R 75251, a new inhibitor of steroid biosynthesis

R 75251, a new imidazole derivative, inhibited the conversion of androgens to estrogens, of progestins to androstenedione and testosterone, and of 11-deoxycorticosterone to corticosterone in human placenta microsomes, subcellular fraction of rat testis, bovine adrenocortical mitochondria, in cultured rat granulosa, testicular and adrenal cells, respectively. In vitro, no effect on cholesterol synthesis and cholesterol side-chain cleavage was found at concentrations up to 10 microM. In rat granulosa cells, no effect on progesterone production was detected. In vitro, no effect on steroid radioligand binding was observed. In male volunteers, a single dose of 300 mg of R 75251 significantly lowered plasma testosterone and estradiol for 24 hours and increased plasma concentration of 17 alpha-hydroxyprogesterone and progesterone. As compared with ketoconazole high dose (600 mg b.i.d), R 75251 (300 mg b.i.d) was at least as efficacious as inhibitor of testosterone synthesis when studied during ACTH stimulation. In contrast to ketoconazole, R 75251 did not significantly affect circulating adrenal androgen levels in male volunteers. Precursors of gluco- and mineralocorticoids such as 11-deoxycortisol and 11-deoxycorticosterone accumulated more than after ketoconazole administration. The data show that the cytochrome P450-dependent aromatase, 17-hydroxylase/17,20-lyase, and 11-hydroxylase are the target enzymes for R 75251.     

Effect of a glutamine-supplemented enteral diet on methotrexate-induced enterocolitis

Administration of an elemental diet to rats given methotrexate (MTX), 20 mg/kg intraperitoneally (ip), results in 100% mortality from severe enterocolitis. Previous studies indicate that glutamine (GLN), which is not present in elemental diets, is the preferred oxidative substrate for the gut and may facilitate intestinal recovery after injury. This study investigated the effects of a glutamine-supplemented elemental diet (GLN-ED) on nutritional status, intestinal morphometry, bacterial translocation and survival in this lethal model of intestinal injury. Three experiments were performed. In the first experiment, rats received an intragastric elemental diet supplemented with either 2% GLN or an equivalent amount of glycine (Control). After 4 days animals received either MTX, 20 mg/kg ip, or saline ip and were killed 3 days later. The GLN-ED resulted in significantly decreased weight loss, improved nitrogen retention, and increased mucosal weight, protein, and DNA content of the jejunum and colon. In the second experiment rats were assigned to diet as in the first experiment, but all animals received MTX. Control diet animals died within 120 hrs of MTX administration. The GLN-ED group had significantly longer survival time and decreased mortality. In the third experiment animals were assigned to diet and MTX as in the first experiment. Ninety-six hrs later aortic blood cultures revealed enteric bacteremia in animals administered MTX. GLN-ED resulted in a significant reduction in the incidence of bacteremia. These experiments showed that a GLN-ED significantly improved nutritional status, decreased intestinal injury, decreased bacterial translocation, and resulted in improved survival in a lethal model of enterocolitis.     

Instrumentation and patient characteristics that influence postoperative haemorrhage rates following tonsil and adenoid surgery

Objectives: To investigate the effect of the type instrumentation used and the age and gender characteristics of patients on postoperative haemorrhage rates following tonsil and adenoid surgery. Design: A retrospective analysis of 13 593 procedures was performed from The Patient Episode Database for Wales between 1 January 1999 and 31 March 2004. Setting: National health policy changes created four periods of different instrument usage (reusable, single‐use with diathermy, single‐use alone, specified single‐use with diathermy). These and the age and gender distribution of the patients were examined against four categories of postoperative haemorrhage. Main outcome measures: Postoperative haemorrhage rates were expressed as the number of complications per operations performed. Primary postoperative haemorrhage that occurred during the initial admission either required a return to theatre [R1] or was managed conservatively [N1]; secondary postoperative haemorrhage that required a return to hospital either returned to theatre [R2] or was managed conservatively [N2], were compared. Results: Primary haemorrhage with return to theatre doubled, from the baseline rate with reusable instruments, from 0.6% (CI 0.5–0.8) to 1.2% (CI 0.7–1.9) when single‐use instruments were introduced and remained high at 1.4% (CI 0.9–2.1) after the withdrawal of single‐use diathermy. This haemorrhage rate returned to the baseline rate (0.6% CI 0.3–1.0) when specified single‐use instruments were introduced. None of the other haemorrhage rates changed significantly throughout the four observation periods. Adenotonsillectomy and tonsillectomy patients have different age and gender patterns. In a univariate analysis, males over the age of 12 years were twice as likely to have haemorrhage with return to theatre than girls of the same age, 3.8% (CI 3.0–4.7) versus 1.7% (CI 1.4–2.1). Conclusions: A significant rise in serious postoperative primary haemorrhage but not secondary haemorrhage was seen following the initial introduction of single‐use instruments that reverted to baseline with the introduction of specified single‐use instruments. Diathermy does not appear to have affected the haemorrhage rates. There is a distinct age and gender pattern for tonsil and adenoid surgery and risk of postoperative haemorrhage. The use of arbitrary divisions of age may be misleading in studies that examine post‐tonsillectomy haemorrhage.     

Genotype/phenotype correlation of the G85E mutation in a large cohort of cystic fibrosis patients.

In this European study, the phenotype in 68 patients, homozygous or compound heterozygous for the G85E mutation, was investigated. Each index case was compared with two cystic fibrosis (CF) patients from the same clinic, matched for age and sex: one with pancreatic sufficiency (PS) and one with pancreatic insufficiency (PI). When comparing 31 G85E/F508del and F508del/F508del patients, there were no differences in median age at diagnosis, mean sweat chloride value, most recent weight for height, most recent forced expiratory volume in one second % predicted, prevalence of chronic Pseudomonas aeruginosa colonisation and typical CF complications. However, PI was less frequent in the G85E/F508del group. Comparison of 55 G85E patients (with second mutation known and not classified as mild) with PS controls (n=44) showed that the G85E patients had a significantly higher sweat chloride, more often failure to thrive at diagnosis, higher prevalence of PI, worse current weight for height, higher prevalence of chronic P. aeruginosa colonisation and liver cirrhosis. Pulse-chase experiments revealed that G85E cystic fibrosis transmembrane conductance regulator failed to mature on a M470 as well as on a V470 background. Therefore, G85E is a class II mutation. Although there is variability in its clinical presentation, G85E mutation results in a severe phenotype.     

Historical overview of analytical methods for the measurement of transthyretin.

The history of prealbumin dates back to the early forties and may be divided into three parts, based on a chronological and functional approach. The first part--the discovery and the identification of prealbumin--was essentially based on classical protein chemistry methods. The second--the demonstration of prealbumin as a thyroid hormone-binding protein (thyroxine-binding prealbumin)--has greatly benefited from isotopic techniques. The third one--establishing prealbumin as a nutritional marker--was a result of field studies on nutrition. The discovery of the role of prealbumin in retinol binding led to a change in its name, prealbumin becoming transthyretin. Finally, structural studies and mutation analysis of transthyretin in patients with amyloid neuropathy have opened a new area of research.     

Burnout in nursing.

OBJECTIVE: Previous research has suggested that organisational change can contribute to stress-related outcomes for workers. Burnout, one such stress-related outcome, has been conceptualised as a multidimensional construct consisting of emotional exhaustion, depersonalisation and reduced personal accomplishment. Many health care organisations have undergone substantial organisational change over the last decade. The purpose of this study was to assess levels of burnout in nurses and to ascertain if there were individual or work characteristics that were associated with this syndrome. DESIGN: Randomised survey methodology. SETTING: Registered nurses (Division 1) in Victoria who were ANF members. SUBJECTS: A random sample of 574 Victorian ANF nurse members. MAIN OUTCOME MEASURES: The assessment of levels of burnout in Victorian ANF nurse members and the identification of individual or work characteristics that may be associated with it. RESULTS: Victorian ANF nurse members exhibited lower depersonalisation and higher personal accomplishment compared to medical and overall normative data. Increasing age and fewer working hours were associated with lower levels of emotional exhaustion and depersonalisation. Working overtime was positively associated with emotional exhaustion however further analyses demonstrated that those who worked overtime voluntarily did not differ from workers not working overtime. However feeling pressured/expected to work overtime was positively associated with emotional exhaustion and depersonalisation. CONCLUSION: Victorian ANF nurse members were not experiencing high levels of burnout. However the study highlighted the need for health care management to recognise the importance of working reasonable hours and in particular, to understand the potential detrimental effect that having to work pressured or unexpected overtime has on staff.