Pharmacology of HIV integrase inhibitors.
The purpose of this study is to review recent and relevant pharmacology data for three HIV integrase inhibitors: raltegravir (marketed), dolutegravir, and elvitegravir (both in phase III drug development). Data from January 2011 to April 2012 were evaluated. These data better characterized integrase inhibitor pharmacokinetics, assessed dosing regimens, and investigated previously undescribed drug-drug interactions. Due to formulation challenges, raltegravir inter-patient and intra-patient pharmacokinetic variability is high. Twice-daily 400 mg dosing has been shown to be clinically superior to 800 mg once-daily dosing. A pediatric formulation of raltegravir with less variable pharmacokinetics and greater bioavailability was US Food and Drug Administration (US FDA)-approved in December 2011. Cobicistat-boosted elvitegravir, and the second-generation integrase inhibitor dolutegravir, have lower pharmacokinetic variability and are dosed once daily. Dolutegravir drug interactions are similar to raltegravir, whereas boosted elvitegravir participates in additional CYP3A-mediated interactions. Raltegravir's potent antiretroviral activity has resulted in widespread use in both treatment-naïve and experienced patients. Dolutegravir and cobicistat-boosted elvitegravir have some pharmacokinetic advantages. Pharmacokinetic data in special populations (pregnancy, pediatrics) to optimize dosing are still required.


[Damping method of traction].
Damping of the system of skeletal extension with steel coil springs, ball bearing blocks and capron fishing-line was shown by the authors to be a necessity, since the routinely used "rigid" systems proved to be less effective. The authors have elaborated a new method of elimination of angular deviations of fragments and dislocations in width.


Mucosal and cutaneous human papillomaviruses detected in raw sewages.
Epitheliotropic viruses can find their way into sewage. The aim of the present study was to investigate the occurrence, distribution, and genetic diversity of Human Papillomaviruses (HPVs) in urban wastewaters. Sewage samples were collected from treatment plants distributed throughout Italy. The DNA extracted from these samples was analyzed by PCR using five PV-specific sets of primers targeting the L1 (GP5/GP6, MY09/MY11, FAP59/64, SKF/SKR) and E1 regions (PM-A/PM-B), according to the protocols previously validated for the detection of mucosal and cutaneous HPV genotypes. PCR products underwent sequencing analysis and the sequences were aligned to reference genomes from the Papillomavirus Episteme database. Phylogenetic analysis was then performed to assess the genetic relationships among the different sequences and between the sequences of the samples and those of the prototype strains. A broad spectrum of sequences related to mucosal and cutaneous HPV types was detected in 81% of the sewage samples analyzed. Surprisingly, sequences related to the anogenital HPV6 and 11 were detected in 19% of the samples, and sequences related to the "high risk" oncogenic HPV16 were identified in two samples. Sequences related to HPV9, HPV20, HPV25, HPV76, HPV80, HPV104, HPV110, HPV111, HPV120 and HPV145 beta Papillomaviruses were detected in 76% of the samples. In addition, similarity searches and phylogenetic analysis of some sequences suggest that they could belong to putative new genotypes of the beta genus. In this study, for the first time, the presence of HPV viruses strongly related to human cancer is reported in sewage samples. Our data increases the knowledge of HPV genomic diversity and suggests that virological analysis of urban sewage can provide key information useful in supporting epidemiological studies.


Contamination of hospital surfaces with respiratory pathogens in Bangladesh.
With limited infection control practices in overcrowded Bangladeshi hospitals, surfaces may play an important role in the transmission of respiratory pathogens in hospital wards and pose a serious risk of infection for patients, health care workers, caregivers and visitors. In this study, we aimed to identify if surfaces near hospitalized patients with respiratory infections were contaminated with respiratory pathogens and to identify which surfaces were most commonly contaminated. Between September-November 2013, we collected respiratory (nasopharyngeal and oropharyngeal) swabs from patients hospitalized with respiratory illness in adult medicine and paediatric medicine wards at two public tertiary care hospitals in Bangladesh. We collected surface swabs from up to five surfaces near each case-patient including: the wall, bed rail, bed sheet, clinical file, and multipurpose towel used for care giving purposes. We tested swabs using real-time multiplex PCR for 19 viral and 12 bacterial pathogens. Case-patients with at least one pathogen detected had corresponding surface swabs tested for those same pathogens. Of 104 patients tested, 79 had a laboratory-confirmed respiratory pathogen. Of the 287 swabs collected from surfaces near these patients, 133 (46%) had evidence of contamination with at least one pathogen. The most commonly contaminated surfaces were the bed sheet and the towel. Sixty-two percent of patients with a laboratory-confirmed respiratory pathgen (49/79) had detectable viral or bacterial nucleic acid on at least one surface. Klebsiella pneumoniae was the most frequently detected pathogen on both respiratory swabs (32%, 33/104) and on surfaces near patients positive for this organism (97%, 32/33). Surfaces near patients hospitalized with respiratory infections were frequently contaminated by pathogens, with Klebsiella pneumoniae being most common, highlighting the potential for transmission of respiratory pathogens via surfaces. Efforts to introduce routine cleaning in wards may be a feasible strategy to improve infection control, given that severe space constraints prohibit cohorting patients with respiratory illness.


The response of phytoplankton and microlayer-adapted bacteria to monolayer application in a humic, eutrophic irrigation dam.
Repeat applications of artificial monolayers to farm irrigation dams to reduce evaporative loss may adversely affect water quality by enhancing populations of microlayer-adapted bacteria and blue-green algae. The microlayer, subsurface and water column of a 16 ha dam were monitored every two weeks for 18 months, to benchmark the seasonal dynamics of phytoplankton and microlayer-adapted bacteria prior to monolayer application. Results for Secchi depth, total P, total N, chlorophyll a, phytobiovolume and UV254 absorbance, characterise Logan's Dam as humic and hypereutrophic. Seasonal peaks in the cyanobacterial species Microcystis aeruginosa and Anabaena sp. associated with regular thermal stratification periods over summer, exceeded the Queensland algal bloom alert level. Dissolved organic matter derived from aromatic char in the black soil used to construct the dam was the main substrate for microlayer-adapted bacteria. Intermittent monolayer application over seven weeks in late summer temporarily increased surface pressure, indicating a condensed monolayer had formed, with no increase in chemical oxygen demand or in populations of cyanobacteria or microlayer-adapted bacteria. The increase in dissolved organic carbon was well below the concentration recorded after a pump ingress event in late spring. In this humic hypereutrophic irrigation dam, repeat applications of the experimental monolayer formulation did not adversely affect water quality.


Immunocytological effects of varied inocula of influenza virus.
Variation in the amount and quality of influenza virus injected into the amniotic sac of the chick embryo led to differences not only in the yield of virus but also in the immunofluorescent cytology of the infection. The production of infectious virus was associated with a predominance of cells in which the virus antigens were first detected along the cell surface in contact with the amniotic fluid, later deeper in the cytoplasm, and finally, though to a lesser extent, in the nucleus. When the virus yield was primarily non-infectious hemagglutinin the virus antigens appeared in reverse sequence; i.e., nucleus first, then adjacent cytoplasm, and ultimately throughout the entire cell. Under conditions of "autointerference," the immunofluorescence seen in some of the cells failed to progress beyond the nuclear or early cytoplasmic stage, while many other cells remained unreactive throughout the experimental period. With the largest dose used a pale intranuclear reaction was localized 1 hour after injection but the embryo died shortly thereafter.


UNITE: a database providing web-based methods for the molecular identification of ectomycorrhizal fungi.
Identification of ectomycorrhizal (ECM) fungi is often achieved through comparisons of ribosomal DNA internal transcribed spacer (ITS) sequences with accessioned sequences deposited in public databases. A major problem encountered is that annotation of the sequences in these databases is not always complete or trustworthy. In order to overcome this deficiency, we report on UNITE, an open-access database. UNITE comprises well annotated fungal ITS sequences from well defined herbarium specimens that include full herbarium reference identification data, collector/source and ecological data. At present UNITE contains 758 ITS sequences from 455 species and 67 genera of ECM fungi. UNITE can be searched by taxon name, via sequence similarity using blastn, and via phylogenetic sequence identification using galaxie. Following implementation, galaxie performs a phylogenetic analysis of the query sequence after alignment either to pre-existing generic alignments, or to matches retrieved from a blast search on the UNITE data. It should be noted that the current version of UNITE is dedicated to the reliable identification of ECM fungi. The UNITE database is accessible through the URL http://unite.zbi.ee


[Determination of severity of harm caused to health in depressed skull deformation by «ping-pong» type in an infant].
Is to develop a differential approach to determining the severity of harm caused to health in case of depressed skull injuries in infants, depending on their morphological features and the character of required treatment. The material included data from literature sources on the study of brain injuries in infants, clinical guidelines, describing the features of clinical picture and diagnosis of depressed skull fractures in infants and legal and regulatory framework of forensic medical evaluation of harm caused to health in injury. The following methods of research were used: logical-analytical, logical-synthetic (generalization), comparative, system-analytical (analysis of relations between facts) and radiological method. An algorithm for determining the severity of harm caused to health in depressed skull deformations by «ping-pong» type in an infant is proposed for discussion. The algorithm is based on the data from injury imaging techniques, including X-ray computed tomography, takes into account the clinical picture and the availability of indications for surgical treatment, and will allow to objectively assess the severity of harm caused to health in such cases.


Cuproptosis/ferroptosis-related gene signature is correlated with immune infiltration and predict the prognosis for patients with breast cancer.
Background: Breast invasive carcinoma (BRCA) is a malignant tumor with high morbidity and mortality, and the prognosis is still unsatisfactory. Both ferroptosis and cuproptosis are apoptosis-independent cell deaths caused by the imbalance of corresponding metal components in cells and can affect the proliferation rate of cancer cells. The aim in this study was to develop a prognostic model of cuproptosis/ferroptosis-related genes (CFRGs) to predict survival in BRCA patients. Methods: Transcriptomic and clinical data for breast cancer patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Cuproptosis and ferroptosis scores were determined for the BRCA samples from the TCGA cohort using Gene Set Variation Analysis (GSVA), followed by weighted gene coexpression network analysis (WGCNA) to screen out the CFRGs. The intersection of the differentially expressed genes grouped by high and low was determined using X-tile. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) were used in the TGCA cohort to identify the CFRG-related signature. In addition, the relationship between risk scores and immune infiltration levels was investigated using various algorithms, and model genes were analyzed in terms of single-cell sequencing. Finally, the expression of the signature genes was validated with quantitative real-time PCR (qRT‒PCR) and immunohistochemistry (IHC). Results: A total of 5 CFRGs (ANKRD52, HOXC10, KNOP1, SGPP1, TRIM45) were identified and were used to construct proportional hazards regression models. The high-risk groups in the training and validation sets had significantly worse survival rates. Tumor mutational burden (TMB) was positively correlated with the risk score. Conversely, Tumor Immune Dysfunction and Exclusion (TIDE) and tumor purity were inversely associated with risk scores. In addition, the infiltration degree of antitumor immune cells and the expression of immune checkpoints were lower in the high-risk group. In addition, risk scores and mTOR, Hif-1, ErbB, MAPK, PI3K/AKT, TGF-β and other pathway signals were correlated with progression. Conclusion: We can accurately predict the survival of patients through the constructed CFRG-related prognostic model. In addition, we can also predict patient immunotherapy and immune cell infiltration.


A low energy oxide-based electronic synaptic device for neuromorphic visual systems with tolerance to device variation.
Neuromorphic computing is an emerging computing paradigm beyond the conventional digital von Neumann computation. An oxide-based resistive switching memory is engineered to emulate synaptic devices. At the device level, the gradual resistance modulation is characterized by hundreds of identical pulses, achieving a low energy consumption of less than 1 pJ per spike. Furthermore, a stochastic compact model is developed to quantify the device switching dynamics and variation. At system level, the performance of an artificial visual system on the image orientation or edge detection with 16 348 oxide-based synaptic devices is simulated, successfully demonstrating a key feature of neuromorphic computing: tolerance to device variation.


Total synthesis of (±)-maistemonine, (±)-stemonamide, and (±)-isomaistemonine.
A full account of the total synthesis of (±)-maistemonine, (±)-stemonamide, and (±)-isomaistemonine is presented. Two approaches have been developed to construct the basic pyrrolo[1,2-a]azepine core of the Stemona alkaloids, featuring a tandem semipinacol/Schmidt rearrangement of a secondary azide and a highly stereoselectively desymmetrizing intramolecular Schmidt reaction, respectively. To build the common spiro-γ-butyrolactone, a new protocol was carried out by utilizing an intramolecular ketone-ester condensation as the key transformation. The vicinal butyrolactone moiety of (±)-maistemonine was stereoselectively introduced via a one-pot procedure involving the epimerization at C-3 and carbonyl allylation/lactonization. Moreover, (±)-stemonamide was divergently synthesized from a common intermediate, and (±)-isomaistemonine was obtained via the epimerization of (±)-maistemonine at C-12.


Cell cycle control by Xenopus p28Kix1, a developmentally regulated inhibitor of cyclin-dependent kinases.
We have isolated Xenopus p28Kix1, a member of the p21CIP1/p27KIP1/p57KIP2 family of cyclin-dependent kinase (Cdk) inhibitors. Members of this family negatively regulate cell cycle progression in mammalian cells by inhibiting the activities of Cdks. p28 shows significant sequence homology with p21, p27, and p57 in its N-terminal region, where the Cdk inhibition domain is known to reside. In contrast, the C-terminal domain of p28 is distinct from that of p21, p27, and p57. In co-immunoprecipitation experiments, p28 was found to be associated with Cdk2, cyclin E, and cyclin A, but not the Cdc2/cyclin B complex in Xenopus egg extracts. Xenopus p28 associates with the proliferating cell nuclear antigen, but with a substantially lower affinity than human p21. In kinase assays with recombinant Cdks, p28 inhibits pre-activated Cdk2/cyclin E and Cdk2/cyclin A, but not Cdc2/cyclin B. However, at high concentrations, p28 does prevent the activation of Cdc2/cyclin B by the Cdk-activating kinase. Consistent with the role of p28 as a Cdk inhibitor, recombinant p28 elicits an inhibition of both DNA replication and mitosis upon addition to egg extracts, indicating that it can regulate multiple cell cycle transitions. The level of p28 protein shows a dramatic developmental profile: it is low in Xenopus oocytes, eggs, and embryos up to stage 11, but increases approximately 100-fold between stages 12 and 13, and remains high thereafter. The induction of p28 expression temporally coincides with late gastrulation. Thus, although p28 may play only a limited role during the early embryonic cleavages, it may function later in development to establish a somatic type of cell cycle. Taken together, our results indicate that Xenopus p28 is a new member of the p21/p27/p57 class of Cdk inhibitors, and that it may play a role in developmental processes.


Association between General Sense of Mastery and Income in White- and African-American Adults.
Some research has shown that general sense of mastery (i.e., sense of control over the forces that impact one's life) does not have universal causes and consequences in racial groups. For instance, sense of mastery better predicts depression and mortality for non-Hispanic Whites (NHWs) than that of African-Americans (AAs). The objective of this study was to test the heterogeneity in the association between the sense of mastery and income by race in a nationally representative sample of NHW and AA adults. This study included a total of 3570 AA and 891 NHW adults who were enrolled to the National Survey of American Life. Variables included race/ethnicity, age, gender, socioeconomic status (SES and household income), and sense of mastery. Linear regression models were applied in the overall sample and also by race. Overall, high sense of mastery was associated with high household income. In race-specific models, higher levels of sense of mastery were associated with high household income in AAs but not NHWs. Racial differences exist in how sense of mastery and income are correlated. It is not clear whether high income generates more sense of mastery for AAs or high sense of mastery is more essential for generating high income for AAs. Policy-makers and clinicians should be aware that SES and sense of mastery are differently linked in AAs and NHWs.


Origins of the problem of health-related behaviours: a genealogical study.
In recent years a number of public health, prevention and disease management strategies have emerged that depend on changing health-related behaviours. The definition of those behaviours, indeed of the very idea of behaviour, remains unchallenged in these initiatives, as behaviour is a taken-for-granted concept. Yet the idea of a changeable behaviour is a relatively recent phenomenon and the aim of this paper is to map its emergence and transformation over the last century. Its origins are shown to lie in the first half of the 20th century when it was derived from the ideas of conduct and movement. From mid-century onwards, it has been increasingly construed as being underpinned by a sense of agency and as a legitimate target for healthcare interventions. Finally, in the 21st century it has become stabilized as a core dimension of health and illness.


[The shape of proton magnetic resonance band of lipid bilayers].
An approximation of isolated spin pairs is used to obtain the equation for PMR line shape of lipid bilayers. The internuclear vector order parameter dependence on the position of the proton pair of lipid molecule is taken into account. Good agreement with experimental curves leads to the conclusion that the main reason for the unusual PMR line shape of lipid bilayers is decrease of order parameters on approaching hydrophobic tails of lipid molecules of bilayer.


[Comparative study of 5 European tables of food composition (study of European tables of food composition)].
A comparative study has been made of the following nutritional data base: (A) C.S.I.C. (Spain); (B) Deutsche Forschungsanstalt für Lebensmittel Chemie, Garching; (C) INSERM (France); (D) Geigy; (E) Wander. The following values were researched: calorie, protein, carbohydrate, fiber, calcium, iron, magnesium, Vit. B1, Vit B2, Niacin, Folic Acid, Vit. B12 and Vit. C. In order to assess the use of these tables under different conditions, the following were researched: 1) A group of 10 essential representative foods. 2) A group of 25 foods corresponding to a 24-hour count of what can be considered a standard diet. 3) Data obtained from a food survey (24-hour count) applied to 72, 13-year-old students at a Barcelona public school (winter 1988). In this case, the Spanish data base was used as reference. Computerized data processing, especially variation coefficient studies revealed that macronutrients correlated well with the different data bases. On the other hand, the greatest differences were observed among micronutrients, especially vitamin B12, niacin, folic acid, calcium and particularly fiber. The role different national data bases may play within the context of a more integrated european system was assessed.


Alcohol consumption and risk of stomach cancer: A meta-analysis.
Stomach cancer is one of the most common cancers in the world. The relationship between alcohol consumption and the risk of stomach cancer remains unclear. Epidemiology studies investigating this relationship have shown inconsistent findings. A meta-analysis was performed to explore the association between alcohol consumption and increased stomach cancer risk. Eighty-one epidemiology studies, including 68 case-control studies and 13 cohort studies, were included in this study. A significant association was found between alcohol consumption and increased risk of stomach cancer (OR = 1.20, 95% CI 1.12-1.27). To explore the source of the significant heterogeneity (p < 0.05, I2 = 86%), analysis was stratified by study type (case-control study and cohort study), control type (hospital-based control and population-based control), gender (male, female, and mix), race (White and Asian), region (United States, Sweden, China, Japan), subsite of stomach cancer, and type of alcohol. The stratified analyses found that region and cancer subsite are major sources of the high heterogeneity. The inconsistent results in different regions and different subsites might be related to smoking rates, Helicobacter pylori infection, obesity, and potential genetic susceptibility. The positive association between drinking and increased risk of stomach cancer is consistent in stratified analyses. The dose-response analysis showed a clear trend that a higher daily intake of alcohol is associated with a higher risk of stomach cancer.


Flexible free-standing luminescent two-component fiber films with tunable hierarchical structures based on hydrogen-bonding architecture.
Although the fabrication of hierarchical architectures with highly ordered functional units is of great importance for both fundamental science and practical application, the development of one-dimensional (1D) organic hierarchical micro/nanostructures based on low-molecular-weight (LMW) building blocks remains at an early stage. Herein, we report two types of micro/nanoscaled multicomponent fluorescent fiber systems with tunable hierarchical morphologies through a one-step coassembly process. With the aid of hydrogen-bonding motifs, LMW precursors (1,4-bis(5-phenyloxazol-2-yl)benzene (A) and two coassembled building blocks: 4-bromotetrafluorobenzene carboxylic acid (B) and 2,3,4,5,6-pentafluorophenol (C)) have been self-organized into fibers and flexible free-standing films, which show hierarchical micro/nanostructures as well as tunable one-/two-photon luminescence. The disassembly of the multicomponent A.B and A.C fibers occurs at high temperature, which further alters the luminescence properties of the multicomponent materials. Therefore, this work provides a facile wet chemical route for fabricating multicomponent LMW self-assembled fibers and free-standing film systems with tunable hierarchical structures and photoemission behaviors, and such self-organized systems may have potential applications in fields of two-photon luminescence and thermal sensors.


Composition of corn dry-grind ethanol by-products: DDGS, wet cake, and thin stillage.
DDGS and wet distillers' grains are the major co-products of the dry grind ethanol facilities. As they are mainly used as animal feed, a typical compositional analysis of the DDGS and wet distillers' grains mainly focuses on defining the feedstock's nutritional characteristics. With an increasing demand for fuel ethanol, the DDGS and wet distillers' grains are viewed as a potential bridge feedstock for ethanol production from other cellulosic biomass. The introduction of DDGS or wet distillers' grains as an additional feed to the existing dry grind plants for increased ethanol yield requires a different approach to the compositional analysis of the material. Rather than focusing on its nutritional value, this new approach aims at determining more detailed chemical composition, especially on polymeric sugars such as cellulose, starch and xylan, which release fermentable sugars upon enzymatic hydrolysis. In this paper we present a detailed and complete compositional analysis procedure suggested for DDGS and wet distillers' grains, as well as the resulting compositions completed by three different research groups. Polymeric sugars, crude protein, crude oil and ash contents of DDGS and wet distillers' grains were accurately and reproducibly determined by the compositional analysis procedure described in this paper.


A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus.
An increased frequency of atherosclerosis (ATH) in systemic lupus erythematosus (SLE) is well-documented but not fully explained by the presence of traditional cardiac risk factors. Several nontraditional biomarkers, including proinflammatory high-density lipoprotein (piHDL) and leptin, have been individually associated with subclinical ATH in SLE. The aim of this study was to examine whether these and other biomarkers can be combined into a risk profile, the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular Disease in Patients with SLE (PREDICTS), that could be used to better predict future progression of ATH. In total, 210 patients with SLE and 100 age-matched healthy control subjects (all women) participated in this prospective cohort study. The longitudinal presence of carotid plaque and intima-media thickness (IMT) were measured at baseline and followup (mean ± SD 29.6 ± 9.7 months). At followup, carotid plaque was present in 29% of SLE patients. Factors significantly associated with plaque, determined using Salford Predictive Modeling and multivariate analysis, included age ≥48 years (odds ratio [OR] 4.1, P = 0.002), high piHDL function (OR 9.1, P < 0.001), leptin levels ≥34 ng/dl (OR 7.3, P = 0.001), plasma soluble TWEAK levels ≥373 pg/ml (OR 28.8, P = 0.004), and history of diabetes (OR 61.8, P < 0.001). Homocysteine levels ≥12 μmoles/liter were also a predictor. However, no single variable demonstrated an ideal combination of good negative predictive values (NPVs), positive predictive values (PPVs), sensitivity, and specificity. A high-risk PREDICTS profile was defined as ≥3 positive biomarkers or ≥1 positive biomarker plus a history of diabetes; for high-risk SLE patients, the PPV was 64%, NPV was 94%, sensitivity was 89%, and specificity was 79%. In multivariate analysis, SLE patients with the high-risk profile had 28-fold increased odds for the longitudinal presence of plaque (P < 0.001) and increased progression of IMT (P < 0.001). A high-risk PREDICTS score confers 28-fold increased odds of the presence of any current, progressive, or acquired carotid plaque, both in patients with SLE and in control subjects, and is significantly associated with higher rates of IMT progression.


Synthesis of lactams via copper-catalyzed intramolecular vinylation of amides.
Copper-catalyzed intramolecular vinylation of iodoenamides were investigated for the first time. With CuI as the catalyst and N,N'-dimethylethylenediamine as the ligand, a number of iodoenamides underwent cyclization in dioxane leading to the formations of five- to seven-membered lactams in moderate to excellent yields.


Fibrinolysis and the bleeding tendency in patients with hepatosplenic schistosomiasis.
Fifty seven patients with schistosomiasis of the liver and spleen in both the compensated and decompensated states and 15 non-bilharzial subjects were studied. Fibrinogen, plasminogen, fibrinogen/fibrin degradation products, alpha 2-macroglobulin, antithrombin III and Cl-activator concentrations were evaluated in an attempt to assess abnormalities at various stages of the disease. The results showed a progressive decrease in fibrinogen and plasminogen concentrations; fibrin degradation products showed a progressive increase as the disease progressed. Together with a falling platelet count, these data indicate the possible occurrence of disseminated intravascular coagulation with enhanced fibrinolysis which was most pronounced in those who vomited blood. Antithrombin III concentration showed a progressive decrease in parallel with the progress of the disease, possibly due to decreased synthesis or increased consumption, or both. Cl-activator concentration showed no significant change from that in normal controls at any stage of the disease. These findings provide further evidence that disseminated intravascular coagulation and enhanced fibrinolysis in the late stages of schistosomiasis may contribute to the haemorrhagic diathesis seen in the liver and spleen.


[Cloacal and nasal bacterial flora of Lepidochelys olivacea (Testudines: Cheloniidae) from the North Pacific Coast of Costa Rica].
Cloacal and nasal bacterial flora of Lepidochelys olivacea (Testudines: Cheloniidae) from the North Pacific coast of Costa Rica. The aerobic cloacal and nasal bacterial flora of 45 apparently healthy female olive ridley sea turtles (Lepidochelys olivacea) was studied at Nancite nesting beach, in Santa Rosa National Park (Costa Rican North Pacific) during July and August 2002. Bacterial samples were obtained by inserting sterile swabs directly into the cloaca and the nasal cavities of the turtles. Ninety-nine aerobic bacterial isolates, including 10 Gram-negative and 5 Gram-positive bacteria, were recovered. The most common bacteria cultured were Aeromonas spp. (13/45) and Citrobacter freundi (6/45) from cloacal samples and Bacillus spp. (32/45), Staphylococcus aureus (6/45) and Corynebacterium spp. (5/45) from nasal ducts. The results of the present study showed that the aerobic bacterial flora of nesting female olive ridleys was composed of several potential human and animal microbe pathogens.


Serum sodium, model for end-stage liver disease, and a recent invasive procedure are risk factors for severe acute-on-chronic liver failure and death in cirrhotic patients hospitalized with bacterial infection.
Bacterial infection is present in up to 30% of hospitalized cirrhotic patients. It can lead, even after its resolution, to organ dysfunction and even acute-on-chronic liver failure (ACLF). It is the precipitating factor of ACLF in one third of the cases and is the main cause of mortality in patients with liver cirrhosis. The aim of this study was to evaluate the prevalence and identify early risk factors for severe ACLF and death in hospitalized patients with liver cirrhosis with bacterial infection. This was a prospective observational study. Hospitalized patients with liver cirrhosis and bacterial infection were included. Clinical and laboratory data and their evolution to organ dysfunction and death were assessed. A statistical analysis were carried out to identify predictors of severe ACLF and in-hospital mortality. This study included 88 patients. ACLF was observed in 62 (70%) patients, with 48 (55%) grade 2 or higher. Of the 27 deaths (31% of all patients), 26 had severe ACLF (54% mortality) (P<0.0001). The independent risk factors for ACLF of at least 2 and death were baseline serum sodium [odds ratio (OR): 0.874; P=0.01, and OR: 0.9, P=0.04], initial MELD (OR: 1.255, P=0.0001, and OR: 1.162, P=0.005), and a recent invasive procedure (OR: 3.169, P=0.01, and OR: 6.648, P=0.003). Lower serum sodium values, higher MELD scores at diagnosis of infection, and a recent history of invasive procedures were independent risk factors for severe ACLF and death in patients with cirrhosis and bacterial infection.


The effect of inducible nitric oxide synthase (iNOS) inhibition on smoke inhalation injury in sheep.
Recent studies on smoke inhalation injury have been focused on nitric oxide (NO) as an essential factor of progressive lung injury. We studied the effects of inducible nitric oxide synthase (iNOS) inhibition on inhalation injury in sheep. Sheep (n = 14) were prepared surgically for chronic study. After recovery period, the sheep received 48 breaths of cotton smoke. The animals were then randomised into two groups: MEG group [30 mg/kg mercaptoethylguanidine (MEG), selective inhibitor of iNOS and peroxynitrite scavenger, was given 1 h after injury and then 8 h for 41 h, n = 7] and control group (0.9% NaCl, n = 7). All animals were ventilated mechanically, and airway blood flow was measured using colored microspheres. In the control group, following significant increase in airway blood flow, deterioration in the PaO2/FiO2 ratio was observed. Whereas in the MEG group, it was not observed. In addition, the MEG group did not show significant increase in pulmonary vascular resistance and intrapulmonary shunt fraction. Lung wet/dry ratios, a marker of pulmonary edema, were significantly lower in the MEG group. At 48 h after injury, lung tissue-conjugated dienes, an index of lung oxidative tissue injury, were significantly lower in the MEG group than in the control group. Our data suggest that 1) iNOS-NO produced in the airway circulation plays a major role on the significant increase in airway blood flow, which may contribute to the spread of injury from injured airway to the lung parenchyma; 2) iNOS-NO induced in the pulmonary circulation contributes to the loss of hypoxic pulmonary vasoconstriction; and 3) iNOS-NO plays an important role on the lung oxidative tissue injury.


Green tea polyphenols provide photoprotection, increase microcirculation, and modulate skin properties of women.
Dietary constituents including polyphenols and carotenoids contribute to endogenous photoprotection and modulate skin characteristics related to structure and function of the tissue. Animal and in-vitro studies indicate that green tea polyphenols affect skin properties. In a 12-wk, double-blind, placebo-controlled study, 60 female volunteers were randomized to an intervention or control group. Participants consumed either a beverage with green tea polyphenols providing 1402 mg total catechins/d or a control beverage. Skin photoprotection, structure, and function were measured at baseline (wk 0), wk 6, and wk 12. Following exposure of the skin areas to 1.25 minimal erythemal dose of radiation from a solar simulator, UV-induced erythema decreased significantly in the intervention group by 16 and 25% after 6 and 12 wk, respectively. Skin structural characteristics that were positively affected included elasticity, roughness, scaling, density, and water homeostasis. Intake of the green tea polyphenol beverage for 12 wk increased blood flow and oxygen delivery to the skin. Likewise, in a separate, randomized, double-blind, single-dose (0.5, 1.0, and 2.0 g) study of green tea polyphenols, blood flow was maximized at 30 min after ingestion. In summary, green tea polyphenols delivered in a beverage were shown to protect skin against harmful UV radiation and helped to improve overall skin quality of women.


Intussusception among Japanese children: an epidemiologic study using an administrative database.
The epidemiology of intussusception, including its incidence, can vary between different countries. The aim of this study was to describe the epidemiology of childhood intussusception in Japan using data from a nationwide inpatient database. We screened the database for eligible cases ≤ 18 years of age, who were coded with a discharge diagnosis of intussusception (International Classification of Diseases, 10th revision: K-561) between July to December in 2007 and 2008. We then selected cases according to Level 1 of the diagnostic certainty criteria developed by the Brighton Collaboration Intussusception Working Group. We examined the demographics, management, and outcomes of cases, and estimated the incidence of intussusception. We identified 2,427 cases of intussusception. There were an estimated 2,000 cases of infantile intussusception annually in Japan, an incidence of 180-190 cases per 100,000 infants. The median age at diagnosis was 17 months, and two-thirds of the patients were male. Treatment with an enema was successful in 93.0% of cases (2255/2427). The remainder required surgery. Secondary cases accounted for 3.1% (76/2427). Median length of hospital stay was 3 days. Of the 2,427 cases, we found 2 fatal cases associated with intussusception. This is currently the largest survey of childhood intussusception in Asia using a standardized case definition. Our results provide an estimate of the baseline risk of intussusception in Japan, and it is higher than the risk observed in other countries.


Persistent increases of PKMζ in memory-activated neurons trace LTP maintenance during spatial long-term memory storage.
PKMζ is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other kinases that are transiently stimulated by second messengers, PKMζ is persistently activated through sustained increases in protein expression of the kinase. Therefore, visualizing increases in PKMζ expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain. Using quantitative immunohistochemistry validated by the lack of staining in PKMζ-null mice, we examined the amount and distribution of PKMζ in subregions of the hippocampal formation of wild-type mice during LTP maintenance and spatial long-term memory storage. During LTP maintenance in hippocampal slices, PKMζ increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 hr. During spatial memory storage, PKMζ increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. During the initial expression of the memory, we tagged principal cells with immediate-early gene Arc promoter-driven transcription of fluorescent proteins. The subset of memory-tagged CA1 cells selectively increases expression of PKMζ during memory storage, and the increase persists in dendritic compartments within stratum radiatum for 1 month, indicating long-term storage of information in the CA3-to-CA1 pathway. We conclude that persistent increases in PKMζ trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.


Exploring a structural protein-drug interactome for new therapeutics in lung cancer.
The pharmacology of drugs is often defined by more than one protein target. This property can be exploited to use approved drugs to uncover new targets and signaling pathways in cancer. Towards enabling a rational approach to uncover new targets, we expand a structural protein-ligand interactome () by scoring the interaction among 1000 FDA-approved drugs docked to 2500 pockets on protein structures of the human genome. This afforded a drug-target network whose properties compared favorably with previous networks constructed using experimental data. Among drugs with the highest degree and betweenness two are cancer drugs and one is currently used for treatment of lung cancer. Comparison of predicted cancer and non-cancer targets reveals that the most cancer-specific compounds were also the most selective compounds. Analysis of compound flexibility, hydrophobicity, and size showed that the most selective compounds were low molecular weight fragment-like heterocycles. We use a previously-developed screening approach using the cancer drug erlotinib as a template to screen other approved drugs that mimic its properties. Among the top 12 ranking candidates, four are cancer drugs, two of them kinase inhibitors (like erlotinib). Cellular studies using non-small cell lung cancer (NSCLC) cells revealed that several drugs inhibited lung cancer cell proliferation. We mined patient records at the Regenstrief Medical Record System to explore the possible association of exposure to three of these drugs with occurrence of lung cancer. Preliminary in vivo studies using the non-small cell lung cancer (NCLSC) xenograft model showed that losartan- and astemizole-treated mice had tumors that weighed 50 (p < 0.01) and 15 (p < 0.01) percent less than the treated controls. These results set the stage for further exploration of these drugs and to uncover new drugs for lung cancer therapy.


Coronary artery spasm induced in atherosclerotic miniature swine.
Angiographically demonstrable coronary artery spasm could be provoked repeatedly by giving intracoronary or intravenous injections of histamine to miniature swine with experimentally induced atherosclerotic lesions of the coronary artery. The spasm induced in this way subsided either spontaneously or after the administration of nitroglycerin and was prevented by a calcium antagonist or an agent that blocks histamine H1 receptors. This model, which suggests that atherosclerotic changes may be one of the primary factors in the occurrence of coronary artery spasm, should facilitate studies on the pathogenesis of this condition.


NCBI GEO: archive for gene expression and epigenomics data sets: 23-year update.
The Gene Expression Omnibus (GEO) is an international public repository that archives gene expression and epigenomics data sets generated by next-generation sequencing and microarray technologies. Data are typically submitted to GEO by researchers in compliance with widespread journal and funder mandates to make generated data publicly accessible. The resource handles raw data files, processed data files and descriptive metadata for over 200 000 studies and 6.5 million samples, all of which are indexed, searchable and downloadable. Additionally, GEO offers web-based tools that facilitate analysis and visualization of differential gene expression. This article presents the current status and recent advancements in GEO, including the generation of consistently computed gene expression count matrices for thousands of RNA-seq studies, and new interactive graphical plots in GEO2R that help users identify differentially expressed genes and assess data set quality. The GEO repository is built and maintained by the National Center for Biotechnology Information (NCBI), a division of the National Library of Medicine (NLM), and is publicly accessible at https://www.ncbi.nlm.nih.gov/geo/.


Interleukin-6 Stromal Expression is Correlated with Epithelial-Mesenchymal Transition at Tumor Budding in Colorectal Cancer.
Background. Tumor budding is a poor prognostic factor in colorectal adenocarcinoma, but the underlying mechanism remains unclear. Interleukin-6 (IL6) is one of the main cytokines produced by cancer-associated fibroblasts. IL6 is linked with cancer progression and poor prognosis by activating cancer cells and modifying the cancer microenvironment. However, little is known about the expression of IL6 in tumor budding and its association with tumor budding in colorectal adenocarcinoma. Methods. The clinicopathological and prognostic significance of IL6 in tumor budding was examined using a tissue microarray consisting of 36 patient samples of tumor budding in colorectal adenocarcinoma. IL6 mRNA was detected by RNAscope. Patients were stratified into negative and positive IL6 expression groups. Results. IL6 expression was overwhelmingly observed in cancer stroma but was negligible in cancer cells. Tumor budding grade was higher in the IL6-positive group in cancer stroma than in the IL6-negative group (P = .0161), while the IL6-positive group significantly exhibited the epithelial-mesenchymal transition phenotype compared with the IL6-negative group in cancer stroma (P = .0301). There was no significant difference in overall survival between colorectal adenocarcinoma patients in the IL6-positive and -negative groups in cancer stroma. Conclusion. Tumor budding may be affected by IL6 expression, and IL6 expression in cancer stroma at tumor budding may be an important prognostic marker.


Periodontal management of Glanzmann's thrombasthenia: report of 3 cases.
Glanzmann's thrombasthenia was reported and described as a bleeding diathesis seen in children and characterized by diminished clot retraction. It is an autosomal recessive bleeding disorder. The disease is marked by frequent mucocutaneous hemorrhages either due to defective function of the platelets or lack of fibrinogen binding membrane receptor glycoproteins IIb/IIIa which are located on the surface of the platelets. Case reports on 3 siblings, a girl of 11, and 2 boys of 12 and 16 years old with Glanzmann's thrombasthenia are reviewed. The major complaint of the patients was gingival bleeding. Periodontal treatment was performed under platelet transfusion and proper oral hygiene instruction was given. The patients were followed for 6 months and no periodontal complications developed during this time. Proper periodontal care for such patients is essential both for local and systemic health.


Small intestinal motor abnormalities in patients with functional dyspepsia demonstrated by ambulatory manometry.
In 30 patients with functional dyspepsia and in 20 healthy volunteers, ambulatory duodenojejunal manometry was performed to examine the interdigestive and postprandial small intestinal motility patterns in relation to symptoms. In the fasting state, the number of migrating motor complex cycles mean (SEM) was significantly lower in patients, especially in patients with dysmotility-like dyspepsia, than in control subjects (3.8 (0.4), 2.6 (0.5), and 5.3 (0.7) cycles, respectively; p < 0.05), due to a longer duration of phase II. Non-propagated and retrogradely propagated phase III activity was more prevalent in patients than in control subjects (48% v 15%; p = 0.020). During phase II and after dinner no differences were found in contraction incidence, mean amplitude or motility index. However, 1 1/2 hours after completing breakfast the motility index was higher in patients at all three recording levels (p < 0.05). Burst activity was more prevalent in patients than in control subjects (22% v 6% of the subjects; p = 0.003). In 41% of the patients the symptom index was > 75%. These results suggest that small intestinal motor abnormalities, especially during fasting, participate in the pathogenesis of symptoms in patients with functional dyspepsia. Ambulatory manometry of the small intestine is a valuable tool to demonstrate these abnormalities in outpatients pursuing their daily activities.


Blue light from light-emitting diodes elicits a dose-dependent suppression of melatonin in humans.
Light suppresses melatonin in humans, with the strongest response occurring in the short-wavelength portion of the spectrum between 446 and 477 nm that appears blue. Blue monochromatic light has also been shown to be more effective than longer-wavelength light for enhancing alertness. Disturbed circadian rhythms and sleep loss have been described as risk factors for astronauts and NASA ground control workers, as well as civilians. Such disturbances can result in impaired alertness and diminished performance. Prior to exposing subjects to short-wavelength light from light-emitting diodes (LEDs) (peak λ = 469 nm; 1/2 peak bandwidth = 26 nm), the ocular safety exposure to the blue LED light was confirmed by an independent hazard analysis using the American Conference of Governmental Industrial Hygienists exposure limits. Subsequently, a fluence-response curve was developed for plasma melatonin suppression in healthy subjects (n = 8; mean age of 23.9 ± 0.5 years) exposed to a range of irradiances of blue LED light. Subjects with freely reactive pupils were exposed to light between 2:00 and 3:30 AM. Blood samples were collected before and after light exposures and quantified for melatonin. The results demonstrate that increasing irradiances of narrowband blue-appearing light can elicit increasing plasma melatonin suppression in healthy subjects (P < 0.0001). The data were fit to a sigmoidal fluence-response curve (R(2) = 0.99; ED(50) = 14.19 μW/cm(2)). A comparison of mean melatonin suppression with 40 μW/cm(2) from 4,000 K broadband white fluorescent light, currently used in most general lighting fixtures, suggests that narrow bandwidth blue LED light may be stronger than 4,000 K white fluorescent light for suppressing melatonin.


Polymorphism in endothelin-related genes limits exercise-induced decreases in arterial stiffness in older subjects.
Increase in arterial stiffness is associated with aging, which is improved by regular exercise. Endothelin (ET) system has crucial roles in regulating vascular tone and in the progression of atherosclerosis. We hypothesized that molecular variations (ie, gene polymorphisms) in ET-related gene might affect exercise-induced improvement in arterial stiffness with age in human subjects. The present study provides a cross-sectional investigation of 191 healthy middle-aged and older (65+/-1 years) human subjects to clarify the relationship between the regular exercise-induced improvement of arterial stiffness and the gene polymorphisms of ET converting enzyme (ECE)-1, ECE-2, ET-A receptor (ET-A), and ET-B receptor (ET-B). The study subjects were divided into active and inactive groups based on the median value (186 kcal/d) of energy expenditure. Brachial-ankle arterial pulse wave velocity (baPWV) was used to evaluate arterial stiffness. All individuals were genotyped for 4 different polymorphisms of the ET system: 2013(+289)A/G in intron 17 of ECE-1, 669(+17)T/C in intron 5 of ECE-2, 958A/G in exon 6 of ET-A, and 831A/G in exon 4 of ET-B. The baseline baPWV was significantly lower in the active group without any change in blood pressure. Polymorphisms in ECE-1 influenced basal blood pressure. Polymorphisms in ECE-1 and ECE-2 had no effect on baPWV between active and inactive groups. However, polymorphisms in both ET-A and ET-B affected baPWV in the 2 groups. The present results suggest that differences in ET-A and ET-B polymorphisms may influence the response of the vascular wall to exercise whereas ECE-1 polymorphisms may affect basal blood pressure.


Competitive stem cell recruitment by multiple cytotactic cues.
A multitude of cytotactic cues direct cell migration in development, cancer metastasis and wound healing. However, our understanding of cell motility remains fragmented partially because current migration devices only allow the study of independent factors. We developed a cell motility assay that allows competitive recruitment of a given cell population simultaneously by gradients of multiple cytotactic cues, observable under real-time imaging. Well-defined uniform gradients of cytotactic cues can be independently generated and sustained in each channel. As a case study, bone marrow mesenchymal stem/stromal cells (MSCs) were exposed to 15 cytokines that are commonly present in arthritis. Cytokines that induced robust recruitment of MSCs in multiple groups were selected to 'compete' in a final round to yield the most chemotactic factor(s) based on cell migration numbers, distances, migration indices and motility over time. The potency of a given cytokine in competition frequently differed from its individual action, substantiating the need to test multiple cytokines concurrently due to synergistic or antagonistic effects. This new device has the rare capacity to screen molecules that induce cell migration in cancer therapy, drug development and tissue regeneration.


Histone deacetylase activity modulates exercise-induced skeletal muscle plasticity in zebrafish (Danio rerio).
Aerobic exercise has a positive impact on animals by enhancing skeletal muscle function and locomotor performance. Responses of skeletal muscle to exercise involve changes in energy metabolism, calcium handling, and the composition of contractile protein isoforms, which together influence contractile properties. Histone deacetylases (HDAC) can cause short-term changes in gene expression and may thereby mediate plasticity in contractile properties of skeletal muscle in response to exercise. The aim of this project was to determine (in zebrafish, Danio rerio) the traits that mediate interindividual differences in sustained and sprint performance and to determine whether inhibiting class I and II HDACs mediates exercise-induced changes in these traits. High sustained performers had greater aerobic metabolic capacity [citrate synthase (CS) activity], calcium handling capacity [sarco/endoplasmic reticulum ATPase (SERCA) activity], and slow contractile protein concentration [slow myosin heavy chain (MHC)] compared with low performers. High sprint performers had lower CS activity and slow MHC concentrations compared with low performers, but there were no significant differences in lactate dehydrogenase activity or fast MHC concentrations. Four weeks of aerobic exercise training increased sustained performance, CS activity, SERCA activity, and slow MHC concentration. Inhibiting class I and II HDACs increased slow MHC concentration in untrained fish but not in trained fish. However, inhibiting HDACs reduced SERCA activity, which was paralleled by a reduction in sustained and sprint performance. The regulation of muscle phenotypes by HDACs could be a mechanism underlying the adaptation of sustained locomotor performance to different environmental conditions, and may therefore be of therapeutic and ecological significance.


Memory efficient error diffusion.
Because of its good image quality and moderate computational requirements, error diffusion has become a popular halftoning solution for desktop printers, especially inkjet printers. By making the weights and thresholds tone-dependent and using a predesigned halftone bitmap for tone-dependent threshold modulation, it is possible to achieve image quality very close to that obtained with far more computationally complex iterative methods. However, the ability to implement error diffusion in very low cost or large format products is hampered by the requirement to store the tone-dependent parameters and halftone bitmap, and also the need to store error information for an entire row of the image at any given point during the halftoning process. For the first problem, we replace the halftone bitmap by deterministic bit flipping, which has been previously applied to halftoning, and we linearly interpolate the tone-dependent weights and thresholds from a small set of knot points. We call this implementation a reduced lookup table. For the second problem, we introduce a new serial block-based approach to error diffusion. This approach depends on a novel intrablock scan path and the use of different parameter sets at different points along that path. We show that serial block-based error diffusion reduces off-chip memory access by a factor equal to the block height. With both these solutions, satisfactory image quality can only be obtained with new cost functions that we have developed for the training process. With these new cost functions and moderate block size, we can obtain image quality that is very close to that of the original tone-dependent error diffusion algorithm.


A novel COX-2 inhibitor pyrazole derivative proven effective as an anti-inflammatory and analgesic drug.
The introduction of new COX-2 inhibitors with high efficacy and enhanced safety profile would be a great achievement in the development of anti-inflammatory drugs. This study was designed to screen and assess the anti-inflammatory and analgesic activities as well as some of the expected side effects of some pyrazole derivatives, newly synthesized as potential COX-2 inhibitors at the Faculty of Pharmacy, Alexandria University and compared to indomethacin and celecoxib. Twelve compounds were screened for their anti-inflammatory activity using carrageenan-induced paw oedema and cotton pellet granuloma tests. On the basis of their apparent anti-inflammatory activity, four compounds with different substitutions were selected for the evaluation of their analgesic activity using the formalin-induced hyperalgesia and hot-plate tests. Compound AD 532, ((4-(3-(4-Methylphenyl)-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide)), showed very promising results. In the single-dose and subchronic toxicity studies, compound AD 532 showed no ulcerogenic effect and produced minimal effects on renal function. Furthermore, compound AD 532 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It is concluded that compound AD 532 appears to be a promising and safe option for the management of chronic inflammatory conditions. This study recommends more in-depth investigation into the therapeutic effects and toxicity profile of this compound including its cardiovascular toxicity.


Current limitations to high-resolution structure determination by single-particle cryoEM.
CryoEM has become the method of choice for determining the structure of large macromolecular complexes in multiple conformations, at resolutions where unambiguous atomic models can be built. Two effects that have limited progress in single-particle cryoEM are (i) beam-induced movement during image acquisition and (ii) protein adsorption and denaturation at the air-water interface during specimen preparation. While beam-induced movement now appears to have been resolved by all-gold specimen support grids with very small holes, surface effects at the air-water interface are a persistent problem. Strategies to overcome these effects include the use of alternative support films and new techniques for specimen deposition. We examine the future potential of recording perfect images of biological samples for routine structure determination at atomic resolution.


Design and semisynthesis of photoactivable split-GFP by incorporation of photocleavable functionality.
The design of proteins whose structure and function can be manipulated by the external stimuli has been of great interest in the field of protein engineering. In particular, caged proteins which can be activated by photo-irradiation become powerful tools for investigating a variety of biological events. Although protein caging is straightforward to render light-responsive protein functions, this approach mostly have difficulties based on the preparation of caged proteins in which amino acid residues required for biological activities must be specifically modified with synthetic photolabile groups. The synthetic peptide-based strategy for photoactivation of protein function may expand the versatility of protein caging approaches since the photolabile protecting group can be easily introduced into the peptide by means of standard solid-phase methods in a site-specific manner. In this study, we designed a new photoactivable green fluorescent protein (GFP), in which a relatively short C-terminal fragment (residues 214-230) of a dissected protein was modified with 7-diethylamino-4-hydroxymethylcoumarin (DECM) as a photoresponsive-protecting group. The introduced DECM unit completely inhibited the reconstitution with the GFP N-terminal fragment (residues 2-214). However, irradiation of visible light (>400 nm) resulted in efficient cleavage of DECM group, leading to acceleration of protein reassembly and concomitant GFP fluorescence recovery. These results demonstrated direct control of protein structure and function by application of the synthetic photocleavable functionality to a fragmented protein. The combined system of fragmented proteins and synthetic photocleavable elements will provide the useful and potentially wide applicable strategy for the regulation of protein structure and function by the light in a temporal and spacial manner.


Resonance Raman spectroscopy reveals that substrate structure selectively impacts the heme-bound diatomic ligands of CYP17.
An important function of steroidogenic cytochromes P450 is the transformation of cholesterol to produce androgens, estrogens, and the corticosteroids. The activities of cytochrome P450c17 (CYP17) are essential in sex hormone biosynthesis, with severe developmental defects being a consequence of deficiency or mutations. The first reaction catalyzed by this multifunctional P450 is the 17α-hydroxylation of pregnenolone (PREG) to 17α-hydroxypregnenolone (17-OH PREG) and progesterone (PROG) to 17α-hydroxyprogesterone (17-OH PROG). The hydroxylated products then either are used for production of corticoids or undergo a second CYP17 catalyzed transformation, representing the first committed step of androgen formation. While the hydroxylation reactions are catalyzed by the well-known Compound I intermediate, the lyase reaction is believed to involve nucleophilic attack of the earlier peroxo- intermediate on the C20-carbonyl. Herein, resonance Raman (rR) spectroscopy reveals that substrate structure does not impact heme structure for this set of physiologically important substrates. On the other hand, rR spectra obtained here for the ferrous CO adducts with these four substrates show that substrates do interact differently with the Fe-C-O fragment, with large differences between the spectra obtained for the samples containing 17-OH PROG and 17-OH PREG, the latter providing evidence for the presence of two Fe-C-O conformers. Collectively, these results demonstrate that individual substrates can differentially impact the disposition of a heme-bound ligand, including dioxygen, altering the reactivity patterns in such a way as to promote preferred chemical conversions, thereby avoiding the profound functional consequences of unwanted side reactions.


The adrenal psoas sign: surgical outcomes following a simple technique to maximize removal of extracortical adrenal tissue during bilateral laparoscopic adrenalectomy.
Bilateral laparoscopic adrenalectomy (BLA) is an effective therapy for the management of persistent hypercortisolism in patients after failed transphenoidal pituitary tumor resection for Cushing's disease. Extracortical adrenal tissue has been identified as a source of persistent hypercortisolism and, if not resected along with both adrenal glands, may lead to treatment failure. We report a reliable and reproducible technique called the "psoas sign" for BLA in patients with Cushing's disease which reduces the likelihood of retained extra-adrenal cortical rests and may reduce intraoperative complications. A 16-year retrospective review of all consecutive patients who underwent transabdominal BLA at a single tertiary care center was performed. All patients underwent BLA utilizing the psoas sign technique and all procedures were performed replicating these predetermined surgical steps: (1) Identification of the inferior pole of the gland. (2) Identification of the inferior aspect of the adreno-caval groove on the right or the adrenal vein/renal vein confluence on the left. (3) Division of the adrenal vein. (4) Dissection and removal of the adrenal gland with clearance of all retroperitoneal fat overlying the psoas muscle. Between October 1996 and December 2012, 92 patients underwent BLA for refractory Cushing's disease. Patients were predominantly female (90 %) with a median age of 40 years (17-71). There were 3 intraoperative complications (3.2 %), 2 conversions (2.2 %), and 1 death (1.09 %). Four patients were identified as having extracortical rests of adrenal tissue within the retroperitoneal fat (4.3 %). Mean operative time was 272 min (±79.25, n = 68) and median estimated blood loss was 50 mL (10-800 mL). The psoas sign technique provides a clear view of the adrenal fossa and facilitates careful dissection of the anatomic planes around the adrenal gland. This technique is feasible, reproducible and in our experience allows for safe removal of both adrenal glands and all surrounding extracortical adrenal tissue.


Chemistry of Hydrogen Sulfide-Pathological and Physiological Functions in Mammalian Cells.
Hydrogen sulfide (H2S) was recognized as a gaseous signaling molecule, similar to nitric oxide (-NO) and carbon monoxide (CO). The aim of this review is to provide an overview of the formation of hydrogen sulfide (H2S) in the human body. H2S is synthesized by enzymatic processes involving cysteine and several enzymes, including cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), cysteine aminotransferase (CAT), 3-mercaptopyruvate sulfurtransferase (3MST) and D-amino acid oxidase (DAO). The physiological and pathological effects of hydrogen sulfide (H2S) on various systems in the human body have led to extensive research efforts to develop appropriate methods to deliver H2S under conditions that mimic physiological settings and respond to various stimuli. These functions span a wide spectrum, ranging from effects on the endocrine system and cellular lifespan to protection of liver and kidney function. The exact physiological and hazardous thresholds of hydrogen sulfide (H2S) in the human body are currently not well understood and need to be researched in depth. This article provides an overview of the physiological significance of H2S in the human body. It highlights the various sources of H2S production in different situations and examines existing techniques for detecting this gas.


Species composition, abundance, and seasonal dynamics of stink bugs (Hemiptera: Pentatomidae) in Minnesota soybean fields.
Stink bugs (Hemiptera: Pentatomidae) have historically not been pests of soybean in Minnesota. In response to the invasion of Halyomorpha halys (Stål) and reports of increasing abundance of species native to North America, a state-wide survey of soybean was conducted over 3 yr in Minnesota to determine species composition, abundance, and seasonal dynamics of Pentatomidae associated with soybean. Fourteen species of Pentatomidae (12 herbivorous and two predatory) were collected from soybean. H. halys was not detected in this survey. Among the herbivorous species found, adults of Euschistus variolarius (Palisot de Beauvois) had the greatest relative abundance (60.51%) and frequency of detection (18.44%), followed by Euschistus servus euschistoides (Say) (19.37 and 3.04%, respectively) and Chinavia hilaris (Say) (5.50 and 1.69%, respectively). Abundance of herbivorous nymphs and adults exceeded an economic threshold (20 nymphs and adults per 100 sweeps) in 0.82% of fields in 2012 but not in 2011 or 2013. The frequency of detection of herbivorous species and ratio of nymphs to adults increased with increasing reproductive growth stage of soybean. In two of three years, herbivorous adults were more abundant in the edge compared with interior of fields. Two predatory Pentatomidae, Podisus maculiventris (Say) and Podisus placidus Uhler, comprised 5.95 and 1.62% of the pentatomid adults. Though the species composition of Pentatomidae in Minnesota soybean differs from that in eastern and southern states, the spatial (i.e., greater abundance near field edge) and seasonal dynamics (i.e., increasing abundance and reproduction with increasing reproductive maturity of soybean) in soybean appear similar.


Mastery of fundamental motor skills among New South Wales school students: prevalence and sociodemographic distribution.
Mastery of fundamental motor skills among children and adolescents is a potentially important contribution to satisfying participation in sports, games and other physical activities and may enhance the development of an active lifestyle. However, few attempts have been made to determine the prevalence of fundamental motor skill mastery among young Australians. The NSW Schools Fitness and Physical Activity Survey, 1997 (N = 5518) randomly selected schools proportionally from all three education sectors and selected students in Years 4, 6, 8 and 10. Performance on six fundamental motor skills (run, vertical jump, catch, overhand throw, forehand strike and kick) was assessed qualitatively. The prevalence of mastery and near mastery of each skill and mastery of each skill component is reported for boys and girls in each school year. The findings indicate that the prevalence of mastery and near mastery of each of the fundamental motor skills was generally low. There were no differences between students from urban or rural schools and the prevalence of skill mastery was directly associated with socioeconomic status more consistently among girls than among boys. Greater curriculum time and resourcing and training of teachers is required to increase the proportion of students who have mastered the skills fundamental to common sports, games and other physical activities.


Experiences of burnout among drug counselors in a large opioid treatment program: A qualitative investigation.
Little is known about possible experiences of burnout among drug counselors in opioid treatment programs that are scaling up capacity to address the current opioid treatment gap. Participants in this quality improvement study were 31 drug counselors employed by large opioid treatment programs whose treatment capacities were expanding. Experiences of burnout and approaches for managing and/or preventing burnout were examined using individual semi-structured interviews, which were audiotaped, transcribed, and systematically coded by a multidisciplinary team using grounded theory. Rates of reported burnout (in response to an open-ended question) were lower than expected, with approximately 26% of participants reporting burnout. Counselor descriptions of burnout included cognitive, affective, behavioral, and physiological symptoms; and job-related demands were identified as a frequent cause. Participants described both self-initiated (e.g., engaging in pleasurable activities, exercising, taking breaks during workday) and system-supported strategies for managing or preventing burnout (e.g., availing of supervision and paid time off). Counselors provided recommendations for system-level changes to attenuate counselor risk of burnout (e.g., increased staff-wide encounters, improved communication, accessible paid time off, and increased clinical supervision). Findings suggest that drug counselor burnout is not inevitable, even in opioid treatment program settings whose treatment capacities are expanding. Organizations might benefit from routinely assessing counselor feedback about burnout and implementing feasible recommendations to attenuate burnout and promote work engagement.


Phenotype modulators in myophosphorylase deficiency.
Myophosphorylase deficiency is characterized by exercise intolerance, muscle cramps, and recurrent myoglobinuria. Some patients are severely affected, whereas others are minimally affected or asymptomatic. The molecular basis of the disease has been elucidated but does not provide an explanation for the clinical variability. In a large cohort of patients with myophosphorylase deficiency, we tested the hypothesis that polymorphic variants in either myoadenylate deaminase (MADA) or angiotensin-converting enzyme (ACE) could act as modulators of phenotype expression. Forty-seven patients were evaluated. Clinical severity was assessed according to a severity scale of four grades. MADA activity was studied by histochemical and biochemical analysis of muscle, and the Q12X mutation in the adenine monophosphate deaminase 1 gene (AMPD1) and the insertion/deletion polymorphism in the ACE gene were assessed genetically. A complete MADA defect together with the Q12X mutation was detected in one severely affected patient. Eleven patients were heterozygous for the Q12X mutation. There was no association between clinical grading and MADA status. In contrast, we found a highly significant (p < 0.01) association between ACE genotype and clinical severity, with strong correlation between severe phenotype and number of D alleles. We show that ACE insertion/deletion polymorphism may play a significant role as phenotype modulator in McArdle's disease.


Hazardous drinking and drinking patterns among the reindeer-herding Sami population in Sweden.
The objective of this study was to investigate hazardous drinking among reindeer-herding Sami in Sweden. A cross-sectional questionnaire study was conducted in 2007, which included the Alcohol Use Disorder Identification Test. A total of 319 reindeer-herding Sami were compared with urban and rural reference populations of 1,393 persons. Data were analyzed with regard to population, gender, age group, education, anxiety, depression, and work-related stress. The Sami population did not report a higher prevalence of hazardous drinking compared with the reference groups; however, subgroups of Sami men with symptoms of depression were revealed as at risk, in contrast to Sami women who were not found to be at risk at all. Limitations of the study are discussed.


[Reaction of sensory neurons of the spinal ganglia to sectioning of their peripheral and central processes].
Transversal ++semi-sectioning of the spinal ganglion (SG) is a good model for studying the reaction of the ganglional sensory neurons to sectioning of their peripheral and central processes. At sectioning the peripheral and central processes of the SG neurons degeneration of the neurons and their death take place. The degenerative processes are more pronounced in the neurons with the peripheral processes sectioned, and the restorative ones-with the central processes sectioned. The dynamics of the posttraumatic changes in absolute number of the neurons, profile areas of the body fields and neuronal nuclei, amount of neurons with certain signs of axonal reactions in the SG demonstrate a maximally pronounced reaction on the 7th day and beginning of restorative processes on the 15th day. They are not completed by the 180th day.


Hydration and Cooling Practices Among Farmworkers in Oregon and Washington.
Although recommendations for preventing occupational heat-related illness among farmworkers include hydration and cooling practices, the extent to which these recommendations are universally practiced is unknown. The objective of this analysis was to compare hydration and cooling practices between farmworkers in Oregon and Washington. A survey was administered to a purposive sample of Oregon and Washington farmworkers. Data collected included demographics, work history and current work practices, hydration practices, access and use of cooling measures, and headwear and clothing worn. Oregon farmworkers were more likely than those in Washington to consume beverages containing sugar and/or caffeine. Workers in Oregon more frequently reported using various cooling measures compared with workers in Washington. Availability of cooling measures also varied between the two states. These results highlight the large variability between workers in two states regarding access to and use of methods to stay cool while working in the heat.


Tissue Proteome Signatures Associated with Five Grades of Prostate Cancer and Benign Prostatic Hyperplasia.
The histology-based Gleason score (GS) of prostate cancer (PCa) tissue biopsy is the most accurate predictor of disease aggressiveness and an important measure to guide treatment strategies and patient management. The variability associated with PCa tumor sampling and the subjective determination of the GS are challenges that limit accurate diagnostication and prognostication. Thus, novel molecular signatures are needed to distinguish between indolent and aggressive forms of PCa for better patient management and outcomes. Herein, label-free LC-MS/MS proteomics is used to profile the proteome of 50 PCa tissues spanning five grade groups (n = 10 per group) relative to tissues from individuals with benign prostatic hyperplasia (BPH). Over 2000 proteins are identified albeit at different levels between and within the patient groups, revealing biological processes associated with specific grades. A panel of 11 prostate-derived proteins including IGKV3D-20, RNASET2, TACC2, ANXA7, LMOD1, PRCP, GYG1, NDUFV1, H1FX, APOBEC3C, and CTSZ display the potential to stratify patients from low and high PCa grade groups. Parallel reaction monitoring of the same sample cohort validate the differential expression of LMOD1, GYG1, IGKV3D-20, and RNASET2. The four proteins associated with low and high PCa grades reported here warrant further exploration as candidate biomarkers for PCa aggressiveness.


Functional activity limitation of leprosy cases in an endemic area in Indonesia and recommendations for integrated participation program in society.
Leprosy continues to be a health problem in Indonesia, with incidence reaching over 10,000 new cases by 2021. Leprosy-related disabilities cause limitation of patients' activity and participation in social activities. To date, no studies have been conducted in Indonesia which investigates disability in terms of bodily function, structure impairment, limitations in performing daily activities, and restrictions in participation in social activities in leprosy patients. This study is aimed to determine the demographic and clinical characteristics that might affect functional activity limitations of leprosy patients in endemic areas in Indonesia. A cross-sectional study was conducted on 267 retrospectively-diagnosed cases of leprosy. The Screening of Activity Limitation and Safety Awareness (SALSA) scale was used to measure functional activity limitation, which comprises five domains: vision, mobility, self-care, work with hands, and dexterity. Differences among variables were evaluated using Kruskal-Wallis and Mann-Whitney test. The mean age of participants was 51.89±13.66 years, the majority of which were men (62.5%), uneducated (48.3%), and classified as type 2 in the World Health Organization (WHO) disability grading for hands and feet (66.3% and 68.2%, respectively). Assessment using the SALSA Scale showed 28.5% of subjects were without limitation, 43.8% with mild limitation, 13.5% with moderate limitation, 9.4% with severe limitation, and 4.9% with extreme limitation. Significant differences in the total SALSA Scale were found between age groups (p = 0.014), educational level (p = 0.005), occupation (p<0.001), and WHO disability grades (p<0.001). Multivariate analysis showed that the most significant factor influencing the total score of SALSA was disability grading for feet (score = 0.31, p <0.001) followed by occupational status, disability grading for eyes, and age. Limitation of functional activity was significantly correlated to becoming unemployed with the odds 2.59. People affected by leprosy are prone to have functional activity limitation, especially the elderly, uneducated, unemployed and those with multiple disabilities. If they can overcome their barriers in functional activities, they will have better occupational opportunities.


Alcohol tax policy and related mortality. An age-period-cohort analysis of a rapidly developed Chinese population, 1981-2010.
To delineate the temporal dynamics between alcohol tax policy changes and related health outcomes, this study examined the age, period and cohort effects on alcohol-related mortality in relation to changes in government alcohol policies. We used the age-period-cohort modeling to analyze retrospective mortality data over 30 years from 1981 to 2010 in a rapidly developed Chinese population, Hong Kong. Alcohol-related mortality from 1) chronic causes, 2) acute causes, 3) all (chronic+acute) causes and 4) causes 100% attributable to alcohol, as defined according to the Alcohol-Related Disease Impact (ARDI) criteria developed by the US Centers for Disease Control and Prevention, were examined. The findings illustrated the possible effects of alcohol policy changes on adult alcohol-related mortality. The age-standardized mortality trends were generally in decline, with fluctuations that coincided with the timing of the alcohol policy changes. The age-period-cohort analyses demonstrated possible temporal dynamics between alcohol policy changes and alcohol-related mortality through the period effects, and also generational impact of alcohol policy changes through the cohort effects. Based on the illustrated association between the dramatic increase of alcohol imports in the mid-1980s and the increased alcohol-related mortality risk of the generations coming of age of majority at that time, attention should be paid to generations coming of drinking age during the 2007-2008 duty reduction.


Streptococcus intermedius: an unusual cause of spinal epidural abscess.
Spinal epidural abscess (SEA) following dental procedures is a rarely reported entity. Here, we present a unique case of a 74-year-old immunocompetent man who developed severe lower back pain and bilateral lower extremity weakness 4 days following two root canal procedures. Lumbar spine magnetic resonance imaging (MRI) showed several pockets of epidural abscesses extending from L1 through L5. Blood cultures grew Streptococcus intermedius, an anaerobic commensal bacterium of the normal flora of the mouth and upper airways. The patient was treated with IV penicillin for 7 days but his symptoms continued to deteriorate. A repeat MRI showed extension of the epidural abscess to T10-T11 level. The patient was emergently transferred to our hospital where he underwent bilateral decompressive laminectomy of T10 through S1 and abscess evacuation. Pus culture was positive for Streptococcus intermedius, which confirmed the diagnosis and the treatment plan. He was discharged on intravenous (IV) penicillin for 6 weeks. His symptoms improved significantly postoperatively as he retained his baseline strength in his lower extremity.


Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma.
Tyrosine kinase inhibitors (TKI) have poor efficacy in patients with glioblastoma (GBM). Here, we studied whether this is predominantly due to restricted blood-brain barrier penetration or more to biological characteristics of GBM. Tumor drug concentrations of the TKI sunitinib after 2 weeks of preoperative treatment was determined in 5 patients with GBM and compared with its in vitro inhibitory concentration (IC50) in GBM cell lines. In addition, phosphotyrosine (pTyr)-directed mass spectrometry (MS)-based proteomics was performed to evaluate sunitinib-treated versus control GBM tumors. The median tumor sunitinib concentration of 1.9 μmol/L (range 1.0-3.4) was 10-fold higher than in concurrent plasma, but three times lower than sunitinib IC50s in GBM cell lines (median 5.4 μmol/L, 3.0-8.5; P = 0.01). pTyr-phosphoproteomic profiles of tumor samples from 4 sunitinib-treated versus 7 control patients revealed 108 significantly up- and 23 downregulated (P < 0.05) phosphopeptides for sunitinib treatment, resulting in an EGFR-centered signaling network. Outlier analysis of kinase activities as a potential strategy to identify drug targets in individual tumors identified nine kinases, including MAPK10 and INSR/IGF1R. Achieved tumor sunitinib concentrations in patients with GBM are higher than in plasma, but lower than reported for other tumor types and insufficient to significantly inhibit tumor cell growth in vitro. Therefore, alternative TKI dosing to increase intratumoral sunitinib concentrations might improve clinical benefit for patients with GBM. In parallel, a complex profile of kinase activity in GBM was found, supporting the potential of (phospho)proteomic analysis for the identification of targets for (combination) treatment.


Prefrontal cortical neuregulin-ErbB modulation of inhibitory control in rats.
Impulse control disturbances are key features of various neuropsychiatric and neurological disorders, such as attention-deficit/hyperactivity disorder, drug addiction, Parkinson disease and schizophrenia. Whereas over the last years accumulating evidence has highlighted monoaminergic modulation of the processes underlying impulse control, investigating novel mechanisms beyond monoamines may provide new intervention strategies to ameliorate impulse control disturbances. Recent work has associated the neuregulin (Nrg)-ErbB pathway with several neuropsychiatric diseases, as well as indicated its involvement in murine measures of impulse control. The aim of the present study was to investigate whether this Nrg-ErbB signaling pathway also modulates impulsive action in rats. To this end, a group of rats was trained in the 5-choice serial reaction time task (5-CSRTT), an operant paradigm that provides measures of visuospatial attention and inhibitory control processes. Upon stable baseline performance, the ErbB tyrosine kinase receptor inhibitor JNJ-28871063 (JNJ) was intracranially infused into the medioprefrontal cortex prior to test sessions. Results showed that JNJ dose-dependently improved measures of impulsive action. Importantly, other measures in the 5-CSRTT reflecting visuospatial attention or aspects of motivational behavior were not altered by JNJ. In conclusion, the present data strengthen a role for the Nrg-ErbB4 pathway in the prefrontal cortex in cognitive functioning, and in particular point towards involvement in the processes underlying impulse control.


Oxidative stress, DNA damage and repair in heart failure patients after implantation of continuous flow left ventricular assist devices.
To study the status of oxidative stress and DNA damage repair in circulating blood leukocytes of heart failure patients supported by continuous flow left ventricular assist devices (LVADs). Ten HF patients implanted with LVAD as bridge to transplant or destination therapy were enrolled in the study and 10 age and sex matched volunteers were recruited as the study control. Reactive oxygen species (ROS) in blood leukocytes and superoxide dismutase (SOD) in erythrocytes were measured by flow cytometry/immunofluorescence microscopy and spectrophotometry, respectively. ELISA was used to measure oxidized low density lipoproteins (oxLDL) in plasma. Markers of DNA damage (γ-H2AX) and repairs (Mre11, DNA ligase IV, Ku70, and Ku80) were quantified in blood lymphocytes by immunocytochemistry. Levels of ROS and oxLDL were significantly higher in HF patients with LVAD than baseline as well as the control group; moreover, SOD levels were decreased with increasing post-operative periods. All the changes indicated enhanced oxidative stress among LVAD recipients. Significantly higher γ-H2AX foci in lymphocytes confirmed DNA double strand breaks in LVAD recipients. γ-H2AX foci numbers in lymphocytes were positively correlated with the ROS and oxLDL and negatively with SOD levels (p<0.0001). Expressions of DNA ligase IV, Ku70 and Ku80 proteins were highest after one week and Mre11 protein after 3 months of LVAD transplantation; indicated abnormal DNA repair. The study, for the first time shows that, continuous flow LVAD implanted HF patients not only exhibit elevated oxidative stress and DNA damage in blood leukocytes but also have abnormalities in DNA repair pathways.


Linear-scaling quantum calculations using non-orthogonal localized molecular orbitals.
An absolute energy minimum variational principle is used for carrying out linear scaling calculations with non-orthogonal localized orbitals. Compared with results based on orthogonal localized molecular orbitals, the method is shown to give significantly more accurate results when the localized molecular orbitals are allowed to be non-orthogonal. This is made possible by introducing a second minimization for approximating the inverse overlap matrix. We also show how an exact line search may be used efficiently with the conjugate gradient method for minimizing the energy functional.


Body-related comments experienced by Chinese young women: A cross-sectional study.
Within Chinese culture, one way that family and friends demonstrate that they care about one-another is by making body-related comments. How such comments are experienced by young women, in particular, including how they relate to their psychological disposition and/or use of unhealthy weight control behaviors, is unknown. The purposes of this study were to understand the frequency and type of body-related comments Chinese college women received, from whom, and their associations with body mass index (BMI), body satisfaction, body change motivations, and unhealthy weight control behaviors. Women from a comprehensive university in Southwest China (N = 236) participated in this cross-sectional study. Results showed that female Chinese college students received body-related comments most frequently from their friends, followed by parents, and romantic partners. While the frequency of receiving body-related comments was not associated with BMI, higher frequencies were associated with stronger motivation to lose weight/fat and to practice unhealthy weight control behaviors. Additionally, positive body-related comments from romantic partners were associated with higher motivation to gain weight/muscle and/or to maintain weight. Furthermore, positive body-related comments from friends were associated with higher body satisfaction. Educational programs are needed to help female Chinese college students and members of their social networks recognize and understand the potential impact associated with giving body-related comments. Screening protocols for unhealthy weight control behaviors and appropriate counseling services should also be developed and made available.


Regulatory B cells, A to Z.
B cells play a central role in the immune system through the production of antibodies. During the past two decades, it has become increasingly clear that B cells also have the capacity to regulate immune responses through mechanisms that extend beyond antibody production. Several types of human and murine regulatory B cells have been reported that suppress inflammatory responses in autoimmune disease, allergy, infection, transplantation, and cancer. Key suppressive molecules associated with regulatory B-cell function include the cytokines IL-10, IL-35, and TGF-β as well as cell membrane-bound molecules such as programmed death-ligand 1, CD39, CD73, and aryl hydrocarbon receptor. Regulatory B cells can be induced by a range of different stimuli, including microbial products such as TLR4 or TLR9 ligands, inflammatory cytokines such as IL-6, IL-1β, and IFN-α, as well as CD40 ligation. This review provides an overview of our current knowledge on regulatory B cells. We discuss different types of regulatory B cells, the mechanisms through which they exert their regulatory functions, factors that lead to induction of regulatory B cells and their role in the alteration of inflammatory responses in different diseases.


Invasive candidiasis in low birth weight preterm infants: risk factors, clinical course and outcome in a prospective multicenter study of cases and their matched controls.
This multicenter prospective study of invasive candidiasis (IC) was carried out to determine the risk factors for, incidence of, clinical and laboratory features, treatment and outcome of IC in infants of birth weight <1250 g. Neonates <1250 g with IC and their matched controls (2:1) were followed longitudinally and descriptive analysis was performed. Survivors underwent neurodevelopmental assessment at 18 to 24 months corrected age. Neurodevelopmental impairment (NDI) was defined as blindness, deafness, moderate to severe cerebral palsy, or a score <70 on the Bayley Scales of Infant Development 2nd edition. Multivariable analyses were performed to determine risk factors for IC and predictors of mortality and NDI. Cumulative incidence rates of IC were 4.2%, 2.2% and 1.5% for birth-weight categories <750 g, <1000 g, <1500 g, respectively. Forty nine infants with IC and 90 controls were enrolled. Necrotizing enterocolitis (NEC) was the only independent risk factor for IC (p=0.03). CNS candidiasis occurred in 50% of evaluated infants, while congenital candidiasis occurred in 31%. Infants with CNS candidiasis had a higher mortality rate (57%) and incidence of deafness (50%) than the overall cohort of infants with IC. NDI (56% vs. 33%; p=0.017) and death (45% vs. 7%; p=0.0001) were more likely in cases than in controls, respectively. IC survivors were more likely to be deaf (28% vs. 7%; p=0.01). IC independently predicted mortality (p=0.0004) and NDI (p=0.018). IC occurred in 1.5% of VLBW infants. Preceding NEC increased the risk of developing IC. CNS candidiasis is under-investigated and difficult to diagnose, but portends a very poor outcome. Mortality, deafness and NDI were independently significantly increased in infants with IC compared to matched controls.


Attributable costs of enterococcal bloodstream infections in a nonsurgical hospital cohort.
Vancomycin-resistant Enterococcus (VRE) bloodstream infections (BSIs) are associated with increased morbidity and mortality. To determine the hospital costs and length of stay attributable to VRE BSI and vancomycin-sensitive Enterococcus (VSE) BSI and the independent effect of vancomycin resistance on hospital costs. A retrospective cohort study was conducted of 21,154 nonsurgical patients admitted to an academic medical center during the period from 2002 through 2003. Using administrative data, attributable hospital costs (adjusted for inflation to 2007 US dollars) and length of stay were estimated with multivariate generalized least-squares (GLS) models and propensity score-matched pairs. The cohort included 94 patients with VRE BSI and 182 patients with VSE BSI. After adjustment for demographics, comorbidities, procedures, nonenterococcal BSI, and early mortality, the costs attributable to VRE BSI were $4,479 (95% confidence interval [CI], $3,500-$5,732) in the standard GLS model and $4,036 (95% CI, $3,170-$5,140) in the propensity score-weighted GLS model, and the costs attributable to VSE BSI were $2,250 (95% CI, $1,758-$2,880) in the standard GLS model and $2,023 (95% CI, $1,588-$2,575) in the propensity score-weighted GLS model. The median values of the difference in costs between matched pairs were $9,949 (95% CI, $1,579-$24,693) for VRE BSI and $5,282 (95% CI, $2,042-$8,043) for VSE BSI. The costs attributable to vancomycin resistance were $1,713 (95% CI, $1,338-$2,192) in the standard GLS model and $1,546 (95% CI, $1,214-$1,968) in the propensity score-weighted GLS model. Depending on the statistical method used, attributable length of stay estimates ranged from 2.2 to 3.5 days for patients with VRE BSI and from 1.1 to 2.2 days for patients with VSE BSI. VRE BSI and VSE BSI were independently associated with increased hospital costs and increased length of stay. Vancomycin resistance was associated with increased costs.


Can non-fatal burden estimates from the Global Burden of Disease study be used locally? An investigation using models of stroke and diabetes for South Africa.
Background: The Global Burden of Disease (GBD) approach estimates disease burden by combining fatal (years of life lost) and non-fatal burden prevalence-based years of life lived with disability (PYLDs) estimates. Although South Africa has data to estimate mortality, prevalence data to estimate non-fatal burden are sparse. PYLD estimates from the GBD study for South Africa can potentially be used. However, there is a divergence in mortality estimates for South Africa between the second South African National Burden of Disease (SANBD2) and 2013 GBD studies. Objective: We investigated the feasibility of utilising GBD PYLD estimates for stroke and diabetes by exploring different disease modelling scenarios. Method: DisMod II software-generated South African stroke and diabetes PYLDs for 2010 from models using local epidemiological parameters and demographic data for people 20-79 years old. We investigated the impact on PYLD estimates of 1) differences in the cause-of-death envelope, 2) differences in the cause-specific mortality estimates (increase/decrease by 15% for stroke and 30% for diabetes), and 3) difference using local disease parameters compared to other country or region parameters. Differences were expressed as ratios, average ratios and ratio ranges. Results: Using the GBD cause-of-death envelope (16% more deaths than SANBD2) and holding other parameters constant yielded age-specific ratios of PYLDs for stroke and diabetes ranging between 0.89 and 1.07 (average 0.98) for males. Similar results were observed for females. A 15% change in age-specific stroke mortality showed little difference in the ratio comparison of PYLDs (range 0.98-1.02) while a 30% change in age-specific diabetes mortality resulted in a ratio range of 0.96-1.07 for PYLDs depending on age. Conclusion: This study showed that GBD non-fatal burden estimates (PYLDs) can be used for stroke and diabetes non-fatal burden in the SANBD2 study.