic development process specifically in the context of lung cancer. Therefore, it is questionable whether existing tools can adequately identify healthcare needs that people with lung cancer consider most important. To ensure that SCNs of people with lung cancer are adequately and promptly identified, rigorous development and systematic testing of content-specific SCN tools are warranted. Collaborative work between patients with lung cancer, health professionals, and tool developers is required for an SCN tool not only to be content-specific but also to take into consideration the reality of clinical practice in providing supportive care to people with lung cancer.


Photocrosslinking of the signal sequence of nascent preprolactin to the 54-kilodalton polypeptide of the signal recognition particle.
Photoreactive moieties were incorporated into nascent polypeptides in a wheat germ protein-synthesizing system by using a plasmid-derived preprolactin mRNA and a Lys-tRNA analog, N epsilon-(5-azido-2-nitrobenzoyl)-Lys-tRNA (epsilon ANB-Lys-tRNA). The presence of the abnormally large amino acid side chains in the nascent chains did not impair function: complete preprolactin chains were synthesized in the absence of the signal recognition particle (SRP), elongation was arrested in the presence of SRP, and SRP-dependent translocation across the membrane of the endoplasmic reticulum and signal peptidase cleavage were observed in the presence of salt-extracted microsomes. Photolysis of elongation-arrested ribosomes resulted in several light- and epsilon ANB-Lys-tRNA-dependent crosslinks. By using antibodies specific for each of the proteins, one covalent complex was shown to be a photocrosslink between the preprolactin nascent chain and the 54-kDa protein subunit of SRP. This demonstrates that the N-terminal end of a secretory protein is located adjacent to the SRP in elongation-arrested ribosomes and strongly suggests that the signal sequence is recognized by and binds to the 54-kDa subunit of SRP. The other photocrosslinks involve as-yet-unidentified proteins in the large ribosomal subunit, indicating that this method of incorporating probes provides a powerful approach to examining the environment and interactions of the nascent chain during translation and translocation across the membrane of the endoplasmic reticulum. The Lys-tRNA analog also successfully photoaffinity-labeled the Escherichia coli elongation factor Tu (EF-Tu) in the epsilon ANB-Lys-tRNA.EF-Tu.GTP ternary complex.


Screening for delirium with the Intensive Care Delirium Screening Checklist (ICDSC): a re-evaluation of the threshold for delirium.
With its high incidence and subsequent adverse consequences in the intensive care setting, several instruments have been developed to screen for and detect delirium. One of the more commonly used is the Intensive Care Delirium Screening Checklist (ICDSC); however, the optimal cut-off score indicating delirium has been debated. In this prospective cohort study, the ICDSC threshold for delirium set at ≥3, ≥4, or ≥5 was compared with the DSM-IV-TR-determined diagnosis of delirium (used as standard), and with the Confusion Assessment Method for the ICU (CAM-ICU), with respect to their concurrent validity. In total, 289 patients were assessed, including 122 with delirium. The cut-off score of ≥4 had several shortcomings: although 90% of patients with delirium were correctly classified, 23% remained undetected. The agreement with the DSM-IV-TR diagnosis of delirium was only moderate (Cohen's κ 0.59) and the sensitivity was only 62%. In contrast, when the cut-off was ≥3, 83% of patients with delirium were correctly classified and only 14.5% remained undetected. The agreement with DSM-IV-TR was substantial (Cohen's κ 0.68) and the sensitivity increased to 83%. The benefit of setting the cut-off at ≥5 was not convincing: although 90% of patients with delirium were correctly classified, 30% remained undetected. The concurrent validity was only moderate (Cohen's κ 0.44), and the sensitivity reached only 44%. Changing the ICDSC cut-off score did not strengthen the moderate agreement with the CAM-ICU (Cohen's κ 0.45-0.56). In clinical routine, decreasing the ICDSC threshold for delirium to ≥3 increased the accuracy in detecting delirium at the cost of over-identification and is therefore recommended as the optimal threshold. Increasing the cut-off score to ≥5 decreased the concurrent validity and sensitivity; in addition, the under-detection of delirium was substantial.


High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells.
Previous studies revealed that exposure of mesangial cells to high glucose concentration induces the production of matrix proteins mediated by TGF-beta1. We tested if structural analogues of D-glucose may mimic the high glucose effect and found that D-glucosamine was strikingly more potent than D-glucose itself in enhancing the production of TGF-beta protein and subsequent production of the matrix components heparan sulfate proteoglycan and fibronectin in a time- and dose-dependent manner. D-Glucosamine also promoted conversion of latent TGF-beta to the active form. Therefore, we suggested that the hexosamine biosynthetic pathway (the key enzyme of which is glutamine:fructose-6-phosphate amidotransferase [GFAT]) contributes to the high glucose-induced TGF-beta1 production. Inhibition of GFAT by the substrate analogue azaserine or by inhibition of GFAT protein synthesis with antisense oligonucleotide prevented the high glucose-induced increase in cellular glucosamine metabolites and TGF-beta1 expression and bioactivity and subsequent effects on mesangial cell proliferation and matrix production. Overall, our study indicates that the flux of glucose metabolism through the GFAT catalyzed hexosamine biosynthetic pathway is involved in the glucose-induced mesangial production of TGF-beta leading to increased matrix production.


Category I pressure ulcers: how reliable is clinical assessment?
Pressure ulcer prevention is an indicator of quality of care. Reliable identification of Category I pressure ulcers is essential in prevalence studies and to prevent further tissue damage. The primary purpose of this study was to establish interrater reliability between blanching and nonblanching erythema assessed by 2 independent assessors. The secondary purpose was to investigate potential correlations between risk factors and pressure ulcers. Ninety-seven patients 65 years or older with hip fractures were consecutively recruited for this prospective, comparative observation study. Seventy-eight patients completed the study. The sacral area of each patient was visually assessed and a finger-press test was administered to each patient by 2 independent assessors. Kappa statistics were used for analysis. finger-press tests and visual observation alone were not reliable methods to discriminate between blanching and nonblanching erythema. Forty-seven percent of the patients had a risk score 20 or fewer (high risk for pressure ulcers). Forty-four patients (56%) had pressure ulcers at discharge.


Light- induced electron transfer and ATP synthesis in a carotene synthesizing insect.
A singular adaptive phenotype of a parthenogenetic insect species (Acyrthosiphon pisum) was selected in cold conditions and is characterized by a remarkable apparition of a greenish colour. The aphid pigments involve carotenoid genes well defined in chloroplasts and cyanobacteria and amazingly present in the aphid genome, likely by lateral transfer during evolution. The abundant carotenoid synthesis in aphids suggests strongly that a major and unknown physiological role is related to these compounds beyond their canonical anti-oxidant properties. We report here that the capture of light energy in living aphids results in the photo induced electron transfer from excited chromophores to acceptor molecules. The redox potentials of molecules involved in this process would be compatible with the reduction of the NAD+ coenzyme. This appears as an archaic photosynthetic system consisting of photo-emitted electrons that are in fine funnelled into the mitochondrial reducing power in order to synthesize ATP molecules.


A case of spontaneous rectus sheath hematoma induced by lateral semi-prone positional changes during extracorporeal membrane oxygenation.
Spontaneous abdominal wall hematomas are relatively rare and mainly attributed to anticoagulation and severe cough. Despite the high incidence of anticoagulation-related bleeding complications, there are no reports of spontaneous abdominal wall hematomas during extracorporeal membrane oxygenation (ECMO). We report a case of a spontaneous rectus sheath hematoma caused by alternation of the lateral semi-prone position during ECMO in a 76-year-old female patient with severe acute respiratory distress syndrome. Unfractionated heparin 12,000-14,000 units/day was administered for anticoagulation during ECMO. From Day 6 of ECMO, the patient who was under deep sedation was alternately placed in the left and right lateral semi-prone positions every 4 h, for approximately 20 h per day. On Day 12 of ECMO, the patient developed hypotension with anemia and a palpable mass in the right lower abdomen. Abdominal ultrasonographic imaging revealed a huge echo-free space centered in the right lower abdomen. Emergency contrast-enhanced computed tomography (CT) scanning showed extravasation from the superior and inferior epigastric arteries as well as a rectus sheath hematoma. Despite no apparent contrast leakage, an inferior epigastric artery embolization was undertaken because the patient was on ECMO. On Day 13 after ECMO initiation, ECMO and anticoagulation were discontinued. On CT scanning a week later, the hematoma had reduced. In conclusion, spontaneous abdominal wall hematoma is a rare and important complication that might occur during ECMO. Thus, careful physical examination should be routinely conducted when the patient is semi-prone during ECMO.


Ethical Dilemmas in Postnatal Treatment of Severe Congenital Hydrocephalus.
Severe congenital hydrocephalus manifests as accumulation of a large amount of excess fluid in the brain. It is a paradigmatic example of a condition in which diagnosis is relatively straightforward and long-term survival is usually associated with severe disability. It might be thought that, should parents agree, palliative care and limitation of treatment would be clearly permissible on the basis of the best interests of the infant. However, severe congenital hydrocephalus illustrates some of the neuroethical challenges in pediatrics. The permissibility of withholding or withdrawing treatment is limited by uncertainty in prognosis and the possibility of "palliative harm." Conversely, although there are some situations in which treatment is contrary to the interests of the child, or unreasonable on the grounds of limited resources, acute surgical treatment of hydrocephalus rarely falls into that category.


A conformational study of protonated noradrenaline by UV-UV and IR dip double resonance laser spectroscopy combined with an electrospray and a cold ion trap method.
The conformer-selected ultraviolet (UV) and infrared (IR) spectra of protonated noradrenaline were measured using an electrospray/cryogenic ion trap technique combined with photo-dissociation spectroscopy. By comparing the UV photo dissociation (UVPD) spectra with the UV-UV hole burning (HB) spectra, it was found that five conformers coexist under ultra-cold conditions. Based on the spectral features of the IR dip spectra of each conformer, two different conformations on the amine side chain were identified. Three conformers (group I) were assigned to folded and others (group II) to extended structures by comparing the observed IR spectra with the calculated ones. Observation of the significantly less-stable extended conformers strongly suggests that the extended structures are dominant in solution and are detected in the gas phase by kinetic trapping. The conformers in each group are assignable to rotamers of OH orientations in the catechol ring. By comparing the UV-UV HB spectra and the calculated Franck-Condon spectra obtained by harmonic vibrational analysis of the S1 state, with the aid of relative stabilization energies of each conformer in the S0 state, the absolute orientations of catechol OHs of the observed five conformers were successfully determined. It was found that the 0-0 transition of one folded conformer is red-shifted by about 1000 cm-1 from the others. The significant red-shift was explained by a large contribution of the πσ* state to S1 in the conformer in which an oxygen atom of the meta-OH group is close to the ammonium group.


Molecular cloning of chicken vasoactive intestinal polypeptide receptor complementary DNA, tissue distribution and chromosomal localization.
Chicken vasoactive intestinal polypeptide receptor (VIPR) cDNA was cloned by the reverse transcription-polymerase chain reaction method using primers designed on the basis of other species of VIPR cDNA. The cDNA obtained was sequenced by the dideoxy-mediated chain-termination method. Of the 2227 nucleotides that were sequenced, 84, 855, and 1338 bases represent the 5'-untranslated region (UTR), the 3'-UTR, and the open reading frame that predicts a peptide of 446 amino acids. The cDNA of the chicken VIPR shows 65% and 60% homologies to human cDNA of VIP1 and VIP2 receptors, respectively. The clone had the expected similarity to highly conserved features of the other G protein-coupled receptors (GPCRs) such as six cysteine residues that are functionally important in the VIPR subfamily. In addition, the seven potential membrane-spanning domains characteristic of the family B group III GPCR superfamily and highly conserved motif within the third cellular loop between transmembrane regions 5 and 6. Northern blot hybridization analysis in this study indicated mRNA expression of VIPRs in the various tissues of the chicken. Strong signal was detected in the brain and anterior pituitary gland. High levels of VIPR mRNA in the brain was consistent with VIP-binding experiments and with the function of VIP in the brain as a neuroendocrine factor or neurotransmitter. Expression of VIPR was detected in the anterior pituitary gland of chick embryos. The expression of VIPR mRNA in the chick anterior pituitary gland may indicate a regulatory function of VIP on prolactin (PRL) production or PRL cell proliferation during embryogenesis. Chicken VIPR shows high homology with mammalian type I VIPR but, in some part, possesses similarity of amino acid sequence. Expression of VIPR in various tissues supports diverse functions for VIP in the chicken.


The global problem of genetic disease.
Inherited haemoglobin disorders will undoubtedly cause an increasing health burden in many developing countries. Although much is known about their molecular pathology and the mechanisms for their phenotypic diversity, many important questions remain, not least the role of the environment in modifying the clinical course. Methods for screening these conditions are now well established and inexpensive and it is vital that they are applied to define the magnitude of the problem that will be posed by these conditions in the future. Similarly, they form the basis for widespread screening and counselling programmes directed at developing prenatal diagnosis expertise where this is not available. Answers to some relatively simple questions about the role of the environment could also make a major difference to the management of the haemoglobin disorders. There is a major case for the development of regional networks to apply such technology as has been developed for the control and prevention of the important haemoglobin disorders, particularly in Asian countries.


Recommendations for Developing Support Tools With People Suffering From Chronic Obstructive Pulmonary Disease: Co-Design and Pilot Testing of a Mobile Health Prototype.
Gaps exist between developers, commissioners, and end users in terms of the perceived desirability of different features and functionalities of mobile apps. The objective of this study was to co-design a prototype mobile app for people with chronic obstructive pulmonary disease (COPD). We present lessons learned and recommendations from working on a large project with various stakeholders to develop a mobile app for patients with COPD. We adopted a user-centered, participatory approach to app development. Following a series of focus groups and interviews to capture requirements, we developed a prototype app designed to enable daily symptom recording (experience sampling). The prototype was tested in a usability study applying the think aloud protocol with people with COPD. It was then released via the Android app store, and experience sampling data and event data were captured to gather further usability data. A total of 5 people with COPD participated in the pilot study. Identified themes include familiarity with technology, appropriate levels for feeding back information, and usability issues such as manual dexterity. Moreover, 37 participants used the app over a 4-month period (median age 47 years). The symptoms most correlated to perceived well-being were tiredness (r=0.61; P<.001) and breathlessness (r=0.59; P<.001). Design implications for COPD apps include the need for clearly labeled features (rather than relying on colors or symbols that require experience using smartphones), providing weather information, and using the same terminology as health care professionals (rather than simply lay terms). Target users, researchers, and developers should be involved at every stage of app development, using an iterative approach to build a prototype app, which should then be tested in controlled settings as well as in the wild (ie, when deployed and used in real-world settings) over longer periods.


HSP70 from the Antarctic sea urchin Sterechinus neumayeri: molecular characterization and expression in response to heat stress.
Heat stress proteins are implicated in stabilizing and refolding denatured proteins in vertebrates and invertebrates. Members of the Hsp70 gene family comprise the cognate heat shock protein (Hsc70) and inducible heat shock protein (Hsp70). However, the cDNA sequence and the expression of Hsp70 in the Antarctic sea urchin are unknown. We amplified and cloned a transcript sequence of 1991 bp from the Antarctic sea urchin Sterechinus neumayeri, experimentally exposed to heat stress (5 and 10 °C for 1, 24 and 48 h). RACE-PCR and qPCR were employed to determine Hsp70 gene expression, while western blot and ELISA methods were used to determine protein expression. The sequence obtained from S. neumayeri showed high identity with Hsp70 members. Several Hsp70 family features were identified in the deduced amino acid sequence and they indicate that the isolated Hsp70 is related to the cognate heat shock protein type. The corresponding 70 kDa protein, called Sn-Hsp70, was immune detected in the coelomocytes and the digestive tract of S. neumayeri using a monospecific polyclonal antibody. We showed that S. neumayeri do not respond to acute heat stress by up-regulation of Sn-Hsp70 at transcript and protein level. Furthermore, the Sn-Hsp70 protein expression was not induced in the digestive tract. Our results provide the first molecular evidence that Sn-Hsp70 is expressed constitutively and is non-induced by heat stress in S. neumayeri.


Use of Simulation to Assess Incoming Interns' Recognition of Opportunities to Choose Wisely.
Despite increasing healthcare costs, training on cost-consciousness is lacking in graduate medical education (GME). Medical centers must consider how best to incorporate value-based training into their GME curricula. To incorporate low-value principles into an existing GME simulation exercise and assess incoming interns' recognition of low-value care. Choosing Wisely™ lists were reviewed to identify 4 low-value hazards to be embedded into a simulated hospital room in addition to the 8 patient safety hazards used previously. Interns were given 10 minutes to independently review a mock chart and list all hazards they identified in the simulation. Interns completed a short survey on their prior training in medical school and a follow-up survey one month into internship. 𝑡 tests used to compare identification of low-value vs safety hazards and to associate performance with prior training. The mean percentage of hazards correctly identified was 50.4% (standard deviation [SD] 11.8%). Interns identified significantly fewer low-value hazards (mean 19.2%, SD 18.6%) than safety hazards (mean 66.0%, SD 16.0%; 𝑃 < .001). For example, while 96% of interns identified the hand hygiene hazard, only 6% identified the unnecessary blood transfusion and none identified the unnecessary stress ulcer prophylaxis. Interns who self-reported as confident in their ability to identify hazards were not any more likely to correctly identify hazards than those who were not confident. The "Room of Horrors" simulation revealed poor awareness of low-value care among interns. The simulation highlights a promising model for the prioritization and inclusion of value-based experiential training in GME.


Efficacy and safety of sublingual immunotherapy in Asian children.
Sublingual immunotherapy is currently accepted as a suitable alternative to subcutaneous immunotherapy because of its easy and painless administration and improved safety. Many clinical trials have demonstrated that sublingual immunotherapy is an effective and safe treatment for pollen or mite allergic rhinitis. However, there have been very few studies overall on children with allergic rhinitis who are sensitized to house-dust mites in Asia. The purpose of the present study was to investigate the efficacy and safety of sublingual immunotherapy in children with allergic rhinitis to house-dust mites. A total of 112 patients under the age of 15 who had allergic rhinitis to Dermatophagoides pteronyssinus and Dermatophagoides farinae were included. All patients were treated with sublingual immunotherapy (Staloral(®)). Symptom scores and quality of life were evaluated by questionnaires until one year after sublingual immunotherapy. The medication score was assessed monthly using a diary medication card and serologic tests were evaluated before and 6 and 12 months after treatment. Adverse effects and compliance were also investigated. All nasal and non-nasal symptoms and quality of life were significantly improved after treatment. The total medication score was decreased significantly after sublingual immunotherapy. There was no significant change in serologic tests. Some minor adverse effects were reported, however there were no systemic reactions. The drop-out rate was 21%. Sublingual immunotherapy is a valuable therapy for the treatment of allergic rhinitis in Asian children sensitized to house-dust mites.


Demonstration of insulin transformation products in insulin vials by high-performance liquid chromatography.
To assess the importance of temperature, light, agitation, and regular withdrawal of insulin on the rates of appearance of three groups of insulin transformation products (ITPs) in vials of human and beef soluble insulin. Twelve insulin-treated patients (6 receiving human soluble insulin, 6 receiving beef soluble insulin) participated in the study. Reverse-phase high-performance liquid chromatography was used to measure ITP in serial samples from vials stored in various laboratory environments or issued to patients. Vials in the laboratory were analyzed on nine occasions over 26 wk; those issued to patients were analyzed weekly. Results were expressed as rates of change (% total protein/wk). Except for human insulin stored at 4 degrees C, sampling did not accelerate transformation. Storage at higher temperatures caused more rapid transformation to all ITP groups, and human insulin was more susceptible than beef insulin. Exposure to light accelerated transformation mainly to group 3 ITP. Fibrillation occurred in beef but not human insulin carried in a shirt pocket. Results from patients' vials were consistent with reported storage conditions. All three ITP groups form in human and beef soluble insulin. Their rate of production is a function of temperature and light exposure. Differences between the two insulins were probably due to differences in formulation. Patients should be discouraged from hoarding vials and storing insulin in direct sunlight. One or more ITPs could contribute to the residual immunogenicity of modern insulin preparations.


Performance and costs of particle air filtration technologies.
This paper predicts the reductions in the indoor mass concentrations of particles attainable from use of filters in building supply airstreams and also from use of stand-alone fan-filter units. Filters with a wide efficiency range are considered. Predicted concentration reductions are provided for indoor-generated particles containing dust-mite and cat allergen, for environmental tobacco smoke (ETS) particles, and for outdoor air fine-mode particles. Additionally, this paper uses a simple model and available data to estimate the energy and total costs of the filtration options. Predicted reductions in cat and dust-mite allergen concentrations range from 20 to 80%. To obtain substantial, e.g. 50%, reductions in indoor concentrations of these allergens, the rate of airflow through the filter must be at least a few indoor volumes per hour. Increasing filter efficiencies above approximately ASHRAE Dust Spot 65% does not significantly reduce predicted indoor concentrations of these allergens. For ETS particles and outdoor fine-mode particles, calculations indicate that relatively large, e.g. 80%, decreases in indoor concentrations are attainable with practical filter efficiencies and flow rates. Increasing the filter efficiency above ASHRAE 85% results in only modest predicted incremental decreases in indoor concentration. Energy costs and total costs can be similar for filtration using filters with a wide range of efficiency ratings. Total estimated filtration costs of approximately $0.70 to $1.80 per person per month are insignificant relative to salaries, rent, or health insurance costs.


The molecular chaperone Cdc37 is required for Ste11 function and pheromone-induced cell cycle arrest.
The molecular chaperone Cdc37 is thought to act in part as a targeting subunit of the heat-shock protein 90 (Hsp90) chaperone complex. We demonstrate here that Cdc37 is required for activity of the kinase Ste11 in budding yeast. A cdc37 mutant strain is defective in Ste11-mediated pheromone signaling and in accumulation and functional maturation of the constitutively active Ste11 version Ste11DeltaN. Moreover, Cdc37, Ste11DeltaN and Hsp90 coprecipitate pairwise. Thus, Hsp90 and Cdc37 may transiently associate with Ste11 to promote proper folding and/or association with additional regulatory factors. Our results establish Ste11 as the first endogenous Cdc37 client protein in yeast.


Harnessing Pandemonium: The Clinical Implications of Tumor Heterogeneity in Ovarian Cancer.
Heterogeneity has emerged as a key feature of ovarian cancer between different ovarian cancer subtypes; within single ovarian cancer subtypes; and within individual patient tumors. At the genomic level, with the advent of ultra-deep sequencing technologies alongside RNA-Seq, epigenomics, and proteomics, the complexity surrounding heterogeneity has deepened. Here, we summarize the emerging understanding of heterogeneity in cancer as a whole and the key discoveries in this area relating to ovarian cancer. We explore the therapeutic limitations and possibilities posed by heterogeneity and how these will influence the future of ovarian cancer treatment and research.


Alterations of serum brain type natriuretic peptide (BNP) in patients with Crimean-Congo hemorrhagic fever.
Crimean-Congo hemorrhagic fever (CCHF) is known to be associated with cardiac damage. Brain type natriuretic peptide (BNP) is secreted from stressed myocardium. This study investigated that BNP levels in CCHF and its association with clinical course of disease. Consecutive CCHF diagnosis confirmed patients were enrolled to the study. Results of patients were compared with age-sex-matched healthy volunteers. Blood samples for BNP levels were collected from the patients during emergency room applications. Mortality, hospitalization duration and other disease severity predictors (thrombocyte count, hemoglobin, white blood cell count, alanine aminotransferase, aspartate aminotransferase, prothrombin time, lactate dehydrogenase, international normalized ratio, activated partial thromboplastin time) were recorded. These parameters' correlations with BNP levels were analyzed. Forty-three CCHF patients and 28 control subjects recruited to the study. Groups were similar for age and gender. There was no mortality. Levels of BNP were found to be significantly higher in patients than control subjects (100.4±45.4 vs. 78.0±40.4, P=0.033). But BNP levels were not correlated with duration of hospitalization and disease severity predictors (P > 0.05). This study showed that BNP levels are modestly increased in CCHF but this increase does not correlated with disease severity predictors.


Taking your place or matching your face: two paths to empathic embarrassment.
Empathic responding may be elicited by different processes, depending on the available situational and affective cues. We investigated two such processes, perspective-taking and nonverbal mimicry. In Study 1, participants watched an embarrassed or unembarrassed confederate dancing to music while either remaining objective or engaging in perspective-taking. Both manipulations affected empathic embarrassment. Study 2 further examined the effects of targets' embarrassment displays and observers' prior experience with the situation upon spontaneous perspective-taking, expressive mimicry, and empathic embarrassment. Embarrassment displays increased mimicry, but also spontaneous perspective-taking and subsequent empathy. Prior experience moderated the effects of embarrassment displays on perspective-taking and empathy. Path analyses demonstrated that embarrassment displays exerted indirect effects on empathic embarrassment through both perspective-taking and mimicry. The results suggest that available affective and situational cues can activate different routes to empathy, and highlight the value of simultaneously investigating target- and observer-based sources of influence.


The mitigating effect of Citrullus colocynthis (L.) fruit extract against genotoxicity induced by cyclophosphamide in mice bone marrow cells.
Possible genoprotective effect of Citrullus colocynthis (L.) (CCT) fruits extract against cyclophosphamide- (CP-)induced DNA damage in mice bone marrow cells was evaluated using micronucleus assay, as an index of induced chromosomal damage. Mice were preadministered with different doses of CCT via intraperitoneal injection for 7 consecutive days followed by injection with CP (70 mg/kg b.w.) 1 hr after the last injection of CCT. After 24 hr, mice were scarified to evaluate the frequency of micronucleated polychromatic erythrocytes (MnPCEs). In addition, the number of polychromatic erythrocytes (PCEs) among 1000 normochromatic erythrocytes (NCEs) per animal was recorded to evaluate bone marrow. Pretreatment with CCT significantly reduced the number of MnPCEs induced by CP in bone marrow cells (P < 0.0001). At 200 mg/kg, CCT had a maximum chemoprotective effect and reduced the number of MnPCEs by 6.37-fold and completely normalized the mitotic activity. CCT also led to marked proliferation and hypercellularity of immature myeloid elements after mice were treated with CP and mitigated the bone marrow suppression. Our study revealed that CCT has an antigenotoxic effect against CP-induced oxidative DNA damage in mice. Therefore, it could be used concomitantly as a supplement to protect people undergoing chemotherapy.


Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome.
The effect of FBN1 mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results. This study aims to determine the impact of the FBN1 mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality). MFS patients with a pathogenic FBN1 mutation followed at two specialised units were included. FBN1 mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of non-mutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients. Two hundred and ninety patients with MFS were included: 113 (39%) with an HI-FBN1 mutation and 177 (61%) with a DN-FBN1. At baseline, patients with HI-FBN1 had a larger aortic root diameter than patients with DN-FBN1 (HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI-FBN1 (HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI-FBN1 tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN-FBN1 (HR: 3.3, 95% CI 1.0 to 11.4, p=0.060). Patients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation.


Health Decline Is Associated with Reports of No Coffee Consumption Years After Reporting Coffee Consumption Among Older Adults in Spain.
Part of the health benefits of coffee reported in observational studies might be due to health status influencing coffee intake rather than the opposite. We examined whether changes in health influenced subsequent reports of no coffee consumption in older adults. Data came from 718 coffee drinkers aged ≥60 y recruited in the Seniors-Estudio de Nutrición y Salud Cardiovascular en España (ENRICA) cohort in 2008-2010 (wave 0) and followed-up in 2012 (wave 1), 2015 (wave 2), and 2017 (wave 3). Health status was measured with a 52-item deficit accumulation index (DAI) with 4 domains: functionality, self-rated health/vitality, mental health, and morbidity/health services use. Coffee intake was estimated with a validated diet history. We examined how changes in health status over a 3-y period (wave 0 to wave 1) influenced reports of no coffee consumption during the subsequent 5 y (wave 1 to wave 3) by using logistic regression models. Health deterioration over 3 y was associated with a higher frequency of reports of no regular coffee consumption during the subsequent 5 y (fully adjusted OR: 1.48 per 1-SD increment in DAI; 95% CI: 1.17-1.87). Deteriorating function (OR: 1.38 per 1-SD increment; 95% CI: 1.06-1.81) and mental health (OR: 1.34 per 1-SD increment; 95% CI: 1.04-1.73) were the DAI domains associated with increased reports of no regular coffee consumption. Also, individuals with worsened perceived health or hypertension onset were more likely to report no regular coffee consumption. No associations were found for decaffeinated coffee. Health deterioration was associated with reports of no regular coffee consumption years after reporting regular coffee consumption among older adults in Spain. A potential implication of this finding is that part of the beneficial effect of coffee consumption on health in observational studies might be due to reverse causation, which should be confirmed in future research.


Learning to use an invisible visual signal for perception.
How does the brain construct a percept from sensory signals? One approach to this fundamental question is to investigate perceptual learning as induced by exposure to statistical regularities in sensory signals [1-7]. Recent studies showed that exposure to novel correlations between sensory signals can cause a signal to have new perceptual effects [2, 3]. In those studies, however, the signals were clearly visible. The automaticity of the learning was therefore difficult to determine. Here we investigate whether learning of this sort, which causes new effects on appearance, can be low level and automatic by employing a visual signal whose perceptual consequences were made invisible-a vertical disparity gradient masked by other depth cues. This approach excluded high-level influences such as attention or consciousness. Our stimulus for probing perceptual appearance was a rotating cylinder. During exposure, we introduced a new contingency between the invisible signal and the rotation direction of the cylinder. When subsequently presenting an ambiguously rotating version of the cylinder, we found that the invisible signal influenced the perceived rotation direction. This demonstrates that perception can rapidly undergo "structure learning" by automatically picking up novel contingencies between sensory signals, thus automatically recruiting signals for novel uses during the construction of a percept.