Managing geriatric hypertension: a brief review

The possibility of "pseudo hypertension" should be suspected in geriatric patients who, despite high blood pressure measurements, have vessels that feel rigid, have minimal vascular damage in the retina or elsewhere, and who experience inordinate postural dizziness despite cautious therapy. It should be remembered that sluggish baroreceptor function and reduced cardiovascular sensitivity to catecholamines make the elderly more sensitive to natural or drug-induced falls in blood pressure.     

Comparison of nucleotide interactions in water, proteins, and vacuum: model for DNA polymerase fidelity.

We propose a model for DNA polymerase fidelity in which free energy differences, delta delta G, between matched and mismatched nucleotides are magnified at the enzyme's active site. Both hydrogen bonding and stacking components of the interaction energy are amplified, with the most profound effect being on the magnitude of hydrogen-bonding interactions. Magnification in delta delta G values follows from the exclusion of water around base pairs in the active site cleft of the enzyme. After showing that base-pair dissociation energies calculated from hydrogen-bonding and base-stacking interactions in vacuo are greatly reduced by water, it is proposed that water removal results in a proportional restoration of these contributions to base pairing. Assuming approximately equal to 40% exclusion of surrounding water, one predicts magnified values of delta delta G sufficient to account for polymerase insertion and proofreading fidelity, thereby avoiding the need to postulate additional active site constraints in order to select or reject nucleotides.     

The relationship of longitudinal change in reproductive hormones and vasomotor symptoms during the menopausal transition

CONTEXT: The relationship of reproductive hormones to vasomotor symptoms (VMS) has been incompletely explored, although an increase in such symptoms at midlife and their reduction with hormone therapy suggest a strong and direct relationship. Vasomotor symptoms are reported by 65-76% of women traversing the menopausal transition and are a primary reason for medical intervention during this life stage. OBJECTIVE: The purpose of this report was to relate longitudinal serum concentrations of the reproductive hormones estradiol (E2), FSH, testosterone (T), dehydroepiandrosterone sulfate (DHEAS), and SHBG and the free hormone indices free E2 index (FEI) and free T index (FTI) with the occurrence of VMS in women traversing the menopausal transition. Design and Setting: The Study of Women's Health Across the Nation is a multisite, longitudinal, cohort study of the menopausal transition being conducted in community-based groups of women. PARTICIPANTS AND MAIN OUTCOME MEASURES: At baseline, 3302 menstruating women who belonged to one of five ethnic/racial groups were recruited and followed up with annual visits. Frequencies of symptoms (hot flashes, night sweats) for the prior 2 wk and measures of other covariates as well as potentially confounding variables were self-reported in the annual interview. Serum was obtained annually, on d 2-5 of a spontaneous cycle in cycling women or within 90 d of the anniversary of the baseline study visit in noncycling women and assayed for FSH, E2, T, SHBG, and DHEAS. FTI and FEI were calculated. This analysis incorporated available longitudinal data from 3293 women, excluding information collected at or after first report of hormone therapy use or hysterectomy. Data were analyzed using longitudinal marginal logistic regression models and a partial proportional odds model. RESULTS: After adjusting for age, body mass index, and other related covariates, VMS prevalence increased with higher (log)FSH concentrations, and the increase was greater when blood was drawn more than 5 d after menses began. FSH concentrations were positively associated with the frequency of either hot flashes or night sweats, and higher FSH concentrations were associated with greater odds of reporting more frequent symptoms. Vasomotor symptom prevalence decreased with higher (log)E2, (sqrt)SHBG, and (log)FEI but only when these hormone values were modeled independently of (log)FSH values and the specimens were obtained outside the d 2-5 window. When modeled simultaneously with (log)FSH, (log)E2, (sqrt)SHBG, and (log)FEI were no longer significantly associated with symptom prevalence. (Cubic root)T and (sqrt)DHEAS concentrations and (log)FTI were not associated with the prevalence of VMS. CONCLUSIONS: Annual serum FSH concentrations, but not E2, T, DHEAS, FTI, or FEI when collectively modeled longitudinally, are associated with both the prevalence and frequency of VMS in women at midlife.     

Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common health problem and includes a spectrum of hepatic steatosis, steatohepatitis and fibrosis. The renin-angiotensin system (RAS) plays a vital role in blood pressure regulation and appears to promote hepatic fibrogenesis. We hypothesized that increased RAS activity causes NAFLD due to increased hepatic oxidative stress. METHODS: We employed the transgenic TG(mRen2)27(Ren2) hypertensive rat, harboring the mouse renin gene with elevated tissue Angiotensin II (Ang II). RESULTS: Compared with normotensive Sprague-Dawley (SD) control rats, Ren2 developed significant hepatic steatosis by 9 weeks of age that progressed to marked steatohepatitis and fibrosis by 12 weeks. These changes were associated with increased levels of hepatic reactive oxygen species (ROS) and lipid peroxidation. Accordingly, 9-week-old Ren2 rats were treated for 3 weeks with valsartan, an angiotensin type 1 receptor blocker, or tempol, a superoxide dismutase/catalase mimetic. Hepatic indices for oxidative stress, steatosis, inflammation and fibrosis were markedly attenuated by both valsartan and tempol treatment. CONCLUSIONS: This study suggests that Ang II causes development and progression of NAFLD in the transgenic Ren2 rat model by increasing hepatic ROS. Our findings also support a potential role of RAS in prevention and treatment of NAFLD.     

Oxidative Stress in Insulin-Resistant Conditions

The risk of cardiovascular disease (CVD) in patients with diabetes mellitus is increased more than 3-fold and is the major cause of mortality and morbidity in diabetic patients. Historically, diabetes has been considered an inadequate insulin response leading to elevated plasma glucose levels with morbidities attributable to hyperglycemia. However, diabetes represents a complex pathology that often includes hypertension, dyslipidemia, endothelial dysfunction, microalbuminuria, platelet disaggregation, abnormal fibrinolysis, and chronic inflammation. Furthermore, oxidative stress has been shown to contribute to the pathology of diabetic CVD, having implications in the development of hypertension, renal disease, and stroke. Hypertension is a common feature of diabetes and is the primary contributor to CVD, which highlights the importance of blood pressure control (<130/80 mm Hg). Recent investigations have also implicated the renin-angiotensin-aldosterone system in promoting oxidative stress-induced endothelial dysfunction, inflammation, and insulin resistance. These pathophysiologic considerations will be important in developing prevention strategies for CVD in diabetes. Further research is needed to identify antioxidant and insulin-sensitizing agents that will improve CVD outcomes in patients with diabetes.     

Relationship between arterial blood pressure and plasma norepinephrine levels in a patient with neurogenic hypertension

This study examined the relationship between arterial blood pressure and plasma norepinephrine levels during 12 hours of monitored sleep in a 35-year-old man in whom neurogenic hypertension developed immediately after surgical removal of a large hemangioblastoma at the obex region of the cervical-medullary junction. Plasma norepinephrine levels throughout the 12-hour sampling period correlated (r = 0.81, p less than 0.01) with mean arterial blood pressures, suggesting that sleep-related changes in blood pressure were dependent on associated changes in sympathetic nervous system activity in this patient with neurogenic hypertension.     

Modeling a safer smallpox vaccination regimen, for human immunodeficiency virus type 1-infected patients, in immunocompromised macaques

We have modeled smallpox vaccination with Dryvax (Wyeth) in rhesus macaques that had depletion of CD4(+) T cells induced by infection with simian immunodeficiency virus or simian/human immunodeficiency virus. Smallpox vaccination induced significantly larger skin lesions in immunocompromised macaques than in healthy macaques. Unexpectedly, "progressive vaccinia" was infrequent. Vaccination of immunocompromised macaques with the genetically-engineered, replication-deficient poxvirus NYVAC, before or after retrovirus infection, was safe and lessened the severity of Dryvax-induced skin lesions. Neutralizing antibodies to vaccinia were induced by NYVAC, even in macaques with severe CD4(+) T cell depletion, and their titers inversely correlated with the time to complete resolution of the skin lesions. Together, these results provide the proof of concept, in macaque models that mirror human immunodeficiency virus type 1 infection, that a prime-boost approach with a highly attenuated poxvirus followed by Dryvax increases the safety of smallpox vaccination, and they highlight the importance of neutralizing antibodies in protection against virulent poxvirus.