Effect of HCV treatment response on insulin resistance: A systematic review and meta-analysis.
Sustained virological response (SVR) in hepatitis C virus (HCV) patients treated with pegylated interferon α-2a and ribavirin is associated with reduced insulin resistance (IR), measured as a reduction of homeostasis model assessment (HOMA) scores after 24 weeks of therapy, and reduced fasting serum insulin and serum glucose levels. The present meta-analysis aimed to evaluate the effect of HCV treatment response on IR in HCV patients who achieved SVR and those who did not (non-SVR) after receiving interferon (IFN)-based therapy. The PubMed, Cochrane and Embase databases were searched using combinations of the following search terms: 'HCV', 'hepatitis C', 'interferon', 'antiviral', 'treatment response' and 'insulin resistance'. The incidence of IR, HOMA-IR and HOMA-β, as well as fasting glucose and fasting insulin levels, were summarized in terms of basal values and values after the end of treatment for each study. A total of 8 studies were included in the final analysis. There was no significant difference in the reduction in IR between the SVR and non-SVR groups (odds ratio, 0.995; 95% CI=0.613-1.616; P=0.984). However, the SVR group had a significantly higher mean reduction in HOMA-IR (difference in means=-0.485; 95%CI=-0.713 to -0.256; P<0.001) and HOMA-β (difference in means=-15.448; 95%CI=-23.326 to -7.570; P<0.001) compared to the non-SVR group. In conclusion, HCV patients who achieved SVR after IFN-based therapy exhibited improvement in HOMA-IR and HOMA-β. The present results suggest that clinical management of IR and serum glucose levels may be an important way to impact the therapeutic response in HCV patients.


Kinetics of P2X7 receptor-operated single channels currents.
Human P2X7 receptors were expressed in Xenopus laevis oocytes and single channels were recorded using the patch-clamp technique in the outside-out configuration. ATP4- evoked two types of P2X7 receptor-mediated single channel currents characterized by short-lived and long-lived openings. The short- and long-lasting open states had mean open times of approximately 5 and approximately 20 ms and slope conductances near -60 mV of 9 and 13 pS, respectively. The open probabilities of the short and long openings were strongly [ATP4-]-dependent with EC50 values of approximately 0.3 mM and approximately 0.1 mM ATP4-, respectively. The channel kinetics did not change significantly during sustained P2X7 receptor activation for several minutes, as was also observed in recordings in the cell-attached patch-clamp configuration. Activation and deactivation of the short openings followed exponential time courses with time constants in the range of 20 ms, and displayed a shallow [ATP4-] dependence of the activation process. The kinetics of the short channel openings at negative membrane potentials fitted well to a linear C-C-C-O model with two ATP4- binding steps at equal binding sites with a dissociation constant Kd of 139 microM.


Analysis of breast cancer-associated glycosphingolipids using electrospray ionization-linear ion trap quadrupole mass spectrometry.
Abnormal glycosphingolipids (GSLs) are expressed in many human tumors. These tumor-associated GSLs may have important roles in tumor progression. However, they are hard to be detected because of their low concentration and the limited availability of antibodies and lectins that recognize them. Thus, mass spectrometry is an effective method to analyze GSLs with high sensitivity. Here, we use electrospray ionization-linear ion trap quadrupole mass spectrometry (ESI-LTQ-MS) and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) to determine the structure of a certain GSL in human breast cancer tissue. To obtain the breast cancer-associated GSLs, we applied relative abundance contrast of GSLs and signal-to-noise ratio (SNR) analyses. We also used α1,2 fucosidase and fucosyltransferases as tools in the structural analysis. Based on this analysis, we identified the ion with m/z 1184 molecular ion as fucosyl-lactoceramide (Fuc-LacCer) with a C16 fatty acid ceramide. Quantitative analysis of GSLs revealed both Fuc-LacCer and Globo-H increased in breast cancer tissues. However, these two breast cancer-associated GSLs had different roles. The results of SNR analysis suggested the abnormal Fuc-LacCer is specific to breast cancer. The GSL profiling of breast cancer cells showed fucosyltransferase 1 contributed to the biosynthesis of Globo-H and Fuc-LacCer. In conclusion, MS analysis identified an accumulation of Fuc-LacCer in breast cancer tissue. Our findings provide GSL profiles of human breast cancer and develop an MS method for the study of cancer-associated GSLs.


[Correlation of Transluminal Attenuation Gradientdistal with Corrected Contrast Opacification with Anterior Coronary Atherosclerosis].
Objective To explore the correlation between the transluminal attenuation gradient with corrected contrast opacification(TAG-CCO)and the severity of atherosclerotic stenosis in the anterior segment of myocrardial bridge(MB). Methods The imaging data of 200 patients diagnosed with left anterior descending branch(LAD)single MB and coronary atherosclerosis in the anterior segment of MB were retrospectively analyzed.According to MB types,the patients were divided into two groups:incomplete and complete.There were some significant differences in TAG-CCO between patients with the same degree of coronary atherosclerosis(mild,moderate,and severe stenosis)in two groups.The relationships among groups with different degrees(mild,moderate,and severe stenosis)of the same type of MB were further compared. Results Among 84 patients with complete MB,36,30,and 18 patients had mild,moderate,or severe coronary atherosclerosis in the anterior segment of MB;among 116 patients with incomplete MB,45,42,and 29 patients had mild,moderate,or severe coronary atherosclerosis in the anterior segment of MB.In the complete MB group,the TAG-CCO in the anterior segment of MB subgroups were(-0.0086±0.0014)/10 mm,(-0.0170±0.0180)/10 mm,and(-0.0230±0.0026)/10 mm,respectively,in mild,moderate,and severe subgroups(F = 404.728, P<0.001).In the incomplete MB group,the TAG-CCO of patients with mild,moderate and severe coronary stenosis in the anterior segment of MB were(-0.0039±0.0011)/10 mm,(-0.0100±0.0140)/10 mm,and(-0.0160±0.0020)/10 mm,respectively,and the difference among the different stenosis groups was statistically significant(F = 17.756, P < 0.001);the TAG-CCO of patients with mild(t = 16.519, P < 0.001),moderate(t = 2.570, P = 0.012)and severe anterior segment coronary stenosis(t = 10.714, P < 0.001)were significantly lower in the complete MB group than in the incomplete MB group. Conclusions TAG-CCO is correlated with the MB type and the degree of anterior coronary artery stenosis.Thus,TAG-CCO can be used as a predictive indicator for the degree of atheroscleratic stenosis in the anterior segment of MB.


Emergency department-based study of risk factors for acute injury from domestic violence against women.
To evaluate the associations between selected socioeconomic risk factors and acute injury from domestic violence against women. We conducted a preliminary matched case-control study to measure the association of selected predictor variables with acute injury from domestic, violence against women. Patients identified as cases were Hispanic or white female emergency department patients, 16 to 65 years of age, with acute injury sustained from physical assault by an intimate male partner. Cases were selected for inclusion in the study if they reported or admitted acute physical assault by their male partners. Controls were selected from non-case female ED patients so as to represent the base population of the cases and enhance comparability. Two controls were matched to each case. The socioeconomic predictor variables examined were the education level, employment status, history of alcohol abuse, and history of drug abuse of the male partner and the education level and cohabitation status of the female partner. Forty-six cases were identified and included in the study. The age range was 16 to 51 years (mean, 33 years). There were 26 (57%) Hispanic and 20 (43%) white cases. The strongest predictor for acute injury from domestic violence in these patients was a history of alcohol abuse by the male partner, as reported by the female partner (odds ratio, 12.9). The remaining predictor variables were weakly associated or not associated with domestic violence. One half of the cases stated that their male partners were intoxicated with alcohol at the time of assault. Of the socioeconomic variables examined in this preliminary study, a history of alcohol abuse by the male partner, as reported by the female partner, was the strongest predictor for acute injury from domestic violence. A large-scale, multicenter, ED-based study is needed to clarify the relation between alcohol abuse, other socioeconomic factors, and acute physical assaults against women by their intimate male partners.


Expression of hepcidin at the choroid plexus in normal aging rats is associated with IL-6/Stat3 signaling pathway.
Accumulating evidence has revealed that brain iron concentrations increase with aging, and the choroid plexus (CP) may be at the basis of iron-mediated toxicity and the increase in inflammation and oxidative stress that occurs with aging. The mechanism involves not only hepcidin, the key hormone in iron metabolism, but also iron-related proteins and signaling-transduction molecules, such as IL-6 and signal transducer and activator of transcription 3 (Stat3). The aim of the present study was to investigate the correlation between the IL-6/Stat3 signaling pathway and hepcidin at the CP in normal aging. Quantitative real time PCR and Western blot were used to determine the alterations in specific mRNA and corresponding protein changes at the CP at ages of 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36 months in Brown-Norway/Fischer (B-N/F) rats. The results demonstrated that hepcidin mRNA level at the CP kept stable in young rats (from 3 to 18 months), and increased with aging (from 21 to 36 months). The alterations of IL-6/p-Stat3 mRNA and protein expressions in normal aging were in accordance with that of hepcidin mRNA. Our data suggest that IL-6 may regulate hepcidin expression at the CP, upon interaction with the cognate cellular receptor, and through the Stat3 signaling transduction pathway.


The Advocacy Journal Club.
To describe a method of educating pathologists about health policy. The Advocacy Journal Club was a series of six conferences. Topics were of those in the news or affecting local practice. Participants reviewed preparatory readings, completed a six- to 10-question pretest, attended an interactive presentation stressing advocacy groups' efforts, and completed a posttest. All were invited to complete a survey after the sessions. Faculty and residents had increased posttest scores following each presentation with a significant difference in four and three sessions, respectively. More than 80% agreed they could discuss the topics with others and understood how regulations affect practice. More than 90% agreed that they gained an understanding of how involvement in organizations' advocacy initiatives affects policy. We present a method for educating pathologists about policy and the role of professional societies that could be implemented by nearly all graduate medical education programs.


Germanium-Based Nanomaterials for Rechargeable Batteries.
Germanium-based nanomaterials have emerged as important candidates for next-generation energy-storage devices owing to their unique chemical and physical properties. In this Review, we provide a review of the current state-of-the-art in germanium-based materials design, synthesis, processing, and application in battery technology. The most recent advances in the area of Ge-based nanocomposite electrode materials and electrolytes for solid-state batteries are summarized. The limitations of Ge-based materials for energy-storage applications are discussed, and potential research directions are also presented with an emphasis on commercial products and theoretical investigations.


A mathematical model for the growth of a single cell of E. coli on a glucose/glutamine/ammonium medium.
Extension of a single cell model of E. coli B/r to make predictions of culture response to variations in glutamine/glucose/ammonium ion concentrations is described. A biphasic glutamine transport system, a nitrogen metabolism scheme that includes glutamate dehydrogenase (GDH), glutamine synthetase/glutamate synthase (GS/GOGAT), the glutaminase routes, and a transaminase mechanism for glutamine carbon usage are added to the prototype model. The predictions of the extended model with regard to nutrient concentrations and cell size compare well with the experimental data and the prototype model predictions, demonstrating the capability of the integrated kinetic model to illustrate important enzymological interactions in a biological system. The discrepancies between the experimental data and the model predictions on growth yield suggest that a more detailed regulatory system of the TCA cycle is required for a more accurate energy budget.


Nucleic acids and protein content of some fetal and neonatal rat organs after insulin treatment.
In 17 1/2--21 1/2 day-old fetuses and 1--4 day-old rats the DNA, RNA and protein content of the liver, heart and brain was daily investigated 6 hours after injecting approximately 40 mU . g-1 insulin. The DNA content in the mentioned organs was not affected by the insulin. The RNA content in the fetal and neonatal brain and neonatal heart was significantly elevated, while the liver RNA was not altered. Only in the 4 day-old brain did the protein content increase. The experimental dates indicate that the cell RNA content of some perinatal tissues can be elevated by insulin depending on the type of tissue and its developmental stage.


Plasma endogenous digitalis-like factors in healthy individuals and in dialysis-dependent and kidney transplant patients.
Plasma digitalis-like factors (DLF), dehydroepiandrosterone sulfate (DHEAS) and cortisol were assayed in 20 healthy subjects, 22 dialysis dependent subjects and 30 patients with kidney transplants. DLF were assayed on plasma extracts by digoxin radioimmunoassay (RIA), and by Na,K-ATPase inhibition and [3H]-ouabain displacement using hogbrain Na,K-ATPase. Values for the 3 methods strongly intercorrelated (r = 0.99, p less than .001). Mean values for plasma DLF, assayed by all three methods, were significantly greater in dialysis dependent subjects, than in healthy subjects (p less than .0001). Mean plasma DLF values measured by digoxin RIA in renal transplant recipients, were significantly lower than in dialysis dependent subjects (p less than 0.0001) and higher than in healthy subjects. Plasma DLF values correlated inversely with creatinine clearance (p less than 0.01). Plasma DHEAS levels were significantly lower and contributed substantially less to digoxin antibody reactivity and ouabain displacement in dialysis subjects and in renal transplants compared with healthy subjects. There was no change in plasma immunoreactive DLF, DHEAS or cortisol measured before and after dialysis. DHEAS is a major digoxin like immunoreactive DLF and a minor Na,K-ATPase inhibitor in healthy subjects but makes only a minor contribution to DLF in dialysis and transplant subjects. We found the assays involving Na,K-ATPase inhibition and [3H]-ouabain displacement from Na,K-ATPase to be more sensitive for plasma DLF than the digoxin RIA, but because of the strong correlation between the methods, we suggest the RIA on plasma extracts can be used as a screening procedure.


Effects of calcimimetics on extraskeletal calcifications in chronic kidney disease.
While the precise mechanisms of vascular calcification (VC) in chronic kidney disease (CKD) remain to be elucidated, there is a close association between VC and secondary hyperparathyroidism (HPT). The elevations in calcium, phosphorus, the Ca x P product, and parathyroid hormone (PTH) observed in patients with CKD and secondary HPT have been associated with VC and increased risk of cardiovascular morbidity and mortality. We have investigated the development of extraskeletal calcification in uremic rats with secondary HPT treated with vitamin D derivatives (calcitriol or paricalcitol), calcimimetics (R-568 or AMG 641), or the combination of both types drugs. Treatment with calcitriol resulted in a significant increase in the extraosseous calcium and phosphorus content and high mortality. By contrast, treatment with calcimimetics, which provided a better control of plasma PTH levels, did not result in extraskeletal mineral accumulation and did not cause mortality. More important, when added to calcitriol, calcimimetics prevented the development of VC and reduced mortality. Paricalcitol administration to uremic rats resulted in calcification levels and mortality rates that were lower than in rats treated with calcitriol but higher than in rats treated with calcimimetics. The mechanism(s) of action responsible for the anticalcification effect of calcimimetics are likely related to the fact that these drugs can control PTH levels without increasing the plasma Ca x P product. In addition calcimimetic activation of vascular calcium-sensing receptor may also modulate the expression of proteins that prevent the development of VC, like matrix Gla protein.


How to promote the social-emotional competence of rural left-behind children? An empirical study based on propensity score matching.
Social-emotional competence (SEC) played an important role in promoting the physical and mental development of children, but there exist huge gaps in SEC development between rural left-behind children. This study used propensity score matching (PSM) to investigate 578 rural children about the effects of being left behind as well as individual characteristics and teacher support on their development of SEC. The results showed that being left behind had significant negative effects on the SEC of rural children. The development of SEC varies among left-behind children of different genders and length of left-behind duration. Teacher support had a significant moderating effect on the influence path of SEC, which could effectively mitigate the negative effects of left-behind children. Therefore, this study played an implicative role in studying the development of left-behind children's SEC. The government and society should provide adequate cultural capital by completing the support system for compensating the lack of cultural capital. Schools and teachers should pay more attention to the development of left-behind children's SEC through curriculum development and performance evaluation to create a positive atmosphere. Parents should promote SEC development for left-behind children by improving their communication and family parenting styles.


Is clinical trial registration for simulation-based research necessary?
Summary statement: The International Committee of Medical Journal Editors requires that all clinical trials be prospectively registered before being considered for publication in their member journals. Clinical trial registries are Web-based databases of clinical trials, providing researchers, journal editors, and reviewers detailed study information to help inform trial results. What is unclear is whether clinical trial registration is required for simulation-based studies, where typically health care providers are the subjects and where the outcomes may be provider based or patient based. In this article, we describe the background and reasoning behind clinical trial registration and discuss whether simulation-based studies should be registered as a prerequisite to publication.


Innovative Integrated Motivational Interviewing for Dual Management in Tuberculosis Patients with Diabetes (MID-DOT) in Malaysia.
(1) Background: Achieving successful tuberculosis (TB) treatment outcomes among diabetic patients is a real challenge as TB complicates control of diabetes. This study aimed to evaluate the effectiveness of an integrated dual management educational module, MID-DOTS, which uses the mmotivational interviewing (MI) technique implemented within directly observed treatment as part of a short course (DOTS) program in TB patients with diabetes (TB/DM). A randomized controlled trial was conducted in the northeastern state of Malaysia. (2) Methods: One hundred and twenty-four TB patients with diabetes received educational intervention using a MID-DOT module that used the MI technique, which was repetitively applied by TB nurses throughout a 6-month DOTS program while another 122 patients were given standard health education. Study outcomes include the proportion of patients with successful TB treatment, and changes in HbA1c and diabetic self-care scores at 6 months. (3) Results: The successful TB treatment outcome was 88% in the intervention group versus 72% in the control group (RR = 1.24; 95%CI 1.16, 1.58). A significant reduction of HbA1c (mean difference 0.82%; 95%CI 0.66, 0.98) and significantly higher diabetes self-care score (mean difference 8.49; 95%CI 7.38, 9.59) were also shown in the intervention group. (4) Conclusions: A dual TB/DM educational strategy which integrates the MI technique applied repetitively within the DOTS program is effective in increasing successful TB treatment as well as improving diabetic outcomes.


[Acute posterior multifocal placoid pigment epitheliopathy (APMPPE)--a report of three cases].
The aim of this study is to present and discuss three cases of acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Three young patients (one woman and two men), developed rapid loss of vision in one or both eyes. Basic ophthalmic examination and additional diagnostic methods including: fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT) and human leucocyte antigen (HLA) class I test were performed. Based on the results of performed investigations the diagnosis of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) was established. Fundus examination revealed characteristic multifocal, placoid, creamy or grey/white subretinal lesions. Fluorescein angiography in acute stage of the disease demonstrated early hypofluorescence followed by later hyperfluorescence of the lesions. Indocyanine green angiography demonstrated hypofluorescence in all stages of the angiogram. In one case, class I HLA-B7 antigen was found. In all presented cases visual acuity markedly improved with general glicocorticosteroids. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is characterized by rapid, but transient loss of visual acuity. Diagnosis is established in fluorescein angiography and prognosis for recovery is good, however in cases with poor visual acuity glicocorticosteroids might be beneficial.


PMAT variant rs3889348 is associated with metformin-induced gastrointestinal among Chinese Type 2 diabetes patients.
Aim: This study examined intronic gene variants for their association with metformin intolerance in a Chinese population, focusing on the plasma monoamine transporter (PMAT) cis-protein expression quantitative trait loci (cis-eQTL) variant rs3889348. Methods: We recruited Type 2 diabetes patients from two hospitals and identified 111 metformin-intolerant patients using a questionnaire, and selected 206 metformin-tolerant patients from 2180 Type 2 diabetes mellitus patients. Genetic testing revealed an association between adverse gastrointestinal (GI) effects and SLC22A1 and PMAT. Results: The single-nucleotide polymorphism rs3889348 is associated with metformin-induced adverse GI effects. Each additional copy of the G allele increases the score by 5.23 (95% CI: 1.82-8.64; p = 0.003). Patients taking more transporter inhibitors were more likely to respond to metformin-induced GI intolerance (p = 0.042). Conclusion: PMAT cis-eQTL rs3889348 was significantly associated with metformin-induced adverse GI effects.


Feasibility of biogas and energy generation from poultry manure in Brazil.
The aim of the present study is to experimentally measure the volume and composition of biogas produced from the anaerobic biodigestion of laying-hen manure from poultry farms in Itanhandu-MG, Brazil, so that the biogas can be used to generate energy. Two experiments (E1 and E2) were used to characterise the biogas quantities and compositions at room temperature and at a controlled temperature of 36 °C, respectively. The biogas production and calculated net power from the exploitation of biogas energy were compared with the results obtained from methods proposed by the Environmental Company of the State of São Paulo (CETESB, an acronym in Portuguese) using the 'Biogas: Generation and energy use - effluent and rural waste' software 1.0, Brasília-DF, Brazil. In addition, after a time equal to the hydraulic retention time subsequent to biodigester loading, the parameters were analysed and correlated with the organic matter content in the substrates. The effluents were subsequently compared with verify the degree of degradability. The biogas volumes were estimated to be 0.143 m3 kg VTS-1 for E1 and 0.283 m3 kg VTS-1 for E2. If the poultry farm considered in this case study uses manure to generate energy, then the estimated energy generation based on the data from experiments E1 and E2 will result in net energy values of 683 MW h y-1 and 27,160 MW h y-1, given 620 MW h y-1 for sludge heating in E2. The energy production values from the simulations of the E1 and E2 experiments did not demonstrate economic viability under the studied conditions.


Airports, localities and disease: representations of global travel during the H1N1 pandemic.
During summer 2009, the UK experienced one of the highest incidences of H1N1 infection outside of the Americas and Australia. Building on existing research into biosecurity and the spread of infectious disease via the global airline network, this paper explores the biopolitics of public health in the UK through an in-depth empirical analysis of the representation of H1N1 in UK national and regional newspapers. We uncover new discourses relating to the significance of the airport as a site for control and the ethics of the treatment of the traveller as a potential transmitter of disease. We conclude by highlighting how the global spread of infectious diseases is grounded in particular localities associated with distinctive notions of biosecurity and the traveller.


Feeding resistance and gastroesophageal reflux in infancy.
Resistance to oral feedings occurring during the course of chronic gastroesophageal reflux (GER) in infants has received little attention in the literature. Accordingly, we reviewed the clinical courses of 600 infants of < 24 months of age with GER seen over an 8-year period to determine the prevalence and course of this problem. After excluding infants with severe neurologic disease, craniofacial disorders, or a history of esophageal surgery, 25 infants were found to have resistance to oral feedings that was severe enough to warrant tube feedings for nutritional support. Sixteen of these 25 infants had a history of resistance to oral feeding antedating a diagnosis of GER, whereas nine developed resistance to feeding during the course of therapy. Gestational age, age at onset of GER symptoms, severity of GER, presence/severity of esophagitis, type of medical therapy, need for fundoplication, or postfundoplication complications were similar in these two groups. When the clinical records of these 25 infants were compared to an age- and sex-matched infant population with GER but without feeding resistance, no differences were noted in severity of GER or the presence/severity of esophagitis. However, failure to thrive and the need for fundoplication were significantly more common in the feeding resistance group (p < 0.001). Among those infants with neurodevelopmental evaluation, mild delay was seen more commonly in the infants with feeding resistance but fell short of statistical significance (p = 0.08). Our observations suggest that resistance to oral feedings is an uncommon but severe problem associated with GER in infancy.(ABSTRACT TRUNCATED AT 250 WORDS)


Rapeseed meal glucosinolates: metabolism and effect on performance in laying hens.
Two experiments were conducted with Hyline Leghorn hens to study the metabolism and detrimental effects of rapeseed meal (RSM) glucosinolates. Raw Target RSM was force fed to 12 hens which were killed after varying time intervals (15 min., 30 min., 60 min.) and the contents of areas of the digestive tract (crop; proventriculus and gizzard; duodenum and ileum) were analyzed for the presence of hydrolysis products of progoitrin. Nitrile compounds were found to be present in all areas of the digestive tract in much larger relative amounts than was oxazolidinethione. When commercially prepared RSMs of varying glucosinolate content were fed to laying hens at a 50% level of dietary inclusion, high glucosinolate-content RSM depressed egg production (P less than 0.05) more than low glucosinolate-content RSM but did not cause a greater frequency of liver hemorrhage. Histological examination of liver tissues from hens suffering liver hemorrhage revealed a severe reticulolysis.


How Should Cancer Surveillance in Primary Sclerosing Cholangitis Be Performed?
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease affecting the intra- and extrahepatic bile duct system that can ultimately cause liver cirrhosis. Apart from the risk of progression to end-stage liver disease the prognosis of PSC is primarily determined by the risk to develop hepatobiliary or extrahepatic malignancies. A reasonable surveillance strategy for PSC patients must allow the detection of early cancer that will permit a potentially curative therapy. Current guidelines on malignancy within the context of PSC as well as the primary literature were reviewed for this article. Here, we focus on a concise review of the three tumors most commonly associated with PSC: cholangiocellular carcinoma (CCA), gallbladder cancer, and colorectal carcinoma. For cancer surveillance in this patient group, endoscopy, cholangiography, cross-sectional imaging, and the use of serum tumor markers are principally available. Furthermore, for the diagnosis of CCA novel approaches were recently suggested to improve sensitivity and specificity to detect this malignancy. We review different aspects of cancer surveillance in patients with PSC. Since prospective data on the surveillance of malignant tumors is unavailable, we discuss a rational approach on how to perform cancer surveillance in patients with PSC.


Effect of cold stress on expression of AMPKalpha-PPARalpha pathway and inflammation genes.
Animals are exposed to various environmental stresses every day, including the stress associated with living in cold temperatures. The aim of this study was to investigate the possible mechanisms of interaction between lipid metabolism and inflammation induced by cold stress in the livers of chickens. Fifteen-day-old male chicks were randomly allocated into 12 groups (10 chickens per group). After exposure of the chickens to the cold stress, cholesterol fractionation was used to examine high-density lipoprotein (HDL) and low-density lipoprotein (LDL) concentrations. Aminotransferase activities were examined with the use of the aspartate transaminase (AST) and alanine transaminase (ALT) assay. The AMP-activated protein kinase alpha-proliferator-activated receptor alpha (AMPKalpha-PPARalpha) pathway genes (AMPKalpha1, AMPKalpha2, PPARalpha, carnitine palmitoyltransferaseI [CPTI], acetyl-CoA carboxylase [ACC]) and inflammatory cytokines (prostaglandin E synthase [PGEs], inducible nitric oxide synthase [iNOS], heme oxygenase-1 [HO-1], nuclear factor kappa-light-chain-enhancer of activated B cells [NF-kappaB], cyclooxygenase-2 [COX-2], and TNF-alpha-like factor [LITAF]) were also measured. The results showed that during the response to cold stress, serum LDL and HDL cholesterol concentrations increased. Histopathologic analyses provided evidence that liver tissues were seriously injured in the chickens exposed to the cold stress. Serum aminotransferase activities were also increased in the group of animals exposed to the cold stress. Additionally, the expressions of AMPKalpha-PPARalpha pathway genes and inflammatory cytokine genes were significantly increased in the animals exposed to cold temperatures. These results suggested that increased inflammation was a feature associated with a lipid-metabolism disorder in the livers of chickens exposed to cold stress.


Output Feedback-Based Boundary Control of Uncertain Coupled Semilinear Parabolic PDE Using Neurodynamic Programming.
In this paper, neurodynamic programming-based output feedback boundary control of distributed parameter systems governed by uncertain coupled semilinear parabolic partial differential equations (PDEs) under Neumann or Dirichlet boundary control conditions is introduced. First, Hamilton-Jacobi-Bellman (HJB) equation is formulated in the original PDE domain and the optimal control policy is derived using the value functional as the solution of the HJB equation. Subsequently, a novel observer is developed to estimate the system states given the uncertain nonlinearity in PDE dynamics and measured outputs. Consequently, the suboptimal boundary control policy is obtained by forward-in-time estimation of the value functional using a neural network (NN)-based online approximator and estimated state vector obtained from the NN observer. Novel adaptive tuning laws in continuous time are proposed for learning the value functional online to satisfy the HJB equation along system trajectories while ensuring the closed-loop stability. Local uniformly ultimate boundedness of the closed-loop system is verified by using Lyapunov theory. The performance of the proposed controller is verified via simulation on an unstable coupled diffusion reaction process.


Developmental and Functional Effects of Steroid Hormones on the Neuroendocrine Axis and Spinal Cord.
This review highlights the principal effects of steroid hormones at central and peripheral levels in the neuroendocrine axis. The data discussed highlight the principal role of oestrogens and testosterone in hormonal programming in relation to sexual orientation, reproductive and metabolic programming, and the neuroendocrine mechanism involved in the development of polycystic ovary syndrome phenotype. Moreover, consistent with the wide range of processes in which steroid hormones take part, we discuss the protective effects of progesterone on neurodegenerative disease and the signalling mechanism involved in the genesis of oestrogen-induced pituitary prolactinomas.


The pH sensitive properties of carboxymethyl chitosan nanoparticles cross-linked with calcium ions.
In environmental applications the applied materials are required to be non-toxic and biodegradable. Carboxymethyl chitosan nanoparticles cross-linked with Ca2+ ions (CMC-Ca) fulfill these requirements, and they are also renewable. These nanoparticles were applied to oil-spill treatment in our previous study and here we focused on enhancing their properties. It was found that while the divalent Ca2+ ions are crucial for the formation of the CMC-Ca, the attractive interaction between NH3+ and COO- groups contributed significantly to the formation and stability of the CMC-Ca. The stability decreased as a function of pH due to the deprotonation of the amino groups. Therefore, the nanoparticles were found to be fundamentally pH sensitive in solution, if the pH deviated from the pH (7-9) that was used in the synthesis of the nanoparticles. The pH sensitive CMC-Ca synthesized in pH 7 and 8 were most stable in the studied conditions and could find applications in oil-spill treatment or controlled-release of substances.


Structural and Electrical Investigation of Cobalt-Doped NiOx/Perovskite Interface for Efficient Inverted Solar Cells.
Inorganic hole-transporting materials (HTMs) for stable and cheap inverted perovskite-based solar cells are highly desired. In this context, NiOx, with low synthesis temperature, has been employed. However, the low conductivity and the large number of defects limit the boost of the efficiency. An approach to improve the conductivity is metal doping. In this work, we have synthesized cobalt-doped NiOx nanoparticles containing 0.75, 1, 1.25, 2.5, and 5 mol% cobalt (Co) ions to be used for the inverted planar perovskite solar cells. The best efficiency of the devices utilizing the low temperature-deposited Co-doped NiOx HTM obtained a champion photoconversion efficiency of 16.42%, with 0.75 mol% of doping. Interestingly, we demonstrated that the improvement is not from an increase of the conductivity of the NiOx film, but due to the improvement of the perovskite layer morphology. We observe that the Co-doping raises the interfacial recombination of the device but more importantly improves the perovskite morphology, enlarging grain size and reducing the density of bulk defects and the bulk recombination. In the case of 0.75 mol% of doping, the beneficial effects do not just compensate for the deleterious one but increase performance further. Therefore, 0.75 mol% Co doping results in a significant improvement in the performance of NiOx-based inverted planar perovskite solar cells, and represents a good compromise to synthesize, and deposit, the inorganic material at low temperature, without losing the performance, due to the strong impact on the structural properties of the perovskite. This work highlights the importance of the interface from two different points of view, electrical and structural, recognizing the role of a low doping Co concentration, as a key to improve the inverted perovskite-based solar cells' performance.


Genomics and epigenomics of colorectal cancer.
Colorectal cancer is one of the most common cancer types worldwide and accounts for approximately 600,000 deaths annually. Work over the last decades has uncovered a number of tumor-suppressor and oncogenes which are frequently mutated and might thus be responsible for the malignant transformation. However, only with the development of new high-throughput technologies systematic analyses of the genome and epigenomes became feasible. While data generation has increased exponential, we are now faced with new challenges to transform these data into useful models that help predicting the outcome of genomic aberrations and to develop novel diagnostic and therapeutic strategies. As a basis for the modeling it is essential to understand and integrate current knowledge. We review previous and current ideas in colorectal cancer development and focus on a pathway oriented view. We show that colorectal cancer is a multilayer complex disease affecting the genome as well as the epigenome with direct consequences on the gene and microRNA (miRNA) expression signatures. The goal is to illustrate the current principles of colorectal cancer pathogenesis and to illustrate the need for elaborate computer modeling systems.


Capillary zone electrophoresis of bile acids with indirect photometric detection.
Investigations in our laboratory have demonstrated that capillary zone electrophoresis (CZE) with indirect photometric detection is a viable approach to the separation and identification of free bile acids along with their taurine and glycine derivatives. Various parameters such as pH, organic solvent concentrations, column temperature, and type of chromophore electrolyte were investigated to optimize the electrophoretic separation and to maximize the peak capacity. The quality of separation of bile acids can be dramatically improved by incorporating gamma-cyclodextrin (gamma-CD) in the running electrolyte. This improvement in resolution is accompanied by a decreased migration time, suggestive of an increase in association of gamma-CD with bile acids. As a result, a CZE separation of all 15 bile acids was possible in approximately 30 min using 5 mM adenosine 5'-monophosphate, 7 mM gamma-CD in 75% (v/v) methanol at pH 7.0.


Serum from rats with acute pancreatitis induces expression of the PAP mRNA in the pancreatic acinar cell line AR-42J.
PAP is a pancreatic secretory protein expressed in the pancreas during the acute phase of pancreatitis. We have investigated the effect of the serum from rats with acute pancreatitis (SAP) on the expression of the PAP mRNA in AR-42J cells. PAP mRNA is strongly induced by SAP in a dose-dependent manner. This induction is abolished by preheating the SAP or diminished by treating the cells with cycloheximide. In addition, amylase but not actin mRNA expression was induced by a different SAP factor. We transfected the AR-42J cells with a chimeric gene containing 1.2 kbp 5'-flanking region of the PAP promoter linked to the CAT reporter gene. The CAT activity was significatively increased in the cells, on treating them with SAP. Our results show: first, SAP contains factors responsible for the PAP mRNA expression and secondly, the cis-acting elements are localized within the 1.2 kbp upstream region of the transcription initiation site.


Association of Pulmonary Function with Osteosarcopenic Obesity in Older Adults Aged over 50 Years.
Osteosarcopenic obesity (OSO) is a newly described coexistence of osteopenia/osteoporosis, sarcopenia, and obesity. We examined the association between pulmonary function, OSO, and its composition in adults aged ≥ 50 years. A total of 26,343 participants (8640 men; 17,703 women) were classified into four groups based on the number of abnormal body compositions (osteopenia/osteoporosis, sarcopenia, and obesity): 0 (control), 1+, 2+, and 3+ (OSO) abnormal body compositions. The values of forced volume vital capacity (FVC)%, forced expiratory volume in 1 s (FEV1%), and FEV1/FVC% were significantly decreased by increasing the number of adverse body compositions (p < 0.0001). Although the prevalence of restrictive spirometry pattern (RSP) was positively associated with a higher number of abnormal body composition parameters (p < 0.001), obstructive spirometry pattern (OSP) had no association with adverse body composition. In multivariate analyses, the adjusted odds ratios (ORs) for RSP compared to the control group were 1.36 in 1+, 1.47 in 2+, and 1.64 in 3+ abnormal body compositions (p for trend < 0.001). Multiple abnormal body composition, especially osteosarcopenic obesity, was independently associated with poor lung function showing RSP in older adults over 50 years. The coexistence of these abnormal body compositions may be a predisposing factor for pulmonary function deterioration.


CuAAC in a Distal Pocket: Metal Active-Template Synthesis of Strapped-Porphyrin [2]Rotaxanes.
The synthesis of a porphyrin rotaxane by dipolar cycloaddition takes advantage of the ditopic character of a phenanthroline-strapped porphyrin. The success of the click reaction was conditioned by the presence of both a coordinatively unsaturated metal in the porphyrin and a copper(I) bound to the phenanthroline, pointing at a new "tandem active metal template" mechanism.


Trace minerals and atherosclerosis.
Although there is no evidence for a direct cause-effect relationship between mineral and trace element status and atherosclerosis in humans, many elements exert a strong influence on individual risk factors for cardiovascular disease, such as disorders of blood lipids, blood pressure, coagulation, glucose tolerance, and circulating insulin. Studies in humans and animals have shown that optimal intakes of elements such as sodium, magnesium, calcium, chromium, copper, zinc, and iodine can reduce individual risk factors; some of these studies are consistent with the results of epidemiologic correlations. Influences of local geochemical environment and of dietary practices can result in mineral and trace element imbalances; deficiencies of chromium, iron, copper, zinc, selenium, and iodine are well defined. Detection and correction of such imbalances in populations, through diminishing individual risk factors, might ultimately reduce the incidence of atherosclerotic heart disease.


Development of a multiplex PCR targeting eae, stx and cdt genes in genus Escherichia and detection of a novel cdtB gene in Providencia rustigianii.
This study was aimed to develop a multiplex PCR (m-PCR) for the detection of Escherichia coli attaching and effacing (eae), Shiga toxin (stx) and cytolethal distending toxin (cdt) genes encoding important virulence factors of diarrheagenic E. coli such as EPEC, STEC, and Escherichia albertii. For this purpose, the m-PCR was designed to detect eae, all the subtypes of stx (stx1, stx2a-g except stx2f) and cdt (I-V) genes. The m-PCR was validated with 58 and 55 target gene-positive and negative strains of different sources, respectively. Sensitivity and specificity of the m-PCR were 100%. The m-PCR could also detect the eae, stx and cdt genes in bacteria spiked into stool specimens with or without enrichment culture. Clinical specimens collected from children with diarrhea were tested by the m-PCR, and 27 eae and 32 cdt genes were detected. Among them, three cdt-II and one untypable cdt gene-positive bacteria were isolated and identified as E. albertii and Providencia rustigianii, respectively. This is the first report demonstrating the presence of cdtB gene in P. rustigianii. These results indicate that the m-PCR is useful for surveillance of eae, stx and cdt gene-positive bacteria, not only EPEC, STEC and E. albertii but also P. rustigianii.


[Efficacy evaluation of laparoscopic complete mesocolic excision for transverse colon cancer].
To investigate the safety, feasibility and long-term outcomes of laparoscopic complete mesocolic excision for the transverse colon cancer. Clinical data of 61 patients who underwent laparoscopic complete mesocolic excision for transverse colon cancer (transverse group) in our department from January 2011 to January 2014 were retrospectively analyzed, which were compared with those of 155 patients undergoing laparoscopic complete mesocolic excision for ascending colon cancer (ascending group) and 230 patients undergoing laparoscopic complete mesocolic excision for sigmoid colon cancer (sigmoid group). Differences in operative details, postoperative recovery, postoperative complications and long-term survival among 3 groups were evaluated. No significant differences in the baseline information were found among 3 groups(all P>0.05). The average operative time was significantly longer in transverse group as compared to ascending group and sigmoid group [(192.1±58.7) min vs. (172.2±54.7) min and (169.1±53.6) min]( P<0.05), while the blood loss [(89.7±63.6) ml, (86.3±66.3) ml, (82.6±61.5) ml], conversion rate [3.3%(2/61), 2.6%(4/155), 2.2%(5/230)], number of harvested lymph node (13.0±4.7, 14.4±6.5, 13.4±5.6), time to flatus [(2.7±1.1) d, (2.6±1.1) d, (2.5±1.0) d], time to liquid diet [(3.0±1.7) d, (2.8±1.5) d, (2.7±1.4) d], incidence of postoperative complication(6.6%, 9.0%, 11.7%), and hospital stay [(11.6±5.8) d, (10.7±5.8) d, (10.6±5.7) d] among 3 groups were not significantly different (all P>0.05). A total of 436 patients received postoperative follow-up of median 36 (5 to 67) months. The overall 5-year survival rate was 73.1%, 73.7% and 74.8%, and the 5-year disease-free survival rate was 71.5%, 71.1% and 72.7% in transverse, ascending and sigmoid colon cancer groups respectively, whose differences were not significant among 3 groups (all P>0.05). Laparoscopic complete mesocolic excision for transverse colon cancer is safe and feasible with slightly longer operation time, and has quite good long-term oncologic efficacy.


Psoriasis following growth hormone therapy in a child.
To report a case of psoriasis that developed following growth hormone treatment. An 8-year-old boy was admitted to our pediatric endocrinology department because of short stature (<3rd percentile). A dopamine stimulation test and an insulin tolerance test revealed growth hormone (GH) deficiency with a normal cortisol response. His insulin-like growth factor 1 (IGF-1) level (9 ng/mL; reference range 113-261) was under the limits for his age and sex. Six months after the initiation of treatment with recombinant human GH 0.33 mg/kg/wk, the patient presented with a 10 day history of desquamation and a burning sensation in his right knee and hip. Lesions of erythematous papules consistent with plaques of psoriasis were present. Histologic findings from skin biopsies were consistent with psoriasis. The GH dose was reduced to 0.2 mg/kg/wk and treatment for psoriasis (including hydrocortisone and clemastine) was started. Three months after those interventions, the plaques had resolved. Previous studies proposed that the extent and severity of psoriasis correlate with GH levels, although psoriatic patients, in general, have normal GH and IGF-1 levels. The Naranjo probability scale indicated that the development of psoriasis was probably associated with GH therapy. This case suggests that the development of psoriasiform lesions in a previously unaffected individual represents an adverse effect of GH treatment, occurring at higher doses, with higher IGF-1 levels.


Optimising use of electronic health records to describe the presentation of rheumatoid arthritis in primary care: a strategy for developing code lists.
Research using electronic health records (EHRs) relies heavily on coded clinical data. Due to variation in coding practices, it can be difficult to aggregate the codes for a condition in order to define cases. This paper describes a methodology to develop 'indicator markers' found in patients with early rheumatoid arthritis (RA); these are a broader range of codes which may allow a probabilistic case definition to use in cases where no diagnostic code is yet recorded. We examined EHRs of 5,843 patients in the General Practice Research Database, aged ≥ 30 y, with a first coded diagnosis of RA between 2005 and 2008. Lists of indicator markers for RA were developed initially by panels of clinicians drawing up code-lists and then modified based on scrutiny of available data. The prevalence of indicator markers, and their temporal relationship to RA codes, was examined in patients from 3 y before to 14 d after recorded RA diagnosis. Indicator markers were common throughout EHRs of RA patients, with 83.5% having 2 or more markers. 34% of patients received a disease-specific prescription before RA was coded; 42% had a referral to rheumatology, and 63% had a test for rheumatoid factor. 65% had at least one joint symptom or sign recorded and in 44% this was at least 6-months before recorded RA diagnosis. Indicator markers of RA may be valuable for case definition in cases which do not yet have a diagnostic code. The clinical diagnosis of RA is likely to occur some months before it is coded, shown by markers frequently occurring ≥ 6 months before recorded diagnosis. It is difficult to differentiate delay in diagnosis from delay in recording. Information concealed in free text may be required for the accurate identification of patients and to assess the quality of care in general practice.


Vitamin A Affects Flatfish Development in a Thyroid Hormone Signaling and Metamorphic Stage Dependent Manner.
Vitamin A (VA) and retinoid derivatives are known morphogens controlling vertebrate development. Despite the research effort conducted during the last decade, the precise mechanism of how VA induces post-natal bone changes, and particularly those operating through crosstalk with the thyroid hormones (THs) remain to be fully understood. Since effects and mechanisms seem to be dose and time-dependent, flatfish are an interesting study model as they undergo a characteristic process of metamorphosis driven by THs that can be followed by external appearance. Here, we studied the effects of VA imbalance that might determine Senegalese sole (Solea senegalensis) skeletogenetic phenotype through development of thyroid follicles, THs homeostasis and signaling when a dietary VA excess was specifically provided during pre-, pro- or post-metamorphic stages using enriched rotifers and Artemia as carriers. The increased VA content in enriched live prey was associated to a higher VA content in fish at all developmental stages. Dietary VA content clearly affected thyroid follicle development, T3 and T4 immunoreactive staining, skeletogenesis and mineralization in a dose and time-dependent fashion. Gene expression analysis showed that VA levels modified the mRNA abundance of VA- and TH-specific nuclear receptors at specific developmental stages. Present results provide new and key knowledge to better understand how VA and TH pathways interact at tissue, cellular and nuclear level at different developmental periods in Senegalese sole, unveiling how dietary modulation might determine juvenile phenotype and physiology.


Growth of Isolated Mesophyll Cells of Arachis hypogaea in Simple Defined Medium in vitro.
Isolated mesophyll cells from leaflets of Arachis hypogaea can be cultured in a simple, defined liquid nutrient medium containing minerals, with an appropriate source of ammonia, sugar, 2,4-dichlorophenoxyacetic acid, and kinetin. The significance of such a simple medium in understanding the problems of cell metabolism, growth, and morphogenesis is discussed.


Group living homes for older people with dementia: the effects on psychological distress of informal caregivers.
The aim of this study was to investigate the effects of group living care for people with dementia on the psychological distress of informal caregivers, compared with regular nursing home care. This study had a quasi-experimental design with two measurements. 67 primary informal caregivers in 19 group living homes and 99 primary informal caregivers in seven regular nursing homes filled in a questionnaire upon admission (baseline measurement) of their relative and six months later (effect measurement). Linear and logistic regression analyses were performed on three outcomes of psychological distress - psychopathology, caregiving competence and caregiver burden. There were no significant differences in caregiver competence and caregiver burden between informal caregivers of residents in group living homes and those in regular nursing homes, although there was a trend towards less psychopathology in group living homes after adjustment for confounding. Informal caregivers of residents in group living homes do not have less psychological distress than informal caregivers of residents in regular nursing homes. Although there was a trend towards less psychopathology in informal caregivers of group living homes, the amount of symptoms remained very high in both caregiver groups. This means that the psychological well-being of caregivers deserves the continuing attention of health care providers, also after admittance of their relative in a nursing home facility.


Arf GAPs as Regulators of the Actin Cytoskeleton-An Update.
Arf GTPase-activating proteins (Arf GAPs) control the activity of ADP-ribosylation factors (Arfs) by inducing GTP hydrolysis and participate in a diverse array of cellular functions both through mechanisms that are dependent on and independent of their Arf GAP activity. A number of these functions hinge on the remodeling of actin filaments. Accordingly, some of the effects exerted by Arf GAPs involve proteins known to engage in regulation of the actin dynamics and architecture, such as Rho family proteins and nonmuscle myosin 2. Circular dorsal ruffles (CDRs), podosomes, invadopodia, lamellipodia, stress fibers and focal adhesions are among the actin-based structures regulated by Arf GAPs. Arf GAPs are thus important actors in broad functions like adhesion and motility, as well as the specialized functions of bone resorption, neurite outgrowth, and pathogen internalization by immune cells. Arf GAPs, with their multiple protein-protein interactions, membrane-binding domains and sites for post-translational modification, are good candidates for linking the changes in actin to the membrane. The findings discussed depict a family of proteins with a critical role in regulating actin dynamics to enable proper cell function.


A Protocol Demonstrating 60 Different Drosophila Behaviors in One Assay.
The fruit fly Drosophila melanogaster performs many behaviors, from simple motor actions to complex social interactions, that are of interest to neurobiologists studying how the brain controls behavior. Here, an undergraduate laboratory exercise uses cutting-edge methods to activate sets of neurons thermogenetically, triggering 60 different behaviors. Students learn how to recognize this large repertoire of behaviors from 16 fly strains that are publicly available, and from a large set of training videos provided here. A full protocol, timeline and handouts are included. Instructors need not have any experience working with flies. Student feedback is reported; in our experience, students are fascinated and highly engaged by watching animals perform such a broad array of behaviors. This exercise teaches fly husbandry and crossing, careful scientific observation, and principles of behavioral screening.


Effect of Organic Manures on the Growth of Cymbopogon citratus and Chrysopogon zizanioides for the Phytoremediation of Chromite-Asbestos Mine Waste: A Pot Scale Experiment.
The abandoned chromite-asbestos mines are located in the Roro hills, West Singhbhum, Jharkhand, India, where mining operation ceased in 1983, and since then these mines are causing environmental pollution. The present study was planned to phytoremediate these metalloid and metal contaminated mine waste by using two aromatic grasses, Cymbopogon citratus and Chrysopogon zizanioides by applying different proportions of amendments (chicken manure, farmyard manure and garden soil). Mine waste has neutral pH, low electrical conductivity and organic carbon with higher concentration of total metals (Cr and Ni) as compared to soil. Application of manures resulted significant improvements of mine waste characteristics and plant growth, reduction in the availability of total extractable toxic metals (Cr, Ni) and increase in Mn, Zn and Cu concentration in the substrate. The maximum growth and biomass production for C. citratus and C. zizanioides were found in T-IV combination comprising of mine waste (90%), chicken manure (2.5%), farmyard manure (2.5%) and garden soil (5%). Addition of T-IV combination also resulted in low Cr and Ni accumulation in roots and reduction in translocation to shoots. Study indicates that C. citratus and C. zizanioides can be used for phytostabilization of abandoned chromite-asbestos mine waste with amendments.


Senior students' evaluations of the usefulness of the Glaxo Pathway Evaluation Program.
To examine the influence of the Glaxo Pathway Evaluation Program on fourth-year medical students' specialty-choice decisions. In February 1992, 274 seniors at three medical schools were asked to complete a 19-item questionnaire regarding their evaluations of the usefulness of the Pathway program in helping them to make their specialty-choice decisions. A total of 237 seniors responded to the survey (though not all responded to all 19 items), indicating that they found the program to be moderately useful. More than half of the students (107 of 207, 51.7%) reported that they had followed the program's decision-making model and found it moderately useful. The students' responses indicated that those components intended to facilitate self-assessment and provide information about the various specialty options were fairly well utilized, i.e., 59.9% of the students had reevaluated the Critical Factors, and 73.6% had compared their individual profiles with the Specialty Profiles, finding both exercises moderately useful. Other follow-up activities had been used variably. The students evaluated the program as being moderately useful. The authors conclude that the program is a useful, comprehensive, and reasonably objective tool. Whether students using the program achieve long-term commitment to and satisfaction in their chosen specialties remains to be determined.


CRIB conditional on gender: nonparametric ROC curve.
The purpose of this paper is to use the kernel method to produce a smoothed receiver operating characteristic (ROC) curve and show how baby gender can influence Clinical Risk Index for Babies (CRIB) scale according to survival risks. To obtain the ROC curve, conditioned by covariates, two methods may be followed: first, indirect adjustment, in which the covariate is first modeled within groups and then by generating a modified distribution curve; second, direct smoothing in which covariate effects is modeled within the ROC curve itself. To verify if new-born gender and weight affects the classification according to the CRIB scale, the authors use the direct method. The authors sampled 160 Portuguese babies. The smoothing applied to the ROC curves indicates that the curve's original shape does not change when a bandwidth h = 0.1 is used. Furthermore, gender seems to be a significant covariate in predicting baby deaths. A higher value was obtained for the area under curve (AUC) when conditional on female babies. The challenge is to determine whether gender discriminates between dead and surviving babies. The authors constructed empirical ROC curves for CRIB data and empirical ROC curves conditioned on gender. The authors calculate the corresponding AUC and tested the difference between them. The authors also constructed smooth ROC curves for two approaches.


Impact of differential and time-dependent autophagy activation on therapeutic efficacy in a model of Huntington disease.
Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. In this study, we used a mouse model of HTT (huntingtin) protein aggregation to investigate how different methods and timing of autophagy activation influence the efficacy of autophagy-activating treatment in vivo. We found that overexpression of human TFEB, a master regulator of autophagy, did not decrease mutant HTT aggregation. On the other hand, Becn1 overexpression, an autophagic regulator that plays a key role in autophagosome formation, partially cleared mutant HTT aggregates and restored neuronal pathology, but only when administered early in the disease progression. When Becn1 was administered at a later stage, when prominent mutant HTT accumulation and autophagy impairments have occurred, Becn1 overexpression did not rescue the mutant HTT-associated phenotypes. Together, these results demonstrate that the targets used to activate autophagy, as well as the timing of autophagy activation, are crucial for achieving efficient therapeutic effects.Abbreviations: AAV: adeno-associated viral vectors; ACTB: actin beta; BECN1: beclin 1, autophagy related; DAPI: 4',6-diamidino-2-phenylindole; GO: gene ontology; HD: Huntington disease; HTT: huntingtin; ICQ: Li's intensity correlation quotient; IHC: immunohistochemistry; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mHTT: mutant huntingtin; PCA: principal component analysis; PPP1R1B/DARPP-32: protein phosphatase 1 regulatory inhibitor subunit 1B; SQSTM1: sequestosome 1; TFEB: transcription factor EB; WB: western blot; WT: wild-type.


[The effect of the activation of cannabinoid receptor on the proliferation and apoptosis of hepatoma HepG2 cells].
To study the effect of the activation of cannabinoid receptor on the proliferation and apoptosis of hepatoma HepG2 cells. HepG2 cells were treated with different doses of the activator of cannabinoid receptor-WIN-55, 212-2(WIN), MTT was used to detect the effects of WIN on HepG2 cells; Flow cytometry (FCM) was used to examine the effects of WIN on the apoptosis of HepG2 cells. Caspase 3 and c-myc proteins were determined by Western blot assay, and caspase 3, 8, 9 activity was measured using a colorimetric method. WIN could inhibit HepG2 cell proliferation and induce cell apoptosis dose-dependently. WIN increased caspase 3 protein levels and caspase 3, 8, 9 activity. WIN can induce apoptosis, the effect might be associated with up-regulating expression of caspases protein and down-regulating expression of c-myc protein.


Ablation of renin-expressing juxtaglomerular cells results in a distinct kidney phenotype.
Renin-expressing cells are peculiar in that they act as differentiated cells, producing the hormone renin, while they also seem to act as progenitors for other renal cell types. As such, they may have functions independent of their ability to generate renin/angiotensin. To test this hypothesis, we ablated renin-expressing cells during development by placing diphtheria toxin A chain (DTA) under control of the Ren1d mouse renin promoter by homologous recombination in a two-renin gene strain (Ren2 and Ren1d). Renin-expressing cells are essentially absent from kidneys in homozygotes (DTA/DTA) which, unlike wild-type mice, are unable to recruit renin-expressing cells when homeostasis is threatened. In contrast, renin staining in the submandibular gland (SMG), which expresses mainly Ren2, is normal. Homozygous mice survive normally, but the kidneys are small and have morphological abnormalities: 25% of the glomeruli are hyperplastic or atrophic, tubules are dilated and atrophic, and areas of undifferentiated cells exist near the atrophic glomeruli and tubules. However, in contrast to the very abnormal renal vessels found when renin-angiotensin system genes are deleted, the kidney vessels in homozygotes have normal wall thickness and no decrease in lumen size. Homozygotes have severely reduced kidney and plasma renin concentrations and females have reduced blood pressure. Homozygotes have elevated blood urea nitrogen and potassium levels, which are suggestive of altered renal function. We conclude that renin cells per se are necessary for the morphological integrity of the kidney and may have a role in maintenance of normal kidney function.


Reflections on Career Pathways of Simulation-Focused Experts in the Field.
This article presents reflections of career pathways of simulation researchers as well as a discussion of the themes found in the stories presented. It is the intent of the authors to present and foster a discussion around the ways in which we as a simulation community wish to promote recognition of scholarship among simulation researchers and help support newcomers find success as simulation researchers in academia. We also present recommendations for those considering entering the field based on tactics that were successful and not successful among the scholars who shared their stories.


A combination of sensitizers with high LET radiations.
Preliminary measurements of OER for pion beams in combination with a concentration of Misonidazole (0.4 mM) that is realistic in radiotherapeutic application are reported. These results indicate that 0.4 mM of misonidazole is as effective in reducing OER for negative pions as for X-rays. The application of high LET radiations in combination with hypoxic cell sensitizers is discussed.


Combined closures in reconstructive surgery.
It is common for dermatology surgery patients to present on the day of surgery with more than one skin cancer needing Mohs micrographic surgery. When these carcinomas are located near one another, it may be more practical to treat both at the same time as the reconstruction for one defect may involve or otherwise affect the treatment or reconstruction for the other carcinoma. Treating both cancers on the same day creates an opportunity for efficient repairs where a creative single reconstruction may minimize the amount of tissue wasted during reconstruction,and minimize morbidity for the patient. Further,combining multiple defects into one closure may reduce cost as it has been shown that reconstructive choice affects the cost-effectiveness of Mohs surgery relative to a traditional excision and Mohs surgeons more commonly select less costly options for wound management. We present a case series of two-in-one closures - repairing two defects with one closure.


Adjacent implant-supported restorations in the esthetic zone: understanding the biology.
Traditionally, whe n considering adjacent implants in the esthetic zone, clinicians have encountered problems associated with deficient interproximal soft tissues. These discrepancies were often solved either by fabricating restorations with long interproximal contacts or by adding pink ceramics, both of which represent an esthetic compromise in today's demanding standard of care for restorative dentistry. This challenge has led to the recent introduction of scalloped implants. An understanding of the biology of wound healing of bone and soft tissue around implants and the remodeling process with implant-supported restorations allows the dental team to offer patients an alternative restorative solution consisting of combining conventional flat prosthetic table implants and scalloped implants. This article illustrates the biologic behavior of wound healing associated with dental implants and shows a step-by-step clinical case in which a patient received four adjacent implants in the esthetic zone. It also describes key elements in laboratory communication when dealing with the aforementioned restorations.


Emergence of patterns in driven and in autonomous spatiotemporal systems.
The relationship between a driven extended system and an autonomous spatiotemporal system is investigated in the context of coupled map lattice models. Specifically, a locally coupled map lattice subjected to an external drive is compared to a coupled map system with similar local couplings plus a global interaction. It is shown that, under some conditions, the emergent patterns in both systems are analogous. Based on the knowledge of the dynamical responses of the driven lattice, we present a method that allows the prediction of parameter values for the emergence of ordered spatiotemporal patterns in a class of coupled map systems having local coupling and general forms of global interactions.


The role of human papillomavirus testing in the management of women with low-grade abnormalities: multicentre randomised controlled trial.
To assess the value of a single human papillomavirus (HPV) test in making decisions on management of women with cervical cytology showing borderline nuclear abnormality (BNA) or mild dyskaryosis. In particular, to determine whether information on high-risk (hr) HPV status would be valuable in the choice between (1) cytological surveillance versus immediate referral to colposcopy, and (2) at colposcopy, between biopsy and recall versus immediate large loop excision of the transformation zone (LLETZ). Multicentre individually randomised controlled trial, nested within the NHS Cervical Screening Programmes, investigating the value of HPV testing by testing for interactions between HPV status and (1) cytological surveillance versus colposcopy, and (2) biopsy and recall versus immediate LLETZ. Setting Grampian, Tayside and Nottingham. Population Women (n = 4439), aged 20-59 years, with a cytology test showing borderline nuclear abnormalities or mild dyskaryosis during October 1999 to October 2002. High-risk HPV status was determined at recruitment using the polymerase chain reaction assay with the GP5+/6+ general primer system. The results of this HPV testing were not disclosed to either the participating women or to those involved in their management. Women were randomised to either (1) 6-monthly cytological screening in primary care or (2) referral for colposcopy. Human papillomavirus status was used to stratify both randomisations. All women were followed for 3 years, concluding with an invitation to an exit appointment at which colposcopic examination was undertaken. In addition, in women who were randomised to initial colposcopy and underwent colposcopy, the association between hrHPV status and presence of cervical intraepithelial neoplasia (CIN) grade 2 or more severe disease (henceforth CIN2 or worse) was examined. Sensitivity, specificity, positive and negative predictive values of the HPV test for predicting CIN2 or worse and the implications for the choice of management between cytological surveillance and immediate referral for colposcopy. There were no significant interactions between management and HPV status. Hence, in women with mild dyskaryosis or BNA who are HPV positive, there is no advantage of (1) immediate colposcopy over cytological surveillance (P = 0.76) or (2) immediate LLETZ over biopsy and recall (P = 0.27). The sensitivity of HPV testing for detection of CIN2 or worse was 75.2% (95% CI 68.8-81.0%) among women with mild dyskaryosis and 69.9% (95% CI 61.7-77.3%) among those with BNA. Specificity was higher in those with BNA (71.3%; 95% CI 68.5-74.1%) than in those with mild dyskaryosis (46.9%; 95% CI 42.2-51.6%). Sensitivity decreased with increasing age whereas specificity increased. The negative predictive value was high, particularly among women with BNA (94.5%; 95% CI 92.9-96.0%). Across all ages, 22% of women who had CIN2 or worse were HPV negative. Conversely, 40% of those who were HPV positive did not have CIN. HPV was a much more reliable predictor in women aged over 40 years. We conclude that in younger women with low-grade cytological abnormalities, a single HPV test would not be useful in determining who should be referred for colposcopy or the most effective management at colposcopy. In women over 40, a negative HPV test could be used to rule out further investigation.


Astaxanthin blocks preeclampsia progression by suppressing oxidative stress and inflammation.
To investigate the antioxidative effect of astaxanthin on Nω-nitro-L-arginine methyl ester (L-NAME)-induced preeclamptic rats. Cell survival, the level of reactive oxygen species (ROS) and the changes in mitochondrial membrane potential (MMP) were examined in astaxanthin and H2O2-treated human umbilical vein endothelial cells (HUVECs). The preeclamptic Sprague-Dawley (SD) rat model was established by injection of L‑NAME and treatment with astaxanthin. The activities of malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide synthase (NOS) in serum were analyzed. Pathological changes were examined by hematoxylin and eosin (H&E) staining. The expression of nuclear factor (NF)‑κB, Rho‑associated protein kinase II (ROCK II), heme oxygenase‑1 (HO‑1) and caspase 3 in preeclamptic placentas were examined by immunohistochemistry. Astaxanthin significantly reduced H2O2‑induced HUVEC cell death, decreased ROS and increased MMP. Astaxanthin significantly reduced blood pressure and the content of MDA, but significantly increased the activity of SOD in preeclamptic rats. The urinary protein and the level of NO and NOS were also decreased. H&E staining revealed that the thickness of the basilar membrane was increased, while the content of trophoblast cells and spiral arteries were reduced following astaxanthin treatment. Immunohistochemistry results showed that the expression of NF‑κB, ROCK II and caspase 3 in preeclamptic placentas was significantly decreased after astaxanthin treatment, while HO‑1 expression was increased. In conclusion, astaxanthin inhibited H2O2‑induced oxidative stress in HUVECs. Astaxanthin treatment significantly improved L‑NAME‑induced preeclamptic symptoms and reduced the oxidative stress and inflammatory damages in preeclamptic placentas. Astaxanthin treatment may effectively prevent and treat preeclampsia.


Effect of selenium supplementation on biochemical markers and outcome in critically ill patients.
This study aimed to assess the effect of high dose selenium (Se) supplementation on Se status in blood, oxidative stress, thyroid function and possible effects on requirement for renal replacement therapy (RRT) in severely septic patients admitted to the intensive care unit (ICU). This prospective single-centre study was carried out in 40 septic ICU patients who were randomized to high dose Se (Se+ group, N=18 (474, 316, 158 microg/day), each for 3 consecutive days followed by a standard dose of 31.6 microg/day of Se given as sodium selenite whereas the control group (Se-, N=22) received only the standard dose of Se. Plasma Se, glutathione peroxidase (GSH-Px), F2 isoprostanes, thyroid function tests (total T4 and total T3), C-reactive protein (CRP) and red blood cell (RBC) GSH-Px were estimated on day 0, 3, 7, 14. In the Se+ group, plasma Se increased by day 3 and 7 (P<0.0001) and day 14 (P=0.02), plasma GSH-Px increased by day 3 and 7 (P=0.01) as compared to Se- group. There was a significant negative correlation between plasma Se and SOFA (sepsis related organ failure assessment) (r=-0.36, P=0.03) along with low plasma Se and high CRP at the time of admission. Requirement for renal replacement therapy was not significantly different between the groups. Although high dose Se supplementation increased plasma Se and GSH-Px activity, it did not reduce oxidative damage or the requirement for RRT. Se levels in blood are influenced by redistribution and severity of illness and therefore should be interpreted with caution.


Comparative study of thermochemical processes for hydrogen production from biomass fuels.
Different thermochemical configurations (gasification, combustion, electrolysis and syngas separation) are studied for producing hydrogen from biomass fuels. The aim is to provide data for the production unit and the following optimization of the "hydrogen chain" (from energy source selection to hydrogen utilization) in the frame of the Italian project "Filiera Idrogeno". The project focuses on a regional scale (Tuscany, Italy), renewable energies and automotive hydrogen. Decentred and small production plants are required to solve the logistic problems of biomass supply and meet the limited hydrogen infrastructures. Different options (gasification with air, oxygen or steam/oxygen mixtures, combustion, electrolysis) and conditions (varying the ratios of biomass and gas input) are studied by developing process models with uniform hypothesis to compare the results. Results obtained in this work concern the operating parameters, process efficiencies, material and energetic needs and are fundamental to optimize the entire hydrogen chain.


Kinetics of bilirubin oxidase and modeling of an immobilized bilirubin oxidase reactor for bilirubin detoxification.
The unbound bilirubin concentration and the enzymatic rate of bilirubin degradation by bilirubin oxidase in bilirubin-serum albumin solutions have been investigated experimentally and theoretically. A stoichiometric bilirubin-serum albumin binding analysis shows that the unbound bilirubin concentration depends only on the molar ratio of the total bilirubin concentration to the total serum albumin concentration. From the theoretical analysis and the measured unbound bilirubin concentrations, serum albumin may be modelled as a molecule having two binding sites, primary and secondary, with stoichiometric equilibrium constants of K(1) = 6 x 10(7)M(-1) and K(2) = 4.5 x 10(6)M(-1), respectively. The rate of total bilirubin degradation in bilirubin-serum albumin mixtures is zero order. An immobilized bilirubin oxidase reactor model, which shows good agreement with experimental bilirubin conversions, is presented. At a flow rate of 1 mL/min with a 8-mL reactor volume, a 50% bilirubin conversion per pass was observed with an inlet bilirubin concentration of 350muM and a serum albumin concentration of 500muM.


Case Report: Effect of Electroconvulsive Therapy on Obsessive-Compulsive Disorder Comorbid With Body Dysmorphic Disorder.
Obsessive-compulsive disorder (OCD) is a chronic psychiatric condition that is associated with considerable morbidity, and ~90% of individuals with OCD have another psychiatric comorbidity. Patients with comorbid OCD and body dysmorphic disorder (BDD) have limited insight and poor psychosocial function, respond poorly to drug treatment, and have an increased risk of suicide. Modified electroconvulsive therapy (ECT) has been attempted to improve symptoms of OCD when drug treatment does not have a satisfactory effect. This report describes a patient who had OCD comorbid with BDD that was successfully treated with modified ECT. Although the mechanism of its effect is unclear, modified ECT may be an alternative treatment for patients with comorbid OCD and BDD. Its efficacy and mechanism of action require further investigation in a large sample of patients with these comorbid disorders.


Relationship of glomerular filtration rate and hypoalbuminaemia to renal glucose reabsorption.
Ten glucose titration studies were performed on 10 patients with chronic renal disease without renal failure. Six of them had nephrotic syndrome. The results show that patients with marked hypoalbuminaemia (i.e. patients with nephrotic syndrome) have a marked splay in the glucose titration curve. This observation is consistent with the hypothesis that physical factors play a main role in tubular reabsorption and indicate that proximal tubular reabsorption is decreased in nephrotic syndrome.


Congenital Hypotrichosis and Congenital Atrichia.
A wide range of conditions can present with congenital hypotrichoses/atrichia. Awareness of these conditions can help in the proper and timely diagnosis and counseling of affected families, and in some cases avoid unnecessary investigations. The rapid growth in genetic analysis of diseases has also led to an increased knowledge of the genetic and molecular basis of many of these conditions. This contribution briefly reviews updates on some of the most common conditions associated with congenital hypotrichosis/atrichia.


A Dimeric 2,9-Diamino-1,10-phenanthroline Derivative Improves Alternative Splicing in Myotonic Dystrophy Type 1 Cell and Mouse Models.
Expanded r(CUG) repeats are the cause of the neurological disorder myotonic dystrophy type 1 (DM1). The pathological features of DM1 include the formation of ribonuclear foci containing expanded r(CUG) repeats, which sequester the MBNL1 protein and lead to the misregulation of alternative pre-mRNA splicing. Small molecules that bind to the r(CUG) repeats and improve alternative splicing have therapeutic potential in the treatment of DM1. Herein, the synthesis of DDAP (a dimeric form of the CUG-binding molecule DAP reported previously), its binding properties to r(CUG) repeats, and its effect on the misregulation of splicing are reported. The surface plasmon resonance assay, circular dichroism spectra, and ESI-TOF mass spectrometry results confirmed the binding of DDAP to r(CUG)9 repeats. Studies on a DM1 cell model and a DM1 mouse model revealed that DDAP was partially effective in the recovery of the pre-mRNA splicing defects. The mechanism underlying this recovery was studied in vitro through a competitive binding assay, and suggested that DDAP could interfere with the binding of MBNL1 to r(CUG) repeats in a concentration-dependent manner.


Self-Supported Hierarchical IrO2@NiO Nanoflake Arrays as an Efficient and Durable Catalyst for Electrochemical Oxygen Evolution.
Although traditional IrO2 nanoparticles loaded on a carbon support (IrO2@C) have been taken as a benchmark catalyst for the oxygen evolution reaction (OER), their catalytic efficiency, operation stability, and IrO2 utilization are far from satisfactory due to the inferior powdery structure and inevitable corrosion of both IrO2 and C under the oxidizing potentials. Here, a rational design of a self-supported hierarchical nanocomposite, composed of IrO2@NiO nanoparticle-built porous nanoflake arrays vertically growing on nickel foam, is proposed, which is demonstrated as a versatile strategy to achieve improved OER activity, remarkable long-term stability, and significantly reduced loading of IrO2 (0.62 atom %). Impressively, the resultant catalyst drives a steady OER current density of 10 mA cm-2, requiring 278 mV overpotential in 1.0 M KOH electrolyte for 25 h and outmaneuvring commercial IrO2@C with much higher mass loading. Further electrochemical investigation and mechanism analysis disclose that the greatly improved electrocatalytic activity stems from the advantageous hierarchical structure and the synergistic effect between IrO2 and underlying potential-induced NiOOH, whereas the outstanding durability is attributed to the unique role of NiO in preventing IrO2 dissolution.


[Evaluation of the inhibition of allergen-specific and nonspecific skin responses by topical oxatomide].
A double blind study against placebo was carried out in order to assess the inhibition induced by oxatomide gel in specific and aspecific cutaneous responses (prick test). Twenty allergic patients (8 M, 12 F) aged between 15 and 59 years (average 31) were treated for 7 days with oxatomide gel 5% or with placebo (2 applications a day). The results show a significant reduction of itching and of wheal size (considering either major diameter and area) only in the oxatomide group (p less than 0.01 between times and p less than 0.001 between treatments), whereas among controls itching remained unchanged and wheal size increased. During the follow-up a gradual return of wheal size to initial values in the patients treated was observed.


Tyrosyl-tRNA synthetase from Escherichia coli. Stoichiometry of ligand binding and half-of-the-sites reactivity in aminoacylation.
The tyrosyl-tRNA synthetase from Escherichia coli binds only 1 mol of tRNA, tyrosine, and tyrosyl adenylate per mol of enzyme dimer. However, like the enzyme from Bacillus stearothermophilus, once one active site is occupied by tyrosyl adenylate the other becomes accessible to bind a further molecule each of tyrosine and ATP. Both bacterial enzymes show biphasic kinetics with respect to tyrosine in the aminoacylation of tRNA. Equilibrium dialysis experiments show that this is due to 2 mol of tyrosine binding in the presence of ATP and tRNA. A method is given for a correction for the effects of hydrolysis of the charged tRNA on the aminoacylation kinetics.


Changing trends in anti-psychotic prescription pattern in Pakistan.
This study was designed to identify the changing trends in Anti-psychotic prescription pattern in Pakistan. It was part of the research project Research on East Asian Psychotropic Prescription Pattern (REAP) carried out to identify the prescription patterns of schizophrenic patients in different countries located in Asia.Our objective was to assess the trend and change of psychotropic drug prescriptions for patients with schizophrenia. The design of the study was quantitative and of descriptive epidemiology. This study was carried out from 30th March 2017. Data was collected on a unified protocol by the Psychiatrists from Pakistan. Three (3) centers i.e., Lahore, Karachi and Islamabad provided the data. Indoor and outdoor cases with Schizophrenia were recruited. A web based recording system for collection of data done at Taipei Taiwan, and statistical analysis was performed and transferred to all participating centers including Pakistan. The main findings of the study were that majority of the patients were prescribed antipsychotic poly pharmacy drug. It was also found that Anxiolytics, anti-depressants and Anti-parkinsonian drugs were also co-prescribed. It was concluded that antipsychotic poly pharmacy along with Anxiolytics, anti-depressants and Anti-parkinsonian drugs were prescribed to patients with schizophrenia in Pakistan.


On recurrent-event win ratio.
The win ratio approach proposed by Pocock et al. (2012) has become a popular tool for analyzing composite endpoints of death and non-fatal events like hospitalization. Its standard version, however, draws on the non-fatal event only through the first occurrence. For statistical efficiency and clinical interpretability, we construct and compare different win ratio variants that make fuller use of recurrent events. We pay special attention to a variant called last-event-assisted win ratio, which compares two patients on the cumulative frequency of the non-fatal event, with ties broken by the time of its latest episode. It is shown that last-event-assisted win ratio uses more data than the standard win ratio does but reduces to the latter when the non-fatal event occurs at most once. We further prove that last-event-assisted win ratio rejects the null hypothesis with large probability if the treatment stochastically delays all events. Simulations under realistic settings show that the last-event-assisted win ratio test consistently enjoys higher power than the standard win ratio and other competitors. Analysis of a real cardiovascular trial provides further evidence for the practical advantages of the last-event-assisted win ratio. Finally, we discuss future work to develop meaningful effect size estimands based on the extended rules of comparison. The R-code for the proposed methods is included in the package WR openly available on the Comprehensive R Archive Network.


[Inhibitive effects of recombinant adenovirus-mediated human endostatin on the growth of human hepatocellular carcinoma xenograft in nude mice].
To investigate the inhibitive effect on the growth of hepatocellular carcinoma (HCC) xenografted in nude mice by adenovirus-mediated human endostatin gene. The expression efficiency of endostatin was examined after ECV-304 cells infected with Ad/hEndo by western blot. The hepatoma BEL-7402 cells were injected into Balb/c nude mice to detect the inhibition of Ad/hEndo on the growth of HCC xenografted in nude mice. The expression of endostatin mRNA in tumor tissue was analyzed with RT-PCR, and its distribution in vivo was also analyzed. High level expression of endostatin achieved in infected ECV-304 cells by western blot. Ad/hEndo significantly inhibited the growth of xenografted BEL-7402 tumors (F=4.061, P<0.05). The intratumoral microvessel density (MVD) decreased significantly in the treated mice (6.88+/-1.08 vs 13.60+/-1.71, t=9.216, P<0.01). The expression of endostatin mRNA in tumor tissue was detected by RT-PCR in 3 days after administration intratumorally with Ad/hEndo and almost disappeared in 7 days. Endostatin mRNA was mainly located in tumor tissue with a higher concentration than that in heart, lung, spleen and liver after Ad/hEndo administration. Adenovirus-mediated human endostatin gene can be expressed efficiently in vitro and in vivo, and significantly inhibit the growth of BEL-7402 xenografted tumors in nude mice.


Clinical Study of New Tetravalent (Type A, B, E, and F) Botulinum Toxoid Vaccine Derived from M Toxin in Japan.
Botulinum toxin is the most poisonous substance known, and is believed to be a highly lethal as a biological weapon; researchers of the toxin are exposed to this hazard. Botulinum toxoid vaccines have been produced and used in Japan. However, since clinical studies involving these vaccines were conducted before establishment of the Ethical Guidelines for Clinical Research in Japan, their immunogenicity and safety were not systematically assessed. In this study, we produced a new tetravalent (type A, B, E, and F) botulinum toxoid vaccine, the first ever to be derived from M toxin, and conducted quality control tests with reference to the Minimum Requirements in Japan for adsorbed tetanus toxoid vaccine. Subsequently, a clinical study using the new vaccine in 48 healthy adult volunteers was conducted according to the guidelines in Japan. No clinically serious adverse event was noted. Neutralizing antibody titers for each type of toxin in the participants' sera, 1 month after the 4th injection were more than 0.25 IU/mL, indicating sufficient protection. This study demonstrated that the vaccine has marked immunogenicity and is safe for use in humans.


Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon.
Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of short-bowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition that included a significant increase in total body bone mass. This article describes the effect of GLP-2 on spinal and hip bone mineral density (BMD) and biochemical markers of bone turnover in these patients. In an open-labelled pilot study, eight short-bowel patients (3M, 5F; mean age 49 years) with small-bowel resection and no colon received 400 microg s.c. of GLP-2 twice daily for 5 weeks. Four received home parenteral nutrition (mean length of residual jejunum 83 cm) and 4 did not (mean length of ileum resected 106 cm). The outcome measures were the mean percent change from baseline in spinal and hip BMD measured by dual-energy X-ray absorptiometry, changes in four biochemical markers of bone-turnover, PTH, 25-hydroxy vitamin-D, and the intestinal absorption of calcium. Mean +/- s(x) (SEM) percent changes in spinal and hip BMD were 1.1+/-0.4% (P < 0.05) and 1.9+/-0.8% (P = 0.06), respectively. The intestinal calcium absorption increased by 2.7% (P = 0.87). Serum ionized calcium increased in 5/8 patients with a concomitant decrease in serum PTH values. Three of the four markers of bone turnover decreased. A 5-week GLP-2 administration significantly increased spinal BMD in short-bowel patients with no colon. The mechanism by which GLP-2 affects bone metabolism remains unclear, but may be related to an increased mineralization of bone resulting from an improved intestinal calcium absorption.


Quantum criticality out of equilibrium: steady state in a magnetic single-electron transistor.
Quantum critical systems out of equilibrium are of extensive interest, but are difficult to study theoretically. We consider here the steady-state limit of a single-electron transistor with ferromagnetic leads. In equilibrium (i.e., bias voltage V = 0), this system features a continuous quantum phase transition with a critical destruction of the Kondo effect. We construct an exact quantum Boltzmann treatment in a dynamical large-N limit, and determine the universal scaling functions of both the nonlinear conductance and fluctuation-dissipation ratios. We also elucidate the decoherence properties as encoded in the local spin response.


Gene for integrin-associated protein (IAP, CD47): physical mapping, genomic structure, and expression studies in skeletal muscle.
Integrin-associated protein (IAP) is a widely expressed membrane protein with multiple functions in immunological and neuronal processes. Having physically mapped the IAP gene into a BAC/PAC contig covering approximately 1 Mb on human chromosome 3ql3.1-q13.2, we determined the genomic organization of the gene, established its expression in skeletal muscle, and identified a novel splice variant. Our expression studies demonstrate expression of integrin-associated protein in the t-tubular system and the euchromatin of skeletal muscle cells where its function thus far is not known.


Effect of cytoskeleton-disrupting agents on the metastatic behavior of melanoma cells.
The effects of treatment with colchicine, cytochalasin B, and low temperature (4 degrees C) on the metastatic behavior of the B16-F10 melanoma cell line were examined. The growth of metastases and the distribution of radiolabeled tumor cells were monitored in inbred C57/BL6 mice given iv injections of B16-F10 cells. Cells treated previously with both drugs, but not with low temperature, produced fewer lung nodules than did control cells and displayed alterations in tumor dissemination patterns. In vitro studies revealed that both drugs reduced the rate of adhesion of the tumor cells to bovine endothelial cell monolayers, the rate of migration from agarose droplets, the formation of homotypic aggregates, and agglutination by wheat germ agglutinin. The drugs also induced morphologic alterations of the cells grown in monolayer culture but had little effect on cell volume.


In vivo dual effects of vitamin C on paraquat-induced lung damage: dependence on released metals from the damaged tissue.
Vitamin C, a potent antioxidant, can act as a pro-oxidant in the presence of free transition metal ions by accelerating the Fenton reaction. An in vivo pro-oxidant role of vitamin C has been suggested, but direct evidence for it is scant. Here, we report the dual role of vitamin C on paraquat-induced lung injury, which appears to depend on the metal ions released from damaged cells. Vitamin C (10 mg/kg) given at the time when the extensive tissue damage was in progress aggravated the oxidative damage, while it protected against the damage when given before the initiation of the damage. The extent of oxidative tissue damage was monitored by measuring the expiratory ethane, one of the hydrocarbons produced during lipid peroxidation. Deferoxamine, given intraperitoneally as a bolus dose of 50 mg/kg, completely blocked the aggravation of oxidative damage by vitamin C. Moreover, deferoxamine unmasked the antioxidant effect of vitamin C. The results show that vitamin C can either aggravate or alleviate the oxidative tissue damage depending on the presence of metal ions released from damaged cells.


Thioflexithrix psekupsensis gen. nov., sp. nov., a filamentous gliding sulfur bacterium from the family Beggiatoaceae.
A sulfur-oxidizing, filamentous, gliding micro-organism, strain D3T, was isolated from a sulfidic spring in Goryachy Klyuch, Krasnodar, Russia. The cell walls were Gram-negative. The new isolate was a microaerophilic facultative anaerobe and an obligate chemolithoautotroph. The pH range for growth was pH 6.8-7.6, with an optimum at pH 7.2. The temperature range for growth was 10-46 °C, with an optimum at 32 °C. The G+C content of DNA was 42.1 mol%. Phylogenetic analysis of the 16S rRNA gene showed that strain D3T belongs to the family Beggiatoaceae, order Thiotrichales and was distantly related to the genera of the family Beggiatoaceae(86-88 % sequence similarity). The major respiratory quinone was ubiquinone-6. Major fatty acids were C18:1 ω7 (37.6 %), C16 : 0 (34.7 %) and C16: 1 ω7 (27.7 %). On the basis of its physiological properties and the results of phylogenetic analysis, strain D3T is considered to represent a novel species of a new genus, for which the name Thioflexithrix psekupsensis gen. nov., sp. nov. is proposed. The type strain is D3T (=KCTC 62399=UNIQEM U981).