Conduction disturbances caused by high current density electric fields.
During internal defibrillation, potential gradients greater than 100 V/cm occur near defibrillation electrodes. Such strong fields may cause deleterious effects, including arrhythmias. This study determined 1) the effects of such strong fields on the propagation of activation and 2) whether these effects were different for monophasic and biphasic shocks. Voltages and potential gradients during the shock, as well as activation sequences before and after the shock, were mapped from 117 epicardial electrodes placed over a 3 x 3-cm area on the right ventricle in six dogs. Pacing at a cycle length of 350 msec was given from a long narrow electrode on the right side of the mapped area to generate parallel activation isochrones. A monophasic shock, 10 msec in duration, or a biphasic shock with both phases 5 msec in duration was delivered 300 msec after the last paced stimulus via a mesh electrode on the left side of the mapped area as the cathode, with the anode on the right atrium. Shocks of 70-850 V were given, and the potential gradient and current density at each recording electrode were calculated from the measured potentials and fiber orientation by using a finite element method. Pacing was resumed 200 msec after the shock, and activation sequences were mapped for up to 5 minutes. Potential gradients ranged from 1 to 189 V/cm with high fields on the left side and low fields on the right side of the mapped area. Where the potential gradient was weak, the first activation sequence after the shock was similar to that before the shock, but activation blocked without conducting into areas where the gradient was greater than 64 +/- 4 (mean +/- SD) V/cm for monophasic and greater than 71 +/- 6 V/cm for biphasic shocks. These values are significantly different (p less than 0.003). The higher the potential gradient, the longer was the duration of block before conduction returned. Block duration, however, was generally shorter for biphasic than for monophasic waveforms of the same field strength. In conclusion, conduction block can follow either waveform, but biphasic waveforms cause less block than monophasic waveforms. This effect may partially explain the increased defibrillation efficacy of biphasic shocks.


Dynamical regimes in neural network models of matching behavior.
The matching law constitutes a quantitative description of choice behavior that is often observed in foraging tasks. According to the matching law, organisms distribute their behavior across available response alternatives in the same proportion that reinforcers are distributed across those alternatives. Recently a few biophysically plausible neural network models have been proposed to explain the matching behavior observed in the experiments. Here we study systematically the learning dynamics of these networks while performing a matching task on the concurrent variable interval (VI) schedule. We found that the model neural network can operate in one of three qualitatively different regimes depending on the parameters that characterize the synaptic dynamics and the reward schedule: (1) a matching behavior regime, in which the probability of choosing an option is roughly proportional to the baiting fractional probability of that option; (2) a perseverative regime, in which the network tends to make always the same decision; and (3) a tristable regime, in which the network can either perseverate or choose the two targets randomly approximately with the same probability. Different parameters of the synaptic dynamics lead to different types of deviations from the matching law, some of which have been observed experimentally. We show that the performance of the network depends on the number of stable states of each synapse and that bistable synapses perform close to optimal when the proper learning rate is chosen. Because our model provides a link between synaptic dynamics and qualitatively different behaviors, this work provides us with insight into the effects of neuromodulators on adaptive behaviors and psychiatric disorders.


Endothelial adhesion molecules and multiple organ failure in patients with severe sepsis.
To determine if serum levels of endothelial adhesion molecules were associated with the development of multiple organ failure (MOF) and in-hospital mortality in adult patients with severe sepsis. This study was a secondary data analysis of a prospective cohort study. Patients were admitted to two tertiary intensive care units in San Antonio, TX, between 2007 and 2012. Patients with severe sepsis at the time of intensive care unit (ICU) admission were enrolled. Inclusion criteria were consistent with previously published criteria for severe sepsis or septic shock in adults. Exclusion criteria included immunosuppressive medications or conditions. None. Baseline serum levels of the following endothelial cell adhesion molecules were measured within the first 72h of ICU admission: Intracellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), and Vascular Endothelial Growth Factor (VEGF). The primary and secondary outcomes were development of MOF (⩾2 organ dysfunction) and in-hospital mortality, respectively. Forty-eight patients were enrolled in this study, of which 29 (60%) developed MOF. Patients that developed MOF had higher levels of VCAM-1 (p=0.01) and ICAM-1 (p=0.01), but not VEGF (p=0.70) compared with patients without MOF (single organ failure only). The area under the curve (AUC) to predict MOF according to VCAM-1, ICAM-1 and VEGF was 0.71, 0.73, and 0.54, respectively. Only increased VCAM-1 levels were associated with in-hospital mortality (p=0.03). These associations were maintained even after adjusting for APACHE and SOFA scores using logistic regression. High levels of serum ICAM-1 was associated with the development of MOF. High levels of VCAM-1 was associated with both MOF and in-hospital mortality.


The representativeness of a European multi-center network for influenza-like-illness participatory surveillance.
The Internet is becoming more commonly used as a tool for disease surveillance. Similarly to other surveillance systems and to studies using online data collection, Internet-based surveillance will have biases in participation, affecting the generalizability of the results. Here we quantify the participation biases of Influenzanet, an ongoing European-wide network of Internet-based participatory surveillance systems for influenza-like-illness. In 2011/2012 Influenzanet launched a standardized common framework for data collection applied to seven European countries. Influenzanet participants were compared to the general population of the participating countries to assess the representativeness of the sample in terms of a set of demographic, geographic, socio-economic and health indicators. More than 30,000 European residents registered to the system in the 2011/2012 season, and a subset of 25,481 participants were selected for this study. All age classes (10 years brackets) were represented in the cohort, including under 10 and over 70 years old. The Influenzanet population was not representative of the general population in terms of age distribution, underrepresenting the youngest and oldest age classes. The gender imbalance differed between countries. A counterbalance between gender-specific information-seeking behavior (more prominent in women) and Internet usage (with higher rates in male populations) may be at the origin of this difference. Once adjusted by demographic indicators, a similar propensity to commute was observed for each country, and the same top three transportation modes were used for six countries out of seven. Smokers were underrepresented in the majority of countries, as were individuals with diabetes; the representativeness of asthma prevalence and vaccination coverage for 65+ individuals in two successive seasons (2010/2011 and 2011/2012) varied between countries. Existing demographic and national datasets allowed the quantification of the participation biases of a large cohort for influenza-like-illness surveillance in the general population. Significant differences were found between Influenzanet participants and the general population. The quantified biases need to be taken into account in the analysis of Influenzanet epidemiological studies and provide indications on populations groups that should be targeted in recruitment efforts.


Pathogenesis of Abnormal Hepatic Lipid Metabolism Induced by Chronic Intermittent Hypoxia in Rats and the Therapeutic Effect of N-Acetylcysteine.
BACKGROUND The pathogenesis of chronic intermittent hypoxia (CIH)-induced abnormal hepatic lipid metabolism in rats remains unclear. Here, we investigated the therapeutic effect of N-acetylcysteine (NAC) on abnormal hepatic lipid metabolism. MATERIAL AND METHODS Rats were subjected to hypoxia and NAC treatment, and evaluated in terms of hepatic lipid metabolism, hepatocyte ultrastructure, oxidative stress in hepatocytes, expression of nuclear factor-kappa B (NF-κB) and inflammatory cytokines (IL-1β, IL-6, and TNFα), serum lipoprotein lipase (LPL) levels, and blood lipids (triglycerides and cholesterol). RESULTS Compared to the normoxic control group, animals in the hypoxic model group showed significant body weight gain; abnormal hepatic lipid metabolism; lipid vacuolization; accumulation of lipid droplets; abundant autophagosomes and lysosomes; significant increases in oxidative stress, inflammation level, and blood lipid levels; and significantly reduced LPL levels. Compared to control animals, rats in the treatment group exhibited normal body weight gain, improved lipid metabolism, fewer lipid droplets, alleviated ultrastructural injuries, decreased oxidative stress and inflammation level, as well as elevated LPL and reduced blood lipid levels. CONCLUSIONS The harmful effects of CIH on rat liver are possibly associated with the reactive oxygen species (ROS)/NF-κB signaling pathway. NAC is capable of attenuating lipid metabolism alterations and abnormal body weight gain in the CIH rat model, via a possible mechanism related to inhibition of ROS/NF-κB signaling.


Medical Resource Use and Costs of Treating Sickle Cell-related Vaso-occlusive Crisis Episodes: A Retrospective Claims Study.
The study investigated the economic burden of vaso-occlusive crisis (VOC) among sickle cell disease (SCD) patients, through assessment of overall utilization and costs and costs per VOC episode (regarding the number of VOC episodes and health care setting, respectively). Using the Medicaid Analytic Extracts database, the first SCD-related diagnosis claim (index claim) between June 1, 2009-December 31, 2012 was identified among eligible adults. Patients were required to have continuous medical and pharmacy benefits for 6 months pre- and 12 months post-index. Discrete VOC claims identified within a 3-day gap were combined as a single VOC episode. Annual all-cause and SCD-related medical resources and costs were identified and stratified by number of VOC episodes during the 1-year follow-up period. Health care costs per VOC episode were also examined, stratified by care setting. Enrollees included 8521 eligible patients with a mean age of 32.88 years (SD=12.21). Of these, 66.5% had a Charlson Comorbidity index (CCI) score of 0 (no comorbidities) and 67.3% were female. The average total medical costs were US$34 136 (median=US$12 691) annually, and SCD accounted for 60% of the total costs (mean=US$20 206, median=US$1204). Patients with >3 episodes had the highest annual SCD-related costs (mean=US$58 950) across all settings. Health care resource utilization (HCRU) and costs increased substantially as the number of VOC episodes increased. This study was limited to observation of associations rather than causal inference, and by possible coding and identification discrepancies and the restricted generalizability of the population. VOC has a severe impact on medical resource use and costs among the adult SCD population. Further research among broader study populations is needed to facilitate the reduction of VOC episodes and thereby improve clinical and economic outcomes for SCD patients.


Spectral estimation theory: beyond linear but before Bayesian.
Most color-acquisition devices capture spectral signals by acquiring only three samples, critically undersampling the spectral information. We analyze the problem of estimating high-dimensional spectral signals from low-dimensional device responses. We begin with the theory and geometry of linear estimation methods. These methods use linear models to characterize the likely input signals and reduce the number of estimation parameters. Next, we introduce two submanifold estimation methods. These methods are based on the observation that for many data sets the deviation between the signal and the linear estimate is systematic; the methods incorporate knowledge of these systematic deviations to improve upon linear estimation methods. We describe the geometric intuition of these methods and evaluate the submanifold method on hyperspectral image data.


Infective Endocarditis Following Transcatheter Aortic Valve Replacement: Comparison of Balloon- Versus Self-Expandable Valves.
No data exist about the characteristics of infective endocarditis (IE) post-transcatheter aortic valve replacement (TAVR) according to transcatheter valve type. We aimed to determine the incidence, clinical characteristics, and outcomes of patients with IE post-TAVR treated with balloon-expandable valve (BEV) versus self-expanding valve (SEV) systems. Data from the multicenter Infectious Endocarditis After TAVR International Registry was used to compare IE patients with BEV versus SEV. A total of 245 patients with IE post-TAVR were included (SEV, 47%; BEV, 53%). The timing between TAVR and IE was similar between groups (SEV, 5.5 [1.2-15] months versus BEV, 5.3 [1.7-11.4] months; P=0.89). Enterococcal IE was more frequent in the SEV group (36.5% versus 15.4%; P<0.01), and vegetation location differed according to valve type (stent frame, SEV, 18.6%; BEV, 6.9%; P=0.01; valve leaflet, SEV, 23.9%; BEV, 38.5%; P=0.01). BEV recipients had a higher rate of stroke/systemic embolism (20.0% versus 8.7%, adjusted OR: 2.46, 95% CI: 1.04-5.82, P=0.04). Surgical explant of the transcatheter valve (SEV, 8.7%; BEV, 13.8%; P=0.21), and in-hospital death at the time of IE episode (SEV, 35.6%; BEV, 37.7%; P=0.74) were similar between groups. After a mean follow-up of 13±12 months, 59.1% and 54.6% of the SEV and BEV recipients, respectively, had died (P=0.66). The characteristics of IE post-TAVR, including microorganism type, vegetation location, and embolic complications but not early or late mortality, differed according to valve type. These results may help to guide the diagnosis and management of IE and inform future research studies in the field.


Localized pulmonary Wegener's granuloma simulating lung cancer: report of four cases.
Clinical features suggesting lung disease in three patients and a chance chest radiograph in the fourth led to films showing localized lung lesions with some characteristics of neoplasms. Two were heavy smokers, two were non-smokers. In two the lesion was peripheral, in one lobar (RUL), and in the fourth it crossed the interlobar fissure (apical and posterior segments LUL and apical LLL). Malignant cells were not seen on sputum cytology examination in any, but in one, atypical cells were reported. All four patients had lung resection for suspected cancer, two by pneumonectomy, one by lobectomy, and one lingulectomy. All patients recovered, and their clinical course has so far been uniformly benign. Two have been followed long term (16 and 10 years), one 2 1/2 years, and one a year. Pathologically, the lesions appeared to be strictly limited without extra-pulmonary involvement, except that the patient followed for one year has developed hyporegenerative anaemia responsive to prednisone therapy. The pathological features of focal necrosis, granulomatous inflammation, and vasculitis were sufficiently striking, although often focal, to suggest that incisional biopsy from frozen-section histological diagnosis could be useful to prevent extensive lung resection for lesions not positively diagnosed before thoracotomy.


Fabrication of multifaceted, micropatterned surfaces and image-guided patterning using laser scanning lithography.
This protocol describes the implementation of laser scanning lithography (LSL) for the fabrication of multifaceted, patterned surfaces and for image-guided patterning. This photothermal-based patterning technique allows for selective removal of desired regions of an alkanethiol self-assembled monolayer on a metal film through raster scanning a focused 532 nm laser using a commercially available laser scanning confocal microscope. Unlike traditional photolithography methods, this technique does not require the use of a physical master and instead utilizes digital "virtual masks" that can be modified "on the fly" allowing for quick pattern modifications. The process to create multifaceted, micropatterned surfaces, surfaces that display pattern arrays of multiple biomolecules with each molecule confined to its own array, is described in detail. The generation of pattern configurations from user-chosen images, image-guided LSL is also described. This protocol outlines LSL in four basic sections. The first section details substrate preparation and includes cleaning of glass coverslips, metal deposition, and alkanethiol functionalization. The second section describes two ways to define pattern configurations, the first through manual input of pattern coordinates and dimensions using Zeiss AIM software and the second via image-guided pattern generation using a custom-written MATLAB script. The third section describes the details of the patterning procedure and postpatterning functionalization with an alkanethiol, protein, and both, and the fourth section covers cell seeding and culture. We end with a general discussion concerning the pitfalls of LSL and present potential improvements that can be made to the technique.


Work-related stress in midlife and all-cause mortality: can sense of coherence modify this association?
Survival reflects the accumulation of multiple influences experienced over the life course. Given the amount of time usually spent at work, the influence of work may be particularly important. We examined the association between work-related stress in midlife and subsequent mortality, investigating whether sense of coherence modified the association. Self-reported work-related stress was assessed in 1393 Swedish workers aged 42-65 who participated in the nationally representative Level of Living Survey in 1991. An established psychosocial job exposure matrix was applied to measure occupation-based stress. Sense of coherence was measured as meaningfulness, manageability and comprehensibility. Mortality data were collected from the Swedish National Cause of Death Register. Data were analyzed with hazard regression with Gompertz distributed baseline intensity. After adjustment for socioeconomic position, occupation-based high job strain was associated with higher mortality in the presence of a weak sense of coherence (HR, 3.15; 1.62-6.13), a result that was stronger in women (HR, 4.48; 1.64-12.26) than in men (HR, 2.90; 1.12-7.49). Self-reported passive jobs were associated with higher mortality in the presence of a weak sense of coherence in men (HR, 2.76; 1.16-6.59). The link between work stress and mortality was not significant in the presence of a strong sense of coherence, indicating that a strong sense of coherence buffered the negative effects of work-related stress on mortality. Modifications to work environments that reduce work-related stress may contribute to better health and longer lives, especially in combination with promoting a sense of coherence among workers.


Complete mitochondrial genome sequence of Aspergillus oryzae RIB 127 and its comparative analysis with related species.
Here, we determined the complete sequence and annotation of the mitochondrial genome of A. oryzae (strain RIB 127). The complete mitochondrial genome is 29,202 base pairs (bp), with low GC content of 26.2%. Conserved genes identified include 26 transfer RNAs, the small and large ribosomal RNA subunits, and 14 protein-coding genes. Phylogenetic analysis based on the complete mitochondrial genome revealed that RIB 127 formed a single clade with two other A. oryzae species.


Characterization and angiogenic potential of xenogeneic bone grafting materials: Role of periodontal ligament cells.
Adequate revascularization is a prerequisite for successful healing of periodontal bone defects. This study characterized three different xenogeneic bone grafting materials: Gen-Os of equine and porcine origins, and anorganic Bio-Oss. We also investigated their angiogenic potential. All materials were composed of poorly crystalline calcium oxide phosphate, with Bio-Oss exhibiting a carbonated phase and larger particle size and both Gen-Os showing the presence of collagen. Both Gen-Os materials significantly enhanced vascular endothelial growth factor (VEGF) secretion by PDL cells. A significant increase in endothelial cell proliferation was observed in cultures with both Gen-Os conditioned media, but not with that of Bio-Oss. Finally, angiogenesis was stimulated by both Gen-Os conditioned media as demonstrated by an increased formation of capillary-like structures. Taken together, these findings indicate an enhanced angiogenic potential of both Gen-Os bone grafting materials when applied on PDL cells, most likely by increasing VEGF production.


Use of weighted multivariate estimates in trials of multi-serotype vaccines to simplify interpretation of treatment differences.
Many vaccines contain multiple components. Licensed pneumococcal conjugate vaccines (PCV) contain polysaccharides from 7, 10, or 13 different serotypes of Streptococcus pneumoniae. The main outcomes in randomised trials of pneumococcal vaccines are serotype-specific antibody measures. Comparisons are made between groups for each serotype, resulting in multiple separate comparisons of treatment effects which can be complicated to interpret. We investigated methods for computing the overall difference between vaccine groups across all serotypes. Pneumococcal antibody concentrations were obtained from a randomised controlled trial of ten-valent pneumococcal vaccine, conducted in Kathmandu, Nepal. Infants received either 2 priming doses of vaccine at 6 and 14 weeks of age followed by a booster (2+1), or 3 priming doses at 6, 10, and 14 weeks of age with no booster (3+0). The overall difference between vaccine schedules across all serotypes was computed at each visit using a multivariate linear model with equal weights for each serotype. Alternative weights were derived from invasive pneumococcal disease cases in Nepal, Bangladesh and Pakistan, and from estimates of the relative invasiveness of each serotype and used in sensitivity analyses. When 10 separate estimates of treatment differences were computed the ratio of antibody responses for each serotype in the 2+1 group compared with the 3+0 group at 10 months of age varied greatly, with serotype-specific GMRs ranging from 2.80 for serotype 14, to 9.14 for serotype 18C. Using equal weights for each serotype, the overall geometric mean ratio (GMR) was 5.02 (95% CI 4.06-6.22) at 10 months of age, and 1.46 (95% CI 1.14-1.88) at 3 years of age. Using weights based on disease incidence gave GMRs ranging from 5.15 to 6.63 at 10 months of age, and 1.47 to 1.78 at 3 years of age. Using weights based on relative invasiveness gave estimates of 6.81 and 1.59, at 10 months and 3 years respectively. PCV clinical trial data have a multivariate structure with correlated outcomes for different serotypes. When analysing each serotype separately, the multiple estimates of the treatment effect can complicate the interpretation of trial results. Reporting a single overall estimate which accounts for the correlation between outcomes can simplify such interpretation. Treatment effects can be weighted equally or alternative weights derived from independent data can be used. Many modern vaccines have multiple components, such as quadrivalent meningococcal group ACWY vaccine or four-component group B meningococcal vaccine, thus these methods are widely applicable.


Local Structure and Point-Defect-Dependent Area-Selective Atomic Layer Deposition Approach for Facile Synthesis of p-Cu2O/n-ZnO Segmented Nanojunctions.
Area-selective atomic layer deposition (AS-ALD) has attracted much attention in recent years due to the possibility of achieving accurate patterns in nanoscale features, which render this technique compatible with the continuous downscaling in nanoelectronic devices. The growth selectivity is achieved by starting from different materials and results (ideally) in localized growth of a single material. We propose here a new concept, more subtle and general, in which a property of the substrate is modulated to achieve localized growth of different materials. This concept is demonstrated by selective growth of high-quality metallic Cu and semiconducting Cu2O thin films, achieved by changing the type of majority point defects in the ZnO underneath film exposed to the reactive species using a patterned bilayer structure composed of highly conductive and highly resistive areas, as confirmed by transmission electron microscopy (TEM) and electron energy loss spectroscopy (EELS). The selective growth of these materials in a patterned ZnO/Al-doped ZnO substrate allows the fabrication of p-Cu2O/n-ZnO nanojunctions showing a nonlinear rectifying behavior typical of a p-n junction, as confirmed by conductive atomic force microscopy (C-AFM). This process expands the spectra of materials that can be grown in a selective manner by ALD and opens up the possibility of fabricating different architectures, taking advantage of the area-selective deposition. This offers a variety of opportunities in the field of transparent electronics, catalysis, and photovoltaics.


Mothers' education but not fathers' education, household assets or land ownership is the best predictor of child health inequalities in rural Uganda.
BACKGROUND: Health and nutrition inequality is a result of a complex web of factors that include socio-economic inequalities. Various socio-economic indicators exist however some do not accurately predict inequalities in children. Others are not intervention feasible. OBJECTIVE: To examine the association of four socio-economic indicators namely: mothers' education, fathers' education, household asset index, and land ownership with growth stunting, which is used as a proxy for health and nutrition inequalities among infants and young children. METHODS: This was a cross-sectional survey conducted in the rural district of Hoima, Uganda. Two-stage cluster sampling design was used to obtain 720 child/mother pairs. Information on indicators of household socio-economic status and child anthropometry was gathered by administering a structured questionnaire to mothers in their home settings. Regression modelling was used to determine the association of socio-economic indicators with stunting. RESULTS: One hundred seventy two (25%) of the studied children were stunted, of which 105 (61%) were boys (p < 0.001). Bivariate analysis indicated a higher prevalence of stunting among children of: non-educated mothers compared to mothers educated above primary school (odds ratio (OR) 2.5, 95% confidence interval (CI) 1.4-4.4); non-educated fathers compared to fathers educated above secondary school (OR 1.7, 95% CI 0.8-3.5); households belonging in the "poorest" quintile for the asset index compared to the "least poor" quintile (OR 2.1, 95% CI 1.2-3.7); Land ownership exhibited no differentials with stunting. Simultaneously adjusting all socio-economic indicators in conditional regression analysis left mothers' education as the only independent predictor of stunting with children of non-educated mothers significantly more likely to be stunted compared to those of mothers educated above primary school (OR 2.1, 95% CI 1.1-3.9). More boys than girls were significantly stunted in poorer than wealthier socio-economic strata. CONCLUSIONS: Of four socio-economic indicators, mothers' education is the best predictor for health and nutrition inequalities among infants and young children in rural Uganda. This suggests a need for appropriate formal education of the girl child aimed at promoting child health and nutrition. The finding that boys are adversely affected by poverty more than their female counterparts corroborates evidence from previous studies.


IL-7 and Flt-3L plasma levels are increased during highly active antiretroviral therapy-associated IL-2 therapy.
IL-2 is used in conjunction with highly active antiretroviral therapy to increase the CD4 cell count in HIV-positive patients. The mechanisms involved remain ill-defined. Here we show that during the first cycle of IL-2 therapy, IL-7 and Flt-3L plasma levels are increased, whereas levels of stem cell factor are unchanged. This supports the hypothesis that aside from stimulating CD4 T cells IL-2 may also indirectly affect lymphocyte production through the stimulation of lymphopoietic cytokines.


Comparison of hematological parameters in untreated and treated subclinical hypothyroidism and primary hypothyroidism patients.
Thyroid hormones play an important physiological role in human metabolism. Erythrocyte abnormalities are frequently associated with thyroid disorder. However, they are rarely investigated and related to the subclinical and primary hypothyroidism in Kashmiri Patients. In this study an attempt was made to study hematological parameters in untreated and treated subclinical hypothyroidism and primary hypothyroidism patients. This retrospective study included 600 subjects, among which were untreated subclinical hypothyroid (n=110), treated subclinical hypothyroid (n=110), untreated primary hypothyroid (n=100), treated primary hypothyroid (n=100) and euthyroid (n=180). This study was carried out at Department of Biochemistry, Government Medical College Srinagar. The hematological parameters and thyroid profile of the subjects were assessed by the Sysmex (Italy) and ECLIA (Germany) 2010 automatic analyzer. Mean, standard deviation (SD), analysis of variance (Two-way ANOVA), and multiple comparisons were used to report our results, with p<0.05 or p<0.01 considered as statistically significant. In this study group we compared the hematological parameters in these groups, untreated subclinical hypothyroid, treated subclinical hypothyroid, untreated primary hypothyroid, treated primary hypothyroid and euthyroid. We found that hematological parameters like Hb, RBC, MCV, HCT, RDW,RBC% were significantly increased in untreated subclinical hypothyroidism and untreated primary hypothyroidsm, with the p value being less than 0.05 whereas, in treated SCH & Pr. Hypothyroid, results were insignificant. The results reported in these groups as mean±SD, were statistically tested by ANOVA and multiple comparison tests. In untreated subclinical hypothyroid the values were: Hb (10.83±1.33 g/dl), RBC (4.21±0.66 10(6)/µl), MCV (84.56±6.84 fL), HCT (38.5±2.2%), RDW (17.91±2.37 fL), RBC% (84.36±13.2%) and in untreated primary hypothyroid, Hb (10.73±0.86 g/dl), RBC (4.63±0.51 10(6)/µl), MCV (83.34±6.92 fL), HCT (38.6±2.6%), RDW (14.93±5.47 fL), RBC% (92.63±10.30%) suggesting that these patients were at risk of anemia and other erythrocyte abnormalities. MCV is an inexpensive approach to study the types of anemia and explore related information like production, destruction, loss and morphological changes of RBC'S. The thyroid dysfunction is frequently associated with anemia in subclinical hypothyroidism and primary hypothyroidism. Subclinical hypothyroidism (SCH) is associated with serious complications. Substantial numbers of patients with the risk of SCH could be getting converted into primary hypothyroidism. Such conditions should be identified and corrected. On the other hand, their presence could move to a thyroid dysfunction, allowing its early management.


Reviewing evidence for the cognitive model of auditory hallucinations: The relationship between cognitive voice appraisals and distress during psychosis.
Individuals who hear voices during psychosis may be vulnerable to increased distress. Cognitive models place emphasis on the role of subjective and cognitive appraisals of voices in influencing different emotional reactions. This paper systematically reviewed literature investigating the relationship between appraisals of voices and distress. The review included 26 studies, published between 1990 and 2008. Several types of appraisals were found to be linked to higher levels of distress in voice hearers, including voices appraised as malevolent, voices appraised as high in supremacy, voices appraised to have personal acquaintance with the individual, and attitudes of disapproval and rejection towards voices. However, results from cognitive therapy trials did not consistently report significant improvements in voice related distress post-intervention. One explanation for this finding is that mediating variables, such as social schemata, exist within the appraisal-distress relationship, variables which were not targeted in the cognitive therapy trials. Areas for future investigation may include developing a greater understanding of mediating variables, such as social schemata, within the appraisal-distress relationship, carrying out interventions aimed at addressing these mediating variables using randomized controlled trial designs, and understanding the relationship between positive affect and voice appraisals.


Using brain MERMER testing to detect knowledge despite efforts to conceal.
This experiment examined the accuracy and reliability of the memory and encoding related multifaceted electroencephalographic response (MERMER) technique for detecting information related to events subjects have experienced, despite subjects' efforts to conceal that knowledge. Information obtained through interviews was used to develop stimulus sets consisting of words and phrases presented to subjects visually by computer. Sets were composed of three types of stimuli: life experience-related (Probes), stimuli the subject was asked to memorize and respond to (Targets), and irrelevant information (Irrelevants). Each set of stimuli was tested on two individuals: (1) one individual who had participated in the event in question--and thus had the relevant information stored in his/her brain, and (2) one who had not. Six subjects were tested. Electrical brain responses to the stimuli were recorded non-invasively from the scalp and analyzed. MERMERs, (memory and encoding related multifaceted electroencephalographic responses), of which the P300 is a sub-component, were used to determine whether the subject had the relevant information stored in his brain (information present) or not (information absent), thus indicating whether or not each subject had participated in the real-life event in question. Bootstrapping was used to analyze and compare the responses to the three types of stimuli. As predicted, MERMERs were elicited by Probe stimuli only in the subjects who had participated in the investigated event, by Target stimuli in all subjects, and in no case by Irrelevant stimuli. For each of the six subjects, brain MERMER testing correctly determined whether the subject had participated in and consequently knew about the event in question (information present) or had not participated (information absent). The statistical confidence for this determination was 99.9% in five cases and 90.0% in one case. The article concludes with a discussion of areas of future research and the potential for using this new technology as an investigative tool in criminal cases.


Early detection of visual impairment in young children using a smartphone-based deep learning system.
Early detection of visual impairment is crucial but is frequently missed in young children, who are capable of only limited cooperation with standard vision tests. Although certain features of visually impaired children, such as facial appearance and ocular movements, can assist ophthalmic practice, applying these features to real-world screening remains challenging. Here, we present a mobile health (mHealth) system, the smartphone-based Apollo Infant Sight (AIS), which identifies visually impaired children with any of 16 ophthalmic disorders by recording and analyzing their gazing behaviors and facial features under visual stimuli. Videos from 3,652 children (≤48 months in age; 54.5% boys) were prospectively collected to develop and validate this system. For detecting visual impairment, AIS achieved an area under the receiver operating curve (AUC) of 0.940 in an internal validation set and an AUC of 0.843 in an external validation set collected in multiple ophthalmology clinics across China. In a further test of AIS for at-home implementation by untrained parents or caregivers using their smartphones, the system was able to adapt to different testing conditions and achieved an AUC of 0.859. This mHealth system has the potential to be used by healthcare professionals, parents and caregivers for identifying young children with visual impairment across a wide range of ophthalmic disorders.


The impact of public involvement in health research: what are we measuring? Why are we measuring it? Should we stop measuring it?
As public involvement in the design, conduct and dissemination of health research has become an expected norm and firmly enshrined in policy, interest in measuring its impact has also grown. Despite a drive to assess the impact of public involvement, and a growing body of studies attempting to do just this, a number of questions have been largely ignored. This commentary addresses these omissions: What is the impact of all this focus on measuring impact? How is the language of impact shaping the debate about, and the practice of, public involvement in health research? And how have shifting conceptualisations of public involvement in health research shaped, and been shaped by, the way we think about and measure impact? We argue that the focus on impact risks distorting how public involvement in health research is conceptualised and practised, blinding us to possible negative impacts. We call for a critical research agenda for public involvement that [a] considers public involvement not as an instrumental intervention but a social practice of dialogue and learning between researchers and the public; [b] explores how power relations play out in the context of public involvement in health research, what empowerment means and whose interests are served by it, and [c] asks questions about possible harms as well as benefits of public involvement, and whether the language of impact is helpful or not.


Evaluation of GATE-RTion (GATE/Geant4) Monte Carlo simulation settings for proton pencil beam scanning quality assurance.
Geant4 is a multi-purpose Monte Carlo simulation tool for modeling particle transport in matter. It provides a wide range of settings, which the user may optimize for their specific application. This study investigates GATE/Geant4 parameter settings for proton pencil beam scanning therapy. GATE8.1/Geant4.10.3.p03 (matching the versions used in GATE-RTion1.0) simulations were performed with a set of prebuilt Geant4 physics lists (QGSP_BIC, QGSP_BIC_EMY, QGSP_BIC_EMZ, QGSP_BIC_HP_EMZ), using 0.1mm-10mm as production cuts on secondary particles (electrons, photons, positrons) and varying the maximum step size of protons (0.1mm, 1mm, none). The results of the simulations were compared to measurement data taken during clinical patient specific quality assurance at The Christie NHS Foundation Trust pencil beam scanning proton therapy facility. Additionally, the influence of simulation settings was quantified in a realistic patient anatomy based on computer tomography (CT) scans. When comparing the different physics lists, only the results (ranges in water) obtained with QGSP_BIC (G4EMStandardPhysics_Option0) depend on the maximum step size. There is clinically negligible difference in the target region when using High Precision neutron models (HP) for dose calculations. The EMZ electromagnetic constructor provides a closer agreement (within 0.35 mm) to measured beam sizes in air, but yields up to 20% longer execution times compared to the EMY electromagnetic constructor (maximum beam size difference 0.79 mm). The impact of this on patient-specific quality assurance simulations is clinically negligible, with a 97% average 2%/2 mm gamma pass rate for both physics lists. However, when considering the CT-based patient model, dose deviations up to 2.4% are observed. Production cuts do not substantially influence dosimetric results in solid water, but lead to dose differences of up to 4.1% in the patient CT. Small (compared to voxel size) production cuts increase execution times by factors of 5 (solid water) and 2 (patient CT). Taking both efficiency and dose accuracy into account and considering voxel sizes with 2 mm linear size, the authors recommend the following Geant4 settings to simulate patient specific quality assurance measurements: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (in the phantom and range-shifter) and 10 mm (world); best agreement to measurement data was found for QGSP_BIC_EMZ reference physics list at the cost of 20% increased execution times compared to QGSP_BIC_EMY. For simulations considering the patient CT model, the following settings are recommended: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (phantom/range-shifter) and 10 mm (world) if the goal is to achieve sufficient dosimetric accuracy to ensure that a plan is clinically safe; or 0.1 mm (phantom/range-shifter) and 1 mm (world) if higher dosimetric accuracy is needed (increasing execution times by a factor of 2); most accurate results expected for QGSP_BIC_EMZ reference physics list, at the cost of 10-20% increased execution times compared to QGSP_BIC_EMY.


Combining radiation with hyperthermia: a multiscale model informed by in vitro experiments.
Combined radiotherapy and hyperthermia offer great potential for the successful treatment of radio-resistant tumours through thermo-radiosensitization. Tumour response heterogeneity, due to intrinsic, or micro-environmentally induced factors, may greatly influence treatment outcome, but is difficult to account for using traditional treatment planning approaches. Systems oncology simulation, using mathematical models designed to predict tumour growth and treatment response, provides a powerful tool for analysis and optimization of combined treatments. We present a framework that simulates such combination treatments on a cellular level. This multiscale hybrid cellular automaton simulates large cell populations (up to 107 cells) in vitro, while allowing individual cell-cycle progression, and treatment response by modelling radiation-induced mitotic cell death, and immediate cell kill in response to heating. Based on a calibration using a number of experimental growth, cell cycle and survival datasets for HCT116 cells, model predictions agreed well (R2 > 0.95) with experimental data within the range of (thermal and radiation) doses tested (0-40 CEM43, 0-5 Gy). The proposed framework offers flexibility for modelling multimodality treatment combinations in different scenarios. It may therefore provide an important step towards the modelling of personalized therapies using a virtual patient tumour.


Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae.
Bacterial infection of the lower respiratory tract in chronic obstructive pulmonary disease (COPD) patients is common both in stable patients and during acute exacerbations. The most frequent bacteria detected in COPD patients is Haemophilus influenzae, and it appears this organism is uniquely adapted to exploit immune deficiencies associated with COPD and to establish persistent infection in the lower respiratory tract. The presence of bacteria in the lower respiratory tract in stable COPD is termed colonization; however, there is increasing evidence that this is not an innocuous phenomenon but is associated with airway inflammation, increased symptoms, and increased risk for exacerbations. In this review, we discuss host immunity that offers protection against H. influenzae and how disturbance of these mechanisms, combined with pathogen mechanisms of immune evasion, promote persistence of H. influenzae in the lower airways in COPD. In addition, we examine the role of H. influenzae in COPD exacerbations, as well as interactions between H. influenzae and respiratory virus infections, and review the role of treatments and their effect on COPD outcomes. This review focuses predominantly on data derived from human studies but will refer to animal studies where they contribute to understanding the disease in humans.


Chimeric antigen receptor T-cell therapy for multiple myeloma: a consensus statement from The European Myeloma Network.
Adoptive cellular therapy using chimeric antigen receptor T-cell (CART) therapy is currently being evaluated in patients with relapsed / refractory multiple myeloma (MM). The majority of CAR-T cell programs now being tested in clinical trials are targeting B-cell maturation antigen. Several recent phase I / II trials show promising preliminary results in patients with MM progressing on proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies targeting CD38. CAR-T cell therapy is a potentially life-threatening strategy that can only be administered in experienced centers. For the moment, CAR-T cell therapy for MM is still experimental, but once this strategy has been approved in relapsed/refractory MM, it will become one of the most important indications for this therapy in Europe and world-wide. This manuscript proposes practical considerations for the use of CAR-T cell therapy in MM, and discusses several important issues for its future development.


Biomimetic transparent and superhydrophobic coatings: from nature and beyond nature.
It is well known that high optical transparency is one of the most crucial criteria for the overwhelming majority of optical devices and correlative functions, including smart windows, camera lenses, solar cell systems and optoelectronic devices. With the frequent exposure of this equipment to all sorts of environments, such as outdoor conditions, a surface with self-cleaning properties can guard against fouling, humidity, bacterial growth and so forth. That is one type of application of the big family of superhydrophobic coatings. Therefore, integrating high transparency with self-cleaning characteristics is of great importance for such applications. In this review, the recent developments in designing, synthesizing and manufacturing transparent and superhydrophobic surfaces are reviewed. Firstly, the established theoretical aspects of surface wetting properties are summarized and then several natural and bio-inspired superhydrophobic surfaces of diverse microcosmic structures are presented as representative examples. With a focus on distinctively employed materials and the corresponding fabrication of superhydrophobic coatings with high transparency, the promising research directions and application prospects of this rapidly developing field are briefly addressed as well.


Molecular Communication Model for Targeted Drug Delivery in Multiple Disease Sites With Diversely Expressed Enzymes.
Targeted drug delivery (TDD) for disease therapy using liposomes as nanocarriers has received extensive attention in the literature. The liposome's ability to incorporate capabilities such as long circulation, stimuli responsiveness, and targeting characteristics, makes it a versatile nanocarrier. Timely drug release at the targeted site requires that trigger stimuli such as pH, light, and enzymes be uniquely overexpressed at the targeted site. However, in some cases, the targeted sites may not express trigger stimuli significantly, hence, achieving effective TDD at those sites is challenging. In this paper, we present a molecular communication-based TDD model for the delivery of therapeutic drugs to multiple sites that may or may not express trigger stimuli. The nanotransmitter and nanoreceiver models for the molecular communication system are presented. Here, the nanotransmitter and nanoreceiver are injected into the targeted body system's blood network. The compartmental pharmacokinetics model is employed to model the transportation of these therapeutic nanocarriers to the targeted sites where they are meant to anchor before the delivery process commences. We also provide analytical expressions for the delivered drug concentration. The effectiveness of the proposed model is investigated for drug delivery on tissue surfaces. Results show that the effectiveness of the proposed molecular communication-based TDD depends on parameters such as the total transmitter volume capacity, the receiver radius, the diffusion characteristic of the microenvironment of the targeted sites, and the concentration of the enzymes associated with the nanotransmitter and the nanoreceiver designs.


Strong Light-Matter Coupling and Hybridization of Molecular Vibrations in a Low-Loss Infrared Microcavity.
Hybridized polaritons are generated by simultaneously coupling two vibrational modes of two different organic materials to the resonance of a low-loss infrared optical microcavity. A thin film of poly methyl methacrylate with solvent molecules of dimethylformamide trapped inside provided two spectrally narrow, closely spaced carbonyl stretches with absorption peaks at 1731 and 1678 cm(-1). Situating this film in a microcavity based on Ge/ZnS distributed Bragg reflector mirrors produced three distinct polariton branches in the dispersion relation due to hybridization of the vibrational resonances. Two anticrossings were observed with Rabi splittings of 9.6 and 5.2 meV, between the upper-to-middle and middle-to-lower polariton branches, respectively. This system marks the first demonstration of polariton hybridization between a solid and solvent molecules and can open new paths toward chemical reaction modification and energy transfer studies in the mid-infrared spectral range.


Enhanced Recovery After Surgery.
Enhanced recovery after surgery (ERAS) is a multimodal perioperative care pathway designed to achieve early recovery for patients undergoing major surgical procedures. Meta-analyses, randomized controlled trials, and large prospective cohort studies were reviewed. Each item of the perioperative treatment pathway in the English language was examined and reviewed. Enhanced recovery after surgery items that were the strongest predictors for a shorter hospital stay and lower morbidity were absence of a nasogastric tube, early mobilization, early oral nutrition, early removal of the epidural, early removal of the urinary catheter, and utilization of nonopioid analgesia. Based on evidence available for each element of the perioperative care pathway, ERAS provides a protocol for perioperative care. This protocol allows for further evidence-based studies that are adequately powered between institutions.


Interleukin-10 therapy--review of a new approach.
Interleukin (IL)-10 is an important immunoregulatory cytokine produced by many cell populations. Its main biological function seems to be the limitation and termination of inflammatory responses and the regulation of differentiation and proliferation of several immune cells such as T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes. However, very recent data suggest IL-10 also mediates immunostimulatory properties that help to eliminate infectious and noninfectious particles with limited inflammation. Numerous investigations, including expression analyses in patients, in vitro and animal experiments suggest a major impact of IL-10 in inflammatory, malignant, and autoimmune diseases. So IL-10 overexpression was found in certain tumors as melanoma and several lymphomas and is considered to promote further tumor development. Systemic IL-10 release is a powerful tool of the central nervous system to prevent hyperinflammatory processes by activation of the neuro-endocrine axis following acute stress reactions. In contrast, a relative IL-10 deficiency has been observed and is regarded to be of pathophysiological relevance in certain inflammatory disorders characterized by a type 1 cytokine pattern such as psoriasis. Recombinant human IL-10 has been produced and is currently being tested in clinical trials. This includes rheumatoid arthritis, inflammatory bowel disease, psoriasis, organ transplantation, and chronic hepatitis C. The results are heterogeneous. They give new insight into the immunobiology of IL-10 and suggest that the IL-10/IL-10 receptor system may become a new therapeutic target.


Presence of Archaea in the Indoor Environment and Their Relationships with Housing Characteristics.
Archaea are widespread and abundant in soils, oceans, or human and animal gastrointestinal (GI) tracts. However, very little is known about the presence of Archaea in indoor environments and factors that can regulate their abundances. Using a quantitative PCR approach, and targeting the archaeal and bacterial 16S rRNA genes in floor dust samples, we found that Archaea are a common part of the indoor microbiota, 5.01 ± 0.14 (log 16S rRNA gene copies/g dust, mean ± SE) in bedrooms and 5.58 ± 0.13 in common rooms, such as living rooms. Their abundance, however, was lower than bacteria: 9.20 ± 0.32 and 9.17 ± 0.32 in bedrooms and common rooms, respectively. In addition, by measuring a broad array of environmental factors, we obtained preliminary insights into how the abundance of total archaeal 16S rRNA gene copies in indoor environment would be associated with building characteristics and occupants' activities. Based on the results, Archaea are not equally distributed within houses, and the areas with greater input of outdoor microbiome and higher traffic and material heterogeneity tend to have a higher abundance of Archaea. Nevertheless, more research is needed to better understand causes and consequences of this microbial group in indoor environments.


Synchronized Video-Review as a Tool to Enhance Reflection and Feedback: A Design-Based Feasibility Study.
UK surgical training currently faces the challenge of expanding surgical skills in a context of reduced training opportunities. Video-review in theatre offers the potential to gain more from each learning opportunity and to enhance feedback. This was a designed-based study to test the feasibility of using synchronized video-review as a reflective tool to enhance surgical training and to gain a deeper understanding of intraoperative feedback. Ten supervised laparoscopic cholecystectomy operations were video-recorded using a synchronized split screen, to show trainees' actions, instrument manipulation, and interactions with other theatre staff. This was followed up by joint review of the operation-recording by both the trainee and supervisor. Video-review sessions were audio-recorded along with the consultant and Specialist Registrar interviews after the review session. Audio recordings were thematically analyzed. Supervisors completed the Procedure-Based Assessment forms, twice: post operation and post video-review to check potential trainers' enhanced insight. Forms were analyzed to note any changes and to triangulate the findings. Overall trainee and supervisor feedback was positive. Trainees and supervisors reported the video-review added value in terms of reflection-on-action. It removed the stress of conducting/supervising the operation in real time and focused the attention on feedback. Satisfaction was reported across trainee levels with both scrubbed and unscrubbed supervisors. Audio-visual review allowed trainees to understand the feedback better and to identify new targets beyond those gained from the verbal feedback during the procedure. It also facilitated appraisal of the trainer's teaching. This study established the feasibility of using synchronized video-review as a reflection-on-action tool to potentially enhance surgical training by improving feedback. It identified trainees' difficulty in processing intraoperative feedback due to mental overload from the operation. It showed the limitations of current verbal feedback practice, using Procedure-Based Assessment forms, with regard to enhancing technical and nontechnical skills due to denial and memory fading.


Hospital resource intensity and cirrhosis mortality in United States.
To determine whether hospital characteristics predict cirrhosis mortality and how much variation in mortality is attributable to hospital differences. We used data from the 2005-2011 Nationwide Inpatient Sample and the American Hospital Association Annual survey to identify hospitalizations for decompensated cirrhosis and corresponding facility characteristics. We created hospital-specific risk and reliability-adjusted odds ratios for cirrhosis mortality, and evaluated patient and facility differences based on hospital performance quintiles. We used hierarchical regression models to determine the effect of these factors on mortality. Seventy-two thousand seven hundred and thirty-three cirrhosis admissions were evaluated in 805 hospitals. Hospital mean cirrhosis annual case volume was 90.4 (range 25-828). Overall hospital cirrhosis mortality rate was 8.00%. Hospital-adjusted odds ratios (aOR) for mortality ranged from 0.48 to 1.89. Patient characteristics varied significantly by hospital aOR for mortality. Length of stay averaged 6.0 ± 1.6 days, and varied significantly by hospital performance (P < 0.001). Facility level predictors of risk-adjusted mortality were higher Medicaid case-mix (OR = 1.00, P = 0.029) and LPN staffing (OR = 1.02, P = 0.015). Higher cirrhosis volume (OR = 0.99, P = 0.025) and liver transplant program status (OR = 0.83, P = 0.026) were significantly associated with survival. After adjusting for patient differences, era, and clustering effects, 15.3% of variation between hospitals was attributable to differences in facility characteristics. Hospital characteristics account for a significant proportion of variation in cirrhosis mortality. These findings have several implications for patients, providers, and health care delivery in liver disease care and inpatient health care design.


High-precision measurement of a fiber connector end face by use of a Mirau interferometer.
What we believe to be a new instrument for measuring the end-face geometrical parameters of fiber connectors is described. In this apparatus, a Mirau-type interferometric objective is employed to measure a small area of the connector end face and generate an interferogram corresponding to the surface profile. Various new technologies are used to ensure excellent performance and high measurement repeatability. A multipoint method is proposed to adjust the inclination of the physical contact sample stage. The physical contact angle of the sample stage is adjusted directly on the instrument by use of a special tool whose angle is calibrated with the reversal method. Measurement results of important parameters of the fiber connector end face are compared with those inspected by a commercial profiler or with a standard sample. Optical insertion losses of connectors inspected by the developed system are also evaluated.


[Trends in emergency admissions in Amsterdam. Fifteen years of emergency psychiatry in an increasingly crowded city].
The Temporary Holding Department (toa) is a link between the 7/24 service and the admissions departments. We examined the make-up of the admission cohorts and the use of isolation between 2001 and 2017 in the context of demographic developments and changes in the mental healthcare sector.
 METHOD: Comparison of patient data in four cohorts who came in during four consecutive periods.
 RESULTS: The number of admissions rose from 408 a year in the period 2001-2003 to 728 in the period 2013-2016. The proportion of voluntary admissions increased from 4 to 33%, while emergency compulsory admissions (ibs) fell from 83 to 54%. The proportion of admissions of Dutch people from outside Amsterdam and of people from other countries rose from 11 to 23%. The percentage of patients with schizophrenic disorder rose from 25 to 32%, the percentage with mood disorder from 14 to 20% and the percentage with drug-related disorders from 3 to 7%. Assessment at a police station and the classification psychotic disorder were predictors of compulsory admissions (under the terms of the Dutch bopz act). Men under the age of 45 who were admitted compulsorily were more likely to be isolated. The percentage of patients isolated during admission fell from 37% to 20%, and the length of the periods of isolation also declined. CONCLUSIONS The increase in the annual number of admissions to the toa indicates, in the context of population growth and the rise in tourism, that there is a shortage of available beds in regular admissions departments in Amsterdam. Over the course of fifteen years, the number of Dutch nationals from outside Amsterdam and foreigners doubled. Due to policy and/or as a result of the increased proportion of patients admitted voluntarily, the use of isolation decreased.


Social network characteristics and HIV risk among African American, Asian/Pacific Islander, and Latino men who have sex with men.
To examine how social networks influence HIV risk among US racial/ethnic minority men who have sex with men (MSM) and whether the associations of social network characteristics with risk vary by race/ethnicity. A chain-referral sample of 403 African American, 393 Asian/Pacific Islander, and 400 Latino MSM recruited in Los Angeles County, California, completed a questionnaire, which asked about their egocentric social networks, safer sex peer norms, and male anal intercourse partners. HIV-nonconcordant partnerships were those reported by respondents as serodisconcordant or where self and/or partner serostatus was unknown. Overall, 26% of the sample reported HIV-nonconcordant unprotected anal intercourse (UAI) with a nonprimary male partner in the previous 6 months. In a generalized estimating equation (GEE) logistic model that controlled for race/ethnicity, age, nativity, incarceration history, and HIV status, being in a more dense network was associated with less HIV-nonconcordant UAI [adjusted odds ratio (AOR) = 0.92, 95% confidence interval (CI): 0.86 to 0.99, P = 0.0467]. In addition, the effect of safer sex peer norms on HIV-nonconcordant UAI was moderated by ego-alter closeness (P = 0.0021). Safer sex peer norms were protective among those reporting "medium" or "high" ego-alter closeness (AOR = 0.70, 95% CI: 0.52 to 0.95, P = 0.0213 and AOR = 0.48, 95% CI: 0.35 to 0.66, P < 0.0001, respectively), but not among those reporting "low" ego-alter closeness (AOR = 0.96, 95% CI: 0.63 to 1.46, P = 0.8333). The effects of density, closeness, and norms on HIV-nonconcordant UAI did not differ by race/ethnicity. The significant association of social network characteristics with UAI point to network-level factors as important loci for both ongoing research and HIV prevention interventions among US MSM of color.


Application of maximum likelihood reconstruction of subaperture data for measurement of large flat mirrors.
Interferometers accurately measure the difference between two wavefronts, one from a reference surface and the other from an unknown surface. If the reference surface is near perfect or is accurately known from some other test, then the shape of the unknown surface can be determined. We investigate the case where neither the reference surface nor the surface under test is well known. By making multiple shear measurements where both surfaces are translated and/or rotated, we obtain sufficient information to reconstruct the figure of both surfaces with a maximum likelihood reconstruction method. The method is demonstrated for the measurement of a 1.6 m flat mirror to 2 nm rms, using a smaller reference mirror that had significant figure error.


The WD40 Domain of HIRA Is Essential for RI-nucleosome Assembly in Xenopus Egg Extracts.
Histone chaperones are a group of histone-binding proteins that facilitate the assembly of nucleosomes, the fundamental structural units of chromatin in eukaryotes. In nucleosome assembly, deposition of a histone H3-H4 tetramer onto DNA is the first and critical step, which is mediated by the histone chaperones HIRA and CAF-1. HIRA and CAF-1 are reportedly involved in DNA replication independent (RI) and replication coupled nucleosome assembly, respectively. However, the mechanisms by which they mediate histone deposition remain unclear. In this study, we focused on the mechanism by which HIRA induces RI-nucleosome assembly. We looked for HIRA domains that are required for nucleosome assembly and its localization to chromatin. We used cell-free extracts from Xenopus eggs that carry out RI-nucleosome assembly of plasmid DNA. We confirmed that HIRA formed stable complexes with Asf1, another histone H3-H4 chaperone, and the HIRA-Asf1 complex was solely responsible for RI-nucleosome assembly in egg extracts. We further demonstrated that the HIRA N-terminus containing the WD40 domain, which comprises seven WD40 repeats, and the B domain, to which Asf1 binds, were essential for RI-nucleosome assembly; the three WD40 repeats from the N-terminus were especially critical. Using egg extracts that reproduce nuclear formation accompanying the duplication of chromatin, we also demonstrated that the Hir domain was indispensable for the binding of HIRA to chromatin. Thus, the WD40 and B domains are the core elements for inducing RI-nucleosome assembly. Hir domain regulates the binding to chromatin. Based on these findings, similarities and differences between HIRA and CAF-1 are discussed.


Mechanisms of phosphine toxicity.
Fumigation with phosphine gas is by far the most widely used treatment for the protection of stored grain against insect pests. The development of high-level resistance in insects now threatens its continued use. As there is no suitable chemical to replace phosphine, it is essential to understand the mechanisms of phosphine toxicity to increase the effectiveness of resistance management. Because phosphine is such a simple molecule (PH(3)), the chemistry of phosphorus is central to its toxicity. The elements above and below phosphorus in the periodic table are nitrogen (N) and arsenic (As), which also produce toxic hydrides, namely, NH(3) and AsH(3). The three hydrides cause related symptoms and similar changes to cellular and organismal physiology, including disruption of the sympathetic nervous system, suppressed energy metabolism and toxic changes to the redox state of the cell. We propose that these three effects are interdependent contributors to phosphine toxicity.


Response and habituation of pro- and anti-inflammatory gene expression to repeated acute stress.
Acute stress induces increases in plasma inflammatory mediators, which do not habituate to repeated stress. Inflammation is a risk factor for age-related illnesses, highlighting the need to understand factors controlling inflammation. No studies have examined changes in pro- and anti-inflammatory gene expression in response to repeated acute stress in humans. RNA was isolated from peripheral blood before, 30 and 120min after exposure of n=32 healthy human participants to the Trier Social Stress Test (TSST) on two days. Gene expression of interleukin (IL)-6, IL-1β, nuclear factor (NF)-κB and IκB was measured repeatedly on both days. We further assessed leukocyte numbers, plasma IL-6, and salivary cortisol. Stress induced IL-6 (F=44.7; p<0.001) and cortisol responses (F=18.6; p<0.001). Cortisol responses habituated (F=5.1, p=0.003), but IL-6 responses did not (n.s.). All genes increased in response to initial stress (IL-6: F=3.8; p=0.029; IL-1β: F=7.1; p=0.008; NF-κB: F=5.1; p=0.009; IκB: F=4.7; p=0.013) and showed habituation to repeated stress (IL-6: t=2.3; p=0.03; IL-1β: t=3.9; p=0.001; NF-κB: t=2.1; p=0.041; IκB: t=3.1; p=0.005). Day 1 responses of IL-1β and IκB were not explained by changes in leukocyte populations, but IL-6 and NF-κB, as well as most day 2 changes were not independent of leukocyte populations. Stress response and habituation of pro- and anti-inflammatory gene expression as found here might indicate that even on an intracellular level, inflammatory responses to acute stress are adaptive in that they respond to initial, but habituate to repeated, similar stress. Future studies will need to test whether non-habituation is predictive of disease.


The analysis of solution self-assembled polymeric nanomaterials.
There has been much interest in the construction of soft nanomaterials in solution due to a desire to emulate the exquisite structure and function of Nature's equivalents (e.g. enzymes, viruses, proteins and DNA). Nature's soft nanomaterials are capable of selectivity, precision and efficiency in areas such as information storage and replication, transportation and delivery, and synthesis and catalysis. To this end, the use of small molecules, amphiphiles, colloids, and polymers have been investigated for the development of advanced materials in myriad fields of biomedicine and synthetic chemistry. Two major challenges are faced in this area of research: the reproducible, scalable and precise synthesis of such constructs and the reliable, accurate and in-depth analysis of these materials. This tutorial review will focus on this second aspect and provide a guide for the characterisation and analysis of soft nanomaterials in solution using scattering and microscopic techniques.


The Onset of Rapid-Guessing Behavior Over the Course of Testing Time: A Matter of Motivation and Cognitive Resources.
Digital tests make it possible to identify student effort by means of response times, specifically, unrealistically fast responses that are defined as rapid-guessing behavior (RGB). In this study, we used latent class and growth curve models to examine (1) how student characteristics (i.e., gender, school type, general cognitive abilities, and working-memory capacity) are related to the onset point of RGB and its development over the course of a test session (i.e., item positions). Further, we examined (2) the extent to which repeated ratings of task enjoyment (i.e., intercept and slope parameters) are related to the onset and the development of RGB over the course of the test. For this purpose, we analyzed data from N = 401 students from fifth and sixth grades in Germany (n = 247 academic track; n = 154 non-academic track). All participants solved 36 science items under low-stakes conditions and rated their current task enjoyment after each science item, constituting a micro-longitudinal design that allowed students' motivational state to be tracked over the entire test session. In addition, they worked on tests that assessed their general cognitive abilities and working-memory capacity. The results show that students' gender was not significantly related to RGB but that students' school type (which is known to be closely related to academic abilities in the German school system), general cognitive abilities, and their working-memory capacity were significant predictors of an early RGB onset and a stronger RGB increase across testing time. Students' initial rating of task enjoyment was associated with RGB, but only a decline in students' task enjoyment was predictive of earlier RGB onset. Overall, non-academic-school attendance was the most powerful predictor of RGB, together with students' working-memory capacity. The present findings add to the concern that there is an unfortunate relation between students' test-effort investment and their academic and general cognitive abilities. This challenges basic assumptions about motivation-filtering procedures and may threaten a valid interpretation of results from large-scale testing programs that rely on school-type comparisons.


Clinical application of injectable calcium sulfate on early bony consolidation in distraction osteogenesis for the treatment of craniofacial microsomia.
The purpose of this project was to study the effect of calcium sulfate on early bony consolidation in distraction osteogenesis. A total of eight patients with craniofacial microsomia were treated between April 2000 and February 2001. The age of the patients ranged from 2 to 40 years, and all were male. The follow-up period was 1 to 15 months. The operative procedure in adults was based on Ortiz Monasterio's simultaneous mandibular and maxillary distraction technique. In children, osteotomy of the mandible was performed for distraction. On the fifth day after the operation, distraction was performed at a rate of 1 mm/d in three adults. In children, distraction was performed at a rate of 1 mm/d in one patient and 2 mm/d in four patients without a latent period. On the day of completion of distraction, calcium sulfate was implanted into the distracted zone. Radiographs showed bony consolidation at 4 weeks in one child at a rate of 1 mm/d, at 5 to 7 weeks in four children at a rate of 2 mm/d, and at 5 weeks in three adults after implantation of the calcium sulfate. In conclusion, these findings suggest that calcium sulfate is effective for early bony consolidation in distraction osteogenesis and that it would shorten the whole treatment period.


Pregnancy outcomes of Q fever: prospective follow-up study on Reunion island.
Q fever has been associated with perinatal complications. We conducted a prospective follow-up study to assess both the incidence of adverse pregnancy outcomes (APOs) associated with Coxiella burnetii infection and the contribution of Q fever to APOs. Between May 1 and October 31, 2013, within the regional perinatal health care centre of Saint Pierre, Reunion island, we investigated unexplained miscarriages, stillbirths, preterm births or small-for-gestational age children. Seropositivity for C. burnetii antibodies was defined using indirect immunofluorescence for a phase 2 IgG titre ≥1:64. Acute Q fever was defined for a high phase 2 IgG titre ≥1:256 (compatible with recent or active infection) or the detection of C. burnetii genome in miscarriage products and placentas. Incidence rate ratios (IRR) for Q fever related APOs (taken as a composite outcome or individually) were assessed using Poisson regression models for dichotomous outcomes controlling major confounders. Over a 6-month period, 179 pregnant women suspected or diagnosed with an APO were investigated for Q fever, of whom 118 met the definition for an APO. Of these, 19 were seropositive and 10 presented a profile indicative of an acute infection. For three women with an acute Q fever, the chronology between the onset of infection, the APO (2 miscarriages, 1 preterm birth) and the seroconversion suggested causality in the pathogenesis. The cumulative incidence of Q fever related APOs was estimated between 2.2‰ and 5.2‰, whether causality was required or not. Both C. burnetii exposure and acute Q fever were independently associated with APOs (IRR 1.55, 95% CI 1.31-1.84; IRR 1.47, 95% CI 1.15-1.89, respectively). In the endemic context of Reunion island, acute Q fever may lead to APOs. To limit the burden of Q fever on reproduction, pregnant women should be kept away from farms and avoid direct contact with ruminants.


De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase.
Recent studies showing a correlation between the levels of DNA (cytosine-5-)-methyltransferase (DNA MTase) enzyme activity and tumorigenicity have implicated this enzyme in the carcinogenic process. Moreover, hypermethylation of CpG island-containing promoters is associated with the inactivation of genes important to tumor initiation and progression. One proposed role for DNA MTase in tumorigenesis is therefore a direct role in the de novo methylation of these otherwise unmethylated CpG islands. In this study, we sought to determine whether increased levels of DNA MTase could directly affect CpG island methylation. A full-length cDNA for human DNA MTase driven by the cytomegalovirus promoter was constitutively expressed in human fibroblasts. Individual clones derived from cells transfected with DNA MTase (HMT) expressed 1- to 50-fold the level of DNA MTase protein and enzyme activity of the parental cell line or clones transfected with the control vector alone (Neo). To determine the effects of DNA MTase overexpression on CpG island methylation, we examined 12 endogenous CpG island loci in the HMT clones. HMT clones expressing > or = 9-fold the parental levels of DNA MTase activity were significantly hypermethylated relative to at least 11 Neo clones at five CpG island loci. In the HMT clones, methylation reached nearly 100% at susceptible CpG island loci with time in culture. In contrast, there was little change in the methylation status in the Neo clones over the same time frame. Taken together, the data indicate that overexpression of DNA MTase can drive the de novo methylation of susceptible CpG island loci, thus providing support for the idea that DNA MTase can contribute to tumor progression through CpG island methylation-mediated gene inactivation.


Stress: Neurobiology, consequences and management.
Stress, both physical and psychological, is attracting increasing attention among neuroresearchers. In the last 20 decades, there has been a surge of interest in the research of stress-induced manifestations and this approach has resulted in the development of more appropriate animal models for stress-associated pathologies and its therapeutic management. These stress models are an easy and convenient method for inducing both psychological and physical stress. To understand the behavioral changes underlying major depression, molecular and cellular studies are required. Dysregulation of the stress system may lead to disturbances in growth and development, and may this may further lead to the development of various other psychiatric disorders. This article reviews the different types of stress and their neurobiology, including the different neurotransmitters affected. There are various complications associated with stress and their management through various pharmacological and non-pharmacological techniques. The use of herbs in the treatment of stress-related problems is practiced in both Indian and Western societies, and it has a vast market in terms of anti-stress medications and treatments. Non-pharmacological techniques such as meditation and yoga are nowadays becoming very popular as a stress-relieving therapy because of their greater effectiveness and no associated side effects. Therefore, this review highlights the changes under stress and stressor and their impact on different animal models in understanding the mechanisms of stress along with their effective and safe management.


Rapid adaptation to microgravity in mammalian macrophage cells.
Despite the observed severe effects of microgravity on mammalian cells, many astronauts have completed long term stays in space without suffering from severe health problems. This raises questions about the cellular capacity for adaptation to a new gravitational environment. The International Space Station (ISS) experiment TRIPLE LUX A, performed in the BIOLAB laboratory of the ISS COLUMBUS module, allowed for the first time the direct measurement of a cellular function in real time and on orbit. We measured the oxidative burst reaction in mammalian macrophages (NR8383 rat alveolar macrophages) exposed to a centrifuge regime of internal 0 g and 1 g controls and step-wise increase or decrease of the gravitational force in four independent experiments. Surprisingly, we found that these macrophages adapted to microgravity in an ultra-fast manner within seconds, after an immediate inhibitory effect on the oxidative burst reaction. For the first time, we provided direct evidence of cellular sensitivity to gravity, through real-time on orbit measurements and by using an experimental system, in which all factors except gravity were constant. The surprisingly ultra-fast adaptation to microgravity indicates that mammalian macrophages are equipped with a highly efficient adaptation potential to a low gravity environment. This opens new avenues for the exploration of adaptation of mammalian cells to gravitational changes.


Expansion of human hepatocyte populations by a retroviral gene transfer of simian virus 40 large T antigen.
A hybrid artificial liver (HAL) could be used to treat acute liver failure or to serve as a temporary support until orthotopic liver transplantation is available. Primary human hepatocytes are ideal as a source of hepatic function in a HAL device. However, the worldwide shortage of human livers available for hepatocyte isolation severely limits this form of therapy. A possible alternative is to use a tightly regulated cell line that can be economically grown in culture to have differentiated liver function. In this work, human hepatocytes were immortalized with a retroviral vector SSR#69 expressing the genes of simian virus 40 large T antigen and herpes simplex virus-thymidine kinase. One of the resulting clones, NKNT-3 , showed the gene expression of differentiated liver function and were sensitive to the antiviral agent ganciclovir. When transplanted into the spleen of rats subjected to 90% hepatectomy, NKNT-3 cells prolonged the survival of 90% hepatectomized rats. The cells provide the advantages of unlimited availability, sterility, uniformity, and freedom from pathogens. This work represents a potential novel strategy for resolving the organ shortage that currently limits the use of primary human hepatocytes to develop a HAL.


Deep probabilistic tracking of particles in fluorescence microscopy images.
Tracking of particles in temporal fluorescence microscopy image sequences is of fundamental importance to quantify dynamic processes of intracellular structures as well as virus structures. We introduce a probabilistic deep learning approach for fluorescent particle tracking, which is based on a recurrent neural network that mimics classical Bayesian filtering. Compared to previous deep learning methods for particle tracking, our approach takes into account uncertainty, both aleatoric and epistemic uncertainty. Thus, information about the reliability of the computed trajectories is determined. Manual tuning of tracking parameters is not necessary and prior knowledge about the noise statistics is not required. Short and long-term temporal dependencies of individual object dynamics are exploited for state prediction, and assigned detections are used to update the predicted states. For correspondence finding, we introduce a neural network which computes assignment probabilities jointly across multiple detections as well as determines the probabilities of missing detections. Training requires only simulated data and therefore tedious manual annotation of ground truth is not needed. We performed a quantitative performance evaluation based on synthetic and real 2D as well as 3D fluorescence microscopy images. We used image data of the Particle Tracking Challenge as well as real time-lapse fluorescence microscopy images displaying virus structures and chromatin structures. It turned out that our approach yields state-of-the-art results or improves the tracking results compared to previous methods.


Early diagnosis of sepsis in emergency departments, time to treatment, and association with mortality: An observational study.
Early recognition of sepsis is critical for timely initiation of treatment. The first objective of this study was to assess the timeliness of diagnostic procedures for recognizing sepsis in emergency departments. We define diagnostic procedures as tests used to help diagnose the condition of patients. The second objective was to estimate associations between diagnostic procedures and time to antibiotic treatment, and to estimate associations between time to antibiotic treatment and mortality. This observational study from 24 emergency departments in Norway included 1559 patients with infection and at least two systemic inflammatory response syndrome criteria. We estimated associations using linear and logistic regression analyses. Of the study patients, 72.9% (CI 70.7-75.1) had documented triage within 15 minutes of presentation to the emergency departments, 44.9% (42.4-47.4) were examined by a physician in accordance with the triage priority, 44.4% (41.4-46.9) were adequately observed through continual monitoring of signs while in the emergency department, and 25.4% (23.2-27.7) received antibiotics within 1 hour. Delay or non-completion of these key diagnostic procedures predicted a delay of more than 2.5 hours to antibiotic treatment. Patients who received antibiotics within 1 hour had an observed 30-day all-cause mortality of 13.6% (10.1-17.1), in the timespan 2 to 3 hours after admission 5.9% (2.8-9.1), and 4 hours or later after admission 10.5% (5.7-15.3). Key procedures for recognizing sepsis were delayed or not completed in a substantial proportion of patients admitted to the emergency department with sepsis. Delay or non-completion of key diagnostic procedures was associated with prolonged time to treatment with antibiotics. This suggests a need for systematic improvement in the initial management of patients admitted to emergency departments with sepsis.


Peripheral neural targets in obesity.
Interest in pharmacological treatments for obesity that act in the brain to reduce appetite has increased exponentially over recent years, but failures of clinical trials and withdrawals due to adverse effects have so far precluded any success. Treatments that do not act within the brain are, in contrast, a neglected area of research and development. This is despite the fact that a vast wealth of molecular mechanisms exists within the gut epithelium and vagal afferent system that could be manipulated to increase satiety. Here we discuss mechano- and chemosensory pathways from the gut involved in appetite suppression, and distinguish between gastric and intestinal vagal afferent pathways in terms of their basic physiology and activation by enteroendocrine factors. Gastric bypass surgery makes use of this system by exposing areas of the intestine to greater nutrient loads resulting in greater satiety hormone release and reduced food intake. A non-surgical approach to this system is preferable for many reasons. This review details where the opportunities may lie for such approaches by describing nutrient-sensing mechanisms throughout the gastrointestinal tract.


Beta3A-adaptin, a subunit of the adaptor-like complex AP-3.
Recent studies have described a widely expressed adaptor-like complex, named AP-3, which is likely involved in protein sorting in exocytic/endocytic pathways. The AP-3 complex is composed of four distinct subunits. Here, we report the identification of one of the subunits of this complex, which we call beta3A-adaptin. The predicted amino acid sequence of beta3A-adaptin reveals that the protein is closely related to the neuron-specific protein beta-NAP (61% overall identity) and more distantly related to the beta1- and beta2-adaptin subunits of the clathrin-associated adaptor complexes AP-1 and AP-2, respectively. Sequence comparisons also suggest that beta3A-adaptin has a domain organization similar to beta-NAP and to beta1- and beta2-adaptins. beta3A-adaptin is expressed in all tissues and cells examined. Co-purification and co-precipitation analyses demonstrate that beta3A-adaptin corresponds to the approximately 140-kDa subunit of the ubiquitous AP-3 complex, the other subunits being delta-adaptin, p47A (now called mu3A) and sigma3 (A or B). beta3A-adaptin is phosphorylated on serine residues in vivo while the other subunits of the complex are not detectably phosphorylated. beta3A-adaptin is not present in significant amounts in clathrin-coated vesicles. The characteristics of beta3A-adaptin reported here lend support to the idea that AP-3 is a structural and functional homolog of the clathrin-associated adaptors AP-1 and AP-2.


Homing to central nervous system vasculature by antigen-specific lymphocytes. II. Lymphocyte/endothelial cell adhesion during the initial stages of autoimmune demyelination.
A previous study from this laboratory on adoptively transferred experimental allergic encephalomyelitis (EAE) induced by myelin basic protein-responsive (MBP+) 11C-labeled lymphocytes showed that MBP+ cells entered the central nervous system (CNS) before signs, migrated through the endothelium, and remained within the perivascular space. The majority of cells effecting CNS damage were nonradiolabeled and appeared to be host-derived and non-CNS antigen specific. The present study defined the immunocytochemical and initial structural events occurring between lymphocytes and endothelial cells (EC) on CNS blood vessels during EAE induced with MBP+ lymph node cells or T-cell lines. Monoclonal antibodies against lymphocyte function-associated molecule LFA-1 and its ligand, intercellular adhesion molecule-1 (ICAM-1), and the addressin MECA-325, a marker of mouse lymph node high endothelial venules, were tested on frozen sections in combination with the avidin-biotin-complex technique. The attachment and infiltration of lymphocytes correlated with the onset of signs and the appearance in the CNS of MECA-325 and ICAM-1 on vessels with cellular infiltrates and sometimes with plump EC. The cellular infiltrates were composed largely of LFA-1+ lymphocytes. Ultrastructurally, pseudopodia from lymphocytes were seen to attach to and penetrate EC in the CNS and form small gap junction-like contacts. On the EC surface, some processes from lymphocytes made larger synapse-like contacts while others were associated with coated pits suggestive of receptor mediation. The results are in accord with specific homing and attachment of lymphocytes to the CNS vasculature being early features of the disease process in EAE and with some CNS vessels acquiring properties of lymph node elements. Understanding of the mechanisms underlying these lymphocyte/EC interactions has therapeutic import for multiple sclerosis, for which EAE is the prime model.


Promoter selectivity of Escherichia coli RNA polymerase sigmaF holoenzyme involved in transcription of flagellar and chemotaxis genes.
The rpoF gene of Escherichia coli codes for the RNA polymerase sigmaF (or sigma28) subunit, which is involved in transcription of the flagellar and chemotaxis genes. Both sigmaF and sigma70 (the major sigma subunit in growing cells) were overexpressed, purified to homogeneity, and compared with respect to activity and specificity. The affinity of sigmaF to core RNA polymerase (E) is higher than that of sigma70, as measured by gel filtration high-pressure liquid chromatography. In an in vitro transcription system, the holoenzyme (E sigmaF) containing sigmaF selectively transcribed the flagellar and chemotaxis genes, all of which could not be transcribed by E sigma70. This strict promoter recognition property of sigmaF is similar to those of other stress response minor sigma subunits but different from those of the principal sigma subunits, sigma70 and sigma38. sigma70-dependent transcription in vitro is inhibited at high concentrations of all salts tested, showing maximum activity at 50 mM. In contrast, sigmaF-dependent transcription was maximum at 50 mM KCI and then decreased to negligible level at 300 mM; in the cases of potassium acetate and potassium glutamate, maximum transcription was between 200 and 300 mM. DNase I foot printing of the fliC and fliD promoters indicated that sigmaF alone is unable to bind DNA, but E sigmaF specifically recognizes -10 and -35 regions of the sigmaF-dependent promoters with rather long upstream protection. Alteration of the promoter structure after binding of E sigmaF was suggested.


Hyperprolactinemia after low dose of amisulpride.
Amisulpride in antipsychotic doses can induce hyperprolactinemia. The aim of this study was to prove whether the same is true for low doses of amisulpride. Plasma prolactin levels were measured in 5 males and 5 females with depressive symptoms who were treated with 50 mg of amisulpride per day as an augmentation to antidepressants (n=5), benzodiazepine anxiolytics (n=8) or in monotherapy (n=1). Six of these patients were assessed prior to onset of amisulpride treatment and after 10 days of amisulpride use. Four patients had been using amisulpride for more than a month. There was a significant increase of prolactin levels from mean 16+/-6 ng/ml to 113+/-65 ng/ml (median 14.5 ng/ml to median 92 ng/ml; Wilcoxon matched pair test, p=0.027). All patients had hyperprolactinemia (30-200 ng/ml). The prolactinemia was significantly higher in females (mean 160+/-50 ng/ml; median 198 ng/ml) than in males (mean 48+/-12 ng/ml; median 48 ng/ml; Mann-Whitney U test, p=0.041). Even low doses of amisulpride used as an augmentation to antidepressant treatment, benzodiazepines or in monotherapy seem to be associated with hyperprolactinemia. The co-medication of antidepressants and benzodiazepines can potentially increase intensity of prolactinemia.


Molecular and behavioral changes in nociception in a novel rat model of chronic pancreatitis for the study of pain.
The approach to the management of painful chronic pancreatitis has been empirical, primarily due to the lack of information about biological mechanisms producing pain. To facilitate research into pain mechanisms, our aim was to assess a rat model of chronic pancreatitis induced by pancreatic infusion of trinitrobenzene sulfonic acid as a model of painful pancreatitis. Nociception was assessed by measuring mechanical sensitivity of the abdomen and by recording the number of nocifensive behaviors in response to electrical stimulation of the pancreas. Expression of neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) in the thoracic dorsal root ganglia receiving input from the pancreas and nerve growth factor (NGF) in the pancreas were measured. Rats with pancreatitis exhibited marked increase in sensitivity to mechanical probing of the abdomen and increased sensitivity to noxious electrical stimulation of the pancreas. There were significant increases in NGF protein in the pancreas and in expression of neuropeptides CGRP and SP in the sensory neurons from dorsal root ganglia receiving input from the pancreas. We have established quantitative measures of referred nociception and pancreatic hyperalgesia in a rat model of chronic pancreatitis that bears histological similarities to the human disease. This model has considerable construct, face and predictive validity for the human condition. It is of importance for the study of the pathogenesis of pain in this condition and can facilitate the development of new therapeutic options.


Conjunctival and corneal pneumatic sensitivity is associated with signs and symptoms of ocular dryness.
To investigate the relationships of dry eye symptoms and corneal and conjunctival sensitivity to pneumatic stimulation, tear film stability, and clinical ocular surface characteristics in symptomatic and asymptomatic subjects. Ninety-seven subjects were enrolled and grouped by a questionnaire-based single score for symptoms of ocular dryness (none to trace, non-dry group; mild to severe, symptomatic group); 43 were symptomatic and 54 were non-dry. Corneal (K) and conjunctival (C) sensitivities were measured with a computer-controlled Belmonte pneumatic (room temperature) stimulus. Symptoms were assessed according to the Ocular Surface Disease Index (OSDI). Ocular surface staining with fluorescein (FL) and lissamine green (LG), noninvasive tear film break-up time (NIBUT), and the phenol red thread test (PRT) were assessed. The symptomatic group showed lower K and C thresholds (P < 0.01), greater corneal FL and conjunctival LG staining, and shorter NIBUT than did the non-dry eye group (all others P < 0.05). The OSDI scores were higher in the symptomatic group (P < 0.001). K and C thresholds and NIBUT were inversely correlated with the OSDI and corneal and conjunctival staining (all P < 0.05). The K and C threshold and NIBUT (all P < 0.01) correlated positively. Step-wise multiple regression analysis showed that ocular surface sensitivity and NIBUT were significant predictors of the OSDI. Ocular irritation assessed with the OSDI is associated with ocular surface hyperesthesia to cooling, corneal epitheliopathy, and tear film instability. Although cause and effect are unclear, the analysis showed that altered corneal and conjunctival sensory processing and tear film attributes are essential aspects of what characterizes dry eye.