Sensory and nurturing nonpharmacological interventions for behavioral and psychological symptoms of dementia.
This article is part three of a four-part series addressing the use of nonpharmacological interventions in place of or in conjunction with psychotropic medications in older adults with cognitive impairment. Acquiring a better understanding of the mechanics for how each intervention works makes selection of an intervention easier at the time it is needed. Selection of the appropriate nonpharmacological intervention is based on person-centered care and how to adapt and implement it for each individual. Selection also depends on target behavior, behavior triggers, and the physical and cognitive functioning of the individual with the behavioral and psychological symptoms of dementia. Nonpharmacological interventions can be implemented by all staff members, not just recreational and activity personnel. The Centers for Medicare & Medicaid Services initiative would like to see all staff involved with these interventions, which can be implemented on the spot, as they are needed, to prevent, reduce, or stop a particular behavior. The current article will describe sensory and nurturing interventions, present the evidence supporting their use, and provide information on effective implementation.


THE HEALTH OF OLDER WOMEN AFTER HIGH PARITY IN TAFT, IRAN.
High parity has been hypothesised to lead to a shorter and less healthy life. Using the 2007 Taft Ageing Health and Fertility Survey consisting of 696 women aged 50-79, this paper examines the extent to which women's health in middle and older ages is affected by their childbearing histories. The results show that high parity (> 8) is associated with a reduction of GP-rated health by 0.094 points on a scale from 1 to 10. These health reductions are four times as large as those of an extra year of age, and are robust to controlling for birth interval, age, area of residence, education, marital status, work history, economic satisfaction and surviving daughters. There is a positive but curvilinear relationship between shorter birth intervals (< 2 years) and GP-rated health accounting for socio-demographic factors. Our analysis suggests that parity and birth intervals, along with socio-demographic characteristics, affect women's well-being in later life.


HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner.
Cardiovascular diseases remain the leading cause of death in the United States. Two factors associated with a decreased risk of developing cardiovascular disease are elevated HDL levels and sex - specifically, a decreased risk is found in premenopausal women. HDL and estrogen stimulate eNOS and the production of nitric oxide, which has numerous protective effects in the vascular system including vasodilation, antiadhesion, and anti-inflammatory effects. We tested the hypothesis that HDL binds to its receptor, scavenger receptor class B type I (SR-BI), and delivers estrogen to eNOS, thereby stimulating the enzyme. HDL isolated from women stimulated eNOS, whereas HDL isolated from men had minimal activity. Studies with ovariectomized and ovariectomized/estrogen replacement mouse models demonstrated that HDL-associated estradiol stimulation of eNOS is SR-BI dependent. Furthermore, female HDL, but not male HDL, promoted the relaxation of muscle strips isolated from C57BL/6 mice but not SR-BI null mice. Finally, HDL isolated from premenopausal women or postmenopausal women receiving estradiol replacement therapy stimulated eNOS, whereas HDL isolated from postmenopausal women did not stimulate eNOS. We conclude that HDL-associated estrodial is capable of the stimulating eNOS. These studies establish a new paradigm for examining the cardiovascular effects of HDL and estrogen.


Microchimerism and regulation in living related kidney transplant families.
Long-term harmful effects of immunosuppressive drugs and chronic rejection are a persistent impetus to establish methods to induce immunological tolerance to allografts. PCR-based studies have found evidence that humans and other placental mammals can have prolonged extremely low levels of maternal cells as well as other non-self cells, referred to as microchimerism. The persistence of these cells suggests a mechanism for the maintenance of the regulatory T-cell (Treg) responses frequently detected in offspring to non-inherited maternal antigens. We test the hypothesis that the detection of very low copy levels of insertion/deletion (Indel) alleles consistent with non-inherited maternal genes, will correlate with immune regulation to non-inherited maternal antigens as detected by a trans-vivo Delayed-Type Hypersensitivity (tvDTH) assay in kidney transplant recipients, normal donors and their immediate biological family members. Preliminary data reported here compares qPCR amplification of rare DNA templates in the peripheral blood polymorphonuclear (PMN) fraction of cells, with the results of tvDTH assays for linked suppression of recall antigen responses in the presence of non-inherited maternal antigens [NIMA]. The two assays do not show a definitive correlation.


Black masculinity matters in attitudes toward gay males.
Recent work on attitudes toward homosexuals promotes the view that males typically have more negative attitudes than females; and African Americans have more negative attitudes than their white counterparts. However, among African Americans, women are thought to have the greatest negative attitudes because they perceive themselves as competing for a limited pool of black male partners. This study uses the National Black Politics Study to examine African American gender differences in attitudes toward homosexual men. Multivariate findings show that of the variables analyzed: (1) Among African American females, age, income, education, and urban residence are statistically significant; and (2) among African American males, frequency of religious attendance was the only statistically significant variable. It is, therefore, argued that black masculinity explains the gendered differences and that negative attitudes within the African American community toward gay men contribute to debilitating both the physical and mental health of the entire black community.


Identification of Differentially Expressed Proteins from Smokeless Tobacco Addicted Patients Suffering from Oral Squamous Cell Carcinoma.
Oral squamous cell carcinoma (OSCC) is the eight most common malignancy worldwide with an incidence rate of 40% in south-east Asia. Lack of effective diagnostic tools at early stage and disease recurrence despite extensive treatments are main reasons for high mortality and low survival rates. The aim of current study was to identify differentially expressed proteins to explore potential candidate biomarkers having diagnostic significance. We performed comparative proteomic analysis of paired protein samples (cancerous buccal mucosa and adjacent normal tissue) from OSCC patients using a combination of two dimensional gel electrophoresis and Mass spectrometric analysis. On the basis of spot intensity, seventeen proteins were found to be consistently differentially expressed among most of the samples which were identified through mass spectrometry. For validation of identified proteins, expression level of stratifin was determined using immuno-histochemistry and Western blot analysis. All identified proteins were analyzed by STRING to explore their interaction. Among uniquely identified proteins in this study, at least two candidate markers (Ig Kappa chain C region and Isoform 2 of fructose bisphosphate aldolase A) were found to be novel with respect to OSCC which can be explored further. Results presented in current study are likely to contribute in understanding the involvement of these molecules in carcinogenesis apart from their plausible role as diagnostic/prognostic markers.


Bayesian spatial analysis of a national urinary schistosomiasis questionnaire to assist geographic targeting of schistosomiasis control in Tanzania, East Africa.
Spatial modelling was applied to self-reported schistosomiasis data from over 2.5 million school students from 12,399 schools in all regions of mainland Tanzania. The aims were to derive statistically robust prevalence estimates in small geographical units (wards), to identify spatial clusters of high and low prevalence and to quantify uncertainty surrounding prevalence estimates. The objective was to permit informed decision-making for targeting of resources by the Tanzanian national schistosomiasis control programme. Bayesian logistic regression models were constructed to investigate the risk of schistosomiasis in each ward, based on the prevalence of self-reported schistosomiasis and blood in urine. Models contained covariates representing climatic and demographic effects and random effects for spatial clustering. Degree of urbanisation, median elevation of the ward and median normalised difference vegetation index (NDVI) were significantly and negatively associated with schistosomiasis prevalence. Most regions contained wards that had >95% certainty of schistosomiasis prevalence being >10%, the selected threshold for bi-annual mass chemotherapy of school-age children. Wards with >95% certainty of schistosomiasis prevalence being >30%, the selected threshold for annual mass chemotherapy of school-age children, were clustered in north-western, south-western and south-eastern regions. Large sample sizes in most wards meant raw prevalence estimates were robust. However, when uncertainties were investigated, intervention status was equivocal in 6.7-13.0% of wards depending on the criterion used. The resulting maps are being used to plan the distribution of praziquantel to participating districts; they will be applied to prioritising control in those wards where prevalence was unequivocally above thresholds for intervention and might direct decision-makers to obtain more information in wards where intervention status was uncertain.


Genetics: how the UKPDS contributed to determining the genetic landscape of Type 2 diabetes.
The identification and functional characterisation of genetic variants that either cause or predispose to diabetes is a major focus of biomedical research. The molecular basis is now known for the majority of monogenic forms of diabetes arising from pancreatic beta-cell dysfunction; however finding the genetic variants underlying susceptibility to Type 2 diabetes (T2DM) has been a greater technical, statistical and biological challenge. The advent of biology-agnostic approaches made possible by the improved arsenal of research platforms and genetic tools available has increased the number of known T2DM genes dramatically and provided important insights into the pathophysiology of T2DM. Over the past 18 months, the list of T2DM susceptibility genes has grown from three to close to 20, illustrating the substantial progress which has been made. These recent milestones have not only illustrated the limited knowledge we have of the pancreatic beta-cell, but have also reinforced our belief in the involvement of common genetic variants in the genes involved in monogenic forms of diabetes in the susceptibility to T2DM and have clearly shown a primary role for pancreatic beta-cell dysfunction in T2DM. Both of these concepts were explored in the early work of the UK Prospective Diabetes Study (UKPDS) genetics research groups.


Modern mass spectrometry for synthetic biology and structure-based discovery of natural products.
Covering: up to 2016In this highlight, we describe the current landscape for dereplication and discovery of natural products based on the measurement of the intact mass by LC-MS. Often it is assumed that because better mass accuracy (provided by higher resolution mass spectrometers) is necessary for absolute chemical formula determination (≤1 part-per-million), that it is also necessary for dereplication of natural products. However, the average ability to dereplicate tapers off at ∼10 ppm, with modest improvement gained from better mass accuracy when querying focused databases of natural products. We also highlight some recent examples of how these platforms are applied to synthetic biology, and recent methods for dereplication and correlation of substructures using tandem MS data. We also offer this highlight to serve as a brief primer for those entering the field of mass spectrometry-based natural products discovery.


Should Health Numeracy Be Assessed Objectively or Subjectively?
Because current evidence suggests that numeracy affects how people make decisions, it is an important factor to account for in studies assessing the effectiveness of medical decision support interventions. Subjective and objective numeracy assessment methods are available that vary in theoretical background, skills assessed, known relationship with decision making skills, and ease of implementation. The best way to use these tools to assess numeracy when conducting medical decision-making research is currently unknown. We conducted Internet surveys comparing numeracy assessments obtained using the subjective numeracy scale (SNS) and 5 objective numeracy scales. Each study participant completed the SNS and 1 objective numeracy measure. Following each assessment, participants indicated willingness to repeat the assessment and rated its user acceptability. The overall response rate was 78%, resulting in a total sample size of 673. Spearman correlations between the SNS and the objective numeracy measures ranged from 0.19 to 0.44. Acceptability assessments for the short form of the Numeracy Understanding in Medicine Instrument and the SNS did not differ significantly. The other objective scales all had lower acceptability ratings than the SNS. These findings are consistent with prior research suggesting that objective and subjective numeracy scales measure related but distinct constructs. Due to current uncertainty regarding which construct is more likely to influence the effectiveness of decision support interventions, these findings warrant further investigation to determine the proper use of objective versus subjective numeracy assessments in medical decision-making research. Pending additional information, a reasonable approach is to measure both objective and subjective numeracy so that the full range of actual and perceived numeracy skills can be taken into account.


Meniscal and Articular Cartilage Predictors of Clinical Outcome After Revision Anterior Cruciate Ligament Reconstruction.
Revision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes compared with primary ACL reconstructions. The purpose of this study was to determine if the prevalence, location, and/or degree of meniscal and chondral damage noted at the time of revision ACL reconstruction predicts activity level, sports function, and osteoarthritis symptoms at 2-year follow-up. The hypothesis was that meniscal loss and high-grade chondral damage noted at the time of revision ACL reconstruction will result in lower activity levels, decreased sports participation, more pain, more stiffness, and more functional limitation at 2 years after revision surgery. Cohort study; Level of evidence, 2. Between 2006 and 2011, a total of 1205 patients who underwent revision ACL reconstruction by 83 surgeons at 52 hospitals were accumulated for study of the relationship of meniscal and articular cartilage damage to outcome. Baseline demographic and intraoperative data, including the International Knee Documentation Committee (IKDC) subjective knee evaluation, Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx activity score, were collected initially and at 2-year follow-up to test the hypothesis. Regression analysis was used to control for age, sex, body mass index, smoking status, activity level, baseline outcome scores, revision number, time since last ACL reconstruction, incidence of having a previous ACL reconstruction on the contralateral knee, previous and current meniscal and articular cartilage injury, graft choice, and surgeon years of experience to assess the meniscal and articular cartilage risk factors for clinical outcomes 2 years after revision ACL reconstruction. At 2-year follow-up, 82% (989/1205) of the patients returned their questionnaires. It was found that previous meniscal injury and current articular cartilage damage were associated with the poorest outcomes, with prior lateral meniscectomy and current grade 3 to 4 trochlear articular cartilage changes having the worst outcome scores. Activity levels at 2 years were not affected by meniscal or articular cartilage pathologic changes. Prior lateral meniscectomy and current grade 3 to 4 changes of the trochlea were associated with worse outcomes in terms of decreased sports participation, more pain, more stiffness, and more functional limitation at 2 years after revision surgery, but they had no effect on activity levels. NCT00625885.


Feasibility and acceptability of a midwife-led health education strategy to reduce exposure to biomass smoke among pregnant women in Uganda, A FRESH AIR project.
Biomass smoke exposure is a threat to child and maternal health in many resource-limited countries and is associated with poor pregnancy outcomes and serious lung diseases in the offspring. We aimed to assess the feasibility, acceptability and impact of a midwife-led education programme on biomass risks and prevention for women attending maternity clinics in Uganda. Education materials were co-developed through an iterative process by midwives and other stakeholders. The materials were serially tested and approved by the Ministry of Health and used by midwives and village health teams (VHTs). The district health team, 12 midwives and 40 VHTs were sensitised on biomass smoke. Two hundred and forty-four women were educated about biomass smoke by midwives; pre- and post-session questionnaires showed major improvements in knowledge of biomass smoke risks. Qualitative interviews with women three months after the sessions showed that they made behavioural changes such as avoiding smoke while cooking, using dry wood, solar power for lighting and improved ventilation. The major barrier to behavioural changes was poverty, but some improvements cost no money. The programme delivered by midwives was feasible and acceptable; implementing this programme has the potential to reduce exposure to smoke with major benefits to mother, foetus, and children throughout their lives.


Oxidative stress and counteracting mechanisms in hormone receptor positive, triple-negative and basal-like breast carcinomas.
Triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC) are breast cancer subtypes with an especially poor prognosis. 8-Hydroxydeoxyguanosine (8-OHdG) is a widely used marker of oxidative stress and the redox-state-regulating enzymes peroxiredoxins (PRDXs) are efficient at depressing excessive reactive oxygen species. NF-E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) are redox-sensitive transcription factors that regulate PRDX expression. This is the first study to assess oxidative stress and or cell redox state-regulating enzymes in TNBC and BLBC. We assessed immunohistochemical expression of 8-OHdG, Nrf2, Keap1, PRDX III and PRDX IV in 79 women with invasive ductal breast carcinomas. Of these tumors, 37 represented TNBC (grade II-III tumors with total lack of ER, PR and human epidermal growth factor receptor 2 [HER2] expression). Control cases (n = 42) were ER-positive, PR-positive and HER2-negative. Of the 37 TNBCs, 31 had BLBC phenotype (TNBC with expression of cytokeratin 5/6 or epidermal growth factor receptor 1). Patients with TNBC had worse breast cancer-specific survival (BCSS) than the control group (p = 0.015). Expression of 8-OHdG was significantly lower in TNBC than in the non-TNBC group (p < 0.005). 8-OHdG immunostaining was associated with better BCSS (p = 0.01), small tumor size (p < 0.0001) and low grade (p < 0.0005). Keap1 overexpression was observed in the TNBC cohort (p = 0.001) and Keap1-positive patients had worse BCSS than Keap1-negative women (p = 0.014). PRDX IV was overexpressed in the TNBC vs. the non-TNBC group (p = 0.022). Cellular redox state markers may be promising targets when elucidating the pathogenesis of TNBC.


Trends and repetition of non-fatal suicidal behaviour: analyses of the Gold Coast University Hospital's Emergency Department.
Objective The aim of the current paper is to analyse time trends of non-fatal suicidal behaviour (NFSB) and its repetition at the Gold Coast in 2005-2015. Methods Data on presentations for NFSB were obtained from the Emergency Department (ED) Information System. Potential cases were identified through keyword searches, which were further scrutinised and coded. Annual person-based age-standardised rates for NFSB were calculated. Chi-square test, Poisson regression and Cox proportional hazards regression were used. There was a significant increase in the age-standardised rates of NFSB for males (incidence Rate Ratio = 1.05; 95% confidence interval (CI): 1.04-1.07) and females (iRR = 1.06; 95% CI: 1.04-1.07). Age-specific rates showed significant increases for all age groups, except 25-34 and 55+ for females. Different types of poisoning were the predominant method of NFSB (poisoning only - 61.7% of episodes), followed by cutting (23%). Within the first year after the index episode, 13.4% of subjects repeated NFSB. Multivariate Cox regression model showed that sex, age and method predicted repetition. The increasing trends of NFSB and relatively high repetition rates emphasise the need for preventative actions. Monitoring of NFSB at the ED level should be further extended in Australia.


Trends in cardiometabolic risk factors in the Americas between 1980 and 2014: a pooled analysis of population-based surveys.
Describing the prevalence and trends of cardiometabolic risk factors that are associated with non-communicable diseases (NCDs) is crucial for monitoring progress, planning prevention, and providing evidence to support policy efforts. We aimed to analyse the transition in body-mass index (BMI), obesity, blood pressure, raised blood pressure, and diabetes in the Americas, between 1980 and 2014. We did a pooled analysis of population-based studies with data on anthropometric measurements, biomarkers for diabetes, and blood pressure from adults aged 18 years or older. A Bayesian model was used to estimate trends in BMI, raised blood pressure (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg), and diabetes (fasting plasma glucose ≥7·0 mmol/L, history of diabetes, or diabetes treatment) from 1980 to 2014, in 37 countries and six subregions of the Americas. 389 population-based surveys from the Americas were available. Comparing prevalence estimates from 2014 with those of 1980, in the non-English speaking Caribbean subregion, the prevalence of obesity increased from 3·9% (95% CI 2·2-6·3) in 1980, to 18·6% (14·3-23·3) in 2014, in men; and from 12·2% (8·2-17·0) in 1980, to 30·5% (25·7-35·5) in 2014, in women. The English-speaking Caribbean subregion had the largest increase in the prevalence of diabetes, from 5·2% (2·1-10·4) in men and 6·4% (2·6-10·4) in women in 1980, to 11·1% (6·4-17·3) in men and 13·6% (8·2-21·0) in women in 2014). Conversely, the prevalence of raised blood pressure has decreased in all subregions; the largest decrease was found in North America from 27·6% (22·3-33·2) in men and 19·9% (15·8-24·4) in women in 1980, to 15·5% (11·1-20·9) in men and 10·7% (7·7-14·5) in women in 2014. Despite the generally high prevalence of cardiometabolic risk factors across the Americas, estimates also showed a high level of heterogeneity in the transition between countries. The increasing prevalence of obesity and diabetes observed over time requires appropriate measures to deal with these public health challenges. Our results support a diversification of health interventions across subregions and countries. Wellcome Trust.


Associations among body condition score, body weight, somatic cell count, and clinical mastitis in seasonally calving dairy cattle.
The objective of this study was to determine if an association existed among body condition score (BCS), body weight (BW), and udder health, as indicated by somatic cell score (SCS) and cases of clinical mastitis (CM). The data consisted of 2,635 lactations from Holstein-Friesian (n = 523) and Jersey (n = 374) cows in a seasonal calving pasture-based research herd between the years 1986 and 2000, inclusive. Increased BCS at calving was associated with reduced SCS in first- and second-parity cows, and greater SCS in cows of third parity or greater. This relationship persisted for most BCS traits throughout lactation. Body weight was positively associated with SCS, although the effect was greater in Jersey cows than in Holstein-Friesians. Increased BCS and BW loss in early lactation were associated with lower SCS and a reduced probability of a high test-day SCC. Body condition score was not significantly related to CM with the exception of a curvilinear relationship between the daily rate of BCS change to nadir and CM in early lactation. Several BW variables were positively associated with a greater likelihood of CM. Nevertheless, most associations with udder health lacked biological significance within the ranges of BCS and BW generally observed on-farm. Results are important in assuring the public that modern dairy systems, where cows are subjected to substantial amounts of BCS mobilization in early lactation, do not unduly compromise cow udder health.


DARC 2.0: Improved Docking and Virtual Screening at Protein Interaction Sites.
Over the past decade, protein-protein interactions have emerged as attractive but challenging targets for therapeutic intervention using small molecules. Due to the relatively flat surfaces that typify protein interaction sites, modern virtual screening tools developed for optimal performance against "traditional" protein targets perform less well when applied instead at protein interaction sites. Previously, we described a docking method specifically catered to the shallow binding modes characteristic of small-molecule inhibitors of protein interaction sites. This method, called DARC (Docking Approach using Ray Casting), operates by comparing the topography of the protein surface when "viewed" from a vantage point inside the protein against the topography of a bound ligand when "viewed" from the same vantage point. Here, we present five key enhancements to DARC. First, we use multiple vantage points to more accurately determine protein-ligand surface complementarity. Second, we describe a new scheme for rapidly determining optimal weights in the DARC scoring function. Third, we incorporate sampling of ligand conformers "on-the-fly" during docking. Fourth, we move beyond simple shape complementarity and introduce a term in the scoring function to capture electrostatic complementarity. Finally, we adjust the control flow in our GPU implementation of DARC to achieve greater speedup of these calculations. At each step of this study, we evaluate the performance of DARC in a "pose recapitulation" experiment: predicting the binding mode of 25 inhibitors each solved in complex with its distinct target protein (a protein interaction site). Whereas the previous version of DARC docked only one of these inhibitors to within 2 Å RMSD of its position in the crystal structure, the newer version achieves this level of accuracy for 12 of the 25 complexes, corresponding to a statistically significant performance improvement (p < 0.001). Collectively then, we find that the five enhancements described here--which together make up DARC 2.0--lead to dramatically improved speed and performance relative to the original DARC method.


Type III secretion systems: the bacterial flagellum and the injectisome.
The flagellum and the injectisome are two of the most complex and fascinating bacterial nanomachines. At their core, they share a type III secretion system (T3SS), a transmembrane export complex that forms the extracellular appendages, the flagellar filament and the injectisome needle. Recent advances, combining structural biology, cryo-electron tomography, molecular genetics, in vivo imaging, bioinformatics and biophysics, have greatly increased our understanding of the T3SS, especially the structure of its transmembrane and cytosolic components, the transcriptional, post-transcriptional and functional regulation and the remarkable adaptivity of the system. This review aims to integrate these new findings into our current knowledge of the evolution, function, regulation and dynamics of the T3SS, and to highlight commonalities and differences between the two systems, as well as their potential applications.


The effects of sexual sensation seeking and alcohol use on risky sexual behavior among men who have sex with men.
Men who have sex with men (MSM) remain most at risk for developing HIV infection. The best prevention in this population is to identify risk factors associated with unprotected sex. Recent research suggests that sexual sensation seeking (SSS) and level of average drinking moderates the relationship between drinking alcohol in the context of sex and risky sexual behavior in a young MSM population (ages 16-20 years). Current study is an exploratory analysis using multilevel modeling to examine if these results are consistent across a MSM population with a wider range of ages who are also heavy drinkers. Participants (n = 181) included MSM (ages 18-75 years) from a longitudinal clinical research trial. Results indicate that MSM with higher SSS were more likely to have unprotected anal sex if they drank alcohol 3 h prior to sex than those who did not, (OR = 1.07; 95 % CI 1.03-1.12). There was no significant interaction effect for average levels of drinking.


Immunotoxins containing Pseudomonas exotoxin that target LeY damage human endothelial cells in an antibody-specific mode: relevance to vascular leak syndrome.
Vascular leak syndrome (VLS) was originally found to be a major dose-limiting toxicity in humans with cancer treated with several immunotoxins (ITs) containing ricin A chain or blocked ricin. Recently, VLS has also been observed in patients treated with an IT containing the murine monoclonal antibody (MAb) B3 coupled to LysPE38, a recombinant truncated form of Pseudomonas exotoxin (PE) A. Antibody B3 (IgG1k) recognizes LewisY and related carbohydrate epitopes present on many human solid tumors, and B3-LysPE38 showed excellent antitumor activity in nude mice bearing tumors that express the B3 antigen. In the clinical trial, the development of VLS has prevented the administration of the amount of IT necessary to achieve blood levels required for good therapeutic responses. We have now investigated the effects of several PE-based ITs on different human endothelial cell lines to elucidate the mechanism of VLS induced by ITs containing PE. To assess the cytotoxic effect of IT on endothelial cells, various ITs were incubated with cells for 2 or 20 h, and the incorporation of [3H]leucine into protein was measured. The endothelial cells studied were human umbilical vein endothelial cells, human lung-derived microvascular endothelial cells (HUVECs), human adult dermal microvascular endothelial cells, human pulmonary artery endothelial cells, and human aortic endothelial cells. We found that both B3-LysPE38 (LMB-1), a chemical conjugate of MAb B3 with PE38, as well as B3(Fv)-PE38 (LMB-7), a recombinant single chain immunotoxin, inhibited protein synthesis, with 50% inhibitory concentrations between 600 and 1000 ng/ml for 20-h incubation in HUVECs, human lung-derived microvascular endothelial cells, and human adult dermal microvascular endothelial cells but not on human pulmonary artery endothelial cells. The cytotoxic effect was specific since PE38 itself or PE coupled to several other antibodies did not inhibit protein synthesis in these cells even at 10,000 ng/ml. Further evidence that the cytotoxicity of B3-containing ITs is due to specific B3 binding to endothelial cells comes from the fact that the cytotoxicity can be blocked by excess free MAb B3. HUVECs undergo overt morphological changes after treatment with B3-LysPE38 or B3(Fv)PE38. Gaps between the cells are formed after a 20-h exposure but not after 2 h. These studies suggest that VLS in patients is due to capillary damage caused by prolonged exposure to high concentrations of LMB-1.


Measuring individual locomotor rhythms in honey bees, paper wasps and other similar-sized insects.
Circadian rhythms in social insects are highly plastic and are modulated by multiple factors. In addition, complex behaviors such as sun-compass orientation and time learning are clearly regulated by the circadian system in these organisms. Despite these unique features of social insect clocks, the mechanisms as well as the functional and evolutionary relevance of these traits remain largely unknown. Here we show a modification of the Drosophila activity monitoring (DAM) system that allowed us to measure locomotor rhythms of the honey bee, Apis mellifera (three variants; gAHB, carnica and caucasica), and two paper wasps (Polistes crinitus and Mischocyttarus phthisicus). A side-by-side comparison of the endogenous period under constant darkness (free-running period) led us to the realization that these social insects exhibit significant deviations from the Earth's 24 h rotational period as well as a large degree of inter-individual variation compared with Drosophila. Experiments at different temperatures, using honey bees as a model, revealed that testing the endogenous rhythm at 35°C, which is the hive's core temperature, results in average periods closer to 24 h compared with 25°C (23.8 h at 35°C versus 22.7 h at 25°C). This finding suggests that the degree of tuning of circadian temperature compensation varies among different organisms. We expect that the commercial availability, cost-effectiveness and integrated nature of this monitoring system will facilitate the growth of the circadian field in these social insects and catalyze our understanding of the mechanisms as well as the functional and evolutionary relevance of circadian rhythms.


DCD pigs' kidneys analyzed by MRI to assess ex vivo their viability.
Magnetic resonance imaging (MRI) gadolinium-perfusion was applied in simulated Donation after Cardiac Death (DCD) in porcine kidneys to measure intrarenal perfusion. Adenosine triphosphate (ATP) resynthesis during oxygenated hypothermic perfusion was compared to evaluate the "ex vivo organ viability". Adenine nucleotide (AN) was measured by P nuclear magnetic resonance (NMR) spectroscopy. Whereas this latter technique requires sophisticated hardware, gadolinium-perfusion can be realized using any standard proton-MRI scanner. The aim of this work was to establish a correlation between the two methods. Twenty-two porcine kidneys presenting up to 90 min warm ischemia were perfused with oxygenation at 4 °C using our magnetic resonance-compatible machine. During the perfusion, P NMR spectroscopy and gadolinium-perfusion sequences were performed. Measures obtained from the gadolinium-perfusion were the speed of elimination of the cortical gadolinium and the presence or absence of a corticomedullar shunt. For ATP resynthesis analysis, P chemical shift imaging was acquired and analyzed. All the kidneys have been submitted to histologic examination. ATP resynthesis was observed in all organs presenting a cortical gadolinium elimination slope of (-) 23° or greater. In organs with lower gadolinium elimination, no AN or only precursors were detected. This study reveals a link between the two methods and demonstrates ex vivo viability in 93% of the analyzed kidneys. Benefits and side effects of both methods are discussed. Oxygenated hypothermic perfusion enables the evaluation of kidneys in DCD simulated situation; gadolinium-perfusion can be introduced into any center equipped with a proton-MRI scanner allowing results superposable with ATP measurement.


Randomized study of aprotinin effect on transfusions and blood loss in primary THA.
A projected increase in total hip arthroplasties, shortfalls in blood availability, and awareness of complications of transfusion make blood management in orthopaedic surgery important. In a multicenter, randomized, double-blind, placebo-controlled study, we hypothesized use of aprotinin would reduce blood transfusions (any and allogeneic) and blood loss in total hip arthroplasty. Using an intent-to-treat approach, we recruited 393 patients stratified by preoperative autologous blood donation or none and then randomized them to receive aprotinin (176 patients receiving a 10,000 kallikrein inhibitor units [KIU] test dose, 2 million KIU load, 0.5 million KIU per hour) or placebo (177 patients). We assessed patients at baseline; postoperative days 1, 2, 3, and 7 (or discharge); and 6 +/- 2 weeks. Primary efficacy was percentage of patients having blood transfusion through day 7 or discharge. We based safety on reported adverse events. Aprotinin reduced transfusions by 46% (30 of 176 versus 56 of 177 patients). Aprotinin reduced the total number of any blood units and the number of allogeneic blood units transfused relative to placebo (48 versus 109 units and 30 versus 72 units, respectively). Serious complications were similar in the two groups (placebo, 11%; aprotinin, 10%). Our data suggest full-dose aprotinin is safe and effective in decreasing blood transfusion in total hip arthroplasty.


Application of MOSFET detectors for dosimetry in small animal radiography using short exposure times.
Digital subtraction angiography (DSA) X-ray imaging for small animals can be used for functional phenotyping given its ability to capture rapid physiological changes at high spatial and temporal resolution. The higher temporal and spatial requirements for small-animal imaging drive the need for short, high-flux X-ray pulses. However, high doses of ionizing radiation can affect the physiology. The purpose of this study was to verify and apply metal oxide semiconductor field effect transistor (MOSFET) technology to dosimetry for small-animal diagnostic imaging. A tungsten anode X-ray source was used to expose a tissue-equivalent mouse phantom. Dose measurements were made on the phantom surface and interior. The MOSFETs were verified with thermoluminescence dosimeters (TLDs). Bland-Altman analysis showed that the MOSFET results agreed with the TLD results (bias, 0.0625). Using typical small animal DSA scan parameters, the dose ranged from 0.7 to 2.2 cGy. Application of the MOSFETs in the small animal environment provided two main benefits: (1) the availability of results in near real-time instead of the hours needed for TLD processes and (2) the ability to support multiple exposures with different X-ray techniques (various of kVp, mA and ms) using the same MOSFET. This MOSFET technology has proven to be a fast, reliable small animal dosimetry method for DSA imaging and is a good system for dose monitoring for serial and gene expression studies.


Elemental sulfur identified in urine of cheetah, Acinonyx jubatus.
The urine of the cheetah, Acinonyx jubatus, is almost odorless, and probably for this reason, it has not attracted much attention from scientists. Using gas chromatography-mass spectrometry, we identified 27 and 37 constituents in the headspace vapor of the urine of male and female cheetah, respectively. These constituents, composed of hydrocarbons, short-chain ethers, aldehydes, saturated and unsaturated cyclic and acyclic ketones, 2-acetylfuran, dimethyl disulfide, dimethyl sulfone, phenol, myristic acid (tetradecanoic acid), urea, and elemental sulfur, are all present in the headspace vapor in very small quantities; dimethyl disulfide is present in such a low concentration that it cannot be detected by the human nose. This is only the second example of elemental sulfur being secreted or excreted by an animal. It is hypothesized that the conversion of sulfur-containing compounds in the cheetah's diet to elemental sulfur and to practically odorless dimethyl sulfone enables this carnivore to operate as if "invisible" to the olfactory world of its predators as well as its prey, which would increase its chances of survival.


Myoelectric correlates of colonic motor complexes and contractile activity.
This report describes the myoelectric correlates of colonic motor complexes and contractile activity. A set of four bipolar electrode/strain-gauge pairs was surgically implanted on the colon of each of the five dogs used in this study. Each recording site showed a cyclic occurrence of bursts of contractions called contractile states. The colonic muscle contracted mainly at two frequencies during a contractile state, long-duration contractions at 0.5-2 cycles/min and short-duration contractions at 4-6 cycles/min. The long-duration contractions at 0.5-2 cycles/min were associated with bursts of contractile electrical complex (electrical oscillations at 25-40 cycles/min) and continuous electrical response activity on a 1:1:1 basis. The short-duration contractions at 4-6 cycles/min were associated with bursts of discrete electrical response activity on a 1:1 basis. Those episodes of contractile electrical complex, continuous electrical response activity, and discrete electrical response activity that migrated orad or aborad over at least half the length of the colon were called colonic migrating myoelectric complexes. All other patterns of occurrence of these episodes were called colonic non-migrating myoelectric complexes. A total of 184 colonic migrating myoelectric complexes were recorded during a total recording period of 148 h: 173 migrated caudad and 11 orad. The mean period of colonic migrating myoelectric complexes was 52.7 +/- 6.5 (SE) min. We conclude that the characteristics of colonic migrating myoelectric complexes are strikingly different from those of migrating myoelectric complexes in the small intestine.


Unique perforated graphene derived from Bougainvillea flowers for high-power supercapacitors: a green approach.
Herein, we demonstrated a green approach for the synthesis of high surface area (850 m2 g-1) mesoporous perforated graphene (PG) from Bougainvillea flower for the first time using a template free single-step method. The existence of PG was confirmed by XRD, Raman spectroscopy, FESEM, and FETEM. Surprisingly, FETEM clearly showed 5-10 nm perforation on the graphene sheets. More significantly, these mesoporous perforated graphene sheets can be produced in large scale using the present green approach. Considering high surface area and unique perforated graphene architecture, these PGs were studied for supercapacitor applications in detail without any chemical or physical activation. The nanoporosity and high conductivity of PG derived from Bougainvillea flower exhibited excellent supercapacitive performance. According to the supercapacitor study, the synthesized perforated graphene sheets conferred a very high specific capacitance of 458 F g-1 and an energy density of 63.7 Wh kg-1 at the power density of around 273.2 Wh kg-1 in aqueous 1 M Na2SO4. Significantly, the areal capacitance of PG was observed to be very high, i.e. 67.2 mF cm-2. The cyclability study results showed excellent stability of synthesized perforated graphene sheets up to 10 000 cycles. Note that the specific and areal capacitance and the energy density of the synthesized PGs are much higher than the earlier reported values. The high supercapacitive performance may be due to high surface area and mesoporosity of PG. The present approach has a good potential to produce cheaper and high surface area PG. These PGs are good candidates as an anode material in the lithium-ion battery.


Role of charge transfer states into the formation of cyclobutane pyrimidine dimers in DNA.
Photoinduced charge transfer between neighboring bases plays an important role in DNA. One of its important effects is shown in its ability to affect the photochemical yields of the formation of cyclobutane pyrimidine dimer (CPD) products between adjacent pyrimidine bases. In this work we examine how the energies of charge transfer states depend on the sequences of oligonucleotides using a hybrid quantum and molecular mechanics (QM/MM) methodology combined with the algebraic diagrammatic construction through a second order electronic structure method for excited states. Specifically, we examine 10 sequences with guanine being on the 5' or 3' position of two pyrimidine bases. The results show that the energies of charge transfer states are affected by the nature of the donor acceptor pair, by the distance between them, and by other electrostatic effects created by the surrounding environment.


Evaluation of humoral immune status in porcine epidemic diarrhea virus (PEDV) infected sows under field conditions.
Porcine epidemic diarrhea virus (PEDV) is an economically devastating enteric disease in the swine industry. The virus infects pigs of all ages, but it cause severe clinical disease in neonatal suckling pigs with up to 100% mortality. Currently, available vaccines are not completely effective and feedback methods utilizing PEDV infected material has variable success in preventing reinfection. Comprehensive information on the levels and duration of effector/memory IgA and IgG antibody secreting B cell response in the intestines and lymphoid organs of PEDV-infected sows, and their association with specific antibody levels in clinical samples such as plasma, oral fluid, and feces is important. Therefore, our goal in this study was to quantify PEDV specific IgA and IgG B cell responses in sows at approximately 1 and 6 months post-infection in commercial swine herds, including parity one and higher sows. Our data indicated that evaluation of both PEDV specific IgA and IgG antibody levels in the plasma and oral fluid (but not feces) samples is beneficial in disease diagnosis. PEDV specific B cell response in the intestine and spleen of infected sows decline by 6 months, and this associates with specific antibody levels in the plasma and oral fluid samples; but the virus neutralization titers in plasma remains high beyond 6 months post-infection. In conclusion, in sows infected with PEDV the presence of effector/memory B cell response and strong virus neutralization titers in plasma up to 6 months post-infection, suggests their potential to protect sows from reinfection and provide maternal immunity to neonates, but challenge studies are required to confirm such responses.


Eosinophilic panniculitis presenting with Kaposi's sarcoma-like plaques in a patient who is human immunodeficiency virus positive: a case report.
Eosinophilic panniculitis is an unusual type of panniculitis characterized by a prominent infiltration of subcutaneous fat with eosinophils without an exact etiopathogenesis. To the best of our knowledge, up to now eosinophilic panniculitis has been described in only one previous case with human immunodeficiency virus disease in the literature. Here we report the case of a 44-year-old Caucasian man, who is human immunodeficiency virus positive, diagnosed with eosinophilic panniculitis. A dermatological examination revealed multiple, confluent Kaposi's sarcoma-like purple colored, deep plaques and nodules on his right gluteal area and right thigh. The presence of the mixed inflammatory infiltrate of lymphocytes, macrophages, and numerous eosinophils involving both septa and lobules of the subcutis were noted on the histopathological examination. On the basis of all these clinical and histopathological findings the patient was diagnosed with eosinophilic panniculitis. He was given intravenous 60mg/day methylprednisolone for 3 consecutive days a week for 6 months. The lesions resolved almost completely after 6 months. The predominance of T helper-2 subset of T helper cells and the consequential increase in interleukin-5 cytokines accompanying peripheral eosinophilia and high serum immunoglobulin E levels may all be blamed for the development of eosinophilic panniculitis in our case study. As a result, we aim to emphasize that eosinophilic panniculitis should be kept in mind in the differential diagnosis of subcutaneous nodular lesions in patients who are human immunodeficiency virus positive. We also focus on the requirement of histopathological examination for the definitive diagnosis because the clinical features of eosinophilic panniculitis may easily be confused with Kaposi's sarcoma.


Clinical outcome prediction from analysis of microelectrode recordings using deep learning in subthalamic deep brain stimulation for Parkinson`s disease.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for improving the motor symptoms of advanced Parkinson's disease (PD). Accurate positioning of the stimulation electrodes is necessary for better clinical outcomes. We applied deep learning techniques to microelectrode recording (MER) signals to better predict motor function improvement, represented by the UPDRS part III scores, after bilateral STN DBS in patients with advanced PD. If we find the optimal stimulation point with MER by deep learning, we can improve the clinical outcome of STN DBS even under restrictions such as general anesthesia or non-cooperation of the patients. In total, 696 4-second left-side MER segments from 34 patients with advanced PD who underwent bilateral STN DBS surgery under general anesthesia were included. We transformed the original signal into three wavelets of 1-50 Hz, 50-500 Hz, and 500-5,000 Hz. The wavelet-transformed MER was used for input data of the deep learning. The patients were divided into two groups, good response and moderate response groups, according to DBS on to off ratio of UPDRS part III score for the off-medication state, 6 months postoperatively. The ratio were used for output data in deep learning. The Visual Geometry Group (VGG)-16 model with a multitask learning algorithm was used to estimate the bilateral effect of DBS. Different ratios of the loss function in the task-specific layer were applied considering that DBS affects both sides differently. When we divided the MER signals according to the frequency, the maximal accuracy was higher in the 50-500 Hz group than in the 1-50 Hz and 500-5,000 Hz groups. In addition, when the multitask learning method was applied, the stability of the model was improved in comparison with single task learning. The maximal accuracy (80.21%) occurred when the right-to-left loss ratio was 5:1 or 6:1. The area under the curve (AUC) was 0.88 in the receiver operating characteristic (ROC) curve. Clinical improvements in PD patients who underwent bilateral STN DBS could be predicted based on a multitask deep learning-based MER analysis.


Online validation of combined mood induction procedures.
Film clips, music, and self-referential statements (termed Velten, after their originator) have been successfully used to temporarily induce sadness and happiness. However, there is little research on the effectiveness of these procedures combined, particularly in internet-based settings, and whether Velten statements contribute to alter mood beyond the effect of simple instructions to close one's eyes and enter the targeted mood. In Study 1 (N = 106) we examined the effectiveness 80 Velten statements (positive, negative, neutral-self, neutral-facts) to create brief and effective sets that might be used in future research. In Study 2 (N = 445) we examined the effect size of 8-min combined mood induction procedures, which presented video clips in the first half and music excerpts with Velten statements or closed eyes instructions in the second half. Participants answered questionnaires on social desirability, joviality, and sadness before being randomly assigned to 1 of 7 groups varying in Valence (positive, negative, neutral) and Velten (closed eyes control, self-referential Velten, and, in the case of neutral condition, factual statements). Subsequently, participants completed the joviality and sadness scales a second time. Compared to the neutral conditions, the positive mood inductions increased joviality (Hedges G = 1.35, 95% CI [1.07, 1.63]), whereas the negative mood inductions increased sadness (Hedges G = 1.28, 95% CI [1.01, 1.55]). We did not observe any significant difference between Velten and closed eyes instructions in inducing joviality or sadness, nor did we observe any significant difference between neutral Velten statements referring to self and facts. Although social desirability bias was associated with reports of greater joviality and lower sadness, it could not account for the effects of the positive and negative mood induction procedures. We conclude that these combined mood induction procedures can be used in online research to study happy and sad mood.


Psychosocial factors associated with the self-reported frequency of cell phone use while driving in Iran.
Cell phone use while driving is a common contributing factor in thousands of road traffic injuries every year globally. Despite extensive research investigating the risks associated with cell phone use while driving, social media campaigns to raise public awareness and a number of laws banning phone use while driving, this behaviour remains prevalent throughout the world. The current study was conducted in Iran, where road traffic injuries are the leading causes of death and disability, and where drivers continue to use their cell phones, despite legislative bans restricting this behaviour. A total of 255 drivers in the city of Mashhad (male = 66.3%; mean age = 30.73 years; SD = 9.89) completed either an online or a paper-based survey assessing the self-reported frequency of using a cell phone while driving. Psychosocial factors contributing to cell phone use while driving and support for legislation restricting this behaviour, as well as the Big Five personality traits, were also measured. Overall, the results showed that almost 93% of drivers use their cell phones while driving at least once a week, with 32.5% reporting they always use their cell phones while driving. Ordinal logistic regression revealed that the presence of a child passenger, age, perceived benefits and risks of using cell phones while driving, as well as the perceived ability to drive safely while using a cell phone, were strongly associated with the frequency of cell phone use while driving. As for personality traits-extraversion, agreeableness and conscientiousness significantly predicted the frequency of cell phone use in this sample of Iranian drivers.


FOLFIRINOX-induced reversible dysarthria: A case report and review of previous cases.
FOLFIRINOX is a standard chemotherapeutic regimen for patients with advanced pancreatic cancer who have a good performance status. In this study, we present the case of a 64-year-old male who developed dysarthria following FOLFIRINOX treatment, and review all four cases of dysarthria encountered among the nine patients who received this treatment in our hospital. In all cases, dysarthria occurred during the infusion of irinotecan in the first course of treatment, persisted for several hours, and then resolved rapidly without any sequelae. Physical and neurological examinations at the onset of dysarthria revealed no other abnormalities. Imaging studies revealed no abnormal findings. Atropine was prophylactically administered in the second and subsequent courses of treatment and effectively prevented or alleviated dysarthria. This acute neurological symptom is surprising and uncommon in traditional cancer chemotherapy, and medical oncologists may initially suspect the onset of stroke or cerebrovascular disease. However, consistent with our experience, all reported cases resolved completely, with no need for dose reduction or treatment interruption.


Genetic characterization of the endangered Kiso horse using 31 microsatellite DNAs.
In order to contribute to conservation of the endangered Kiso horse, we clarified their genetic information using 31 microsatellite DNAs, and genotyped 125 horses, 83% of the existing breed. First, we clarified the current status of the horses. The horses were confirmed to have experienced rapid loss of population causing a bottleneck, and their effective population size was much smaller than their census size. Moreover, the number of alleles (6.3), observed heterozygosity (0.674), and expected heterozygosity (0.662) were in the same range as other endangered horses all over the world. Therefore, although their inbreeding level was not so severe (F(is): -0.017), the Kiso horse is surely one of the endangered. Second, we obtained genetic information of individuals. This information allowed us to understand the genetic distance of individuals, and might help in development of a reproductive strategy concerning the genetic distance between the mating pairs. Moreover, there appeared to be 4 subpopulations of Kiso horse, and this result was in good agreement with their historical background. Third, we confirmed that the parentage test for identification using the 31 microsatellite DNAs was highly reliable (probability of exclusion: 0.999999993). This identification increases the reliability of stud certification, and is also helpful for effective management. Understanding the genetic diversity within the population and the relationships among individuals is important to ensuring effective management for maintenance of genetic variation, and this study may help in conservation of the endangered Kiso horse.


One year after CAPRIE, IST and ESPS 2. Any changes in concepts?
The IST, CAPRIE and ESPS-2 have shown that large collaborative randomised trials can be conducted in stroke medicine and can provide statistically and clinically significant results. They, and other concurrent studies, have highlighted the potential hazards of early anticoagulation, and the effectiveness and safety of early (and continuous) antiplatelet therapy in limiting early stroke recurrence and its consequences. In addition, they have shown that antiplatelet agents with differing mechanisms of action can have different effects, and perhaps additive effects when combined. The ESPRIT trial should delineate the roles of oral anticoagulant therapy, and the combination of aspirin and dipyridamole, in the prevention of stroke due to arterial disease. Future trials will hopefully determine the role in secondary stroke prevention of inhibitors of the platelet GPIIb/IIIa complex (the final common pathway of platelet aggregation), the combination of anitplatelet agents with different mechanisms of action (e.g. aspirin and clopidogrel, aspirin and IIb/IIIa inhibitors), the combination of antiplatelet agents and oral anticoagulants (which may simultaneously modify platelet function and fibrin production), and the combination of antithrombotic and cholesterol-lowering (statin) medications.


[Hypersalivation - Update of the S2k guideline (AWMF) in short form].
Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This update presents recent changes and innovation in the treatment of hypersalivation.Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, saliva aspiration, and oro-motor deficiencies. Clinical screening tools and diagnostics such as fiberoptic endoscopic evaluation of swallowing generate important data on therapy selection and control. Many cases profit from swallowing therapy programmes in order to activate compensation mechanisms as long compliances is given. In children with hypotonic oral muscles, oral stimulation plates can induce a relevant symptom release because of the improved lip closure. The pharmacologic treatment improved for pediatric cases as glycopyrrolate fluid solution (Sialanar®) is now indicated for hypersalivation within the E. U. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long lasting saliva reduction. Here, a phase III trial is completed for Incobotulinum toxin A and, in the U. S., is indicated for the treatment of adult patients with chronic hypersalivation. Surgical treatment should be reserved for isolated cases. External radiation is judged as a safe and effective therapy when using modern 3 D techniques to minimize tissue damage. Therapy effects and symptom severity has to be followed, especially in cases with underlying neurodegenerative disease.


Identification of a membrane-cytoskeletal complex containing the cell adhesion molecule uvomorulin (E-cadherin), ankyrin, and fodrin in Madin-Darby canine kidney epithelial cells.
Cell-cell contact is an important determinant in the formation of functionally distinct plasma membrane domains during the development of epithelial cell polarity. In cultures of Madin-Darby canine kidney (MDCK) epithelial cells, cell-cell contact induces the assembly and accumulation of the Na+,K+-ATPase and elements of the membrane-cytoskeleton (ankyrin and fodrin) at the regions of cell-cell contact. Epithelial cell-cell contact appears to be regulated by the cell adhesion molecule uvomorulin (E-cadherin) which also becomes localized at the lateral plasma membrane of polarized cells. We have sought to determine whether the colocalization of these proteins reflects direct molecular interactions which may play roles in coordinating cell-cell contact and the assembly of the basal-lateral domain of the plasma membrane. Recently, we identified a complex of proteins containing the Na+,K+-ATPase, ankyrin, and fodrin in extracts of whole MDCK cells (Nelson, W.J., and R. W. Hammerton. 1989. J. Cell Biol. 108:893-902). We have now examined cell extracts for protein complexes containing the cell adhesion molecule uvomorulin. Proteins were solubilized from whole MDCK cells and fractionated in sucrose gradients. The sedimentation profile of solubilized uvomorulin is well separated from the majority of cell surface proteins, suggesting that uvomorulin occurs in a protein complex. A distinct portion of uvomorulin (30%) cosediments with ankyrin and fodrin (approximately 10.5S). Further fractionation of cosedimenting proteins in nondenaturing polyacrylamide gels reveals a discrete band of proteins that binds antibodies specific for uvomorulin, Na+,K+-ATPase, ankyrin, and fodrin. Significantly, ankyrin and fodrin, but not Na+K+-ATPase, coimmunoprecipitate in a complex with uvomorulin using uvomorulin antibodies. This result indicates that separate complexes exist containing ankyrin and fodrin with either uvomorulin or Na+,K+-ATPase. These results are discussed in the context of the possible roles of uvomorulin-induced cell-cell contact in the assembly of the membrane-cytoskeleton and associated membrane proteins (e.g., Na+,K+-ATPase) at the contact zone and in the development of cell polarity.


Single-Dose Daily Fractionation Is Not Inferior to Twice-a-Day Fractionated Total-Body Irradiation Before Allogeneic Stem Cell Transplantation for Acute Leukemia: A Useful Practice Simplification Resulting From the SARASIN Study.
Total-body irradiation (TBI) is a major constituent of myeloablative conditioning regimens. The standard technique consists of 12 Gy in 6 fractions over a period of 3 days. The Standard-fractionation compAred to one-daily fRaction total body irrAdiation prior to tranSplant In LEUkemia patieNts (SARASIN) study aimed to compare standard fractionation with once-daily fractionation before transplant in leukemia. We retrospectively compared TBI regimens delivered in 2993 patients from the European Society for Blood and Marrow Transplantation database, who underwent transplantation between 2000 and 2014 for acute lymphoblastic leukemia (ALL, n = 1729) or acute myeloid leukemia (AML, n = 1264). TBI was delivered as either 12 Gy in 6 fractions (group 1, considered the reference group; 1362 ALL and 857 AML patients), 9 to 12 Gy in 2 fractions (group 2, 173 ALL and 256 AML patients), or 12 Gy in 3 to 4 fractions (group 3, 194 ALL and 151 AML patients). The median follow-up was 60 and 84 months in ALL and AML patients, respectively. At 5 years, the leukemia-free survival rate, overall survival rate, relapse incidence, and nonrelapse mortality rate were 46.6%, 50.4%, 28.8%, and 24.6%, respectively, in ALL patients and 46.6%, 48.9%, 29.7%, and 23.6%, respectively, in AML patients. In multivariate analyses, the outcomes of groups 2 and 3 were not statistically different from those in group 1. The cumulative incidence of secondary malignancies (SMs) was significantly higher in group 2 (7.2%; P < 10-6 for group 2 vs group 1). However, group 2 was not associated with an increase in SMs when we considered non-T-cell-depleted transplant patients. We showed that the 12-Gy fractionated TBI dose delivered either in 2 fractions or in 1 fraction per day over a period of 3 to 4 days resulted in nonsignificant differences in disease control and survival. However, 1-day fractionation may be associated with a higher risk of mucositis and hemorrhagic cystitis. The absence of a significant difference in the SM incidence in the non-T-cell-depleted group should be interpreted with caution in the context of a retrospective study design. Our findings are important to consider for radiation therapy department organization. In-depth analyses of other nonlethal toxicities and late effects are required.


Contrasting effects of changing rhythm and content on auditory distraction in immediate memory.
Across 5 experiments, the temporal regularity and content of an irrelevant speech stream were varied and their effects on a serial recall task examined. Variations of the content, but not the rhythm, of the irrelevant speech stimuli reliably disrupted serial recall performance in all experiments. Bayesian analyses supported the null hypothesis over the hypothesis that irregular rhythms would disrupt memory to a greater extent than regular rhythms. Pooling the data in a combined analysis revealed that regular presentation of the irrelevant speech was significantly more disruptive to serial recall than irregular presentation. These results are consistent with the idea that auditory distraction is sensitive to both intraitem and interitem relations and challenge an orienting-based account of auditory distraction.


Decreased rate of obstetrical anal sphincter laceration is associated with change in obstetric practice.
A study was conducted to describe the rate of obstetrical anal sphincter laceration in a large cohort of women and to identify the characteristics associated with this complication. Data from all vaginal deliveries occurring between January 1996 and December 2004 at one institution were used to compare women with and without anal sphincter lacerations. Among 16,667 vaginal deliveries, 1,703 (10.2%) anal sphincter lacerations occurred. Regression models suggested that episiotomy (OR 1.36; 95% CI 1.16, 1.58), vacuum delivery (OR 3.19; 95% CI 2.69, 3.79), and forceps delivery (OR 2.79; 95% CI 1.94, 4.02) were each associated with the increased risk of anal sphincter laceration. Year of delivery was associated with a decreased risk of anal sphincter laceration (OR 0.94; 95% CI 0.92, 0.96) with the rate of laceration decreasing from 11.2% to 7.9% during the study period. Episiotomy and operative vaginal delivery are significant, modifiable risk factors. Changes in obstetric practice may have contributed to the dramatic reduction in anal sphincter laceration during the study period.


Pacing-associated left ventricular dysfunction? Think reprogramming first!
Heart failure and left ventricular systolic dysfunction (LVSD) are common in patients with permanent pacemakers, but whether right ventricular (RV) pacing is contributory or merely a bystander in patients with more severe cardiac disease is controversial. The aim of the present study was to determine whether reprogramming of existing pacemakers to reduce RV pacing is safe and leads to improvements in cardiac function. This was a prospective service evaluation of the effects of optimising pacemaker programming to avoid RV pacing in 66 consecutive attendees of a teaching hospital pacemaker clinic without complete heart block. The main outcome measures were left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels, quality of life and cardiopulmonary exercise testing at baseline and after 6 months. At 6 months, the protocol reduced absolute RV pacing by a mean of 49% (95% CI 41% to 57%) (p<0.0001 from baseline) and resulted in a mean absolute improvement in LVEF of 6% (4% to 8%) (p<0.0001 from baseline) but no reduction in exercise capacity, NT-pro-BNP or quality of life. There was a relationship between the magnitude of change in EF and the reduction in RV pacing (p=0.04) and changes in NT-pro-BNP seemed to relate to change in RV pacing (p=0.07). Programming standard pacemakers to avoid RV pacing is safe, does not adversely affect patients' symptoms or quality of life and is associated with improved LV function, related to the reductions in RV pacing percentage.


Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase.
Protein catabolic states (i.e., sepsis and trauma) are thought to be associated with accelerated oxidation of branched-chain amino acids (BCAA). Branched-chain alpha-keto acid dehydrogenase (BCKAD), the rate-limiting enzyme for BCAA oxidation by muscle, is regulated by phosphorylation/dephosphorylation. Skeletal muscle BCKAD was only 2-4% active in control rats. Intravenous injection of Salmonella enteritidis endotoxin (0.25-10 mg/kg) did not change total BCKAD activity, but increased the percent active enzyme in muscle three- to four-fold in 4-6 h. Identical results were observed in adrenalectomized rats pretreated with one dose of alpha-methylprednisolone (2.5 mg/kg i.p.) 30-60 min before saline or endotoxin injection, indicating that endotoxin's effect was not mediated by hypersecretion of adrenal hormones. Cortisone pretreatment of normal rats (100 mg/kg per d) for 2 d prevented endotoxin-induced activation of muscle BCKAD, suggesting that endogenous secretion products mediated BCKAD activation by endotoxin. Human recombinant tumor necrosis factor-alpha and/or IL-1 beta or alpha (50 micrograms/kg) increased muscle BCKAD activation two- to fourfold in normal rats 4-6 h after intravenous injection. We conclude that cytokine-mediated activation of muscle BCKAD may contribute to accelerated BCAA oxidation in septicemia.


How recent history affects perception: the normative approach and its heuristic approximation.
There is accumulating evidence that prior knowledge about expectations plays an important role in perception. The Bayesian framework is the standard computational approach to explain how prior knowledge about the distribution of expected stimuli is incorporated with noisy observations in order to improve performance. However, it is unclear what information about the prior distribution is acquired by the perceptual system over short periods of time and how this information is utilized in the process of perceptual decision making. Here we address this question using a simple two-tone discrimination task. We find that the "contraction bias", in which small magnitudes are overestimated and large magnitudes are underestimated, dominates the pattern of responses of human participants. This contraction bias is consistent with the Bayesian hypothesis in which the true prior information is available to the decision-maker. However, a trial-by-trial analysis of the pattern of responses reveals that the contribution of most recent trials to performance is overweighted compared with the predictions of a standard Bayesian model. Moreover, we study participants' performance in a-typical distributions of stimuli and demonstrate substantial deviations from the ideal Bayesian detector, suggesting that the brain utilizes a heuristic approximation of the Bayesian inference. We propose a biologically plausible model, in which decision in the two-tone discrimination task is based on a comparison between the second tone and an exponentially-decaying average of the first tone and past tones. We show that this model accounts for both the contraction bias and the deviations from the ideal Bayesian detector hypothesis. These findings demonstrate the power of Bayesian-like heuristics in the brain, as well as their limitations in their failure to fully adapt to novel environments.


Risk of second cancer after lymphohematopoietic neoplasm.
People living with lymphohematopoietic neoplasms (LHNs) are known to have increased risks of second cancer; however, the incidence of second cancers after LHNs has not been studied extensively in Australia. The Australian Cancer Database was used to analyze site-specific risk of second primary cancer after LHNs in 127,707 patients diagnosed between 1983 and 2005. Standardized incidence ratios (SIRs) were calculated using population rates. Overall, patients with an LHN had nearly twice the risk of developing a second cancer compared to the Australian population. Among 40,321 patients with non-Hodgkin's lymphoma (NHL), there was over a fourfold significant increase in melanoma, Kaposi sarcoma, cancer of the lip, connective tissue and peripheral nerves, eye, thyroid, Hodgkin's disease (HD) and myeloid leukemia. Among 6,396 patients with HD, there was over a fourfold significant increase in melanoma, Kaposi sarcoma, cancer of the lip, oral cavity and pharynx, female breast, uterine cervix, testis, thyroid, NHL and myeloid leukemia. Among the 33,025 patients with lymphoid and myeloid leukemia, significant excess were seen for cancers of the lip, eye, connective tissue and peripheral nerves, NHL and HD. Among the 13,856 patients with plasma cell tumors, there was over fourfold significant increase for melanoma, cancer of the connective tissue and peripheral nerves and myeloid leukemia. Our findings provide evidence of an increased risk of cancer, particularly ultraviolet radiation- and immunosuppression-related cancers, after an LHN in Australia.


Pre-Diagnostic Circulating Resistin Concentrations Are Not Associated with Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition Study.
Resistin is a polypeptide implicated in inflammatory processes, and as such could be linked to colorectal carcinogenesis. In case-control studies, higher resistin levels have been found in colorectal cancer (CRC) patients compared to healthy individuals. However, evidence for the association between pre-diagnostic resistin and CRC risk is scarce. We investigated pre-diagnostic resistin concentrations and CRC risk within the European Prospective Investigation into Cancer and Nutrition using a nested case-control study among 1293 incident CRC-diagnosed cases and 1293 incidence density-matched controls. Conditional logistic regression models controlled for matching factors (age, sex, study center, fasting status, and women-related factors in women) and potential confounders (education, dietary and lifestyle factors, body mass index (BMI), BMI-adjusted waist circumference residuals) were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for CRC. Higher circulating resistin concentrations were not associated with CRC (RR per doubling resistin, 1.11; 95% CI 0.94-1.30; p = 0.22). There were also no associations with CRC subgroups defined by tumor subsite or sex. However, resistin was marginally associated with a higher CRC risk among participants followed-up maximally two years, but not among those followed-up after more than two years. We observed no substantial correlation between baseline circulating resistin concentrations and adiposity measures (BMI, waist circumference), adipokines (adiponectin, leptin), or metabolic and inflammatory biomarkers (C-reactive protein, C-peptide, high-density lipoprotein cholesterol, reactive oxygen metabolites) among controls. In this large-scale prospective cohort, there was little evidence of an association between baseline circulating resistin concentrations and CRC risk in European men and women.


Plasma IL-6 levels correlate with clinical and ultrasound measures of arthritis in patients with systemic lupus erythematosus.
The objective of this paper is to elucidate the role of specific cytokines in lupus (SLE) arthritis. Fifty SLE and 40 RA patients had an ultrasound (US) scan of their hand as per standardized protocols. US scores were expressed per joint and as a total 'US activity' score, (sum of power Doppler (PD) and grey-scale synovial hypertrophy scores in all joints) and a total erosion score. SLE disease activity was assessed (BILAG and SELENA-SLEDAI). Plasma levels of IL-6, TNF-alpha and BLyS were measured using sandwich ELISA kits (Quantikine kits, R & D). On the basis of the US results SLE patients were divided into three groups: erosive arthritis (n = 20), non-erosive arthritis (n = 18) and those with a normal US scan (n = 12). Across the SLE groups plasma IL-6 levels correlated with CRP (p < 0.001), hand deformity scores (p = 0.005), BILAG musculoskeletal score (p = 0.009), wrist PD score (p = 0.01), the presence of tenosynovitis (p = 0.008) and total US activity score (p < 0.001) (which remained constant when corrected for total BILAG score). Neither TNF-alpha nor BLyS levels correlated with US or clinical measures of lupus arthritis; however, TNF-alpha correlated with total BILAG score (p < 0.001). This is the first study to examine levels of specific cytokines in a cohort of SLE patients stratified in terms of joint disease by US, where the most significant finding is that IL-6 levels correlated both with clinical and US measures of arthritis disease activity.


Use of fibrinolytic agents in the management of complicated parapneumonic effusions and empyemas.
Standard treatment for pleural infection includes catheter drainage and antibiotics. Tube drainage often fails if the fluid is loculated by fibrinous adhesions when surgical drainage is needed. Streptokinase may aid the process of pleural drainage, but there have been no controlled trials to assess its efficacy. Twenty four patients with infected community acquired parapneumonic effusions were studied. All had either frankly purulent/culture or Gram stain positive pleural fluid (13 cases; 54%) or fluid which fulfilled the biochemical criteria for pleural infection. Fluid was drained with a 14F catheter. The antibiotics used were cefuroxime and metronidazole or were guided by culture. Subjects were randomly assigned to receive intrapleural streptokinase, 250,000 IU daily, or control saline flushes for three days. The primary end points related to the efficacy of pleural drainage--namely, the volume of pleural fluid drained and the chest radiographic response to treatment. Other end points were the number of pleural procedures needed and blood indices of inflammation. The streptokinase group drained more pleural fluid both during the days of streptokinase/control treatment (mean (SD) 391 (200) ml versus 124 (44) ml; difference 267 ml, 95% confidence interval (CI) 144 to 390; p < 0.001) and overall (2564 (1663) ml versus 1059 (502) ml; difference 1505 ml, 95% CI 465 to 2545; p < 0.01). They showed greater improvement on the chest radiograph at discharge, measured as the fall in the maximum dimension of the pleural collection (6.0 (2.7) cm versus 3.4 (2.7) cm; difference 2.9 cm, 95% CI 0.3 to 4.4; p < 0.05) and the overall reduction in pleural fluid collection size (p < 0.05, two tailed Fisher's exact test). Systemic fibrinolysis and bleeding complications did not occur. Surgery was required by three control patients but none in the streptokinase group. Intrapleural streptokinase probably aids the treatment of pleural infections by improving pleural drainage without causing systemic fibrinolysis or local haemorrhage.


Cellular and molecular parameters of mesothelioma.
Malignant mesotheliomas (MM) are neoplasms arising from mesothelial cells that line the body cavities, most commonly the pleural and peritoneal cavities. Although traditionally recognized as associated with occupational asbestos exposures, MMs can appear in individuals with no documented exposures to asbestos fibers, and emerging data suggest that genetic susceptibility and simian virus 40 (SV40) infections also facilitate the development of MMs. Both asbestos exposure and transfection of human mesothelial cells with SV40 large and small antigens (Tag, tag) cause genetic modifications and cell signaling events, most notably the induction of cell survival pathways and activation of receptors, and other proteins that favor the growth and establishment of MMs as well as their resistance to chemotherapy. Recent advances in high-throughput technologies documenting gene and protein expression in patients and animal models of MMs can now be validated in human MM tissue arrays. These have revealed expression profiles that allow more accurate diagnosis and prognosis of MMs. More importantly, serum proteomics has revealed two new candidates (osteopontin and serum mesothelin-related protein or SMRP) potentially useful in screening individuals for MMs. These mechanistic approaches offer new hope for early detection and treatment of these devastating tumors.


Characterization of the 110-kdalton actin-calmodulin-, and membrane-binding protein from microvilli of intestinal epithelial cells.
One of the major proteins of the chicken intestinal microvillus is a calmodulin-binding protein of 105-110 kdaltons which has been tentatively identified as the bridge linking the microvillar filament bundle laterally to the membrane. We have treated isolated, membrane-intact brush borders with ATP and obtained solubilization of the 110-kdalton protein, calmodulin (CM), myosin, and lesser amounts of several other cytoskeletal proteins. Electron micrographs of ATP-extracted brush borders showed loss of the linkers between the actin filament bundle and the microvillar membrane, with "ballooning" of the membrane away from the filament bundle, particularly at the tip end. In brush borders treated with calcium and trifluoperazine to solubilize CM, precise arrangement and morphology of lateral bridges was unperturbed, but ATP treatment would no longer solubilize the 110-kdalton protein. This result suggests that associated CM is necessary for the ATP-induced solubilization of the 110-kdalton protein. A 110-kdalton protein-CM complex, with 110-kdalton protein: CM ratios of 1:1-2, was partially purified from ATP-extracts of brush borders by a combination of gel filtration and hydroxylapatite chromatography. The 110-kdalton protein-CM complex is an irregular, elongated molecule that ranged in size from 5 X 8 nm to 8 X 14 nm, with a Stokes' radius of 6.1 nm. This 110-kdalton protein-CM complex exhibited no Mg++-ATPase activity and no detectable myosin light chain kinase activity. In co-sedimentation assays, the 110-kdalton protein-CM bound to F-actin in the absence but not the presence of ATP. Both the interaction of the complex with actin and the binding of CM to the 110-kdalton protein were calcium-independent. Negative stains of F-actin and 110-kdalton protein-CM in the absence of ATP showed loosely organized aggregates of actin with the 110-kdalton protein-CM complex coating the surface of the filaments. On the basis of our data, and in agreement with previous calculations (Matsudaira, P.T., and D.R. Burgess, 1979, J. Cell Biol. 83:667-673), we suggest that the lateral bridge of the microvillus is composed of a dimer of the 110-kdalton protein with four associated calmodulins.


Cost-effectiveness of a home-based environmental intervention for inner-city children with asthma.
Exposure to indoor allergens contributes to increased asthma morbidity. The Inner-City Asthma Study, a randomized trial involving home environmental allergen and irritant remediation among children aged 6 through 11 years with moderate-to-severe asthma, successfully reduced asthma symptoms. A cost-effectiveness analysis can help stakeholders to evaluate the potential costs and benefits of adopting such a program. We sought to assess the cost-effectiveness of the environmental intervention of the Inner-City Asthma Study. Incremental cost-effectiveness ratios for a 2-year study period were calculated. Health outcome was measured as symptom-free days. Resource use measures included ambulatory visits, hospitalizations, and pharmaceutical use. CIs were obtained by using bootstrapping. The intervention, which cost $1469 per family, led to statistically significant reductions in symptom days, unscheduled clinic visits, and use of beta-agonist inhalers. Over the year of the intervention and a year of follow-up, the intervention cost was $27.57 per additional symptom-free day (95% CI, $7.46-$67.42). Subgroup analysis showed that targeting the intervention to selected high-risk subgroups did not reduce the incremental cost-effectiveness ratio. A targeted home-based environmental intervention improved health and reduced service use in inner-city children with moderate-to-severe asthma. The intervention is cost-effective when the aim is to reduce asthma symptom days and the associated costs.


Long-term posttraumatic stress symptoms among 3,271 civilian survivors of the September 11, 2001, terrorist attacks on the World Trade Center.
Although the September 11, 2001, terrorist attacks were the largest human-made disaster in US history, there is little extant research documenting the attacks' consequences among those most directly affected, that is, persons who were in the World Trade Center towers. Data from a cross-sectional survey conducted 2-3 years after the attacks ascertained the prevalence of long-term, disaster-related posttraumatic stress symptoms and probable posttraumatic stress disorder (PTSD) in 3,271 civilians who evacuated World Trade Center towers 1 and 2. Overall, 95.6% of survivors reported at least 1 current posttraumatic stress symptom. The authors estimated the probable rate of PTSD at 15.0% by using the PTSD Checklist. Women and minorities were at an increased risk of PTSD. A strong inverse relation with annual income was observed. Five characteristics of direct exposure to the terrorist attacks independently predicted PTSD: being on a high floor in the towers, initiating evacuation late, being caught in the dust cloud that resulted from the tower collapses, personally witnessing horror, and sustaining an injury. Working for an employer that sustained fatalities also increased risk. Each addition of an experience of direct exposure resulted in a 2-fold increase in the risk of PTSD (odds ratio = 2.09, 95% confidence interval: 1.84, 2.36). Identification of these risk factors may be useful when screening survivors of large-scale terrorist events for long-term psychological sequelae.


Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci.
Multiple regulatory elements distant from their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale. Single-nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci allows us to identify key long-range chromatin interactions in cis and trans involving these loci.


Pupillometry: A Window to the Preconscious?
The measurement of pupil diameter in psychology (in short, "pupillometry") has just celebrated 50 years. The method established itself after the appearance of three seminal studies (Hess & Polt, 1960, 1964; Kahneman & Beatty, 1966). Since then, the method has continued to play a significant role within the field, and pupillary responses have been successfully used to provide an estimate of the "intensity" of mental activity and of changes in mental states, particularly changes in the allocation of attention and the consolidation of perception. Remarkably, pupillary responses provide a continuous measure regardless of whether the participant is aware of such changes. More recently, research in neuroscience has revealed a tight correlation between the activity of the locus coeruleus (i.e., the "hub" of the noradrenergic system) and pupillary dilation. As we discuss in this short review, these neurophysiological findings provide new important insights to the meaning of pupillary responses for mental activity. Finally, given that pupillary responses can be easily measured in a noninvasive manner, occur from birth, and can occur in the absence of voluntary, conscious processes, they constitute a very promising tool for the study of preverbal (e.g., infants) or nonverbal participants (e.g., animals, neurological patients).


Efficacy of tinidazole for treatment of cats experimentally infected with Tritrichomonas foetus.
To determine the efficacy of tinidazole for treatment of cats with experimentally induced Tritrichomonas foetus infection. 8 specific-pathogen-free kittens. Tinidazole was tested for activity against a feline isolate of T foetus in vitro. Kittens were infected orogastrically with the same isolate and treated or not with tinidazole (30 mg/kg, PO, q 24 h for 14 days). Amoxicillin was administered 28 weeks after completion of tinidazole administration to induce diarrhea. Feces were repeatedly tested for T foetus by use of PCR assay and microbial culture for 33 weeks. Tinidazole killed T foetus at concentrations >or= 10 microg/mL in vitro. In experimentally induced infection, tinidazole administered at 30 mg/kg decreased T foetus below the limit of molecular detection in 2 of 4 cats. Recrudescent shedding of T foetus, as elicited by amoxicillin-induced diarrhea, was diminished in cats that received prior treatment with tinidazole. Although tinidazole decreased the detection of T foetus and treated cats were resistant to later efforts to incite the infection, inability of tinidazole to eradicate infection in many cats poses a serious impediment to the drug's effectiveness in practice.


Gestural communication in children with autism spectrum disorders during mother-child interaction.
Children with autism spectrum disorders display atypical development of gesture production, and gesture impairment is one of the determining factors of autism spectrum disorder diagnosis. Despite the obvious importance of this issue for children with autism spectrum disorder, the literature on gestures in autism is scarce and contradictory. The purpose of this study was to analyze gestural communication in children with autism spectrum disorder during spontaneous mother-child interaction. Participants were children with autism spectrum disorder (n = 20), Down's syndrome (n = 20), and typical development (n = 20) and their mothers. Children's mean developmental age was 24.16 months (standard deviation = 1.45 months) and did not differ across the groups. Gestural communication was analyzed with a specific coding scheme allowing a quantitative and qualitative analysis of gestural production. Results showed the following: (a) differences between autism spectrum disorder, typical development, and Down's syndrome groups in the total number of gestures produced; (b) differences between the three groups in the distribution of gesture types; and (c) specific correlations between gestural production, cognitive development, and autism severity scores. The study of gestures in autism spectrum disorder could help us to identify different phenotypes in autism and could also lead to the development of new therapies.


Factors governing the transepithelial potential difference across the proximal tubule of the rat kidney.
Previous measurements of the transepithelial potential difference (PD) of the proximal tubule have yielded widely conflicting values (range -20 to +3 mV). In a recent study, Kokko has demonstrated that the PD of the in vitro perfused isolated proximal tubule of the rabbit varies in a predictable way from -6 to +3 mV, depending on the concentration of chloride, bicarbonate, glucose, and amino acids in the perfusing solution. The present micropuncture study examines the effect of tubular fluid composition on the PD profile along the proximal tubule of the in vivo rat kidney. Low resistance measuring electrodes with large tips (3-5 microns OD) filled with 3 M KCl, were used to provide stable PD recordings. Experiments were performed to validate the use of these electrodes. Transepithelial PD measurements were made in immediate postglomerular segments identified by injection of dye into Bowman's space of accessible surface glomeruli and in randomly selected more distal segments of the proximal tubule. In the control state, the first loop was found to have a small but consistently negative PD which could be obliterated by an infusion of phloridzin. In contrast, the PD in later segments was consistently positive. Infusion of acetazolamide abolished the positive PD in the later segments. Acetazolamide and glucose infusion resulted in a negative PD which was abolished by the additional infusion of phloridzin. These data provide evidence that glucose reabsorption is electrogenic and can account for the small negative PD normally present in the early proximal tubule. The positive PD in later segments appears to be a passive chloride diffusion potential. This positive potential is discussed as an important electrochemical driving force for significant passive reabsorption of sodium in the proximal tubule.


Fluid Resuscitation for Hemorrhagic Shock in Tactical Combat Casualty Care: TCCC Guidelines Change 14-01--2 June 2014.
This report reviews the recent literature on fluid resuscitation from hemorrhagic shock and considers the applicability of this evidence for use in resuscitation of combat casualties in the prehospital Tactical Combat Casualty Care (TCCC) environment. A number of changes to the TCCC Guidelines are incorporated: (1) dried plasma (DP) is added as an option when other blood components or whole blood are not available; (2) the wording is clarified to emphasize that Hextend is a less desirable option than whole blood, blood components, or DP and should be used only when these preferred options are not available; (3) the use of blood products in certain Tactical Field Care (TFC) settings where this option might be feasible (ships, mounted patrols) is discussed; (4) 1:1:1 damage control resuscitation (DCR) is preferred to 1:1 DCR when platelets are available as well as plasma and red cells; and (5) the 30-minute wait between increments of resuscitation fluid administered to achieve clinical improvement or target blood pressure (BP) has been eliminated. Also included is an order of precedence for resuscitation fluid options. Maintained as recommendations are an emphasis on hypotensive resuscitation in order to minimize (1) interference with the body's hemostatic response and (2) the risk of complications of overresuscitation. Hextend is retained as the preferred option over crystalloids when blood products are not available because of its smaller volume and the potential for long evacuations in the military setting.


Mathematical modelling of Wnt/β-catenin signalling.
The Wnt/β-catenin pathway plays an important role in development and disease. Theoretical approaches have been used to describe this pathway and have provided intriguing insights into its signalling characteristics. In the present paper, we review mathematical models of the pathway. We focus on a quantitative kinetic model for canonical Wnt/β-catenin signalling describing the reactions of the pathway's core compounds [Lee, Salic, Krüger, Heinrich and Kirschner (2003) PLoS Biol. 1, 116-132]. Numerous modifications and further analyses with respect to signalling characteristics, transcriptional feedback and cross-talk were performed. In addition, the role of β-catenin in gene expression and cell-cell adhesion as well as spatial aspects of signalling are investigated in various theoretical models.


Different stress-related gene expression in depression and suicide.
Suicide occurs in some, but not all depressed patients. So far, it remains unknown whether the studied stress-related candidate genes change in depression, suicide or both. The prefrontal cortex (PFC) is involved in, among other things, impulse control and inhibitory behavior and plays an important role in both suicide and depression. We have employed qPCR to study 124 anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC) brain samples, obtained from two brain banks, from: i) young depressed patients (average age 43 years) who committed suicide (MDD-S) and depressed patients who died from causes other than suicide (MDD-NS) and from ii) elderly depressed patients (average age 75 years) who did not commit suicide (DEP). Both cohorts were individually matched with non-psychiatric non-suicide control subjects. We determined the transcript levels of hypothalamic-pituitary-adrenal axis-regulating molecules (corticotropin-releasing hormone (CRH), CRH receptors, CRH binding protein, mineralocorticoid receptor/glucocorticoid receptor), transcription factors that regulate CRH expression, CRH-stimulating cytokines, chaperone proteins, retinoid signaling, brain-derived neurotrophic factor and tropomyosin-related kinase B, cytochrome proteins, nitric oxide synthase (NOS) and monoamines. In the MDD-S group, expression levels of CRH and neuronal NOS-interacting DHHC domain-containing protein with dendritic mRNA (NIDD) were increased. Other changes were only present in the DEP group, i.e. decreased NIDD, and increased and 5-hydroxytryptamine receptor 1A (5-HT1A) expression levels. Changes were found to be more pronounced in the anterior cingulate cortex than in the dorsolateral PFC. Depressed patients who committed suicide have different gene expression patterns than depressed patients who died of causes other than suicide.