Estradiol increases angiotensin II type 1 receptor in hearts of ovariectomized rats.

We tested the hypothesis that 17beta-estradiol (E(2)) has dual effects on the heart, increasing levels of proteins thought to have beneficial cardiovascular effects (e.g. endothelial nitric oxide (NO) synthase (eNOS)) as well as those thought to have detrimental cardiovascular effects (e.g. type 1 angiotensin II (AngII) receptor (AT(1)R)). Ovariectomized Wistar rats consuming a high-sodium diet received one of four treatments (n=7 per group): group 1, placebo pellets; group 2, E(2) (0 x 5 mg/pellet, 21-day release); group 3, NOS inhibitor, N(omega)-nitro-L-arginine-methyl-ester (L-NAME; 40 mg/kg per day for 14 days) plus Ang II (0 x 225 mg/kg per day on days 11-14); group 4, E(2) plus L-NAME/Ang II. E(2) increased cardiac levels of estrogen receptors ESR1 and ESR2, an ESR-associated membrane protein caveolin-3, eNOS, and phosphorylated (p)eNOS, thus, exerting potentially beneficial cardiovascular effects on NO. However, E(2) also increased cardiac levels of proteins associated with cardiovascular injury and inflammation including, AT(1)R, protein kinase C delta (PRKCD), phosphorylated PRKC, and phosphorylated extracellular signal regulated kinase (pMAPK)3/1, plasminogen activator inhibitor-1 (PAI-1), osteopontin and ED-1, a monocyte/macrophage-specific protein. E(2) treatment led to similar protein changes in the hearts of L-NAME/Ang II-treated rats except that the increase in peNOS was prevented, and L-NAME/Ang II and E(2) had additive effects in increasing cardiac PRKCD and PAI-1. Thus, the highest levels of cardiac PAI-1 and PRKCD occurred in L-NAME/Ang II-treated rats receiving E(2). In summary, E(2) treatment increased cardiac expression of AT(1)R as well as the expression of pro-inflammatory and prothrombotic factors.

Usefulness of aminoterminal pro-brain natriuretic peptide testing for the diagnostic and prognostic evaluation of dyspneic patients with diabetes mellitus seen in the emergency department (from the PRIDE Study).

Despite widespread testing, the utility of aminoterminal pro-brain natriuretic peptide (NT-pro-BNP) for diagnosis or risk assessment in patients with diabetes mellitus (DM) in the emergency department (ED) remains unclear. NT-pro-BNP was measured in subjects with dyspnea in the ED. A final diagnosis of acute heart failure (HF) was determined by blinded study physicians using all available hospital records. Vital status was assessed at 1 year; independent predictors of death were identified using Cox analysis. Of 599 subjects, 157 (26.2%) had DM, which was an independent predictor of a final diagnosis of acute HF. In patients diagnosed with acute HF, median concentrations of NT-pro-BNP were similar in patients with and without DM (4,784 vs 3,382 pg/ml, respectively, p = 0.93). In dyspneic subjects without acute HF, median concentrations of NT-pro-BNP were significantly higher in patients with DM (242 vs 115 pg/ml, p = 0.01), but this difference was no longer significant after adjusting for relevant covariates. The area under the curve for NT-pro-BNP to diagnose acute HF in subjects with DM was 0.94 (p <0.001). Using age-adjusted cutpoints, NT-pro-BNP was 92% sensitive and 90% specific for the diagnosis of HF in diabetic subjects. In diabetic patients, a NT-pro-BNP level > or =986 pg/ml was independently associated with an increased risk of death at 1 year (hazard ratio 3.42, 95% confidence interval 1.09 to 10.7, p <0.001). In conclusion, NT-pro-BNP testing offers valuable diagnostic and prognostic information in the evaluation of dyspneic patients with DM in the ED, using identical cutpoints as the population as whole.

Amino-terminal pro-brain natriuretic peptide, brain natriuretic peptide, and troponin T for prediction of mortality in acute heart failure.

BACKGROUND: Combining testing for natriuretic peptides [amino-terminal pro-brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP)] and cardiac troponin T (cTnT) may help predict mortality in patients with acute heart failure (HF). METHODS: We studied 209 patients with acute HF at an urban academic center and used ROC curves and multivariate analyses to examine the relationship of outcome to natriuretic peptide and cTnT concentrations at presentation. RESULTS: Higher concentrations of natriuretic peptides and cTnT at presentation were predictors of death at 60 days and 1 year (P <0.001 and P <0.01, respectively, at both time points). Optimal cutoff points for NT-proBNP, BNP, and cTnT for predicting death by 60 days or 1 year were 5562 and 3174 ng/L, 428 and 352 ng/L, and 0.01 and 0.01 microg/L, respectively. Most decedents demonstrated increased concentrations of both natriuretic peptides and cTnT and had a 25% mortality rate at the 60-day time point (P <0.001). Mortality rates were low (<4%) among patients with either no increase or an increase in only 1 marker. Decedents with increases in both a natriuretic peptide and cTnT at presentation had the highest death rate at 1 year (45%, P <0.001). This combination was strongly predictive of death [NT-proBNP plus cTnT: hazard ratio (HR), 7.66; 95% confidence interval (CI), 3.06-17.8; BNP plus cTnT: HR, 6.82; 95% CI, 2.99-16.5]. CONCLUSIONS: A dual-marker strategy incorporating a natriuretic peptide and cTnT is superior to either marker alone for estimating short- and longer-term risk in patients with acute HF.

Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus.

To determine whether mineralocorticoid receptor (MR) activation plays a role in diabetic renal injury and whether this role differs in types 1 and 2 diabetes mellitus, we examined the effect of a MR antagonist on renal injury in rodent models of type 1 (streptozotocin-treated rat) and type 2 (db/db mouse) diabetes. We studied three groups of 8-wk-old, uninephrectomized Wistar rats for 4 wk: diabetic streptozotocin- (55 mg/kg) treated rats (n = 11), diabetic streptozotocin-treated rats receiving the MR antagonist eplerenone (n = 15), and nondiabetic rats (n = 9). In addition, we studied three groups of 8-wk-old mice for 16 wk: diabetic db/db mice (n = 10), diabetic db/db mice treated with eplerenone (n = 8), and nondiabetic, db/+ littermates (n = 11). Diabetic rats and mice developed albuminuria and histopathological evidence of renal injury, including glomerular hypertrophy, mesangial expansion, and tubulointerstitial injury as well as increased renal cortical levels of MR protein, MR mRNA, TGFbeta mRNA, and osteopontin mRNA. All of these changes were significantly reduced by treatment with eplerenone except for the elevated MR levels. The beneficial effects of eplerenone were not attributable to changes in blood pressure or glycemia. In summary, MR expression was increased in kidneys of diabetic rodents, and MR antagonists effectively reduced diabetic renal injury irrespective of the species or specific cause of the diabetes. Thus, these data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.

Reversal of hypogonadotropic hypogonadism with tamoxifen in a patient with hyperprolactinemia resistant to dopamine agonists.

OBJECTIVE: To determine the response to tamoxifen in a woman with hypogonadotropic hypogonadism induced by hyperprolactinemia resistant to dopamine agonist drugs. DESIGN: Case report. SETTING: Academic fertility center. PATIENT(S): A young woman with persistent amenorrhea, symptomatic hypogonadotropic hypogonadism, and hyperprolactinemia. INTERVENTION(S): Tamoxifen was administered in addition to bromocriptine. MAIN OUTCOME MEASURE(S): Measurements of follicle-stimulating hormone, estradiol, prolactin, and progesterone. RESULT(S): Recovery of gonadal-hypothalamic-pituitary axis. CONCLUSION(S): Tamoxifen can revert the effects of chronic hypogonadotropic hypogonadism induced by hyperprolactinemia resistant to dopamine agonists.

Bilateral oophorectomy in a pregnant woman: hormonal profile from late gestation to post-partum: case report.

BACKGROUND: A 16 week pregnant woman presented with massive theca-lutein cysts requiring bilateral oophorectomy. Pregnancy progressed uneventfully and spontaneous lactation ensued after delivery. METHODS: To study the role of the ovary on the hormonal profile at the end of gestation and in post-partum, we measured FSH, estradiol (E2), unconjugated estrone (E1), unconjugated estriol (E3), sex hormone-binding globulin, progesterone, dehydroepiandrosterone sulphate and prolactin at 37 weeks gestation and at 8 h, 4 days, 5 weeks, and 2 months post-partum. RESULTS: These hormones were within the range expected for ovary-intact pregnant and puerperal women until 4 days post-partum. At 5 weeks post-partum, FSH increased to a peri-menopausal range (31.4 IU/l) while estrogens remained within the normal puerperal range (E2=239 pmol/l; E1=102 pmol/l), contrasting with their rapid changes in non-pregnant women after bilateral oophorectomy. At 2 months, while partially breastfeeding, FSH, E2 and E1 were closer to menopausal range (68 IU/l, 136 and 70.2 pmol/l respectively), and hormone replacement was started. CONCLUSIONS: We conclude that the ovary is not required to maintain a normal hormonal profile in late pregnancy and early puerperium. However, the increase in FSH to peri-menopausal levels at 5 weeks post-partum, despite breastfeeding, suggests that the ovary is needed to maintain low FSH concentrations during lactation.

Novel intronic mutation of MEN1 gene causing familial isolated primary hyperparathyroidism.

Primary hyperparathyroidism may occur as part of hereditary syndromes, including multiple endocrine neoplasia types 1 and 2A (MEN1 and MEN2A), hyperparathyroidism-jaw tumor syndrome, and the familial isolated hyperparathyroidism (FIHP). It is unclear whether FIHP corresponds to a different genetic entity or a variant of MEN1 (or hyperparathyroidism-jaw tumor syndrome). We report a patient and 11 family members with FIHP in whom we identified a heterozygous G-to-A mutation at nucleotide 7361 of tumor suppressor MEN1 gene. This mutation is located in the first base of intron 9 (IVS9 + 1 G>A). All the family members with hyperparathyroidism were heterozygous for the intronic mutation. In vitro studies were performed in COS cells transfected with minigenes carrying the coding regions spanning exon-intron 9 and 10 with the mutant and the wild-type sequences. RT-PCR analyses showed an abnormal mRNA of greater size (829 bp) in the mutated MEN1 gene than the normal transcript (629 bp). The longer PCR product includes the exon 9, the unspliced intron 9, and part of exon 10. RT-PCR of MEN1 mRNA from patient's blood confirmed the existence of unspliced intron 9 in mature mRNA. In summary, we report a case of FIHP associated with a new intronic heterozygous germline mutation (IVS9 + 1 G>A) of MEN1 gene. This mutation produces an aberrant splicing of mRNA that could lead to a truncated protein, without activity, explaining the clinical picture of this patient and his family.

Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/NG-nitro-L-arginine methyl ester-induced myocardial injury.

BACKGROUND: Angiotensin II (Ang II) increases levels of aldosterone and plasminogen activator inhibitor-1 (PAI-1). Both aldosterone and PAI-1 seem to promote cardiovascular (CV) injury. Our objective was to determine the roles of PAI-1 and aldosterone in the development of myocardial and renal damage in a model with high Ang II and low nitric oxide (NO) availability, a pattern seen in patients with heart failure, diabetes mellitus, and arteriosclerosis. METHODS AND RESULTS: Mice on a moderately high sodium diet were treated with the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) for 14 days plus Ang II during days 8 through 14. The roles of aldosterone and PAI-1 in the development of CV injury were assessed using the mineralocorticoid receptor antagonist spironolactone (0, 1.5, 15, and 50 mg x 100 g(-1) x day(-1)) and PAI-1-deficient mice (PAI-1-/-). Ang II/L-NAME-treated mice showed glomerular ischemia, proteinuria, and necrosis of myocytes and vascular smooth muscle cells with an associated mixed inflammatory response, deposition of loose collagen, and neovascularization. Compared with saline-drinking mice, Ang II/L-NAME-treated mice had significantly increased heart to body weight (HW/BW) ratios, cardiac and renal damage assessed by histological examination, PAI-1 immunoreactivity, and proteinuria. Spironolactone treatment decreased PAI-1 immunoreactivity and reduced in a dose-dependent fashion cardiac and renal damage. PAI-1-/- animals had a similar degree of CV injury as PAI-1+/+ animals. CONCLUSIONS: Mineralocorticoid receptor antagonism, but not PAI-1 deficiency, protected mice from developing Ang II/L-NAME-mediated myocardial and vascular injury and proteinuria, suggesting that aldosterone, but not PAI-1, plays a key role in the development of early Ang II/L-NAME-induced cardiovascular injury.

Cardiac damage prevention by eplerenone: comparison with low sodium diet or potassium loading.

To determine the extent to which dietary sodium modulates aldosterone-induced cardiovascular damage, and to determine whether increased dietary potassium can prevent this damage, we used the Nomega-nitro-L-arginine methyl ester (L-NAME)/angiotensin II (Ang II) rat model of cardiac injury. This model is dependent on the presence of aldosterone for the occurrence of myocardial damage. Two sets of experiments were performed. In the first set, the following groups were studied: (1) 1% NaCl to drink (control group); (2) L-NAME/Ang II with water to drink (low salt group); (3) L-NAME/Ang II/1% NaCl (high salt group); (4) L-NAME/Ang II/1% NaCl/eplerenone (eplerenone group). Systolic blood pressure increased similarly in all groups compared with controls. Compared with the controls, the high salt group, but not the low salt or eplerenone groups, developed significant myocardial damage. In the second set of experiments three groups of animals were studied: (1) L-NAME/Ang II/1%NaCl (high salt group) (2) L-NAME/Ang II/1%NaCl/eplerenone (eplerenone group), and (3) L-NAME/Ang II/1%NaCl with an extra 1% KCl in food (high dietary potassium group). Eplerenone, but not dietary potassium supplementation, prevented the development of cardiac damage. Thus, mineralocorticoid receptor antagonist treatment and low sodium diet were effective in preventing cardiac damage, which suggests that a minimal level of aldosterone and a moderately high sodium diet are both required for the development of the cardiovascular damage in the L-NAME/Ang II model. The inability of potassium supplementation to reduce myocardial damage suggests that eplerenone's protective effect is not due to its potassium-sparing ability, but is rather related to some other feature of its selective aldosterone antagonism.

Actualizaciones en la terapia médica de la neuralgia postherpética (NPH) / Updating in the therapy of the post-herpetic neuralgia (PHN)

El Herpes Zoster es una neuritis sensitiva causada por reactivación del virus Varicela-Zoster, latente en uno o más ganglios de las raíces dorsales. Se presenta generalmente con hiperalgia y dolor lancinante en la superficie cutánea inervada por la raíz afectada, durante 3 a 4 días; seguido de la aparición de una erupción vesicular, con base eritematosa, habitualmente en el mismo dermatomo. El dolor suele ser de tipo urente; se acompaña de anestesia, hiperestesia (80 por ciento de los casos) o de alodinia (50 por ciento de los casos). En el 90 por ciento de los pacientes el curso es autolimitado, desapareciendo las lesiones dérmicas y el dolor en 4 a 6 semanas. La persistencia del dolor, posterior a la curación de las lesiones cutáneas, por más de 6 semanas constituye la principal complicación del Herpes-Zoster: La Neuralgia Postherpética (NPH)