Hypertensive nephrosclerosis in the Dahl/Rapp rat. Initial sites of injury and effect of dietary L-arginine supplementation

BACKGROUND: The Dahl/Rapp strains of salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rat were developed to examine pathogenetic mechanisms that produce hypertension in response to an increase in dietary salt. We have shown that providing SS/Jr rats with L-arginine, the metabolic precursor of nitric oxide, acutely prevented salt-sensitive hypertension, suggesting that SS/Jr rats developed hypertension because of inadequate nitric oxide production while on a high-salt diet. EXPERIMENTAL DESIGN: Male 23-day SS/Jr and SR/Jr rats were placed on chow that contained 8% sodium chloride. One group of SS/Jr rats also received L-arginine, 1.25 g/liter, in their drinking water. These three groups were examined at weekly intervals for 4 weeks. RESULTS: SS/Jr rats rapidly developed hypertension when placed on the high-salt chow. After 2 weeks on this diet, inulin clearance dramatically decreased, and albumin excretion rate increased. By the fourth week of study, SS/Jr rats on the high-salt diet had died or were dying. Coincident with the progressive decline in inulin clearance, renal morphologic analysis confirmed development of myointimal thickening, fibrinoid necrosis, and glomerulosclerosis. In contrast, over the 4 weeks of study, SS/Jr rats supplemented with oral L-arginine did not develop hypertension and any of the associated renal complications seen in age-matched SS/Jr rats on the high-salt diet. L-Arginine also corrected hypertension in SS/Jr rats exposed to the high-salt chow for 2 weeks before the inception of L-arginine. L-Arginine administration after 3 weeks on this chow, however, failed to reverse hypertension and the depressed inulin clearance and morphologic renal damage. CONCLUSIONS: Along with previous work (Chen PY, Sanders PW, J Clin Invest 88:1559-67), these studies were consistent with the hypothesis that hypertension and hypertensive nephrosclerosis developed in SS/Jr rats because, while on a high-salt diet, substrate (L-arginine) became a rate-limiting factor in the synthesis of nitric oxide.     

Immunogold localization of plant surface arabinogalactan-proteins using glycerol liquid substitution and scanning electron microscopy

We have studied the spatial distributions of arabinogalactan-protein (AGP) epitopes on the surface of maize embryogenic calli and roots using monoclonal antibodies JIM4 and MAC207. For this purpose, a new immunogold-scanning electron microscopy (SEM) method was employed which is based on liquid substitution of samples with glycerol. Using this method, we were able to show that the AGP epitopes are distributed along callus and root surfaces and they decorate filamentous structures. In callus cells, the JIM4 epitope was specifically enriched in the outer extracellular layers covering compact clusters of embryogenic meristematic callus cells. In roots, the MAC207 epitope was abundant on the root epidermal surface corresponding to the outer root pellicle, but was only occasionally found on the mucilage layer covering the root cap cells. Silver-enhanced gold particles, indicating AGP epitopes, were often linearly arranged suggesting that AGPs associate with filamentous structures both on the surface of embryogenic calli and root epidermal cells. These results indicate that AGPs are components of the outer extracellular layers and networks that cover the surface of roots and cells undergoing somatic embryogenesis.     

An intracellular study of the contrast-dependence of neuronal activity in cat visual cortex

Extracellular recordings indicate that mechanisms that control contrast gain of neuronal discharge are found in the retina, thalamus and cortex. In addition, the cortex is able to adapt its contrast response function to match the average local contrast. Here we examine the neuronal mechanism of contrast adaptation by direct intracellular recordings in vivo. Both simple (n = 3) and complex cells (n = 4) show contrast adaptation during intracellular recording. For simple cells, that the amplitude of fluctuations in membrane potential induced by a drifting grating stimulus follows a contrast response relation similar to lateral geniculate relay cells, and does not reflect the high gain and adaptive properties seen in the action potential discharge of the neurons. We found no evidence of significant shunting inhibition that could explain these results. In complex cells there was no change in the mean membrane potential for different contrast stimuli or different states of adaptation, despite marked changes in discharge rate. We use a simplified electronic model to discuss the central features of our results and to explain the disparity between the contrast response functions of the membrane potential and action potential discharge in simple cells.     

Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats

Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia.     

A longitudinal causal model of cardiac invalidism following myocardial infarction

OBJECTIVE: To measure the distribution of the seriousness of illnesses and patients in primary care with the Duke Severity of Illness Scale (DUSOI) and relate it to resource use. DESIGN: Observational prospective study. SETTING: Eight primary care centres from the centre sub-section of the Catalan Health Service. PATIENTS AND OTHER PARTICIPANTS: For the first two months of the study, patients who attended for consultation at 9 general/family doctors' clinics were systematically sampled. 1,868 patients were selected and observed for 6 months. MEASUREMENTS AND MAIN RESULTS: The DUSOI was used to work out the seriousness of the illness and of the patient. The variables used as indicators of the use of resources for an illness were: the number of attendances, the time and costs of care. The same for the patient were: the number of attendances, number of episodes and costs of care. The average score for the seriousness of the episode was 31.4 with a standard deviation (SD) of 16.4. The correlations between use of resources and seriousness were under 0.4. The seriousness of the patient had an average of 44.9 (SD 21.3) and statistically significant correlations above 0.6 with the use of resources. CONCLUSIONS: The seriousness of the illnesses attended in primary care is low and is related moderately to the use of resources. DUSOI could be better employed in research, inasmuch as there are systems for classifying patients which have greater explanatory power and can be constructed from pre-existing data.     

Genetic and antigenic analysis of human rotavirus prevalent in Al-Taif, Saudi Arabia

The subgroup, serotype and electropherotype diversity of human rotavirus strains was investigated in Al-Taif, Saudi Arabia. Out of 349 faecal samples collected from diarrhoeic children, 150 (43 percent) tested rotavirus positive by a group-A specific enzyme-linked immunosorbent assay (ELISA). The majority (87 percent) of the infected children were below 2 years of age. Subgrouping and serotyping of rotaviruses with specific monoclonal antibodies showed that of the 150 rotavirus positive specimens, 17 percent belonged to subgroup I, 59 per cent belonged to subgroup II, and 24 percent were neither subgroup I nor subgroup II. The specimens were typed, as serotype 1 (43 percent), serotype 2 (5 percent), serotype 3 (11 percent), serotype 4 (10 percent) or mixed serotypes (3 percent). The remaining 41 (27 percent) specimens were untypeable. None of the serotypes showed association with a particular age group. An electrophoretic analysis of viral RNA revealed 11 distinct patterns (six long and five short). The majority, 78 percent were long patterns and 22 percent were short patterns. Analysis of the specimens for which subgroups, serotypes and electropherotypes were available indicated that a given RNA pattern does not correspond to a particular subgroup or serotype.     

Cardiopulmonary responses to experimental venous carbon dioxide embolism

BACKGROUND: Although the low-flow CO2 insufflation rate used to initiate pneumoperitoneum may reduce the severity of potential venous embolism, its safety is not established. METHODS: Anesthetized pigs were ventilated with room air at a fixed minute ventilation. After 1 h of baseline, they were intravenously infused with CO2 at the rate of 0.3, 0.75, or 1.2 ml/kg/min for 2 h (n = 5 for each group), followed by 1 h of recovery. RESULTS: All animals experienced pulmonary hypertension, depressed stroke volume, hypoxemia, hypercarbia, and acidemia during intravenous CO2 infusion. They had systemic hypertension at the low rate of hypotension at the highest rate of infusion. End-tidal CO2 levels briefly decreased, then increased in all cases. In the highest rate group, three of the five animals (60%) died at 50, 65, and 100 min of infusion. These three animals had severe hypotension and hypoxemia, with visible coronary gas embolism. There was no patent foramen ovale at necropsy in any animals. CONCLUSIONS: The low-flow insufflation rate exceeds the fatal rate of continuous intravenous CO2 infusion. End-tidal CO2 levels were increased in venous CO2 embolism, not decreased as seen in venous air embolism. Severe hypoxemia and hypotension are predictors of potentially fatal cases.     

Vitamin E levels in human atherosclerotic plaque: the influence of risk factors

Recent studies suggest that vitamin E may be an important preventative factor in the development and progression of atherosclerosis. In order to more clearly define the role of vitamin E in atherosclerosis, we measured vitamin E, conjugated diens, and lipid flurochromes, as well as cholesterol, triglycerides and phospholipid in arterial and venous tissue of 83 patients. Serum cholesterol and triglyceride levels were significantly higher (P < 0.05) in patients with aortic occlusive (AIOD) and aneurysmal (AAA) disease than in control organ donors (OD). Tissue cholesterol concentrations were significantly elevated in AAA tissue when compared to OD and tissue from patients with peripheral occlusive disease (POD). Tissue from patients with AIOD contained greater concentrations of phospholipid (PL) than were measured in patients with POD and in OD. Vitamin E concentrations were highest in POD tissue and approximately 3.0, 2.0, and 1.6 fold greater than OD, AIOD and AAA tissue respectively. Diene conjugates and lipid flurochromes, measures of early and intermediate products of lipid peroxidation, were markedly elevated in all diseased arterial tissue compared to controls. There were no significant differences in tissue or serum lipid levels between saphenous vein (SVBG) and diseased vein grafts (DVG). However, conjugated diene concentrations were elevated in DVG compared to SVBG. Vitamin E levels were significantly elevated in diseased arterial and venous tissue (AIOD, AAA, POD, DVG) removed from patients with diabetes (P = 0.013) and hypertension (P = 0.049) compared to those without these risk factors. Diabetes was the only risk factor associated with significantly increased (P = 0.005) levels of vitamin E when only data from atherosclerotic arterial tissue (AAA, POD, AIOD) were analyzed. These preliminary data provide additional evidence of altered vitamin E metabolism and free radical processes in the tissues of patients with various manifestations of atherosclerosis.     

Final examination performance of medical students from ethnic minorities

Cause of death among 917 of the 959 subjects in a population-based incidence cohort with Alzheimer's disease (AD) during the years 1960 to 1984 was compared to that of an age- and gender-matched control group (n = 703). In general, a summary of the diagnostic codes entered anywhere on a death certificate suggests that control subjects had more cardiovascular disease and neoplasms than did patients, while patients more often had a diagnostic code of bronchitis/pneumonia (P < 0.01). By logistic regression, this difference remained statistically significant after adjusting for age and gender.