Background-The basis for progressive attenuation of the effects of organic nitrates during long-term therapy (nitrate tolerance) remains controversial; proposed mechanisms include impaired nitrate bioconversion resulting in decreased release of nitric oxide (NO) from nitrates and/or increased NO clearance through a reaction with incrementally generated superoxide (O 2 -). Methods and Results-Patients undergoing elective coronary artery bypass were randomized to receive 24 hours of intravenously infused nitroglycerin (NTG; nitrate group) or no nitrate therapy (control group). Discarded segments of the internal mammary artery and saphenous vein were used to examine (1) vascular responsiveness to NTG, sodium nitroprusside, and the calcium ionophore A23187; (2) bioconversion of NTG to 1,2-and 1,3-glyceryl dinitrate; and (3) the generation of O 2 -. Responses to NTG were reduced 3-to 5-fold in vessels from the nitrate group compared with control vessels (PϽ0.01 for both types of segments), whereas responses to sodium nitroprusside and A23187 were unchanged. Tissue content of 1,2-glyceryl dinitrate was lower (Pϭ0.012) in the saphenous veins from the nitrate group than in those from the control group. O 2 -generation was greater (PϽ0.01) in internal mammary artery samples from the nitrate group than in those from the control group. However, incremental O 2 -generation induced by an inhibitor of superoxide dismutase did not affect NTG responses. Conclusions-NTG tolerance in patients with coronary artery disease is nitrate-specific and is associated with evidence of impaired NTG bioconversion. Tolerance was associated with incremental O 2 -generation, but short-term elevation of O 2

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The self-reported prevalence of, and attitudes to and perceptions of, osteoporosis in the South Australian community were assessed using data collected as part of the 1995 South Australian Health Omnibus Survey (household interviews)--a clustered, self-weighting, multistage sample of households in metropolitan and country centers. The self-reported prevalence was 4.8 (95% CI: 3.7-5.8) and 1.4% (95% CI: 0.8-2.0) for women (n = 1531) and men (n = 1485) respectively. For individuals with osteoporosis, calcium was the favored treatment (52%), while 33% of women were on hormone replacement therapy. An appropriate definition of osteoporosis was given by 62% of women and 37% of men. The main risk factors were reported as lack of calcium and age. There was a significant association between knowledge of the definition of osteoporosis and identification of correct risk factors. A high perceived risk of osteoporosis was reported in 23% of women and 7% of men. Osteoporosis risk was assessed as higher in those who did not adopt recognized prevention measures. Perception of risk was not related to the individual's own risk factors. Self-reported prevalence of osteoporosis significantly underestimates the likely true prevalence and general awareness and knowledge is much lower for men than women. The importance of individual risk factors for osteoporosis are not understood by the general community.

Objective: To assess the management of patients with type 2 diabetes mellitus in the primary care setting, with respect to risk factors associated with coronary heart disease. Design: Retrospective cross‐sectional audit. Setting: Specialised diabetes assessment clinic in a tertiary referral teaching hospital. Participants: 328 patients with type 2 diabetes mellitus (mean age, 58.3 years [95% CI, 57.5–59.1]) and no existing coronary heart disease (CHD) referred to the clinic by general practitioners during 2004–2005. Main outcome measures: Comparison of glycated haemoglobin (HbA1c), systolic blood pressure and total cholesterol levels and smoking frequency with current RACGP (Royal Australian College of General Practitioners) targets (< 7.0%; < 130/80 mmHg; < 4 mmol/L; and smoking cessation, respectively). Estimation of patients’ 10‐year absolute risk of CHD events using the United Kingdom Prospective Diabetes Study risk engine, and its relation to primary prevention of CHD. Results: 42%, 61% and 43% of patients were receiving medication to treat hyperglycaemia, hypertension and hypercholesterolaemia, respectively; 46%, 29% and 15% of patients, respectively, had achieved the recommended RACGP target values for HbA1c, blood pressure, and total cholesterol; and 22% of patients were current smokers. The mean 10‐year absolute risk of CHD was 16.8% (95% CI, 15.7%–17.9%), and 48% of patients were classified as “high risk” (absolute risk, > 15%). Based on the 10‐year absolute risk, there was no difference between high‐ and low‐risk groups with respect to prescription of aspirin, statins or angiotensin‐converting enzyme inhibitors. If all the recommended RACGP goals were achieved, the mean 10‐year absolute risk would decrease to 12.6% (95% CI, 11.8%–13.4%). Conclusions: Recommended treatment targets are not being uniformly achieved. Medication for primary CHD prevention is not being preferentially directed at those patients at highest risk, based on the estimated 10‐year absolute risk of CHD events. Our findings suggest new initiatives are required in the way target goals and primary CHD prevention measures are set for patients with type 2 diabetes mellitus.

We describe two female siblings who had production of cortisol (F; as determined from excretion of urinary metabolites) high enough to give rise to Cushing's disease, but who had no clinical indications of the condition. The teenage patients were hirsute as a result of adrenal hyperandrogenism. A notable feature of the condition was the elevated excretion of corticosteroid metabolites with 11-carbonyl groups and very low excretion of 11 beta-hydroxylated steroids. We termed this disorder apparent cortisone (E) reductase disorder. The steroid metabolite phenotype appeared to be the opposite of that seen in the apparent mineralocorticoid excess syndrome, in which the excretion of 11-keto compounds is attenuated. As an example, the tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone ratio was about 0.04 compared to normal values of about 1.0 and apparent mineralocorticoid excess syndrome values of 5.0-50.0. Paradoxically, among the F metabolites that had not undergone A-ring reduction, 11 beta-hydroxylated steroids dominated over 11-carbonyl compounds. The F/E ratio was about 1.8 compared to an average normal value of 0.54. Neither the father nor the mother of the patient had abnormal F metabolite/E metabolite ratios, although the father did excrete highly elevated free E and F, possibly an unrelated condition. A conclusion was not reached regarding the basis of the disorder. We considered that the most likely causes were 1) defective hepatic 11 beta-hydroxysteroid dehydrogenase-1, 2) failure to develop the adult form of F metabolism, or 3) excessive activity of A ring reduction enzymes acting on E.

Abstract-Mutations in the kidney isozyme of human 11-hydroxysteroid dehydrogenase (11-HSD2) cause apparent mineralocorticoid excess, an autosomal recessive form of familial hypertension. We studied 4 patients with AME, identifying 4 novel and 3 previously reported mutations in the HSD11B2 (HSD11K) gene. Point mutations causing amino acid substitutions were introduced into a pCMV5/11HSD2 expression construct and expressed in mammalian CHOP cells. Mutations L179R and R208H abolished activity in whole cells. Mutants S180F, A237V, and A328V had 19%, 72%, and 25%, respectively, of the activity of the wild-type enzyme in whole cells when cortisol was used as the substrate and 80%, 140%, and 55%, respectively, of wild-type activity when corticosterone was used as the substrate. However, these mutant proteins were only 0.6% to 5.7% as active as the wild-type enzyme in cell lysates, suggesting that these mutations alter stability of the enzyme. In regression analyses of all AME patients with published genotypes, several biochemical and clinical parameters were highly correlated with mutant enzymatic activity, demonstrated in whole cells, when cortisol was used as the substrate. These included the ratio of urinary cortisone to cortisol metabolites (R 2 ϭ0.648, PϽ0.0001), age at presentation (R 2 ϭ0.614, PϽ0.0001), and birth weight (R 2 ϭ0.576, Pϭ0.0004). Approximately 5% conversion of cortisol to cortisone is predicted in subjects with mutations that completely inactivate HSD11B2, suggesting that a low level of enzymatic activity is mediated by another enzyme, possibly 11-HSD1. (Hypertension. 1999;34:638-642.)

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