Job insecurity during recessions: effects on survivors' work stress.
Previous studies show a variety of negative health consequences for the remaining workforce after downsizing events. This study examined self-reported work stress from 2009-2012 in the context of a large multi-site aluminum manufacturing company that underwent severe downsizing in 2009. This study examined the association between work stress and working at a work site that underwent severe downsizing. We assessed the level of downsizing across thirty plants in 2009 and categorized seven as having undergone severe downsizing. We linked plant-level downsizing information to individual workers' responses to an annual work engagement survey, which included three work stress questions. From 2009 to 2012 over 14, 000 employees were asked about their experience of work stress. Though the surveys were anonymous, the surveys captured employees' demographic and employment characteristic as well as plant location. We used hierarchical logistic regressions to compare responses of workers at severely downsized plants to workers at all other plant while controlling for demographic and plant characteristics. Responses to the work stress questions and one control question were examined. In all yearly surveys salaried workers consistently reported having more work stress than hourly workers. There was no differential in work stress for workers at severely downsized plants in 2009. In 2010 to 2012, salaried workers who remained at severely downsized plants reported significantly higher work stress than salaried workers at all other plants across multiple work stress questions. Examination of the 2006 survey confirmed that there were no pre-existing differences in work stress among salaried employees working at plants that would eventually experience severe downsizing. In addition, there was no difference in responses to the control question at severely downsized plants. Salaried workers at plants with high layoffs experienced more work stress after 2009 than their counterparts at non-high layoff plants. Increased work stress is important to monitor and may be a mediating pathway through which the external economic environment leads to adverse health outcomes.


[Ventricular arrhythmias and arterial hypertension: role of inflammatory biomarkers in arrhythmia development].
Arrhythmogenic role of proinflammatory cytokines is still unclear despite of wide discussion on inflammatory arrhythmogenic mechanisms. The main goal of study was to compare levels of tumor necrosis factor a, interleukin 6 and interleukin 4 in hypertensive patients with and without ventricular rhythm disturbances. The study included 100 cases, 50 of those had ventricular arrhythmias. Levels of tumor necrosis factor a, interleukin 6 and interleukin 4 were studied. Possible connections of above mentioned biomarkers with ventricular arrhythmias, blood pressure, echocardiography left ventricle data were evaluated. Higher level of biomarkers was associated with presence of ventricular arrhythmias; higher rate of ventricular extrasystoles was accompanied with insignificantly lower biomarker level.


Influence of the facility caseload on the subsequent survival of men with localized prostate cancer undergoing radical prostatectomy.
Several studies have investigated the relationship between experience measured by caseload and oncological outcomes, economics, and access to care for prostate cancer care. Oncological outcomes have been limited to biochemical failure after radical prostatectomy. Questions remain regarding the more definitive measures of outcomes and their relationship with caseload. The National Cancer Database was used to investigate the outcomes of radical prostatectomy in the United States. With overall survival (OS) as the primary outcome, the relationship between the facility annual caseload (FAC) for all prostate cancer encounters and the facility annual surgical caseload (FASC) for those requiring radical prostatectomy was examined with a Cox proportional hazards model. Four volume groups were defined by caseload: <50th percentile (volume group 1 [VG1]), 50th to 74th percentiles (volume group 2 [VG2]), 75th to 89th percentiles (volume group 3 [VG3]), and ≥90th percentile (volume group 4 [VG4]). By FAC/FASC, 11%/8%, 17%/18%, 25%/26%, and 47%/49% of patients were treated in VG1 through VG4, respectively. Between 2004 and 2014, 488,389 patients underwent radical prostatectomy. At a median follow-up of 60.75 months, the median OS was not reached. There was a significant OS benefit as the caseload increased. For FAC, the adjusted OS difference between VG1 and VG4 at 90th percentile survivorship reached 13.2 months (hazard ratio [HR], 1.30; 95% CI, 1.23-1.36; P < .0001). For FASC, this was 11.3 months (HR, 1.25; 95% CI, 1.192-1.321; P < .0001). There is a statistically significant OS advantage from performing radical prostatectomy at a facility with a high annual caseload. Caseload measured by all prostate cancer encounters is a better predictor of favorable outcomes than the number of surgeries performed at a facility. An in-depth analysis of 488,389 cases of radical prostatectomy performed in more than 1000 facilities over a 10-year period showed better survival when surgery was performed in facilities with more experience and greater caseload. A survival difference of up to 13 months was observed when comparing patients treated at less experienced versus more experienced centers. Experience across all stages of prostate cancer was a stronger predictor of survival outcome than just the number of surgeries performed.


WITHDRAWN: Vaccines for preventing malaria.
Four types of malaria vaccine, SPf66 and MSP/RESA vaccines (against the asexual stages of the Plasmodium parasite) and CS-NANP and RTS,S vaccines (against the sporozoite stages), have been tested in randomized controlled trials in endemic areas. To assess malaria vaccines against Plasmodium falciparum, P. vivax, P. malariae and P ovale in preventing infection, disease and death. We searched the Cochrane Infectious Diseases Group Specialized Register (April 2004), CENTRAL (The Cochrane Library Issue 2, 2004), MEDLINE (1966 to April 2004), EMBASE (1980 to April 2004), Science Citation Index (1981 to April 2004), and reference lists of articles. We also contacted organizations and researchers in the field. Randomized controlled trials comparing vaccines against Plasmodium falciparum, P. vivax, P. malariae or P. ovale with placebo or routine antimalarial control measures in people of any age receiving a challenge malaria infection. Two reviewers independently assessed trial quality and extracted data. Eighteen efficacy trials involving 10,971 participants were included. There were ten trials of SPf66 vaccine, four trials of CS-NANP vaccines, two trials of RTS,S vaccine, and two of MSP/RESA vaccine. Results with SPf66 in reducing new malaria infections (P. falciparum) were heterogeneous: it was not effective in four African trials (Peto odds ratio (OR) 0.96, 95% confidence interval (CI) 0.81 to 1.14), but in five trials outside Africa the number of first attacks was reduced (Peto OR 0.77, 95% CI 0.67 to 0.88). Trials to date have not indicated any serious adverse events with SPf66 vaccine. In three trials of CS-NANP vaccines, there was no evidence for protection by these vaccines against P. falciparum malaria (Peto OR 1.12, 95% CI 0.64 to 1.93). In a small trial in non-immune adults in the USA, RTS,S gave strong protection against experimental infection with P. falciparum. In a trial in an endemic area of the Gambia in semi-immune people, there was a reduction in clinical malaria episodes in the second year of follow up, corresponding to a vaccine efficacy of 66% (CI 14% to 85%). In a trial in Papua New Guinea, MSP/RESA had no protective effect against episodes of clinical malaria. There was evidence of an effect on parasite density, but this differed according to whether the participants had been pretreated with sulfadoxine/pyrimethamine or not. The prevalence of infections with the parasite subtype of MSP2 in the vaccine was reduced compared with the other subtype (Peto OR 0.35, CI 0.23 to 0.53). There is no evidence for protection by SPf66 vaccines against P. falciparum in Africa. There is a modest reduction in attacks of P. falciparum malaria following vaccination with SPf66 in other regions. Further research with SPf66 vaccines in South America or with new formulations of SPf66 may be justified. There was not enough evidence to evaluate the use of CS-NANP vaccines. The RTS,S vaccine showed promising result, as did the MSP/RESA vaccine, but it should include the other main allelic form of MSP2. The MSP/RESA trial demonstrated that chemotherapy during a vaccine trial may reduce vaccine efficacy, and trials should consider very carefully whether this practice is justified.


How T cells talk to target cells.
T cell defects are very often involved in haematological diseases and occur even more frequently as a consequence of our therapeutic interventions. T cells play a central role in the immune defence of the organism. To perform this function, they move around the body to achieve a particular stage of development and in search for antigenic insult. In the course of this, they have to communicate and cooperate with various cells. T cells carry a high number of structurally and functionally defined and even more as yet undefined surface structures. The variability and functional pleitropism of these molecules and as a consequence that of their interactions with surface structures of other cells is infinite. This paper will be limited to discuss briefly the following subjects: the presentation of antigens to T cells, structure and function of the T cell receptor (TCR) and its interactions with the antigen, presenting major histocompatibility complex (MHC) molecule, accessory molecules and other modulating surface structures, the role of carbohydrates, pitfalls of inferences on interacting cell surface structures.


Transjugular Intrahepatic Porto-Caval Shunt (TIPS) in treatment of portal hypertension in liver transplant recipiens.
TIPS, as non-operative treatment of portal hypertension allows for safe awaiting liver transplantation for patients otherwise at high risk of hemorrhage from oesophageal varices veins. When endoscopic treatment fails, TIPS is a plausible and less hazardous alternative for surgical porto-systemic shunts. It is of particular importance in patients with liver failure and unacceptable operative risk (group C in Child-Pugh classification). TIPS was done in 96 patients aged 16-68 years (average 52 years). According to Child-Pugh classification, which documents a stage of liver failure, 60 patients (62%) were in group B, and 36 (38%) in group C. Patients from group C are in most severe condition and at highest operative risk. Postalcoholic and postinflammatory liver cirrhosis is a main cause of portal hypertension. TIPS was done in 26 patients expecting liver transplantation. Twenty patients had subsequently undergone liver transplantation while remaining 6 are still on the waiting list. In 15 patients stenosis of the shunt was observed within a year. Stenosis was then treated with intervention radiology and implantation of supplemental stents. TIPS as a non-operative option for treatment of portal hypertension gives a patient an opportunity to await liver transplantation with maximum possible safety. Considering these facts, TIPS is called a bridge to liver transplantation.


Virologic and serologic studies of progressive multifocal leukoencephalopathy.
The human polyomavirus JCV has been associated with diseased brain tissue from 54 cases of PML. The disease occurred in persons of all ages--the youngest being 5 years old--whose immune mechanisms were depressed for any of a variety of reasons. In six patients the disease ceased progressing and they stabilized or improved. The brains of two of these, who died months or years later, were found to be free of active PML at autopsy. Sera from 21 patients had HAI antibodies against JCV, but none had antibodies against T or the common internal antigens, and only one had IgM antibodies detectable by immunofluorescent staining. Nine CSF were devoid of JCV-related antibodies except for one which gave an HAI titer of 8. Virus has been isolated from 15 PML brains, and preliminary studies indicate that one isolate, while clearly of JCV type, is serologically distinguishable from prototype Mad 1 JCV.


Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques.
Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.


Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility.
The promising clinical benefits of delivering human mesenchymal stem cells (hMSCs) for treating heart disease warrant a better understanding of underlying mechanisms of action. hMSC exosomes increase myocardial contractility; however, the exosomal cargo responsible for these effects remains unresolved. This study aims to identify lead cardioactive hMSC exosomal microRNAs to provide a mechanistic basis for optimizing future stem cell-based cardiotherapies. Integrating systems biology and human engineered cardiac tissue (hECT) technologies, partial least squares regression analysis of exosomal microRNA profiling data predicted microRNA-21-5p (miR-21-5p) levels positively correlate with contractile force and calcium handling gene expression responses in hECTs treated with conditioned media from multiple cell types. Furthermore, miR-21-5p levels were significantly elevated in hECTs treated with the exosome-enriched fraction of the hMSC secretome (hMSC-exo) versus untreated controls. This motivated experimentally testing the human-specific role of miR-21-5p in hMSC-exo-mediated increases of cardiac tissue contractility. Treating hECTs with miR-21-5p alone was sufficient to recapitulate effects observed with hMSC-exo on hECT developed force and expression of associated calcium handling genes (eg, SERCA2a and L-type calcium channel). Conversely, knockdown of miR-21-5p in hMSCs significantly diminished exosomal procontractile and associated calcium handling gene expression effects on hECTs. Western blots supported miR-21-5p effects on calcium handling gene expression at the protein level, corresponding to significantly increased calcium transient amplitude and decreased decay time constant in comparison to miR-scramble control. Mechanistically, cotreating with miR-21-5p and LY294002, a PI3K inhibitor, suppressed these effects. Finally, mathematical simulations predicted the translational capacity for miR-21-5p treatment to restore calcium handling in mature ischemic adult human cardiomyocytes. miR-21-5p plays a key role in hMSC-exo-mediated effects on cardiac contractility and calcium handling, likely via PI3K signaling. These findings may open new avenues of research to harness the role of miR-21-5p in optimizing future stem cell-based cardiotherapies.


Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA.
We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the in vitro activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of M. tuberculosis infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).IMPORTANCE Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA-a key component for biosynthesis of the mycolic acid layer of the bacterium's cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.


[Childbirth practices and challenges for humanization of care in two public hospitals in Southern Brazil].
The aim of this study was to characterize hospital care for childbirth in two hospitals affiliated with the Unified National Health System in Maringá, Paraná, Brazil, and identify both obstacles and facilitating factors for the implementation of humanized care, based on women's perception of the care received. This was an exploratory and descriptive study with a cross-sectional design, analyzing hospital patient charts and interviews with 569 women who gave birth at the two hospitals from March 2005 to February 2006. Hospital care was characterized on the basis of WHO quality-of-care guidelines for labor and delivery. The data pointed to a healthcare model marked by the hygienist legacy in physician-centered hospital protocols and professional practices. Institutional factors, identified as difficulties in institutional and infrastructure organization, hospital protocols, and health professionals' individual practices and stances, denote barriers that jointly hinder the implementation of a humanized model for childbirth care.


Regulatory Compliance of Health Warnings on Tobacco Packs in Karnataka, India.
In September 2014, the Government of India introduced legislation requiring all tobacco packaging to display a health warning covering 85% (60% pictorial, 25% text) of the principal display area of the pack, of at least 4 cm in height and 3.5 cm width, with legible text in a white font on a black background and in English and/or the same Indian language as the language used on the pack. We evaluated compliance with this legislation in the Udupi district of Karnataka, India. We procured one example of every tobacco pack of cigarettes, beedis, chewing tobacco, and snuff sold by a convenience sample of retailers in one urban and two rural areas in each of the five administrative blocks of the Udupi district between June and August 2018. For each pack we measured the size of the health warning, calculated the proportion of the pack covered, and assessed the legibility. A total of 365 packs were collected from retailers, with 357 of these branded and eight, all packs of snuff, unbranded. Warnings on 320 (87.3%) packs did not reach the legally required proportional magnitude, warnings on 140 (38.4%) packs were not legible, and warnings on 117 packs (32.1%) did not meet the language requirement. Only 45 packs (12.3%) were fully compliant. Compliance with warning legislation in this district of India is low, highlighting the need for more effective enforcement. Warnings on tobacco packaging are an important and inexpensive means of communicating the harms associated with tobacco use. However, relatively few studies have explored regulatory compliance with warnings. We collected all unique tobacco packs from 66 retailers in a district in Karnataka in India and assessed whether each met the legislative requirements in terms of warning size and proportion of the pack covered, legibility, and the language used. Of the 365 packs collected, only one in eight was compliant with the legislative requirements. This study highlights the importance of assessing warning compliance and the need for enforcement in India.


Novel small GTPase subfamily capable of associating with tubulin is required for chromosome segregation.
The small GTPase superfamily, which includes the Ras, Rho/Rac, Rab, Arf and Ran subfamilies, serves as a signal transducer to regulate cell proliferation and differentiation, actin cytoskeleton, membrane trafficking, and nuclear transport. Here, we identify novel GTPases (human Gie1 and Gie2) that form a distinct subfamily of the small GTPases in terms of their sequences and intracellular function. Gie stands for 'novel GTPase indispensable for equal segregation of chromosomes', and this subfamily is conserved in multicellular organisms. Expression of dominant-negative Gie mutants in mammalian cells or knockdown of Gie transcripts using RNA interference in Drosophila S2 cells induced abnormal morphology in the chromosome segregation. Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis. Furthermore, overexpression of Gie mutants that lack putative effector domains but have tubulin-binding ability induced micronucleus formation. Thus, this is the first report showing that a small GTPase subfamily capable of associating with microtubules might be involved in chromosome segregation.


The change of beta-adrenergic system in lead-induced hypertension.
Lead exposure is considered to be a risk factor of cardiovascular disease. To investigate the relationship between lead and cardiovascular disease/hypertension in lead exposure, beta-adrenergic system is explored in this study. We address three topics in this study: (a) the relationship between beta-adrenergic receptor and lead level in heart, aorta, and kidney of lead-exposed rats; (b) the relationship between beta-adrenergic receptor in heart, aorta, kidney, and blood pressure in lead-exposed rats; and (c) the change of cyclic AMP level in heart, aorta, and kidney of rats with different lead levels. Wistar rats were chronically fed with 2, 1, 0. 5, 0.1, 0.05, and 0.01% lead acetate and water for 2 months. Plasma catecholamine level was measured by high-performance liquid chromatography. Radioligand binding assay was measured by a method that fulfilled strict criteria of beta-adrenoceptor using the ligand [(125)I]iodocyanopindolol. Cyclic AMP (cAMP) level was determined by radioimmunoassay. The levels of lead were determined by electrothermal atomic absorption spectrometry. The results showed that increased plasma norepinephrine level, decreased aorta beta-adrenergic receptor and cAMP, and increased kidney beta-adrenergic receptor and cAMP contributed to the elevation of blood pressure in lead-induced hypertension. The decrement of beta-adrenoceptor and cAMP in heart resulted in decreased contractility in heart.


Clinical Significance of Carbapenem-Tolerant Pseudomonas aeruginosa Isolated in the Respiratory Tract.
We often come across difficult to treat infections-even after administering appropriate antibiotics according to the minimal inhibitory concentration of the causative bacteria. Antibiotic tolerance has recently started to garner attention as a crucial mechanism of refractory infections. However, few studies have reported the correlation between clinical outcomes and antibiotic tolerance. This study aims to clarify the effect of antibiotic tolerance on clinical outcomes of respiratory tract infection caused by Pseudomonas aeuginosa (P. aeruginosa). We examined a total of 63 strains isolated from sputum samples of different patients and conducted a retrospective survey with the medical records of 37 patients with imipenem-sensitive P. aeruginosa infections. Among them, we selected 15 patients with respiratory infections, and they were divided into high-tolerance minimal bactericidal concentration for adherent bacteria (MBCAD)/minimal inhibitory concentration for adherent bacteria (MICAD) ≥ 32 (n = 9) group and low-tolerance MBCAD/MICAD ≤ 16 (n = 6) group for further investigations. The findings indicated that the high-tolerance group consisted of many cases requiring hospitalization. Chest computed tomography findings showed that the disease was more extensive in the high-tolerance group compared to the low-tolerance group. Regarding the bacterial phenotypic characterization, the high-tolerance group significantly upregulated the production of the virulence factors compared to the low-tolerance group. Our study provided evidence that carbapenem tolerance level is a potent prognostic marker of P. aeruginosa infections, and carbapenem tolerance could be a potential target for new antimicrobial agents to inhibit the progression of persistent P. aeruginosa infections.


A comparative review of the adverse effects of calcium antagonists.
A large number of drugs within the 3 currently classes of calcium antagonists are in common medical use for the treatment of hypertension and ischaemic heart disease. The reported adverse effect profile for each of these drugs varies, but tends to hold true to drug class and are typified by the adverse reactions reported for nifedipine and amlodipine (dihydropyridines), diltiazem (benzothiazepines) and verapamil (phenylalkylamines). Minor adverse effects such as flushing, headache, ankle oedema, palpitations and constipation are not uncommon and frequently require the cessation of treatment. Of greater concern affecting the wide and common first-line use of calcium antagonists is the as-yet unresolved issue of a reportedly greater risk of myocardial infarction and death following the use of short-acting nifedipine in patients with a history of hypertension, myocardial infarction or angina. Until this issue is fully resolved, it would seem prudent to limit the use of this agent in 'at-risk' patients and to await the results of further prospective studies before a final conclusion can be made.


Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness.
Despite the availability of published data on 4 pandemics that have occurred over the past 120 years, there is little modern information on the causes of death associated with influenza pandemics. We examined relevant information from the most recent influenza pandemic that occurred during the era prior to the use of antibiotics, the 1918-1919 "Spanish flu" pandemic. We examined lung tissue sections obtained during 58 autopsies and reviewed pathologic and bacteriologic data from 109 published autopsy series that described 8398 individual autopsy investigations. The postmortem samples we examined from people who died of influenza during 1918-1919 uniformly exhibited severe changes indicative of bacterial pneumonia. Bacteriologic and histopathologic results from published autopsy series clearly and consistently implicated secondary bacterial pneumonia caused by common upper respiratory-tract bacteria in most influenza fatalities. The majority of deaths in the 1918-1919 influenza pandemic likely resulted directly from secondary bacterial pneumonia caused by common upper respiratory-tract bacteria. Less substantial data from the subsequent 1957 and 1968 pandemics are consistent with these findings. If severe pandemic influenza is largely a problem of viral-bacterial copathogenesis, pandemic planning needs to go beyond addressing the viral cause alone (e.g., influenza vaccines and antiviral drugs). Prevention, diagnosis, prophylaxis, and treatment of secondary bacterial pneumonia, as well as stockpiling of antibiotics and bacterial vaccines, should also be high priorities for pandemic planning.


A model of L-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function.
L-DOPA-induced dyskinesia is a major complication of L-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. In this study, we have addressed the possibility to model L-DOPA-induced dyskinesia in the mouse at both the behavioral and the molecular level. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) either in the medial forebrain bundle (MFB) or in the sensorimotor part of the striatum. Both types of lesion produced a similar degree of forelimb akinesia on the contralateral side of the body. The lowest dose of L-DOPA that could significantly relieve this akinetic deficit (i.e., 6 mg/kg) did not differ between MFB and intrastriatal lesions. The L-DOPA threshold dose for the induction of dyskinesia did however differ between the two lesion types. A daily dose of 6 mg/kg L-DOPA caused MFB lesioned mice to develop abnormal movements affecting orofacial, trunk, and forelimb muscles on the side contralateral to the lesion, whereas a daily dose of 18 mg/kg was required to produce comparable dyskinetic effects in the intrastriatally lesioned animals. The development of abnormal movements was accompanied by a striatal induction of DeltaFosB-like proteins and prodynorphin mRNA, that is, molecular markers that are associated with L-DOPA-induced dyskinesia in both rats and nonhuman primates. We conclude that 6-OHDA lesioned mice exhibit behavioral and cellular features of akinesia and L-DOPA-induced dyskinesia that are similar to those previously characterized in rats. The mouse model of L-DOPA-induced dyskinesia will provide a useful tool to study the molecular determinants of this movement disorder in transgenic mice strains.


Multivariate diallel analysis by factor analysis for establish mega-traits.
In plant breeding, the dialelic models univariate have aided the selection of parents for hybridization. Multivariate analyses allow combining and associating the multiple pieces of information of the genetic relationships between traits. Therefore, multivariate analyses might refine the discrimination and selection of the parents with greater potential to meet the goals of a plant breeding program. Here, we propose a method of multivariate analysis used for stablishing mega-traits (MTs) in diallel trials. The proposed model is applied in the evaluation of a multi-environment complete diallel trial with 90 F1's of simple maize hybrids. From a set of 14 traits, we demonstrated how establishing and interpreting MTs with agronomic implication. The diallel analyzes based on mega-traits present an important evolution in statistical procedures since the selection is based on several traits. We believe that the proposed method fills an important gap of plant breeding. In our example, three MTs were established. The first, formed by plant stature-related traits, the second by tassel size-related traits, and the third by grain yield-related traits. Individual and joint diallel analysis using the established MTs allowed identifying the best hybrid combinations for achieving F1's with lower plant stature, tassel size, and higher grain yield.


BETA-GALACTOSIDASE AND LACTOSE FERMENTATION IN THE IDENTIFICATION OF ENTEROBACTERIA INCLUDING SALMONELLAE.
One hundred and fourteen strains of non-lactose fermenters and 127 lactose fermenters on MacConkey's agar have been compared in the 5% and 1% lactose tests and in beta-galactosidase production, using ortho-nitro-phenyl-beta-D-galactopyranoside (O.N.P.G.) as a test substance. The superiority of the O.N.P.G. test in the number of positive results and its rapidity is shown. In general, late or non-lactose fermenting strains of genera, usually lactose-positive, yield a rapidly positive O.N.P.G. reaction. Forty-one wild strains of Salmonella, Proteus, Providencia, and Pseudomonas aeruginosa were found negative in all three tests. Of 1,075 stock strains of Salmonella examined in the O.N.P.G. test, all were negative except nine; four of these were lactose-positive strains. For practical purposes, Salmonella strains in Great Britain may be regarded as O.N.P.G. negative. Among 100 stock strains of Arizona there was considerable variation of behaviour in the O.N.P.G. test and in the 5% and 1% lactose tests. Most strains of Arizona can be considered to yield a positive O.N.P.G. test but a minority give a negative result. The test is recommended for routine use in the differentiation of Salmonella from other enterobacteria and for use in bacterial identification. The 5% lactose fermentation test in parallel is suggested when the O.N.P.G. test is used for isolating routine pathogens, because organisms such as Shigella sonnei, Shigella dysenteriae 1, and Pasteurella pseudotuberculosis are O.N.P.G. positive.


Effect of thymectomy on development of Lucké renal adenocarcinomas in virus-infected leopard frog tadpoles.
Thymectomy of very young leopard frog (Rana pipiens) larvae dramatically reduced in vitro lymphocyte responses to the nitrogen phytohemagglutinin-P and prolonged survival of Lucké tumor alloimplants. However, tumor incidence in premetamorphic or metamorphosing frogs that had received injections as embryos of Lucké tumor herpesvirus (LTHV) was the same in thymectomized and normal immunocompetent animals. This result suggests that T-cell-mediated cytotoxicity does not prevent development of Lucké tumors in immunocompetent larvae and that if tumor-specific transplantation antigens appear, they may induce tolerance rather than destructive immunity in normal LTHV-injected larvae.


Anxiety in rats selectively bred for Fast and Slow kindling rates: situation-specific outcomes.
Rats selectively bred for amygdala excitability, realized by fast or slow kindling epileptogenesis, were previously reported to exhibit differential levels of anxiety. Although the Slow kindling rats generally appeared more anxious in several behavioral tests, under certain test conditions the Fast kindling rats displayed greater anxiety or stressor reactivity. The present investigation confirmed that in a test of anxiety comprising suppression of consumption of a palatable snack in an unfamiliar environment, the Slow kindling rats exhibited greater anxiety and that this effect was attenuated by diazepam. Likewise, the acoustic startle response was greater in the Slow kindling rats. However, the fear-potentiated startle response was more pronounced in Fast kindling rats, particularly among females, irrespective of whether the test parameters elicited moderate or high startle amplitudes. The elevated startle in the Slow rats, and the fear potentiated startle in the Fast rats, were attenuated by diazepam. These data indicate the need to differentiate subtypes of anxiety in animal models, and raise the issue that anxiety elicited by specific environmental triggers may interact with genetically determined trait characteristics.


Health System Competency for Maternal Health Services in Balasore District and Jaleswar Block, Balasore, Odisha, India: An Assessment.
A competent health system is of paramount importance in delivering the desired health services in a particular community. The broad objective of this study was to assess the health system competency for the maternal health services in Balasore District and Jaleswar block of Balasore district, Odisha, India. A mixed method approach was adopted in order to understand the health system competency for maternal health services in the study area. There was poor accessibility through road, poor electricity connection and piped water for the health care centers in the district. Even, existing Primary Health Centres (PHCs) lack ECG and X-Ray machines for proper diagnostic services which jeopardize the catering of health services. Community Health Centres (CHC) lack basic diagnostic and ambulance services making the tribal pockets inaccessible. The tribal dominated Jaleswar block shows poor performance in terms of total registered Antenatal Checkups (ANC) (only 77%). A gradual decrease in the rate of ANC, from first to fourthcheckup, was observed in the district. Lack of public health infrastructure in general and non-compliance to Indian Public Health Standards (IPHS) in particular, affect the health of tribal women resulting in lack of interest in availing the institutional delivery services and other pertinent maternal health services.


Aortic dissection precedes formation of aneurysms and atherosclerosis in angiotensin II-infused, apolipoprotein E-deficient mice.
We sought to define the temporal characteristics of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) and to provide mechanistic insight into the development of this vascular pathology in apolipoprotein E-deficient (apoE-/-) mice. Male apoE-/- mice were infused with AngII for 1 to 56 days. Suprarenal arteries were sequentially sectioned, and cellular features were defined by histologic and immunocytochemical techniques. The initial identified event was medial accumulation of macrophages in regions of elastin degradation. Subsequent medial dissection was associated with luminal dilation and thrombus formation. Thrombi were usually constrained by adventitial tissue, although approximately 10% of mice died due to rupture. Thrombi led to profound inflammation that was characterized by infiltration of macrophages and T and B lymphocytes. Remodeling of the tissues was associated with regeneration of elastin fibers and reendothelialization of the dilated luminal surface. Aneurysmal tissue underwent profound neovascularization. Atherosclerotic lesions were only detected after development of the aneurysms. The initial event in AngII-induced AAA is a focal dissection in the suprarenal region. The progression of AAA precedes the development of overt atherosclerotic lesions.


[Osteochondritis dissecans of the knee].
Osteochondritis dissecans of the knee is diagnosed at an increasing rate among adolescents and young adults. One of the reasons is due to the increasing number of sports participants among these populations. Although many theories exist, the cause of osteochondritis dissecans is unknown. Early diagnosis is very important. While adult type osteochondritis dissecans is unstable, in most young patients it is stable, and patients with an intact articular surface have a good chance to heal with non-operative treatment and cessation of physical activity. The value of complementary treatment (bed rest, partial weight bearing, bracing aimed at reducing weight bearing of the involved knee) is unknown. Patients with open physes and stable lesions, who failed non-operative treatment, may be treated with local bone drilling, encouraging lesion healing. As the disease progresses, more aggressive measures should to be taken, whilst decreasing success ratios are expected. The healing potential of the lesion may be evaluated by magnetic resonance imaging. Most adult type osteochondritis dissecans patients, as most young patients, with unstable lesions and loose bodies within their knees, are treated with fixation of the lesions and even bone grafting. Many unstable lesions will heal after fixation, but the long-term prognosis is elusive. Chronic loose bodies are very difficult to fix, with less favorable outcomes. Excision of large lesions originating from weight bearing cartilage is not favorable and different rehabilitation measures of local cartilage damage are not encouraging.


Characterising Functional Venom Profiles of Anthozoans and Medusozoans within Their Ecological Context.
This review examines the current state of knowledge regarding toxins from anthozoans (sea anemones, coral, zoanthids, corallimorphs, sea pens and tube anemones). We provide an overview of venom from phylum Cnidaria and review the diversity of venom composition between the two major clades (Medusozoa and Anthozoa). We highlight that the functional and ecological context of venom has implications for the temporal and spatial expression of protein and peptide toxins within class Anthozoa. Understanding the nuances in the regulation of venom arsenals has been made possible by recent advances in analytical technologies that allow characterisation of the spatial distributions of toxins. Furthermore, anthozoans are unique in that ecological roles can be assigned using tissue expression data, thereby circumventing some of the challenges related to pharmacological screening.


Gastrointestinal transit survival of an Enterococcus faecium probiotic strain administered with or without vancomycin.
The primary aim of this study was to evaluate if an ingested probiotic, containing viable Enterococcus faecium could survive gastrointestinal transit and if so, correlate the amount of the recovered probiotic strain with the host's own enterococci. The second aim was to investigate if simultaneous vancomycin intake influenced the survival and persistence of the probiotic strain and the stability of endogenous enterococci strains. Twenty healthy volunteers were given the probiotic product once daily for 10 days. Half of the subjects were simultaneously given vancomycin. Isolates of E. faecium strains were genotypically or phenotypically analysed with pulsed-field gel electrophoresis (PFGE) and the PhenePlate system, respectively. In eight of the ten volunteers given only the probiotic, the ingested E. faecium could be detected on day 10, while in none on day 31. From subjects given both probiotic and vancomycin no ingested E. faecium could be detected on day 10 or day 31. The estimated amount of ingested E. faecium recovered from faeces on day 10 ranged from 1.2 x 10(3) to 4.2 x 10(6) colony forming units per gram faeces, which in several cases were a substantial part of the total amount of E. faecium. The E. faecium isolated before probiotic plus vancomycin administration showed no close relationship to the ones isolated 3 weeks after ceased intake in any subjects. In conclusion, the ingested E. faecium strain can survive gastrointestinal transit. After intake, the E. faecium probiotic strain might become a large part of the total E. faecium population. The occurrence of the probiotic strain in the human gut seems to be transient after intake stop. Re-colonization of E. faecium after simultaneous probiotic plus vancomycin intake occurs mainly with strains without close genetic relationship to the strains harboured before treatment or to the ingested E. faecium strain.


Review of hormonal treatment of breast cancer.
This critical review focuses on the role of steroid hormones and their receptors in the development and treatment of breast cancer, with special reference to estrogen receptors, as well as mechanisms of receptor-ligand interactions, response or resistance to hormonal therapy against breast cancer, in conjunction with other modalities like surgery and chemotherapy. Tamoxifen is used in hormonal treatment of breast cancer for up to five years, depending on the presentation. However, there have been recent developments in hormonal therapy of breast cancer in the last ten years, with the introduction of many different alternative therapies for this condition. A critical review of published articles in Pubmed/Medline, Athens, AJOL, NHS Evidence, Science Direct and Google, relating to hormonal treatment of breast cancer, was undertaken, in order to evaluate the mechanisms of estrogen receptor-ligand interactions, their involvement in the etio-pathogenesis of breast cancer, resistance of breast cancer cells to anti-hormonal agents, as well as ways of treating breast cancer using anti-hormone drugs like tamoxifen. Although tamoxifen is the established drug for hormonal treatment of breast cancer, cases of hormone resistance breast cancer have been described recently in the literature. This can happen from the beginning, or during treatment. Therefore, we aim to examine the causes of resistance to hormonal treatment with a view to understand the options of tackling this problem, and suggest other novel alternative hormonal therapies that can be tried, which may overtake tamoxifen in the future. We also seek to emphasize that hormonal therapy has a definite place in the treatment of breast cancer along with surgery, chemotherapy and radiotherapy, as the disease is often considered to be multi-systemic even from the beginning.


The effects of the organophosphorous insecticides Dursban and Lorsban on the ciliated epithelium of the frog palate in vitro.
The ciliotoxic potential of the organophosphorous insecticides Dursban and Lorsban, their active ingredient, chlorpyrifos, and their carrier ingredients (Blanks) were assessed. Since chlorpyrifos inhibits acetylcholinesterase, the acetylcholine-innervated ciliated epithelial cultures of frog palate were used as the model. All compounds caused a decrease in frequency of ciliary beat overtime. EC50 values followed the same order as the time to inhibition. The orders were Lorsban > Dursban > chlorpyrifos, and Lorsban > Dursban approximately Lorsban Blank > Dursban Blank. Stimulation of ciliary beating occurred immediately after exposure to all compounds, followed by inhibition. Dursban, Lorsban, and both Blanks elicited stimulatory effects in the presence of atropine. Atropine only blocked the initial stimulatory response with chlorpyrifos. In addition to chlorpyrifos, some component(s) of the inert ingredients were initially stimulatory but ultimately inhibitory to ciliary beating in the frog palate model. All compounds caused mitochondrial damage, including swelling, disruption of cristae, and loss of matrix.


Neurohumoral mechanisms associated with orthostasis: reaffirmation of the significant contribution of the heart rate response.
The inability to compensate for acute central hypovolemia underlies the clinical development of orthostatic hypotension and instability (e.g., syncope). Although neuro-humoral control of both cardiac output and peripheral vascular resistance contributes to hemodynamic stability during orthostasis, a notion has been proposed that the failure of adequate peripheral vascular constriction rather than cardiac responses represents the primary mechanism underlying the development of orthostatic intolerance. This review article provides an opportunity to present compelling evidence captured over the past 30 years in our laboratory to support the concept that neural-mediated tachycardia during orthostasis in healthy individuals represents a critical response to tolerating acute reduction in central blood volume in addition to, and independent of, peripheral vascular constriction. In this review paper, data are presented from experiments using graded lower body negative pressure (LBNP) as a method to induce orthostatic intolerance in two experimental human models: (1) comparison of heart rate and autonomic responses in individuals with relatively high and low tolerance to LBNP; and (2) vagal and sympathetic blockade of cardiac neural control. These experiments revealed that: (1) greater elevations in heart rate are associated with higher orthostatic (LBNP) tolerance; (2) higher orthostatic heart rate is associated with greater sympathetic nerve activity and withdrawal of vagally-mediated cardiac baroreflex response; and (3) non-specific sympathetic blockade causes a pronounced reduction in heart rate and LBNP tolerance. Cardiac parasympathetic withdrawal contributes to protection against development of hypotension during the initial seconds of transition to an orthostatic challenge, while the primary mechanism by which tachycardia defends orthostatic stability in healthy subjects for extended durations is mediated predominantly through sympathetic adrenergic control.


Stem cell-bearing suture improves Achilles tendon healing in a rat model.
Tendon healing is a slow and complicated process that results in inferior structural and functional properties when compared to healthy tendon tissue. It may be possible to improve outcomes of tendon healing with enhancement of biological aspects of the repair including tissue structure, organization, and composition. The purpose of this study was to determine whether use of a stem cell-bearing suture improves Achilles tendon healing in a rat model. The Achilles tendon was transected in 108 bilateral hind limbs from 54 rats. Each limb was randomized to repair with suture only (SO), suture plus injection (SI) of mesenchymal stem cells (MSCs) at the repair site, or suture loaded with MSCs (suture with stem cells, SCS). One half of the animals were randomly sacrificed at 14 and 28 days after surgery and the Achilles tendon was harvested. From each repair group at each time point, 12 limbs were randomized to biomechanical testing and 6 to histologic analysis. Tendons were loaded using a 223-N load cell at 0.17 mm/s. A blinded pathologist scored the histology sections. Ultimate failure strength (N/mm(2)) was significantly higher in the SI and SCS groups versus the SO group. In the SI group, ultimate failure strength decreased significantly at 28 days versus 14 days. Histology score in the SCS group was significantly lower (better) than in both other groups (P ≤ .001). Histology findings at day 28 were significantly higher versus day 14 for all groups (P = .01). Both the SI and the SCS groups had significantly higher ultimate failure strength versus the SO group, and strength was maintained at 28 days in the SCS group but not in the SI group. Histology in the SCS group was significantly better than in both other groups. These findings in a rat model suggest that the use of stem cells enhances healing after Achilles repair and that embedding of stem cells directly into suture offers sustained early benefit to tendon healing.


Diagnostic Yield and Outcomes of Computed Tomography of the Head in Critically Ill Nontrauma Patients.
Computed tomography of the head (HCT) is a widely used diagnostic tool, especially for emergency and trauma patients. However, the diagnostic yield and outcomes of HCT for patients on medical intensive care units (MICUs) are largely unknown. We retrospectively evaluated all head CTs from patients admitted to a single-center MICU during a 5-year period for CT indications, diagnostic yield, and therapeutic consequences. Uni- and multivariate analyses for the evaluation of risk factors for positive head CT were conducted. Six hundred ninety (18.8%) of all patients during a 5-year period underwent HCT; 78.7% had negative CT results, while 21.3% of all patients had at least 1 new pathological finding. The main indication for acquiring CT scan of the head was an altered mental state (AMS) in 23.5%, followed by a new focal neurology in 20.7% and an inadequate wake up after stopping sedation in 14.9% of all patients. The most common new finding was intracerebral bleeding in 6.4%. In 6.7%, the CT scan itself led to a change of therapy of any kind. Admission after resuscitation or a new focal neurology were independent predictors of a positive CT. Psychic alteration and AMS were both independent predictors of a higher chance of a negative head CT. Positive HCT during MICU is an independent predictor of lower survival. New onset of focal neurologic deficit seems to be a good predictor for a positive CT, while AMS and psychic alterations seem to be very poor predictors. A positive head CT is an independent predictor of death for MICU patients.


Assessing network-based methods in the context of system toxicology.
Introduction: Network-based methods are promising approaches in systems toxicology because they can be used to predict the effects of drugs and chemicals on health, to elucidate the mode of action of compounds, and to identify biomarkers of toxicity. Over the years, the network biology community has developed a wide range of methods, and users are faced with the task of choosing the most appropriate method for their own application. Furthermore, the advantages and limitations of each method are difficult to determine without a proper standard and comparative evaluation of their performance. This study aims to evaluate different network-based methods that can be used to gain biological insight into the mechanisms of drug toxicity, using valproic acid (VPA)-induced liver steatosis as a benchmark. Methods: We provide a comprehensive analysis of the results produced by each method and highlight the fact that the experimental design (how the method is applied) is relevant in addition to the method specifications. We also contribute with a systematic methodology to analyse the results of the methods individually and in a comparative manner. Results: Our results show that the evaluated tools differ in their performance against the benchmark and in their ability to provide novel insights into the mechanism of adverse effects of the drug. We also suggest that aggregation of the results provided by different methods provides a more confident set of candidate genes and processes to further the knowledge of the drug's mechanism of action. Discussion: By providing a detailed and systematic analysis of the results of different network-based tools, we aim to assist users in making informed decisions about the most appropriate method for systems toxicology applications.


BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer.
The BRCA/Fanconi anemia (FA) pathway plays a key role in the repair of DNA double strand breaks. We focused on this pathway to clarify chemoresistance mechanisms in biliary tract cancer (BTC). We also investigated changes in the CD24(+)/44(+) population that may be involved in chemoresistance, as this population likely includes cancer stem cells. We used three BTC cell lines to establish gemcitabine (GEM)-resistant (GR) cells and evaluated the expression of BRCA/FA pathway components, chemoresistance, and the effect of BRCA/FA pathway inhibition on the CD24(+)/44(+) population. FANCD2 and CD24 expression were evaluated in 108 resected BTC specimens. GR cells highly expressed the BRCA/FA components. The BRCA/FA pathway was upregulated by GEM and cisplatin (CDDP) exposure. Inhibition using siRNA and RAD51 inhibitor sensitized GR cells to GEM or CDDP. The CD24(+)/44(+) population was increased in GR and parent BTC cells treated with GEM or CDDP and highly expressed BRCA/FA genes. FANCD2 was related to CD24 expression in resected BTC specimens. Inhibition of the BRCA/FA pathway under GEM reduced the CD24(+)/44(+) population in MzChA1-GR cells. Thus, high expression of the BRCA/FA pathway is one mechanism of chemoresistance against GEM and/or CDDP and is related to the CD24(+)/44(+) population in BTC.


Effect of sodium heparin and antithrombin III concentration on activated partial thromboplastin time in the dog.
Regulation of blood coagulation was studied in 12 dogs, using subcutaneous administration of sodium heparin. Dosage of heparin needed to achieve the desired 1.5- to 2.5-fold increase in the activated partial thromboplastin time (APTT) was 250 to 500 IU/kg of body weight. Increased APTT lasted less than 6 hours. Repeated heparin administration, using the lowest dosage (250 IU/kg) every 6 hours, induced an unacceptable prolongation of clotting times during the first 2 days of treatment. Prolonged administration at a dosage of 200 IU/kg every 6 hours adequately maintained the desired hypocoagulative state initially; after 2 days, however, the prolonged APTT steadily decreased. The decreasing effect was proportionate to a decrease in plasma antithrombin III (AT III). To sustain a correctly balanced hypocoagulative state from prolonged subcutaneous administration of heparin, APTT values should be determined regularly to monitor therapy. In addition, transfusion of AT III-rich donor plasma may be necessary when low plasma AT III reduces the effects of heparin.


Theranostic self-assembly structure of gold nanoparticles for NIR photothermal therapy and X-Ray computed tomography imaging.
The controllable self-assembly of amphiphilic mixed polymers grafted gold nanoparitcles (AuNPs) leads to strong interparticle plasmonic coupling, which can be tuned to the near-infrared (NIR) region for enhanced photothermal therapy (PTT). In this study, an improved thiolation method was adopted for ATRP and ROP polymer to obtain amphiphilic brushes of PMEO2MA-SH and PCL-SH. By anchoring PCL-SH and PMEO2MA-SH onto the 14 nm AuNPs, a smart hybrid building block for self-assembly was obtained. Increasing the PCL/PMEO2MA chain ratio from 0.8:1, 2:1 and 3:1 to 7:1, the structure of gold assemblies (GAs) was observed to transfer from vesicle to large compound micelle (LCM). Contributed to the special dense packed structure of gold nanoparticles in LCM, the absorption spectrometry of gold nanoparticles drastically red-shifted from 520 nm to 830 nm, which endowed the GAs remarkable NIR photothermal conversion ability. In addition, gold has high X-ray absorption coefficient which qualifies gold nanomaterial a potential CT contrast agent Herein, we obtain a novel gold assembly structure which can be utilized as potential photothermal therapeutic and CT contrast agents. In vitro and In vivo studies testified the excellent treatment efficacy of optimum GAs as a PTT and CT contrast agent. In vitro degradation test, MTT assay and histology study indicated that GAs was a safe, low toxic reagent with good biodegradability. Therefore, the optimum GAs with strong NIR absorption and high X-ray absorption coefficient could be used as a theranostic agent and the formation of novel gold large compound micelle might offers a new theory foundation for engineering design and synthesis of polymer grafted AuNPs for biomedical applications.


Periodontal surgical management of impacted maxillary cuspids.
The diagnosis and surgical management of impacted maxillary cuspids has been discussed. The general practitioner must be aware of the normal and abnormal pathways as well as the correct age of eruption of the maxillary cuspid. The proper management of impacted maxillary canine teeth requires the careful cooperation and communication between the general practitioner, the orthodontist and the periodontist or oral surgeon.


Vanilloid receptors in hearing: altered cochlear sensitivity by vanilloids and expression of TRPV1 in the organ of corti.
Capsaicin, the vanilloid that selectively activates vanilloid receptors (VRs) on sensory neurons for noxious perception, has been reported to increase cochlear blood flow (CBF). VR-related receptors have also been found in the inner ear. This study aims to address the question as to whether VRs exist in the organ of Corti and play a role in cochlear physiology. Capsaicin or the more potent VR agonist, resiniferatoxin (RTX), was infused into the scala tympani of guinea pig cochlea, and their effects on cochlear sensitivity were investigated. Capsaicin (20 microM) elevated the threshold of auditory nerve compound action potential and reduced the magnitude of cochlear microphonic and electrically evoked otoacoustic emissions. These effects were reversible and could be blocked by a competitive antagonist, capsazepine. Application of 2 microM RTX resulted in cochlear sensitivity alterations similar to that by capsaicin, which could also be blocked by capsazepine. A desensitization phenomenon was observed in the case of prolonged perfusion with either capsaicin or RTX. Brief increase of CBF by capsaicin was confirmed, and the endocochlear potential was not decreased. Basilar membrane velocity (BM) growth functions near the best frequency and BM tuning were altered by capsaicin. Immunohistochemistry study revealed the presence of vanilloid receptor type 1 of the transient receptor potential channel family in the hair cells and supporting cells of the organ of Corti and the spiral ganglion cells of the cochlea. The results indicate that the main action of capsaicin is on outer hair cells and suggest that VRs in the cochlea play a role in cochlear homeostasis.


Pre-transplant sTIM-3 levels may have a predictive impact on transplant outcome in acute leukemia patients.
Objectives: T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) is considered as a negative regulator of T-cell driven immune response. This study is planned to investigate the prognostic role of pre-transplant soluble TIM-3 (sTIM-3) levels in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods: Pre-transplant serum sTIM-3 levels were measured in 177 allo-HSCT recipients [median age: 36(16-66) years; male/female: 111/66]. Results: Pre-transplant sTIM-3 levels were significantly higher in acute myeloid leukemia (AML) patients compared to acute lymphoblastic leukemia (ALL) patients (p = 0.01). Pre-transplant sTIM-3 levels were significantly lower in patients with abnormal cytogenetics (p = 0.017). Pre-transplant sTIM-3 levels were significantly higher in patients who developed viral hemorrhagic cystitis (p = 0.034). A positive correlation was demonstrated between sTIM-3 levels and acute graft versus host disease (GvHD) grade (p = 0.013; r = 0.299). Overall survival (OS) was not statistically different between low- and high-TIM-3 groups (%35.2 vs %20.4; p > 0.05). Primary diagnosis (p = 0.042), sinusoidal obstruction syndrome (p < 0.001), acute GvHD (p = 0.001), chronic GvHD (p = 0.009) and post-transplant relapse (p = 0.003) represented significant impact on OS. Discussion: Increased sTIM-3 levels in AML patients seem to be compatible with the previous reports. The inhibitor role of TIM-3 in cellular immune response may be a possible explanation for the association of sTIM-3 with viral infections and GvHD. However, the main challenge remains to be the ambiguous association of pre-transplant sTIM-3 levels and post-transplant complications, as allo-HSCT recipients are expected to represent donor genetic features in the post-transplant setting. Conclusion: Further studies are warranted to clarify the particular role of sTIM-3 in the allo-HSCT setting.


[Ursolic acid inhibits corneal graft rejection following orthotopic allograft transplantation in rats].
To investigate the effects of ursolic acid on corneal graft rejection in a rat model of othotopic corneal allograft transplantation. Forty-eight recipient Wistar rats were divided into normal control group with saline treatment (group A), autograft group with saline treatment (group B), SD rat allograft group with saline treatment (group C), and SD rat allograft group with intraperitoneal ursolic acid (UA) treatment group (group D). The rats received saline or UC (20 mg·kg(-1)·d(-1)) treatment for 12 days following othotopic graft transplantation. The grafts were evaluated using the Larkin corneal rejection rating system, and the graft survival was assessed with Kaplan-Meier analysis. On day 14, the grafts were harvested for histological examination, Western blotting, and assessment of expressions of interlukin-2 (IL-2), interferon-γ (IFN-γ), nuclear transcription factor-κB (NF-κB) p65, vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1). The allograft survival was significantly longer in group D than in group C (29.12±9.58 vs 9.67±2.16 days, P<0.05). UC treatment obviously reduced the expression levels of IL-2, IFN-γ, NF-κBp65, ICAM-1 and VEGF and increased inhibitory kappa B alpha (IκB-α) expression in the grafts, where no obvious inflammatory cell infiltration or corneal neovascularization was found. As a NF-κB inhibitor, ursolic acid can prevent corneal neovascularization and corneal allograft rejection to promote graft survival in rats following orthotopic corneal allograft transplantation.


Incidence of age-related cataract: the Beaver Dam Eye Study.
To estimate the incidence of nuclear, cortical, and posterior subcapsular cataract in the Beaver Dam Eye Study cohort. A population-based study of the prevalence of age-related eye diseases was conducted between 1988 and 1990 (n=4926), and a follow-up study was conducted between 1993 and 1995 (n=3684). The evaluations included photographic documentation of the lens. Slitlamp photographs were taken to assess nuclear opacity, and retroillumination photographs were taken to assess cortical and posterior subcapsular cataract. The grading of photographs was done in a masked manner by trained graders using the same protocols for baseline and follow-up photographs. The graders were the same for both evaluations. Persons aged 43 to 86 years who were identified through a private census conducted from 1987 to 1988 of the population of Beaver Dam, Wis, were invited for a baseline examination held between 1988-1990 and again for a follow-up examination held between 1993-1995. Incident nuclear cataract occurred in 13.1%, cortical cataract in 8.0%, and posterior subcapsular cataract in 3.4% of right eyes. The cumulative incidence of nuclear cataract in right eyes increased from 2.9% in persons aged 43 to 54 years at baseline to 40.0% in those aged 75 years or older. For cortical and posterior subcapsular cataract, the corresponding values were 1.9% and 21.8% and 1.4% and 7.3%, respectively. Women were more likely than men to have nuclear cataract even after adjusting for age. Incident cataracts are common age-related problems, and incidence increases with increasing age at baseline. These data will help in planning for future care (eg, cataract surgery and change in spectacle correction) and in investigating the importance of risk factors.


Meningitis due to an unusual type of Haemophilus influenzae.
An infant was admitted to hospital with suspected meningitis. Haemophilus influenzae type 'a' was isolated from cerebrospinal fluid (C.S.F.) and blood. Haemophilus meningitis due to types other than type 'b' is rare, and only a few due to type 'a' have so far been recorded. Investigations of the family are included together with a discussion of the implications for the diagnostic bacteriologist.


Sleep-wake states in transgenic mouse models overexpressing the human beta-amyloid precursor protein.
Studies testing the amyloid hypothesis and recent advances in mouse molecular genetic technologies have played a critical role in improving our understanding of Alzheimer's disease (AD). Mouse models of AD currently available show only some of the characteristic neuropathology in human AD. Studies have demonstrated, however, that these models are excellent tools for characterizing different aspects of the molecular pathology of AD and the neurobiological basis for the clinical heterogeneity in AD. The present discussion focuses on behavioral and physiological data obtained in transgenic (Tg) mice overexpressing the mutant human beta-amyloid precursor protein (hbetaAPP). This mouse model exhibits memory and neurophysiological deficits at ages preceding amyloid-beta-peptide (Abeta) plaque formation that worsened with age and Abeta plaque formation. In spite of these findings, very little emphasis has been placed on characterizing the neurobiological basis of the diverse neuropsychiatric symptoms that are also observed in AD, including sleep disturbances. Taking into consideration the relationship between memory processes and sleep, the use of animal models of AD as a preclinical bioassay has the potential to characterize the neural substrates mediating clinical manifestations of AD, such as sleep-wake states, and contribute to the development of treatments for early stages of AD.


Within-treatment changes in a novel addiction treatment program using traditional Amazonian medicine.
The therapeutic use of psychedelics is regaining scientific momentum, but similarly psychoactive ethnobotanical substances have a long history of medical (and other) uses in indigenous contexts. Here we aimed to evaluate patient outcomes in a residential addiction treatment center that employs a novel combination of Western and traditional Amazonian methods. The study was observational, with repeated measures applied throughout treatment. All tests were administered in the center, which is located in Tarapoto, Peru. Data were collected between 2014 and 2015, and the study sample consisted of 36 male inpatients who were motivated to seek treatment and who entered into treatment voluntarily. Around 58% of the sample was from South America, 28% from Europe, and the remaining 14% from North America. We primarily employed repeated measures on a psychological test battery administered throughout treatment, measuring perceived stress, craving frequency, mental illness symptoms, spiritual well-being, and physical and emotional health. Addiction severity was measured on intake, and neuropsychological performance was assessed in a subsample from intake to at least 2 months into treatment. Statistically significant and clinically positive changes were found across all repeated measures. These changes appeared early in the treatment and were maintained over time. Significant improvements were also found for neuropsychological functioning. These results provide evidence for treatment safety in a highly novel addiction treatment setting, while also suggesting positive therapeutic effects.


Modern metal-on-metal hip implants.
This Technology Overview was prepared using systematic review methodology and summarizes the findings of studies published as of July 15, 2011, on modern metal-on-metal hip implants. Analyses conducted on outcomes by two joint registries indicate that patients who receive metal-on-metal total hip arthroplasty (THA) and hip resurfacing are at greater risk for revision than are patients who receive THA using a different bearing surface combination. Data from these registries also indicate that larger femoral head components have higher revision rates and risk of revision and that older age is associated with increased revision risks of large-head metal-on-metal THA. Several studies noted a correlation between suboptimal hip implant positioning and higher wear rates, local metal debris release, and consequent local tissue reactions to metal debris. In addition, several studies reported elevated serum metal ion concentrations in patients with metal-on-metal hip articulations, although the clinical significance of these elevated ion concentrations remains unknown.


Client feedback in psychological therapy for children and adolescents with mental health problems.
Childhood and adolescent mental health problems are a serious and growing concern worldwide. Research suggests that psychotherapy can have a significant and positive impact on children and adolescents with mental health problems, such as anxiety disorders, depression and conduct disorders. Client feedback tools serve as a method of monitoring clients' progress and providing feedback from clients to therapists during the therapeutic process. These tools may help to enhance clinicians' decision-making by allowing them to adapt their treatment plans as the therapy progresses, resulting in a reduction of treatment failures. Research has shown that client feedback tools have a positive effect on adults' psychotherapy. This review addresses whether feedback tools in child and adolescent therapy could help therapists to better treat their young clients. To assess the effects of client feedback in psychological therapy on child and adolescent mental health outcomes. We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR, Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (1946-), Embase (1974-) and PsycINFO (1967-) to 3 April 2018. We did not apply any restriction on date, language or publication status to the search. We included randomised controlled trials (RCTs) that compared client feedback to no client feedback in psychological therapies for children and adolescents. Two review authors independently assessed references for inclusion eligibility and extracted outcome, risk of bias and study characteristics data into customised forms. We contacted study authors to obtain missing data. We analysed dichotomous data using risk ratios (RRs) and calculated their 95% confidence intervals (CIs). For continuous data, we calculated mean differences (MDs), or standardised mean differences (SMDs) if different scales were used to measure the same outcome. We used a random-effects model for all analyses. We included six published RCTs, conducted in the USA (5 RCTs) and Israel (1 RCT), with 1097 children and adolescents (11 to 18 years old), in the review.We are very uncertain about the effect of client feedback on improvement of symptoms, as reported by youth in the short term because we considered evidence to be of very low-certainty due to high risk of bias and very serious inconsistency in the effect estimates from the different studies. Similarly, we are very uncertain about the effect of client feedback on treatment acceptability, due to high risk of bias, imprecision in the results, and indirectness of measuring the outcome (RR 1.08, 95% CI 0.73 to 1.61; 2 studies, 237 participants; very low-certainty).Overall, most studies reported and carried out randomisation and allocation concealment adequately. None of the studies were blinded or attempted to blind participants and personnel and were at high risk of performance bias, and only one study had blind outcome assessors. All of the studies were at high or unclear risk of attrition bias mainly due to poor, non-transparent reporting of participants' flow through the studies. Due to the paucity of high-quality data and considerable inconsistency in results from different studies, there is currently insufficient evidence to reach any firm conclusions regarding the role of client feedback in psychological therapies for children and adolescents with mental health problems, and further research on this important topic is needed.Future studies should avoid risks of performance, detection and attrition biases, as seen in the studies included in this review. Studies from countries other than the USA are needed, as well as studies including children younger than 10 years.


Interfacial nanoarchitectonics of nickel phosphide supported on activated carbon for transfer hydrogenation of nitroarenes under mild conditions.
Metal phosphides are promising catalysts for hydrogenation reactions due to their unique ability to generate active hydrogen species which are essential for desired reactions. In this work, the hydrogenation potential of nickel phosphide (Ni2P) is explored for the transfer hydrogenation of aromatic nitro compounds using hydrazine hydrate as hydrogen source. The Ni2P was supported on activated carbon (AC) to facilitate highly exposed active reaction sites. The as-synthesized Ni2P-AC catalyst showed excellent catalytic potential for the hydrogenation of nitro compounds to corresponding amines with 100% conversion efficiency and resulted in excellent yields. The reaction conditions were optimized by varying different reaction parameters, such as time, temperature, solvents, catalyst amount and hydrogen sources. The developed reaction protocol is highly selective for nitro compounds having reduction susceptible functional groups like -Cl, -Br, -CHO, etc. The structure-activity relationship of the Ni2P-AC was also examined which suggested that both acidic and basic sites present in Ni2P-AC catalyst plays crucial role in hydrogenation reaction. Besides, an in-depth insight into the reaction mechanism illustrates that the reaction proceeds via N-phenyl hydroxylamine as the reaction intermediate. In addition, decent recyclability and stability of Ni2P-AC catalyst demonstrates its highly versatile nature for potential large-scale applications. The use of highly efficient Ni2P-AC catalyst for hydrogenation reactions can lead the way towards sustainable and effective industrial organic catalysis.


Use of synthetic antigens improves detection by enzyme-linked immunosorbent assay of antibodies against abortigenic Chlamydia psittaci in ruminants.
Synthetic peptide antigens were prepared for use in enzyme-linked immunosorbent assays (ELISAs) to detect serum antibodies against abortigenic strains of Chlamydia psittaci in livestock. Peptide antigens were identified with C. psittaci B577-immune sera by solid-phase scanning of overlapping octapeptides of variable domains (VDs) of the major outer membrane protein of C. psittaci serovar 1 (omp1 type C. psittaci B577). Two VD 4 regions and one VD 2 region were strongly reactive with all C. psittaci B577 antisera. Peptides encompassing these regions were synthesized with biotin and a serine-glycine-serine-glycine spacer at the N terminus and were attached to streptavidin-coated microtiter plates. In direct ELISAs with these plates, the synthetic peptides reacted with C. psittaci B577 antisera, but not with sera from specific-pathogen-free animals. Serum specimens from 40 sheep and 40 cattle, obtained from herds with abortion problems, were screened for antibodies by these C. psittaci B577 peptide ELISAs and an ELISA with recombinant, genus-specific Chlamydia lipopolysaccharide (LPS) antigen. Results from these newly developed ELISAs were compared to those from the reference C. psittaci B577 elementary body (EB) ELISA and the Chlamydia complement fixation test (CFT). The C. psittaci B577 peptide ELISAs, the LPS ELISA, and the EB ELISA correctly identified the presence or absence of antibodies against chlamydiae in all sheep and bovine sera. The Chlamydia CFT, which is the most widely accepted serodiagnostic method for chlamydial infections in animals, correctly identified the presence or absence of antibodies against chlamydiae in only 78 and 4.9% of sheep and bovine sera, respectively. These results suggest that the C. psittaci B577-peptide and Chlamydia LPS ELISAs are superior for the serodiagnosis of ruminant infections with abortigenic chlamydiae, since they are more sensitive than the CFT, they are easy to standardize, and they use readily available synthetic antigens instead of organism-derived CFT antigen.


Vitamin D Receptor Polymorphisms Are Associated with Reduced Esophageal Vitamin D Receptor Expression and Reduced Esophageal Adenocarcinoma Risk.
Epidemiological studies indicate that vitamin D exerts a protective effect on the development of various solid cancers. However, concerns have been raised regarding the potential deleterious role of high vitamin D levels in the development of esophageal adenocarcinoma (EAC). This study investigated genetic variation in the vitamin D receptor (VDR) in relation to its expression and risk of Barrett esophagus (BE) and EAC. VDR gene regulation was investigated by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and gel shift assays. Fifteen haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene were analyzed in 858 patients with reflux esophagitis (RE), BE or EAC and 202 healthy controls. VDR mRNA expression was higher in BE compared with squamous epithelium. VDR protein was located in the nucleus in BE. An rs1989969T/rs2238135G haplotype was identified in the 5' regulatory region of the VDR gene. It was associated with an approximately two-fold reduced risk of RE, BE and EAC. Analysis of a replication cohort was done for BE that confirmed this. The rs1989969T allele causes a GATA-1 transcription factor binding site to appear. The signaling of GATA-1, which is regarded as a negative transcriptional regulator, could explain the findings for rs1989969. The rs2238135G allele was associated with a significantly reduced VDR expression in BE; for the rs1989969T allele, a trend in reduced VDR expression was observed. We identified a VDR haplotype associated with reduced esophageal VDR expression and a reduced incidence of RE, BE and EAC. This VDR haplotype could be useful in identifying individuals who benefit most from vitamin D chemoprevention.


Glycosyltransferase-Mediated Biofilm Matrix Dynamics and Virulence of Streptococcus mutans.
Streptococcus mutans is a key cariogenic bacterium responsible for the initiation of tooth decay. Biofilm formation is a crucial virulence property. We discovered a putative glycosyltransferase, SMU_833, in S. mutans capable of modulating dynamic interactions between two key biofilm matrix components, glucan and extracellular DNA (eDNA). The deletion of smu_833 decreases glucan and increases eDNA but maintains the overall biofilm biomass. The decrease in glucan is caused by a reduction in GtfB and GtfC, two key enzymes responsible for the synthesis of glucan. The increase in eDNA was accompanied by an elevated production of membrane vesicles, suggesting that SMU_833 modulates the release of eDNA via the membrane vesicles, thereby altering biofilm matrix constituents. Furthermore, glucan and eDNA were colocalized. The complete deletion of gtfBC from the smu_833 mutant significantly reduced the biofilm biomass despite the elevated eDNA, suggesting the requirement of minimal glucans as a binding substrate for eDNA within the biofilm. Despite no changes in overall biofilm biomass, the mutant biofilm was altered in biofilm architecture and was less acidic in vitro Concurrently, the mutant was less virulent in an in vivo rat model of dental caries, demonstrating that SMU_833 is a new virulence factor. Taken together, we conclude that SMU_833 is required for optimal biofilm development and virulence of S. mutans by modulating extracellular matrix components. Our study of SMU_833-modulated biofilm matrix dynamics uncovered a new target that can be used to develop potential therapeutics that prevent and treat dental caries.IMPORTANCE Tooth decay, a costly and painful disease affecting the vast majority of people worldwide, is caused by the bacterium Streptococcus mutans The bacteria utilize dietary sugars to build and strengthen biofilms, trapping acids onto the tooth's surface and causing demineralization and decay of teeth. As knowledge of our body's microbiomes increases, the need for developing therapeutics targeted to disease-causing bacteria has arisen. The significance of our research is in studying and identifying a novel therapeutic target, a dynamic biofilm matrix that is mediated by a new virulence factor and membrane vesicles. The study increases our understanding of S. mutans virulence and also offers a new opportunity to develop effective therapeutics targeting S. mutans In addition, the mechanisms of membrane vesicle-mediated biofilm matrix dynamics are also applicable to other biofilm-driven infectious diseases.


Condensin I recruitment and uneven chromatin condensation precede mitotic cell death in response to DNA damage.
Mitotic cell death (MCD) is a prominent but poorly defined form of death that stems from aberrant mitosis. One of the early steps in MCD is premature mitosis and uneven chromatin condensation (UCC). The mechanism underlying this phenomenon is currently unknown. In this study, we show that DNA damage in cells with a compromised p53-mediated G2/M checkpoint triggers the unscheduled activation of cyclin-dependent kinase 1 (Cdk1), activation and chromatin loading of the condensin I complex, and UCC followed by the appearance of multimicronucleated cells, which is evidence of MCD. We demonstrate that these processes engage some of the players of normal mitotic chromatin packaging but not those that drive the apoptotic chromatin condensation. Our findings establish a link between the induction of DNA damage and mitotic abnormalities (UCC) through the unscheduled activation of Cdk1 and recruitment of condensin I. These results demonstrate a clear distinction between the mechanisms that drive MCD-associated and apoptosis-related chromatin condensation and provide mechanistic insights and new readouts for a major cell death process in treated tumors.


Pancreatic pseudocyst drainage--the needle or the scalpel?
A sizable number of pancreatic pseudocysts resolve spontaneously. Some, however, require intervention. Surgery was the only option available for many years. Recently, however, newer methods, such as percutaneous drainage and endoscopic cystotenterostomy have been used. Percutaneous drainage is inexpensive, has a low complication rate, and is done under local anesthesia. The recurrence rate is high with a one-time needle aspiration; this rate can be reduced to less than 10% by using an indwelling catheter. All these factors tend to make percutaneous continuous catheter drainage the first choice in the management of pseudocysts that require intervention. Experience with the endoscopic technique is still limited.


Cyclic Single Atom Vertical Manipulation on a Nonmetallic Surface.
Motivated by the quest for experimental procedures capable of controlled manipulation of single atoms on surfaces, we set up a computational strategy that explores the cyclical vertical manipulation of a broad set of single atoms on the GaAs(110) surface. First-principles simulations of atomic force microscope tip-sample interactions were performed considering families of GaAs and Au-terminated tip apexes with varying crystalline termination. We identified a subset of tips capable of both picking up and depositing an adatom (Ga, As, Al, and Au) any number of times via a modify-restore cycle that "resets" the apex of the scanning probe to its original structure at the end of each cycle. Manipulation becomes successful within a certain window of lateral and vertical tip distances that are observed to be different for extracting and depositing each atom. A practical experimental protocol of special utility for potential cyclical manipulation of single atoms on a nonmetallic surface is proposed.


Effects of Particulate Matter 10 Inhalation on Lung Tissue RNA expression in a Murine Model.
Particulate matter 10 (PM10; airborne particles <10 μm) inhalation has been demonstrated to induce airway and lung diseases. In this study, we investigate the effects of PM10 inhalation on RNA expression in lung tissues using a murine model. Female BALB/c mice were affected with PM10, ovalbumin (OVA), or both OVA and PM10. PM10 was administered intranasally while OVA was both intraperitoneally injected and intranasally administered. Treatments occurred 4 times over a 2-week period. Two days after the final challenges, mice were sacrificed. Full RNA sequencing using lung homogenates was conducted. While PM10 did not induce cell proliferation in bronchoalveolar fluid or lead to airway hyper-responsiveness, it did cause airway inflammation and lung fibrosis. Levels of interleukin 1β, tumor necrosis factor-α, and transforming growth factor-β in lung homogenates were significantly elevated in the PM10-treated group, compared to the control group. The PM10 group also showed increased RNA expression of Rn45a, Snord22, Atp6v0c-ps2, Snora28, Snord15b, Snora70, and Mmp12. Generally, genes associated with RNA splicing, DNA repair, the inflammatory response, the immune response, cell death, and apoptotic processes were highly expressed in the PM10-treated group. The OVA/PM10 treatment did not produce greater effects than OVA alone. However, the OVA/PM10-treated group did show increased RNA expression of Clca1, Snord22, Retnla, Prg2, Tff2, Atp6v0c-ps2, and Fcgbp when compared to the control groups. These genes are associated with RNA splicing, DNA repair, the inflammatory response, and the immune response. Inhalation of PM10 extensively altered RNA expression while also inducing cellular inflammation, fibrosis, and increased inflammatory cytokines in this murine mouse model.


An Update on Novel Antiplatelets in Vascular Patients.
Acetylsalicylic acid, clopidogrel and cilostazol are well-established agents inhibiting the normal function of platelets with known advantages and limitations. The development of novel antiplatelet agents aims to provide equal or superior outcomes for patients and simultaneously minimize side effects. The aim of this manuscript is to review the latest data on the use of novel antiplatelet agents in vascular patients. Based on our 2016 review, a further search in the English medical literature has yielded a number of publications on cangrelor, prasugrel, ticagrelor, vorapaxar and a number of other - still experimental - agents (Ir- 6, UBO-QIC, W1, revacept and YM-254890). Recently published data have not altered the use and indications of cangrelor, prasugrel and vorapaxar; all of them now approved by both FDA and EMA. The EUCLID trial has recently provided valuable data on the clinical use of ticagrelor, although results regarding vascular patients and administration of ticagrelor are still under scrutiny. Vorapaxar remains the only novel antiplatelet that is approved for PAD. Randomized control trials that focus on vascular patients are necessary to establish the safety and efficacy of these novel agents. Despite their positive initial results, most novel experimental antiplatelets are still in early development, thus in preclinical or early clinical phases of their trials. Research on three novel antiplatelets is currently discontinued (atopaxar, darexaban and elinogrel). Vorapaxar remains the only novel antiplatelet that is approved for PAD. Other novel antiplatelets demonstrate positive results, but further studies focused on vascular patients are necessary. Novel experimental antiplatelets are still in the early phases of the clinical and preclinical studies.


The clinical basis of orthorexia nervosa: emerging perspectives.
Orthorexia nervosa describes a pathological obsession with proper nutrition that is characterized by a restrictive diet, ritualized patterns of eating, and rigid avoidance of foods believed to be unhealthy or impure. Although prompted by a desire to achieve optimum health, orthorexia may lead to nutritional deficiencies, medical complications, and poor quality of life. Despite its being a distinct behavioral pattern that is frequently observed by clinicians, orthorexia has received very little empirical attention and is not yet formally recognized as a psychiatric disorder. In this review, we synthesize existing research to identify what is known about the symptoms, prevalence, neuropsychological profile, and treatment of orthorexia. An examination of diagnostic boundaries reveals important points of symptom overlap between orthorexia and anorexia nervosa, obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), somatic symptom disorder, illness anxiety disorder, and psychotic spectrum disorders. Neuropsychological data suggest that orthorexic symptoms are independently associated with key facets of executive dysfunction for which some of these conditions already overlap. Discussion of cognitive weaknesses in set-shifting, external attention, and working memory highlights the value of continued research to identify intermediate, transdiagnostic endophenotypes for insight into the neuropathogenesis of orthorexia. An evaluation of current orthorexia measures indicates a need for further psychometric development to ensure that subsequent research has access to reliable and valid assessment tools. Optimized assessment will not only permit a clearer understanding of prevalence rates, psychosocial risk factors, and comorbid psychopathology but will also be needed to index intervention effectiveness. Though the field lacks data on therapeutic outcomes, current best practices suggest that orthorexia can successfully be treated with a combination of cognitive-behavioral therapy, psychoeducation, and medication.


[Series: Caries prevention in a historical perspective. Food].
Different ideas on the impact of diet on the occurrence of dental caries that have been of influence during the last 125 years are discussed. The initial premise was that deficits in calcium and vitamins during the formation phase of the teeth were the cause of their high caries susceptibility. That idea has been abandoned. The frequency with which someone eats or drinks after the eruption of the teeth and the avoidance of quickly degradable carbohydrates in the diet now appear to be the most important factors for the development of caries lesions. The question whether nutrition education is still needed now that caries can be prevented by cleaning teeth with fluoride toothpaste, is discussed.


Identification of association of common AGGF1 variants with susceptibility for Klippel-Trenaunay syndrome using the structure association program.
Klippel-Trenaunay syndrome (KTS) is a severe congenital disorder characterized by capillary malformations, venous malformations or varicose veins, and hypertrophy of the affected tissues. The angiogenic factor gene AGGF1 was previously identified as a candidate susceptibility gene for KTS, but further genetic studies are needed to firmly establish the genetic relationship between AGGF1 and KTS. We analyzed HapMap data and identified two tagSNPs, rs13155212 and rs7704267 that capture information for all common variants in AGGF1. The two SNPs were genotyped in 173 Caucasian KTS patients and 477 Caucasian non-KTS controls, and both significantly associated with susceptibility for KTS (P= 0.004 and 0.013, respectively). Permutation testing also showed a significant empirical P value for the association (empirical P= 0.006 and 0.015, respectively). To control for potential confounding due to population stratification, the population structure for both cases and controls was characterized by genotyping of 38 ancestry-informative markers (AIMs) and the STRUCTURE program. The association between the AGGF1 SNPs and KTS remained significant after multivariate analysis by incorporating the inferred cluster scores as a covariate or after removal of outlier individuals identified by STRUCTURE. These results suggest that common AGGF1 variants confer risk of KTS.


Population structure of the olive flounder (Paralichthys olivaceus) in Korea inferred from microsatellite marker analysis.
The population structure of olive flounder Paralichthys olivaceus was estimated using nine polymorphic microsatellite (MS) loci in 459 individuals collected from eight populations, including five wild and three hatchery populations in Korea. Genetic variation in hatchery (mean number of alleles per locus, A = 10.2-12.1; allelic richness, A(R) = 9.3-10.1; observed heterozygosity, H(O) = 0.766-0.805) and wild (mean number of alleles per locus, A = 11.8-19.6; allelic richness, A(R) = 10.9-16.1; observed heterozygosity, H(O) = 0.820-0.888) samples did not differ significantly, suggesting a sufficient level of genetic variation in these well-managed hatchery populations, which have not lost a substantial amount of genetic diversity. Neighbour-joining tree and principal component analyses showed that genetic separation between eastern and pooled western and southern wild populations in Korea was probably influenced by restricted gene flow between regional populations due to the barrier effects of sea currents. The pooled western and southern populations are genetically close, perhaps because larval dispersal may depend on warm currents. One wild population (sample from Wando) was genetically divergent from the main distribution, but it was genetically close to hatchery populations, indicating that the genetic composition of the studied populations may be affected by hydrographic conditions and the release of fish stocks. The estimated genetic population structure and potential applications of MS markers may aid in the proper management of P. olivaceus populations.


A glimpse towards the vestigiality and fate of human vermiform appendix-a histomorphometric study.
The vermiform appendix in human is considered to be a vestigial organ by most of the authors. Absence of appendix is already reported in Indian population. Whether the human appendix is performing any function is debatable but when present it can create trouble. So if there is no appendix we can escape the ill-effects of the organ. With this hope the study has been done to see whether the appendix is really going to be rudimentary or absent or not. Marerials and Methods: Length, external diameter, number of lymphoid follicles, maximum diameter of the follicle or submucous coat, thickening of the muscle coat and seromucosal thickening of freshly removed appendix from human cadavers were seen. After fixation in 10% formal saline tissues were stained with haematoxylin-eosin stain and photographs were taken. The results had been tabulated and statistically correlated. The parameters like number of lymphoid follicles, length and diameter all are changed as per the age advancement which is strictly indicating some functional activities of the organ which is against the idea of vestigiality of the appendix. Human appendix cannot be called a vestigial organ unless the functional inactivity is proved. Lymphoid changes which occur after birth to provide the gut immunity is needed to be proved by further studies. There might be incidental absence or rudimentary appendix in human body, but that does not indicate that we would not have any appendix in future.


Early specification of sensory neuron fate revealed by expression and function of neurogenins in the chick embryo.
The generation of sensory and autonomic neurons from the neural crest requires the functions of two classes of basic helix-loop-helix (bHLH) transcription factors, the Neurogenins (NGNs) and MASH-1, respectively (Fode, C., Gradwohl, G., Morin, X., Dierich, A., LeMeur, M., Goridis, C. and Guillemot, F. (1998) Neuron 20, 483-494; Guillemot, F., Lo, L.-C., Johnson, J. E., Auerbach, A., Anderson, D. J. and Joyner, A. L. (1993) Cell 75, 463-476; Ma, Q., Chen, Z. F., Barrantes, I. B., de la Pompa, J. L. and Anderson, D. J. (1998 Neuron 20, 469-482). We have cloned two chick NGNs and found that they are expressed in a subset of neural crest cells early in their migration. Ectopic expression of the NGNs in vivo biases migrating neural crest cells to localize in the sensory ganglia, and induces the expression of sensory neuron-appropriate markers in non-sensory crest derivatives. Surprisingly, the NGNs can also induce the expression of multiple pan-neuronal and sensory-specific markers in the dermomyotome, a mesodermal derivative. Taken together, these data suggest that a subset of neural crest cells may already be specified for a sensory neuron fate early in migration, as a consequence of NGN expression.