Pathologic evaluation of normal and perfused term placental tissue.
This study reports for the 1st time the incidence and interobserver variation of morphologic findings in a series of 34 term placentas from pregnancies with normal outcome used for perfusion studies. Histologic evaluation of placental tissue is challenging, especially when it comes to defining "normal tissue" versus "pathologic lesions." A scoring system for registration of abnormal morphologic findings was developed. Light microscopic examination was performed independently by 2 pathologists, and interobserver variation was analyzed. Findings in normal and perfused tissue were compared and selected findings were tested against success parameters from the perfusions. Finally, the criteria for frequent lesions with fair to poor interobserver variation in the nonperfused tissue were revised and reanalyzed. In the perfused tissue, the perfusion artefact "trophoblastic vacuolization," which is believed to represent dilated transtrophoblastic channels, was reproducible and significantly correlated to the perfusion marker "fetal leakage." In longer perfusions, microscopy of the perfused cotyledon revealed bacteria in the fetal vessels. This finding led to an adjustment in the perfusion protocol with addition of antibiotics to the medium. In the "normal" tissue, certain lesions were very frequent and showed only fair or poor interobserver agreement. Revised minimum criteria for these lesions were defined and found reproducible. This study has emphasized the value of pathologic examination as a supplement in placental perfusion models. Examination of the perfused cotyledon for trophoblastic vacuolization is recommended as an additional quality marker in perfusion models. The study also underlines the need for exact definitions of abnormality in frequent placental lesions.


Ranking transitive chemical-disease inferences using local network topology in the comparative toxicogenomics database.
Exposure to chemicals in the environment is believed to play a critical role in the etiology of many human diseases. To enhance understanding about environmental effects on human health, the Comparative Toxicogenomics Database (CTD; http://ctdbase.org) provides unique curated data that enable development of novel hypotheses about the relationships between chemicals and diseases. CTD biocurators read the literature and curate direct relationships between chemicals-genes, genes-diseases, and chemicals-diseases. These direct relationships are then computationally integrated to create additional inferred relationships; for example, a direct chemical-gene statement can be combined with a direct gene-disease statement to generate a chemical-disease inference (inferred via the shared gene). In CTD, the number of inferences has increased exponentially as the number of direct chemical, gene and disease interactions has grown. To help users navigate and prioritize these inferences for hypothesis development, we implemented a statistic to score and rank them based on the topology of the local network consisting of the chemical, disease and each of the genes used to make an inference. In this network, chemicals, diseases and genes are nodes connected by edges representing the curated interactions. Like other biological networks, node connectivity is an important consideration when evaluating the CTD network, as the connectivity of nodes follows the power-law distribution. Topological methods reduce the influence of highly connected nodes that are present in biological networks. We evaluated published methods that used local network topology to determine the reliability of protein-protein interactions derived from high-throughput assays. We developed a new metric that combines and weights two of these methods and uniquely takes into account the number of common neighbors and the connectivity of each entity involved. We present several CTD inferences as case studies to demonstrate the value of this metric and the biological relevance of the inferences.


The rat caudal nerves: a model for experimental neuropathies.
This study provides a detailed investigation of the anatomy of the rat caudal nerve along its entire length, as well as correlated nerve conduction measures in both large and small diameter axons. It determines that rodent caudal nerves provide a simple, sensitive experimental model for evaluation of the pathophysiology of degeneration, recovery, and prevention of length-dependent distal axonopathy. After first defining the normal anatomy and electrophysiology of the rat caudal nerves, acrylamide monomer, a reliable axonal toxin, was administered at different doses for escalating time periods. Serial electrophysiological recordings were obtained, during intoxication, from multiple sites along caudal and distal sciatic nerves. Multiple sections of the caudal and sciatic nerves were examined with light and electron microscopy. The normal distribution of conduction velocities was determined and acrylamide-induced time- and dose-related slowing of velocities at the vulnerable ultraterminal region was documented. Degenerative morphological changes in the distal regions of the caudal nerves appeared well before changes in the distal sciatic nerves. Our study has shown that (1) rat caudal nerves have a complex neural structure that varies along a distal-to-proximal gradient and (2) correlative assessment of both morphology and electrophysiology of rat caudal nerves is easily achieved and provides a highly sensitive index of the onset and progression of the length-dependent distal axonopathy.


Supported employment: cost-effectiveness across six European sites.
A high proportion of people with severe mental health problems are unemployed but would like to work. Individual Placement and Support (IPS) offers a promising approach to establishing people in paid employment. In a randomized controlled trial across six European countries, we investigated the economic case for IPS for people with severe mental health problems compared to standard vocational rehabilitation. Individuals (n=312) were randomized to receive either IPS or standard vocational services and followed for 18 months. Service use and outcome data were collected. Cost-effectiveness analysis was conducted with two primary outcomes: additional days worked in competitive settings and additional percentage of individuals who worked at least 1 day. Analyses distinguished country effects. A partial cost-benefit analysis was also conducted. IPS produced better outcomes than alternative vocational services at lower cost overall to the health and social care systems. This pattern also held in disaggregated analyses for five of the six European sites. The inclusion of imputed values for missing cost data supported these findings. IPS would be viewed as more cost-effective than standard vocational services. Further analysis demonstrated cost-benefit arguments for IPS. Compared to standard vocational rehabilitation services, IPS is, therefore, probably cost-saving and almost certainly more cost-effective as a way to help people with severe mental health problems into competitive employment.


Mortality from trauma haemorrhage and opportunities for improvement in transfusion practice.
The aim of this study was to describe the prevalence, patterns of blood use and outcomes of major haemorrhage in trauma. This was a prospective observational study from 22 hospitals in the UK, including both major trauma centres and smaller trauma units. Eligible patients received at least 4 units of packed red blood cells (PRBCs) in the first 24 h of admission with activation of the massive haemorrhage protocol. Case notes, transfusion charts, blood bank records and copies of prescription/theatre charts were accessed and reviewed centrally. Study outcomes were: use of blood components, critical care during hospital stay, and mortality at 24 h, 30 days and 1 year. Data were used to estimate the national trauma haemorrhage incidence. A total of 442 patients were identified during a median enrolment interval of 20 (range 7-24) months. Based on this, the national incidence of trauma haemorrhage was estimated to be 83 per million. The median age of patients in the study cohort was 38 years and 73·8 per cent were men. The incidence of major haemorrhage increased markedly in patients aged over 65 years. Thirty-six deaths within 24 h of admission occurred within the first 3 h. At 24 h, 79 patients (17·9 per cent) had died, but mortality continued to rise even after discharge. Patients who received a cumulative ratio of fresh frozen plasma to PRBCs of at least 1 : 2 had lower rates of death than those who received a lower ratio. There were delays in administration of blood. Platelets and cryoprecipitate were either not given, or transfused well after initial resuscitation. There is a high burden of trauma haemorrhage that affects all age groups. Research is required to understand the reasons for death after the first 24 h and barriers to timely transfusion support.


Vision-Based Detection and Distance Estimation of Micro Unmanned Aerial Vehicles.
Detection and distance estimation of micro unmanned aerial vehicles (mUAVs) is crucial for (i) the detection of intruder mUAVs in protected environments; (ii) sense and avoid purposes on mUAVs or on other aerial vehicles and (iii) multi-mUAV control scenarios, such as environmental monitoring, surveillance and exploration. In this article, we evaluate vision algorithms as alternatives for detection and distance estimation of mUAVs, since other sensing modalities entail certain limitations on the environment or on the distance. For this purpose, we test Haar-like features, histogram of gradients (HOG) and local binary patterns (LBP) using cascades of boosted classifiers. Cascaded boosted classifiers allow fast processing by performing detection tests at multiple stages, where only candidates passing earlier simple stages are processed at the preceding more complex stages. We also integrate a distance estimation method with our system utilizing geometric cues with support vector regressors. We evaluated each method on indoor and outdoor videos that are collected in a systematic way and also on videos having motion blur. Our experiments show that, using boosted cascaded classifiers with LBP, near real-time detection and distance estimation of mUAVs are possible in about 60 ms indoors (1032 × 778 resolution) and 150 ms outdoors (1280 × 720 resolution) per frame, with a detection rate of 0.96 F-score. However, the cascaded classifiers using Haar-like features lead to better distance estimation since they can position the bounding boxes on mUAVs more accurately. On the other hand, our time analysis yields that the cascaded classifiers using HOG train and run faster than the other algorithms.


Factors influencing bactericidal activity of blue mussel (Mytilus edulis) haemocytes against Salmonella typhimurium.
This study showed that in vitro survival of Salmonella typhimurium, after exposure to haemocytes of Mytilus edulis, was significantly affected by the lipopolysaccharides (LPS) structures expressed on the cell surface of the bacteria. Survival seemed to be affected by the surrounding temperature as well. Mussel haemocytes were in vitro exposed to mutants of S. typhimurium, expressing differences in O -antigen polysaccharide chains and core sugars of LPS on their cell surface. Surviving cells of the mutants were determined after incubation with the haemocytes at different temperatures, using a colorimetric assay. In addition, a complementary study on clearance of these mutants, inoculated into the adductor muscle of mussels, was performed at 6 and 20 degrees C. It was concluded that the survival index (SI%) measured in vitro for the mutant with complete LPS was significantly lower at 6 degrees C (c.15%) compared to that at 14 and 20 degrees C (c.70%). SI% for the other mutants was c.35-45% and was not affected by temperature. The in vivo study at 20 degrees C showed that during the first 24h, the clearance rate for the mutants with complete LPS was significantly higher than for the others. Thereafter all mutants, with exception for the most deficient, started to increase in numbers and caused death to the mussels. At 6 degrees C the mutants were slowly reduced and after 17 days, viable cells of the mutant with complete LPS were still detectable in the haemolymph. The study indicated that the mussel haemocytes responded in relation to the LPS of the mutants. However, more intact LPS also seemed to protect the bacteria from being killed. The higher temperatures favoured the growth of the mutants that managed to resist the haemocyte defence. Cell surface properties and temperature seem to affect the survival of bacteria in mussels, which consequently can affect risk assessments in regard to public health.


Care-seeking during fatal childhood illness in rural South Africa: a qualitative study.
This study aimed to better understand reasons why children in South Africa die at home, including caregivers' care-seeking experiences, decision-making, choice of treatment provider and barriers to accessing care during a child's final illness. This qualitative study included semi-structured in-depth interviews and focus group discussions with caregivers of children who died below the age of 5 years. Data were thematically analysed, and key findings compared with the Pathways to Survival Framework-a model frequently used in the study of child mortality. An adapted model was developed. Two rural health and demographic surveillance system (HDSS) sites in South Africa-the Agincourt HDSS and the Africa Health Research Institute. Thirty-eight caregivers of deceased children (29 participated in in-depth interviews and 9 were participants in two focus group discussions). Caregivers were purposively sampled to ensure maximum variation across place of death, child age at death, household socioeconomic status, maternal migration status and maternal HIV status. Although caregivers faced barriers in providing care to children (including insufficient knowledge and poor transport), almost all did seek care from the formal health system. Negative experiences in health facilities did not deter care-seeking, but most respondents still received poor quality care and were not given adequate safety-netting advice. Traditional healers were only consulted as a last resort when other approaches had failed. Barriers to accessing healthcare disrupt the workings of previously accepted care-seeking models. The adapted model presented in this paper more realistically reflects care-seeking experiences and decision-making during severe childhood illness in rural South Africa and helps explain both the persistence of home deaths despite seeking healthcare, and the impact of a child's death on care-seeking in future childhood illness. This model can be used as the basis for developing interventions to reduce under-5 mortality.


Diabetes and thyroid cancer risk in the National Institutes of Health-AARP Diet and Health Study.
We hypothesized that diabetes may play a role in thyroid cancer risk due to the parallel secular rise in diabetes prevalence and morbidity in the United States, the higher prevalence of thyroid disorders among diabetics compared with the general population, and the potential roles of metabolic syndrome, obesity, and diabetes as precipitating factors in cancer development. We assessed the association between self-reported diabetes and the risk of differentiated thyroid cancer in the NIH-AARP Diet and Health Study, a prospective cohort of 200,556 women and 295,992 men, 50-71 years of age, in 1995-1996. Diabetes status and information on potential confounders was ascertained using a self-administered questionnaire. During an average of 10 years of follow-up, 585 thyroid cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer and thyroid cancer subtypes in men and women according to diabetes status. Nine percent of the total baseline cohort reported a history of diabetes (7% of women, 10% of men). A nonsignificant 25% increase in thyroid cancer risk (HR = 1.25; 95% CI: 0.95-1.64) was associated with diabetes. Among women, the risk was significantly increased (HR = 1.46, 95% CI: 1.01-2.10). The risk was not elevated among men (HR = 1.04, 95% CI: 0.69-1.58). In this cohort, diabetic women with differentiated thyroid cancer were at somewhat higher risk of follicular thyroid cancer (HR = 1.92; 95% CI: 0.86-4.27) than papillary thyroid cancer (HR = 1.25; 95% CI: 0.80-1.97). This study lends support to the hypothesis that diabetes increases the risk of differentiated thyroid cancer.


Genomic masking of nondefective recombinant murine leukemia virus in Moloney virus stocks.
HIX virus cloned from Moloney leukemia virus stocks is a nondefective, leukemogenic, and amphotropic murine oncornavirus with a recombinant-type major glycoprotein. Although Moloney leukemia virus stocks generally contain little or no free amphotropic virus, dilution analysis of several virus stocks and the examination of virus progeny from individual foci revealed that HIX virus is present and functionally coated with ecotropic Moloney virus envelopes. Because most mice have serum factors that inactivate recombinant viruses, masking may represent a general survival mechanism for HIX as well as other analogous recombinant viruses.


Helicobacter pylori-induced IL-1β secretion in innate immune cells is regulated by the NLRP3 inflammasome and requires the cag pathogenicity island.
Infection with the gram-negative bacterium Helicobacter pylori is the most prevalent chronic bacterial infection, affecting ∼50% of the world's population, and is the main risk factor of gastric cancer. The proinflammatory cytokine IL-1β plays a crucial role in the development of gastric tumors and polymorphisms in the IL-1 gene cluster leading to increased IL-1β production have been associated with increased risk for gastric cancer. To be active, pro-IL-1β must be cleaved by the inflammasome, an intracellular multiprotein complex implicated in physiological and pathological inflammation. Recently, H. pylori was postulated to activate the inflammasome in murine bone marrow-derived dendritic cells; however, the molecular mechanisms as well as the bacterial virulence factor acting as signal 2 activating the inflammasome remain elusive. In this study, we analyzed the inflammasome complex regulating IL-1β upon H. pylori infection as well as the molecular mechanisms involved. Our results indicate that H. pylori-induced IL-1β secretion is mediated by activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome. We also show that reactive oxygen species, potassium efflux, and lysosomal destabilization are the main cellular mechanisms responsible of nucleotide-binding oligomerization domain family, pyrin domain-containing 3 inflammasome activation upon H. pylori infection, and identify vacuolating cytotoxin A and cag pathogenicity island as the bacterial virulence determinants involved. Moreover, in vivo experiments indicate an important role for the inflammasome in the onset and establishment of H. pylori infection and in the subsequent inflammatory response of the host.


Rationale and design of a randomized pragmatic trial of patient-centered models of hepatitis C treatment for people who inject drugs: The HERO study.
Although people who inject drugs (PWID) having the highest incidence and prevalence of hepatitis C virus (HCV) in the US, HCV treatment is rarely provided to PWID due to assumptions about poor adherence and reinfection risk. As direct-acting antiviral agents (DAAs) have achieved sustained virologic response (SVR) rates of 95% or more, evidence-based strategies are urgently needed to demonstrate real-world effectiveness in marginalized patient populations such as PWID. The objectives of this study are: 1) to determine whether either of two patient-centered treatment models - patient navigation (PN) or modified directly observed therapy (mDOT) - results in more forward movement along the HCV care cascade including treatment initiation, adherence, and SVR; 2) using quantitative and qualitative methods, to understand factors associated with lack of treatment uptake, poor adherence (<80%), failure to achieve SVR, DAA resistance, and HCV reinfection. The HERO study is a multi-site, pragmatic randomized clinical trial conducted in eight states where 754 HCV-infected PWID were randomly assigned to either PN or mDOT. This study addresses an urgent need for timely and accurate information on optimal models of care to promote HCV treatment initiation, adherence, treatment completion and SVR among PWID, as well as rates and factors associated with reinfection and resistance after treatment. This clinical trial has the potential to provide valuable information on how to reduce the burden of the HCV epidemic in PWID.


Predicting human movement with multiple accelerometers using movelets.
The study aims were 1) to develop transparent algorithms that use short segments of training data for predicting activity types and 2) to compare the prediction performance of the proposed algorithms using single accelerometers and multiple accelerometers. Sixteen participants (age, 80.6 yr (4.8 yr); body mass index, 26.1 kg·m (2.5 kg·m)) performed 15 lifestyle activities in the laboratory, each wearing three accelerometers at the right hip and left and right wrists. Triaxial accelerometry data were collected at 80 Hz using ActiGraph GT3X+. Prediction algorithms were developed, which, instead of extracting features, build activity-specific dictionaries composed of short signal segments called movelets. Three alternative approaches were proposed to integrate the information from the multiple accelerometers. With at most several seconds of training data per activity, the prediction accuracy at the second-level temporal resolution was very high for lying, standing, normal/fast walking, and standing up from a chair (the median prediction accuracy ranged from 88.2% to 99.9% on the basis of the single-accelerometer movelet approach). For these activities, wrist-worn accelerometers performed almost as well as hip-worn accelerometers (the median difference in accuracy between wrist and hip ranged from -2.7% to 5.8%). Modest improvements in prediction accuracy were achieved by integrating information from multiple accelerometers. It is possible to achieve high prediction accuracy at the second-level temporal resolution with very limited training data. To increase prediction accuracy from the simultaneous use of multiple accelerometers, a careful selection of integrative approaches is required.


Defect roles in the excitation of Eu ions in Eu:GaN.
Eu ions in situ doped in GaN with V/III ratios varying from 3200 to 9600 have been investigated using resonant site-selective photoluminescence (PL), power dependent cathodoluminescence (CL), and a unique electron beam power dependent dual excitation experiment combining the techniques of PL and CL. The results of these experiments reveal the role of defects in the electronic excitation of Eu ions and the link between the GaN host and Eu ion dopants. The relative number of beneficial defects present in each sample for a majority Eu site (Eu1) and a specific secondary site (Eu2) are revealed. Also, a room temperature activated non-radiative recombination pathway linked to a specific, sample dependent Eu2 excitation pathway is identified. Unlike conventional GaN LEDs, Eu:GaN device performance does not rely completely on crystalline quality, but on the presence of specific excitation enhancing defects and the absence of non-radiative de-excitation channels.


Forgetting what was where: the fragility of object-location binding.
Although we frequently take advantage of memory for objects locations in everyday life, understanding how an object's identity is bound correctly to its location remains unclear. Here we examine how information about object identity, location and crucially object-location associations are differentially susceptible to forgetting, over variable retention intervals and memory load. In our task, participants relocated objects to their remembered locations using a touchscreen. When participants mislocalized objects, their reports were clustered around the locations of other objects in the array, rather than occurring randomly. These 'swap' errors could not be attributed to simple failure to remember either the identity or location of the objects, but rather appeared to arise from failure to bind object identity and location in memory. Moreover, such binding failures significantly contributed to decline in localization performance over retention time. We conclude that when objects are forgotten they do not disappear completely from memory, but rather it is the links between identity and location that are prone to be broken over time.


Clinicopathologic analysis of CD10+ and CD10- diffuse large B-cell lymphoma. Identification of a high-risk subset with coexpression of CD10 and bcl-2.
We analyzed 53 cases of diffuse large B-cell lymphoma (DLBCL) to determine whether expression of CD10 is a relevant biologic parameter. Tumor morphologic features were assessed semiquantitatively. Bcl-2 protein expression was studied by immunohistochemical analysis. The presence or absence of CD10 by flow cytometry was correlated with clinical and pathologic characteristics. CD10+ (23 cases) and CD10- (30 cases) DLBCLs were indistinguishable based on age, sex, extranodal presentation, B symptoms, clinical stage, morphologic features, or bcl-2 expression. However, cases with a CD10+ phenotype showed a significantly lower rate of complete remission. Cases expressing bcl-2 showed trends toward a lower rate of complete remission and poorer overall survival. Examination of CD10 and bcl-2 interaction revealed that the prognostic effects for both of these antigens were due to a subset of CD10+ bcl-2-positive cases. Compared with cases expressing one or neither of these markers, patients with dual-positive tumors had a poorer complete response rate to initial therapy and strikingly worse overall survival. While CD10+ and CD10- DLBCLs are similar with regard to a variety of clinical and pathologic features, CD10 and bcl-2 coexpressing tumors are an extremely high-risk subset based on response to therapy and overall survival.


Loss of B7.2 (CD86) and intracellular adhesion molecule 1 (CD54) expression is associated with decreased tumor-infiltrating T lymphocytes in diffuse B-cell large-cell lymphoma.
Tumor-infiltrating CD8+ T-lymphocytes (T-TILs) are thought to be relevant to immunosurveillance of several tumor types including B-cell non-Hodgkin's lymphoma. B- and T-lymphocyte interactions via cellular adhesion molecules (CAMs), recognition molecules (HLAs), and costimulatory molecules (CSMs) are necessary for optimal antigen-specific T-cell activation to occur and may be important in generating effective host T-TIL responses. We previously found that low T-TIL response (CD8+ T cells < 6%) correlates with statistically shorter relapse-free survival in patients with diffuse large-cell lymphoma (DLCL). We now extend our observations in 71 DLCL patients by analyzing malignant B-cell expression of the following molecules important in T-cell activation: (a) recognition molecules [MHC I (MAS and MCA) and MHC II (HLA-DR, -DP, -DQ)]; (b) CAMs [leukocyte function antigen 1 (CD11a and CD18) and intracellular adhesion molecule 1 (CD54)]; and (c) CSMs [B7.1 (CD80) and B7.2 (CD86)]. Eighteen patients (25%) had low a T-TIL response, and 53 patients (75%) had a high T-TIL response. Overall, expression of the MHC class H molecules HLA-DR and HLA-DQ was most conserved. The loss of B7.2 (P = 0.04), intracellular adhesion molecule 1 (P = 0.0004), MAS (P = 0.02), and HLA-DR (P = 0.0004) expression was significantly associated with decreased T-TIL response. In 100% of patients with low T-TIL responses, at least one HLA, CAM, or CSM was undetectable on the malignant B cells by immunohistochemical staining (mean number of molecules lost = 2.67). In contrast, 49% of patients with high T-TIL responses had no losses in HLA, CAM, or CSM expression (mean number of molecules lost = 0.89). The mean number of absent molecules (HLA, CAM, or CSM) was significantly associated with T-TIL response (P = 0.0001). We conclude that loss of HLA, CAM, or CSM expression on malignant B cells is associated with a poor host T-cell immune response. In addition, because patients with low T-TIL response had lost expression of multiple cellular adhesion, recognition, and costimulatory molecules, our results suggest that a combination of immunorestorative therapies may be required to generate effective antitumor T-cell responses in B-cell DLCL.


Plasmonic distributed feedback lasers at telecommunications wavelengths.
We investigate electrically pumped, distributed feedback (DFB) lasers, based on gap-plasmon mode metallic waveguides. The waveguides have nano-scale widths below the diffraction limit and incorporate vertical groove Bragg gratings. These metallic Bragg gratings provide a broad bandwidth stop band (~500 nm) with grating coupling coefficients of over 5000/cm. A strong suppression of spontaneous emission occurs in these Bragg grating cavities, over the stop band frequencies. This strong suppression manifests itself in our experimental results as a near absence of spontaneous emission and significantly reduced lasing thresholds when compared to similar length Fabry-Pérot waveguide cavities. Furthermore, the reduced threshold pumping requirements permits us to show strong line narrowing and super linear light current curves for these plasmon mode devices even at room temperature.


An approach to risk assessment.
A strategy for delineating risk factors from use of neurotoxic chemicals was applied to the Danish working environment. An analysis using this strategy disclosed the need for internationally adopted criteria for neurotoxicity, and consequently a working group was established by the Nordic Council of Ministers with the task to propose criteria for neurotoxicity. Functional effects on the nervous system, such as reduction in memory and learning ability, decrease in attention, and alteration of behavior due to toxic chemicals in the environment is now being acknowledged as an important public health problem. This change in concern from obvious effects of high dose exposure to the more subtle effects of environmental exposure to neurotoxicants was incorporated in the criteria. The new criteria for evaluating neurotoxicity data has subsequently been used on 79 common industrial chemicals. The results indicate that numerous persons are exposed in the working as well as in the general environment to several chemicals, for which almost no data on the effect on subtle neurophysiological functions are available. Development of an approach to risk assessment dealing with this problem is a major challenge in the nineties. Different approaches to risk assessment are discussed, the quality of the databases available for hazard assessment are evaluated, and the needs for further research are identified.


Ultrastructural evidence of microglial heterogeneity in Alzheimer's disease amyloid pathology.
Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by the deposition of extracellular fibrillar amyloid β (fΑβ) and the intracellular accumulation of neurofibrillary tangles. As AD progresses, Aβ drives a robust and prolonged inflammatory response via its recognition by microglia, the brain's immune cells. Microglial reactivity to fAβ plaques may impair their normal surveillance duties, facilitating synaptic loss and neuronal death, as well as cognitive decline in AD. In the current study, we performed correlative light, transmission, and scanning electron microscopy to provide insights into microglial structural and functional heterogeneity. We analyzed microglial cell bodies and processes in areas containing fAβ plaques and neuronal dystrophy, dystrophy only, or appearing healthy, among the hippocampus CA1 of 14-month-old APPSwe-PS1Δe9 mice versus wild-type littermates. Our quantitative analysis revealed that microglial cell bodies in the AD model mice were larger and displayed ultrastructural signs of cellular stress, especially nearby plaques. Microglial cell bodies and processes were overall less phagocytic in AD model mice. However, they contained increased fibrillar materials and non-empty inclusions proximal to plaques. Microglial cell bodies and processes in AD model mice also displayed reduced association with extracellular space pockets that contained debris. In addition, microglial processes in healthy subregions of AD model mice encircled synaptic elements more often compared with plaque-associated processes. These observations in mice were qualitatively replicated in post-mortem hippocampal samples from two patients with AD (Braak stage 5). Together, our findings identify at the ultrastructural level distinct microglial transformations common to mouse and human in association with amyloid pathology.


Description of a pharmacist-led clinical video telehealth group clinic for opioid overdose prevention and naloxone education.
To achieve the nationwide goal of reducing opioid-related deaths, a clinical pharmacy specialist-led clinical video telehealth (CVT) clinic was created at a Veterans Affairs medical center (VAMC) to deliver opioid overdose prevention and naloxone education to at-risk patients. The purpose of this innovative practice was to improve access to this potentially life-saving intervention to patients across urban and rural areas. This study is a single-center, descriptive analysis of adult patients across 2 VAMC campuses and 4 community-based outpatient clinics from July 11, 2016, through December 31, 2016. The purpose of this innovative practice was to increase access to overdose education and naloxone distribution (OEND) to at-risk patients across urban and rural areas. Patient-specific factors were also examined among those receiving naloxone through the CVT clinic compared to other prescribers. During the first 6 months from the initiation of the clinic, 1 pharmacist prescribed 21% of the health care system's naloxone. These patients identified by the pharmacist-led CVT clinic were more likely to be considered high-risk due to concomitant use of opioids and benzodiazepines. In conclusion, the pharmacist-led CVT group clinic has been an efficient strategy to extend OEND services to high-risk patients beyond central, urban areas.


Hypothesis: Bacterial induced inflammation disrupts the orderly progression of the stem cell hierarchy and has a role in the pathogenesis of breast cancer.
The hierarchical model of stem cell genesis is based on the idea that the number of cell divisions between the zygote and fully differentiated epithelial cells is kept close to the minimum, which is log to the base 2 of the total number of cells produced in a human lifetime. The model assumes the orderly progression of stem cell divisions requires precise control at every stage in development. If the orderly progression is maintained then cancer will be rare. A prediction of the model is that if the orderly progression of the stem cell hierarchy is disturbed by trauma, ulceration or inflammation then cancer will occur. Bacterial induced inflammation in breast ducts disturbs the stem cell hierarchy and is a cause of breast cancer. Mammalian milk is not sterile. It contains a range of bacteria, derived endogenously by the entero-mammary circulation. The dominant flora consists of lactose fermenting bacteria. Pregnancy and breast feeding reduce the risk of subsequent breast cancer. The implication is that a lactose fermenting bacterial flora in breast ducts is protective. Malignant and benign breast tissue contains bacteria derived endogenously, but studies so far have not revealed a specific flora associated with malignancy. Periodontitis is associated with oral, oesophageal, colonic, pancreatic, prostatic and breast cancer. The pathogenic bacteria which cause periodontitis spread endogenously to cause inflammation at other epithelial sites. Meta-analysis of epidemiological studies shows that the consumption of yoghurt is associated with a reduction in the risk of breast cancer. The hypothesis, although not proven, is supported by the available evidence. Lactose fermenting bacteria protect but pathogenic bacteria which induce inflammation raise the risk of breast cancer. The consumption of yoghurt also appears to be protective.


Findings of universal cystoscopy at incontinence surgery and their sequelae.
The purpose of this study was to report the frequency of abnormal cystoscopy at incontinence surgery and to identify risk factors and sequelae of injury. Findings of cystoscopy were collected prospectively in 3 multicenter surgical trials. Clinical, demographic, and procedure characteristics and surgeon experience were analyzed for association with iatrogenic injury and noninjury abnormalities. Impact of abnormalities on continence outcomes and adverse events during 12 months after the procedure were assessed. Abnormal findings in the bladder or urethra were identified in 95 of 1830 women (5.2%). Most injuries (75.8%) were iatrogenic. Lower urinary tract (LUT) injury was most common at retropubic urethropexy and retropubic midurethral sling (MUS) procedures (6.4% each), followed by autologous pubovaginal sling procedures (1.7%) and transobturator MUS (0.4%). Increasing age (56.9 vs 51.9 years; P = .04), vaginal deliveries (3.2 vs 2.6; P = .04), and blood loss (393 vs 218 mL; P = .01) were associated with LUT injury during retropubic urethropexy; however, only age (62.9 vs 51.4 years; P = .02) and smoking history (P = .04) were associated for pubovaginal sling procedures. No factors correlated with increased risk of injury at retropubic and transobturator MUS. Notably, previous incontinence surgery, concomitant procedures, anesthesia type, and trainee participation did not increase LUT injury frequency. Although discharge with an indwelling catheter was more common after trocar perforation compared with the noninjury group (55.6% vs 18.5%; P < .001), they did not differ in overall success, voiding dysfunction, recurrent urinary tract infections, or urge urinary incontinence. Universal cystoscopy at incontinence surgery detects abnormalities in 1 in 20 women. Urinary trocar perforations that are addressed intraoperatively have no long-term adverse sequelae.


Hearing screening for school children: utility of noise-cancelling headphones.
Excessive ambient noise in school settings is a major concern for school hearing screening as it typically masks pure tone test stimuli (particularly 500 Hz and below). This results in false positive findings and subsequent unnecessary follow-up. With advances in technology, noise-cancelling headphones have been developed that reduce low frequency noise by superimposing an anti-phase signal onto the primary noise. This research study examined the utility of noise-cancelling headphone technology in a school hearing screening environment. The present study compared the audiometric screening results obtained from two air-conduction transducers-Sennheiser PXC450 noise-cancelling circumaural headphones (NC headphones) and conventional TDH-39 supra-aural earphones. Pure-tone hearing screening results (500 Hz to 4000 Hz, at 30 dB HL and 25 dB HL) were obtained from 232 school children, aged 6 to 8 years, in four Hong Kong primary schools. Screening outcomes revealed significant differences in referral rates between TDH-39 earphones and NC headphones for both 30 dB HL and 25 dB HL criteria, regardless of the inclusion or exclusion of 500 Hz results. The kappa observed agreement (OA) showed that at both screening intensities, the transducers' referral agreement value for the 500 Hz inclusion group was smaller than for the 500 Hz exclusion group. Individual frequency analysis showed that the two transducers screened similarly at 1000 Hz and 2000 Hz at 25 dB HL, as well as at both 30 dB HL and 25 dB HL screening levels for 4000 Hz. Statistically significant differences were found for 500 Hz at 30 dB HL and at 25 dB HL, and for 1000 Hz and 2000 Hz at 30 dB HL. OA for individual frequencies showed weaker intra-frequency agreement between the two transducers at 500 Hz at both intensity criterion levels than at higher frequencies. NC headphones screening results differed from those obtained from TDH-39 earphones, with lower referral rates at 500 Hz, particularly at the 25 dB HL criterion level. Therefore, NC headphones may be able to operate at lower screening intensities and subsequently increase pure-tone screening test sensitivity, without compromising specificity. NC headphones show some promise as possible replacements for conventional earphones in school hearing screening programs.


Heritability of objectively assessed daily physical activity and sedentary behavior.
Twin and family studies that estimated the heritability of daily physical activity have been limited by poor measurement quality and a small sample size. We examined the heritability of daily physical activity and sedentary behavior assessed objectively by using combined heart rate and movement sensing in a large twin study. Physical activity traits were assessed in daily life for a mean (± SD) 6.7 ± 1.1 d in 1654 twins from 420 monozygotic and 352 dizygotic same-sex twin pairs aged 56.3 ± 10.4 y with body mass index (in kg/m(2)) of 26.1 ± 4.8. We estimated the average daily movement, physical activity energy expenditure, and time spent in moderate-to-vigorous intensity physical activity and sedentary behavior from heart rate and acceleration data. We used structural equation modeling to examine the contribution of additive genetic, shared environmental, and unique environmental factors to between-individual variation in traits. Additive genetic factors (ie, heritability) explained 47% of the variance in physical activity energy expenditure (95% CI: 23%, 53%) and time spent in moderate-to-vigorous intensity physical activity (95% CI: 29%, 54%), 35% of the variance in acceleration of the trunk (95% CI: 0%, 44%), and 31% of the variance in the time spent in sedentary behavior (95% CI: 9%, 51%). The remaining variance was predominantly explained by unique environmental factors and random error, whereas shared environmental factors played only a marginal role for all traits with a range of 0-15%. The between-individual variation in daily physical activity and sedentary behavior is mainly a result of environmental influences. Nevertheless, genetic factors explain up to one-half of the variance, suggesting that innate biological processes may be driving some of our daily physical activity.


Parametric and adsorption kinetic studies of methylene blue removal from simulated textile water using durian (Durio zibethinus murray) skin.
In this study, durian (Durio zibethinus Murray) skin was examined for its ability to remove methylene blue (MB) dye from simulated textile wastewater. Adsorption equilibrium and kinetics of MB removal from aqueous solutions at different parametric conditions such as different initial concentrations (2-10 mg/L), biosorbent dosages (0.3-0.7 g) and pH solution (4-9) onto durian skin were studied using batch adsorption. The amount of MB adsorbed increased from 3.45 to 17.31 mg/g with the increase in initial concentration of MB dye; whereas biosorbent dosage increased from 1.08 to 2.47 mg/g. Maximum dye adsorption capacity of the durian skin was found to increase from 3.78 to 6.40 mg/g, with increasing solution pH. Equilibrium isotherm data were analyzed according to Langmuir and Freundlich isotherm models. The sorption equilibrium was best described by the Freundlich isotherm model with maximum adsorption capacity of 7.23 mg/g and this was due to the heterogeneous nature of the durian skin surface. Kinetic studies indicated that the sorption of MB dye tended to follow the pseudo second-order kinetic model with promising correlation of 0.9836 < R(2) < 0.9918.


Efficacy of moclobemide in burning mouth syndrome: a nonrandomized, open-label study.
To compare burning mouth syndrome (BMS) patients with age- and gender-matched controls for psychologic conditions, to analyze the effect of menstrual state on the intensity of burning, and to assess the efficacy of an antidepressant medication on the burning pain and psychologic status. Ninety-four patients with BMS and 94 matched control subjects participated in the study. Anxiety and depression were analyzed by means of the Spielberger State-Trait Anxiety Inventory and Zung Self-Rating Depression Scale, and the severity of the burning sensation was measured by means of a visual analog scale (VAS). In female BMS patients and controls, the menstrual state was noted (menstruating, menopausal, or postmenopausal). BMS patients were treated with the antidepressant moclobemide (150 mg 2 times daily) for 3 months. Thereafter, anxiety, depression, and burning pain intensity were reassessed. Patient-perceived satisfactory improvement for burning sensation was assessed using a 5-point categorical rating of change scale. BMS patients had significantly higher anxiety and depression scores than controls (P < .05). After treatment, anxiety and depression scores as well as the VAS values for burning pain decreased significantly (P < .001). Thirty-seven patients reported good to very good improvement, and 44 reported satisfactory improvement. No adverse reactions were reported. The study confirmed earlier reports that BMS patients have higher anxiety and depression levels than controls. An antidepressant medication may be effective in alleviating the burning pain, at least in the short-term.


Relationship between visual field sensitivity and macular ganglion cell complex thickness as measured by spectral-domain optical coherence tomography.
To evaluate the strength and pattern of the relationship between visual field (VF) mean sensitivity (MS), assessed by standard automated perimetry (SAP), and macular ganglion cell complex thickness (GCCT), measured with spectral-domain optical coherence tomography (SD-OCT). Ninety-seven glaucoma patients were enrolled. GCCT, determined by ganglion cell complex (GCC) scanning, and two peripapillary retinal nerve fiber layer thickness (pRNFLT) measurements, using the NHM4 (RNFL1) and RNFL 3.45 (RNFL2) modes, were recorded. MS was recorded on the decibel (dB) and 1/L scales. The relationship between function (MS) and structure (GCC, pRNFLT) was sought. The association of MS (in decibels) with GCC global (r = 0.445) and sectoral (superior, r = 0.528; inferior, r = 0.370) thicknesses was not significantly different from that of MS to global (RNFL1, r = 0.505; RNFL2, r = 0.498) and sectoral (RNFL 1 superior, r = 0.559; inferior, r = 0.440; RNFL 2 superior, r = 0.535; inferior, r = 0.443) pRNFLT, on linear regression analysis. The relationship pattern was curvilinear on the dB scale against GCCT and RNFLT. Logarithmic regression of MS (using both the dB and 1/L scales) against GCCT and RNFLT was better than linear regression in describing the pattern of association. GCCT, determined by SD-OCT, showed correlation to MS of a strength similar to that demonstrated between MS and pRNFLT.


Carry-Over or Compensation? The Impact of Winter Harshness and Post-Winter Body Condition on Spring-Fattening in a Migratory Goose Species.
Environmental conditions at one point of the annual cycle of migratory species may lead to cross-seasonal effects affecting fitness in subsequent seasons. Based on a long-term mark-resighting dataset and scoring of body condition in an arctic breeding goose species, we demonstrate a substantial effect of winter harshness on post-winter body condition. However, this effect was compensated along the spring migration corridor, and did not persist long enough to influence future reproduction. This highlights the importance of temporal scale when assessing impacts of environmental effects, and suggests a state-dependent physiological mechanism adjusting energy accumulation according to internal energy stores carried into spring. In support of these findings, the development of body condition was unaffected by whether geese used supplementary feeding sites or not. While there was no effect of winter harshness on the average population pre-breeding body condition, individual variations in early spring body condition (probably related to different life-histories) were partly traceable throughout spring. This strongly indicates a carry-over effect on the individual level, possibly related to differences in dominance, site use, disturbance or migration strategy, which may potentially affect future reproduction.


An inducer of molluscan metamorphosis transforms activity patterns in a larval nervous system.
Larvae of the nudibranch mollusc Phestilla sibogae metamorphose in response to a small organic compound released into seawater by their adult prey, the scleractinian coral Porites compressa. The transformations that occur during metamorphosis, including loss of the ciliated velum (swimming organ), evacuation of the shell, and bodily elongation, are thought to be controlled by a combination of neuronal and neuroendocrine activities. Activation of peripheral chemosensory neurons by the metamorphosis-inducing compound should therefore elicit changes within the central nervous system. We used extracellular recording techniques in an attempt to detect responses of neurons within the larval central ganglia to seawater conditioned by P. compressa, to seawater conditioned by the weakly inductive coral Pocillopora damicornis, and to non-inductive seawater controls. The activity patterns within the nervous systems of semi-intact larvae changed in response to both types of coral exudates. Changes took place in two size classes of action potentials, one of which is known to be associated with velar ciliary arrests.


Lessons on malaria control in the ethnic minority regions in Northern Myanmar along the China border, 2007-2014.
For many countries where malaria is endemic, the burden of malaria is high in border regions. In ethnic minority areas along the Myanmar-China border, residents have poor access to medical care for diagnosis and treatment, and there have been many malaria outbreaks in such areas. Since 2007, with the support of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM), a malaria control project was introduced to reduce the malaria burden in several ethnic minority regions. A malaria control network was established during the period from 2007 to 2014. Multiple malaria interventions, including diagnosis, treatment, distribution of LLINs and health education, were conducted to improve the accessibility and quality of malaria control services for local residents. Annual cross-sectional surveys were conducted to evaluate intervention coverage and indicators of malaria transmission. In ethnic minority regions where a malaria control network was established, both the annual malaria incidence (19.1 per thousand per year, in 2009; 8.7, in 2014) and malaria prevalence (13.6 % in 2008; 0.43 % in 2014) decreased dramatically during the past 5-6 years. A total of 851 393 febrile patients were detected, 202 598 malaria cases (including confirmed cases and suspected cases) were treated, and 759 574 LLINs were delivered to populations at risk. Of households in 2012, 73.9 % had at least one ITNs/LLINs (vs. 28.3 %, in 2008), and 50.7 % of children less than 5 years and 50.3 % of pregnant women slept under LLINs the night prior to their visit. Additionally, malaria knowledge was improved in 68.4 % of residents. There has been great success in improving malaria control in these regions from 2007 to 2014. Malaria burdens have decreased, especially in KOK and WA. The continued maintenance of sustainable malaria control networks in these regions may be a long-term process, due to regional conflicts and the lack of funds, technology, and health workers. Furthermore, information and scientific support from the international community should be offered to these ethnic minority regions to uphold recent achievements.


Band gap of hexagonal 2D photonic crystals with elliptical holes recorded by interference lithography.
Two-dimensional hexagonal photonic crystals can be recorded using the simple superimposition of two interference patterns rotated by 60 masculine. Such process generates high contrast masks, however, it generates elliptical cross section structures instead of cylinders. We study the PBG properties of the experimentally feasible geometries, using this technique and we demonstrate that the effect of this asymmetric shape is a reduction in the PBG map area, for TE polarization, in comparison with cylindrical structures. On the other hand, it appears a PBG for TM polarization.


Numerical analysis of natural convective heat transport of copper oxide-water nanofluid flow inside a quadrilateral vessel.
Nanofluid based heat transfer approaches have a tremendous prospect to develop novel cost-effective cooling technologies. In response to this potential development, a problem of unsteady copper oxide-water nanofluid flow and natural convective heat transfer within a quadrilateral vessel with uniform heating of bottom wall using modified Buongiorno model are investigated. The sloping wall of the vessel is maintained at constant low temperature and the uniform thermal condition on the bottom heated wall is considered, whereas the upper horizontal wall is regarded as adiabatic. The governing equations along with boundary conditions are solved using the Galerkin finite element method. Partial differential equation solver COMSOL Multiphysics with Matlab interface is used in the simulation. The results of the present problem of a certain situation as a special case have been verified by the previously published standard numerical investigations. The flow, thermal and concentration fields, local and average Nusselt number for various pertinent parameters entered into the problem have been analyzed. The time evolutions for a steady-state solution are also examined. The results show that the adjustment factor with the optimal nanoparticle volume fraction and the thermal Rayleigh number controls the optimal heat transfer. The trapezoidal vessel having higher sloping angles with the vertical axis exhibits higher heat transfer. Heat transfer decreases rapidly in 1-10 nm size nanoparticles for a nanofluid solution.


Short-term immunosuppression promotes engraftment of embryonic and induced pluripotent stem cells.
Embryonic stem cells (ESCs) are an attractive source for tissue regeneration and repair therapies because they can be differentiated into virtually any cell type in the adult body. However, for this approach to succeed, the transplanted ESCs must survive long enough to generate a therapeutic benefit. A major obstacle facing the engraftment of ESCs is transplant rejection by the immune system. Here we show that blocking leukocyte costimulatory molecules permits ESC engraftment. We demonstrate the success of this immunosuppressive therapy for mouse ESCs, human ESCs, mouse induced pluripotent stem cells (iPSCs), human induced pluripotent stem cells, and more differentiated ESC/(iPSCs) derivatives. Additionally, we provide evidence describing the mechanism by which inhibition of costimulatory molecules suppresses T cell activation. This report describes a short-term immunosuppressive approach capable of inducing engraftment of transplanted ESCs and iPSCs, providing a significant improvement in our mechanistic understanding of the critical role costimulatory molecules play in leukocyte activation.


Prevalence of viremia in human immunodeficiency virus-infected patients with renal disease.
The prevalence of viremia and its relationship to the pathogenesis of nephropathy in human immunodeficiency virus (HIV)-infected patients with renal disease is unknown. To assess the prevalence of plasma viremia in HIV-infected patients with chronic renal disease, we performed a cohort study in two urban university medical centers. Samples of blood from 11 HIV-infected patients with renal failure who were treated with hemodialysis were analyzed concurrently with control samples from three non-HIV-positive patients receiving hemodialysis treatment. Samples from four HIV-infected patients with chronic renal insufficiency were evaluated concurrently. Thirty-three HIV-infected patients with serum creatinine levels of less than 132 mumol/L (1.5 mg/dL), and trace or absent dipstick proteinuria served as controls for the population with renal disease. The patients infected with HIV were staged by CD4 cell counts and the presence of opportunistic infections. Blood samples were analyzed for plasma HIV p24 antigenemia by antigen capture enzyme-linked immunosorbent assay. Blood samples were analyzed for the presence of viremia by infection of normal stimulated peripheral blood mononuclear cell cultures with plasma samples and detection of HIV p24 antigen in culture supernatants. Two of the 11 patients treated with hemodialysis had evidence of HIV p24 antigenemia, while seven of the 11 had evidence of plasma viremia. The proportion of hemodialysis patients with detectable antigenemia and viremia was similar to that in patients with chronic renal insufficiency. A significantly greater proportion of HIV-infected patients with renal disease had plasma viremia and antigenemia, compared with HIV-infected patients without renal disease. In logistic regression analysis, race, CD4 cell count (either on a continuous scale or dichotomized at 0.2 x 10(9)/L), and treatment with zidovudine were not significantly associated with the presence of plasma viremia, but patient age and the presence of renal disease were factors independently associated with viremia. The similar proportions of HIV-infected patients with viremia in groups of patients with chronic renal insufficiency and with renal disease treated with hemodialysis suggest that dialysis treatment does not increase the prevalence of plasma viremia in HIV-infected patients with renal disease. The similar proportions of HIV-infected hemodialyzed patients and patients with chronic renal insufficiency with plasma viremia, and the greater prevalence of viremia in patients with renal disease compared with HIV-infected patients without clinical renal disease suggest that plasma viremia and renal dysfunction are related. Whether this represents a cause and effect relationship is unknown. The greater prevalence of viremia in HIV-infected patients with renal disease has implications for the pathogenesis of HIV-related renal diseases and for caregivers in clinical settings and dialysis units.


The genetics of the repair of 5-azacytidine-mediated DNA damage in the fission yeast Schizosaccharomyces pombe.
We have recently demonstrated that Schizosaccharomyces pombe cells treated with the nucleoside analogue 5-azacytidine (5-azaC) require previously characterised G2 checkpoint mechanisms for survival. Here we present a survey of known DNA repair mutations which defines those genes required for survival in the presence of 5-azaC. Using a combination of single-mutant and epistasis analyses we find that the excision, mismatch and recombinational repair pathways are all required in some degree for the repair of 5-azaC-mediated DNA damage. There are distinct differences in the epistatic interactions of several of the repair mutations with respect to 5-azaC-mediated DNA damage relative to UV-mediated DNA damage.


Private sector engagement and contributions to immunisation service delivery and coverage in Sudan.
For more than two decades, the private sector in the Sudan (henceforth, Sudan), including non-governmental organisations and for-profit providers, has played a key role in delivering immunisation services, especially in the conflict-affected Darfur region and the most populated Khartoum state. The agreements that the providers enter into with state governments necessitate that they are licenced; follow the national immunisation policy and reporting and supervision requirements; use the vaccines supplied by government; and offer vaccinations free-of-charge. These private providers are well integrated into the states' immunisation programmes as they take part in the Ministry of Health immunisation trainings and district review meetings and they are incorporated into annual district immunisation microplans. The purpose of this article is to describe the private sector contributions to equitable access to immunisation services and coverage, as well as key challenges, lessons learned and future considerations. Fifty-five per cent of private health facilities in Sudan (411 out of 752) provide immunisation services, with 75% (307 out of 411) based in Khartoum state and the Darfur region. In 2017, private providers administered around 16% of all third doses of pentavalent (diphtheria, pertussis, tetanus, hepatitis B and Haemophilus influenzae type b) vaccines to children. Private health providers of immunisation services have especially been critical in filling the gaps in government services in hard-to-reach or conflict-affected areas and among marginalised populations, and thus in reducing inequities in access. Through its experience in engaging the private sector, Sudan has learned the importance of regulating and licencing private facilities and incorporating them into the immunisation programme's decision-making, planning, regular evaluation and supervision system to ensure their compliance with immunisation guidelines and the overall quality of services. In moving forward, strategic engagement with the private sector will become more prominent as Sudan transitions out of donors' financial assistance with its projected income growth.


Complete heart block and severe aortic incompetence in relapsing polychondritis: clinicopathologic findings.
We describe a patient with relapsing polychondritis who developed fatal cardiac involvement comprising complete heart block, acute aortic incompetence, and cardiovascular collapse. Pathologic studies showed fibrosis of the cardiac conducting system and necrotizing inflammation of the aortic valve, features not previously described in relapsing polychondritis, as well as evidence of coronary artery vasculitis.


Signal transduction of platelet-induced liver regeneration and decrease of liver fibrosis.
Platelets contain three types of granules: alpha granules, dense granules, and lysosomal granules. Each granule contains various growth factors, cytokines, and other physiological substances. Platelets trigger many kinds of biological responses, such as hemostasis, wound healing, and tissue regeneration. This review presents experimental evidence of platelets in accelerating liver regeneration and improving liver fibrosis. The regenerative effect of liver by platelets consists of three mechanisms; i.e., the direct effect on hepatocytes, the cooperative effect with liver sinusoidal endothelial cells, and the collaborative effect with Kupffer cells. Many signal transduction pathways are involved in hepatocyte proliferation. One is activation of Akt and extracellular signal-regulated kinase (ERK)1/2, which are derived from direct stimulation from growth factors in platelets. The other is signal transducer and activator of transcription-3 (STAT3) activation by interleukin (IL)-6 derived from liver sinusoidal endothelial cells and Kupffer cells, which are stimulated by contact with platelets during liver regeneration. Platelets also improve liver fibrosis in rodent models by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cyclic adenosine monophosphate (cyclic AMP) is increased by adenosine through its receptors on hepatic stellate cells, resulting in inactivation of these cells. Adenosine is produced by the degradation of adenine nucleotides such as adenosine diphosphate (ADP) and adenosine tri-phosphate (ATP), which are stored in abundance within the dense granules of platelets.


The Roots of Linguistic Organization in a New Language.
It is possible for a language to emerge with no direct linguistic history or outside linguistic influence. Al-Sayyid Bedouin Sign Language (ABSL) arose about 70 years ago in a small, insular community with a high incidence of profound prelingual neurosensory deafness. In ABSL, we have been able to identify the beginnings of phonology, morphology, syntax, and prosody. The linguistic elements we find in ABSL are not exclusively holistic, nor are they all compositional, but a combination of both. We do not, however, find in ABSL certain features that have been posited as essential even for a proto-language. ABSL has a highly regular syntax as well as word-internal compounding, also highly regular but quite distinct from syntax in its patterns. ABSL, however, has no discernable word-internal structure of the kind observed in more mature sign languages: no spatially organized morphology and no evident duality of phonological patterning.


The Socioeconomic Benefit to Individuals of Achieving the 2020 Targets for Five Preventive Chemotherapy Neglected Tropical Diseases.
Lymphatic filariasis (LF), onchocerciasis, schistosomiasis, soil-transmitted helminths (STH) and trachoma represent the five most prevalent neglected tropical diseases (NTDs). They can be controlled or eliminated by means of safe and cost-effective interventions delivered through programs of Mass Drug Administration (MDA)-also named Preventive Chemotherapy (PCT). The WHO defined targets for NTD control/elimination by 2020, reinforced by the 2012 London Declaration, which, if achieved, would result in dramatic health gains. We estimated the potential economic benefit of achieving these targets, focusing specifically on productivity and out-of-pocket payments. Productivity loss was calculated by combining disease frequency with productivity loss from the disease, from the perspective of affected individuals. Productivity gain was calculated by deducting the total loss expected in the target achievement scenario from the loss in a counterfactual scenario where it was assumed the pre-intervention situation in 1990 regarding NTDs would continue unabated until 2030. Economic benefits from out-of-pocket payments (OPPs) were calculated similarly. Benefits are reported in 2005 US$ (purchasing power parity-adjusted and discounted at 3% per annum from 2010). Sensitivity analyses were used to assess the influence of changes in input parameters. The economic benefit from productivity gain was estimated to be I$251 billion in 2011-2020 and I$313 billion in 2021-2030, considerably greater than the total OPPs averted of I$0.72 billion and I$0.96 billion in the same periods. The net benefit is expected to be US$ 27.4 and US$ 42.8 for every dollar invested during the same periods. Impact varies between NTDs and regions, since it is determined by disease prevalence and extent of disease-related productivity loss. Achieving the PCT-NTD targets for 2020 will yield significant economic benefits to affected individuals. Despite large uncertainty, these benefits far exceed the investment required by governments and their development partners within all reasonable scenarios. Given the concentration of the NTDs among the poorest households, these investments represent good value for money in efforts to share the world's prosperity and reduce inequity.


Mortality rates after subarachnoid hemorrhage: variations according to hospital case volume in 18 states.
The goal of this study was to determine whether a hospital's volume of subarachnoid hemorrhage (SAH) cases affects mortality rates in patients with SAH. For certain serious illnesses and surgical procedures, outcome has been associated with hospital case volume. Subarachnoid hemorrhage, usually resulting from a ruptured cerebral aneurysm, yields a high mortality rate. There has been no multistate study of a diverse set of hospitals to determine whether in-hospital mortality rates are influenced by hospital volume of SAH cases. The authors conducted an analysis of a retrospective, administrative database of 16,399 hospitalizations for SAH (9290 admitted through emergency departments). These hospitalizations were from acute-care hospitals in 18 states representing 58% of the US population. Both univariate and multivariate analyses were used to assess the case volume-mortality rate relationship. The authors used patient age, sex, Medicaid status, hospital region, data source year, hospital case volume quartile, and a comorbidity index in multivariate generalized estimating equations to model the relationship between hospital volume and mortality rates after SAH. Patients with SAH who were treated in hospitals in which low volumes of patients with SAH are admitted through the emergency department had 1.4 times the odds of dying in the hospital (95% confidence interval 1.2-1.6) as patients admitted to high-volume hospitals after controlling for patient age, sex, Medicaid status, hospital region, database year, and comorbid conditions. Patients with a diagnosis of SAH on their discharge records who initially presented through the emergency department of a hospital with a high volume of SAH cases had significantly lower mortality rates. Concentrating care for this disease in high-volume SAH treatment centers may improve overall survival.


Mass treatment with single-dose azithromycin for yaws.
Mass treatment with azithromycin is a central component of the new World Health Organization (WHO) strategy to eradicate yaws. Empirical data on the effectiveness of the strategy are required as a prerequisite for worldwide implementation of the plan. We performed repeated clinical surveys for active yaws, serologic surveys for latent yaws, and molecular analyses to determine the cause of skin ulcers and identify macrolide-resistant mutations before and 6 and 12 months after mass treatment with azithromycin on a Papua New Guinean island on which yaws was endemic. Primary-outcome indicators were the prevalence of serologically confirmed active infectious yaws in the entire population and the prevalence of latent yaws with high-titer seroreactivity in a subgroup of children 1 to 15 years of age. At baseline, 13,302 of 16,092 residents (82.7%) received one oral dose of azithromycin. The prevalence of active infectious yaws was reduced from 2.4% before mass treatment to 0.3% at 12 months (difference, 2.1 percentage points; P<0.001). The prevalence of high-titer latent yaws among children was reduced from 18.3% to 6.5% (difference, 11.8 percentage points; P<0.001) with a near-absence of high-titer seroreactivity in children 1 to 5 years of age. Adverse events identified within 1 week after administration of the medication occurred in approximately 17% of the participants, included nausea, diarrhea, and vomiting, and were mild in severity. No evidence of emergence of resistance to macrolides against Treponema pallidum subspecies pertenue was seen. The prevalence of active and latent yaws infection fell rapidly and substantially 12 months after high-coverage mass treatment with azithromycin, with the reduction perhaps aided by subsequent activities to identify and treat new cases of yaws. Our results support the WHO strategy for the eradication of yaws. (Funded by Newcrest Mining and International SOS; YESA-13 ClinicalTrials.gov number, NCT01955252.).


Effects of high-pressure processing on in vitro infectivity of Encephalitozoon cuniculi.
High-pressure processing (HPP) has been shown to be an effective means of eliminating bacteria and destructive enzymes from a variety of food products. HPP extends the shelf life of products while maintaining the sensory features of food and beverages. In this study, we examined the effects of HPP on the infectivity of Encephalitozoon cuniculi spores in vitro. Spores were exposed to between 140 and 550 MPa for 1 min in a commercial HPP unit. Following treatment, the spores were loaded onto cell culture flasks or were kept for examination by transmission electron microscopy. No effect was observed on the infectivity of spores treated with 140 MPa. Spores treated with between 200 and 275 MPa showed reduction in infectivity. Following treatment of 345 MPa or more, spores were unable to infect host cells. No morphologic changes were observed in pressure-treated spores with transmission electron microscopy.


Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB.
Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC) with constitutive NF-κB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-κB activity as well as modulating the Bcl-2 family proteins. We examined the efficacy of celastrol both in vitro and in vivo, and evaluated the role of NF-κB in celastrol-mediated AIPC regression. We found that celastrol inhibited cell proliferation in all three AIPC cell lines (PC-3, DU145 and CL1), with IC₅₀ in the range of 1-2 µM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as evidenced by increased sub-G1 population, caspase activation and PARP cleavage. Moreover, celastrol promoted cleavage of the anti-apoptotic protein Mcl-1 and activated the pro-apoptotic protein Noxa. In addition, celastrol rapidly blocked cytosolic IκBα degradation and nuclear translocation of RelA. Likewise, celastrol inhibited the expression of multiple NF-κB target genes that are involved in proliferation, invasion and anti-apoptosis. Celastrol suppressed AIPC tumor progression by inhibiting proliferation, increasing apoptosis and decreasing angiogenesis, in PC-3 xenograft model in nude mouse. Furthermore, increased cellular IκBα and inhibited expression of various NF-κB target genes were observed in tumor tissues. Our data suggest that, via targeting the proteasome, celastrol suppresses proliferation, invasion and angiogenesis by inducing the apoptotic machinery and attenuating constitutive NF-κB activity in AIPC both in vitro and in vivo. Celastrol as an active ingredient of traditional herbal medicine could thus be developed as a new therapeutic agent for hormone-refractory prostate cancer.


The role of concussion history and gender in recovery from soccer-related concussion.
This study was designed to investigate differences in recovery in male and female soccer athletes. Soccer players with a history of concussion will perform worse on neurocognitive testing than players without a history of concussion. Furthermore, female athletes will demonstrate poorer performance on neurocognitive testing than male athletes. Cohort study (prognosis): Level of evidence, 2. Computer-based neuropsychological testing using reaction time, memory, and visual motor-speed composite scores of the ImPACT test battery was performed postconcussion in soccer players ranging in age from 8 to 24 years (N = 234; 141 females, 93 males). A multivariate analysis of variance was conducted to examine group differences in neurocognitive performance between male and female athletes with and without a history of concussion. Soccer players with a history of at least 1 previous concussion performed significantly worse on ImPACT than those who had not sustained a prior concussion (F = 2.92, P =.03). In addition, female soccer players performed worse on neurocognitive testing (F = 2.72, P =.05) and also reported more symptoms (F = 20.1, P =.00001) than male soccer players. There was no significant difference in body mass index between male and female players (F =.04, P =.85). A history of concussion and gender may account for significant differences in postconcussive neurocognitive test scores in soccer players and may play a role in determining recovery. These differences do not appear to reflect differences in mass between genders and may be related to other gender-specific factors that deserve further study.


Ferrate(vi) initiated oxidative degradation mechanisms clarified by DFT calculations: a case for sulfamethoxazole.
Ferrate(vi) is an efficient and environmentally friendly oxidant for the degradation of organic micropollutants. However, the related mechanism for the degradation is ambiguous and can hardly be elucidated empirically due to the rapid oxidation process and unstable intermediates for experimental trapping. Herein we performed density function theory (DFT) calculations to unveil the mechanism of ferrate(vi)-mediated degradation, taking sulfamethoxazole as a model compound. The results show that nucleophilic attack (rather than electrophilic attack) of HFeO4- on the isoxazole moiety of sulfamethoxazole initiates the subsequent degradations, and ferrate(vi) rather than the water molecule provides O atoms for the oxidation of the nitroso group and isoxazole moiety. Electron delocalization from the Fe atom to the isoxazole moiety is crucial for the ring-opening of isoxazole, and organometallic intermediates suggested previously are not the necessary ones in the oxidation of sulfamethoxazole by HFeO4-. Thus, this study has theoretically clarified the ferrate(vi) oxidation mechanisms for a representative sulfonamide, which were also partially corroborated by the intermediates and products observed in the previous experimental studies for phosphite and tryptophan. This study provides an exemplification on the application of quantum chemical calculations to clarify the degradation pathways of organic micropollutants, which is important for the prediction of degradation products needed in their engineering design.


Global monitoring of wetlands--the value of ENVISAT ASAR Global mode.
This paper elaborates on recent advances in the use of ScanSAR technologies for wetland-related research. Applications of active satellite radar systems include the monitoring of inundation dynamics as well as time series analyses of surface soil wetness. For management purposes many wetlands, especially those in dry regions, need to be monitored for short and long-term changes. Another application of these technologies is monitoring the impact of climate change in permafrost transition zones where peatlands form one of the major land cover types. Therefore, examples from boreal and subtropical environments are presented using the analysed ENVISAT ASAR Global mode (GM, 1 km resolution) data acquired in 2005 and 2006. In the case of the ENVISAT ASAR instrument, data availability of the rather coarse Global Mode depends on request priorities of other competing modes, but acquisition frequency may still be on average fortnightly to monthly depending on latitude. Peatland types covering varying permafrost regimes of the West Siberian Lowlands can be distinguished from each other and other land cover by multi-temporal analyses. Up to 75% of oligotrophic bogs can be identified in the seasonal permafrost zone in both years. The high seasonal and inter-annual dynamics of the subtropic Okavango Delta can also be captured by GM time series. Response to increased precipitation in 2006 differs from flood propagation patterns. In addition, relative soil moisture maps may provide a valuable data source in order to account for external hydrological factors of such complex wetland ecosystems.


Light-scattering technique for the study of orientation and deformation of red blood cells in a concentrated suspension.
The backscattered and transmitted diagrams of He-Ne laser light illuminating a concentrated suspension of red blood cells (RBC's) are investigated. The shapes of these diagrams are closely related to the state of the suspension (at rest or submitted to a simple shear flow) and to the parameters that govern the non-Newtonian behavior of the blood suspension (such as the viscosity of the suspending medium and the volume concentration of the cells). An asymmetry in the backscattering diagram, which is absent on transmitted diagrams, is observed when the suspension is in a simple shear flow. This asymmetry is related to the deformation and orientation of the RBC's. The propagation of light through the suspension is modeled and a set of Monte Carlo simulations is performed to substantiate the inference that the relative variation of the backscattered flux is proportional to the gradients of deformation of the RBC's, and that such gradients must be known in order to apply a rheological model describing the non-Newtonian behavior of RBC membranes.


In Vitro and in Vivo Effect of MAPK Signal Transduction Pathway Inhibitors on Echinococcus multilocularis.
To evaluate the effect of mitogen-activated protein kinase (MAPK) signal transduction pathway inhibitors against alveolar echinococcosis in vitro and in vivo, Echinococcus multilocularis metacestode cysts and protoscolices were obtained from infected mice. Protein chip technology was utilized to screen for key highly expressed target proteins in the MAPK pathway in this parasite and their corresponding inhibitors. Four-week-old Balb/c female mice used for the in vivo experiment underwent inoculation of E. multilocularis by intraperitoneal injection, as well as intragastric administration of MAPK inhibitors for 6 wk. We included 6 groups of mice: a phosphate-buffered saline (PBS) group (negative control); an albendazole-treated group (positive group); and 4 experimental groups treated with TRx0237 mesylate, GDC-0994, pifithrin-β hydrobromide, or Selonsertib. Echinococcus multilocularis protoscolices were collected and cultured in 1066 medium with penicillin/streptomycin and 10% fetal bovine serum. The in vitro experiment included a PBS group (negative control), a dimethyl sulfoxide-treated group (solvent group), and 4 inhibitor-treated groups as in the in vivo experiment (experimental groups). Each inhibitor group received 4 drug concentrations (5, 30, 55, and 80 μM), and the experiment was performed in triplicate per sample. Fluorescence microscopy was used to evaluate the survival rate of the protoscolices every 48 hr beginning from the first 24 hr. The same grouping was used to evaluate cytotoxicity on E. multilocularis germinal cells and L02 cells. The average weights of E. multilocularis metacestode cyst tissue from each group of the in vivo experiment were 873 mg (PBS), 335 mg (albendazole), 323 mg (TRx0237 mesylate), 420 mg (GDC-0994), 340 mg (pifithrin-β hydrobromide), and 642 mg (Selonsertib). Results showed albendazole, TRx0237 mesylate, and pifithrin-β hydrobromide had significant inhibitory effects on inhibition of E. multilocularis. We found a positive correlation between drug concentrations and the inhibitory effects seen in the in vitro experiment, with the differences in contrast with the control group becoming statistically significant after 72 hr of treatment ( P < 0.05). The inhibition rates of TRx0237 mesylate to germinal cells by drug concentration were 23.73, 46.59, 74.71, and 77.44%. Other drugs had no effect on germinal cells. All the inhibitors had low toxicity on L02 cells. Inhibitors of the MAPK signal transduction pathway showed significant inhibitory effects on E. multilocularis, suggesting these may be potential candidates for the treatment of alveolar echinococcosis.


Increased primary non-function in transplanted deceased-donor kidneys flushed with histidine-tryptophan-ketoglutarate solution.
Histidine-Tryptophan-Ketoglutarate (HTK) solution is increasingly used to flush and preserve organ donor kidneys, with efficacy claimed equivalent to University of Wisconsin (UW) solution. We observed and reported increased graft pancreatitis in pancreata flushed with HTK solution, which prompted this review of transplanting HTK-flushed kidneys. We analyzed outcomes of deceased-donor kidneys flushed with HTK and UW solutions with a minimum of 12 months follow-up, excluding pediatric and multi-organ recipients. We evaluated patient and graft survival and rejection rates, variables that might constitute hazards to graft survival and renal function. Two-year patient survival, rejection, renal function and graft survival were not different, but early graft loss (<6 months) was worse in HTK-flushed kidneys (p < 0.03). A Cox analysis of donor grade, cold ischemic time, panel reactive antibodies (PRA), donor race, first vs. repeat transplant, rejection and flush solution showed that only HTK use predicted early graft loss (p < 0.04; relative risk = 3.24), almost exclusively attributable to primary non-function (HTK, n = 5 (6.30%); UW, n = 1 (0.65%); p = 0.02). Delayed graft function and early graft loss with HTK occurred only in lesser grade kidneys, suggesting it should be used with caution in marginal donors.


Biologically based computational models of high-level cognition.
Computer models based on the detailed biology of the brain can help us understand the myriad complexities of human cognition and intelligence. Here, we review models of the higher level aspects of human intelligence, which depend critically on the prefrontal cortex and associated subcortical areas. The picture emerging from a convergence of detailed mechanistic models and more abstract functional models represents a synthesis between analog and digital forms of computation. Specifically, the need for robust active maintenance and rapid updating of information in the prefrontal cortex appears to be satisfied by bistable activation states and dynamic gating mechanisms. These mechanisms are fundamental to digital computers and may be critical for the distinctive aspects of human intelligence.


Manipulation of a spider peptide toxin alters its affinity for lipid bilayers and potency and selectivity for voltage-gated sodium channel subtype 1.7.
Huwentoxin-IV (HwTx-IV) is a gating modifier peptide toxin from spiders that has weak affinity for the lipid bilayer. As some gating modifier toxins have affinity for model lipid bilayers, a tripartite relationship among gating modifier toxins, voltage-gated ion channels, and the lipid membrane surrounding the channels has been proposed. We previously designed an HwTx-IV analogue (gHwTx-IV) with reduced negative charge and increased hydrophobic surface profile, which displays increased lipid bilayer affinity and in vitro activity at the voltage-gated sodium channel subtype 1.7 (NaV1.7), a channel targeted in pain management. Here, we show that replacements of the positively-charged residues that contribute to the activity of the peptide can improve gHwTx-IV's potency and selectivity for NaV1.7. Using HwTx-IV, gHwTx-IV, [R26A]gHwTx-IV, [K27A]gHwTx-IV, and [R29A]gHwTx-IV variants, we examined their potency and selectivity at human NaV1.7 and their affinity for the lipid bilayer. [R26A]gHwTx-IV consistently displayed the most improved potency and selectivity for NaV1.7, examined alongside off-target NaVs, compared with HwTx-IV and gHwTx-IV. The lipid affinity of each of the three novel analogues was weaker than that of gHwTx-IV, but stronger than that of HwTx-IV, suggesting a possible relationship between in vitro potency at NaV1.7 and affinity for lipid bilayers. In a murine NaV1.7 engagement model, [R26A]gHwTx-IV exhibited an efficacy comparable with that of native HwTx-IV. In summary, this study reports the development of an HwTx-IV analogue with improved in vitro selectivity for the pain target NaV1.7 and with an in vivo efficacy similar to that of native HwTx-IV.


Haploinsufficiency of the cdc2l gene contributes to skin cancer development in mice.
The Cdc2L gene encodes for the cyclin-dependent kinase 11 (CDK11) protein. Loss of one allele of Cdc2L and reduced CDK11 expression has been observed in several cancers, implicating its association with carcinogenesis. To directly investigate the role of CDK11 in carcinogenesis, we first generated cdc2l haploinsufficient mice by gene trap technology and then studied the susceptibility of these gene-trapped (cdc2l(GT)) mice to chemical-mediated skin carcinogenesis in the 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis model. Wild-type and cdc2l(GT) mice were subjected to a single topical application of initiation by DMBA and promotion twice a week for 19 weeks with TPA. At 19 weeks, 70% of the cdc2l(GT) mice and 60% of the cdc2l+/+ mice developed benign papillomas. However, there was an overall 3-fold increase in the average number of tumors per mouse observed in cdc2l(GT) mice as compared with cdc2l+/+ mice. There was also an increased frequency of larger papillomas in cdc2l(GT) mice. By using the polymerase chain reaction-restriction fragment length polymorphism assay, we found A to T transversion mutations at the 61st codon of H-ras gene in the papilloma tissue of both cdc2l(GT) mice and cdc2l+/+ mice. Ki-67 staining revealed increased proliferation in the papillomas of cdc2l(GT) (77.75%) as compared with cdc2l+/+ (30.84%) tumors. These studies are the first to show that loss of one allele of cdc2l gene, encoding CDK11, facilitates DMBA/TPA-induced skin carcinogenesis in vivo.


Double-dot quantum ratchet driven by an independently biased quantum point contact.
We study a double quantum dot (DQD) coupled to a strongly biased quantum point contact (QPC), each embedded in independent electric circuits. For weak interdot tunneling we observe a finite current flowing through the Coulomb blockaded DQD in response to a strong bias on the QPC. The direction of the current through the DQD is determined by the relative detuning of the energy levels of the two quantum dots. The results are interpreted in terms of a quantum ratchet phenomenon in a DQD energized by a nearby QPC.


Subcellular fractionation of human neutrophils and analysis of subcellular markers.
The neutrophil has long been recognized for its impressive number of cytoplasmic granules that harbor proteins indispensable for innate immunity. Analysis of isolated granules has provided important information on how the neutrophil grades its response to match the challenges it meets on its passage from blood to tissues. Nitrogen cavitation was developed as a method for disruption of cells on the assumption that sudden reduction of the partial pressure of nitrogen would lead to aeration of nitrogen dissolved in the lipid bilayer of plasma membranes. We find that cells are broken by the shear stress that is associated with passage through the outlet valve under high pressure and that this results in disruption of the neutrophil cell membrane while granules remain intact. The unique properties of Percoll as a sedimentable density medium with no inherent tonicity or viscosity are used for creation of continuous density gradients with shoulders in the density profile created to optimize the physical separation of granule subsets and light membranes. Immunological methods (sandwich enzyme-linked immunosorbent assays) are used for quantitation of proteins that are characteristic constituents of the granule subsets of neutrophils.


Hyperchloremia Is Associated With Acute Kidney Injury in Patients With Subarachnoid Hemorrhage.
To assess the prevalence of acute kidney injury in patients with subarachnoid hemorrhage patients. Retrospective analysis of all subarachnoid hemorrhage admissions. Neurocritical care unit. All patients with a diagnosis of subarachnoid hemorrhage between 2009 and 2014. None. Of 1,267 patients included in this cohort, 16.7% developed acute kidney injury, as defined by Kidney Disease Improving Global Outcome criteria (changes in creatinine only). Compared to patients without acute kidney injury, patients with acute kidney injury had a higher prevalence of diabetes mellitus (21.2% vs 9.8%; p < 0.001) and hypertension (70.3% vs 50.5%; p < 0.001) and presented with higher admission creatinine concentrations (1.21 ± 0.09 vs 0.81 ± 0.01 mg/dL [mean ± SD], respectively; p < 0.001). Patients with acute kidney injury also had higher mean serum chloride and sodium concentrations during their ICU stay (113.4 ± 0.6 vs 107.1 ± 0.2 mmol/L and 143.3 ± 0.4 vs 138.8 ± 0.1 mmol/L, respectively; p < 0.001 for both), but similar chloride exposure. The mortality rate was also significantly higher in patients with acute kidney injury (28.3% vs 6.1% in the non-acute kidney injury group [p < 0.001]). Logistic regression analysis revealed that only male gender (odds ratio, 1.82; 95% CI, 1.28-2.59), hypertension (odds ratio, 1.64; 95% CI, 1.11-2.43), diabetes mellitus (odds ratio, 1.88; 95% CI, 1.19-2.99), abnormal baseline creatinine (odds ratio, 2.48; 95% CI, 1.59-3.88), and increase in mean serum chloride concentration (per 10 mmol/L; odds ratio, 7.39; 95% CI, 3.44-18.23), but not sodium, were associated with development of acute kidney injury. Kidney recovery was noted in 78.8% of the cases. Recovery reduced mortality compared to non-recovering subgroup (18.6% and 64.4%, respectively; p < 0.001). Critically ill patients with subarachnoid hemorrhage show a strong association between hyperchloremia and acute kidney injury as well as acute kidney injury and mortality.


Influence of freezing rate on pore structure in freeze-dried collagen-GAG scaffolds.
The cellular structure of collagen-glycosaminoglycan (CG) scaffolds used in tissue engineering must be designed to meet a number of constraints with respect to biocompatibility, degradability, pore size, pore structure, and specific surface area. The conventional freeze-drying process for fabricating CG scaffolds creates variable cooling rates throughout the scaffold during freezing, producing a heterogeneous matrix pore structure with a large variation in average pore diameter at different locations throughout the scaffold. In this study, the scaffold synthesis process was modified to produce more homogeneous freezing by controlling of the rate of freezing during fabrication and obtaining more uniform contact between the pan containing the CG suspension and the freezing shelf through the use of smaller, less warped pans. The modified fabrication technique has allowed production of CG scaffolds with a more homogeneous structure characterized by less variation in mean pore size throughout the scaffold (mean: 95.9 microm, CV: 0.128) compared to the original scaffold (mean: 132.4 microm, CV: 0.185). The pores produced using the new technique appear to be more equiaxed, compared with those in scaffolds produced using the original technique.


Signal transduction molecules as targets for cancer prevention.
Environmental and life-style aspects are major contributors to human carcinogenesis and, therefore, many human cancers may be preventable. Cancer is the end result of defects in cellular signaling processes that play a key role in the control of cell growth, survival, division, and differentiation. Therefore, identifying molecular and cellular targets critical in cancer development and prevention is an area of intensive research, driving the development of highly specific small-molecule inhibitors. A major idea today is that cancer may be prevented or treated by targeting the products of specific cancer-related genes, frequently encoding signaling proteins or transcription factors. Participants in these joint conferences discussed their latest findings in the identification of promising molecular targets and the development of agents directed against these targets with the goal of effectively transitioning these into the clinical setting.


The epidemiology and household distribution of seroreactivity to Trypanosoma cruzi in a rural community in northeast Brazil.
The prevalence rates and household distribution of seroreactivity to Trypanosoma cruzi by complement fixation (CF) and indirect immunofluorescent antibody methods were determined in a population of 1,087 persons living in a rural area endemic for Chagas' disease in northeast Brazil. There was a gradual rise in the rate of seropositivity to 60% by age 20. Between ages 20 and 55 the prevalence rate remained at about 60%, but declined thereafter. The decline in the older age groups was not accompanied by a fall in geometric mean titer, suggesting that the decline might better be explained by an increased mortality among those seropositive than by a decrease in CF reactivity associated with age. There was variation in the rates of seropositivity in children among the geographic subunits, but the rates among adults were fairly uniform. Household clustering of seropositivity was demonstrated when both household size and age distribution were taken into account. The presence of a seropositive child less than 5 years of age was a good indicator of a household with a high rate of seropositivity; screening for young seropositive children might be a useful tool to locate high risk households. Seropositive children in households where the mother was seropositive but the father seronegative were significantly younger than seropositive children in households where the father was seropositive but the mother seronegative even though the age distribution and the overall rate of seropositivity in both groups of children were similar; thus, conversion to seropositivity earlier in life in children of seropositive mothers may not be due solely to increased exposure, but may indicate that the immunologic response in such children differed from that of children from seronegative mothers.


Adapting to the global shortage of cholera vaccines: targeted single dose cholera vaccine in response to an outbreak in South Sudan.
Shortages of vaccines for epidemic diseases, such as cholera, meningitis, and yellow fever, have become common over the past decade, hampering efforts to control outbreaks through mass reactive vaccination campaigns. Additionally, various epidemiological, political, and logistical challenges, which are poorly documented in the literature, often lead to delays in reactive campaigns, ultimately reducing the effect of vaccination. In June 2015, a cholera outbreak occurred in Juba, South Sudan, and because of the global shortage of oral cholera vaccine, authorities were unable to secure sufficient doses to vaccinate the entire at-risk population-approximately 1 million people. In this Personal View, we document the first public health use of a reduced, single-dose regimen of oral cholera vaccine, and show the details of the decision-making process and timeline. We also make recommendations to help improve reactive vaccination campaigns against cholera, and discuss the importance of new and flexible context-specific dose regimens and vaccination strategies.