Candidate polyanion microbicides inhibit HIV-1 infection and dissemination pathways in human cervical explants.

BACKGROUND: Heterosexual intercourse remains the major route of HIV-1 transmission worldwide, with almost 5 million new infections occurring each year. Women increasingly bear a disproportionate burden of the pandemic, thus there is an urgent need to develop new strategies to reduce HIV-1 transmission that could be controlled by women themselves. The potential of topical microbicides to reduce HIV transmission across mucosal surfaces has been clearly identified, and some agents are currently under evaluation in clinical trials. Many of these "first generation" microbicides consist of polyanionic compounds designed to interfere with viral attachment. Here we have evaluated two candidate polyanion compounds in clinical trials, PRO 2000 and dextrin sulphate (DxS) to determine their safety and efficacy against in vitro HIV-1 and HSV-2 infection using cellular and tissue explant models. RESULTS: PRO 2000 and DxS potently inhibited infection by HIV-1 X4 and R5 isolates when present during viral exposure. However PRO 2000 required 10-fold and DxS 2000-fold more compound to block infection with R5 virus than X4. While both compounds were virucidal for X4 HIV-1, neither was virucidal for R5 virus. PRO 2000 efficiently inhibited infection of cervical explants and dissemination of virus by migratory DC. DxS was less active, able to completely inhibit cervical explant infection, but providing only partial reduction of virus dissemination by DC. PRO 2000, but not DxS, also inhibited HIV-1 binding to DC-SIGN+ cells and trans infection of co-cultured target cells. The inflammatory potential of both compounds was screened by measurement of cytokine production from cervical explants, and statistically significant increases were only observed for IL-1beta and RANTES following treatment with PRO 2000. Both compounds also demonstrated potent activity against HSV-2 infection of cervical epithelial cells. CONCLUSION: Our results demonstrate that PRO 2000 is a potent inhibitor of R5 HIV-1 infection and dissemination pathways in human cervical explants. DxS, while demonstrating significant inhibition of R5 infection, was less active against DC mediated dissemination pathways. PRO 2000 has now entered human phase III efficacy trials

Insulin response and changes in composition of non-esterified fatty acids in blood plasma of middle-aged men following isoenergetic fatty and carbohydrate breakfasts

It was previously shown that a high plasma concentration of non-esterified fatty acids (NEFA) persisted after a fatty breakfast, but not after an isoenergetic carbohydrate breakfast, adversely affecting glucose tolerance. The higher concentration after the fatty breakfast may in part have been a result of different mobilization rates of fatty acids. This factor can be investigated as NEFA mobilized from tissues are monounsaturated to a greater extent than those deposited from a typical meal. Twenty-four middle-aged healthy Caucasian men were given oral glucose tolerance tests (OGTT), and for 28 d isoenergetic breakfasts of similar fat composition but of low (L) or moderate (M) fat content. The composition of NEFA in fasting and postprandial plasma was determined on days 1 and 29. No significant treatment differences in fasting NEFA composition occurred on day 29. During the OGTT and 0-1 h following breakfast there was an increase in plasma long-chain saturated NEFA but a decrease in monounsaturated NEFA (mug/100 mug total NEFA; Pg/100 mug total NEFA; P<0.05), expressed as an increase in 18:1 and decreases in 16:0 and 17:0 in treatment M relative to treatment L (P<0.05). Serum insulin attained 35 and 65 mU/l in treatments M and L respectively during this period. Negative correlations were found between 16:0 in fasting plasma and both waist:hip circumference (P=0.0009) and insulin response curve area during OGTT (within treatment M, P=0.0001). It is concluded that a normal postprandial insulin response is associated with a rapid change in plasma saturated:monounsaturated NEFA. It is proposed that this change is the result of a variable suppression of fat mobilization, which may partly account for a large difference in postprandial total plasma NEFA between fatty and carbohydrate meals

The promises and pitfalls of sex integration in sport and physical culture

Scholars working in the academic field of sport studies have long debated the relationship between modern sport and gender (e.g. Hargreaves and Anderson, 2014; Hargreaves, 1994; Lenskyj, 1986; Messner, 2002). Within this body of work, modern sport forms – along with a great diversity of related activities, including dance, fitness training, physical education, etc. – have consistently been shown to carry meanings relative to the structures of gender prevailing in the wider social settings within which they take place, with patterns of participation and consumption clearly mapping onto gendered ideals. However, rather than simply mirroring such social norms, research suggests that many sporting practices were invented or have been purposefully developed in order to train young men and women in socially-approved gender behaviors to begin with (Cahn 1994; Hargreaves 1994; Theberge, 2000). Thus, much of contemporary physical culture finds its roots in the process which scholars describe as the ‘social construction of gender’; in other words, doing sports and other activities in gender-differentiated ways has long been a means of producing and maintaining difference in the lives of men and women, girls and boys.Peer reviewedAccepted author manuscript of a peer reviewed article accepted for publication by Taylor & Francis in Sport in Society: Cultures, Commerce, Media, Politics online on 28/12/2015

Electroencephalogram of Healthy Horses During Inhaled Anesthesia.

BackgroundPrevious study of the diagnostic validity of electroencephalography (EEG) to detect abnormalities in equine cerebral cortical function relied on the administration of various drugs for sedation, induction, and maintenance of general anesthesia but used identical criteria to interpret recordings.ObjectivesTo determine the effects of 2 inhalation anesthetics on the EEG of healthy horses.AnimalsSix healthy horses.MethodsProspective study. After the sole administration of one of either isoflurane or halothane at 1.2, 1.4, and 1.6 times the minimum alveolar concentration, EEG was recorded during controlled ventilation, spontaneous ventilation, and nerve stimulation.ResultsBurst suppression was observed with isoflurane, along with EEG events that resembled epileptiform discharges. Halothane results were variable between horses, with epileptiform-like discharges and bursts of theta, alpha, and beta recorded intermittently. One horse died and 2 were euthanized as the result of anesthesia-related complications.Conclusions and clinical importanceThe results of this study indicate that the effects of halothane and isoflurane on EEG activity in the normal horse can be quite variable, even when used in the absence of other drugs. It is recommended that equine EEG be performed without the use of these inhalation anesthetics and that general anesthesia be induced and maintained by other contemporary means

Qualitative and Quantitative Characteristics of the Electroencephalogram in Normal Horses during Administration of Inhaled Anesthesia.

BackgroundThe effects of anesthesia on the equine electroencephalogram (EEG) after administration of various drugs for sedation, induction, and maintenance are known, but not that the effect of inhaled anesthetics alone for EEG recording.ObjectiveTo determine the effects of isoflurane and halothane, administered as single agents at multiple levels, on the EEG and quantitative EEG (qEEG) of normal horses.AnimalsSix healthy horses.MethodsProspective study. Digital EEG with video and quantitative EEG (qEEG) were recorded after the administration of one of the 2 anesthetics, isoflurane or halothane, at 3 alveolar doses (1.2, 1.4 and 1.6 MAC). Segments of EEG during controlled ventilation (CV), spontaneous ventilation (SV), and with peroneal nerve stimulation (ST) at each MAC multiple for each anesthetic were selected, analyzed, and compared. Multiple non-EEG measurements were also recorded.ResultsSpecific raw EEG findings were indicative of changes in the depth of anesthesia. However, there was considerable variability in EEG between horses at identical MAC multiples/conditions and within individual horses over segments of a given epoch. Statistical significance for qEEG variables differed between anesthetics with bispectral index (BIS) CV MAC and 95% spectral edge frequency (SEF95) SV MAC differences in isoflurane only and median frequency (MED) differences in SV MAC with halothane only.Conclusions and clinical importanceUnprocessed EEG features (background and transients) appear to be beneficial for monitoring the depth of a particular anesthetic, but offer little advantage over the use of changes in mean arterial pressure for this purpose