Acute injection of 17beta-estradiol enhances cardiovascular reflexes and autonomic tone in ovariectomized female rats

Among the many benefits of long-term hormone replacement therapy to postmenopausal women is a significant reduction in risk for and progression of cardiovascular disease. However, long-term estrogen replacement therapy has been associated with several undesirable, and likely dose-dependent, side-effects. There is some evidence to suggest that the dose of estrogen which confers optimal beneficial effects on the cardiovascular system is much lower than that which is currently prescribed for postmenopausal women. The following experiments were conducted to determine the dose-response relationship of acutely administered estrogen on autonomic tone and reflex control of heart rate in ovariectomized Sprague-Dawley female rats. Rats were anaesthetized with sodium thiobutabarbital (100 mg/kg) and instrumented to record blood pressure, heart rate and efferent parasympathetic and sympathetic nerve activities. The sensitivity of the cardiac baroreflex was tested using intravenous injection of either phenylephrine hydrochloride (0.025-0.1 mg/kg) or sodium nitroprusside (0.0025-0.01 mg/kg). Intravenous injection of estrogen produced dose-dependent increases in the magnitude of the baroreflex sensitivity and parasympathetic tone while reducing sympathetic tone with a maximal effect observed at 1 x 10(-3) mg/kg. Prior administration of the selective estrogen receptor antagonist, ICI 182,780 blocked the estrogen-induced changes in baroreflex sensitivity and autonomic tone. These results demonstrate that acutely administered, low-dose estrogen has beneficial effects on autonomic tone and cardiovascular reflexes.     

Synthesis and biological activity of analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid: discovery of a novel aminoguanidinoacetic acid antidiabetic agent

3-Guanidinopropionic acid (1, PNU-10483) has been demonstrated to both improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate 4. In an effort to identify novel entities that maintain antidiabetic potency without susceptibility to creatine-like metabolism, an analogue program was undertaken to explore the effects of various structural modifications, including homologation, simple substitution, single atom mutations, and bioisosteric replacements for the guanidine and carboxylic acid. Overall, the scope of activity encompassed by the set of new analogues proved to be exceedingly narrow. Notable exceptions demonstrating equivalent or improved antidiabetic activity included the alpha-amino derivative 29, aminopyridine 47, isothiourea 67, and aminoguanidine 69. On the basis of its superior therapeutic ratio, aminoguanidine 69 was selected for preclinical development and became the foundation for a second phase of analogue work. Furthermore, in vitro studies demonstrated that 69 is markedly less susceptible to phosphorylation by creatine kinase than the lead 1, suggesting that it should have less potential for accumulation in muscle tissue than 1.     

Volunteers at risk.

An experiment is described in which three male volunteers, who fully understood the nature of the project, were given doses of heroin which could have led to addiction if the subjects had proved to be physiologically or psychologically vulnerable to developing a state of addiction. The experiment was discussed most carefully by the Ethics Committee of the unit where it was conducted, and the subjects were themselves the investigators. The objective was to learn about the initial stages of the adaptation to heroin, of which nothing was known as heroin addicts usually come to the doctor when the habit is firmly established. A physician, who has studied the subject of drug addiction in a special clinic, is the first commentator, the second a lawyer and the third an associate professor of social ethics. These three experts are not discussing the results or the methodology of the experiment but whether the decision of the Ethics Committe was the right one.     

Clostridium difficile enteritis: A new role for an old foe

BackgroundSmall bowel involvement of Clostridium difficile is increasingly encountered. Data on many management aspects are lacking.AimTo synthesis existing reports and assess the frequency, pathophysiology, outcomes, risk factors, diagnosis and management of C. difficle enteritis.MethodsA systematic review of the literature was conducted to evaluate evidence regarding frequency, pathophysiology, risk factors, optimal diagnosis, management and outcomes for C. difficle enteritis. Three major databases (PubMed, MEDLINE and the Cochrane Library) were searched. The review included original articles reporting C. difficle enteritis from January 1950 to December 2012.ResultsC. difficle enteritis is rare but increasingly encountered. Presentation is variable and distinct predisposing factors include emergency surgery, white race and increased age. Diagnosis generally involves a sensitive but often non specific screening test for C. difficile antigens. Oral metronidazole represents first line therapy and surgery may be required for complications. Outcomes are inconsistent but may be improving.ConclusionsA high index of clinical suspicion, early diagnosis and treatment are vital. Further prospective studies are needed to determine the significance of asymptomatic small bowel C. difficile infections.     

Decreased insulin sensitivity during dietary sodium restriction is not mediated by effects of angiotensin II on insulin action

We have previously reported that modest dietary sodium restriction, as advocated in management guidelines for diabetes, may reduce insulin sensitivity. It has since been suggested that this effect may be mediated via cross-talk between insulin and angiotensin II (AII)-stimulated intracellular second messengers. In order to assess the effect of 5 days of modest sodium restriction (to <80 mmol/day target sodium intake) on insulin sensitivity, 15 healthy males underwent a double-blind, placebo-controlled, randomized, cross-over euglycaemic hyperinsulinaemic clamp study. One phase was supplemented with sodium tablets and the other with matched placebo. Insulin sensitivity (M) was reduced during dietary sodium restriction [median M value, 10.2 mg/kg per min (interquartile range 9.50-13.85) versus 12.8 mg/kg per min (interquartile range 9.60-14.30), P <0.05]. To elucidate potential mechanisms that may explain this observation, we investigated the effect of AII on insulin action in isolated adipocytes obtained from healthy females. No effect of AII on insulin-mediated glucose transport or suppression of lipolysis was observed. In conclusion, despite the observation that dietary sodium restriction was associated with a median 15% reduction in insulin sensitivity, we found no evidence of a direct effect of AII on insulin action in human adipocytes.     

Determination of the burden of hepatitis C virus infection in Ireland

Information on the burden of hepatitis C virus (HCV) disease is needed to inform policy decisions on primary and secondary prevention. Specimen-based laboratory data (1989-2004) were converted to person-based data and combined with notification data (2004-2009) to describe the burden of HCV infection in Ireland. More than 10,000 people were confirmed as HCV infected in 1989-2004, with the numbers peaking in 2000. The predominant genotypes were 1 (55%) and 3 (39%). Drug use was the most likely risk factor in 80%, with receipt of blood or blood products in 16%. It is estimated that 20 000-50,000 people in Ireland are chronically infected with HCV, a population prevalence of 0·5-1·2%, which is similar to other countries in Northern Europe. This is the first published estimate of the number of chronic HCV infections in Ireland. These data will be of value in health service planning and will contribute to the understanding of HCV infection in Europe.