A Model of Methotrexate Encephalopathy: Neurotransmitter and Pathologic Abnormalities

Methotrexate may cause seizures, dementia, and leukoencephalopathy when given in toxic doses to children with leukemia or solid tumors. Even in therapeutic doses, treatment with this drug is associated with an increased incidence of seizures in children with leukemia. To study mechanisms of injury, juvenile rats were given multiple intraventricular injections of methotrexate and the brains were analyzed for histopathology and biogenic amine metabolites of dopamine and serotonin. Disruption of monoamine metabolism has been proposed as a cause of brain dysfunction from this chemotherapy. Multiple injections (1 or 2 mg/kg) produced convulsions in an increasingly larger percentage of animals at higher cumulative doses, and five doses produced the neuropathological changes seen in human leukoencephalopathy. A single dose reduced the concentration of brain metabolites of dopamine, but not serotonin, six hours later. The effect was less pronounced after five doses. This rodent model should be useful for studying the metabolic basis of methotrexate encephalopathy. (J Child Neurol 1986;1:351-357)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67332/2/10.1177_088307388600100406.pd

Automated Analysis of Cryptococcal Macrophage Parasitism Using GFP-Tagged Cryptococci

The human fungal pathogens Cryptococcus neoformans and C. gattii cause life-threatening infections of the central nervous system. One of the major characteristics of cryptococcal disease is the ability of the pathogen to parasitise upon phagocytic immune effector cells, a phenomenon that correlates strongly with virulence in rodent models of infection. Despite the importance of phagocyte/Cryptococcus interactions to disease progression, current methods for assaying virulence in the acrophage system are both time consuming and low throughput. Here, we introduce the first stable and fully characterised GFP–expressing derivatives of two widely used cryptococcal strains: C. neoformans serotype A type strain H99 and C. gattii serotype B type strain R265. Both strains show unaltered responses to environmental and host stress conditions and no deficiency in virulence in the macrophage model system. In addition, we report the development of a method to effectively and rapidly investigate macrophage parasitism by flow cytometry, a technique that preserves the accuracy of current approaches but offers a four-fold improvement in speed

High HIV Prevalence Among Men Who have Sex with Men in Soweto, South Africa: Results from the Soweto Men’s Study

The Soweto Men’s Study assessed HIV prevalence and associated risk factors among MSM in Soweto, South Africa. Using respondent driven sampling (RDS) recruitment methods, we recruited 378 MSM (including 15 seeds) over 30 weeks in 2008. All results were adjusted for RDS sampling design. Overall HIV prevalence was estimated at 13.2% (95% confidence interval 12.4–13.9%), with 33.9% among gay-identified men, 6.4% among bisexual-identified men, and 10.1% among straight-identified MSM. In multivariable analysis, HIV infection was associated with being older than 25 (adjusted odds ratio (AOR) 3.8, 95% CI 3.2–4.6), gay self-identification (AOR 2.3, 95% CI 1.8–3.0), monthly income less than ZAR500 (AOR 1.4, 95% CI 1.2–1.7), purchasing alcohol or drugs in exchange for sex with another man (AOR 3.9, 95% CI 3.2–4.7), reporting any URAI (AOR 4.4, 95% CI 3.5–5.7), reporting between six and nine partners in the prior 6 months (AOR 5.7, 95% CI 4.0–8.2), circumcision, (AOR 0.2, 95% CI 0.1–0.2), a regular female partner (AOR 0.2, 95% CI 0.2–0.3), smoking marijuana in the last 6 months (AOR 0.6, 95% CI 0.5–0.8), unprotected vaginal intercourse in the last 6 months (AOR 0.5, 95% CI 0.4–0.6), and STI symptoms in the last year (AOR 0.7, 95% CI 0.5–0.8). The results of the Soweto Men’s Study confirm that MSM are at high risk for HIV infection, with gay men at highest risk. HIV prevention and treatment for MSM are urgently needed

The Sun Health Research Institute Brain Donation Program: Description and Eexperience, 1987–2007

The Brain Donation Program at Sun Health Research Institute has been in continual operation since 1987, with over 1000 brains banked. The population studied primarily resides in the retirement communities of northwest metropolitan Phoenix, Arizona. The Institute is affiliated with Sun Health, a nonprofit community-owned and operated health care provider. Subjects are enrolled prospectively to allow standardized clinical assessments during life. Funding comes primarily from competitive grants. The Program has made short postmortem brain retrieval a priority, with a 2.75-h median postmortem interval for the entire collection. This maximizes the utility of the resource for molecular studies; frozen tissue from approximately 82% of all cases is suitable for RNA studies. Studies performed in-house have shown that, even with very short postmortem intervals, increasing delays in brain retrieval adversely affect RNA integrity and that cerebrospinal fluid pH increases with postmortem interval but does not predict tissue viability

Predictors of low cervical cancer screening among immigrant women in Ontario, Canada

<p>Abstract</p> <p>Background</p> <p>Disparities in cervical cancer screening are known to exist in Ontario, Canada for foreign-born women. The relative importance of various barriers to screening may vary across ethnic groups. This study aimed to determine how predictors of low cervical cancer screening, reflective of sociodemographics, the health care system, and migration, varied by region of origin for Ontario's immigrant women.</p> <p>Methods</p> <p>Using a validated billing code algorithm, we determined the proportion of women who were not screened during the three-year period of 2006-2008 among 455 864 identified immigrant women living in Ontario's urban centres. We created eight identical multivariate Poisson models, stratified by eight regions of origin for immigrant women. In these models, we adjusted for various sociodemographic, health care-related and migration-related variables. We then used the resulting adjusted relative risks to calculate population-attributable fractions for each variable by region of origin.</p> <p>Results</p> <p>Region of origin was not a significant source of effect modification for lack of recent cervical cancer screening. Certain variables were significantly associated with lack of screening across all or nearly all world regions. These consisted of not being in the 35-49 year age group, residence in the lowest-income neighbourhoods, not being in a primary care patient enrolment model, a provider from the same region, and not having a female provider. For all women, the highest population-attributable risk was seen for not having a female provider, with values ranging from 16.8% [95% CI 14.6-19.1%] among women from the Middle East and North Africa to 27.4% [95% CI 26.2-28.6%] for women from East Asia and the Pacific.</p> <p>Conclusions</p> <p>To increase screening rates across immigrant groups, efforts should be made to ensure that women have access to a regular source of primary care, and ideally access to a female health professional. Efforts should also be made to increase the enrolment of immigrant women in new primary care patient enrolment models.</p

Can being gay provide a boost in the hiring process? Maybe if the boss is female

Purpose – The purpose of this study was to investigate whether men and women differentially prefer hiring gay and lesbian job applicants relative to equally qualified heterosexual job applicants. Design/methodology/approach – Data were collected from two samples of non-student participants. Each participant evaluated the perceived hirability of an ostensibly real job applicant by reviewing the applicant’s resume. In reality, all participants were randomly assigned to evaluate the same fictitious resume that differed only in the gender and sexual orientation of the applicant. Findings – We find that men perceived gay and lesbian job applicants as less hirable, while women perceived gay and lesbian job applicants as more hirable than heterosexual job applicants. Additionally, we show perceptions of hirability are mediated by perceptions of gay and lesbian job applicants’ competence. Implications – These results show that bias against gays and lesbians is much more nuanced than previous work suggests. One implication is that placing more women in selection roles within organizations could be a catalyst for the inclusion of gay and lesbian employees. Additionally, these results could influence when and how gays and lesbians disclose their gay identities at work. Originality/value –These studies are the first to identify a positive bias in favor of gay and lesbian job applicants. As attitudes toward gays and lesbians become more positive, results like these are important to document as they signal a shift in intergroup relations. These results will also help managers and organizations design selection processes to minimize bias towards applicants. Keywords: gender, sexual orientation, selection, bia

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

A retrospective analysis of clinical outcome of patients with chemo-refractory metastatic breast cancer treated in a single institution phase I unit

BACKGROUND AND METHODS: Novel approaches to treat chemo-refractory metastatic breast cancer (MBC) are currently under investigation. This retrospective series reviews the outcome of 70 MBC patients who have participated in 30 phase I trials at the Royal Marsden Hospital from 2002 to 2009. RESULTS: The median treatment lines before phase I trial entry for MBC was 5 (range: 1-12 lines). The overall response rate was 11.4% (95% CI: 4.0-18.9%) and the clinical benefit rate at 4 months was 20% (95% CI: 10.6-29.3). The median time to progression was 7.0 weeks (95% CI: 6.4-7.5) and median overall survival was 8.7 months (95% CI: 7.6-9.8) from start of first phase I treatment. No patients discontinued trial because of treatment-related toxicities. Abnormal lactate dehydrogenase, serum albumin <35 mg per 100 ml, >or=5 previous treatment lines, liver metastases and Eastern Cooperative Group performance status >or=2 at study entry were significantly associated with poor overall survival in multivariate analysis. CONCLUSION: This retrospective analysis provides evidence that patients with MBC tolerate phase I clinical trials and a significant proportion of patients with chemo-refractory disease, particularly those with triple-negative or Her2-positive breast cancer, may benefit from treatment

Metabolism before, during and after anaesthesia in colic and healthy horses

<p>Abstract</p> <p>Background</p> <p>Many colic horses are compromised due to the disease state and from hours of starvation and sometimes long trailer rides. This could influence their muscle energy reserves and affect the horses' ability to recover. The principal aim was to follow metabolic parameter before, during, and up to 7 days after anaesthesia in healthy horses and in horses undergoing abdominal surgery due to colic.</p> <p>Methods</p> <p>20 healthy horses given anaesthesia alone and 20 colic horses subjected to emergency abdominal surgery were anaesthetised for a mean of 228 minutes and 183 minutes respectively. Blood for analysis of haematology, electrolytes, cortisol, creatine kinase (CK), free fatty acids (FFA), glycerol, glucose and lactate was sampled before, during, and up to 7 days after anaesthesia. Arterial and venous blood gases were obtained before, during and up to 8 hours after recovery. Gluteal muscle biopsy specimens for biochemical analysis of muscle metabolites were obtained at start and end of anaesthesia and 1 h and 1 day after recovery.</p> <p>Results</p> <p>Plasma cortisol, FFA, glycerol, glucose, lactate and CK were elevated and serum phosphate and potassium were lower in colic horses before anaesthesia. Muscle adenosine triphosphate (ATP) content was low in several colic horses. Anaesthesia and surgery resulted in a decrease in plasma FFA and glycerol in colic horses whereas levels increased in healthy horses. During anaesthesia muscle and plasma lactate and plasma phosphate increased in both groups. In the colic horses plasma lactate increased further after recovery. Plasma FFA and glycerol increased 8 h after standing in the colic horses. In both groups, plasma concentrations of CK increased and serum phosphate decreased post-anaesthesia. On Day 7 most parameters were not different between groups. Colic horses lost on average 8% of their initial weight. Eleven colic horses completed the study.</p> <p>Conclusion</p> <p>Colic horses entered anaesthesia with altered metabolism and in a negative oxygen balance. Muscle oxygenation was insufficient during anaesthesia in both groups, although to a lesser extent in the healthy horses. The post-anaesthetic period was associated with increased lipolysis and weight loss in the colic horses, indicating a negative energy balance during the first week post-operatively.</p

Fish under exercise

Improved knowledge on the swimming physiology of fish and its application to fisheries science and aquaculture (i.e., farming a fitter fish) is currently needed in the face of global environmental changes, high fishing pressures, increased aquaculture production as well as increased concern on fish well-being. Here, we review existing data on teleost fish that indicate that sustained exercise at optimal speeds enhances muscle growth and has consequences for flesh quality. Potential added benefits of sustained exercise may be delay of ovarian development and stimulation of immune status. Exercise could represent a natural, noninvasive, and economical approach to improve growth, flesh quality as well as welfare of aquacultured fish: a FitFish for a healthy consumer. All these issues are important for setting directions for policy decisions and future studies in this area. For this purpose, the FitFish workshop on the Swimming Physiology of Fish (http://www.ub.edu/fitfish2010) was organized to bring together a multidisciplinary group of scientists using exercise models, industrial partners, and policy makers. Sixteen international experts from Europe, North America, and Japan were invited to present their work and view on migration of fishes in their natural environment, beneficial effects of exercise, and applications for sustainable aquaculture. Eighty-eight participants from 19 different countries contributed through a poster session and round table discussion. Eight papers from invited speakers at the workshop have been contributed to this special issue on The Swimming Physiology of Fish