Hypertension: pathophysiology and treatment

Arterial hypertension is a major cause of morbidity and mortalitybecause of its association with coronary heart disease, cerebrovasculardisease and renal disease. The extent of target organ involvement(i.e. heart, brain and kidneys) determines outcome. North Americanstudies have shown that hypertension is a major contributorto 500 000 strokes (250 000 deaths) and 1 000 000 myocardialinfarctions (500 000 deaths) per annum.     

The surgical hypertensive patient

We reviewed the pathophysiology and treatment of hypertensionin a recent edition of this journal (see key references). Inthis article, we discuss the management of the hypertensivepatient presenting for surgery and anaesthesia.     

A framework for assessing risks to children from exposure to environmental agents

In recent years there has been an increasing focus in environmental risk assessment on children as a potentially susceptible population. There also has been growing recognition of the need for a systematic approach for organizing, evaluating, and incorporating the available data on children's susceptibilities in risk assessments. In this article we present a conceptual framework for assessing risks to children from environmental exposures. The proposed framework builds on the problem formulation-->analysis-->risk characterization paradigm, identifying at each phase the questions and issues of particular importance for characterizing risks to the developing organism (from conception through organ maturation). The framework is presented and discussed from the complementary perspectives of toxicokinetics and toxicodynamics.     

p42/44MAPK regulates baseline permeability and cGMP-induced hyperpermeability in endothelial cells

We tested the hypothesis that p42/44MAPK and p38MAPK (mitogen-activated protein kinases; MAPK) signaling pathways regulate endothelial cell permeability to macromolecules. Passage 2-4 human umbilical vein endothelial cells (HUVEC) were grown to confluence on fibronectin-coated Snapwell membranes. The flux of fluorescein isothiocyanate-labeled dextran-70 across the HUVEC monolayers served to determine permeability. Application of 1 mM 8-bromo 3' 5'-cyclic guanosine monophosphate (8-Br-cGMP) increased permeability from 7.0 +/- 1.6 x 10(-6) to 12.5 +/- 2.8 x 10(-6) cm/s (P < 0.05). Pretreatment of HUVEC for 60 min with a selective p42/44MAPK inhibitor (AG126 at 2.7 and 27 microM) blocked 8-Br-cGMP-induced hyperpermeability. However, inhibition of p38MAPK (SB203580 at 0.6 microM) did not influence the cGMP-induced hyperpermeability response. AG126, administered at 27 microM, decreased baseline permeability from 7.9 +/- 0.5 x 10(-6) to 5.9 +/- 0.5 x 10(-6) cm/s (P < 0.05). Our results indicate that the p42/44MAPK signaling pathway is important in the regulation of baseline permeability and cGMP-induced hyperpermeability.     

Association between insulin-like growth factor status and physical activity levels in rheumatoid arthritis

OBJECTIVE: To determine if the altered insulin-like growth factor (IGF) status in rheumatoid arthritis (RA) is due to inflammation, altered body composition, or lack of exercise. METHODS: Subjects included 73 patients with RA, 54 patients with other rheumatic diseases, both inflammatory and noninflammatory, and 28 healthy, physically active controls. Serum levels of IGF-I, IGF-II, and IGF binding protein-3 (IGFBP-3) were measured by radioimmunoassay. Body composition was estimated by bioelectrical impedance analysis, and habitual exercise level approximated by questionnaire. Statistical analysis was performed by 2 and 3 way ANOVA and moderated hierarchical regression. RESULTS: Serum IGF-I (p < 0.001), IGFBP-3 (p < 0.001), and the BP-3:total IGF molar ratio (p < 0.001) were depressed in both patient groups relative to controls. In contrast, IGF-II levels were depressed only in patients with RA (p < 0.01). Differences in the IGF proteins between patients and controls could not be attributed to inflammation. Habitual exercise level, but not body composition, was shown to be a significant predictor for IGF-I, IGFBP-3, and BP-3:total IGF molar ratio (p < 0.001). CONCLUSION: Our results indicate that the reduction in circulating IGF proteins observed in our patients is more related to their sedentary lifestyle than to the inflammatory process. This conclusion is in agreement with reports that show that highly active individuals typically exhibit higher levels of systemic IGF proteins than age matched sedentary controls.     

Influence of caloric restriction on the development of atherosclerosis in nonhuman primates: progress to date

Caloric restriction (CR) has been observed to retard aging processes and extend the maximum life span in rodents. In an effort to evaluate the effect of this nutritional intervention on physiologic variables in higher species, several nonhuman primate trials are ongoing. In particular, a study evaluating the independent effect of CR on the extent of atherosclerosis was initiated in 1993 in 32 adult cynomolgus monkeys. Therefore, the trial was designed to achieve identical cholesterol intake after animals were randomized to a control group or a calorie-restricted group (30% reduction from baseline caloric intake). The animals were routinely evaluated for glycated proteins, plasma insulin and glucose levels, insulin sensitivity, and specific measures for abdominal fat distribution by CT scans over a 4-year interval. The results from 4 years of intervention demonstrate that CR improves cardiovascular risk factors (such as visceral fat accumulation) and improves insulin sensitivity. In contrast to other primate studies with normolipidemic animals, CR had no independent effects on plasma lipid levels and composition in the presence of equivalent amounts of dietary cholesterol intake. Preliminary analysis of atherosclerotic lesion extent in the abdominal aorta has failed to demonstrate differences between control animals and CR animals. Follow- up studies are being conducted to determine the effect of CR on atherosclerosis extent in coronary and carotid arteries.      

Special considerations in breast cancer risk and survival.

Experimental and clinical evidence suggests that breast neoplasia appears to be a hormone-dependent process that may also be influenced by dietary factors in many women. Conflicting reports on the relationship between exogenous hormones and the development, progression, and recurrence of breast cancer are critically examined in this report. The absolute breast cancer risk associated with either hormone replacement therapy or oral contraceptive use has not been clearly defined. Data from some large prospective studies have actually documented lower mortality rates for women taking hormone replacement compared with those for women who did not have hormone replacement therapy. In this regard, age, duration of use, and preexisting breast cancer risk factors must be taken into account. Although the results of two major prospective clinical trials addressing the role of timing of surgery within the menstrual cycle are forthcoming, the majority of studies have found no consistent association between timing of surgery and breast cancer survival. Recently reported prospective randomized data showing that selective-estrogen-receptor-modulators can act as effective chemoprevention agents in women at increased risk for breast cancer development are presented. Finally, information regarding the effect of dietary manipulation on breast cancer risk and survival is reviewed.