Immediate Post-Concussion and Cognitive Testing (ImPACT): Effects of Data Integration Strategies on Classification Accuracy.
The current study aimed to evaluate varying data integration procedures and their effects on the classification accuracy of Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). Data were collected from an independent secondary school that included students in grades 9 to 12. The study examined 300 consecutive ImPACT score reports generated by secondary school students between 2010 and 2015. To appraise ImPACT's utility as a serialized measure, standardized regression-based equations were formulated to compute reliable change index scores. Discriminant function analyses (DFAs) consisting of varying combinations of ImPACT composite scores were conducted and their accuracy was compared to that produced by the standard interpretive procedure. Varying combinations of scores produced on Verbal Memory, Visual Memory, Visual Motor Speed, Reaction Speed, and the Postconcussion Symptom Scale were included in analyses. DFAs yielded sensitivities ranging from 31% to 49%, specificities from 88% to 95%, positive predictive values (PPVs) from 61% to 83%, and negative predictive values (NPVs) from 67% to 75%. Conversely, the standard interpretive procedure yielded a sensitivity of 73%, specificity of 43%, PPV of 45%, and NPV of 72%. The standard interpretive procedure produced a higher sensitivity than the DFAs; however, its PPV did not exceed chance levels. Conversely, DFA equations produced superior PPVs; however, their sensitivity hovered around 50%, leaving a substantial proportion of individuals with concussion undetected. Cognitive composite scores did not appear to offer significant incremental utility in relation to symptom self-report. Base rate conditions and psychometric factors appeared to contribute to ImPACT's limited classification accuracy.


A multifunctional, synthetic Gaussia princeps luciferase reporter for live imaging of Candida albicans infections.
Real-time monitoring of the spatial and temporal progression of infection/gene expression in animals will contribute greatly to our understanding of host-pathogen interactions while reducing the number of animals required to generate statistically significant data sets. Sensitive in vivo imaging technologies can detect low levels of light emitted from luciferase reporters in vivo, but the existing reporters are not optimal for fungal infections. Therefore, our aim was to develop a novel reporter system for imaging Candida albicans infections that overcomes the limitations of current luciferase reporters for this major fungal pathogen. This luciferase reporter was constructed by fusing a synthetic, codon-optimized version of the Gaussia princeps luciferase gene to C. albicans PGA59, which encodes a glycosylphosphatidylinositol-linked cell wall protein. Luciferase expressed from this PGA59-gLUC fusion (referred to as gLUC59) was localized at the C. albicans cell surface, allowing the detection of luciferase in intact cells. The analysis of fusions to strong (ACT1 and EFT3), oxidative stress-induced (TRX1, TRR1, and IPF9996), and morphogenesis-dependent (HWP1) promoters confirmed that gLUC59 is a convenient and sensitive reporter for studies of gene regulation in yeast or hyphal cells, as well as a flexible screening tool. Moreover, the ACT1-gLUC59 fusion represented a powerful tool for the imaging of disease progression in superficial and subcutaneous C. albicans infections. gLUC59 and related cell surface-exposed luciferase reporters might find wide applications in molecular biology, cell biology, pathobiology, and high-throughput screens.


Cognition in People With End-Stage Kidney Disease Treated With Hemodialysis: A Systematic Review and Meta-analysis.
Cognitive impairment is associated with poorer quality of life, risk for hospitalization, and mortality. Cognitive impairment is common in people with end-stage kidney disease treated with hemodialysis, yet the severity and specific cognitive deficits are uncertain. Systematic review and meta-analysis. Adults receiving hemodialysis compared with the general population, people with non-dialysis-dependent chronic kidney disease (NDD-CKD), people receiving peritoneal dialysis, or people with nondialyzed chronic kidney failure. Randomized controlled trials, cohort or cross-sectional studies without language restriction. Validated neuropsychological tests of cognition. Cognitive test scores, aggregated by cognitive domain: orientation and attention, perception, memory, language, construction and motor performance, concept formation and reasoning, and executive functions. 42 studies of 3,522 participants. Studies were of high or uncertain risk of bias, assessed by the Newcastle-Ottawa Scale. People treated with hemodialysis had worse cognition than the general population, particularly in attention (n=22; standardized mean difference [SMD], -0.93; 95% CI, -1.18 to -0.68). Hemodialysis patients performed better than nondialyzed patients with chronic kidney failure in attention (n=6; SMD, 0.70; 95% CI, 0.45 to 0.96) and memory (n=6; SMD, 0.36; 95% CI, 0.08 to 0.63), but had poorer memory than the general population (n=16; SMD, -0.41; 95% CI, -0.91 to 0.09) and people with NDD-CKD (n=5; SMD, -0.40; 95% CI, -0.60 to -0.21). There were insufficient data to show other differences among people receiving hemodialysis and those receiving peritoneal dialysis or with NDD-CKD. Potentially biased studies, not wholly adjusted for education. High heterogeneity, mainly due to the large variety of tests used to assess cognition. People treated with hemodialysis have impaired cognitive function compared to the general population, particularly in the domains of orientation and attention and executive function. Cognitive deficits in specific domains should be further explored in this population and should be considered when approaching education and chronic disease management.


Adult separation anxiety in patients with complicated grief versus healthy control subjects: relationships with lifetime depressive and hypomanic symptoms.
Around 9% to 20% of bereaved individuals experience symptoms of complicated grief (CG) that are associated with significant distress and impairment. A major issue is whether CG represents a distinctive nosographic entity, independent from other mental disorders, particularly major depression (MD), and the role of symptoms of adult separation anxiety. The purpose of this study was to compare the clinical features of patients with CG versus a sample of healthy control subjects, with particular focus on adult separation anxiety and lifetime mood spectrum symptoms. A total of 53 patients with CG and 50 healthy control subjects were consecutively recruited and assessed by means of the Structured Clinical Interview for DSM-IV Axis-I disorders (SCID-I/P), Inventory of Complicated Grief (ICG), Adult Separation Anxiety Questionnaire (ASA-27), Work and Social Adjustment Scale (WSAS) and Mood Spectrum-Self Report (MOODS-SR) lifetime version. Patients with CG reported significantly higher scores on the MOODS-SR, ASA-27, and WSAS with respect to healthy control subjects. The scores on the ASA-27 were significantly associated with the MOODS-SR depressive and manic components amongst both patients and healthy control subjects, with a stronger association in the latter. A major limitation of the present study is the small sample size that may reduce the generalizability of the results. Moreover, lifetime MOODS-SR does not provide information about the temporal sequence of the manic or depressive symptoms and the loss. The frequent comorbidity with MD and the association with both depressive and manic lifetime symptoms do not support the independence of CG from mood disorders. In our patients, CG is associated with high levels of separation anxiety in adulthood. However, the presence of lifetime mood instability, as measured by the frequent presence of depressive and hypomanic lifetime symptoms, suggests that cyclothymia might represent the common underlying feature characterizing the vulnerability to both adult separation anxiety and CG.


Isolation of polymorphic microsatellite loci in the New Zealand endemic sand-binder, Ficinia spiralis (Cyperaceae).
Ficinia spiralis (Cyperaceae) is a declining sand-binding sedge of ecological and cultural importance. Microsatellite primers were developed in F. spiralis to investigate how population genetic structure is related to the pronounced morphological, physiological, and ecological variation observed in this species. A 454 shotgun-sequencing approach was used to generate 157,274 raw sequence reads, 536 of which contained microsatellites. After initial primer testing for 40 loci, 14 polymorphic loci were isolated, containing five to 27 alleles per locus. Ten of these loci also amplified in a congener, F. nodosa. These loci will enable the assessment of the population genetic structure of F. spiralis, improving our understanding of the population processes underlying the observed morphological, physiological, and ecological variation in this endemic species. As the first microsatellites developed in Ficinia, these loci are a valuable resource for population genetic studies within this genus.


Persistent at-level thermal hyperalgesia and tactile allodynia accompany chronic neuronal and astrocyte activation in superficial dorsal horn following mouse cervical contusion spinal cord injury.
In humans, sensory abnormalities, including neuropathic pain, often result from traumatic spinal cord injury (SCI). SCI can induce cellular changes in the CNS, termed central sensitization, that alter excitability of spinal cord neurons, including those in the dorsal horn involved in pain transmission. Persistently elevated levels of neuronal activity, glial activation, and glutamatergic transmission are thought to contribute to the hyperexcitability of these dorsal horn neurons, which can lead to maladaptive circuitry, aberrant pain processing and, ultimately, chronic neuropathic pain. Here we present a mouse model of SCI-induced neuropathic pain that exhibits a persistent pain phenotype accompanied by chronic neuronal hyperexcitability and glial activation in the spinal cord dorsal horn. We generated a unilateral cervical contusion injury at the C5 or C6 level of the adult mouse spinal cord. Following injury, an increase in the number of neurons expressing ΔFosB (a marker of chronic neuronal activation), persistent astrocyte activation and proliferation (as measured by GFAP and Ki67 expression), and a decrease in the expression of the astrocyte glutamate transporter GLT1 are observed in the ipsilateral superficial dorsal horn of cervical spinal cord. These changes have previously been associated with neuronal hyperexcitability and may contribute to altered pain transmission and chronic neuropathic pain. In our model, they are accompanied by robust at-level hyperaglesia in the ipsilateral forepaw and allodynia in both forepaws that are evident within two weeks following injury and persist for at least six weeks. Furthermore, the pain phenotype occurs in the absence of alterations in forelimb grip strength, suggesting that it represents sensory and not motor abnormalities. Given the importance of transgenic mouse technology, this clinically-relevant model provides a resource that can be used to study the molecular mechanisms contributing to neuropathic pain following SCI and to identify potential therapeutic targets for the treatment of chronic pathological pain.


Diagnosing acute heart failure in patients with undifferentiated dyspnea: a lung and cardiac ultrasound (LuCUS) protocol.
The primary goal of this study was to determine accuracy for diagnosing acutely decompensated heart failure (ADHF) in the undifferentiated dyspneic emergency department (ED) patient using a lung and cardiac ultrasound (LuCUS) protocol. Secondary objectives were to determine if US findings acutely change management and if findings are more accurate than clinical gestalt. This was a prospective, observational study of adult patients presenting to the ED with undifferentiated dyspnea. The intervention consisted of a 12-view LuCUS protocol performed by experienced emergency physician sonographers. The primary objective was measured by comparing US findings to the final diagnosis independently determined by two physicians blinded to the LuCUS result. Acute treatment changes based on US findings were tracked in real time through a standardized data collection form. Data on 99 patients were analyzed; ADHF was the final diagnosis in 36%. The LuCUS protocol had sensitivity of 83% (95% confidence interval [CI] = 67% to 93%), specificity of 83% (95% CI = 70% to 91%), positive likelihood ratio of 4.8 (95% CI = 2.7 to 8.3), and negative likelihood ratio of 0.20 (95% CI = 0.09 to 0.42). Forty-seven percent of patients had changes in acute management, and 42% had changes in acute treatment. Observed agreement for the LuCUS protocol was 93% between coinvestigators. Overall, accuracy improved by 20% (83% vs. 63%, 95% CI = 8% to 31% for the difference) over clinical gestalt alone. The LuCUS protocol may accurately identify ADHF and may improve acute clinical management in dyspneic ED patients. This protocol has improved diagnostic accuracy over clinical gestalt alone.


Improved reference genome of the arboviral vector Aedes albopictus.
The Asian tiger mosquito Aedes albopictus is globally expanding and has become the main vector for human arboviruses in Europe. With limited antiviral drugs and vaccines available, vector control is the primary approach to prevent mosquito-borne diseases. A reliable and accurate DNA sequence of the Ae. albopictus genome is essential to develop new approaches that involve genetic manipulation of mosquitoes. We use long-read sequencing methods and modern scaffolding techniques (PacBio, 10X, and Hi-C) to produce AalbF2, a dramatically improved assembly of the Ae. albopictus genome. AalbF2 reveals widespread viral insertions, novel microRNAs and piRNA clusters, the sex-determining locus, and new immunity genes, and enables genome-wide studies of geographically diverse Ae. albopictus populations and analyses of the developmental and stage-dependent network of expression data. Additionally, we build the first physical map for this species with 75% of the assembled genome anchored to the chromosomes. The AalbF2 genome assembly represents the most up-to-date collective knowledge of the Ae. albopictus genome. These resources represent a foundation to improve understanding of the adaptation potential and the epidemiological relevance of this species and foster the development of innovative control measures.


DNA-protein crosslink proteases in genome stability.
Proteins covalently attached to DNA, also known as DNA-protein crosslinks (DPCs), are common and bulky DNA lesions that interfere with DNA replication, repair, transcription and recombination. Research in the past several years indicates that cells possess dedicated enzymes, known as DPC proteases, which digest the protein component of a DPC. Interestingly, DPC proteases also play a role in proteolysis beside DPC repair, such as in degrading excess histones during DNA replication or controlling DNA replication checkpoints. Here, we discuss the importance of DPC proteases in DNA replication, genome stability and their direct link to human diseases and cancer therapy.


The forebrain is not essential for sympathoadrenal hyperglycemic response to glucoprivation.
The reduction of glycolysis by hypoglycemia or the glucose analog 2-deoxy-D-glucose (2DG) stimulates compensatory sympathetic alterations of metabolism. Considerable attention has been focused on the hypothalamus as the probable locus of requisite metabolic signal detection. We report, however, that unanesthetized chronically decerebrate rats are capable of exhibiting sympathoadrenal hyperglycemia in response to the metabolic challenge presented by 2DG. This findings demonstrates that the forebrain is not necessary for glucoprivic stimulation of this reflex. Since cervical cord transection has been shown to eliminate hyperglycemia induced by 2DG, we conclude that the caudal brainstem contains an essential part of the neural mechanism which both detects metabolic need and ameliorates that need through the release of stored fuels.


Remarks on signal-processing explanations of the trichromacy of vision.
We present criticism of signal-processing arguments recently used to explain the trichromacy of color vision. In particular, we note that illuminant spectral power distributions (SPD's) can be metameric even when the signal-processing arguments state that trichromatic vision represents such SPD's without ambiguity. Being statistical in nature, these arguments need not apply to each individual SPD; however, further use of the arguments calls for attributing them to some ensemble of SPD's and then testing whether the ensemble satisfies the underlying statistical assumptions.


Perioperative intravenous corticosteroids reduce incidence of atrial fibrillation following cardiac surgery: a randomized study.
Corticosteroids decrease side effects after noncardiac elective surgery. A randomized, double blinded, placebo-controlled study was plan to test the hypothesis that standard doses of dexamethasone (6X2) would decrease the incidence of atrial fibrillation (AF) following cardiac surgery. A total of 185 patients undergoing coronary revascularization surgery were enrolled in this clinical study. The anesthetic management was standardized in all patients. Dexamethasone (6 mg/ml) or saline (1 ml) was administered after the induction of anesthesia and a second dose of the same study drug was given on the morning after surgery. The incidence of AF was determined by analyzing the first 72 hours of continuously recorded electrocardiogram records after cardiac surgery, to determine the incidence and severity of postoperative side effects. The incidence of 48 hours postoperative AF was significantly lower in the Dexamethasone group (21/ 92[37.5%]) than in the placebo group (35/92 [62.5%], adjusted hazard ratio, 2.07; 95% confidence interval, 1.09-3.95 (P<0.05). Compared with placebo, patients receiving dexamethasone did not have higher rates of superficial or deep wound infections, or other major complications. Prophylactic short-term dexamethasone administration in patients undergoing coronary artery bypasses grafting significantly reduced postoperative atrial fibrillation.


Remini-Sing: A Feasibility Study of Therapeutic Group Singing to Support Relationship Quality and Wellbeing for Community-Dwelling People Living With Dementia and Their Family Caregivers.
Background: Living at home following a diagnosis of dementia can be difficult for both the person living with dementia (PwD) and their family caregivers (FCG). Active group music participation may provide an avenue for emotional release, offer psychosocial support to caregivers and stimulate meaningful interaction between caregivers and loved ones with dementia. Therapeutic music interventions also have the capacity to facilitate reminiscence and social engagement and can help to manage challenging symptoms associated with dementia, such as anxiety, apathy, and agitation. Method: This feasibility study examined the acceptability of a 20-week therapeutic group singing intervention (Remini-Sing) and quantitative research assessments for PwD/FCG dyads living in the community. Quantitative measures for the following outcomes were tested for sensitivity and acceptability: relationship quality (PwD and FCG); life satisfaction, caregiver satisfaction, flourishing, and depression for FCGs; and anxiety, apathy, agitation, and quality of life for PwD. Quantitative assessments were conducted before, during (midway) and after 20 weeks of participation in a therapeutic singing group attended by the PwD and FCG together. The Remini-Sing intervention incorporated vocal warm ups, singing familiar songs, learning new songs, and opportunities for social interaction. Qualitative interviews were conducted with all dyads that completed the intervention. Results: Twelve PWD/FCG dyads were recruited and enrolled in the study. High participation and retention rates indicated that the intervention was received favorably by participants. There were no statistically significant changes on measures from pre to post intervention. However, favorable baseline scores on relationship quality and wellbeing measures were sustained over the 20-week intervention. The testing of these measures for feasibility also revealed that some were too difficult for PwD and thus yielded questionable results, some were potentially less relevant, and there were likely floor and ceiling effects on several of the measures utilized. Conclusions: This study demonstrated good feasibility for a research protocol and therapeutic group singing intervention for community-dwelling PwD and their FCGs. Participant reflections and researcher observations yielded useful information guiding the selection of quantitative outcome measures for future research in this area.


Metabolic Effects of Intermittent Fasting.
The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved health outcomes. A MEDLINE search was performed using PubMed and the terms "intermittent fasting," "fasting," "time-restricted feeding," and "food timing." Modified fasting regimens appear to promote weight loss and may improve metabolic health. Several lines of evidence also support the hypothesis that eating patterns that reduce or eliminate nighttime eating and prolong nightly fasting intervals may result in sustained improvements in human health. Intermittent fasting regimens are hypothesized to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and (c) modifiable lifestyle behaviors, such as sleep. If proven to be efficacious, these eating regimens offer promising nonpharmacological approaches to improving health at the population level, with multiple public health benefits.


Exploring the possibility of early cataract diagnostics based on tryptophan fluorescence.
A novel route for early cataract diagnostics is investigated based on the excitation of tryptophan fluorescence (TF) at the red edge of its absorption band at 317 nm. This allows penetration through the cornea and aqueous humour to provide excitation of the ocular lens. The steepness of the red edge gives the potential of depth control of the lens excitation. Such wavelength selection targets the population of tryptophan residues, side chains of which are exposed to the polar aqueous environment. The TF emissions around 350 nm of a series of UV-irradiated as well as control lenses were observed. TF spectra of the UV cases were red-shifted and the intensity decreased with the radiation dose. In contrast, intensity of non-tryptophan emission with maximum at 435 nm exhibited an increase suggesting photochemical conversion of the tryptophan population to 435 nm emitting molecules. We demonstrate that the ratio of intensities at 435 nm to that around 350 nm can be used as a measure of early structural changes caused by UV irradiation in the lens by comparison with images from a conventional slit-lamp, which can only detect defects of optical wavelength size. Such diagnostics at a molecular level could aid research on cataract risk investigation and possible pharmacological research as well as assisting surgical lens replacement decisions.


Cystic echinococcosis: a 10-year experience from a middle-income country.
Cystic echinococcosis (CE), or hydatid disease, is a neglected tropical disease (NTD) afflicting one million people globally. This study aims to elucidate the presentation, treatment and outcomes of the disease in Pakistan. A review of charts of 225 patients (median age = 42.3 years) with CE admitted at Aga Khan Hospital, Karachi during 2007-2017, was carried out. Abdominal pain was present in 34.7% followed by fever in 26.2%. There were 142 (63.1%) cases of hepatic cysts and 55 (24.4%) of pulmonary hydatid cysts. Combined surgical and medical therapy was given to 130 (57.8%) patients. Surgery only was performed in 23 (10.2%) patients, medical therapy only was given to 35 (15.6%) patients, and puncture, aspiration, injection and reaspiration (PAIR) with medical therapy was given to 15 (6.7%) patients. Recurrence occurred in 14 (6.2%) patients and mortality in 7 (3.1%) patients. Owing to its non-specific presentation, a high index of suspicion is required to diagnose and treat CE in a timely manner.


Negative electrospray ionization mass spectrometry of synthetic and chemically modified oligonucleotides.
We report here on the analysis of synthetic oligonucleotides by electrospray ionization mass spectrometry (ESI-MS). After intensive removal of salt ions (especially sodium cations), negative ion mass spectra, allowing mass measurement with an accuracy of 0.01%, were obtained on several oligonucleotides up to 80 nucleotides. In most cases, the resolution was sufficient to observe n-1 and n-2 forms due to internal deletions during automated synthesis, and to identify the missing nucleotides. A 132-mer, whose size is close to the limit of automated chemical synthesis, was also successfully mass measured. A quantitative study showed that ESI-MS can provide quantitative data on oligonucleotides of similar size and structure. The described methodology is used to characterize oligonucleotide analogues such as phosphorothioate oligonucleotides designed for antisense applications. Finally, analyses in the positive ion mode on a trimer TpTpT in the presence of different amine bases were performed and allowed a better understanding of the influence of these bases on the ions formation.


Inhibitory role of sex steroid in the regulation of ovarian follicle-stimulating hormone receptors during pregnancy.
The present study was conducted to determine the role of sex steroids in the regulation of FSH receptors in pregnant rats. In the normal physiological condition, FSH bindings per unit ovarian weight (density of binding) and per 2 ovaries (total binding) increased during days 14-21 gestation. Scatchard plot analyses of the binding suggested that the increase in FSH binding was due to an increase in the number of FSH-binding sites. The plasma FSH concentration in pregnant rats was stable during the receptor change. In contrast, the plasma estradiol-17 beta concentration continuously increased from gestation day 14 to 21, and the testosterone level showed a large peak on gestation day 18. Estradiol-17 beta (one silastic plate containing 13 mg crystal)-implanted pregnant rats during 14-21 days of gestation induced significant decreases in the total FSH binding and ovarian weight on gestation day 21. Estradiol administration increased the plasma estradiol level 2.3-fold but did not change the FSH level. Testosterone or 5 alpha-dihydrotestosterone, a nonaromatizable androgen, did not influence the binding level under the same dose treatment. In contrast, continuous treatment with aminoglutethimide (2 plates containing 20 mg crystal), an inhibitor of adrenocortical steroidogenesis, for 7 days significantly increased the total FSH binding without a significant change in the ovarian weight. The plasma titers of estradiol and testosterone in pregnant rats treated with aminoglutethimide were reduced by 37% and 51%, respectively. Aminoglutethimide did not influence plasma FSH levels. These results suggest that circulating estradiol acts as a negative factor in the regulation of ovarian FSH receptors, at least during the second half of pregnancy. Other factor(s) that is (are) independent of sex steroids and FSH may contribute to FSH receptor induction.


Analytic methods for modeling longitudinal data from rolling therapy groups with membership turnover.
Interventions for a variety of emotional and behavioral problems are commonly delivered in the context of treatment groups, with many using rolling admission to sustain membership (i.e., admission, dropout, and discharge from group are perpetual and ongoing). The authors present an overview of the analytic challenges inherent in rolling group data and outline commonly used (but flawed) analytic and design approaches to addressing (or sidestepping) these issues. Moreover, the authors propose use of latent class pattern mixture models (LCPMMs) as a statistically and conceptually defensible approach for modeling treatment data from rolling groups. The LCPMM approach is illustrated with rolling group data from a group-based alcoholism pilot treatment trial (N = 128). Different inferences were made with regard to treatment efficacy under LCPMM vs. the commonly used standard group-clustered latent growth model (LGM); coupled with other preliminary findings in this area, inferences from LGMs may be overly liberal when applied to data from rolling groups. Continued work on data analytic difficulties in groups with membership turnover is critical for furthering the ecological validity of research on behavioral treatments.


Elective cesarean section and decision making: a critical review of the literature.
The cesarean section rate continues to rise in many countries with routine access to medical services, yet this increase is not associated with improvement in perinatal mortality or morbidity. A large number of commentaries in the medical literature and media suggest that consumer demand contributes significantly to the continued rise of births by cesarean section internationally. The objective of this article was to critically review the research literature concerning women's preference or request for elective cesarean section published since that critiqued by Gamble and Creedy in 2000. A search of key databases using a range of search terms produced over 200 articles, of which 80 were potentially relevant. Of these, 38 were research-based articles and 40 were opinion-based articles. A total of 17 articles fitted the criteria for review. A range of methodologies was used, with varying quality, making meta-analysis of findings inappropriate, and simple summaries of results difficult to produce. The range and quality of studies had increased since 2001, reflecting continuing concern. Women's preference for cesarean section varied from 0.3 to 14 percent; however, only 3 studies looked directly at this preference in the absence of clinical indications. Women's preference for a cesarean section related to psychological factors, perceptions of safety, or in some countries, was influenced by cultural or social factors. Research between 2000 and 2005 shows evidence of very small numbers of women requesting a cesarean section. A range of personal and societal reasons, including fear of birth and perceived inequality and inadequacy of care, underpinned these requests.


A discoidin domain receptor 1 knock-out mouse as a novel model for osteoarthritis of the temporomandibular joint.
Discoidin domain receptor 1 (DDR-1)-deficient mice exhibited a high incidence of osteoarthritis (OA) in the temporomandibular joint (TMJ) as early as 9 weeks of age. They showed typical histological signs of OA, including surface fissures, loss of proteoglycans, chondrocyte cluster formation, collagen type I upregulation, and atypical collagen fibril arrangements. Chondrocytes isolated from the TMJs of DDR-1-deficient mice maintained their osteoarthritic characteristics when placed in culture. They expressed high levels of runx-2 and collagen type I, as well as low levels of sox-9 and aggrecan. The expression of DDR-2, a key factor in OA, was increased. DDR-1-deficient chondrocytes from the TMJ were positively influenced towards chondrogenesis by a three-dimensional matrix combined with a runx-2 knockdown or stimulation with extracellular matrix components, such as nidogen-2. Therefore, the DDR-1 knock-out mouse can serve as a novel model for temporomandibular disorders, such as OA of the TMJ, and will help to develop new treatment options, particularly those involving tissue regeneration.


Dysphagia in head and neck cancer patients following intensity modulated radiotherapy (IMRT).
To evaluate the objective and subjective long term swallowing function, and to relate dysphagia to the radiation dose delivered to the critical anatomical structures in head and neck cancer patients treated with intensity modulated radiation therapy (IMRT, +/- chemotherapy), using a midline protection contour (below hyoid, ~level of vertebra 2/3). 82 patients with stage III/IV squamous cell carcinoma of the larynx, oropharynx, or hypopharynx, who underwent successful definitive (n = 63, mean dose 68.9Gy) or postoperative (n = 19, mean dose 64.2Gy) simultaneous integrated boost (SIB) -IMRT either alone or in combination with chemotherapy (85%) with curative intent between January 2002 and November 2005, were evaluated retrospectively. 13/63 definitively irradiated patients (21%) presented with a total gross tumor volume (tGTV) >70cc (82-173cc; mean 106cc). In all patients, a laryngo-pharyngeal midline sparing contour outside of the PTV was drawn. Dysphagia was graded according subjective patient-reported and objective observer-assessed instruments. All patients were re-assessed 12 months later. Dose distribution to the swallowing structures was calculated. At the re-assessment, 32-month mean post treatment follow-up (range 16-60), grade 3/4 objective toxicity was assessed in 10%. At the 32-month evaluation as well as at the last follow up assessment mean 50 months (16-85) post-treatment, persisting swallowing dysfunction grade 3 was subjectively and objectively observed in 1 patient (1%). The 5-year local control rate of the cohort was 75%; no medial marginal failures were observed. Our results show that sparing the swallowing structures by IMRT seems effective and relatively safe in terms of avoidance of persistent grade 3/4 late dysphagia and local disease control.


Functional and Morphological Changes Induced in Mytilus Hemocytes by Selected Nanoparticles.
Nanoparticles (NPs) show various properties depending on their composition, size, and surface coating, which shape their interactions with biological systems. In particular, NPs have been shown to interact with immune cells, that represent a sensitive surveillance system of external and internal stimuli. In this light, in vitro models represent useful tools for investigating nano-bio-interactions in immune cells of different organisms, including invertebrates. In this work, the effects of selected types of NPs with different core composition, size and functionalization (custom-made PVP-AuNP and commercial nanopolystyrenes PS-NH2 and PS-COOH) were investigated in the hemocytes of the marine bivalve Mytilus galloprovincialis. The role of exposure medium was evaluated using either artificial seawater (ASW) or hemolymph serum (HS). Hemocyte morphology was investigated by scanning electron microscopy (SEM) and different functional parameters (lysosomal membrane stability, phagocytosis, and lysozyme release) were evaluated. The results show distinct morphological and functional changes induced in mussel hemocytes depending on the NP type and exposure medium. Mussel hemocytes may represent a powerful alternative in vitro model for a rapid pre-screening strategy for NPs, whose utilization will contribute to the understanding of the possible impact of environmental exposure to NPs in marine invertebrates.


Focal drug-resistant temporal lobe epilepsy associated with an ipsilateral anterior choroidal artery aneurysm: illustrative case.
The occurrence of both an intracranial aneurysm and epilepsy, especially drug-resistant epilepsy (DRE), is rare. Although the overall incidence of aneurysms associated with DRE is unclear, it is thought to be particularly infrequent in the pediatric population. Surgical ligation of the offending aneurysm has been reported in conjunction with resolving seizure activity, although few cases have cited a combined approach of aneurysm ligation and resection of an epileptogenic focus. We present the case of a 14-year-old female patient with drug-resistant temporal lobe epilepsy and an ipsilateral supraclinoid internal carotid artery aneurysm. Seizure semiology, electroencephalography monitoring, and magnetic resonance imaging all indicated a left temporal epileptogenic focus, in addition to an incidental aneurysm. The authors recommended a combined surgery involving resection of the temporal lesion and surgical clip ligation of the aneurysm. Near-total resection and successful ligation were achieved, and the patient has remained seizure free since surgery at 1 year postoperatively. In patients with focal DRE and an adjacent intracranial aneurysm, a combined surgical approach involving both resection and surgical ligation can be used. Several surgical timing and neuroanesthetic considerations should be made to ensure the overall safety and efficacy of this procedure.


Frequency dependence 3.0: an attempt at codifying the evolutionary ecology perspective.
The fitness concept and perforce the definition of frequency independent fitnesses from population genetics is closely tied to discrete time population models with non-overlapping generations. Evolutionary ecologists generally focus on trait evolution through repeated mutant substitutions in populations with complicated life histories. This goes with using the per capita invasion speed of mutants as their fitness. In this paper we develop a concept of frequency independence that attempts to capture the practical use of the term by ecologists, which although inspired by population genetics rarely fits its strict definition. We propose to call the invasion fitnesses of an eco-evolutionary model frequency independent when the phenotypes can be ranked by competitive strength, measured by who can invade whom. This is equivalent to the absence of weak priority effects, protected dimorphisms and rock-scissor-paper configurations. Our concept differs from that of Heino et al. (TREE 13:367-370, 1998) in that it is based only on the signs of the invasion fitnesses, whereas Heino et al. based their definitions on the structure of the feedback environment, summarising the effect of all direct and indirect interactions between individuals on fitness. As it turns out, according to our new definition an eco-evolutionary model has frequency independent fitnesses if and only if the effect of the feedback environment on the fitness signs can be summarised by a single scalar with monotonic effect. This may be compared with Heino et al.'s concept of trivial frequency dependence defined by the environmental feedback influencing fitness, and not just its sign, in a scalar manner, without any monotonicity restriction. As it turns out, absence of the latter restriction leaves room for rock-scissor-paper configurations. Since in 'realistic' (as opposed to toy) models frequency independence is exceedingly rare, we also define a concept of weak frequency dependence, which can be interpreted intuitively as almost frequency independence, and analyse in which sense and to what extent the restrictions on the potential model outcomes of the frequency independent case stay intact for models with weak frequency dependence.


Early post-operative morbidity of total prostatectomy.
Complications were analysed in a contemporary series of 100 total prostatectomies performed, for carcinoma of the prostate, under the supervision of one surgeon. There were 7 major complications including 1 death. No patient had a rectal injury. Minor complications occurred in 33 patients. Severe stress incontinence persisted in only 2 patients and 12 had minor stress incontinence. Of 38 patients potent before surgery and in whom it was possible to preserve both "neurovascular bundles of Walsh", 45% retained post-operative potency. Preservation of potency was related to the pathological extent of the tumour. It was concluded that in selected patients, total retropubic prostatectomy can be performed safely with good quality of post-operative life.


CONTRIBUTIONS OF SEXUAL AND ASEXUAL REPRODUCTION TO POPULATION STRUCTURE IN THE CLONAL SOFT CORAL, ALCYONIUM RUDYI.
Numerous studies of population structure in sessile clonal marine invertebrates have demonstrated low genotypic diversity and nonequilibrium genotype frequencies within local populations that are monopolized by relatively few, highly replicated genets. All of the species studied to date produce planktonic sexual propagules capable of dispersing long distances; despite local genotypic disequilibria, populations are often panmictic over large geographic areas. The population structure paradigm these species represent may not be typical of the majority of clonal invertebrate groups, however, which are believed to produce highly philopatric sexual propagules. I used allozyme variation to examine the population structure of the temperate soft coral, Alcyonium rudyi, a typical clonal species whose sexually produced larvae and asexually produced ramets both have very low dispersal capabilities. Like other clonal plants and invertebrates, the local population dynamics of A. rudyi are dominated by asexual reproduction, and recruitment of new sexually produced genets occurs infrequently. As expected from its philopatric larval stage, estimates of genetic differentiation among populations of A. rudyi were highly significant at all spatial scales examined (mean θ = 0.300 among 20 populations spanning a 1100-km range), suggesting that genetic exchange seldom occurs among populations separated by as little as a few hundred meters. Mapping of multilocus allozyme genotypes within a dense aggregation of A. rudyi ramets confirmed that dispersal of asexual propagules is also very limited: members of the same genet usually remain within < 50 cm of one another on the same rock surface. Unlike most previously studied clonal invertebrates, populations of A. rudyi do not appear to be dominated by a few widespread genets: estimates of genotypic diversity (Go ) within 20 geographically distinct populations did not differ from expectations for outcrossing, sexual populations. Despite theoretical suggestions that philopatric dispersal combined with typically small effective population sizes should promote inbreeding in clonal species, inbreeding does not appear to contribute significantly to the population structure of A. rudyi. Genet genotype frequencies conformed to Hardy-Weinberg expectations in all populations, and inbreeding coefficients (f) were close to zero. In general, the population structure of A. rudyi did not differ significantly from that observed among outcrossing sexual species with philopatric larval dispersal. Age estimates suggest, however, that genets of A. rudyi live for many decades. Genet longevity may promote high genotypic diversity within A. rudyi populations and may be the most important evolutionary consequence of clonal reproduction in this species and the many others that share its dispersal characteristics.


Diabetes Incidence and Glucose Tolerance after Termination of Pioglitazone Therapy: Results from ACT NOW.
Thiazolidinediones have proven efficacy in preventing diabetes in high-risk individuals. However, the effect of thiazolidinediones on glucose tolerance after cessation of therapy is unclear. To examine the effect of pioglitazone (PIO) on incidence of diabetes after discontinuing therapy in ACT NOW. Design, Settings and Patients: Two-hundred ninety-three subjects (placebo [PLAC], n = 138; PIO, n = 152) completed a median followup of 11.7 mo after study medication was stopped. Diabetes developed in 138 (12.3%) of PLAC vs 17 of 152 PIO patients (11.2%; P = not significant, PIO vs PLAC). However, the cumulative incidence of diabetes from start of study medication to end of washout period remained significantly lower in PIO vs PLAC (10.7 vs 22.3%; P < .005). After therapy was discontinued, 23.0% (35/152) of PIO-treated patients remained normal-glucose tolerant (NGT) vs 13.8% (19/138) of PLAC-treated patients (P = .04). Insulin secretion/insulin resistance index (I0-120/G0-120 × Matsuda index) was markedly lower in subjects with impaired glucose tolerance (IGT) who converted to diabetes during followup vs those who remained IGT or NGT. The decline in-cell function (insulin secretion/insulin resistance index) was similar in subjects with IGT who developed diabetes, irrespective of whether they were treated with PIO or PLAC. 1) The protective effect of PIO on incidence of diabetes attenuates after discontinuation of therapy, 2) cumulative incidence of diabetes in individuals exposed to PIO remained significantly (56%) lower than PLAC and a greater number of PIO-treated individuals maintained NGT after median followup of 11.4 mo, and 3) low insulin secretion/insulin resistance index is a strong predictor of future diabetes following PIO discontinuation.


Circumscribed Interests and Attention in Autism: The Role of Biological Sex.
Recent studies suggest that circumscribed interests (CI) in females with Autism Spectrum Disorder (ASD) may align more closely with interests reported in typical female development than those typically reported for ASD males. We used eye-tracking to quantify attention to arrays containing combinations of male, female and neutral images in elementary-aged males and females with and without ASD. A number of condition × sex effects emerged, with both groups attending to images that corresponded with interests typically associated with their biological sex. Diagnostic effects reported in similar studies were not replicated in our modified design. Our findings of more typical attention patterns to gender-typical images in ASD females is consistent with evidence of sex differences in CI and inconsistent with the "Extreme Male Brain" theory of ASD.


Development and validation of the Diabetes Numeracy Test (DNT).
Low literacy and numeracy skills are common. Adequate numeracy skills are crucial in the management of diabetes. Diabetes patients use numeracy skills to interpret glucose meters, administer medications, follow dietary guidelines and other tasks. Existing literacy scales may not be adequate to assess numeracy skills. This paper describes the development and psychometric properties of the Diabetes Numeracy Test (DNT), the first scale to specifically measure numeracy skills used in diabetes. The items of the DNT were developed by an expert panel and refined using cognitive response interviews with potential respondents. The final version of the DNT (43 items) and other relevant measures were administered to a convenience sample of 398 patients with diabetes. Internal reliability was determined by the Kuder-Richardson coefficient (KR-20). An a priori hypothetical model was developed to determine construct validity. A shortened 15-item version, the DNT15, was created through split sample analysis. The DNT had excellent internal reliability (KR-20 = 0.95). The DNT was significantly correlated (p < 0.05) with education, income, literacy and math skills, and diabetes knowledge, supporting excellent construct validity. The mean score on the DNT was 61% and took an average of 33 minutes to complete. The DNT15 also had good internal reliability (KR-20 = 0.90 and 0.89). In split sample analysis, correlations of the DNT-15 with the full DNT in both sub-samples was high (rho = 0.96 and 0.97, respectively). The DNT is a reliable and valid measure of diabetes related numeracy skills. An equally adequate but more time-efficient version of the DNT, the DNT15, can be used for research and clinical purposes to evaluate diabetes related numeracy.


Broadening perspectives on clinical performance assessment: rethinking the nature of in-training assessment.
In-training assessment (ITA), defined as multiple assessments of performance in the setting of day-to-day practice, is an invaluable tool in assessment programmes which aim to assess professional competence in a comprehensive and valid way. Research on clinical performance ratings, however, consistently shows weaknesses concerning accuracy, reliability and validity. Attempts to improve the psychometric characteristics of ITA focusing on standardisation and objectivity of measurement thus far result in limited improvement of ITA-practices. The aim of the paper is to demonstrate that the psychometric framework may limit more meaningful educational approaches to performance assessment, because it does not take into account key issues in the mechanics of the assessment process. Based on insights from other disciplines, we propose an approach to ITA that takes a constructivist, social-psychological perspective and integrates elements of theories of cognition, motivation and decision making. A central assumption in the proposed framework is that performance assessment is a judgment and decision making process, in which rating outcomes are influenced by interactions between individuals and the social context in which assessment occurs. The issues raised in the article and the proposed assessment framework bring forward a number of implications for current performance assessment practice. It is argued that focusing on the context of performance assessment may be more effective in improving ITA practices than focusing strictly on raters and rating instruments. Furthermore, the constructivist approach towards assessment has important implications for assessment procedures as well as the evaluation of assessment quality. Finally, it is argued that further research into performance assessment should contribute towards a better understanding of the factors that influence rating outcomes, such as rater motivation, assessment procedures and other contextual variables.


Occipital condyle fractures: clinical decision rule and surgical management.
Occipital condyle fractures (OCFs) are rare injuries and their treatment remains controversial. Several classification systems have been proposed, first by Anderson and Montesano and more recently by Tuli and colleagues and Hanson and associates, who sought to stratify these fractures in a manner that would guide treatment that has typically ranged from semirigid collar immobilization to halo fixation or occipitocervical fusion. It has been the authors' impression, based on experience with OCFs at their institution, that classification is cumbersome and contributes little to the clinical decision-making process, while the identification of craniocervical misalignment and neural element compromise is paramount, and sufficient, for the planning of treatment. The authors performed a retrospective review of 24,745 consecutive trauma presentations to a single Level I trauma center (UPMC Presbyterian Hospital) over a 6-year period, identifying 100 patients with 106 OCFs. All patients were evaluated by the spine trauma service and underwent imaging of the craniocervical junction using reconstructed CT scans. Patient characteristics, fracture characteristics (including fracture classification according to the 2 major classification systems), initial management, and status at follow-up were recorded. The incidence of OCF in this trauma population was 0.4%. Two patients had evidence of craniocervical misalignment on reconstructed CT imaging at the time of admission; both patients underwent occipitocervical fusion. One patient underwent occipitocervical fusion for unrelated C1-2 fractures. The remainder of those surviving to discharge, whose fractures represented all fracture subtypes, received treatment with a rigid cervical collar or counseling alone. No patients, including 4 patients with bilateral OCFs, were found to have developed delayed craniocervical instability or misalignment on follow-up, or to require further neurosurgical intervention for an OCF. Neural element compression was not identified in any of the patients, and there were no cases of delayed cranial neuropathy. Beyond the identification of craniocervical misalignment on reconstructed CT scans at admission, further classification of OCFs is unnecessary. Management should consist of up-front occipitocervical fusion or halo fixation in cases demonstrating occipitocervical misalignment, or of immobilization in a rigid cervical collar followed by delayed clinical and radiographic evaluation in a spine trauma clinic if misalignment is not present.


The interactions between patient preferences, expectancies, and stigma contribute to posttraumatic stress disorder treatment outcomes.
Cognitive processing therapy (CPT) is an effective treatment for posttraumatic stress disorder (PTSD); however, some patients do not improve to the same extent as others. It is important to understand potential factors that can be modified for better patient outcomes. This clinical trial implemented a three-arm, equipoise-stratified randomization design to allow for the accommodation of patient preference before randomization to one of three CPT treatment modalities: in-home, in-office, or telehealth. This study examined whether satisfaction with the modality, perceived stigma, expectations of therapy, and credibility of the therapist differed between modalities and whether these factors impacted treatment outcomes. We hypothesized that the contributions of these variables would depend upon whether participants opted out of any treatment arms and that these factors would predict treatment outcomes. Participants who endorsed less perceived stigma demonstrated larger reductions in PTSD symptom severity than those with similar levels of perceived stigma in the telehealth and in-office conditions, η2 = .12-.18. Participants who endorsed lower satisfaction with their treatment modality and were assigned to the in-home condition experienced larger PTSD symptom reductions than those with similar dissatisfaction in the telehealth and in-office conditions, η2 = .20. The results show the robustness of evidence-based therapies for PTSD given that dissatisfaction did not impede treatment success. In addition, they demonstrate that it is important for clinicians to address stigma before initiating evidence-based therapies for PTSD. Strategies to address these factors are discussed.


A real-time examination of context effects on alcohol cognitions.
This research used context aware experiential sampling to investigate the effect of contexts on in vivo alcohol-related outcome expectancies. A time-stratified random sampling strategy was adopted to assess 72 students and young professionals at 5 daily intervals over the course of a week using a specifically designed smartphone application. This application recorded respondents' present situational and social contexts, alcohol consumption, and alcohol-related cognitions in real-time. In vivo social and environmental contexts and current alcohol consumption accounted for a significant proportion of variance in outcome expectancies. For instance, prompts which occurred while participants were situated in a pub, bar, or club and in a social group of friends were associated with heightened outcome expectancies in comparison with other settings. Alcohol-related expectancies do not appear to be static but instead demonstrate variation across social and environmental contexts. Modern technology can be usefully employed to provide a more ecologically valid means of measuring such beliefs.


Syntheses and applications of periodic mesoporous organosilica nanoparticles.
Periodic Mesoporous Organosilica (PMO) nanomaterials are envisioned to be one of the most prolific subjects of research in the next decade. Similar to mesoporous silica nanoparticles (MSN), PMO nanoparticles (NPs) prepared from organo-bridged alkoxysilanes have tunable mesopores that could be utilized for many applications such as gas and molecule adsorption, catalysis, drug and gene delivery, electronics, and sensing; but unlike MSN, the diversity in chemical nature of the pore walls of such nanomaterials is theoretically unlimited. Thus, we expect that PMO NPs will attract considerable interest over the next decade. In this review, we will present a comprehensive overview of the synthetic strategies for the preparation of nanoscaled PMO materials, and then describe their applications in catalysis and nanomedicine. The remarkable assets of the PMO structure are also detailed, and insights are provided for the preparation of more complex PMO nanoplatforms.


Routine culture-based screening versus risk-based management for the prevention of early-onset group B streptococcus disease in the neonate: a systematic review.
Early-onset group B streptococcus disease, recognized as the most common cause of early onset neonatal sepsis in developed countries, is transmitted vertically from the group B streptococcus carrier mother to the neonate in the peripartum. Accordingly, early-onset group B streptococcus disease is prevented by halting the transmission of the microorganism from the mother to the infant. Two main methods, routine culture-based screening and risk-based management, may be used in the identification of mothers requiring intrapartum antibiotic prophylaxis in labor. While there are advantages and disadvantages to each, there is limited high level evidence available as to which method is superior. To identify the effectiveness of risk-based management versus routine culture-based screening in the prevention of early-onset group B streptococcus disease in the neonate. This review considered studies which treated pregnant women with intrapartum antibiotic prophylaxis following risk- and culture-based protocols for the prevention of early-onset group B streptococcus disease in the neonate. Types of intervention: This review considered studies that evaluated risk-based management against routine culture-based screening for the prevention of early-onset group B streptococcus disease in the neonate. Types of studies: This review looked for highest evidence available which in this case consisted of one quasi experimental study and eight comparative cohort studies with historical or concurrent control groups. Types of outcomes: Incidence of early-onset group B streptococcus disease in neonates as measured by positive group B streptococcus culture from an otherwise sterile site. Secondary outcomes include neonatal death due to group B streptococcus sepsis and percentage of women who received intrapartum antibiotic prophylaxis. A multi-step search strategy was used to find studies which were limited to the English language and published between January 2000 and June 2013. The quality of the eligible studies was assessed independently by two reviewers using the Joanna Briggs Institute quality assessment tool for observational studies. Data was extracted using a standardized extraction tool from the Joanna Briggs Institute. Quantitative papers were, where possible, pooled for meta-analysis using Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument effect sizes expressed as odds ratio and their 95% confidence intervals were calculated. Heterogeneity was assessed statistically using the standard Chi-square. The results of this review come from nine studies published in peer reviewed journals. The treatment group consists of those screened as per the culture-based protocol, the control group the risk-based protocol. For combined term and preterm infants the odds of early-onset group B streptococcus disease for the treatment vs control groups is 0.45 (95% CI 0.37 to 0.53). The odds ratio in term infants is 0.45 (95% CI 0.36 to 0.57). Preterm infants are four times (OR 4.20 [95% CI 3.36 to 5.24]) more likely to develop early-onset group B streptococcus disease than term infants regardless of prevention technique. One study provides information on neonatal mortality in which there is one neonatal death in the risk-based cohort and none in the culture-based. The TRUNCATED AT 500 WORDS.


Depressive Symptoms After Ischemic Stroke: Population-Based Comparisons of Patients and Caregivers With Matched Controls.
Background and Purpose- Persistent depression after ischemic stroke is common in stroke survivors and may be even higher in family caregivers, but few studies have examined depressive symptom levels and their predictors in patient and caregiver groups simultaneously. Methods- Stroke survivors and their family caregivers (205 dyads) were enrolled from the national REGARDS study (Reasons for Geographic and Racial Differences in Stroke) into the CARES study (Caring for Adults Recovering from the Effects of Stroke) ≈9 months after a first-time ischemic stroke. Demographically matched stroke-free dyads (N=205) were also enrolled. Participants were interviewed by telephone, and depressive symptoms were assessed with the 20-item Center for Epidemiological Studies-Depression scale. Results- Significant elevations in depressive symptoms (Ps<0.03) were observed for stroke survivors (M=8.38) and for their family caregivers (M=6.42) relative to their matched controls (Ms=5.18 and 4.62, respectively). Stroke survivors reported more symptoms of depression than their caregivers (P=0.008). No race or sex differences were found, but differential prediction of depressive symptom levels was found across patients and caregivers. Younger age and having an older caregiver were associated with more depressive symptoms in stroke survivors while being a spouse caregiver and reporting fewer positive aspects of caregiving were associated with more depressive symptoms in caregivers. The percentage of caregivers at risk for clinically significant depression was lower in this population-based sample (12%) than in previous studies of caregivers from convenience or clinical samples. Conclusions- High depressive symptom levels are common 9 months after first-time ischemic strokes for stroke survivors and family caregivers, but rates of depressive symptoms at risk for clinical depression were lower for caregivers than previously reported. Predictors of depression differ for patients and caregivers, and standards of care should incorporate family caregiving factors.


Seasonal changes in general activity, body mass and reproduction of two small nocturnal primates: a comparison of the golden brown mouse lemur ( Microcebus ravelobensis) in Northwestern Madagascar and the brown mouse lemur ( Microcebus rufus) in Eastern Madagascar.
To investigate for the first time the relationship between contrasting patterns of seasonal changes of the environment and activity, body mass and reproduction for small nocturnal primates in nature, we compared a population of golden brown mouse lemur ( Microcebus ravelobensis) in a dry deciduous forest of northwestern Madagascar and of the brown mouse lemur ( Microcebus rufus) in an evergreen rain forest of eastern Madagascar. Both species live under similar photoperiodic conditions. Golden brown mouse lemurs (GBML) were active during the whole period (May to December) irrespective of changing environmental conditions. In contrast, a part of the population of brown mouse lemurs (BML) showed prolonged seasonal torpor, related to body mass during periods of short day length and low ambient temperatures. Differences between species might be due to differences in ambient temperature and food supply. Body weight and tail thickness (adipose tissue reserve) did not show prominent differences between short and long photoperiods in GBML, whereas both differ significantly in BML, suggesting species-specific differences in the photoperiodically driven control of metabolism. Both species showed a seasonal reproduction. The rate of growth and size of the testes were similar and preceded estrous onset in both species suggesting a photoperiodic control of reproduction in males. The estrous onset in females occurred earlier in GBML than in BML. Estrous females were observed over at least 4 months in the former, but in only 1 month in the latter species. Intraspecific variation of estrous onset in GBML may be explained by body mass. Interspecific variation of female reproduction indicates species-specific differences in the control of reproduction. Thus, environmentally related differences in annual rhythms between closely related small nocturnal lemurs emerged that allow them to cope with contrasting patterns of seasonal changes in their habitats.


Structure-function dissection of the frizzled receptor in Drosophila melanogaster suggests different mechanisms of action in planar polarity and canonical Wnt signaling.
Members of the Frizzled family of sevenpass transmembrane receptors signal via the canonical Wnt pathway and also via noncanonical pathways of which the best characterized is the planar polarity pathway. Activation of both canonical and planar polarity signaling requires interaction between Frizzled receptors and cytoplasmic proteins of the Dishevelled family; however, there has been some dispute regarding whether the Frizzled-Dishevelled interactions are the same in both cases. Studies looking at mutated forms of Dishevelled suggested that stable recruitment of Dishevelled to membranes by Frizzled was required only for planar polarity activity, implying that qualitatively different Frizzled-Dishevelled interactions underlie canonical signaling. Conversely, studies looking at the sequence requirements of Frizzled receptors in the fruit fly Drosophila melanogaster for canonical and planar polarity signaling have concluded that there is most likely a common mechanism of action. To understand better Frizzled receptor function, we have carried out a large-scale mutagenesis in Drosophila to isolate novel mutations in frizzled that affect planar polarity activity and have identified a group of missense mutations in cytosolic-facing regions of the Frizzled receptor that block Dishevelled recruitment. Interestingly, although some of these affect both planar polarity and canonical activity, as previously reported for similar lesions, we find a subset that affect only planar polarity activity. These results support the view that qualitatively different Frizzled-Dishevelled interactions underlie planar polarity and canonical Wnt signaling.


Comparison of CD4+CD25hiFoxP3+ Treg Induction by pIL-10-Transfected Dendritic Cells in Different Mouse Strains.
Tolerogenic dendritic cells (tolDCs) and T-regulatory cells (Tregs) are involved in maintaining tolerance to self-antigens and foreign antigens. The cells are used as therapeutic tools for inducing tolerance to transplanted organs or tissues. We investigated the possibility of inducing Tregs in splenocyte cultures using DCs transfected with a DNA construct encoding mouse interleukin-10 (DCpIL-10). DCs were derived from bone marrow cells in the presence of rmGM-CSF and rmIL-4 and electroporated with a plasmid encoding mouse IL-10. Furthermore, DCpIL-10 was cocultured with syngeneic splenocytes. The CD4+CD25hiFoxP3+ Treg frequency, IL-10 expression, and inhibition of the mixed lymphocyte reaction were evaluated. C57Bl/6 and CBA mice differ in their initial frequency of CD4+CD25hiFoxP3+ Tregs and baseline IL-10 production. Also, the effectiveness of CD4+CD25hiFoxP3+ Treg upregulation by tolDCpIL-10 was different. In this study, DCpIL-10 from C57Bl/6 mice induced CD4+CD25hiFoxP3+ Tregs in syngenic splenocytes, which was accompanied by an increase in the IL-10 production and a decrease in the proliferation of splenocytes in response to the alloantigen. DCpIL-10 may be used to induce CD4+CD25hiFoxP3+ Tregs and the regulatory potential of splenocytes.


Changes in the nuclear distribution of DNA polymerase alpha and PCNA/cyclin during the progress of the cell cycle, in a cell-free extract of Xenopus eggs.
The nuclear distribution of DNA polymerase alpha and PCNA/cyclin in embryonic nuclei has been investigated, in a cell-free extract of Xenopus eggs that recapitulates a basic cell-cycle in vitro, by indirect immunofluorescence microscopy. Both antigens co-distribute with the chromatin in S-phase nuclei; however, as DNA replication is completed and nuclei progress into a G2 state anti-PCNA fluorescence disappears and anti-DNA polymerase alpha fluorescence becomes resolved into bright spots. These spots are initially associated with the chromatin strands and can be seen to share both anti-PCNA and anti-DNA polymerase alpha fluorescence, but as anti-PCNA fluorescence fades the spots become dissociated from the chromatin and are redistributed throughout the nucleus until they are dispersed during nuclear envelope breakdown. The loss of anti-PCNA fluorescence and displacement of anti-DNA polymerase alpha fluorescence from the chromatin can be prevented by inhibiting DNA synthesis with aphidicolin. Under these conditions both antigens remain associated with the chromatin even after nuclear envelope breakdown and lamin dispersal. The association of these antigens with mitotic figures appears to be functional, as both biotin-11-dUTP and [32P]dCTP can be incorporated efficiently into DNA during the mitotic period.


Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up.
To investigate the contribution of neuroleptic drugs to cognitive decline in dementia. Two year prospective, longitudinal study consisting of interviews every four months, with necropsy follow up. Community settings in Oxfordshire. 71 subjects with dementia, initially living at home with informant. Cognitive function (score from expanded minimental state examination); behavioural problems (physical aggression, hallucinations, persecutory ideas, and disturbance of diurnal rhythm); and postmortem neuropathological assessment (cortical Lewy body pathology). The mean (SE) decline in cognitive score in the 16 patients who took neuroleptics was twice that in the patients who did not (20.7 (2.9) v 9.3 (1.3), P = 0.002). An increased rate of decline was also associated with aggression, disturbed diurnal rhythm, and persecutory ideas. However, only use of neuroleptics and severity of persecutory ideas were independently associated with more rapid cognitive decline when all other variables were adjusted for. The start of neuroleptic treatment coincided with more rapid cognitive decline: median rate of decline was 5 (interquartile range 8.5) points per year before treatment and 11 (12) points per year after treatment (P = 0.02). Cortical Lewy body pathology did not account for association between neuroleptic use and more rapid decline. Neuroleptic drugs that are sometimes used to treat behavioural complications of dementia may worsen already poor cognitive function. Randomised controlled trials are needed to confirm a causal relation.


Delayed gastric emptying in the obese: an assessment using the non-invasive (13)C-octanoic acid breath test.
Much of the controversy surrounding the correlation between obesity and gastric emptying lies in the inconsistency of methodology and analysis. This study was designed to overcome some of the discrepancies encountered in previous studies and to test the hypothesis that obese individuals have altered gastric emptying compared to lean individuals. Gastric emptying was measured using the (13)C-octanoic acid breath test in 16 lean and 16 obese women pair-matched for age. Following an overnight fast, subjects were given a standard 2 MJ egg meal labelled with 100 microl of [1-(13)C]-octanoic acid. Breath samples were collected at regular intervals over a 6-h period. (13)C-isotopic enrichment in the breath was analysed using isotope ratio mass spectrometry and the data fitted to the established gastric emptying model. The lag times (t(lag)), half excretion times (t(1/2)), latency phase (t(lat)) and ascension times (t(asc)) were calculated. The mean t(1/2)-values (+/-standard error of the mean) were 3.67 +/- 0.14 h and 4.23 +/- 0.18 h for lean and obese respectively, indicating significantly delayed gastric emptying in the obese (p = 0.019). The obese group also showed a significantly slower lag time (t(lag), p = 0.005) and latency phase (t(lat), p = 0.005), but no significant difference was found in the ascension time (t(asc), p = 0.154). Within groups, no correlation was found between half excretion times and body weight or half excretion times and body mass index. The present study demonstrated a prolonged lag phase and delayed gastric emptying in obese women when compared to lean women. This delay may be as a consequence of high-fat diets, a sedentary lifestyle and increased gastric distension associated with obesity, or a contributing factor in the pathogenesis of obesity resulting from the inactivation of gastrointestinal satiety signals and in an increase in food intake.


SARA-Coffee web server, a tool for the computation of RNA sequence and structure multiple alignments.
This article introduces the SARA-Coffee web server; a service allowing the online computation of 3D structure based multiple RNA sequence alignments. The server makes it possible to combine sequences with and without known 3D structures. Given a set of sequences SARA-Coffee outputs a multiple sequence alignment along with a reliability index for every sequence, column and aligned residue. SARA-Coffee combines SARA, a pairwise structural RNA aligner with the R-Coffee multiple RNA aligner in a way that has been shown to improve alignment accuracy over most sequence aligners when enough structural data is available. The server can be accessed from http://tcoffee.crg.cat/apps/tcoffee/do:saracoffee.


Discovery of parvovirus-related sequences in an unexpected broad range of animals.
Our knowledge of the genetic diversity and host ranges of viruses is fragmentary. This is particularly true for the Parvoviridae family. Genetic diversity studies of single stranded DNA viruses within this family have been largely focused on arthropod- and vertebrate-infecting species that cause diseases of humans and our domesticated animals: a focus that has biased our perception of parvovirus diversity. While metagenomics approaches could help rectify this bias, so too could transcriptomics studies. Large amounts of transcriptomic data are available for a diverse array of animal species and whenever this data has inadvertently been gathered from virus-infected individuals, it could contain detectable viral transcripts. We therefore performed a systematic search for parvovirus-related sequences (PRSs) within publicly available transcript, genome and protein databases and eleven new transcriptome datasets. This revealed 463 PRSs in the transcript databases of 118 animals. At least 41 of these PRSs are likely integrated within animal genomes in that they were also found within genomic sequence databases. Besides illuminating the ubiquity of parvoviruses, the number of parvoviral sequences discovered within public databases revealed numerous previously unknown parvovirus-host combinations; particularly in invertebrates. Our findings suggest that the host-ranges of extant parvoviruses might span the entire animal kingdom.


Can probiotics improve the environmental microbiome and resistome of commercial poultry production?
Food animal production systems have become more consolidated and integrated, producing large, concentrated animal populations and significant amounts of fecal waste. Increasing use of manure and litter as a more "natural" and affordable source of fertilizer may be contributing to contamination of fruits and vegetables with foodborne pathogens. In addition, human and animal manure have been identified as a significant source of antibiotic resistance genes thereby serving as a disseminator of resistance to soil and waterways. Therefore, identifying methods to remediate human and animal waste is critical in developing strategies to improve food safety and minimize the dissemination of antibiotic resistant bacteria. In this study, we sought to determine whether withdrawing antibiotic growth promoters or using alternatives to antibiotics would reduce the abundance of antibiotic resistance genes or prevalence of pathogens in poultry litter. Terminal restriction fragment length polymorphism (T-RFLP) paired with high throughput sequencing was used to evaluate the bacterial community composition of litter from broiler chickens that were treated with streptogramin growth-promoting antibiotics, probiotics, or prebiotics. The prevalence of resistance genes and pathogens was determined from sequencing results or PCR screens of litter community DNA. Streptogramin antibiotic usage did not elicit statistically significant differences in Shannon diversity indices or correlation coefficients among the flocks. However, T-RFLP revealed that there were inter-farm differences in the litter composition that was independent of antibiotic usage. The litter from all farms, regardless of antibiotic usage, contained streptogramin resistance genes (vatA, vatB, and vatE), macrolide-lincosamide-streptogramin B resistance genes (ermA and ermB), the tetracycline resistance gene tetM and class 1 integrons. There was inter-farm variability in the distribution of vatA and vatE with no statistically significant differences with regards to usage. Bacterial diversity was higher in litter when probiotics or prebiotics were administered to flocks but as the litter aged, diversity decreased. No statistically significant differences were detected in the abundance of class 1 integrons where 3%-5% of the community was estimated to harbor a copy. Abundance of pathogenic Clostridium species increased in aging litter despite the treatment while the abundance of tetracycline-resistant coliforms was unaffected by treatment. However some treatments decreased the prevalence of Salmonella. These findings suggest that withdrawing antibiotics or administering alternatives to antibiotics can change the litter bacterial community and reduce the prevalence of some pathogenic bacteria, but may not immediately impact the prevalence of antibiotic resistance.


[Efficacy of general magnetotherapy in conservative therapy of uterine myoma in women of reproductive age].
Sixty women of the reproductive age with uterine myoma were divided into two groups. Thirty patients of the study group received combined therapy plus general magnetotherapy (GMT). Patients of the control group received only combined treatment. Ultrasound investigation registered a reduction in the size of myoma nodes by 16.7% in the study group, while in the controls myoma size did not change (p < 0.05). 1-year follow-up data for the study group demonstrated no cases of the myoma growth while 16.6% of the controls showed growth of myoma nodes, in 6.6% of them supravaginal myoma amputation was made for rapidly growing myoma.


Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance.
Leukemia cells are protected from chemotherapy-induced apoptosis by their interactions with bone marrow mesenchymal stromal cells (BM-MSCs). Yet the underlying mechanisms associated with this protective effect remain unclear. Genome-wide gene expression profiling of BM-MSCs revealed that coculture with leukemia cells upregulated the transcription of genes associated with nuclear factor (NF)-κB signaling. Moreover, primary BM-MSCs from leukemia patients expressed NF-κB target genes at higher levels than their normal BM-MSC counterparts. The blockade of NF-κB activation via chemical agents or the overexpression of the mutant form of inhibitor κB-α (IκBα) in BM-MSCs markedly reduced the stromal-mediated drug resistance in leukemia cells in vitro and in vivo. In particular, our unique in vivo model of human leukemia BM microenvironment illustrated a direct link between NF-κB activation and stromal-associated chemoprotection. Mechanistic in vitro studies revealed that the interaction between vascular cell adhesion molecule 1 (VCAM-1) and very late antigen-4 (VLA-4) played an integral role in the activation of NF-κB in the stromal and tumor cell compartments. Together, these results suggest that reciprocal NF-κB activation in BM-MSCs and leukemia cells is essential for promoting chemoresistance in the transformed cells, and targeting NF-κB or VLA-4/VCAM-1 signaling could be a clinically relevant mechanism to overcome stroma-mediated chemoresistance in BM-resident leukemia cells.


Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.
Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.


Immunohistochemical detection of transgene expression in the brain using small epitope tags.
In vivo overexpression of proteins is a powerful approach to study their biological function, generate disease models or evaluate gene therapy approaches. In order to investigate an exogenously expressed protein, specific and sensitive detection is essential. Unfortunately, antibodies that allow histological detection of the protein of interest are not always readily available. The use of an epitope tag fused to the protein can circumvent this problem as well as provide the possibility to discriminate endogenous from overexpressed proteins. In order to minimize impact on the bioactivity and biodistribution of the overexpressed protein, preference is given to small tags. In the present study, we evaluated several small epitope tags together with corresponding anti-tag antibodies for the detection of overexpressed proteins in rat brain, using eGFP as a reference. We generated several lentiviral vectors encoding eGFP with different N-terminally fused small epitope tags (AU1, flag, 3flag, HA, myc and V5). After confirmation of their functionality in cell culture, we injected these lentiviral vectors stereotactically into the striatum of rats and prepared paraformaldehyde fixed floating sections for immunohistochemical analysis. Using multiple antibodies and antibody dilutions per epitope tag, we extensively assessed the efficiency of several anti-tag antibodies for chromogenic immunohistochemical detection of the epitope tagged eGFPs by determining the proportion of immunoreactivity detected by anti-tag antibodies compared to anti-GFP antibody. Using fluorescence immunohistochemistry and confocal microscopy, we also quantified the proportion of eGFP-positive cells detected by anti-tag antibodies. Our results show that all the examined small epitope tags could be detected by anti-tag antibodies both in cell extracts as well as in vivo, although to varying degrees depending on the tag and antibody used. Using the presented protocol, V5/anti-V5 and HA/HA11 tag/antibody combinations provided the most sensitive detection in brain tissue. We confirmed the applicability of these optimized in vivo tag detection conditions for a difficult to detect protein, firefly luciferase (fLuc), using lentiviral vector constructs expressing V5 tagged and 3flag tagged fLuc protein. We show here that several small epitope tags are useful for immunohistochemical detection of exogenous proteins in vivo. Our study also provides a generic methodology which is broadly applicable for the detection of overexpressed transgenes in mammalian brain tissue.


Rare bleeding disorders.
Deficiencies of coagulation factors other than factor VIII and factor IX (afibrinogenemia, FII, FV, FV+FVIII, FVII, FX, FXI, FXIII) that cause bleeding disorders (RBDs) are inherited as autosomal recessive traits and are rare, with prevalences in the general population varying between 1 in 500,000 and 1 in 2 million for the homozygous forms. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not as well established as for hemophilia A and B. The study of the genetic basis of these disorders could represent an important tool for prevention through prenatal diagnosis. Treatment of patients with RBDs during bleeding episodes or surgery is a challenge because of the lack of experience and the paucity of data. For some deficiency factor concentrates are still non available and severe complications can occur. These complications can be minimized by assessment of risks of bleeding and thrombosis, use of haemostatic means other than blood components or no therapy at all. The RBDs pose a problem for guideline writers because there are no suitable clinical trials to supply good evidence for how these people are best treated. The lack of adequate information on clinical manifestations, treatment and genetic basis of RBDs could be improved by the collection of data in an International Database (http://www.rbdd.org), linkable to others previously published. This could be a useful tool to fill the gap between clinical data and clinical practice. This article reviews the genetic basis of RBDs, problems and complications of treatment, problems in the preparation of suitable guidelines for treatment and the future perspectives of the International Registry on RBDs.


Chromatid cohesion during mitosis: lessons from meiosis.
The equal distribution of chromosomes during mitosis and meiosis is dependent on the maintenance of sister chromatid cohesion. In this commentary we review the evidence that, during meiosis, the mechanism underlying the cohesion of chromatids along their arms is different from that responsible for cohesion in the centromere region. We then argue that the chromatids on a mitotic chromosome are also tethered along their arms and in the centromere by different mechanisms, and that the functional action of these two mechanisms can be temporally separated under various conditions. Finally, we demonstrate that in the absence of a centromeric tether, arm cohesion is sufficient to maintain chromatid cohesion during prometaphase of mitosis. This finding provides a straightforward explanation for why mutants in proteins responsible for centromeric cohesion in Drosophila (e.g. ord, mei-s332) disrupt meiosis but not mitosis.


Balamuthia mandrillaris: An opportunistic, free-living ameba - An updated review.
Balamuthia mandrillaris is an opportunistic, free-living ameba that is pathogenic to humans. It has a worldwide distribution but is mainly detected in warmer regions. Balamuthia infections are rare but have been reported in both immunocompetent and immunocompromised individuals of all ages. B. mandrillaris can enter through wounds on the skin or the nose and cause cutaneous lesions and the usually fatal Balamuthia amebic encephalitis (BAE). Infection usually spreads from the lungs or through nerve fibers, and attacks the central nervous system, forming granulomatous lesions and necrosis in the brain. Balamuthia infection is usually chronic, and patients initially present with nonspecific symptoms, including headache, nausea, myalgia, and low-grade fever. As the disease progresses, the patient becomes paralyzed and comatose, often leading to death. Lack of knowledge of predisposing factors, specific treatment, and standardized detection tools have resulted in a nearly cent percent fatality rate. Although only about 200 cases have been reported worldwide since its characterization in the 1990s, the number of reported cases has increased over the years. BAE is an emerging disease and a major health concern. Few patients have survived Balamuthia infections with antimicrobial treatment that has largely been empirical. Early diagnosis is the key and requires familiarity with the disease and a high degree of suspicion on the part of the diagnostician. There are currently no specific treatment and prevention recommendations. This review highlights our current understanding of B. mandrillaris in terms of its pathogenicity, genomics, and novel diagnostic and therapeutic approaches against BAE infections.


Evolution of pathogenic viruses with special reference to the rates of synonymous and nonsynonymous substitutions.
For pathogenic viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human influenza A virus, and human T-cell leukemia virus type I (HTLV-I), the evolutionary features were briefly reviewed with special reference to the rates of synonymous and nonsynonymous substitutions. In particular, these rates were discussed in connection with the neutral theory of molecular evolution. It was common to all the five pathogenic viruses that the rate of synonymous substitution was higher than that of nonsynonymous substitution particularly when the entire gene regions were compared between different isolates. This suggests that the viral proteins are quite conservative to functional and structural changes even though most of these viral genomes are evolving at a speed extraordinarily higher than their host genomes. Thus, this feature is consistent with the neutral theory. However, it is also pointed out that positive selection may be operating on some specific sites such as antigenic sites in order for the pathogenic viruses to escape from the host immune system.


The effects of chronic trans-resveratrol supplementation on aspects of cognitive function, mood, sleep, health and cerebral blood flow in healthy, young humans.
Single doses of resveratrol have previously been shown to increase cerebral blood flow (CBF) with no clear effect on cognitive function or mood in healthy adults. Chronic resveratrol consumption may increase the poor bioavailability of resveratrol or otherwise potentiate its psychological effects. In this randomised, double-blind, placebo-controlled, parallel-groups study, a total of sixty adults aged between 18 and 30 years received either placebo or resveratrol for 28 d. On the 1st and 28th day of treatment, the performance of cognitively demanding tasks (serial subtractions, rapid visual information processing and 3-Back) (n 41 complete data sets) was assessed, alongside blood pressure (n 26) and acute (near-IR spectroscopy (NIRS)) and chronic (transcranial Doppler) measures of CBF (n 46). Subjective mood, sleep quality and health questionnaires were completed at weekly intervals (n 53/54). The results showed that the cognitive effects of resveratrol on day 1 were restricted to more accurate but slower serial subtraction task performance. The only cognitive finding on day 28 was a beneficial effect of resveratrol on the accuracy of the 3-Back task before treatment consumption. Subjective ratings of 'fatigue' were significantly lower across the entire 28 d in the resveratrol condition. Resveratrol also resulted in modulation of CBF parameters on day 1, as assessed by NIRS, and significantly increased diastolic blood pressure on day 28. Levels of resveratrol metabolites were significantly higher both before and after the day's treatment on day 28, in comparison with day 1. These results confirm the acute CBF effects of resveratrol and the lack of interpretable cognitive effects.


Clusters of leprosy transmission and of late diagnosis in a highly endemic area in Brazil: focus on different spatial analysis approaches.
The Brazilian National Hansen's Disease Control Program recently identified clusters with high disease transmission. Herein, we present different spatial analytical approaches to define highly vulnerable areas in one of these clusters. The study area included 373 municipalities in the four Brazilian states Maranhão, Pará, Tocantins and Piauí. Spatial analysis was based on municipalities as the observation unit, considering the following disease indicators: (i) rate of new cases/100,000 population, (ii) rate of cases <15 years/100,000 population, (iii) new cases with grade-2 disability/100,000 population and (iv) proportion of new cases with grade-2 disabilities. We performed descriptive spatial analysis, local empirical Bayesian analysis and spatial scan statistic. A total of 254 (68.0%) municipalities were classified as hyperendemic (mean annual detection rates >40 cases/100,000 inhabitants). There was a concentration of municipalities with higher detection rates in Pará and in the center of Maranhão. Spatial scan statistic identified 23 likely clusters of new leprosy case detection rates, most of them localized in these two states. These clusters included only 32% of the total population, but 55.4% of new leprosy cases. We also identified 16 significant clusters for the detection rate <15 years and 11 likely clusters of new cases with grade-2. Several clusters of new cases with grade-2/population overlap with those of new cases detection and detection of children <15 years of age. The proportion of new cases with grade-2 did not reveal any significant clusters. Several municipality clusters for high leprosy transmission and late diagnosis were identified in an endemic area using different statistical approaches. Spatial scan statistic is adequate to validate and confirm high-risk leprosy areas for transmission and late diagnosis, identified using descriptive spatial analysis and using local empirical Bayesian method. National and State leprosy control programs urgently need to intensify control actions in these highly vulnerable municipalities.


Local anesthetics: effect of pH on activity.
Lidocaine and dibucaine are more effective in neutral than in alkaline solution when tested on the nonmyelinated fibers of the desheathed vagus nerve of the rabbit. Procaine, however, is more effective in alkaline solution. The activity of benzocaine is unaffected by pH. Both the charged and uncharged forms of local anesthetics thus seem capable of blocking conduction.


Identifying patients likely to be readmitted after transcatheter aortic valve replacement.
Hospital readmission following transcatheter aortic valve replacement (TAVR) contributes considerably to the costs of care. Readmission rates following TAVR have been reported to be as high as 17.4% at 30 days and 53.2% at 1 year. Patient and procedural factors predict an increased likelihood of readmission including non-transfemoral access, acute and chronic kidney impairment, chronic lung disease, left ventricular systolic dysfunction, atrial fibrillation, major bleeding and prolonged index hospitalisation. Recent studies have also found the requirement for new pacemaker implantation and the severity of paravalvular aortic regurgitation and tricuspid regurgitation to be novel predictors of readmission. Post-TAVR readmission within 30 days of discharge is more likely to occur for non-cardiac than cardiac pathology, although readmission for cardiac causes, especially heart failure, predicts higher mortality than readmission for non-cardiac causes. To combat the risk of readmission and associated mortality, the routine practice of calculating and considering readmission risk should be adopted by the heart team. Furthermore, because most readmissions following TAVR occur for non-cardiac reasons, more holistic approaches to readmission prevention are necessary. Familiarity with the most common predictors and causes of readmission should guide the development of initiatives to address these conditions proactively.


Relationship between insertion/deletion (indel) frequency of proteins and essentiality.
In a previous study, we demonstrated that some essential proteins from pathogenic organisms contained sizable insertions/deletions (indels) when aligned to human proteins of high sequence similarity. Such indels may provide sufficient spatial differences between the pathogenic protein and human proteins to allow for selective targeting. In one example, an indel difference was targeted via large scale in-silico screening. This resulted in selective antibodies and small compounds which were capable of binding to the deletion-bearing essential pathogen protein without any cross-reactivity to the highly similar human protein. The objective of the current study was to investigate whether indels were found more frequently in essential than non-essential proteins. We have investigated three species, Bacillus subtilis, Escherichia coli, and Saccharomyces cerevisiae, for which high-quality protein essentiality data is available. Using these data, we demonstrated with t-test calculations that the mean indel frequencies in essential proteins were greater than that of non-essential proteins in the three proteomes. The abundance of indels in both types of proteins was also shown to be accurately modeled by the Weibull distribution. However, Receiver Operator Characteristic (ROC) curves showed that indel frequencies alone could not be used as a marker to accurately discriminate between essential and non-essential proteins in the three proteomes. Finally, we analyzed the protein interaction data available for S. cerevisiae and observed that indel-bearing proteins were involved in more interactions and had greater betweenness values within Protein Interaction Networks (PINs). Overall, our findings demonstrated that indels were not randomly distributed across the studied proteomes and were likely to occur more often in essential proteins and those that were highly connected, indicating a possible role of sequence insertions and deletions in the regulation and modification of protein-protein interactions. Such observations will provide new insights into indel-based drug design using bioinformatics and cheminformatics tools.