Long-term NMDA receptor inhibition affects NMDA receptor expression and alters glutamatergic activity in developing rat hippocampal neurons.
Ketamine and its stereoisomer S(+)-ketamine are widely used for sedation in pediatric anesthesia and intensive care medicine. Numerous experimental studies indicate that ketamine is potentially toxic to the developing brain. Here, we examined the long-term effects of NMDA receptor blockade on NMDA receptor subunit expression, alterations in neuronal Ca(2+)-oscillations and apoptosis. Hippocampal neurons, 15 days in culture, were exposed to either S(+)-ketamine or the NMDA receptor blocker MK801 for 24h. Cytosolic Ca(2+)-concentration was determined by fluorescence microscopy and the expression of the NMDA subunits NR1, NR2A and 2B was assessed by qRT-PCR, whereas Western blots and activated Caspase-3 served to measure the extent of apoptosis. Long-term incubation with MK801 or higher doses of S(+)-ketamine resulted in a dose-dependent decreased ability of MK801 to reduce amplitude and frequency of the Ca(2+)-oscillations 15min following washout of the drug. This was accompanied by an increase in NR1 mRNA but not the NR2A and B subunit expression at the same time point. 24h following washout of the specific drug, a significant elevation of the pro-apoptotic marker BAX, as well as activated Caspase-3 positive neurons, could be detected in cultures exposed to 100μM MK801 and 25μM S(+)-ketamine. Here, we show that long-term blockade of the NMDA receptor in developing rat hippocampal neurons significantly increased NR1 subunit expression, and that this was associated with an alteration in neuronal activity. Apoptosis was only induced 24h after withdrawal of long-term blockade for high doses of S(+)-ketamine.


Characterisation of trials where marketing purposes have been influential in study design: a descriptive study.
Analysis of trial documentation has revealed that some industry-funded trials may be done more for marketing purposes than scientific endeavour. We aimed to define characteristics of drug trials that appear to be influenced by marketing considerations and estimate their prevalence. We examined reports of randomised controlled trials of drugs published in six general medical journals in 2011. Six investigators independently reviewed all publications, characterising them as YES/MAYBE/NO suspected marketing trials, and then met to reach consensus. Blinded researchers then extracted key trial characteristics. We used blinded cluster analysis to determine if key variables could characterise the categories of trials (YES/MAYBE/NO). 41/194 (21 %) trials were categorised as YES, 14 (7 %) as MAYBE, 139 (72 %) as NO. All YES and MAYBE trials were funded by the manufacturer, compared with 37 % of NO trials (p < 0.001). A higher proportion of YES trials had authors or contributors from the manufacturer involved in study design (83 % vs. 19 %), data analysis (85 % vs.15 %) and reporting (81 % vs. 15 %) than NO trials (p < 0.001). There was no significant difference between groups in the median number of participants screened (p = 0.49), but the median number of centres recruiting participants was higher for YES compared with NO trials (171 vs. 13, p < 0.001). YES trials were not more likely to use a surrogate (42 % vs. 30 %; p = 0.38) or composite primary outcome measure (34 % vs. 19 %; p = 0.14) than NO trials. YES trials were often better reported in terms of blinding, safety outcomes and adverse events than NO trials. YES trials more frequently included speculation that might encourage clinicians to use the intervention outside of the study population compared to NO trials (59 % vs.37 %, p = 0.03). Cluster analysis based on study characteristics did not identify a clear variable structure that accurately characterised YES/MAYBE/NO trials. We reached consensus that a fifth of drug trials published in the highest impact general medical journals in 2011 had features that were suggestive of being designed for marketing purposes. Each of the marketing trials appeared to have a unique combination of features reported in the journal publications.


Anabolic steroids.
The term "anabolic steroids" refers to testosterone derivatives that are used either clinically or by athletes for their anabolic properties. However, scientists have questioned the anabolic effects of testosterone and its derivatives in normal men for decades. Most scientists concluded that anabolic steroids do not increase muscle size or strength in people with normal gonadal function and have discounted positive results as unduly influenced by positive expectations of athletes, inferior experimental design, or poor data analysis. There has been a tremendous disconnect between the conviction of athletes that these drugs are effective and the conviction of scientists that they aren't. In part, this disconnect results from the completely different dose regimens used by scientists to document the correction of deficiency states and by athletes striving to optimize athletic performance. Recently, careful scientific study of suprapharmacologic doses in clinical settings - including aging, human immunodeficiency virus, and other disease states - supports the efficacy of these regimens. However, the mechanism by which these doses act remains unclear. "Anabolism" is defined as any state in which nitrogen is differentially retained in lean body mass, either through stimulation of protein synthesis and/or decreased breakdown of protein anywhere in the body. Testosterone, the main gonadal steroid in males, has marked anabolic effects in addition to its effects on reproduction that are easily observed in developing boys and when hypogonadal men receive testosterone as replacement therapy. However, its efficacy in normal men, as during its use in athletes or in clinical situations in which men are eugonadal, has been debated. A growing literature suggests that use of suprapharmacologic doses can, indeed, be anabolic in certain situations; however, the clear identification of these situations and the mechanism by which anabolic effects occur are unclear. Furthermore, the pharmacology of "anabolism" is in its infancy: no drugs currently available are "purely" anabolic but all possess androgenic properties as well. The present review briefly recapitulates the historic literature about the androgenic/anabolic steroids and describes literature supporting the anabolic activity of these drugs in normal people, focusing on the use of suprapharmacologic doses by athletes and clinicians to achieve anabolic effects in normal humans. We will present the emerging literature that is beginning to explore more specific mechanisms that might mediate the effects of suprapharmacologic regimens. The terms anabolic/androgenic steroids will be used throughout to reflect the combined actions of all drugs that are currently available.


Effects of Different Chair-Based Exercises on Salivary Biomarkers and Functional Autonomy in Institutionalized Older Women.
The aim of this study was to test the effects of chair-based exercise programs on salivary stress hormones, physical fitness, and functional autonomy of institutionalized older women. In total, 47 participants (80 ± 8.04 years old) were recruited and allocated into three groups: chair-based aerobic exercises (CAE, n = 19), chair-based elastic-band strength exercises (CSE, n = 15), and a control group (CG, n = 13). A 14-week exercise intervention was done for the CAE and CSE groups, two times per week, in no consecutive days. Members of the CG did not participate in any type of exercise but kept their regular lifestyle. Fear of falling, autonomy, physical fitness, salivary cortisol, and alpha-amylase levels were assessed before and after the intervention. The CAE group improved upper and lower body strength, agility-dynamic balance, and autonomy, with fear of falling decreasing significantly (p < .05, moderate effect size). Both exercise groups showed a trend toward an increase in salivary alpha-amylase levels (CAE = 43%, d = .31, and CSE = 44%, d = .41). Both exercise programs were able to improve functional autonomy, even in elders older than 80 years of age. It might be interesting to investigate the effectiveness of combining both aerobic and strength exercises in a unique protocol. The modulation effect of exercise in the hormonal responses needs to be further explored.


Discriminative Semantic Subspace Analysis for Relevance Feedback.
Content-based image retrieval (CBIR) has attracted much attention during the past decades for its potential practical applications to image database management. A variety of relevance feedback (RF) schemes have been designed to bridge the gap between low-level visual features and high-level semantic concepts for an image retrieval task. In the process of RF, it would be impractical or too expensive to provide explicit class label information for each image. Instead, similar or dissimilar pairwise constraints between two images can be acquired more easily. However, most of the conventional RF approaches can only deal with training images with explicit class label information. In this paper, we propose a novel discriminative semantic subspace analysis (DSSA) method, which can directly learn a semantic subspace from similar and dissimilar pairwise constraints without using any explicit class label information. In particular, DSSA can effectively integrate the local geometry of labeled similar images, the discriminative information between labeled similar and dissimilar images, and the local geometry of labeled and unlabeled images together to learn a reliable subspace. Compared with the popular distance metric analysis approaches, our method can also learn a distance metric but perform more effectively when dealing with high-dimensional images. Extensive experiments on both the synthetic data sets and a real-world image database demonstrate the effectiveness of the proposed scheme in improving the performance of the CBIR.


Do patient race and sex change surgeon recommendations for TKA?
Prior investigations have suggested that physician-related factors may contribute to differential use of TKA among women and ethnic minorities. We sought to evaluate the effect of surgeon bias on recommendations for TKA. Using an experimental approach with standardized patient scenarios, we sought to evaluate surgeon recommendations regarding TKA, specifically to determine whether recommendations for TKA are influenced by (1) patient race, and (2) patient sex. We developed four computerized scenarios for all combinations of race (white or black) and sex (male or female) for otherwise similar patients with end-stage knee osteoarthritis. Patients gave an orthopaedic history of 2 years worsening pain with decreased functional status and failure of oral antiinflammatory medications and corticosteroid intraarticular injections. Orthopaedic surgeons attending the 2012 annual meetings of the New York State Society of Orthopaedic Surgeons and American Association of Hip and Knee Surgeons were recruited for the study. Surgeons passing an open recruitment table at each meeting were asked to participate. Of the 1111 surgeons in attendance at either meeting, 113 (10.2%) participated in the study. All participants viewed the "control" patient's story (white male) and were randomized to view one of the three "experimental" scenarios (white female, black male, black female). After viewing each scenario, the participants were anonymously asked whether they would recommend TKA. An a priori power analysis showed that 112 participants were needed to detect a 15% difference in the likelihood of recommending surgery for white versus nonwhite patients in the test scenarios evaluated with 90% power at a level of significance of 0.05. Of the 39 surgeons who viewed the white male plus black female scenario, there were 33 (85%) concordant responses (TKA offered to both patients) and six discordant responses (TKA offered to only one of the patients), with no effect of patient race and sex (p = 0.99). Of the 37 surgeons who viewed the white male plus black male scenario, there were 33 (89%) concordant responses and four discordant responses, with no effect of patient race (p = 0.32). Of the 37 surgeons who viewed the white male plus white female scenario, there were 30 (77%) concordant responses and seven discordant responses, with no effect of patient sex (p = 0.71). After orthopaedic surgeons viewed video scenarios of patients with end-stage knee osteoarthritis, patient race and sex were not associated with a different likelihood of a surgical recommendation. Our findings support the notion that patient race and sex may be less influential on decision making when there are strong clinical data to support a decision. Physician bias may have a greater effect on decision making in situations where the indications for surgery are less clear.


Expanded Ethical Principles for Research Partnership and Transdisciplinary Natural Resource Management Science.
Natural resource researchers have long recognized the value of working closely with the managers and communities who depend on, steward, and impact ecosystems. These partnerships take various forms, including co-production and transdisciplinary research approaches, which integrate multiple knowledges in the design and implementation of research objectives, questions, methods, and desired outputs or outcomes. These collaborations raise important methodological and ethical challenges, because partnering with non-scientists can have real-world risks for people and ecosystems. The social sciences and biomedical research studies offer a suite of conceptual tools that enhance the quality, ethical outcomes, and effectiveness of research partnerships. For example, the ethical guidelines and regulations for human subjects research, following the Belmont Principles, help prevent harm and promote respectful treatment of research participants. However, science-management partnerships require an expanded set of ethical concepts to better capture the challenges of working with individuals, communities, organizations, and their associated ecosystems, as partners, rather than research subjects. We draw from our experiences in collaborative teams, and build upon the existing work of natural resources, environmental health, conservation and ecology, social science, and humanities scholars, to develop an expanded framework for ethical research partnership. This includes four principles: (1) appropriate representation, (2) self-determination, (3) reciprocity, and (4) deference, and two cross-cutting themes: (1) applications to humans and non-human actors, and (2) acquiring appropriate research skills. This framework is meant to stimulate important conversations about expanding ethics training and skills for researchers in all career-stages to improve partnerships and transdisciplinary natural resources research.


Male first-line managers' experiences of the work situation in elderly care: an empowerment perspective.
To describe male first-line managers' experiences of their work situation in elderly care. First-line managers' work is challenging. However, less attention has been paid to male managers' work situation in health care. Knowledge is needed to empower male managers. Fourteen male first-line managers were interviewed. The interview text was subjected to qualitative content analysis. Work situations were described as complex and challenging; challenges were the driving force. They talked about 'Being on one's own but not feeling left alone', 'Having freedom within set boundaries', 'Feeling a sense of satisfaction and stimulation', 'Feeling a sense of frustration' and 'Having a feeling of dejection and resignation'. Although the male managers report deficiencies in the support structure, they largely experience their work as a positive challenge. To meet increasing challenges, male first-line managers need better access to supportive structural conditions. Better access to resources is needed in particular, allowing managers to be more visible for staff and to work with development and quality issues instead of administrative tasks. Regarding organisational changes and the scrutiny of management and the media, they lack and thus need support and information from superiors.


Whole genome sequencing of peach (Prunus persica L.) for SNP identification and selection.
The application of next generation sequencing technologies and bioinformatic scripts to identify high frequency SNPs distributed throughout the peach genome is described. Three peach genomes were sequenced using Roche 454 and Illumina/Solexa technologies to obtain long contigs for alignment to the draft 'Lovell' peach sequence as well as sufficient depth of coverage for 'in silico' SNP discovery. The sequences were aligned to the 'Lovell' peach genome released April 01, 2010 by the International Peach Genome Initiative (IPGI). 'Dr. Davis', 'F8, 1-42' and 'Georgia Belle' were sequenced to add SNPs segregating in two breeding populations, Pop DF ('Dr. Davis' × 'F8, 1-42') and Pop DG ('Dr. Davis' × 'Georgia Belle'). Roche 454 sequencing produced 980,000 total reads with 236 Mb sequence for 'Dr. Davis' and 735,000 total reads with 172 Mb sequence for 'F8, 1-42'. 84 bp × 84 bp paired end Illumina/Solexa sequences yielded 25.5, 21.4, 25.5 million sequences for 'Dr. Davis', 'F8, 1-42' and 'Georgia Belle', respectively. BWA/SAMtools were used for alignment of raw reads and SNP detection, with custom PERL scripts for SNP filtering. Velvet's Columbus module was used for sequence assembly. Comparison of aligned and overlapping sequences from both Roche 454 and Illumina/Solexa resulted in the selection of 6654 high quality SNPs for 'Dr. Davis' vs. 'F8, 1-42' and 'Georgia Belle', distributed on eight major peach genome scaffolds as defined from the 'Lovell' assembly. The eight scaffolds contained about 215-225 Mb of peach genomic sequences with one SNP/~ 40,000 bases. All sequences from Roche 454 and Illumina/Solexa have been submitted to NCBI for public use in the Short Read Archive database. SNPs have been deposited in the NCBI SNP database.


Obesogenic Behaviors and Depressive Symptoms' Influence on Cardiometabolic Risk Factors in American Indian Children.
American Indian (AI) populations suffer disproportionately from cardiovascular disease and depression as compared to other racial/ethnic groups. Behaviors that contribute to obesity are considered obesogenic and include poor diet, low physical activity, and high screen time. This study examined the relationship between depressive symptoms and obesogenic behaviors on cardiometabolic risk factors in AI youth. Participants (n=121) were evaluated for depressive symptoms, obesogenic behaviors, weight, blood pressure, lipids, and glucose levels. All participants failed to meet guidelines for intake of sugar-sweetened beverages and fruits/vegetables, 74% did not meet physical activity guidelines, and 85% did not meet screen time guidelines. Lower physical activity was associated with higher body fat percentage (b=-4.20 ± 1.82, p=0.022). Elevated depressive symptoms and presence of at-risk cardiometabolic risk factors were found. Higher depressive symptoms were associated with higher blood glucose (random, fasting, and hemoglobin A1c). Low physical activity, high screen time, and the presence of depressive symptomology heighten cardiometabolic risk factors in AI children. Associations between depressive symptoms and blood glucose underscore the impact of emotional health on cardiometabolic disease and emphasize need for proper depression assessment in chronic disease prevention efforts.


From cells to organisms: current topics in mathematical and theoretical biology.
At the beginning of this special issue of Acta Biotheoretica carrying the above title, we present a brief overview on currently important topics that have been brought up during the last "European Conference on Mathematical and Theoretical Biology" in Edinburgh. After emphasizing the need for a "synthetic biology" also from the side of theory, model building and analysis, we survey most plenary talks of this Conference and a selected series of eigth review articles, which are mainly related to corresponding minisymposia, reflecting the current state of the art and the lively discussion within this interdisciplinary field.


Upcoming Role of Prostate Specific Membrane Antigen Positron Emission Tomography-Computed Tomography in Detecting Occult Metastases in Prostate Cancer.
Prostate cancer (PCa) is the second most frequent malignancy in men. Most common sites of disease involvement other than the prostate gland include abdominopelvic lymph nodes and the skeleton. The detection of nodal metastases is of utmost importance to determine prognosis and choice of treatment in patients with PCa. Conventional imaging focuses on morphologic information and takes size criteria for decision-making. Early detection of metastases is further relevant in terms of prognosis and therapy management. Molecular imaging of PCa with Ga-68 prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT) has recently received significant attention and frequently used with a signature to PCa-specific remark. We presented the case of a 69-year-old male presenting with biochemical recurrence after undergoing surgery and in remission for about a year, where Ga-68 PSMA PET-CT identified additional sites of disease apart from the expected regional bed.


The effect of dopant and optical micro-cavity on the photoluminescence of Mn-doped ZnSe nanobelts.
Pure and Mn-doped ZnSe nanobelts were synthesized by a convenient thermal evaporation method. Scanning electron microscopy, X-ray powder diffraction, energy dispersive X-ray spectroscopy and corresponding element mapping, and transmission electron microscope were used to examine the morphology, phase structure, crystallinity, composition, and growth direction of as-prepared nanobelts. Raman spectra were used to confirm the effective doping of Mn2+ into ZnSe nanobelts. Micro-photoluminescence (PL) spectra were used to investigate the emission property of as-prepared samples. A dominant trapped-state emission band is observed in single ZnSeMn nanobelt. However, we cannot observe the transition emission of Mn ion in this ZnSeMn nanobelt, which confirm that Mn powder act as poor dopant. There are weak near-bandgap emission and strong 4T1 → 6A1 transition emission of Mn2+ in single ZnSeMnCl2 and ZnSeMn(CH3COO)2 nanobelt. More interesting, the 4T1 → 6A1 transition emission in ZnSeMn(CH3COO)2 nanobelt split into multi-bands. PL mapping of individual splitted sub-bands were carried out to explore the origin of multi-bands. These doped nanobelts with novel multi-bands emission can find application in frequency convertor and wavelength-tunable light emission devices.


Potential use of the PRI and active fluorescence for the diagnosis of the physiological state of plants under ozone exposure and high atmospheric vapor pressure deficit.
Assessing photosynthesis rates with remote sensing is important for tracking the physiological state of plants. The photochemical reflectance index (PRI) is a good estimator of short-term light-use efficiency (LUE) at the leaf scale but its responses to environmental factors are poorly understood. In this study, we assessed changes in the responses of the PRI to ozone exposure and to an increase in atmospheric drought (separately and combined) in oak (Quercus robur) and holm oak (Quercus ilex) that were planted in climatic cells under controlled conditions. The aim was to evaluate the ability of the PRI as a relevant indicator to assess the impact of abiotic factors on photosynthesis. Leaf-scale measurements of biochemical, physiological and spectral properties, including the PRI in dim light on dark-adapted leaves (PRI0), kinetics of PRI responses to PAR variations (photosynthetically active radiation), and leaf chlorophyll fluorescence parameters were performed. The results show that PRI0 is a good proxy of the leaf chlorophyll content, and is correlated to chlorophyll fluorescence parameters on dark adapted leaves (Fo, Fm). The correction of the PRI from the leaf chlorophyll content variations (PRIc) significantly improves correlations between the PRI and NPQ (non-photochemical quenching). The variability of PARsat (estimated PAR value at PRI saturation using PRI vs. PAR relationships) depends on ozone exposure and on the increase in atmospheric vapor pressure deficit. For Quercus robur, results highlight that PARsat is linked to abiotic stress indicating that the PRI may be used as a relevant indicator of abiotic factors limiting the photosynthesis. Quercus ilex did not show significant variability in PRI0 and PARsat, which suggest that it is a more drought resistant species than Q. robur.


Safety of Fibrinogen Concentrate and Cryoprecipitate in Cardiovascular Surgery: Multicenter Database Study.
To investigate whether administering fibrinogen concentrate or cryoprecipitate is associated with increased postoperative thromboembolic events and improved mortality in patients undergoing thoracic aortic surgery. Multicenter retrospective cohort study using propensity-score analyses and multivariate logistic regression analysis to control for confounders. Four hospitals (1 national cardiovascular center and 3 university hospitals). Patients undergoing thoracic aortic surgery with cardiopulmonary bypass between January 2010 and October 2012 (n = 1,047). Outcomes in patients treated with fibrinogen concentrate or cryoprecipitate (fibrinogen group) were compared with those who did not receive these products (no fibrinogen group) based on propensity-score matching. Multivariate logistic regression analysis then was performed to confirm the results. Among 1,047 patients enrolled in this study, 247 patients received fibrinogen concentrate or cryoprecipitate. The median amount of administered fibrinogen was 3 g (interquartile range 2-4 g). Eighty-seven patients were excluded from the propensity-score matching because of missing data. Propensity-score-matched analysis showed no significant difference in the incidence of thromboembolic events or 30-day mortality rate between the groups. Multivariate analysis revealed that the fibrinogen group showed no significant difference in thromboembolic events (odds ratio 1.22; 95% confidence interval 0.76-1.95; p = 0.408) or mortality rate (odds ratio 0.44; 95% confidence interval 0.18-1.12; p = 0.081) compared with those in the no fibrinogen group. Administering fibrinogen concentrate or cryoprecipitate was associated with neither thromboembolic events nor 30-day mortality in patients undergoing thoracic aortic surgery. Administering fibrinogen concentrate or cryoprecipitate is safe and does not appear to increase thromboembolic events and mortality in thoracic aortic surgery patients.


Mid-elevational Peaks in Diversity of Ground-dwelling Arthropods with High Species Turnover on the Colorado Plateau.
Patterns of biodiversity along elevational gradients elucidate how climate shapes biological communities and help predict ecosystem responses to environmental change. Arid elevational gradients are particularly interesting because temperature limitations at high elevations and precipitation limitations at low elevations cause mid-elevation peaks in diversity. Ground-dwelling arthropods form highly diverse communities but few studies document elevational patterns of their full diversity. Here we investigate the elevational patterns of ground-dwelling arthropods in northern Arizona on the Colorado Plateau, an arid and understudied region in the United States. We sampled seven sites along an elevation gradient from 1,566 to 2,688 m corresponding to a difference of 6.5°C average annual temperature and 620 mm average annual precipitation. We captured 16,942 specimens comprising 169 species, mostly ants and beetles, and discovered a new ant species. First- and second-order elevation terms significantly correlated to multiple measures of arthropod α and β diversity. Arthropod abundance, richness, and Shannon-Wiener diversity index peaked at mid-elevations, with functional groups (i.e., omnivores, predators, detritivores, and herbivores) showing similar patterns. Community composition varied significantly across the gradient, correlated with changes in elevation, and was driven by shifts of ants dominating low- to mid-elevations, to beetles dominating high-elevations. Dissimilarity among sites was driven by high species turnover with 59% of species exclusive to a single site, whereas nestedness among sites was low except at the lowest elevation site. High rates of turnover and elevation-dependent communities suggest that ground-dwelling arthropods are highly vulnerable to environmental change, particularly at lower elevations in arid regions.


Bmp signaling is necessary and sufficient for ventrolateral endoderm specification in Xenopus.
Here we show that Bmp signaling is necessary and sufficient for the specification of ventral endoderm in Xenopus embryos. Overexpression of Bmp4 in ectoderm induces markers of endoderm, including Sox17beta, Mixer, and VegT, but cannot induce the expression of the dorsoanterior markers, Xhex and Cerberus. Furthermore, knockdown approaches using overexpression of Bmp antagonists and morpholinos designed against Bmp4, Bmp2, and Bmp7 demonstrate that Bmp signaling is critical for ventral, but not dorsoanterior endoderm formation. This activity is not simply a result of embryonic dorsalization as markers for dorsal endoderm are not expanded. We further show that endodermal cells of either ventral or dorsal character do not form when both Wnt and Bmp signals are abolished. Overall, this report strongly suggests that Bmp plays an essential role in ventral endoderm specification.


c-AMP dependent protein kinase A inhibitory activity of six algal extracts from southeastern Australia and their fatty acid composition.
c-AMP dependent protein kinase (protein kinase A, PKA) is an important enzyme involved in the regulation of an increasing number of physiological processes including immune function, cardiovascular disease, memory disorders and cancer. The objective of this study was to evaluate the PKA inhibitory activity of a range of algal extracts, along with their fatty acid composition. Six algal species were investigated including two Chlorophyta (Codium dimorphum and Ulva lactuca), two Phaeophyta (Phyllospora comosa and Sargassum sp.) and two Rhodophyta (Prionitis linearis and Corallina vancouveriensis), with the order of PKA inhibitory activity of their extracts identified as follows: brown seaweeds > red seaweeds > green seaweeds with the brown alga Sargassum sp. exhibiting the highest PKA inhibitory activity (84% at 100 microg/mL). GC/MS analysis identified a total of 18 fatty acids in the six algal extracts accounting for 72-87% of each extract, with hexadecanoic acid and 9,12-octadecadienoic acid as the dominant components. The most active extract (Sargassum sp.) also contained the highest percentage of the saturated C14:0 fatty acid (12.8% of the total extract), which is a known to inhibit PKA. These results provide the first description of the PKA inhibitory activity of marine algae along with the first description of the fatty acid composition of these six algal species from South Eastern Australian waters. Importantly, this study reveals that abundant and readily available marine algae are a new and relatively unexplored source of PKA inhibitory compounds.


Eye-tracking in amyotrophic lateral sclerosis: A longitudinal study of saccadic and cognitive tasks.
A relative preservation of eye movements is notable in ALS, but saccadic functions have not been studied longitudinally. ALS overlaps with FTD, typically involving executive dysfunction, and eye-tracking offers additional potential for the assessment of extramotor pathology where writing and speaking are both impaired. Eye-tracking measures (including anti-saccade, trail-making and visual search tasks) were assessed at six-monthly intervals for up to two years in a group of ALS (n = 61) and primary lateral sclerosis (n = 7) patients, compared to healthy age-matched controls (n = 39) assessed on a single occasion. Task performance was explored speculatively in relation to resting-state functional MRI (R-FMRI) network connectivity. Results showed that ALS patients were impaired on executive and visual search tasks despite normal basic saccadic function, and impairments in the PLS patients were unexpectedly often more severe. No significant progression was detected longitudinally in either group. No changes in R-FMRI network connectivity were identified in relation to patient performance. In conclusion, eye-tracking offers an objective means to assess extramotor cerebral involvement in ALS. The relative resistance of pure oculomotor function is confirmed, and higher-level executive impairments do not follow the same rate of decline as physical disability. PLS patients may have more cortical dysfunction than has been previously appreciated.


Lupus and the Lungs: The Assessment and Management of Pulmonary Manifestations of Systemic Lupus Erythematosus.
Pulmonary manifestations of systemic lupus erythematosus (SLE) are wide-ranging and debilitating in nature. Previous studies suggest that anywhere between 20 and 90% of patients with SLE will be troubled by some form of respiratory involvement throughout the course of their disease. This can include disorders of the lung parenchyma (such as interstitial lung disease and acute pneumonitis), pleura (resulting in pleurisy and pleural effusion), and pulmonary vasculature [including pulmonary arterial hypertension (PAH), pulmonary embolic disease, and pulmonary vasculitis], whilst shrinking lung syndrome is a rare complication of the disease. Furthermore, the risks of respiratory infection (which often mimic acute pulmonary manifestations of SLE) are increased by the immunosuppressive treatment that is routinely used in the management of lupus. Although these conditions commonly present with a combination of dyspnea, cough and chest pain, it is important to consider that some patients may be asymptomatic with the only suggestion of the respiratory disorder being found incidentally on thoracic imaging or pulmonary function tests. Treatment decisions are often based upon evidence from case reports or small cases series given the paucity of clinical trial data specifically focused on pulmonary manifestations of SLE. Many therapeutic options are often initiated based on studies in severe manifestations of SLE affecting other organ systems or from experience drawn from the use of these therapeutics in the pulmonary manifestations of other systemic autoimmune rheumatic diseases. In this review, we describe the key features of the pulmonary manifestations of SLE and approaches to investigation and management in clinical practice.


Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report.
In both the United States and Europe there has been an increased interest in using comparative effectiveness research of interventions to inform health policy decisions. Prospective observational studies will undoubtedly be conducted with increased frequency to assess the comparative effectiveness of different treatments, including as a tool for "coverage with evidence development," "risk-sharing contracting," or key element in a "learning health-care system." The principle alternatives for comparative effectiveness research include retrospective observational studies, prospective observational studies, randomized clinical trials, and naturalistic ("pragmatic") randomized clinical trials. This report details the recommendations of a Good Research Practice Task Force on Prospective Observational Studies for comparative effectiveness research. Key issues discussed include how to decide when to do a prospective observational study in light of its advantages and disadvantages with respect to alternatives, and the report summarizes the challenges and approaches to the appropriate design, analysis, and execution of prospective observational studies to make them most valuable and relevant to health-care decision makers. The task force emphasizes the need for precision and clarity in specifying the key policy questions to be addressed and that studies should be designed with a goal of drawing causal inferences whenever possible. If a study is being performed to support a policy decision, then it should be designed as hypothesis testing-this requires drafting a protocol as if subjects were to be randomized and that investigators clearly state the purpose or main hypotheses, define the treatment groups and outcomes, identify all measured and unmeasured confounders, and specify the primary analyses and required sample size. Separate from analytic and statistical approaches, study design choices may strengthen the ability to address potential biases and confounding in prospective observational studies. The use of inception cohorts, new user designs, multiple comparator groups, matching designs, and assessment of outcomes thought not to be impacted by the therapies being compared are several strategies that should be given strong consideration recognizing that there may be feasibility constraints. The reasoning behind all study design and analytic choices should be transparent and explained in study protocol. Execution of prospective observational studies is as important as their design and analysis in ensuring that results are valuable and relevant, especially capturing the target population of interest, having reasonably complete and nondifferential follow-up. Similar to the concept of the importance of declaring a prespecified hypothesis, we believe that the credibility of many prospective observational studies would be enhanced by their registration on appropriate publicly accessible sites (e.g., clinicaltrials.gov and encepp.eu) in advance of their execution.


Suicide and self-harm in adult survivors of critical illness: population based cohort study.
To analyse the association between survival from critical illness and suicide or self-harm after hospital discharge. Population based cohort study using linked and validated provincial databases. Ontario, Canada between January 2009 and December 2017 (inclusive). Consecutive adult intensive care unit (ICU) survivors (≥18 years) were included. Linked administrative databases were used to compare ICU hospital survivors with hospital survivors who never required ICU admission (non-ICU hospital survivors). Patients were categorised based on their index hospital admission (ICU or non-ICU) during the study period. The primary outcome was the composite of death by suicide (as noted in provincial death records) and deliberate self-harm events after discharge. Each outcome was also assessed independently. Incidence of suicide was evaluated while accounting for competing risk of death from other causes. Analyses were conducted by using overlap propensity score weighted, cause specific Cox proportional hazard models. 423 060 consecutive ICU survivors (mean age 61.7 years, 39% women) were identified. During the study period, the crude incidence (per 100 000 person years) of suicide, self-harm, and the composite of suicide or self-harm among ICU survivors was 41.4, 327.9, and 361.0, respectively, compared with 16.8, 177.3, and 191.6 in non-ICU hospital survivors. Analysis using weighted models showed that ICU survivors (v non-ICU hospital survivors) had a higher risk of suicide (adjusted hazards ratio 1.22, 95% confidence interval 1.11 to 1.33) and self-harm (1.15, 1.12 to 1.19). Among ICU survivors, several factors were associated with suicide or self-harm: previous depression or anxiety (5.69, 5.38 to 6.02), previous post-traumatic stress disorder (1.87, 1.64 to 2.13), invasive mechanical ventilation (1.45, 1.38 to 1.54), and renal replacement therapy (1.35, 1.17 to 1.56). Survivors of critical illness have increased risk of suicide and self-harm, and these outcomes were associated with pre-existing psychiatric illness and receipt of invasive life support. Knowledge of these prognostic factors might allow for earlier intervention to potentially reduce this important public health problem.


Applications of bioinformatics to non-coding RNAs in the era of next-generation sequencing.
The human genome encodes a large number of non-coding RNAs, which employ a new and crucial layer of biological regulation in addition to proteins. Technical advancement in recent years, particularly, the wide application of next generation sequencing analysis, provide an unprecedented opportunity to identify new non-coding RNAs and investigate their functions and regulatory mechanisms. The aim of this workshop is to bring together experimental and computational biologist to exchange ideas on non-coding RNA studies.


Muscle wasting and the temporal gene expression pattern in a novel rat intensive care unit model.
Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. To elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness associated with AQM, a gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals. During the observation period, 1583 genes were significantly up- or down-regulated by factors of two or greater. A significant temporal gene expression pattern was constructed at short (6 h-4 days), intermediate (5-8 days) and long (9-14 days) durations. A striking early and maintained up-regulation (6 h-14d) of muscle atrogenes (muscle ring-finger 1/tripartite motif-containing 63 and F-box protein 32/atrogin-1) was observed, followed by an up-regulation of the proteolytic systems at intermediate and long durations (5-14d). Oxidative stress response genes and genes that take part in amino acid catabolism, cell cycle arrest, apoptosis, muscle development, and protein synthesis together with myogenic factors were significantly up-regulated from 5 to 14 days. At 9-14 d, genes involved in immune response and the caspase cascade were up-regulated. At 5-14d, genes related to contractile (myosin heavy chain and myosin binding protein C), regulatory (troponin, tropomyosin), developmental, caveolin-3, extracellular matrix, glycolysis/gluconeogenesis, cytoskeleton/sarcomere regulation and mitochondrial proteins were down-regulated. An activation of genes related to muscle growth and new muscle fiber formation (increase of myogenic factors and JunB and down-regulation of myostatin) and up-regulation of genes that code protein synthesis and translation factors were found from 5 to 14 days. Novel temporal patterns of gene expression have been uncovered, suggesting a unique, coordinated and highly complex mechanism underlying the muscle wasting associated with AQM in ICU patients and providing new target genes and avenues for intervention studies.


Behavioral Counseling to Prevent Skin Cancer: US Preventive Services Task Force Recommendation Statement.
Skin cancer is the most common type of cancer in the United States. Although invasive melanoma accounts for only 2% of all skin cancer cases, it is responsible for 80% of skin cancer deaths. Basal and squamous cell carcinoma, the 2 predominant types of nonmelanoma skin cancer, represent the vast majority of skin cancer cases. To update the 2012 US Preventive Services Task Force (USPSTF) recommendation on behavioral counseling for the primary prevention of skin cancer and the 2009 recommendation on screening for skin cancer with skin self-examination. The USPSTF reviewed the evidence on whether counseling patients about sun protection reduces intermediate outcomes (eg, sunburn or precursor skin lesions) or skin cancer; the link between counseling and behavior change, the link between behavior change and skin cancer incidence, and the harms of counseling or changes in sun protection behavior; and the link between counseling patients to perform skin self-examination and skin cancer outcomes, as well as the harms of skin self-examination. The USPSTF determined that behavioral counseling interventions are of moderate benefit in increasing sun protection behaviors in children, adolescents, and young adults with fair skin types. The USPSTF found adequate evidence that behavioral counseling interventions result in a small increase in sun protection behaviors in adults older than 24 years with fair skin types. The USPSTF found inadequate evidence on the benefits and harms of counseling adults about skin self-examination to prevent skin cancer. The USPSTF recommends counseling young adults, adolescents, children, and parents of young children about minimizing exposure to UV radiation for persons aged 6 months to 24 years with fair skin types to reduce their risk of skin cancer. (B recommendation) The USPSTF recommends that clinicians selectively offer counseling to adults older than 24 years with fair skin types about minimizing their exposure to UV radiation to reduce risk of skin cancer. Existing evidence indicates that the net benefit of counseling all adults older than 24 years is small. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the presence of risk factors for skin cancer. (C recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of counseling adults about skin self-examination to prevent skin cancer. (I statement).


Pattern formation in two-dimensional hard-core/soft-shell systems with variable soft shell profiles.
Hard-core/soft shell (HCSS) particles have been shown to self-assemble into a remarkably rich variety of structures under compression due to the simple interplay between the hard-core and soft-shoulder length scales in their interactions. Most studies in this area model the soft shell interaction as a square shoulder potential. Although appealing from a theoretical point of view, the potential is physically unrealistic because there is no repulsive force in the soft shell regime, unlike in experimental HCSS systems. To make the model more realistic, here we consider HCSS particles with a range of soft shell potential profiles beyond the standard square shoulder form and study the model using both minimum energy calculations and Monte Carlo simulations. We find that by tuning density and the soft shell profile, HCSS particles in the thin shell regime (i.e., shell to core ratio ) can form a large range of structures, including hexagons, chains, squares, rhomboids and two distinct zig-zag structures. Furthermore, by tuning the density and r1/r0, we find that HCSS particles with experimentally realistic linear ramp soft shoulder repulsions can form honeycombs and quasicrystals with 10-fold and 12-fold symmetry. Our study therefore suggests the exciting possibility of fabricating these exotic 2D structures experimentally through colloidal self-assembly.


Genetic Variation Among Colletotrichum graminicola Isolates from Four Hosts Using Isozyme Analysis.
Anthracnose basal rot (ABR) is a serious disease of turfgrasses that is caused by the pathogen Colletotrichum graminicola. The relationships of isolates causing ABR on turfgrasses to those causing disease on important crop hosts (maize, sorghum) remain unresolved. Genetic variation among isolates from annual bluegrass, creeping bentgrass, maize, and sorghum was evaluated based on host origin and geographic origin. Isozymes were used to estimate the genetic variation of the isolates. Five enzyme systems comprising 16 alleles from 5 loci were used. Allele frequencies, genetic distance, and linkage disequilibrium values were calculated for isolates based on both host and geographic origin. Isolates from creeping bentgrass and annual bluegrass were the most closely related based on Nei's genetic distance, while isolates from maize and sorghum were the most distantly related, consistent with their known species-level relationship. Isolates from annual bluegrass and creeping bentgrass had different genetic distances to isolates from both maize and sorghum. Annual bluegrass isolates from different geographic regions had the smallest genetic distance values observed in this study, indicating a very close relationship regardless of geographic origin. Based on these data, it appears that host origin, not geographic origin, plays a more important role in the genetic diversity of these fungi.


Thromboembolism following removal of femoral venous apheresis catheters in patients with breast cancer.
Apheresis catheters have simplified collection of peripheral blood stem cells (PBSC), but may be associated with thrombosis of the instrumented vessels. We performed a retrospective analysis to study the prevalence of thromboembolism associated with the use of femoral apheresis catheters in patients with breast cancer. Patients were participants in clinical trials of high-dose chemotherapy with autologous PBSC rescue. They underwent mobilization with either high-dose cyclophosphamide (n = 21) or cyclophosphamide/paclitaxel (n = 64), followed by filgrastim. Double lumen catheters (12 or 13 Fr) were placed in the femoral vein and removed within 12 h of the last apheresis procedure. Apheresis was performed using a continuous flow cell separator and ACD-A anticoagulant. Thromboembolism was diagnosed by either venous ultrasonography or ventilation-perfusion scan. Nine of 85 patients (10.6%) undergoing large volume apheresis with use of a femoral catheter developed thromboembolic complications. Pulmonary embolus (PE) was diagnosed in five and femoral vein thrombosis in four patients. Four of the five patients who developed PE were symptomatic; one asymptomatic patient had a pleural-based, wedge-shaped lesion detected on a staging computed tomography scan. The mean number of apheresis procedures was 2.4 (range one to four) and the mean interval between removal of the apheresis catheter and diagnosis of thrombosis was 17.6 days. In contrast, none of 18 patients undergoing apheresis using jugular venous access and none of 54 healthy allogeneic donors undergoing concurrent filgrastim-mobilized PBSC donation (mean 1.7 procedures/donor) using femoral access experienced thromboembolic complications. Thromboembolism following femoral venous catheter placement for PBSC collection in patients with breast cancer may be more common than previously recognized. Healthy PBSC donors are not at the same risk. Onset of symptoms related to thrombosis tended to occur several weeks after catheter removal. This suggests that the physicians not only need to be vigilant during the period of apheresis, but also need to observe patients for thromboembolic complications after the catheter is removed. The long interval between the removal of apheresis catheter and the development of thromboembolism may have a potential impact on prophylactic strategies developed in future, such as the duration of prophylactic anticoagulation. Avoidance of the femoral site in breast cancer patients, and close prospective monitoring after catheter removal, are indicated.


Identifying compositionally homogeneous and nonhomogeneous domains within the human genome using a novel segmentation algorithm.
It has been suggested that the mammalian genome is composed mainly of long compositionally homogeneous domains. Such domains are frequently identified using recursive segmentation algorithms based on the Jensen-Shannon divergence. However, a common difficulty with such methods is deciding when to halt the recursive partitioning and what criteria to use in deciding whether a detected boundary between two segments is real or not. We demonstrate that commonly used halting criteria are intrinsically biased, and propose IsoPlotter, a parameter-free segmentation algorithm that overcomes such biases by using a simple dynamic halting criterion and tests the homogeneity of the inferred domains. IsoPlotter was compared with an alternative segmentation algorithm, D(JS), using two sets of simulated genomic sequences. Our results show that IsoPlotter was able to infer both long and short compositionally homogeneous domains with low GC content dispersion, whereas D(JS) failed to identify short compositionally homogeneous domains and sequences with low compositional dispersion. By segmenting the human genome with IsoPlotter, we found that one-third of the genome is composed of compositionally nonhomogeneous domains and the remaining is a mixture of many short compositionally homogeneous domains and relatively few long ones.


Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation.
A minority of inherited prion diseases (IPD) are caused by four to 12 extra octapeptide repeat insertions (OPRI) in the prion protein gene (PRNP). Only four families affected by IPD with 8-OPRI have been reported, one of them was a three-generation Swedish kindred in which four of seven affected subjects had chorea which was initially attributed to Huntington's disease (HD). Following the exclusion of HD, this phenotype was labeled Huntington disease-like 1 (HDL1). Here, we provide an update on the Swedish 8-OPRI family, describe the clinical features of one of its affected members with video-recordings, compare the four 8-OPRI families and study the effect of PRNP polymorphic codon 129 and gender on phenotype. Surprisingly, the Swedish kindred displayed the longest survival of all of the 8-OPRI families with a mean of 15.1 years from onset of symptoms. Subjects with PRNP polymorphic codon 129M in the mutated allele had significantly earlier age of onset, longer survival and earlier age of death than 129V subjects. Homozygous 129MM had earlier age of onset than 129VV. Females had a significantly earlier age of onset and earlier age of death than males. Up to 50% of variability in age of onset was conferred by the combined effect of PRNP polymorphic codon 129 and gender. An inverse correlation between early age of onset and long survival was found for this mutation.


Mention of ethical review and informed consent in the reports of research undertaken during the armed conflict in Darfur (2004-2012): a systematic review.
Armed conflict in Darfur, west Sudan since 2003 has led to the influx of about 100 international humanitarian UN and non-governmental organizations to help the affected population. Many of their humanitarian interventions included the collection of human personal data and/or biosamples, and these activities are often associated with ethical issues. A systematic review was conducted to assess the proportion of publicly available online reports of the research activities undertaken on humans in Darfur between 2004 and 2012 that mention obtaining ethical approval and/or informed consent. This systematic review is based on a systematic literature search of Complex Emergency Database, ReliefWeb, PubMed), followed by a hand search for the hardcopies of the eligible reports archived in the Centre for Research on the Epidemiology of Disasters (CRED) in Brussels. The online search showed that out of the 68 eligible studies, 13.2% (9) reported gaining ethical approval and 42.6% (29) that an informed consent was obtained from the participants. The CRED search included 138 eligible reports. None of these reports mentioned gaining ethical approval and 17 (12.3%) mentioned obtaining informed consent from their participants. The proportion of studies reporting ethical review and informed consent was smaller than might be expected, so we suggest five possible explanations for these findings. This review provides empirical evidence that can help in planning ethical conduct of research in humanitarian settings.


Identification of active site residues in E. coli ketopantoate reductase by mutagenesis and chemical rescue.
Ketopantoate reductase (EC 188.8.131.52) catalyzes the NADPH-dependent reduction of alpha-ketopantoate to D-(-)-pantoate in the biosynthesis of pantothenate. The pH dependence of V and V/K for the E. coli enzyme suggests the involvement of a general acid/base in the catalytic mechanism. To identify residues involved in catalysis and substrate binding, we mutated the following six strictly conserved residues to Ala: Lys72, Lys176, Glu210, Glu240, Asp248, and Glu256. Of these, the K176A and E256A mutant enzymes showed 233- and 42-fold decreases in V(max), and 336- and 63-fold increases in the K(m) value of ketopantoate, respectively, while the other mutants exhibited WT kinetic properties. The V(max) for the K176A and E256A mutant enzymes was markedly increased, up to 25% and 75% of the wild-type level, by exogenously added primary amines and formate, respectively. The rescue efficiencies for the K176A and E256A mutant enzymes were dependent on the molecular volume of rescue agents, as anticipated for a finite active site volume. The protonated form of the amine is responsible for recovery of activity, suggesting that Lys176 functions as a general acid in catalysis of ketopantoate reduction. The rescue efficiencies for the K176A mutant by primary amines were independent of the pK(a) value of the rescue agents (Bronsted coefficient, alpha = -0.004 +/-0.008). Insensitivity to acid strength suggests that the chemical reaction is not rate-limiting, consistent with (a) the catalytic efficiency of the wild-type enzyme (k(cat)/K(m) = 2x10(6) M(-1) s(-1) and (b) the small primary deuterium kinetic isotope effects, (D)V = 1.3 and (D)V/K = 1.5, observed for the wild-type enzyme. Larger primary deuterium isotope effects on V and V/K were observed for the K176A mutant ((D)V = 3.0, (D)V/K = 3.7) but decreased nearly to WT values as the concentration of ethylamine was increased. The nearly WT activity of the E256A mutant in the presence of formate argues for an important role for this residue in substrate binding. The double mutant (K176A/E256A) has no detectable ketopantoate reductase activity. These results indicate that Lys176 and Glu256 of the E. coli ketopantoate reductase are active site residues, and we propose specific roles for each in binding ketopantoate and catalysis.


GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis.
Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS). Here, we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing-remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF). Using a combination of neural network-based representation learning algorithms, we identified an expanded T helper cell subset in patients with MS, characterized by the expression of granulocyte-macrophage colony-stimulating factor and the C-X-C chemokine receptor type 4. This cellular signature, which includes expression of very late antigen 4 in peripheral blood, was also enriched in the central nervous system of patients with relapsing-remitting multiple sclerosis. In independent validation cohorts, we confirmed that this cell population is increased in patients with MS compared with other inflammatory and non-inflammatory conditions. Lastly, we also found the population to be reduced under effective disease-modifying therapy, suggesting that the identified T cell profile represents a specific therapeutic target in MS.


Confirmation of a metastasis-specific microRNA signature in primary colon cancer.
The identification of patients with high-risk stage II colon cancer who may benefit from adjuvant therapy may allow the clinical approach to be tailored for these patients based on an understanding of tumour biology. MicroRNAs have been proposed as markers of the prognosis or treatment response in colorectal cancer. Recently, a 2-microRNA signature (let-7i and miR-10b) was proposed to identify colorectal cancer patients at risk of developing distant metastasis. We assessed the prognostic value of this signature and additional candidate microRNAs in an independent, clinically well-defined, prospectively collected cohort of primary colon cancer patients including stage I-II colon cancer without and stage III colon cancer with adjuvant treatment. The 2-microRNA signature specifically predicted hepatic recurrence in the stage I-II group, but not the overall ability to develop distant metastasis. The addition of miR-30b to the 2-microRNA signature allowed the prediction of both distant metastasis and hepatic recurrence in patients with stage I-II colon cancer who did not receive adjuvant chemotherapy. Available gene expression data allowed us to associate miR-30b expression with axon guidance and let-7i expression with cell adhesion, migration, and motility.


Brominated flame retardants in placental tissues: associations with infant sex and thyroid hormone endpoints.
Brominated flame retardants (BFRs) are endocrine disruptors that bioaccumulate in the placenta, but it remains unclear if they disrupt tissue thyroid hormone (TH) metabolism. Our primary goal was to investigate associations between placental BFRs, TH levels, Type 3 deiodinase (DIO3) activity and TH sulfotransferase (SULT) activities. Placenta samples collected from 95 women who delivered term (>37 weeks) infants in Durham, NC, USA (enrolled 2010-2011) were analyzed for polybrominated diphenyl ethers (PBDEs), 2,4,6-tribromophenol (2,4,6-TBP), THs (T4, T3 and rT3), and DIO3 and TH SULT activities. PBDEs and 2,4,6-TBP were detected in all placenta samples. PBDEs were higher in placental tissues from male infants compared to female infants, with 2,4,6-TBP and BDE-209 levels approximately twice as high. Among male infants, placental BDE-99 and BDE-209 were negatively associated with rT3 placental levels. For female infants, placental BDE-99 and 2,4,6-TBP were positively associated with T3 concentrations. DIO3 activity was also significantly higher in placental tissues from male infants compared to females, while 3,3'-T2 SULT activity was significantly higher in placental tissues from females compared to males. Among males, several PBDE congeners were positively correlated with T3 SULT, while BDE-99 was negatively associated with T3 SULT among females. Associations generally remained after adjustment for potential confounding by maternal age and gestational age at delivery. These results suggest BFRs accumulate in the placenta and potentially alter TH function in a sex-specific manner, a possible mechanism to explain the sex-dependent impacts of environmental exposure on children's growth and development. More research is needed to elucidate the effects of BFRs on placenta function during pregnancy, as well as the biological consequences of exposure and thyroid disruption.


'Trust and teamwork matter': community health workers' experiences in integrated service delivery in India.
A comprehensive and integrated approach to strengthen primary health care has been the major thrust of the National Rural Health Mission (NRHM) that was launched in 2005 to revamp India's rural public health system. Though the logic of horizontal and integrated health care to strengthen health systems has long been acknowledged at policy level, empirical evidence on how such integration operates is rare. Based on recent (2011-2012) ethnographic fieldwork in Odisha, India, this article discusses community health workers' experiences in integrated service delivery through village-level outreach sessions within the NRHM. It shows that for health workers, the notion of integration goes well beyond a technical lens of mixing different health services. Crucially, they perceive 'teamwork' and 'building trust with the community' (beyond trust in health services) to be critical components of their practice. However, the comprehensive NRHM primary health care ideology - which the health workers espouse - is in constant tension with the exigencies of narrow indicators of health system performance. Our ethnography shows how monitoring mechanisms, the institutionalised privileging of statistical evidence over field-based knowledge and the highly hierarchical health bureaucratic structure that rests on top-down communications mitigate efforts towards sustainable health system integration.


Altered expression of neuronal cell adhesion molecules induced by nerve injury and repair.
Peripheral nerve injury results in short-term and long-term changes in both neurons and glia. In the present study, immunohistological and immunoblot analyses were used to examine the expression of the neural cell adhesion molecule (N-CAM) and the neuron-glia cell adhesion molecule (Ng-CAM) within different parts of a functionally linked neuromuscular system extending from skeletal muscle to the spinal cord after peripheral nerve injury. Histological samples were taken from 3 to 150 d after crushing or transecting the sciatic nerve in adult chickens and mice. In unperturbed tissues, both N-CAM and Ng-CAM were found on nonmyelinated axons, and to a lesser extent on Schwann cells and myelinated axons. Only N-CAM was found on muscles. After denervation, the following changes were observed: The amount of N-CAM in muscle fibers increased transiently on the surface and in the cytoplasm, and in interstitial spaces between fibers. Restoration of normal N-CAM levels in muscle was dependent on reinnervation; in a chronically denervated state, N-CAM levels remained high. After crushing or cutting the nerve, the amount of both CAMs increased in the area surrounding the lesion, and the predominant form of N-CAM changed from a discrete Mr 140,000 component to the polydisperse high molecular weight embryonic form. Anti-N-CAM antibodies stained neurites, Schwann cells, and the perineurium of the regenerating sciatic nerve. Anti-Ng-CAM antibodies labeled neurites, Schwann cells and the endoneurial tubes in the distal stump. Changes in CAM distribution were observed in dorsal root ganglia and in the spinal cord only after the nerve was cut. The fibers within affected dorsal root ganglia were more intensely labeled for both CAMs, and the motor neurons in the ventral horn of the spinal cord of the affected segments were stained more intensely in a ring pattern by anti-N-CAM and anti-Ng-CAM than their counterparts on the side contralateral to the lesion. Taken together with the previous studies (Rieger, F., M. Grumet, and G. M. Edelman, J. Cell Biol. 101:285-293), these data suggest that local signals between neurons and glia may regulate CAM expression in the spinal cord and nerve during regeneration, and that activity may regulate N-CAM expression in muscle. Correlations of the present observations are made here with established events of nerve degeneration and suggest a number of roles for the CAMs in regenerative events.(ABSTRACT TRUNCATED AT 400 WORDS)


Extent and nature of unlicensed and off-label medicine use in hospitalised children in Palestine.
To determine the extent and nature of unlicensed/off-label prescribing patterns in hospitalised children in Palestine. Four paediatric wards in two public health system hospitals in Palestine [Caritas children's hospital (Medical and neonatal intensive care units) and Rafidia general hospital (Medical and surgical units)]. A prospective survey of drugs administered to infants and children <18 years old was carried out over a five-week period in the four paediatric wards. Drug-licensing status of all prescriptions was determined according to the Palestinian Registered Product List and the Physician's Desk Reference. Overall, 917 drug prescriptions were administered to 387children. Of all drug prescriptions, 528 (57.5%) were licensed for use in children; 65 (7.1%) were unlicensed; and 324 (35.3%) were used off-label. Of all children, 49.6% received off-label prescriptions, 10.1% received unlicensed medications and 8.2% received both. Seventy-two percent of off-label drugs and 66% of unlicensed drugs were prescribed for children <2 years. Multivariate analysis showed that patients who were admitted to the neonatal intensive care unit and infants aged 0-1 years were most likely to receive a greater number of off-label or unlicensed medications (OR 1.80; 95% CI 1.03-3.59 and OR 1.99; 95% CI 0.88-3.73, respectively). The present findings confirmed the elevated prevalence of unlicensed and off-label paediatric drugs use in Palestine and strongly support the need to perform well designed clinical studies in children.


Controlled space closure with a statically determinate retraction system.
We designed a variant of a cantilever spring, the statically determinate retraction system, and studied its mechanical characteristics. This novel system consisted of a single-force cantilever arm made of 0.017 x 0.025-inch titanium molybdenum alloy wire for active retraction and a passive rigid stabilizing unit. Since the active component for space closure is a cantilever, it is simple to measure the force system of the spring with a force gauge (ie, the system is a statically determinate system). A torque tester apparatus was used to examine the property of this retraction spring with a helix at the posterior and a simple bend at the anterior. Both a standard shape and modified shapes of the spring were studied. At full activation, the standard spring delivered 163 g with a load-deflection rate of six g/mm. When the magnitude of the anterior bend of the spring was increased, the horizontal component of the force increased more than the vertical component. In contrast, when the posterior bend of the spring increased, the vertical component of the force increased more than the horizontal component. A clinical case presented here clearly demonstrates the versatility and applicability of the spring.


Antiviral and immunostimulating effects of lignin-carbohydrate-protein complexes from Pimpinella anisum.
Three antiviral and immunostimulating substances (LC1, LC2 and LC3) were isolated from a hot water extract of seeds of Pimpinella anisum by combination of anion-exchange, gel filtration and hydrophobic interaction column chromatographies. Chemical and spectroscopic analyses revealed them to be lignin-carbohydrate-protein complexes. These lignin-carbohydrate complexes (LCs) showed antiviral activities against herpes simplex virus types 1 and 2 (HSV-1 and -2), human cytomegalovirus (HCMV) and measles virus. LCs were also found to interfere with virus adsorption to the host cell surface and directly inactivate viruses. Furthermore, they enhanced nitric oxide (NO) production by inducing iNOS mRNA and protein expression in RAW 264.7 murine macrophage cells. The induced mRNA expression of cytokines including IL-1β and IL-10 was also apparent. These results suggest that the lignin-carbohydrate-protein complexes from P. anisum possessed potency as functional food ingredients against infectious diseases.


A Retrospective Observational Study of Uveitis in a Single Center in Poland with a Review of Findings in Europe.
BACKGROUND This study aimed to review the causes, presentation, and clinicopathological associations of uveitis in a single department of ophthalmology in Poland, and to compare the findings with previously published studies from other European countries. MATERIAL AND METHODS Review of local patient records between 2005-2015 identified patients diagnosed with uveitis. Data obtained included age, gender, imaging findings, and laboratory diagnostic findings. A literature review identified 24 publications from 1976-2017 that reported observational data from patients with uveitis in Europe. Statistical analysis compared the findings. RESULTS Between 2005-2015, 279 patients were diagnosed with uveitis (mean age, 38.3±15.3 years) (61.6% women) including unilateral uveitis (60.5%), with posterior uveitis (48.4%), anterior uveitis (26.5%), and intermediate uveitis (12.9%). A general etiology was established in 76.3% and included ocular-specific syndromes (31.8%), infection (27.9%), and an association with systemic disease (16.8%), but 23.6% were unclassifiable. Specific causes of uveitis included toxoplasmosis (17.9%), Fuchs uveitis (12.2%), white dot syndromes (WDS) (10.4%), sarcoidosis (6.1%), toxocariasis (6.1%), HLA-B27-associated acute anterior uveitis (AAU) (5.7%), multiple sclerosis (4.7%), ankylosing spondylitis (3.6%) and herpesvirus infection (2.5%). Data from 26 published studies (24,126 patients with uveitis) from 12 European countries showed that idiopathic uveitis was most common (36.6%); the identified causes included toxoplasmosis (9.4%), WDS (7.2%), and Fuchs uveitis (6.1%). CONCLUSIONS In a single ophthalmic center in Poland, and throughout Europe, the causes of uveitis are varied. Genetic, geographic, social and environmental factors are likely to affect the cause of uveitis in different populations.


Simultaneous mineralization and deposition of inorganic nanoparticles onto micropatterns with a perfluoropolyether-decorated surface as a passivating layer.
We achieved simultaneous mineralization and patterning of inorganic nanoparticles on micropatterns using peptide as a linker and perfluoropolyether (PFPE) as a passivating molecule. The peptide was used as a linker molecule immobilizing inorganic nanoparticles on the substrate and PFPE was exploited as a mask material preventing nanoparticle binding. These two substances were used as surface-modifying molecules for the positive and negative patterns, respectively. On the patterned surface, mineralization and selective deposition of inorganic nanoparticles (such as TiO2 and Cu2S) were achieved by exploiting the characteristics of the surface-modifying molecules. The aqueous precursors of inorganic sources were mineralized to the nanoparticles, and the mineralized nanoparticles were bound directly to the peptide-decorated positive pattern, while their deposition on the negative pattern was repelled because of the low surface energy of PFPE. The nanoparticle-bound surface was identified by making a sandwich structure with a fluorescece-decorated peptide and observing the surface topology. The nanoparticle layers retained their inherent electrical properties, suggesting potential applications in micro device fabrication. This study demonstrates that selective deposition of metallic and inorganic nanoparticles can be achieved with the use of PFPE and reactive peptides while keeping the original characteristics of the nanoparticles.


Factors associated with testing for HIV in people aged ≥50 years: a qualitative study.
Despite a decline in the number of new HIV infections in the UK overall, the number and proportion of new HIV diagnoses in people aged ≥50 years continues to increase. People aged ≥50 years are disproportionately affected by late diagnosis, which is associated with poorer health outcomes, increased treatment complexity and increased healthcare costs. Late HIV diagnosis also has significant public health implications in terms of onward HIV transmission. It is not fully understood what factors affect the decision of an older person to test for HIV. The aim of this study was to identify factors associated with testing for HIV in people aged ≥50 years who tested late for HIV. We interviewed 20 people aged ≥50 years diagnosed late with HIV to identify factors associated with HIV testing. Interviews were audio recorded, transcribed verbatim and thematically analysed. Seven themes associated with HIV testing in people aged ≥50 years were identified: experience of early HIV/AIDS campaigns, HIV knowledge, presence of symptoms and symptom attribution, risk and risk perception, generational approaches to health and sexual health, stigma, and type of testing and testing venue. Some factors associated with testing identified in this study were unique to older individuals. People aged ≥50 years often do not perceive themselves to be at risk of HIV. Further, stigma and a lack of knowledge of how to access HIV testing suggest a need for health promotion and suggest current sexual health services may need to adapt to better meet their needs.


Mismatch between birth date and vegetation phenology slows the demography of roe deer.
Marked impacts of climate change on biodiversity have frequently been demonstrated, including temperature-related shifts in phenology and life-history traits. One potential major impact of climate change is the modification of synchronization between the phenology of different trophic levels. High phenotypic plasticity in laying date has allowed many bird species to track the increasingly early springs resulting from recent environmental change, but although changes in the timing of reproduction have been well studied in birds, these questions have only recently been addressed in mammals. To track peak resource availability, large herbivores like roe deer, with a widespread distribution across Europe, should also modify their life-history schedule in response to changes in vegetation phenology over time. In this study, we analysed the influence of climate change on the timing of roe deer births and the consequences for population demography and individual fitness. Our study provides a rare quantification of the demographic costs associated with the failure of a species to modify its phenology in response to a changing world. Given these fitness costs, the lack of response of roe deer birth dates to match the increasingly earlier onset of spring is in stark contrast with the marked phenotypic responses to climate change reported in many other mammals. We suggest that the lack of phenotypic plasticity in birth timing in roe deer is linked to its inability to track environmental cues of variation in resource availability for the timing of parturition.


Energy-selective neutron imaging for morphological and phase analysis of iron-nickel meteorites.
We propose energy-selective neutron imaging as a new and non-destructive method to investigate rare metallic meteorites. It is based on attenuation of a neutron beam of limited spectral distribution in a sample depending on the elemental composition and crystalline structure. Radiography and tomography allow obtaining the presence, morphology and orientation information in the bulk of mineral inclusions, oxide crust and crystalline structure. Its usage in classification and meteor formation studies would be of great value.


Kappa and lambda light chain disease: survival rates and clinical manifestations.
Ninety-seven patients with light chain disease (LCD) were studied. The median survival from diagnosis was 30 mo for 52 patients with kappa-LCD and 10 mo for 45 patients with lambda-LCD (p less than 0.0007). A lower proportion of kappa-LCD patients (15.7%) than lambda-LCD patients (42.2%) died within the first 6 mo after diagnosis. The survival of the remaining patients with kappa-LCD was still much longer than of those with lambda-LCD (p = 0.022). The shorter survival of lambda-LCD patients could not be ascribed to an increased incidence of recognized manifestations indicating a poor prognosis (e.g., anemia, hypercalcemia, azotemia, low albumin, the extent of osteolytic lesions, or proteinuria), the incidence of amyloidosis, the clinical stage of the disease at diagnosis, or the response to treatment, and remains unexplained. A comparison of the clinical manifestations of LCD with those of other myelomas revealed some differences. LCD patients were slightly younger than IgA and IgG patients but older than IgD patients. A 1:1 ratio of males to females was similar to the ratios in IgA and IgG myeloma, but differed from the 3:1 ratio reported for IgD myeloma. Plasma-cell leukemia developed in 7/97 LCD patients, an incidence that was higher than has been reported in other myelomas. The initial BUN was more than or equal to 30 mg/100 ml in 54 of 95 LCD patients, an incidence that was higher than has been reported for IgA and IgG myeloma, but lower than the incidence in IgD myeloma. The incidence of amyloidosis in LCD (23 of 97 patients) was similar to that reported for IgA and IgG myeloma, but less than the incidence in IgD myeloma.


Effect of fragile X status categories and FMRP deficits on cognitive profiles estimated by robust pedigree analysis.
The effect of the fragile X pre-mutation and full mutation categories, and FMRP deficits in these categories, on neurocognitive status, have been assessed in fragile X individuals from 144 extended families, which included fragile X individuals, as well as their non-fragile X relatives. Neuropsychological status was assessed by the Wechsler summary and subtest test scores. A modification of the maximum likelihood estimators for pedigree data that is resistant to outliers was used to analyze the data. The results have demonstrated the effect of large expansions of CGG repeat in the FMR1 (fragile X mental retardation 1) gene (full mutation) in decreasing full scale IQ (FSIQ), as well as several FSIQ-adjusted subtest scores in the performance domain. Moreover, the results have demonstrated significant cognitive deficits in male individuals with pre-mutation. FMRP depletion correlates strongly with neurocognitive status in the full mutation subjects. Evidence for the effect of FMRP in smaller expansions (pre-mutation) in reducing FSIQ, Performance and Verbal scores, as well as subtest scores in males, has also been obtained. The results are also suggestive of factors other than FMRP deficit which may determine some specific cognitive deficits in fragile X pre-mutation carriers. Genetic variance estimated from the models accounts for less than half of the total variance in FSIQ, and it varies widely between individual Wechsler subtests.


Inspiratory muscle training in chronic airflow limitation: effect on exercise performance.
The effect of inspiratory muscle training (IMT) on exercise capacity in patients with chronic airflow limitation (CAL) has been debated. The present study was planned to further investigate the effects of IMT on exercise performance. Twenty patients (aged 62+/-1 yrs; forced expiratory volume in one second/forced vital capacity (FEV1/FVC) 36+/-2%) were trained 30 min daily for 6 days a week during 10 weeks, with either 30% (Group 1) or 10% (Group 2) of peak maximal inspiratory pressure (PI,max) as a training load. Exercise performance was evaluated by the distance walked in 6 min (6MWD) and by changes in oxygen consumption (V'O2) and minute ventilation (V'E) during a progressive exercise test. Changes in PI,max and dyspnoea were also measured. Results showed a significant increment in peak PI,max in both groups, whereas dyspnoea and 6MWD improved only in Group 1 (p<0.05 and p<0.01, respectively). No increment in maximal workload or in peak V'O2 was observed in either group. Patients in Group 1, however, showed a reduction in V'E and V'O2 for the same exercise. A correlation between changes in V'E and V'O2 during a workload of 75 kpm x min(-1) was observed in Group 1 (r=0.92; p<0.001). We conclude that inspiratory muscle training using a load of 30% peak maximal inspiratory pressure, improves dyspnoea, increases walking capacity and reduces the metabolic cost of exercise.


Impact of being overweight on the surgical outcomes of patients with gastric cancer: a meta-analysis.
To investigate the effect of being overweight on the surgical results of patients with gastric cancer. Comprehensive electronic searches of the PubMed, Web of Science, and Cochrane Library databases were conducted. Studies were identified that included patients with surgical complications from gastric cancer who were classified as normal weight [body mass index (BMI) < 25 kg/m(2)] or overweight (BMI ≥ 25 kg/m(2)). The operative time, retrieved lymph nodes, blood loss, and long-term survival were analyzed. A subgroup analysis was conducted based on whether patients received laparoscopic or open gastrectomy procedures. All statistical tests were performed using ReviewerManager 5.1.2 software. This meta-analysis included 23 studies with 20678 patients (15781 with BMI < 25 kg/m(2); 4897 with BMI ≥ 25 kg/m(2)). Overweight patients had significantly increased operation times [MD: -29.14; 95%CI: -38.14-(-20.21); P < 0.00001], blood loss [MD: -194.58; 95%CI: -314.21-(-74.95); P = 0.001], complications (RR: 0.75; 95%CI: 0.66-0.85; P < 0.00001), anastomosis leakages (RR: 0.59; 95%CI: 0.42-0.82; P = 0.002), and pancreatic fistulas (RR: 0.486; 95%CI: 0.34-0.63; P < 0.00001), whereas lymph node retrieval was decreased significantly in the overweight group (MD: 1.69; 95%CI: 0.75-2.62; P < 0.0001). In addition, overweight patients had poorer long-term survival (RR: 1.14; 95%CI: 1.07-1.20; P < 0.0001). No significant difference was detected for the mortality and length of hospital stay. This meta-analysis demonstrates that a high BMI not only increases the surgical difficulty and complications but also impairs the long-term survival of patients with gastric cancer.


A taxonomy of inductive problems.
Inductive inferences about objects, features, categories, and relations have been studied for many years, but there are few attempts to chart the range of inductive problems that humans are able to solve. We present a taxonomy of inductive problems that helps to clarify the relationships between familiar inductive problems such as generalization, categorization, and identification, and that introduces new inductive problems for psychological investigation. Our taxonomy is founded on the idea that semantic knowledge is organized into systems of objects, features, categories, and relations, and we attempt to characterize all of the inductive problems that can arise when these systems are partially observed. Recent studies have begun to address some of the new problems in our taxonomy, and future work should aim to develop unified theories of inductive reasoning that explain how people solve all of the problems in the taxonomy.


Mandibular Mural Ameloblastoma with Unusual Histopathologic Features: a Rare Challenging Case.
Ameloblastomas demonstrate various clinical and microscopic patterns. They typically have been described as possessing three biologic variants including solid, cystic (unicystic) and peripheral, of which about 13% to 21% of all cases are unicystic. Granular cell subtype is a rare variant especially when both the inner and peripheral layers of tumoral islands composed exclusively of eosinophilic granular cells. The purpose of this case report is to present a unique case of cystic ameloblastoma with an unusual radiographic and microscopic pattern affecting a 25-year-old female. Awareness of these rare histopathologic features for oral pathologist is essential to help correct diagnosis.


Surface plasmon hurdles leading to a strongly localized giant field enhancement on two-dimensional (2D) metallic diffraction gratings.
An extensive numerical study of diffraction of a plane monochromatic wave by a single gold cone on a plane gold substrate and by a periodical array of such cones shows formation of curls in the map of the Poynting vector. They result from the interference between the incident wave, the wave reflected by the substrate, and the field scattered by the cone(s). In case of a single cone, when going away from its base along the surface, the main contribution in the scattered field is given by the plasmon surface wave (PSW) excited on the surface. As expected, it has a predominant direction of propagation, determined by the incident wave polarization. Two particular cones with height approximately 1/6 and 1/3 of the wavelength are studied in detail, as they present the strongest absorption and field enhancement when arranged in a periodic array. While the PSW excited by the smaller single cone shows an energy flux globally directed along the substrate surface, we show that curls of the Poynting vector generated with the larger cone touch the diopter surface. At this point, their direction is opposite to the energy flow of the PSW, which is then forced to jump over the vortex regions. Arranging the cones in a two-dimensional subwavelength periodic array (diffraction grating), supporting a specular reflected order only, resonantly strengthens the field intensity at the tip of cones and leads to a field intensity enhancement of the order of 10 000 with respect to the incident wave intensity. The enhanced field is strongly localized on the rounded top of the cones. It is accompanied by a total absorption of the incident light exhibiting large angular tolerances. This strongly localized giant field enhancement can be of much interest in many applications, including fluorescence spectroscopy, label-free biosensing, surface-enhanced Raman scattering (SERS), nonlinear optical effects and photovoltaics.


Noise-enhanced computation in a model of a cortical column.
Varied sensory systems use noise in order to enhance detection of weak signals. It has been conjectured in the literature that this effect, known as stochastic resonance, may take place in central cognitive processes such as memory retrieval of arithmetical multiplication. We show, in a simplified model of cortical tissue, that complex arithmetical calculations can be carried out and are enhanced in the presence of a stochastic background. The performance is shown to be positively correlated to the susceptibility of the network, defined as its sensitivity to a variation of the mean of its inputs. For nontrivial arithmetic tasks such as multiplication, stochastic resonance is a collective property of the microcircuitry of the model network.


Incident disability in older adults: prediction models based on two British prospective cohort studies.
To develop and validate a prediction model for incident locomotor disability after 7 years in older adults. Prospective British cohort studies: British Women's Heart and Health Study (BWHHS) for development and the English Longitudinal Study of Ageing (ELSA) for validation. Community-dwelling older adults. Multivariable logistic regression models after selection of predictors with backward elimination. Model performance was assessed using metrics of discrimination and calibration. Models were internally and externally validated. Locomotor disability was reported in BWHHS by 861 of 1,786 (48%) women after 7 years. Age, a history of arthritis and low physical activity levels were the most important predictors of locomotor disability. Models using routine measures as predictors had satisfactory calibration and discrimination (c-index 0.73). Addition of 31 blood markers did not increase the predictive performance. External validation in ELSA showed reduced discrimination (c-index 0.65) and an underestimation of disability risks. A web-based calculator for locomotor disability is available (http://www.sealedenvelope.com/trials/bwhhsmodel/). We developed and externally validated a prediction model for incident locomotor disability in older adults based on routine measures available to general practitioners, patients and public health workers, and showed an adequate discrimination. Addition of blood markers from major biological pathways did not improve the performance of the model. Further replication in additional data sets may lead to further enhancement of the current model.


The Drosophila trithorax group protein Kismet facilitates an early step in transcriptional elongation by RNA Polymerase II.
The Drosophila trithorax group gene kismet (kis) was identified in a screen for extragenic suppressors of Polycomb (Pc) and subsequently shown to play important roles in both segmentation and the determination of body segment identities. One of the two major proteins encoded by kis (KIS-L) is related to members of the SWI2/SNF2 and CHD families of ATP-dependent chromatin-remodeling factors. To clarify the role of KIS-L in gene expression, we examined its distribution on larval salivary gland polytene chromosomes. KIS-L is associated with virtually all sites of transcriptionally active chromatin in a pattern that largely overlaps that of RNA Polymerase II (Pol II). The levels of elongating Pol II and the elongation factors SPT6 and CHD1 are dramatically reduced on polytene chromosomes from kis mutant larvae. By contrast, the loss of KIS-L function does not affect the binding of PC to chromatin or the recruitment of Pol II to promoters. These data suggest that KIS-L facilitates an early step in transcriptional elongation by Pol II.


Minimum ten-year results of primary bipolar hip arthroplasty for degenerative arthritis of the hip.
Bipolar hip arthroplasty has been advocated by some as an alternative to total hip arthroplasty for the treatment of degenerative arthritis of the hip. We sought to assess the results of this procedure at our institution after a minimum duration of follow-up of ten years. We retrospectively reviewed a consecutive series of 152 patients (173 hips) who underwent primary bipolar hemiarthroplasty for the treatment of symptomatic degenerative arthritis of the hip with a cementless femoral component between 1983 and 1987. Of the original cohort of 152 patients, ninety-two patients (104 hips) were available for clinical and radiographic review at a mean of 12.2 years postoperatively. At the time of the latest follow-up, self-administered Harris hip questionnaires were used to assess pain, mobility, activity level, and overall satisfaction with the procedure. Biplanar hip radiographs were made to evaluate bipolar shell migration, osteolysis, and femoral stem fixation. At the time of the latest follow-up, nineteen patients (nineteen hips) had undergone revision to total hip arthroplasty because of mechanical failure, and three patients (three hips) were awaiting revision because of symptomatic radiographic mechanical failure. Twelve acetabular revisions were performed or scheduled for the treatment of pelvic osteolysis or protrusio acetabuli secondary to component migration. Acetabular reconstruction required bone-grafting, an oversized shell, and/or a pelvic reconstruction ring. The overall rate of mechanical failure was 21.2% (twenty-two of 104 hips), with 91% (twenty) of the twenty-two failures involving the acetabular component. Reaming of the acetabulum at the time of the index arthroplasty was associated with a 6.4-fold greater risk of revision. The rate of implant survival, with revision because of mechanical failure as the end point, was 94.2% for femoral components and 80.8% for acetabular components at a mean of 12.2 years. Of the remaining sixty-nine patients (eighty-one hips) in whom the original prosthesis was retained, seventeen patients (24.6%) rated the pain as moderate to severe. Nearly 30% of patients with an intact prosthesis required analgesics on a regular basis. Radiographs were available for fifty-eight hips (including all of the hips with moderate to severe pain) after a minimum duration of follow-up of ten years; twenty-eight of these fifty-eight hips had radiographic evidence of acetabular component migration. This bipolar cup, when used for hemiarthroplasty in patients with symptomatic arthritis of the hip, was associated with unacceptably high rates of pain, migration, osteolysis, and the need for revision to total hip arthroplasty, especially when the acetabulum had been reamed. To the extent that these findings can be generalized to similar implant designs with conventional polyethylene, we do not recommend bipolar hemiarthroplasty as the primary operative treatment for degenerative arthritis of the hip.


A review of 10 years of experience with indapamide as an antihypertensive agent.
Indapamide is an effective antihypertensive agent for which a dual mechanism of action has been put forward: a limited diuretic activity combined with antivasoconstrictive effects, resulting in decreased peripheral vascular resistance. Results from clinical trials show that 2.5 mg indapamide once daily effectively reduces arterial blood pressure in about two-thirds of patients with mild to moderate hypertension and that this reduction is related to the severity of the hypertension. As a rule, indapamide's blood pressure-reducing effect is rapid in onset (within 1 or 2 weeks) and by 1 month reaches 65% of its maximum, which occurs after 3 to 4 months of treatment. No tachyphylaxis has been observed during long-term treatment, nor has withdrawal syndrome at discontinuation of therapy. Indapamide has been successfully combined with beta blockers, methyldopa, and other antihypertensive agents, adding considerable effectiveness without noticeable increase in adverse reactions. In general, the drug is well tolerated and side effects are mild and rare. Possibly in relation to its limited diuretic activity at 2.5 mg daily, long-term treatment seldom elicits significant changes in electrolyte balance. In addition, indapamide does not induce deleterious effects on carbohydrate and lipid metabolism. Indapamide is an effective, well-tolerated, first-line antihypertensive agent. The fact that long-term administration does not induce biochemical abnormalities that constitute cardiovascular risk factors indicates another advantage of the drug.


Excitation and inhibition compete to control spiking during hippocampal ripples: intracellular study in behaving mice.
High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation of the rhythm and the recruitment of spikes from pyramidal neurons are still poorly understood. Using intracellular, sharp electrode recordings in freely moving, drug-free mice, we observed consistent large depolarizations in CA1 pyramidal cells during sharp wave ripples, which are associated with ripple frequency fluctuation of the membrane potential ("intracellular ripple"). Despite consistent depolarization, often exceeding pre-ripple spike threshold values, current pulse-induced spikes were strongly suppressed, indicating that spiking was under the control of concurrent shunting inhibition. Ripple events were followed by a prominent afterhyperpolarization and spike suppression. Action potentials during and outside ripples were orthodromic, arguing against ectopic spike generation, which has been postulated by computational models of ripple generation. These findings indicate that dendritic excitation of pyramidal neurons during ripples is countered by shunting of the membrane and postripple silence is mediated by hyperpolarizing inhibition.