Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents

Toxoplasma gondii is an opportunistic pathogen responsible for toxoplasmosis. T. gondii is a purine auxotroph incapable of de novo purine biosynthesis and depends on salvage pathways for its purine requirements. Adenosine kinase (EC.2.7.1.20) is the major enzyme in the salvage of purines in these parasites. 6-Benzylthioinosine and analogues were established as "subversive substrates" for the T. gondii, but not for the human adenosine kinase. Therefore, these compounds act as selective anti-toxoplasma agents. In the present study, a series of N(6)-benzyladenosine analogues were synthesized from 6-chloropurine riboside with substituted benzylamines via solution phase parallel synthesis. These N(6)-benzyladenosine analogues were evaluated for their binding affinity to purified T. gondii adenosine kinase. Furthermore, the anti-toxoplasma efficacy and host toxicity of these compounds were tested in cell culture. Certain substituents on the aromatic ring improved binding affinity to T. gondii adenosine kinase when compared to the unsubstituted N(6)-benzyladenosine. Similarly, varying the type and position of the substituents on the aromatic ring led to different degrees of potency and selectivity as anti-toxoplasma agents. Among the synthesized analogues, N(6)-(2,4-dimethoxybenzyl)adenosine exhibited the most favorable anti-toxoplasma activity without host toxicity. The binding mode of the synthesized N(6)-benzyladenosine analogues were characterized to illustrate the role of additional hydrophobic effect and van der Waals interaction within an active site of T. gondii adenosine kinase by induced fit molecular modeling.     

Use of the internal mammary artery as a free graft with reimplantation of the proximal end onto the ascending aorta. Apropos of 39 cases]

From January 1987 to January 1991, 104 patients received bilateral internal mammary artery grafts and 39 of them had coronary bypass with a free graft implanted on the ascending aorta. There were 35 men, with a mean age of 57.35 years (range 41 to 70 years). 87% of them had stable angina, and 23 had preoperative myocardial infarction. The left ventricular function was good in 77 per cent of cases. 23 patients had three vessel disease (61.5%), 13 two vessel diseases (30.7%), 2 one vessel disease (5.12%) and one a left main coronary stenosis. Left internal mammary artery was used in two patients on the left descending artery and the right internal mammary artery was used in 37 patients: 15 on the circumflex, 15 on the right coronary, 4 on the LDA and 3 on the diagonal artery. Five patients had one graft, 32 two grafts and one three grafts (bilateral mammary and saphenous vein). Hospital mortality was 2.56% (1 patient) and there were 2 late deaths (5.12%). There were 5 perioperative myocardial infractions (12.8%) and no sternal infections. The mean follow up is 21 months (range 3 to 46 months). At follow-up, 34 patients (87.2%) were asymptomatic, and there were no myocardial infarctions. Postoperative angiography in 8 patients (mean postoperative time 2.5 months) showed that all the grafts were patent. This analysis demonstrates that free IMA graft has a low operative risk and provides excellent long term functional improvement and survival.     

HIV/AIDS and intimate partner violence: intersecting women's health issues in the United States

This article reviews 35 U.S. studies on the intersection of HIV and adult intimate partner violence (IPV). Most studies describe rates of IPV among women at risk or living with HIV/AIDS and identify correlates, using multiple types of convenience samples (e.g., women in methadone treatment, women in shelters or clinics), cross-sectional designs, and self-reported risk behaviors. HIV-positive women appear to experience any IPV at rates comparable to HIV-negative women from the same underlying populations; however, their abuse seems to be more frequent and more severe. The authors found only four relevant interventions and none addressed sexually transmitted HIV and partner violence risk reduction simultaneously. There is a critical need for research on (a) causal pathways and cumulative effects of the syndemic issues of violence, HIV, and substance abuse and (b) interventions that target IPV victims at risk for HIV, as well as HIV-positive women who may be experiencing IPV.     

National standard for health assessment of rail safety workers: the first year

OBJECTIVE: To determine the prevalence of health problems in New South Wales train drivers and the impact of the new national health-assessment standard on train drivers' fitness for work. DESIGN, SETTING AND PARTICIPANTS: Retrospective audit of files of all RailCorp train drivers (743) and train driver recruits (283) who were assessed under the new national standard for health assessment of rail safety workers between February 2004 and February 2005. MAIN OUTCOME MEASURES: Smoking status; prevalence of hypertension, heart disease, diabetes and obstructive sleep apnoea; alcohol use disorders; body mass index (BMI); total cholesterol level; fasting blood glucose level; cardiac risk score; fitness status. RESULTS: 25.2% of drivers and 27.9% of recruits were smokers; 43.8% of drivers and 21.9% of recruits were hypertensive; 34.6% of drivers and 31.4% of recruits had high total cholesterol levels (> 5.5 mmol/L). Median BMI values were 29 kg/m(2) (range, 18-59 kg/m(2)) for drivers and 28 kg/m(2) (range, 19-55 kg/m(2)) for recruits. The prevalence of obesity (BMI > or =30.0 kg/m(2)) was higher in both male drivers and recruits compared with the general male population. At initial assessment, 65.1% of drivers and 88.0% of recruits were certified as unconditionally fit for work; 12.4% of drivers and 7.1% of recruits were assessed as temporarily unfit; and 22.5% of drivers and 4.6% of recruits were considered fit subject to review (after periods ranging from 3 to 12 months). Two per cent of drivers and 2.5% of recruits were subsequently deemed to be permanently unfit, the most common reasons being heart conditions, psychiatric disorders, orthopaedic problems, colour vision impairment and sleep apnoea. CONCLUSIONS: Cardiovascular risk factors and cardiovascular disease are the most significant health issues affecting train drivers' fitness for work. With the more stringent health assessment and regular review required by the new standard, most drivers can continue with their duties, with the added benefits of improved personal health and greater safety to the rail network and the public.     

Weight management practices and their relationship to knowledge, perception and health status of Saudi females attending diet clinics in Riyadh city

The objective of the study was to identify weight management (WM) practices among women attending diet clinics in Riyadh city, assess their impact on knowledge, perceptions, nutritional and health status and define some predictors for weight reduction among these women. The pretest-posttest research design was used. All female clients attending 8 diet clinics for the first visit within 8 months period and fulfilling the study inclusion criteria (212 out of 263) were included. The results show that out of 170 females who had previously tried to lose weight, only 32.4% reported success in reducing weight, meanwhile 61.7% reported weight regain. The mean total score of dietary practices, physical activity score, self efficacy and satisfaction of self-body image were improved significantly at posttest. Analysis of 24 h. dietary recall revealed that total energy and nutrients intake were significantly reduced at posttest. Dieting related problems increased significantly at posttest. Nutritional knowledge was at moderately fair level at both pretest and posttest; however it showed a significant improvement in the posttest. Perceived severity, perceived barriers and negative modeling effect were significantly decreased at the posttest. Over expectation for weight reduction was clearly evident as posttest body mass index (BMI) revealed a wide discrepancy between the expected and final weights. However, as compared to initial and final BMI, there was an increase in women who attained normal weight and a decrease in the percentage of obese and morbid obese women. All anthropometric indices, blood pressure, biochemical investigation showed significant improvement at posttest. Among the five WM modalities studied, moderate hypo-calorie plan diet modality was the longest (chi = 5.6 month) with the least weight loss (7.8%) and the minimum side effects. Both groups under very low calorie diet and protein diet had the highest weight reduction (13.2% &12.3%), at the same time both diets exhibited the highest number of side effects. The study recommends use of the primary approach for achieving weight loss through therapeutic life style change with banning those modalities accompanied with serious health complications.     

Evaluating meniscus allograft transplant using a cost-effectiveness threshold analysis

Background

It is unknown if meniscal allograft transplant (MAT) delays progression of osteoarthritis (OA). Cost-effectiveness threshold analysis can demonstrate the necessary delay in OA progression required by MAT to be considered cost-effective compared to non-operative management. The purpose of this study is to identify the efficacy MAT requires in delaying progression to OA in previously meniscectomized knees in order to be considered cost-effective compared to non-operative treatment. A secondary goal is to demonstrate the influence of age and BMI on the required efficacy of MAT for cost-effectiveness.

Modulation of cell-mediated immunity in mice with chronic unisexual or bisexual Schistosoma mansoni cercarial infection

Three groups of C57BL/6J female mice were infected with female Schistosoma mansoni cercariae alone, male cercariae alone, or both sexes of cercariae. In a longitudinal study, the spleen cell proliferative responses to the mitogens phytohaemagglutinin (PHA) and Escherichia coli lipopolysaccharide (LPS) were monitored. Significant immune suppression was found in the three infected groups when compared with uninfected controls. Within the infected groups, mice inoculated with both sexes of cercariae were significantly more suppressed than those with single-sex cercarial infection. Thus, in addition to schistosome eggs, either sex of S. mansoni worms is capable, although to a lesser extent, of inducing hyporesponsiveness of cell-mediated immunity (CMI) in chronic schistosomiasis mansoni.     

Leukotriene antagonists and the Churg-Strauss syndrome

BACKGROUND AND OBJECTIVES: Leukotriene antagonists (LTAs), or antileukotrienes, are a new group of anti-inflammatory drugs used for the treatment of asthma. They might substitute for or allow tapering of corticosteroids in asthmatic patients. These drugs have been associated with the development of Churg-Strauss syndrome (CSS), a rare form of vasculitic angiitis. It is unclear whether the development of CSS is a direct drug effect or an unmasking of a preexisting condition on withdrawal of steroids for asthma. We present a case of CSS in a patient treated with montelukast and review the literature to analyze the association between LTAs and the development of CSS. METHOD: We reviewed the literature using MEDLINE from February 1966 to October 2000. To the cases identified, we present an additional case of a patient who underwent a diagnostic lung biopsy. RESULTS: Twenty-two case reports of patients receiving LTAs who developed CSS were identified. The onset of CSS occurred 2 days to 10 months after starting treatment with LTAs. All patients had received inhaled or oral steroids for asthma. The interval between the last oral corticosteroid treatment and CSS onset ranged from 3 days to 8 months. CONCLUSIONS: To date, there is no compelling evidence that the development of CSS in asthmatic patients receiving LTAs results from a direct drug effect. Rather, it appears that tapering of corticosteroids in these patients unmasks the multiorgan manifestations of the disease. We believe that the use of LTAs should not be influenced by the apparent increase in the incidence of CSS and that these are still safe drugs for asthma.