GNRI is a simple and accurate tool for predicting the risk of morbidity and mortality in hospitalized elderly patients and should be recorded systematically on admission.

Background-Elevated circulating aldosterone level is associated with impaired cardiovascular function. Although the mechanisms are not fully understood, aldosterone antagonists decrease total and cardiovascular mortality in heart failure and myocardial infarction. Aldosterone induces cardiac fibrosis in experimental models, and it is synthesized locally in rat heart. These observations suggest pathological effects of aldosterone in heart that remain unclear. Methods and Results-Transgenic mice (TG) that overexpress the terminal enzyme of aldosterone biosynthesis, aldosterone synthase (AS), in heart have been raised by gene targeting with the ␣-myosin heavy chain promoter. AS mRNA increased 100-fold and aldosterone concentration 1.7-fold in hearts of male TG mice relative to wild-type. No structural or myocardial alterations were evidenced, because ventricle/body weight, AT 1 and AT 2 receptor binding, and collagen content were unchanged in TG. No alteration in cardiac function was evidenced by echocardiography, isolated perfused heart, or whole-cell patch clamp experiments. In contrast, coronary function was impaired, because basal coronary flow was decreased in isolated perfused heart (Ϫ55% of baseline values), and vasodilatation to acetylcholine, bradykinin, and sodium nitroprusside was decreased by 75%, 60%, and 75%, respectively, in TG mice compared with wild-type, showing that the defect was not related to NO production. Conclusions-Increased cardiac aldosterone production in male mice induces a major coronary endothelium-independent dysfunction with no detectable alterations in cardiac structure and function. However, coronary dysfunction may be harmful for coronary adaptation to increased flow demand.

In mineralocorticoid target tissues such as the cortical collecting duct in the kidney, the enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) is responsible for the peripheral inactivation of cortisol to cortisone, thereby protecting the mineralocorticoid receptor from inappropriate activation by cortisol. Mutations in the HSD11B2 gene cause the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of inherited hypertension in which cortisol acts as a potent mineralocorticoid. Herein are described six new families with mutations in the HSD11B2 gene causing hypokalemic hypertension, with low plasma aldosterone and low renin levels in affected individuals, indicating mineralocorticoid hypertension. Profiling of urinary steroid metabolites showed decreased cortisol inactivation, with urinary tetrahydrocortisol and tetrahydrocortisone ratio (THF ؉ 5␣THF)/THE ranging 2.4 to 40 and nearly absent urinary free cortisone in all but one case. Genetic analysis of the HSD11B2 gene from these patients with apparent mineralocorticoid excess revealed distinct homozygous point mutations in four families, a compound heterozygous mutation in one family, and a large 23-bp exonic insert with frameshift and disruption of the amino acid sequence in another family. Expression studies of mutants that were expressed in HEK-293 cells showed marked reduction or abolition of 11␤HSD2 enzymatic activity. These cases are reviewed along with previous ones from the authors' extensive personal experience to highlight the importance of 11␤HSD2 in the understanding of a new biologic principle in hormone action, demonstrating that local metabolism of the glucocorticoid hormones into inactive derivatives by the enzyme 11␤HSD2 is one of the mechanisms that intervene to allow specific aldosterone regulatory effects. (1) described a case of a 3-yr-old girl who had short stature, polydipsia, and polyuria without obvious external abnormalities, including her genitalia, and who had features of mineralocorticoid hypertension with hypokalemia and metabolic alkalosis. She had suppressed plasma renin and aldosterone, and gas-chromatographic analysis of her urinary steroid profile excluded hypertensive forms of congenital adrenal hyperplasia but showed an abnormal steroid profile (1). At that time, the authors failed to realize the true nature of the condition that this girl had, a syndrome that later was characterized biochemically and recognized by New et al. (2) and Ulick et al. (3). An inherited deficiency in the enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) has been shown to cause a disorder in the peripheral metabolism of cortisol that presents with hypokalemic hypertension and suppressed circulating renin and aldosterone (1-3). The typical clinical signs and symptoms of the originally described apparent mineralocorticoid excess (AME) also included low birth weight and failure to thrive. This form of mineralocorticoid hypertension was inherited as an autosomal recessive trait. The pathogenesis of AME was found to b...

We have developed a new assay for cortisone (E) in serum, saliva, and urine involving Celite® chromatography followed by RIA with 125I-labeled E and scintillation proximity assay. The chromatography step separates cortisol (F) from E, and in combination with their RIAs, permits assessment of the status of the F–E shuttle. We report the results of basal, postcorticotropin (ACTH), and postdexamethasone E and F concentrations and their circadian fluctuations in the serum, saliva, and urine of healthy volunteers. The serum and urine F/E ratios were increased in patients with ectopic ACTH secretion, whereas in adrenal adenoma and Cushing disease only the urinary ratio was increased. In chronic renal insufficiency this ratio was increased in serum (23.5 ± 3.9) but diminished in saliva (0.38 ± 0.11), and in apparent mineralocorticoid excess the ratios were high in serum (44.3 ± 9.3) and urine (5.35 ± 0.85) compared with those of healthy subjects (serum 9.8 ± 3.5, urine 0.52 ± 0.29, saliva 0.52 ± 0.29).

This attempt at a genotypic-angiographic correlation in an exudative AMD sample suggests an association between occult or MC CNV and the CFH polymorphism and between classic and PC CNV and the HTRA1 polymorphism.

We evaluated the involvement of a possible dysfunction of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the fetal growth retardation and poor growth rates of children born with intrauterine growth retardation (IUGR). Children with IUGR have a nephron deficit and are also at risk of developing cardiovascular diseases, high blood pressure, glucose intolerance, and dyslipidemia later in life. The major site of 11beta-HSD2 production is the kidney and its deficit causes hypertension. We investigated plasma concentrations of cortisol (F) and cortisone (E) and the F/E ratio in 26 control children and in 40 IUGR children without catch-up growth. We also determined cholesterol, HbA1C, insulin, and glucose levels in plasma. Mean F values were 106 +/- 54.2 ng/mL in control children and 114.6 +/- 53.2 ng/mL in IUGR children. Mean E values were 19.5 +/- 7.1 ng/mL in control children and 17.9 +/- 6.85 ng/mL in IUGR children. The mean F/E ratio for control children was 5.5 +/- 1.7. Eight (20%) of the IUGR children (IUGR children of group 1) had high F/E ratios more than 2 SD above the normal mean: 13.15 +/- 4.26, (p < 0.0001) as compared to control children, whereas the other 32 children (IUGR children of group 2) had normal F/E ratios: 5.40 +/- 1.43 (p = 0.68). Childhood height was significantly lower for group 1 than group 2 children (-3.63 SD and -2.92 SD, respectively: p < 0.01) and was negatively correlated with the F/E ratio (p < 0.01). Systolic blood pressure was higher for group 1 (p = 0.005) and for group 2 (p = 0.015) than for control children. The diastolic pressure in IUGR children of group 1 was higher than that in control children (p = 0.013) and slightly higher than that in group 2 (p = 0.1, ns). Cholesterol concentrations were higher in group 1 than in group 2 (p = 0.029), and controls (p = 0.017) and correlated positively with F/E (0.02 < p < 0.05). Fasting insulin concentrations were higher in group 1 than in group 2 (ns) and controls (ns). There was no difference in mean fasting glucose concentrations, or HbA1C between the three groups. Twenty percent of our children with IUGR and poor growth rates had high F/E ratios, suggesting a possible partial 11beta-HSD2 deficit. Whether these children are at high risk of developing cardiovascular diseases as adults remains to be further evaluated.

The BOSSANOVA study, a randomized double-blind trial, was designed to test the ability of very low oral doses of vitamin B-12 to increase the serum vitamin B-12 concentration in elderly subjects with food-bound vitamin B-12 malabsorption, and to determine whether there was a dose response. We also aimed to quantitatively assess the most efficient dose to be added to flour in addition to folic acid (flour cofortification with vitamin B-12 and folic acid). Sixty-seven patients were randomly assigned to 1 of 6 groups receiving various daily oral doses of vitamin B-12 (i.e., 2.5, 5, 10, 20, 40, or 80 microg/d) for 30 d. The dose-response was tested for different biological variables using a mixed model, taking into account the variable's initial value (between-subject effect), a linear log-dose effect, and a linear log (dosextime) interaction, where time was d 15 or d 30. We planned to determine the amount of oral vitamin B-12 that would increase the serum vitamin B-12 concentration by 37 pmol/L (50 ng/L). Significant between-subject effects were found for serum vitamin B-12, plasma homocysteine, and methylmalonic acid concentrations, but a log-dose effect was found only for vitamin B-12 (P<0.001). The slope of the line tended to be higher (P=0.07) at d 30 than at d 15. For a mean serum vitamin B-12 increase of 37 pmol/L, a dose of 5.9 (95% CI, 0.9-12.1) microg/d was needed. We concluded that very low oral doses of vitamin B-12 increased serum vitamin B-12 concentrations in elderly subjects with subclinical vitamin B-12 deficiency, following a log-dose pattern. Our results could be beneficial in the design of a public health program for safe flour cofortification with folic acid.

Cortisol and cortisone concentrations in serum and follicular fluid (FF) from women undergoing in-vitro fertilization (IVF) treatment were monitored. Four groups were included: group 1, women in their natural menstrual cycle having an endogenous mid-cycle surge of gonadotrophins; group 2, women in their natural menstrual cycle receiving human chorionic gonadotrophin (HCG) for ovulation induction; group 3, women receiving exogenous gonadotrophins for ovarian stimulation and HCG for ovulation induction; and group 4, women receiving exogenous gonadotrophins for ovarian stimulation, follicles being aspirated immediately before administration of HCG. In this study, 12 follicles contained oocytes which resulted in clinical pregnancy after IVF. Cortisone concentrations were significantly higher in FF compared with that of matched serum samples, while the opposite was observed for cortisol, resulting in cortisol:cortisone ratios being significantly lower in FF compared with serum. FF from group 4 showed significantly higher cortisone concentrations than FF from each of the other three groups. FF from group 1 showed significantly higher cortisone concentrations and significantly lower cortisol:cortisone ratios in comparison with groups 2 and 3. None of the observed parameters pinpointed any of the follicles containing oocytes which resulted in a clinical pregnancy. The intrafollicular concentrations of cortisol and cortisone suggest that pre-ovulatory follicles actively convert cortisol to cortisone. Neither FF concentrations of cortisol and cortisone nor the cortisol:cortisone ratio seem to reflect implantation potential of the derived pre-embryos.