Physiological responses of medical team members to a simulated emergency in tropical field conditions.
Responses to physical activity while wearing personal protective equipment in hot laboratory conditions are well documented. However less is known of medical professionals responding to an emergency in hot field conditions in standard attire. Therefore, the purpose of this study was to assess the physiological responses of medical responders to a simulated field emergency in tropical conditions. Ten subjects, all of whom were chronically heat-acclimatized health care workers, volunteered to participate in this investigation. Participants were the medical response team of a simulated field emergency conducted at the Northern Territory Emergency Services training grounds, Yarrawonga, NT, Australia. The exercise consisted of setting up a field hospital, transporting patients by stretcher to the hospital, triaging and treating the patients while dressed in standard medical response uniforms in field conditions (mean ambient temperature of 29.3°C and relative humidity of 50.3%, apparent temperature of 27.9°C) for a duration of 150 minutes. Gastrointestinal temperature was transmitted from an ingestible sensor and used as the index of core temperature. An integrated physiological monitoring device worn by each participant measured and logged heart rate, chest temperature and gastrointestinal temperature throughout the exercise. Hydration status was assessed by monitoring the change between pre- and post-exercise body mass and urine specific gravity (USG). Mean core body temperature rose from 37.5°C at the commencement of the exercise to peak at 37.8°C after 75 minutes. The individual peak core body temperature was 38.5°C, with three subjects exceeding 38.0°C. Subjects sweated 0.54 L per hour and consumed 0.36 L of fluid per hour, resulting in overall dehydration of 0.7% of body mass at the cessation of exercise. Physiological strain index was indicative of little to low strain. The combination of the unseasonably mild environmental conditions and moderate work rates resulted in minimal heat storage during the simulated exercise. As a result, low sweat rates manifested in minimal dehydration. When provided with access to fluids in mild environmental conditions, chronically heat-acclimatized medical responders can meet their hydration requirements through ad libitum fluid consumption. Whether such an observation is replicated under a harsher thermal load remains to be investigated.


Reporting ethical matters in the Journal of Physiology: standards and advice.
Reporting of ethical matters in The Journal is very important. To advise and assist authors, particularly those who may be less familiar with the legislation in the UK, this article sets out the basic principles and methods that should be used and provides many key web sources of information. It addresses the structure of regulations, and introduces the concept of research governance. The UK law is summarized. Advice is given on the format and description of experiments, and common problems addressed. Aspects of human studies are addressed. Ethical considerations of publication such as authorship and originality, and problems such as plagiarism and fabrication are described. Updates will be published regularly.


Surface T cell Fas receptor/CD95 regulation, in vivo activation, and apoptosis. Activation-induced death can occur without Fas receptor.
Fas-mediated apoptosis is a form of cell death that operates through a receptor-ligand interaction. The FasR has been implicated directly in peripheral T cell tolerance and activation-induced apoptosis of T cells in vitro, although to date its expression on murine peripheral T cells has been characterized incompletely. In this study, we document substantial expression of FasR on the vast majority of recent thymic emigrants and resting peripheral T lymphocytes. FasR ligation can induce death in a minor (approximately 5%) subset of these cells. By contrast to rather slow activation-mediated FasR up-regulation in vitro, we demonstrate that in vivo T cell activation by alpha CD3 mAb or superantigen results in rapid up-regulation of the FasR. This up-regulation is paralleled by the kinetics of activation-induced apoptosis in lymph node T cells. However, we demonstrate that the FasR is not necessary for activation-induced cell death. Lymph node T cells from young, healthy, FasR expression-deficient MRL-Ipr/Ipr and animals could be activated in vivo through the TCR-CD3 complex. Most importantly, MRL-Ipr/Ipr T cells underwent massive activation-induced apoptosis in response to high and intermediate doses of alpha CD3. At a low alpha CD3 dose, however, both MRL-Ipr/Ipr and MRL +/+ T cells were activated similarly, but only the latter underwent adequate apoptosis. Taken together, these findings suggest that in vivo, the Fas pathway may not be the only regulator of activation-induced T cell death, but that this pathway may be critical in regulating responses to weak stimuli.


Prospectives and retrospectives of microfluidics devices and lab-on-A-chip emphasis on cancer.
Microfluidics is a science and technology that deals with the concept of "less sample-to-more precision" enabling portable device development via fabrication for in vitro analysis. On evolution, microfluidic system lead to the development of Organ-on-chip where recapitulation of organ's functionality and pathophysiological response can be performed under controlled environment. Further microfluidic-based "Lab-on-chip" device, a versatile innovation credited for its number of parameters that has capability to leverage next-generation companion of medicines. This emulsion science has enormous practise in the field of regenerative medicine, drug screening, medical diagnosis and therapy for accuracy in results. In this era of personalized medicine, getting precise tools for applying these theranostics is crucial. Oncological theranostics create a new gateway to develop precision in personalized medicine for cancer, where microfluidic chips are involved in diagnosis and therapy of various cancers using biomarkers for thyroid, lung cancers, and assay based for breast, circulating tumor cells and colorectal cancers and nanoparticles for ovarian cancer. This review shows more comprehensive approach to the state of art with respect to microfluidic devices in cancer theranostics.


Refined crystal structures of human Ca(2+)/Zn(2+)-binding S100A3 protein characterized by two disulfide bridges.
S100A3, a member of the EF-hand-type Ca(2+)-binding S100 protein family, is unique in its exceptionally high cysteine content and Zn(2+) affinity. We produced human S100A3 protein and its mutants in insect cells using a baculovirus expression system. The purified wild-type S100A3 and the pseudo-citrullinated form (R51A) were crystallized with ammonium sulfate in N,N-bis(2-hydroxyethyl)glycine buffer and, specifically for postrefolding treatment, with Ca(2+)/Zn(2+) supplementation. We identified two previously undocumented disulfide bridges in the crystal structure of properly folded S100A3: one disulfide bridge is between Cys30 in the N-terminal pseudo-EF-hand and Cys68 in the C-terminal EF-hand (SS1), and another disulfide bridge attaches Cys99 in the C-terminal coil structure to Cys81 in helix IV (SS2). Mutational disruption of SS1 (C30A+C68A) abolished the Ca(2+) binding property of S100A3 and retarded the citrullination of Arg51 by peptidylarginine deiminase type III (PAD3), while SS2 disruption inversely increased both Ca(2+) affinity and PAD3 reactivity in vitro. Similar backbone structures of wild type, R51A, and C30A+C68A indicated that neither Arg51 conversion by PAD3 nor SS1 alters the overall dimer conformation. Comparative inspection of atomic coordinates refined to 2.15-1.40 Å resolution shows that SS1 renders the C-terminal classical Ca(2+)-binding loop flexible, which are essential for its Ca(2+) binding properties, whereas SS2 structurally shelters Arg51 in the metal-free form. We propose a model of the tetrahedral coordination of a Zn(2+) by (Cys)(3)His residues that is compatible with SS2 formation in S100A3.


The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart study.
The oral glucose tolerance test identifies high-risk subjects for diabetes, but it is costly and inconvenient. To find better predictors of type 2 diabetes, we evaluated two different definitions of the metabolic syndrome because insulin resistance, which is commonly associated with this clustering of metabolic factors, frequently precedes the onset of type 2 diabetes. We compared the ability of the National Cholesterol Education Program (NCEP) definition, a modified version of the 1999 World Health Organization (WHO) definition that excludes the 2-h glucose requirement, and impaired glucose tolerance (IGT) to predict incident type 2 diabetes. In the San Antonio Heart Study, 1734 participants completed a 7- to 8-year follow-up examination. IGT and the NCEP definition had higher sensitivity than the modified WHO definition (51.9, 52.8, and 42.8%, respectively). IGT had a higher positive predictive value than the NCEP and modified WHO definitions (43.0, 30.8, and 30.4%, respectively). The combination of the IGT and NCEP definitions increased the sensitivity to 70.8% with an acceptable positive predictive value of 29.7%. Risk for incidence of type 2 diabetes using the NCEP definition was independent of other risk factors, including IGT and fasting insulin (odds ratio 3.30, 95% CI 2.27-4.80). The NCEP definition performed better with fasting glucose >or=5.4 mmol/l (sensitivity 62.0% and positive predictive value 30.9%). The metabolic syndrome predicts diabetes independently of other factors. However, the NCEP definition performs better than the modified 1999 WHO definition. Lowering the fasting glucose cutoff to 5.4 mmol/l improves the prediction of diabetes by the metabolic syndrome.


Thermal-light-based ranging using second-order coherence.
A novel thermal-light-based ranging scheme utilizing second-order coherence in the time domain is proposed and studied. Such a scheme allows ultrahigh accuracy to be achieved for absolute range measurement. Besides, the scheme has the advantages of high immunity to noise and no measuring dead zone. A proof-of-principle experiment has been done, and the result shows a ±10 cm accuracy at a distance of 1 km, which is currently limited by our detectors. The accuracy can be greatly improved to the nanometer scale by using state-of-the-art detectors with an appropriate data processing algorithm.


CSTP1, a novel protein phosphatase, blocks cell cycle, promotes cell apoptosis, and suppresses tumor growth of bladder cancer by directly dephosphorylating Akt at Ser473 site.
Akt/protein kinase B is a pivotal component downstream of phosphatidylinositol 3-kinase (PI3K) pathway, whose activity regulates the balance between cell survival and apoptosis. Phosphorylation of Akt occurs at two key sites either at Thr308 site in the activation loop or at Ser473 site in the hydrophobic motif. The phosphorylated form of Akt (pAkt) is activated to promote cell survival. The mechanisms of pAkt dephosphorylation and how the signal transduction of Akt pathway is terminated are still largely unknown. In this study, we identified a novel protein phosphatase CSTP1(complete s transactivated protein 1), which interacts and dephosphorylates Akt specifically at Ser473 site in vivo and in vitro, blocks cell cycle progression and promotes cell apoptosis. The effects of CSTP1 on cell survival and cell cycle were abrogated by depletion of phosphatase domain of CSTP1 or by expression of a constitutively active form of Akt (S473D), suggesting Ser473 site of Akt as a primary cellular target of CSTP1. Expression profile analysis showed that CSTP1 expression is selectively down-regulated in non-invasive bladder cancer tissues and over-expression of CSTP1 suppressed the size of tumors in nude mice. Kaplan-Meier curves revealed that decreased expression of CSTP1 implicated significantly reduced recurrence-free survival in patients suffered from non-invasive bladder cancers.


Morphometric and histopathological evaluation of the effect of grape seed proanthocyanidin on alveolar bone loss in experimental diabetes and periodontitis.
Grape seed proanthocyanidine extract (GSPE) is a strong antioxidant derived from the grape seeds (Vitis vinifera, Terral J.F.) and has a polyphenolic structure with a wide range of biological activity. The aim of the present study was to evaluate the effects of GSPE on alveolar bone loss and histopathological changes in rats with diabetes mellitus and ligature-induced periodontitis. Forty rats were divided into 6 study groups. Control (C, 6 rats) group, periodontitis (P, 6 rats) group, diabetes (D, 6 rats) group, diabetes and periodontitis (D+P, 6 rats) group, diabetes, periodontitis and 100 mg/kg/day GSPE (GSPE-100, 8 rats), and diabetes, periodontitis and 200 mg/kg/day GSPE (GSPE-200, 8 rats) group. Diabetes mellitus was induced by intraperitoneal injection of a single dose of streptozotocin (60 mg/kg). Periodontitis was induced via ligation method. Silk ligatures were placed at the mandibular right first molars. GSPE was administered by oral gavage. After 30 days, all rats were killed. Alveolar bone loss was measured morphometrically via a stereomicroscope. For histopathological analyses, Alizarin red staining, and matrix metalloproteinase (MMP)-8, vascular endothelial growth factor and hypoxia inducible factor (HIF)-1α immunohistochemistry were performed. Tartrate-resistant acid phosphatase-positive osteoclast cells and relative total inflammatory cells were also determined. The highest alveolar bone loss was observed in the D+P group (P < .05). GSP-200 group decreased alveolar bone loss (P < .05). The D+P group had the highest osteoclast counts, but the difference was not significant compared to the P, GSPE-100 and GSPE-200 groups (P > .05). The inflammation in the D+P group was also higher than the other groups (P < .05). The osteoblast numbers increased in the GSPE-100 and GSPE-200 groups compared to the P and D+P groups (P < .05). MMP-8 and HIF-1α levels were highest in the D+P group and GSPE significantly decreased these levels (P < .05). Within the limits of this animal study, it can be suggested that GSPE administration may decrease periodontal inflammation and alveolar bone loss via decreasing MMP-8 and HIF-1α levels and increase osteoblastic activity in diabetic rats with experimental periodontitis.


Inhibition of NF-kappaB activity and enhancement of apoptosis by the neuropeptide calcitonin gene-related peptide.
Calcitonin gene-related peptide (CGRP) is a neuropeptide produced by the central and peripheral nervous systems and by endocrine cells. CGRP exerts diverse biological effects on the cardiovascular, gastrointestinal, respiratory, central nervous and immune systems. Little is known, however, about the molecular mechanisms that mediate CGRP effects. Using the NFkappaB-luciferase reporter transgenic mice, here we show that CGRP selectively inhibits NF-kappaB-mediated transcription in thymocytes in vitro and in vivo. In contrast, CGRP does not affect transcription mediated by the AP-1 and NFAT transcription factors. CGRP inhibits the accumulation of NF-kappaB complexes in the nucleus by preventing phosphorylation and degradation of the NF-kappaB inhibitor IkappaB. Inhibition of NF-kappaB activity is associated with the induction of apoptosis by CGRP in thymocytes. Together these results demonstrate for the first time the selective implication of the NF-kappaB signaling pathway in the regulatory function of the neuropeptide CGRP. Our study suggests a potential molecular mechanism by which CGRP can induce cell death in thymocytes.


[Double disposition of the major vessels from the right ventricle of the Fallot tetralogy type].
Forty-six patients with double disposition of the major vessels from the right ventricle in combination with stenosis of the pulmonary artery, in sub-aortal and bi-committed defects of the interventricular septum have undergone biventricular intraventricular correction. The most specific and accurate anatomic characteristics were: 1) position of the major vessels (particularly side-to-side); 2) location of two and a part of the third aortal sinuses above the right ventricle; 3) bilateral cone; 4) absence of aorto-mitral contact; 5) location of valves of aorta and pulmonary artery on the same level. One (2,2%) patient died during surgery due to progressed cardiac insufficiency. One (2,5%) patient died 2 years after radical correction of the defect due to progressive dysfunction of the right ventricle.


[A relationship of congenital brain malformations and tumor growth].
The peritumor-like areas of 12 cerebral hemispheric tumors were examined. Histological study revealed vascular malformations and/or congenital tissue dysplasias in all cases: cortical disorganization, neuronal heterotopy into the white matter, neural location in the molecular cortical layer, and persistence of a subpial granular cell layer. Immunohistochemical study using Ki-67 antibodies in the peritumor-like tissue dysplasias revealed proliferative activity in a number of cases. The associations of the origin of brain tumors and congenital malformations are discussed.


[Remineralizing effectiveness of desensitizing toothpastes in the prevention of dental diseases among workers with harmful working conditions].
The study of desensitizing and remineralizing effect of Sensodyn series toothpastes among 407 medical workers with harmful industrial factors was carried out. It was revealed that harmful working conditions contributed to the development of teeth hard tissues pathology of carious and non-carious origin. The investigated toothpastes eliminate hypersensitivity, stabilize the processes of demineralization and normalize the remineralization processes.


Effect of wearing an ice cooling jacket on repeat sprint performance in warm/humid conditions.
To examine the effect of cooling the skin with an ice jacket before and between exercise bouts (to simulate quarter and half time breaks) on prolonged repeat sprint exercise performance in warm/humid conditions. After an initial familiarisation session, seven trained male hockey players performed two testing sessions (seven days apart), comprising an 80 minute intermittent, repeat sprint cycling exercise protocol inside a climate chamber set at 30 degrees C and 60% relative humidity. On one occasion a skin cooling procedure was implemented (in random counterbalanced order), with subjects wearing an ice cooling jacket both before (for five minutes) and in the recovery periods (2 x 5 min and 1 x 10 min) during the test. Measures of performance (work done and power output on each sprint), heart rates, blood lactate concentrations, core (rectal) and skin temperatures, sweat loss, perceived exertion, and ratings of thirst, thermal discomfort, and fatigue were obtained in both trials. In the cooling condition, chest (torso) skin temperature, thermal discomfort, and rating of thirst were all significantly lower (p<0.05), but no significant difference (p>0.05) was observed between conditions for measures of work done, power output, heart rate, blood lactate concentration, core or mean skin temperature, perceived exertion, sweat loss, or ratings of fatigue. However, high effect sizes indicated trends to lowered lactate concentrations, sweat loss, and mean skin temperatures in the cooling condition. The intermittent use of an ice cooling jacket, both before and during a repeat sprint cycling protocol in warm/humid conditions, did not improve physical performance, although the perception of thermal load was reduced. Longer periods of cooling both before and during exercise (to lower mean skin temperature by a greater degree than observed here) may be necessary to produce such a change.


Development of Risk Prediction Models for Severe Periodontitis in a Thai Population: Statistical and Machine Learning Approaches.
Severe periodontitis affects 26% of Thai adults and 11.2% of adults globally and is characterized by the loss of alveolar bone height. Full-mouth examination by periodontal probing is the gold standard for diagnosis but is time- and resource-intensive. A screening model to identify those at high risk of severe periodontitis would offer a targeted approach and aid in reducing the workload for dentists. While statistical modelling by a logistic regression is commonly applied, optimal performance depends on feature selections and engineering. Machine learning has been recently gaining favor given its potential discriminatory power and ability to deal with multiway interactions without the requirements of linear assumptions. We aim to compare the performance of screening models developed using statistical and machine learning approaches for the risk prediction of severe periodontitis. This study used data from the prospective Electricity Generating Authority of Thailand cohort. Dental examinations were performed for the 2008 and 2013 surveys. Oral examinations (ie, number of teeth and oral hygiene index and plaque scores), periodontal pocket depth, and gingival recession were performed by dentists. The outcome of interest was severe periodontitis diagnosed by the Centre for Disease Control-American Academy of Periodontology, defined as 2 or more interproximal sites with a clinical attachment level ≥6 mm (on different teeth) and 1 or more interproximal sites with a periodontal pocket depth ≥5 mm. Risk prediction models were developed using mixed-effects logistic regression (MELR), recurrent neural network, mixed-effects support vector machine, and mixed-effects decision tree models. A total of 21 features were considered as predictive features, including 4 demographic characteristics, 2 physical examinations, 4 underlying diseases, 1 medication, 2 risk behaviors, 2 oral features, and 6 laboratory features. A total of 3883 observations from 2086 participants were split into development (n=3112, 80.1%) and validation (n=771, 19.9%) sets with prevalences of periodontitis of 34.4% (n=1070) and 34.1% (n=263), respectively. The final MELR model contained 6 features (gender, education, smoking, diabetes mellitus, number of teeth, and plaque score) with an area under the curve (AUC) of 0.983 (95% CI 0.977-0.989) and positive likelihood ratio (LR+) of 11.9 (95% CI 8.8-16.3). Machine learning yielded lower performance than the MELR model, with AUC (95% CI) and LR+ (95% CI) values of 0.712 (0.669-0.754) and 2.1 (1.8-2.6), respectively, for the recurrent neural network model; 0.698 (0.681-0.734) and 2.1 (1.7-2.6), respectively, for the mixed-effects support vector machine model; and 0.662 (0.621-0.702) and 2.4 (1.9-3.0), respectively, for the mixed-effects decision tree model. The MELR model might be more useful than machine learning for large-scale screening to identify those at high risk of severe periodontitis for periodontal evaluation. External validation using data from other centers is required to evaluate the generalizability of the model.


Laboratory to community: chemoprevention is the answer.
In the current issue, Johnson and colleagues present exciting results, using biomarkers involved in aflatoxin B1 (AFB1)-induced hepatocarcinogenesis, as an example of a conceptual framework to target mechanisms of action in developing chemopreventive agents. Their innovative approach offers considerable promise for a field that has long been neglected. Proof-of-principle was demonstrated using a synthetic triterpenoid (CDDO-Im), which activates Nrf2 signal transduction pathway, inhibits formation of AFB1-induced DNA adducts and neoplastic hepatic foci, and alters the expression of genes associated with aflatoxin-mediated toxicity.


Level of knowledge about metalloproteinases in dental students close to graduate from three universities in Peruvian capital city.
Metalloproteinases are proteolytic enzymes that degrade dentin and periodontal collagen; therefore, it is of special interest that dental students know its mechanism of action and how its effects can be inhibited. Therefore, the aim of this research was to evaluate the level of knowledge about metalloproteinases in dental students close to graduate from three universities in Peruvian capital city. In this analytical, observational, cross-sectional and prospective study, 223 dental students close to graduate in three Peruvian universities were evaluated from September to November 2020. A questionnaire of 20 closed questions with three answers was validated and used to measure the level of general and dental knowledge about metalloproteinases. A logit model was used to evaluate the influence of the following variables: "gender" (X1), "type of university" (X2), "marital status" (X3) and "age group" (X4), in the knowledge levels of the students, considering a p-value <.05. Of the 223 dentistry students, it was obtained that the level of knowledge about metalloproteinases was predominantly low with 82.1%, (95% confidence interval (CI): 77.1%-87.1%) of the total. According to multivariate logistic regression analysis, "type of university" was the only variable that proved to have a significant influence (p = .022) on the level of knowledge about metalloproteinases with an odds ratio of (OR = 0.44; CI: 0.21-0.89), whilst the other variables "age group" (p > .05), "gender" (p = .058) and "marital status" (p = .114) were not considered influential factors. The majority of final year dental students in three Peruvian universities presented a low level of overall knowledge about metalloproteinases. In addition, private university students were 56% less likely to pass the subject knowledge test. On contrary, gender, age group and marital status did not significantly influence the level of knowledge of the students.


The characteristics of blood glucose fluctuations in patients with fulminant type 1 diabetes mellitus in the stable stage.
The aim was to characterize blood glucose fluctuations in patients with fulminant type 1 diabetes (FT1DM) at the stable stage using continuous blood glucose monitoring systems (CGMSs). Ten patients with FT1DM and 20 patients with classic type 1 diabetes mellitus (T1DM) (the control group) were monitored using CGMSs for 72 hours. The CGMS data showed that the mean blood glucose (MBG), the standard deviation of the blood glucose (SDBG), the mean amplitude glycemic excursions (MAGE), the blood glucose areas and the percentages of blood glucose levels below 13.9 mmol/L were similar between the two groups. However, the percentage of blood glucose levels below 3.9 mmol/L was significantly higher in the FT1DM group compared to the T1DM group (p < 0.05). The minimum (Min) blood glucose level in the FT1DM group was significantly lower than that of the T1DM group (p < 0.05). Patients with FT1DM had severe dysfunction of the islet beta cells and alpha cells compared to patients with T1DM, as indicated by lower C-peptide values and higher glucagon/C-peptide values. In conclusion, patients with FT1DM at the stable stage were more prone to hypoglycemic episodes as recorded by CGMSs, and they had a greater association with severe dysfunction of both the beta and alpha islet cells compared to patients with T1DM.


Challenges and opportunities for Arabic question-answering systems: current techniques and future directions.
Artificial intelligence-based question-answering (QA) systems can expedite the performance of various tasks. These systems either read passages and answer questions given in natural languages or if a question is given, they extract the most accurate answer from documents retrieved from the internet. Arabic is spoken by Arabs and Muslims and is located in the middle of the Arab world, which encompasses the Middle East and North Africa. It is difficult to use natural language processing techniques to process modern Arabic owing to the language's complex morphology, orthographic ambiguity, regional variations in spoken Arabic, and limited linguistic and technological resources. Only a few Arabic QA experiments and systems have been designed on small datasets, some of which are yet to be made available. Although several reviews of Arabic QA studies have been conducted, the number of studies covered has been limited and recent trends have not been included. To the best of our knowledge, only two systematic reviews focused on Arabic QA have been published to date. One covered only 26 primary studies without considering recent techniques, while the other covered only nine studies conducted for Holy Qur'an QA systems. Here, the included studies were analyzed in terms of the datasets used, domains covered, types of Arabic questions asked, information retrieved, the mechanism used to extract answers, and the techniques used. Based on the results of the analysis, several limitations, concerns, and recommendations for future research were identified. Additionally, a novel taxonomy was developed to categorize the techniques used based on the domains and approaches of the QA system.


Performance characteristics of thromboelastometry assays using incompletely filled and prolonged stored samples.
Thromboelastometry (TEM) is often used to guide transfusion therapy in patients with massive bleeding. The effect of testing incompletely filled samples and those stored for a prolonged time at 4°C was investigated. Whole blood samples were collected from 15 healthy blood donors and were pooled according to ABO group. From these pools, aliquots were taken and diluted to produce final whole blood:citrate buffer ratios ranging from 90:10 (fully filled sample) to 40:60 (extremely under filled samples). These samples were then tested by EXTEM, INTEM, and FIBTEM on calibrated ROTEM delta machines. Separately, the four samples at 90:10 dilution were kept at 4°C for 16-20 hours and then retested on the ROTEM machines. All of the samples at the 90:10 and 80:20 (half-filled sample) whole blood:citrate buffer dilutions demonstrated ROTEM parameters within their respective reference ranges, although the samples from the 80:20 dilution tended to demonstrate slightly longer or slower times, depending on each ROTEM parameter, compared to the completely filled samples. All of the samples with more dilute whole blood to citrate buffer ratios (i.e., 70:30 to 40:60) yielded abnormal TEM results. The TEM results for the 90:10 dilution samples exposed to 16-20 hours of storage at 4°C were within the reference intervals. Completely and half-filled samples, and completely filled samples after prolonged cold storage, produced normal ROTEM results. Tubes that are less than half-filled should not be used for ROTEM testing.


Aneuploidy and high S-phase as biomarkers of poor clinical outcome in poorly differentiated and anaplastic thyroid carcinoma.
This study aimed to investigate the prognostic influence of DNA flow cytometry and RAS gene mutations in patients with poorly differentiated (PDTC) and anaplastic thyroid carcinoma (ATC). The series consisted of 26 patients with PDTC and ATC, and a median follow-up of 10 months (range 1-138). DNA ploidy and S-phase fraction (SPF) were assessed by flow cytometry on frozen samples. RAS point mutations were detected using PCR techniques. Disease staging and tumour angioinvasion were included as prognostic parameters for survival analysis. Nineteen patients (73.1%) succumbed to the disease (median time 5 months; range 1-45). Eighteen tumours (69.2%) were classified as DNA aneuploid. Median SPF was 5.6% (range 1.9-23.1), which was used as a cut-off value to distinguish between low versus high cell proliferation. Three of 20 (15%) patients presented N-RAS gene mutations in codon 61. DNA aneuploidy was most frequently found in female patients (p=0.034). Kaplan-Meier and Cox regression analyses showed that only DNA aneuploidy (p=0.044 and p=0.055, respectively) and high SPF (p=0.001 and p=0.006, respectively) significantly correlated with worse survival. The results indicate that aneuploidy and high SPF are biomarkers of poor clinical outcome in PDTC and ATC, which may provide useful prognostic information with a potentially therapeutic impact in patient management.


Catalytic coal gasification: an emerging technology.
Catalytic coal gasification is being developed as a more efficient and less costly approach to producing methane from coal. With a potassium catalyst all the reactions can take place at one temperature, so that endothermic and exothermic reactions can be integrated in a single reactor. A key aspect of the concept involves continuous recycling of product carbon monoxide and hydrogen to the gasifier following separation of methane. Development of the process has advanced steadily since the basic concept was proposed in 1971. A 23-day demonstration run was recently completed in a process development unit with a coal feed rate of 1 ton per day. The next major step in the program will be to design and construct a large pilot plant to bring the technology to commercial readiness in the late 1980's.


Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.
The enteric peptides, guanylin and uroguanylin, are local regulators of intestinal secretion by activation of receptor-guanylate cyclase (R-GC) signaling molecules that produce cyclic GMP (cGMP) and stimulate the cystic fibrosis transmembrane conductance regulator-dependent secretion of Cl- and HCO3-. Our experiments demonstrate that mRNA transcripts for guanylin and uroguanylin are markedly reduced in colon polyps and adenocarcinomas. In contrast, a specific uroguanylin-R-GC, R-GCC, is expressed in polyps and adenocarcinomas at levels comparable with normal colon mucosa. Activation of R-GCC by uroguanylin in vitro inhibits the proliferation of T84 colon cells and elicits profound apoptosis in human colon cancer cells, T84. Therefore, down-regulation of gene expression and loss of the peptides may interfere with renewal and/or removal of the epithelial cells resulting in the formation of polyps, which can progress to malignant cancers of the colon and rectum. Oral replacement therapy with human uroguanylin was used to evaluate its effects on the formation of intestinal polyps in the Min/+ mouse model for colorectal cancer. Uroguanylin significantly reduces the number of polyps found in the intestine of Min/+ mice by approximately 50% of control. Our findings suggest that uroguanylin and guanylin regulate the turnover of epithelial cells within the intestinal mucosa via activation of a cGMP signaling mechanism that elicits apoptosis of target enterocytes. The intestinal R-GC signaling molecules for guanylin regulatory peptides are promising targets for prevention and/or therapeutic treatment of intestinal polyps and cancers by oral administration of human uroguanylin.


Quick Sepsis-related Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and Early Warning Scores for Detecting Clinical Deterioration in Infected Patients outside the Intensive Care Unit.
The 2016 definitions of sepsis included the quick Sepsis-related Organ Failure Assessment (qSOFA) score to identify high-risk patients outside the intensive care unit (ICU). We sought to compare qSOFA with other commonly used early warning scores. All admitted patients who first met the criteria for suspicion of infection in the emergency department (ED) or hospital wards from November 2008 until January 2016 were included. The qSOFA, Systemic Inflammatory Response Syndrome (SIRS), Modified Early Warning Score (MEWS), and the National Early Warning Score (NEWS) were compared for predicting death and ICU transfer. Of the 30,677 included patients, 1,649 (5.4%) died and 7,385 (24%) experienced the composite outcome (death or ICU transfer). Sixty percent (n = 18,523) first met the suspicion criteria in the ED. Discrimination for in-hospital mortality was highest for NEWS (area under the curve [AUC], 0.77; 95% confidence interval [CI], 0.76-0.79), followed by MEWS (AUC, 0.73; 95% CI, 0.71-0.74), qSOFA (AUC, 0.69; 95% CI, 0.67-0.70), and SIRS (AUC, 0.65; 95% CI, 0.63-0.66) (P < 0.01 for all pairwise comparisons). Using the highest non-ICU score of patients, ≥2 SIRS had a sensitivity of 91% and specificity of 13% for the composite outcome compared with 54% and 67% for qSOFA ≥2, 59% and 70% for MEWS ≥5, and 67% and 66% for NEWS ≥8, respectively. Most patients met ≥2 SIRS criteria 17 hours before the combined outcome compared with 5 hours for ≥2 and 17 hours for ≥1 qSOFA criteria. Commonly used early warning scores are more accurate than the qSOFA score for predicting death and ICU transfer in non-ICU patients. These results suggest that the qSOFA score should not replace general early warning scores when risk-stratifying patients with suspected infection.


Balancing medicine prices and business sustainability: analyses of pharmacy costs, revenues and profit shed light on retail medicine mark-ups in rural Kyrgyzstan.
Numerous not-for-profit pharmacies have been created to improve access to medicines for the poor, but many have failed due to insufficient financial planning and management. These pharmacies are not well described in health services literature despite strong demand from policy makers, implementers, and researchers. Surveys reporting unaffordable medicine prices and high mark-ups have spurred efforts to reduce medicine prices, but price reduction goals are arbitrary in the absence of information on pharmacy costs, revenues, and profit structures. Health services research is needed to develop sustainable and "reasonable" medicine price goals and strategic initiatives to reach them. We utilized cost accounting methods on inventory and financial information obtained from a not-for-profit rural pharmacy network in mountainous Kyrgyzstan to quantify costs, revenues, profits and medicine mark-ups during establishment and maintenance periods (October 2004-December 2007). Twelve pharmacies and one warehouse were established in remote Kyrgyzstan with < US $25,000 due to governmental resource-sharing. The network operated at break-even profit, leaving little room to lower medicine prices and mark-ups. Medicine mark-ups needed for sustainability were greater than originally envisioned by network administration. In 2005, 55%, 35%, and 10% of the network's top 50 products revealed mark-ups of < 50%, 50-99% and > 100%, respectively. Annual mark-ups increased dramatically each year to cover increasing recurrent costs, and by 2007, only 19% and 46% of products revealed mark-ups of < 50% and 50-99%, respectively; while 35% of products revealed mark-ups > 100%. 2007 medicine mark-ups varied substantially across these products, ranging from 32% to 244%. Mark-ups needed to sustain private pharmacies would be even higher in the absence of government subsidies. Pharmacy networks can be established in hard-to-reach regions with little funding using public-private partnership, resource-sharing models. Medicine prices and mark-ups must be interpreted with consideration for regional costs of business. Mark-ups vary dramatically across medicines. Some mark-ups appear "excessive" but are likely necessary for pharmacy viability. Pharmacy financial data is available in remote settings and can be used towards determination of "reasonable" medicine price goals. Health systems researchers must document the positive and negative financial experiences of pharmacy initiatives to inform future projects and advance access to medicines goals.


[Evaluation of the effectiveness of home-based physical activity promotion by community health workers].
This study analyzed the effectiveness of physical activity promotion by community health workers (CHW) during home visits. This was a non-randomized controlled trial that lasted six months, with one group of CHW that received training to promote physical activity during home visits among users of the Brazilian Unified National Health System (SUS) and a control group. Physical activity and stages of behavior change were evaluated in 176 adults (n = 90 in the intervention group and n = 86 in the control group) assisted by the CHW. Associations, prevalence ratios, and generalized estimate equations were conducted to verify differences between groups. No evidence of differences in physical activity and stages of behavior change were observed between the two groups. CHW from the intervention group conducted more home visits promoting physical activity among elders, those with low schooling, unemployed, and those with chronic diseases. It is important to reassess the work and priorities of CHW to expand physical activity promotion under the SUS.


Induction of the nicotinamide riboside kinase NAD+ salvage pathway in a model of sarcoplasmic reticulum dysfunction.
Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11β-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation. We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD+ precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO. H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD+ biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD+ biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD+ levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD+/NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD+ availability. These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD+ salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved.


Haematological status of fullterm healthy infants in the first week of life.
The haematological status of 105 healthy fullterm neonates was studied daily during the first week of life. Hb, MCV, RBC, PCV and WBC were determined with a Coulter 5 Counter, white cell differential reticulocyte and platelet counts manually, and ESR by a micromethod on free flowing capillary blood from heel stabs. A decline in Hb, PCV, MCV, RBC values and reticulocyte count was observed over the 7 days. The platelet count however rose slightly. The white cell count initially declined. The polymorphs initially predominant declined as the lymphocytes increased; by 7 days, both were about equal in proportions and together accounted for about 85% of the white cell population. The micro-ESR was very low, rising only slightly over the week.


Regulation of corticosteroid receptors in the rat brain: the role of serotonin and stress.
It has been suggested that physiological resistance to repeated stress is associated with increased 5-hydroxytryptamine (5-HT) release in the dorsal hippocampus and that dysregulation of this neuroadaptation may be implicated in the psychopathology of depression. This study used 5,7-dihydroxytryptamine lesions to investigate the role of 5-HT projections to the hippocampus in physiological responses to repeated stress and putative changes in corticosteroid receptor immunoreactivity in the brain. Repeated exposure to elevated open platform stress (1 h/day) caused regionally selective changes in glucocorticoid and mineralocorticoid receptor immunoreactivity in the dorsal hippocampus that were not observed in ventral hippocampus, frontal cortex, hypothalamus or parietal cortex. Glucocorticoid receptor immunoreactivity in the dorsal hippocampus was decreased after 5 days but increased after 20 days of stress. Mineralocorticoid receptor immunoreactivity was increased after 5 or 10 days of stress. The increases in glucocorticoid and mineralocorticoid receptor immunoreactivity, evoked by repeated stress, were abolished by lesions of the principal 5-HT projections to the hippocampus. The lesions abolished the increased defecation observed in stressed animals, but had no effects on the plasma corticosterone response to the stressor or the habituation of this response observed following repeated stress. The experiments have revealed a dissociation in the regulation of corticosteroid receptor expression in the dorsal and ventral hippocampus by repeated stress and 5-HT. The data suggest that adaptation to inescapable stress is associated with regionally selective changes in corticosteroid receptor expression in dorsal hippocampus that are largely 5-HT-dependent, although these changes do not mediate habituation of the pituitary adrenocortical response to the stressor.


Antigenic characterization of Trypanosoma evansi using sera from experimentally and naturally infected bovines, equines, dogs, and coatis.
The present research investigated the presence of T. evansi antibodies in animals from the subregion of Nhecolandia, in the Pantanal Sul-mato-grossense, by means of an enzyme linked immunosorbent assay (ELISA) and indirect immunofluorescence antibody test (IFAT), and the pattern of polypeptide recognition by sera from experimentally and naturally infected hosts using Western blotting. Serum samples were obtained from bovines (n = 102), horses (n = 98), and dogs (n = 55), and from 32 free-ranging coatis (Nasua nasua). None of the bovines were found positive, while sera from 16 dogs (29%) and 23 horses (23.4%) were positive by ELISA. Sera from 8 coatis (25%) were found positive using IFAT. Western blotting revealed major polypeptides of T. evansi with molecular weight ranging from 74 to 38 kDa. The polypeptides of 66, 48-46, and 38 kDa were identified by sera from experimentally infected bovines, donkeys, dogs, and coatis. The 48-46 and 38 kDa bands were mainly recognized in chronic phase of infection. The antigen with apparent molecular weight of 66 kDa, revealed by antibodies from all experimental animals, was also recognized in sera of horses and dogs from the Pantanal. The 48-46 kDa polypeptide was identified by antibodies from all naturally infected animals and must be further evaluated for use in specific diagnosis of T. evansi infection.


Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice.
Alopecia areata is a tissue-restricted autoimmune disease of the hair follicle, which results in hair loss and baldness. It is often psychologically devastating. The role of T lymphocytes in this disorder was investigated with cell transfer experiments. Scalp explants from patients were transplanted to severe combined immunodeficiency (SCID) mice and injected with autologous T lymphocytes isolated from involved scalp. T lymphocytes which had been cultured with hair follicle homogenate along with antigen-presenting cells were capable of inducing the changes of alopecia areata, including hair loss and perifollicular infiltrates of T cells, along with HLA-DR and ICAM-1 expression of the follicular epithelium. Similar changes were not noted in grafts injected with scalp-derived T cells that had not been cultured with follicular homogenate. These data indicate that alopecia areata is mediated by T cells which recognize a follicular autoantigen.


Development of a Rapid Fluorescent Diagnostic System to Detect Subtype H9 Influenza A Virus in Chicken Feces.
The circulation of the H9N2 virus results in significant economic losses in the poultry industry, and its zoonotic transmission highlights the need for a highly sensitive and rapid diagnostic and detection system for this virus. In this study, the performance of lateral flow test strips for a fluorescent immunochromatographic test (FICT) was optimized for the diagnosis of H9N2 virus-infected animal samples. The novel monoclonal antibodies (McAbs) against influenza A H9 viruses were developed, and two categories of McAbs with linear and conformational epitopes were compared for the performance of rapid diagnostic performance in the presence of feces sample at different time points (2, 4, and 6 days) post-infection (dpi). The limit of detection (LOD) of FICT and Kd values were comparable between linear and conformational epitope McAbs. However, superior performance of linear epitope McAbs pairs were confirmed by two animal studies, showing the better diagnostic performance showing 100% relative sensitivity in fecal samples at 6 dpi although it showed less than 80% sensitivity in early infection. Our results imply that the comparable performance of the linear epitope McAbs can potentially improve the diagnostic performance of FICT for H9N2 detection in feces samples. This highly sensitive rapid diagnostic method can be utilized in field studies of broiler poultry and wild birds.


Increasing the use of 'smart' pump drug libraries by nurses: a continuous quality improvement project.
The use of infusion pumps that incorporate "smart" technology (smart pumps) can reduce the risks associated with receiving IV therapies. Smart pump technology incorporates safeguards such as a list of high-alert medications, soft and hard dosage limits, and a drug library that can be tailored to specific patient care areas. Its use can help to improve patient safety and to avoid potentially catastrophic harm associated with medication errors. But when one independent community hospital in Massachusetts switched from older mechanical pumps to smart pumps, it neglected to assign an "owner" to oversee the implementation process. One result was that nurses were using the smart pump library for only 37% of all infusions.To increase pump library usage percentage-thereby reducing the risks associated with infusion and improving patient safety-the hospital undertook a continuous quality improvement project over a four-month period in 2009. With the involvement of direct care nurses, and using quantitative data available from the smart pump software, the nursing quality and pharmacy quality teams identified ways to improve pump and pump library use. A secondary goal was to calculate the hospital's return on investment for the purchase of the smart pumps. Several interventions were developed and, on the first of each month, implemented. By the end of the project, pump library usage had nearly doubled; and the hospital had completely recouped its initial investment.


Patterns of searching for information on the World Wide Web: a pilot study.
The influences of task type on search of the World Wide Web using search engines without limitation of search domain were investigated. 9 graduate and undergraduate students studying psychology (1 woman and 8 men, M age=25.0 yr., SD=2.1) participated. Their performance to manipulate the search engines on a closed task with only one answer were compared with their performance on an open task with several possible answers. Analysis showed that the number of actions was larger for the closed task (M=91) than for the open task (M=46.1). Behaviors such as selection of keywords (averages were 7.9% of all actions for the closed task and 16.7% for the open task) and pressing of the browser's back button (averages were 40.3% of all actions for the closed task and 29.6% for the open task) were also different. On the other hand, behaviors such as selection of hyperlinks, pressing of the home button, and number of browsed pages were similar for both tasks. Search behaviors were influenced by task type when the students searched for information without limitation placed on the information sources.


Evaluating the Sun Protection Factor of Cosmetic Formulations Containing Afzelin.
Exposure to UV radiation damages the skin and increases the risk of skin cancer. Sunscreen is used to protect the skin from the harmful effects of UV radiation. However, the chemical UV filters used in sunscreen can show toxicity and cause allergic reactions. A safe sunscreen that includes a lower content of chemical UV filters and exerts an excellent effect on UV protection needs to be developed. The objective of this study was to investigate whether the addition of afzelin to sunscreen could improve the sun protection factor (SPF). A synergistic effect between afzelin and organic sunscreen agents including padimate O and oxybenzone was confirmed. Interestingly, 100% in vitro SPF-boosting was observed when afzelin (0.05%) was applied with a standard SPF formulation containing organic sunscreens while afzelin alone had no contribution to the SPF. In vivo SPF analysis of the standard SPF formulation showed an SPF value of 13.3 that increased to 20.1 when supplemented with afzelin (0.05%). Additionally, afzelin showed no skin irritation in a human trial. These results suggest that afzelin is useful as a natural additive in sunscreen formulations and provides an SPF-boosting effect. Afzelin supplementation to the formulation showed the potential to reduce the use of synthetic photoprotectors, which could minimize the risk of synthetic agent toxicity.


CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism.
CD73, a cell surface-bound nucleotidase, facilitates extracellular adenosine formation by hydrolyzing 5'-AMP to adenosine. Several studies have shown that CD73 plays an essential role in immune escape, cell proliferation and tumor angiogenesis, making it an attractive target for cancer therapies. However, there are limited clinical benefits associated with the mainstream enzymatic inhibitors of CD73, suggesting that the mechanism underlying the role of CD73 in tumor progression is more complex than anticipated, and further investigation is necessary. In this study, CD73 is found to overexpress in the cytoplasm of pancreatic ductal adenocarcinoma (PDAC) cells and promotes metastasis in a nucleotidase-independent manner, which cannot be restrained by the CD73 monoclonal antibodies or small-molecule enzymatic inhibitors. Furthermore, CD73 promotes the metastasis of PDAC by binding to the E3 ligase TRIM21, competing with the Snail for its binding site. Additionally, a CD73 transcriptional inhibitor, diclofenac, a non-steroidal anti-inflammatory drug, is more effective than the CD73 blocking antibody for the treatment of PDAC metastasis. Diclofenac also enhances the therapeutic efficacy of gemcitabine in the spontaneous KPC (LSL-KrasG12D/+ , LSL-Trp53R172H/+ , and Pdx-1-Cre) pancreatic cancer model. Therefore, diclofenac may be an effective anti-CD73 therapy, when used alone or in combination with gemcitabine-based chemotherapy regimen, for metastatic PDAC.


[Megestrol acetate as hormone therapy in oncology].
The structure, properties and therapeutic effect of a synthesized progestin--megestrol acetate (Megace) are discussed. It is most useful in the management of local and metastatic tumors of the breast and endometrium as well as anorexia-cachexia syndrome. It is suggested that other applications in hormone therapy and new ways of avoiding untoward side-effects (weight gain) may be found.


Report of a case: primary mucinous carcinoma of the skin.
Primary mucinous carcinoma of the skin is an extremely rare adnexal tumor that is thought to originate from eccrine sweat glands. The neoplasm usually arises on the head and neck, with the most commonly involved area being the periorbital region. The tumor is typically a solitary, asymptomatic nodule, cyst, or ulcer that is slow growing with low metastatic potential. However, post-excisional local recurrence is common, affecting up to 36 percent of patients. Since primary mucinous carcinoma of the skin is such a rare neoplasm (fewer than 130 cases have been reported to date), a complete workup should be conducted to rule out other internal malignancies that may metastasize to the skin. We report a case of primary mucinous carcinoma of the skin, and discuss the clinical presentation, histology, treatment, course, and prognosis.


HEART OF MYTH - HEART OF SCIENCE Part I: Harriet Martineau's cardiac symptoms: a Victorian case history.
This article explores the history and meanings of the heart and its diseases as aspects of the histories of science and emotion. Analyzing the twofold meanings of the heart as both bodily object and cultural symbol, it explores the reasons for the apparent conflict in meanings of the heart of science and the heart of emotion in Western medical culture since the 19th century. In Part I, a case study of the writer, economist, and philosopher Harriet Martineau is used to demonstrate and trace that conflict, while Part II highlights the manifold meanings of the heart both in the past and in the present.


A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects.
Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). The median age on admission and age of diagnosis were 7 years (0.3-16.5) and 11 years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαβ+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1-3). In total, one patient died from sepsis during adulthood before HSCT. Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.


Nephroprotective Effects of Metformin in Diabetic Nephropathy.
Metformin, a well-known anti-diabetic agent, is very effective in lowering blood glucose in patients with type 2 diabetes with minimal side-effects. Metformin is also being recommended in the treatment of obesity and polycystic ovary syndrome. Metformin elicits its therapeutic effects mainly via activation of AMP-activated kinase (AMPK) pathway. Renal cells under hyperglycemic or proteinuric conditions exhibit inactivation of cell defense mechanisms such as AMPK and autophagy, and activation of pathologic pathways such as mammalian target of rapamycin (mTOR), endoplasmic reticulum (ER) stress, epithelial-to-mesenchymal transition (EMT), oxidative stress, and hypoxia. As these pathologic pathways are intertwined with AMPK signaling, the potential benefits of metformin therapy in patients with type 2 diabetes would extend beyond its anti-hyperglycemic effects. However, since metformin is eliminated unchanged through the kidneys and some studies have shown the incidence of lactic acidosis with its use during severe renal dysfunction, the use of metformin was contraindicated in patients with renal disease until recently. With more studies indicating the relatively low incidence of lactic acidosis and revealing the additional benefits with metformin therapy, the US FDA has now approved metformin to be administered in patients with established renal disease based on their renal function. The purpose of this review is to highlight the various mechanisms by which metformin protects renal cells that have lost its functionality in a diabetic or non-diabetic setting and to enlighten the advantages and therapeutic potential of metformin as a nephroprotectant for patients with diabetic nephropathy and other non-diabetic forms of chronic kidney disease. J. Cell. Physiol. 232: 731-742, 2017. © 2016 Wiley Periodicals, Inc.


Participation and performance on paper- and computer-based low-stakes assessments.
High-stakes assessments, such the Graduate Records Examination, have transitioned from paper to computer administration. Low-stakes research-based assessments (RBAs), such as the Force Concept Inventory, have only recently begun this transition to computer administration with online services. These online services can simplify administering, scoring, and interpreting assessments, thereby reducing barriers to instructors' use of RBAs. By supporting instructors' objective assessment of the efficacy of their courses, these services can stimulate instructors to transform their courses to improve student outcomes. We investigate the extent to which RBAs administered outside of class with the online Learning About STEM Student Outcomes (LASSO) platform provide equivalent data to tests administered on paper in class, in terms of both student participation and performance. We use an experimental design to investigate the differences between these two assessment conditions with 1310 students in 25 sections of 3 college physics courses spanning 2 semesters. Analysis conducted using hierarchical linear models indicates that student performance on low-stakes RBAs is equivalent for online (out-of-class) and paper-and-pencil (in-class) administrations. The models also show differences in participation rates across assessment conditions and student grades, but that instructors can achieve participation rates with online assessments equivalent to paper assessments by offering students credit for participating and by providing multiple reminders to complete the assessment. We conclude that online out-of-class administration of RBAs can save class and instructor time while providing participation rates and performance results equivalent to in-class paper-and-pencil tests.


CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer.
The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC) largely depends on the tumor microenvironment (TME). Here, we demonstrate that CCL7 facilitates anti-PD-1 therapy for the KrasLSL-G12D/+Tp53fl/fl (KP) and the KrasLSL-G12D/+Lkb1fl/fl (KL) NSCLC mouse models by recruiting conventional DC 1 (cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression in NSCLC tumor tissues and is positively correlated with the infiltration of cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8+ and CD4+ T cells in bronchial draining lymph nodes and TME, thereby promoting tumor development in the KP mouse model. Administration of CCL7 into lungs alone or in combination with anti-PD-1 significantly inhibits tumor development and prolongs the survival of KP and KL mice. These findings suggest that CCL7 potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of NSCLC.


What to tell dementia caregivers--the rule of threes.
To determine and prioritise what information dementia caregivers wish to know at the time of diagnosis and later on in the illness, and in what form this information should be presented. 100 carers were recruited from community mental health teams (CMHT) and a memory clinic (MC). A semi-structured Carer Interview was administered covering possible symptoms and management. Carers requested as much information as possible. There was no significant difference between CMHTs and the MC. After carers prioritised the information they wished to receive, we proposed a 'rule of threes'. At diagnosis, carers want information about what dementia is, medications available and behavioural and psychiatric symptoms of dementia. In an early follow-up appointment, they want information about services, the course of the illness and what to do in a crisis. In a later follow-up appointment, they want information about support groups, benefits, and financial and legal issues. At a later stage, they want information about psychological therapies, the effects of the illness on carers and complementary treatments. Most carers wish to receive information from a health professional, backed up by written information. The 'rule of threes' enables health professionals to make informed decisions about primacy of information and strategies to prevent carers becoming overloaded. Information should also be provided in written form and from support groups.


Integration of angiogenesis modules at multiple scales: from molecular to tissue.
Multiscale modeling has emerged as a powerful approach to interpret and capitalize on the biological complexity underlying blood vessel growth. We present a multiscale model of angiogenesis that heralds the start of a large scale initiative to integrate related biological models. The goal of the integrative project is to better understand underlying biological mechanisms from the molecular level up through the organ systems level, and test new therapeutic strategies. Model methodology includes ordinary and partial differential equations, stochastic models, complex logical rules, and agent-based architectures. Current modules represent blood flow, oxygen transport, growth factor distribution and signaling, cell sensing, cell movement and cell proliferation. Challenges of integration lie in connecting modules that are diversely designed, seamlessly coordinating feedback, and representing spatial and time scales from ligand-receptor interactions and intracellular signaling, to cell-level movement and cell-matrix interactions, to vessel branching and capillary network formation, to tissue level characteristics, to organ system response. We briefly introduce the individual modules, discuss our approach to integration, present initial results from the coordination of modules, and propose solutions to some critical issues facing angiogenesis multiscale modeling and integration.


Biochemical composition of temperate and Arctic populations of Saccharina latissima after exposure to increased pCO2 and temperature reveals ecotypic variation.
Previous research suggested that the polar and temperate populations of the kelp Saccharina latissima represent different ecotypes. The ecotypic differentiation might also be reflected in their biochemical composition (BC) under changing temperatures and pCO2. Accordingly, it was tested if the BC of Arctic (Spitsbergen) and temperate S. latissima (Helgoland) is different and if they are differently affected by changes in temperature and pCO2. Thalli from Helgoland grown at 17 °C and 10 °C and from Spitsbergen at 10 °C and 4 °C were all tested at either 380, 800, or 1,500 µatm pCO2, and total C-, total N-, protein, soluble carbohydrate, and lipid content, as well as C/N-ratio were measured. At 10 °C, the Arctic population had a higher content of total C, soluble carbohydrates, and lipids, whereas the N- and protein content was lower. At the lower tested temperature, the Arctic ecotype had particularly higher contents of lipids, while content of soluble carbohydrates increased in the Helgoland population only. In Helgoland-thalli, elevated pCO2 caused a higher content of soluble carbohydrates at 17 °C but lowered the content of N and lipids and increased the C/N-ratio at 10 °C. Elevated pCO2 alone did not affect the BC of the Spitsbergen population. Conclusively, the Arctic ecotype was more resilient to increased pCO2 than the temperate one, and both ecotypes differed in their response pattern to temperature. This differential pattern is discussed in the context of the adaptation of the Arctic ecotype to low temperature and the polar night.


The crystal structure of the human smacovirus 1 Rep domain.
Replication initiator proteins (Reps) from the HUH endonuclease family process specific single-stranded DNA sequences to initiate rolling-circle replication in viruses. Here, the first crystal structure of the apo state of a Rep domain from the smacovirus family is reported. The structure of the human smacovirus 1 Rep domain was obtained at 1.33 Å resolution and represents an expansion of the HUH endonuclease superfamily, allowing greater diversity in bioconjugation-tag applications.


Mechanisms and implications of a type IV functional response for short-term intake rate of dry matter in large mammalian herbivores.
The functional response (i.e. the relationship between consumers' intake rate and resource density) is central in plant-herbivore interactions. Its shape and the biological processes leading to it have significant implications for both foraging theory and ecology of grazing systems. A type IV functional response (i.e. dome-shaped relationship) of short-term intake rate of dry matter (intake while grazing) has rarely been reported for large herbivores and the conditions that can lead to it are poorly understood. We report a type IV functional response observed in heifers grazing monocultures of Cynodon sp. and Avena strigosa. The mechanisms and consequences of this type of functional response for grazed system dynamics are discussed. Intake rate was higher at intermediate than at short or tall sward heights in both grass species. The type IV functional response resulted from changes in bite mass instead of a longer time needed to encounter and process bites. Thus, the decrease of intake rate of dry matter in tall swards is not explained by a shift from process 3 (potential bites are concentrated and apparent) to process 2 (potential bites are apparent but dispersed, Spalinger & Hobbs 1992). Bite mass was smaller in tall than in intermediate swards due to a reduction of bite volume possibly caused by the greater proportion of stem and sheath acting as a physical barrier to bite formation. It is generally accepted that potential bites are abundant and apparent in most grassland and meadow systems, as they were in the present experiments. Therefore, a type IV response of intake rate not directly related to digestive constraints may determine the dynamics of intake and defoliation under a much larger set of conditions than previously thought. These results have implications for foraging theory and stability of grazing systems. For example, if animals prefer patches of intermediate stature that yield the highest intake rate, grazing should lead to the widely observed bimodal distribution of plant mass per unit area, even when tall patches are not of significantly lower digestive quality than the pasture average.


Sympathetic reflex control of subcutaneous blood flow in patients with congestive heart failure.
Central and local regulation of forearm subcutaneous vascular resistance (FSVR) during postural changes were studied in congestive heart failure (CHF). Blood flow was measured by the local 133Xe-washout technique. Nine patients with severe CHF (baseline angiographic ejection fraction, 23 +/- 2%, mean +/- SEM; cardiac index, 2.2 +/- 0.2 litres min-1 m-2; increased left ventricular pressures and dimensions) were compared with seven control subjects who had normal cardiac performance. Baseline FSVR and plasma concentrations of noradrenaline and adrenaline were substantially higher in patients with CHF than control subjects. However, the patients, like control subjects, increased FSVR by 46 +/- 3% in response to increase in local venous transmural pressure and disclosed a normal response to decrease in forearm perfusion pressure. Both responses to changes in vascular transmural pressure were preserved after either proximal nervous blockade or local beta-receptor blockade. Central sympathetic stimulation was induced with use of 45 degrees upright tilt. Control subjects developed vasoconstriction (FSVR increased by 59 +/- 5%), which was completely abolished after proximal nerve blockade. Patients with CHF developed vasodilatation (FSVR decreased by 24 +/- 8%), which was not only abolished but reversed after proximal nerve blockade (FSVR increased by 22 +/- 7%), probably owing to the increased humoral vasoconstrictor activity. The paradoxical vasodilator response to central sympathetic stimulation in these patients was reversed after local beta-receptor blockade (FSVR increased by 19 +/- 9%). The local vasoconstrictor reflex responsiveness and intrinsic vascular reactivity were not affected by the augmented baseline sympathetic vasoconstrictor activity in patients with CHF.(ABSTRACT TRUNCATED AT 250 WORDS)


[Contrast sensitivity in amblyopia, abiotrophy and optic nerve atrophy in children].
The threshold spatial contrast sensitivity was assessed in children with amblyopia, tapetoretinal abiotrophy, and partial atrophy of the optic nerve of different origin. The measurements were carried out at spatial frequencies of 0.5-22 cycle/grad. Tests with white, red, green, and blue arrays against a black background realized in the Zebra software for IBM computers with VGA or SVGA displays were carried out. Classification of curves representing the contrast sensitivity for the above conditions is proposed. Characteristics of the groups with the above diseases are described, based on the height, shape, and mutual position of the curves.


A simple and robust real-time qPCR method for the detection of PIK3CA mutations.
PIK3CA mutations are seemingly the most common driver mutations in breast cancer with H1047R and E545K being the most common of these, accounting together for around 60% of all PIK3CA mutations and have promising therapeutic implications. Given the low sensitivity and the high cost of current genotyping methods we sought to develop fast, simple and inexpensive assays for PIK3CA H1047R and E545K mutation screening in clinical material. The methods we describe are based on a real-time PCR including a mutation specific primer combined with a non-productive oligonucleotide which inhibits wild-type amplification and a parallel internal control reaction. We demonstrate consistent detection of PIK3CA H1047R mutant DNA in genomic DNA extracted from frozen breast cancer biopsies, FFPE material or cancer cell lines with a detection sensitivity of approximately 5% mutant allele fraction and validate these results using both Sanger sequencing and deep next generation sequencing methods. The detection sensitivity for PIK3CA E545K mutation was approximately 10%. We propose these methods as simple, fast and inexpensive diagnostic tools to determine PIK3CA mutation status.


IFITM3 overexpression reverses insufficient healing benefits of small extracellular vesicles from high-fat-diet BMSCs in sepsis via the HMGB1 pathway.
Bone marrow mesenchymal stem cells (BMSCs) are a promising new therapy for sepsis, a common cause of death in hospitals. However, the global epidemic of metabolic syndromes, including obesity and pre-obesity, threatens the health of the human BMSC pool. The therapeutic effects of BMSCs are primarily due to the secretion of the small extracellular vesicles containing lipids, proteins, and RNA. Accordingly, studies on BMSCs, their small extracellular vesicles, and their modifications in obese individuals are becoming increasingly important. In this study, we investigated the therapeutic potential of small extracellular vesicles (sEVs) from high-fat diet BMSCs (sEVsHFD) in sepsis-induced liver-heart axis injury. We found that sEVsHFD yielded diminished therapeutic benefits compared to sEVs from chow diet BMSCs (sEVsCD). We subsequently verified that IFITM3 significantly differed in sEVsCD and sEVsHFD, alternating in septic liver tissue, and indicating its potential as a remodeling target of sEVs. IFITM3-overexpressed high-fat-diet BMSCs (HFD-BMSCs) showed that corresponding sEVs (sEVsHFD-IFITM3) markedly ameliorated liver-heart axis injury during sepsis. Lastly, we identified the protective action mechanisms of sEVsHFD-IFITM3 in sepsis-induced organ failure and HMGB1 expression and secretion was altered in septic liver and serum while HMGB1 has been demonstrated as a critical mediator of multi-organ failure in sepsis. These findings indicate that IFITM3 overexpression regenerates the therapeutic benefit of sEVs from HFD-BMSCs in sepsis via the HMGB1 pathway.


Carbon dot/g-C3N4-mediated self-activated antimicrobial nanocomposite films for active packaging applications.
A novel carbon dot/g-C3N4 nanocomposite (CCN) exhibiting enhanced photocatalytic activity was developed and used as a photoactive nanofiller to construct corn starch/carboxymethyl cellulose (CS/CMC)-based functional films. The morphologies and structures of the CCN-CS/CMC composite films were investigated with scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction. The effects of the CCN on the physicochemical properties and antibacterial activities of the films were analyzed. The properties of the films were optimized with the addition of CCN (0.20 mg/mL), and the tensile strength of the film was increased to 11.9 MPa and the water contact angle was increased to 103.39°. The optimal active film showed > 99.9 % antibacterial efficiencies against Escherichia coli and Staphylococcus aureus under visible light and prolonged the shelf lives of bananas for more than four days compared to the 4-day shelf life of the control. This work provides a novel route for developing antimicrobial active packaging.


Peripatric speciation within Torreya fargesii (Taxaceae) in the Hengduan Mountains inferred from multi-loci phylogeography.
The Hengduan Mountains (HDM) are one of the major global biodiversity hotspots in the world. Several evolutionary scenarios, especially in-situ diversification, have been proposed to account for the high species richness of temperate plants. However, peripatric speciation, an important mode of allopatric speciation, has seldom been reported in this region. Here, two chloroplast DNA regions and 14 nuclear loci were sequenced for 112 individuals from 10 populations of Torreya fargesii var. fargesii and 63 individuals from 6 populations of T. fargesii var. yunnanensis. Population genetic analyses revealed that the two varieties are well differentiated genetically (FST, 0.5765) and have uneven genetic diversity (π, 0.00221 vs. 0.00073 on an average of nuclear loci). The gene genealogical relationship showed that T. fargesii var. yunnanensis is inferred as derived from T. fargesii var. fargesii, which was further supported by the coalescent simulations (DIYABC, fastsimcoal2 and IMa2). By the coalescent simulations, the divergence time (~ 2.50-3.65 Ma) and the weak gene flow between the two varieties were detected. The gene flow was asymmetrical and only occurred in later stages of divergence, which is caused by second contact due to the population expansion (~ 0.61 Ma) in T. fargesii var. fargesii. In addition, niche modeling indicated that the two varieties are differentiated geographically and ecologically and have unbalanced distribution range. Overall, T. fargesii var. fargesii is always parapatric with respect to T. fargesii var. yunnanensis, and the latter derived from the former in peripatry of the HDM following a colonization from central China during the late Pliocene. Our findings demonstrate that peripatric speciation following dispersal events may be an important evolutionary scenario for the formation of biodiversity hotspot of the HDM.


Stoichiometry of substrate binding to rat liver fatty acid synthetase.
Two rat liver fatty acid synthetase preparations, containing 1.6 and 2.0 mol of 4'-phosphopantetheine/mol of synthetase, showed specific activity of 2006 and 2140 nmol of NADPH oxidized/min per mg of protein respectively. The two synthetase preparations could be loaded with either 3.3-4.4 mol of [1-14] acetate or 2.9-3.7 mol of [2-14C]malonate, by incubation with either [1-14C] acetyl-CoA or [2-14C]malonyl-CoA. The 4'-phosphopantetheine site could be more than 90% saturated and the serine site about 80% saturated with malonate derived from malonyl-CoA. However, with acetyl-CoA as substrate, binding at both the 4'-phosphopantetheine and cysteine thiol sites did not reach saturation. We interpret these results to indicate that, whereas the equilibrium constant for transfer of substrates between the serine loading site and the 4'-phosphopantetheine site is close to unity, that for transfer of acetyl moieties between the 4'-phosphopantetheine and cysteine sites favours formation of the 4'-phosphopantetheine thioester. Thus, despite the apparent sub-stoichiometric binding of acetate, the results are consistent with a functionally symmetrical model for the fatty acid synthetase which permits simultaneous substrate binding at two separate active centres.


Moderate coffee consumption reduces the risk of hepatocellular carcinoma in hepatitis B chronic carriers: a case-control study.
Recent epidemiological studies have reported a dose-dependent protective effect of coffee on hepatocellular carcinoma (HCC) with risk reduction ranging from 30% to 80% in daily coffee drinkers compared with non-drinkers. This study examined whether coffee has a similar protective effect when consumed in moderate quantities in chronic hepatitis B virus (HBV) carriers, a group at high risk of developing liver cancer. A case-control design was employed. 234 HBV chronic carriers (109 cases and 125 controls) were recruited from the Prince of Wales Hospital in Hong Kong from December 2007 to May 2008. Data collection included review of medical records and face-to-face interview. Univariate and multivariate logistic regressions adjusting for age, gender, cigarette smoking, alcohol use, tea consumption and physical activity were conducted with dose-response analysis. Moderate coffee consumption significantly reduced the risk of HCC by almost half (OR 0.54, 95% CI 0.30 to 0.97) with a significant dose-response effect (χ²=5.41, df=1, p=0.02), reducing the risk for moderate drinkers by 59% (OR 0.41, 95% CI 0.19 to 0.89). The findings provided evidence to support the protective effect of coffee consumption in moderate quantities in HBV chronic carriers.


Laminar displacement and prelaminar tissue thickness change after glaucoma surgery imaged with optical coherence tomography.
To study changes in lamina cribrosa position and prelaminar tissue thickness (PTT) after surgical IOP reduction in glaucoma patients. Twenty-two patients (mean age, 71.4 years) were imaged with spectral domain optical coherence tomography (SD-OCT; 24 radial B-scans centered on the optic nerve head [ONH]) before trabeculectomy or tube shunt implantation. Follow up images were acquired 1 week, 1 month, 3 months, and 6 months postsurgery. Bruch's membrane opening (BMO), the internal limiting membrane (ILM) and the anterior laminar surface (ALS) were segmented in each radial scan with custom software. Surfaces were fitted to the ILM and ALS with the extracted three-dimesional coordinates. PTT was the distance between the ILM and ALS, perpendicular to a BMO reference plane. Serial postsurgical laminar displacement (LD), relative to the BMO reference plane, and changes in PTT were measured. Positive values indicated anterior LD. Mean (SD) presurgery IOP was 18.1 (6.5) mm Hg, and reduced by 4.7 (5.5), 2.4 (7.7), 7.0 (6.2), and 6.8 (7.5) mm Hg at 1 week, 1 month, 3 months, and 6 months postsurgery, respectively. At the four postsurgery time points, there was significant anterior LD (1.8 [9.5], -1.1 [8.9], 8.8 [20.2], and 17.9 [25.8] μm) and PTT increase (1.7 [13.3], 2.4 [11.9], 17.4 [13.7], and 13.9 [18.6] μm). LD was greater in ONHs with larger BMO area (P = 0.01) and deeper ALS (P = 0.04); however, PTT was not associated with any of the tested independent variables. Both anterior LD and thickening of prelaminar tissue occur after surgical IOP reduction in patients with glaucoma.


Structure and biosynthesis of mayamycin B, a new polyketide with antibacterial activity from Streptomyces sp. 120454.
Mayamycin B, a new antibacterial type II polyketide, together with its known congener mayamycin A, were isolated from Streptomyces sp. 120454. The structure of new compound was elucidated by extensive spectroscopic analysis and comparison with literature data. Sequencing and bioinformatics analysis revealed the biosynthetic gene cluster for mayamycins A and B.


The alpha band of the resting electroencephalogram under pulsed and continuous radio frequency exposures.
The effect of GSM-like electromagnetic fields with the resting electroencephalogram (EEG) alpha band activity was investigated in a double-blind cross-over experimental paradigm, testing the hypothesis that pulsed but not continuous radio frequency (RF) exposure would affect alpha activity, and the hypothesis that GSM-like pulsed low frequency fields would affect alpha. Seventy-two healthy volunteers attended a single recording session where the eyes open resting EEG activity was recorded. Four exposure intervals were presented (sham, pulsed modulated RF, continuous RF, and pulsed low frequency) in a counterbalanced order where each exposure lasted for 20 min. Compared to sham, a suppression of the global alpha band activity was observed under the pulsed modulated RF exposure, and this did not differ from the continuous RF exposure. No effect was seen in the extremely low frequency condition. That there was an effect of pulsed RF that did not differ significantly from continuous RF exposure does not support the hypothesis that "pulsed" RF is required to produce EEG effects. The results support the view that alpha is altered by RF electromagnetic fields, but suggest that the pulsing nature of the fields is not essential for this effect to occur.


Prediction of response in cancer immunotherapy.
This review focuses on the relationship between pre-treatment immune parameter values and outcome of immunotherapy of cancer patients. The evidence presented in this review suggests that there is a relationship between pre-treatment immune parameter values and survival of cancer patients treated with immunotherapy. Tumour-infiltrating immune cells may have a predictive value for immunotherapy, but predictive power might be obtained from peripheral blood leukocytes. Use of peripheral blood may be preferable due to the convenience of collection and analysis compared to using tumour-infiltrating cells. In vivo numbers of cells of the immune system correlate better with clinical outcome than their functional activity ex vivo. This suggests that immunological antitumour mechanisms in vivo are not always related to generally accepted functional parameters of lymphocytes, such as cytotoxicity or cytokine production, ex vivo. The proliferative status of CD8(+) T lymphocytes seems promising for prediction of response in cancer immunotherapy.


The N400 elicited by homonyms in puns: Two primes are not better than one.
To comprehend a pun involving a homonym (e.g., The prince with a bad tooth got a crown), both meanings of the homonym must be accessed and selected. Previous ERP studies have shown that the N400 reflects lexicosemantic processing, but none have directly investigated the N400 elicited by homonyms in the unique context of puns. Here, N400 priming effects showed that the dual context of puns (e.g., the primes prince and tooth) did not facilitate homonym processing in comparison to single dominant biasing (e.g., The prince with a bad leg got a crown) or subordinate biasing (e.g., The adult with a bad tooth got a crown) conditions. However, homonyms did elicit a less negative N400 (i.e., priming) in the pun condition in comparison to the neutral context condition (e.g., The adult with a bad leg got a crown). These findings are interpreted in terms of the dominant advantage and subordinate bias effect posited by the reordered access model of homonym processing, and in terms of N400 amplitude as an index of how consistently various sources of semantic featural information converge on one lexical item, even when two lexical items must be activated for comprehension.


Long-term effects of mental disorders on marital outcomes in the National Comorbidity Survey ten-year follow-up.
Epidemiological research has consistently shown an association between mental disorders and marital dissolution. However, this research mostly examined the association of divorce as a risk factor for mental illness. This study prospectively examined the associations of mood, anxiety, and substance use disorders with future marital dissolution and new marriages in a representative population sample. The study used data from the National Comorbidity Survey panel study-a two-wave community epidemiological survey of 5001 participants interviewed in 1990-1992 and re-interviewed in 2001-2003. Mental disorders were ascertained with the Composite International Diagnostic Interview, a fully structured instrument. Associations of baseline lifetime disorders and disorders with onset after the baseline with subsequent divorce and marriage/remarriage were examined using discrete-time survival analysis models. Mental disorders at baseline or with onset after baseline were associated with significantly greater odds of subsequent divorce among respondents who either were married at baseline or got married after baseline. Mental disorders with onset after baseline were associated with smaller odds of marriage or remarriage. Projections assuming causal effects of mental illness on marital outcomes suggest that preventing the effects of common mood, anxiety, and substance use disorders would be associated with 6.7 million fewer divorces and 3.5 million more marriages in the US population over an 11-year period. Individuals with common mental disorders are at greater risk of marital dissolution and are less likely to enter new marriages. These factors contribute to the diminished social engagement and social support for individuals with these disorders. Interventions aimed at improving marital and family relationships could potentially ameliorate the effect of mental disorders on these vital social ties.


Welander's distal myopathy: clinical, neurophysiological and muscle biopsy observations in young and middle aged adults with early symptoms.
Nine young or middle aged patients with early symptoms of Welander's distal myopathy were subjected to a detailed neurological examination including quantitative sensory testing, determination of motor and sensory nerve conduction velocity (NCV), sensory nerve action potentials, electromyography (EMG) and muscle biopsy from the tibialis anterior muscle (TA). Slight weakness of the extensors of the fingers and hands was found in all nine patients, and of the dorsiflexors of the feet in seven. All patients had a distal sensory disturbance most prominent for temperature which agrees with earlier observations. EMG changes in TA and extensor digitorum communis (EDC) muscles were of myopathic type. Slight abnormalities compatible with either myopathy or early neuropathy were found in one muscle biopsy. These findings indicate that a neurogenic lesion affecting at least the peripheral sensory system is present at an early stage of Welander's distal myopathy and that the neurogenic lesion might precede the myopathic changes.


Pepsin and the esophagus.
Esophagitis results from excessive exposure of the esophagus to gastric juice through an ineffective or dysfunctional lower esophageal sphincter mechanism. A possible role of pepsin in damaging the esophageal mucosa with consequent esophagitis may be examined directly by testing pepsin under various conditions in experimental models of esophagitis. Since gastric juice contains both acid and pepsin, all experiments examine separately effects of perfusion of the esophagus by acid without and with pepsin in various combinations. Acid perfusion alone at concentrations represented by pH 1.3 or above does not produce esophagitis. The addition of pepsin to acid between pH 1 and 3.5 causes considerable acute esophageal damage. Outside the proteolytic range, i.e., higher than pH 3.5, pepsin does not damage the esophagus. The damage caused by acidified pepsin may be made much worse by the further addition of aspirin or other NSAIDs, presumably by further breaking down mucosal barriers.


Multiple ubiquitin-dependent processing pathways regulate hedgehog/gli signaling: implications for cell development and tumorigenesis.
Hedgehog pathway is crucial for the maintenance and self-renewal of neural stem cells and for tumorigenesis. Hedgehog signaling is limited by multiple E3 ubiquitin ligases that process the downstream transcription factors Gli. Cullin family-based ubiquitination results in either Cullin1-Slimb/betaTrCP- or Cullin3-HIB/Roadkill/SPOP-dependent proteolytic processing or degradation of Drosophila Cubitus interruptus or mammalian Gli proteins. We have recently identified Itch as an additional HECT family E3 ligase, able to ubiquitinate and degrade Gli1. A functional link with the influence of Hedgehog signaling on cell development and tumorigenesis is suggested by the identification of Numb as a promoter of such an Itch-dependent ubiquitination process that leads to Gli1 degradation, thus suppressing its transcriptional function. Numb is an evolutionary conserved developmental protein that, during progenitor division, asymmetrically segregates to daughter cells thereby determining distinct binary cell fates. Numb is downregulated in cerebellar progenitors and their malignant derivatives (i.e. medulloblastoma cells). Furthermore, Numb has anti-proliferative and pro-differentiation effects on both cerebellar progenitors and medulloblastoma cells, due to its suppression of functional Gli1. These findings unveil a novel Numb/Itch-dependent regulatory loop that limits the extent and duration of Hedgehog signaling during neural progenitor differentiation. Its subversion emerges as a relevant event in brain tumorigenesis.


Large-Scale Graphene on Hexagonal-BN Hall Elements: Prediction of Sensor Performance without Magnetic Field.
A graphene Hall element (GHE) is an optimal system for a magnetic sensor because of its perfect two-dimensional (2-D) structure, high carrier mobility, and widely tunable carrier concentration. Even though several proof-of-concept devices have been proposed, manufacturing them by mechanical exfoliation of 2-D material or electron-beam lithography is of limited feasibility. Here, we demonstrate a high quality GHE array having a graphene on hexagonal-BN (h-BN) heterostructure, fabricated by photolithography and large-area 2-D materials grown by chemical vapor deposition techniques. A superior performance of GHE was achieved with the help of a bottom h-BN layer, and showed a maximum current-normalized sensitivity of 1986 V/AT, a minimum magnetic resolution of 0.5 mG/Hz(0.5) at f = 300 Hz, and an effective dynamic range larger than 74 dB. Furthermore, on the basis of a thorough understanding of the shift of charge neutrality point depending on various parameters, an analytical model that predicts the magnetic sensor operation of a GHE from its transconductance data without magnetic field is proposed, simplifying the evaluation of each GHE design. These results demonstrate the feasibility of this highly performing graphene device using large-scale manufacturing-friendly fabrication methods.