Biomedical subjects
Publications and source records attributed to F H Epstein.
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This review has addressed the concern that the reduction of the risk of coronary heart disease and other cardiovascular disorders by means of reducing serum cholesterol levels might, at the same time, increase the risk of developing noncardiovascular conditions. This concern is justified because, at face value, prospective epidemiological studies indicate that total mortality and mortality from a number of specific causes of death increase below a threshold value of serum cholesterol (the J-shaped curve phenomenon) and intervention studies to date have mostly failed to show a decrease of total mortality in the experimental group, despite a fall in coronary heart disease mortality (suggesting an increase in noncardiac mortality). Detailed scrutiny of the evidence from prospective studies provides no convincing evidence that low cholesterol levels are associated with an excess of deaths from cancer, except possibly to a minor degree; excess mortality from other causes which account for only a minority of all deaths, are in all likelihood confounded by influences that, in themselves, increase the probability of dying. Preventive trials that have been designed to test whether reduction of serum cholesterol will lower heart disease risk have, so far, provided insufficient numbers of noncardiovascular deaths to test, in addition, whether serum cholesterol lowering is accompanied by an increase in such deaths. According to available evidence, both the apparent excess of noncardiac deaths and total mortality could be attributable to chance. In the light of these findings from prospective studies and preventive trials, as well as the cross-cultural, ecological data that have been summarized, the total evidence provides no justification for depriving either high-risk individuals or populations at high risk as a whole of the benefits of serum cholesterol reduction for preventing heart disease on the grounds that such reduction may increase the risk of noncardiovascular conditions. This latter risk is far from being established and, if present, from all the available evidence is much smaller than the risk of withholding protection from persons and populations exposed to elevated coronary heart disease risk. In addition to the conclusions from epidemiological and intervention studies, a paramount question relates to the biological plausibility of causal connections between low or lowered cholesterol and the hazard of noncardiovascular disorders. Assessment of currently available data provides no evidence for the existence of mechanisms that might explain such a link. Countries in which average serum cholesterol levels are still low, as in Japan, face a different problem.(ABSTRACT TRUNCATED AT 400 WORDS)
The possible protective effect of heat-shock proteins (HSPs) on ischemic injury to renal cells was assessed in two different experimental models: ischemia-reflow in intact rats and medullary hypoxic injury as seen in the isolated perfused rat kidney. Heat shock was induced by raising the core temperature of rats to 42 degrees C for 15 minutes. Following this, Northern blots showed enhanced gene expression of HSP70, HSP60 and ubiquitin at one hour and reaching a maximum by six hours after heat shock in all regions of the kidney, but most prominently in medulla and papilla. The HSP70 protein in the kidney, estimated by immunohistochemical means, was detectable 24 hours following heat shock and further increased at 48 hours following heat shock. In the first set of experiments, the animals underwent uninephrectomy followed by cross clamping of the remaining renal artery for 40 minutes prior to reflow. Serum creatinine and urea nitrogen rose to 3.15 +/- 0.98 and 126.4 +/- 62.5 mg/dl at 24 hours. No significant differences were observed at 24, 48 and 72 hours after reflow between these values in control rats and rats pretreated with heat shock 48 hours earlier. Severe morphological damage to proximal tubules of the renal cortex was observed to the same extent in both groups. In a second set of experiments, the right kidney was removed either 24 or 48 hours after heat shock and perfused in isolation for 90 minutes. Functional and morphological parameters were compared with those of isolated perfused kidneys obtained from animals that had not been subjected to heat shock.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Increasing age is associated with a number of changes in renal function, including a diminished capacity to excrete salt and water loads and an increased susceptibility to acute renal failure. Dopamine is a renal autocoid important in diuresis and natriuresis and may also serve to protect against ischemic renal injury. The aim of this study was to assess the renal response to a low-dose dopamine infusion in healthy young vs elderly individuals. METHODS: Five healthy young (28 +/- 2 yr) and elderly (68 +/- 3 yr) subjects underwent evaluation of renal function and blood pressure before, during, and after a 3-hour infusion of dopamine (1 microgram/kg/min) in the Clinical Research Center of Beth Israel Hospital. RESULTS: Renal plasma flow, estimated by clearance of para-aminohippurate clearance, was significantly lower in the elderly than in the young subjects, but both groups increased estimated renal plasma flow by approximately 30% during dopamine infusion. Endogenous creatinine clearance was also significantly lower in the elderly. During dopamine infusion, creatinine clearance rose significantly only in the young. Both young and old had a similar natriuretic response to dopamine although urine flow and free water clearance were significantly lower in the old. Neither group had significant changes in blood pressure or heart rate. CONCLUSIONS: Resistance to the actions of dopamine on creatinine clearance in the elderly may reflect an inability to respond to endogenous dopamine at times of physiologic stress with resulting susceptibility to azotemia.
Plasma aldosterone levels are reported to be lower in healthy elderly individuals compared with young individuals, a difference exaggerated by sodium depletion or upright posture. The aim of this study was to determine the aldosterone response to increases in serum potassium with advancing age. In the Clinical Research Center, six healthy young (20 to 35 yr of age) and six healthy elderly (65 to 85 yr of age) subjects underwent evaluation of their aldosterone responses to potassium infusion (0.5 mEq/kg over 45 min). Both young and elderly subjects had similar basal serum potassium levels (4.3 +/- 0.2 versus 4.4 +/- 0.1 mEq/L), similar sodium and potassium excretion amounts and similar increase in serum potassium levels during infusion (to 5.0 +/- 0.2 versus 5.1 +/- 0.1 mEq/L). However, elderly subjects had lower basal levels of plasma aldosterone and a blunted aldosterone response to potassium infusion (P < 0.05, analysis of variance). Advancing age is characterized by relative hypoaldosteronism in the basal state as well as in response to hyperkalemia. This may contribute to an increased susceptibility to hyperkalemia if other potassium regulatory systems fail.
A number of pulse sequence techniques, including magnetization-prepared gradient echo (MP-GRE), segmented GRE, and hybrid RARE, employ a relatively large number of variable pulse sequence parameters and acquire the image data during a transient signal evolution. These sequences have recently been proposed and/or used for clinical applications in the brain, spine, liver, and coronary arteries. Thus, the need for a method of deriving optimal pulse sequence parameter values for this class of sequences now exists. Due to the complexity of these sequences, conventional optimization approaches, such as applying differential calculus to signal difference equations, are inadequate. We have developed a general framework for adapting the simulated annealing algorithm to pulse sequence parameter value optimization, and applied this framework to the specific case of optimizing the white matter-gray matter signal difference for a T1-weighted variable flip angle 3D MP-RAGE sequence. Using our algorithm, the values of 35 sequence parameters, including the magnetization-preparation RF pulse flip angle and delay time, 32 flip angles in the variable flip angle gradient-echo acquisition sequence, and the magnetization recovery time, were derived. Optimized 3D MP-RAGE achieved up to a 130% increase in white matter-gray matter signal difference compared with optimized 3D RF-spoiled FLASH with the same total acquisition time. The simulated annealing approach was effective at deriving optimal parameter values for a specific 3D MP-RAGE imaging objective, and may be useful for other imaging objectives and sequences in this general class.
The straight portion (S3) of the proximal tubule lies in close proximity to the thick ascending limbs (TALs) at the cortico-medullary junction. Since a delicate balance exists between oxygen demand and the limited oxygen supply in this region, we hypothesized that reduction of thick limb metabolic activity might augment oxygen availability to S3 segments, which depend heavily upon aerobic metabolism, and prevent hypoxic damage. The degree of functional deterioration and morphological damage to S3 was assessed in isolated rat kidneys perfused with an erythrocyte-free medium. Bumetanide (10(-5) M) and furosemide (10(-4) M) reduced S3 fragmentation from 9.8 +/- 3.9% of tubules in controls to 0 and 1.4 +/- 0.9%, respectively (P < 0.0005). Tubular glucose reabsorption was better preserved in kidneys exposed to loop diuretics than in control kidneys (P < 0.01), and urinary alkaline phosphatase (P < 0.05) and the total amount of LDH released into the perfusate and urine (P < 0.01) were lower in the treatment groups. Morphological damage to S3 was closely correlated with medullary TAL necrosis (r = 0.66, P < 0.001), urinary alkaline phosphatase excretion (r = 0.89, P < 0.001) and glycosuria (r = 0.83, P < 0.001). We conclude that under hypoxic conditions TALs and S3 segments may compete with each other for a limited oxygen supply. Reduction of active transport in the mTAL might augment oxygen availability to S3 segments and improve their survival.
To study renal cortical and medullary oxygen tensions, we used sensitive Clark-type O2 microelectrodes, inserted by micromanipulators into the cortex and medulla of kidneys of anesthetized rats. As previously reported, under basal conditions, medullary PO2 was significantly lower than cortical PO2. Furosemide, which inhibits reabsorptive transport in the medullary thick ascending limb, increased medullary PO2 from 16 +/- 4 to 35 +/- 4 mmHg (P < 0.0005) without altering cortical PO2. This effect, reproduced by ethacrynic acid and bumetanide, was selective for loop diuretics and was directly due to decreased tubular O2 consumption, since medullary blood flow was remarkably reduced by furosemide (-28 +/- 6% from baseline, P < 0.0001, as measured by a laser-Doppler probe). By contrast, acetazolamide, which decreases proximal tubule metabolism, selectively increased cortical PO2. These data are, in general, consistent with tubular metabolism as a major determinant of intrarenal oxygenation and suggest, in particular, that medullary reabsorptive work is at least in part responsible for renal medullary hypoxia.
To study hemodynamic effects on intrarenal oxygenation, O2 microelectrodes were inserted into rat kidneys. In a previous study [M. Brezis, Y. Agmon, and F. H. Epstein. Am. J. Physiol. 267 (Renal Fluid Electrolyte Physiol. 36): F1059-F1062, 1994], we showed that tubular metabolism is a major determinant of intrarenal oxygenation, in part responsible for medullary hypoxia observed under basal conditions. Acute hypotension (by controlled hemorrhage, aortic ligation, or nitroprusside infusion) paradoxically increased medullary PO2 (from 21 +/- 2 to 39 +/- 2 mmHg, P < 0.001) while decreasing cortical PO2 (from 46 +/- 2 to 32 +/- 3 mmHg, P < 0.001), abolishing corticomedullary gradients of oxygen. Laser-Doppler studies indicated that, while cortical blood flow was reduced during hypotension, medullary blood flow was unchanged or increased. The increase in medullary PO2 induced by hypotension was abolished by prior administration of furosemide, suggesting that during hypotension, reduced glomerular filtration rate (GFR), distal delivery, and reabsorption result in decreased oxygen utilization. Acute infusions of atriopeptin III (0.1-1 microgram.kg-1.min-1) decreased both cortical PO2 (from 61 +/- 2 to 55 +/- 2 mmHg, P < 0.001) and medullary PO2 (from 15 +/- 1 to 7 +/- 1 mmHg, P < 0.001), consistent with atriopeptin-induced increases in GFR and tubular reabsorptive work. These data suggest that medullary oxygen availability increases during renal hypoperfusion and may decrease during renal vasodilation.
BACKGROUND: Changes in mortality from heart disease, cancer, and stroke over recent decades in many countries have received much attention. However, comprehensive and concurrent analyses of these trends and their effect on total mortality have been lacking. Moreover, the extent to which the trends for one disease may relate to those for another disease is unknown. Concordance of trends for major diseases would suggest that they have common causes and thus may be responsive to the same preventive measures. METHODS AND RESULTS: Age-adjusted death rates for total mortality and mortality from heart disease, stroke, lung cancer, and cancer other than lung cancer were obtained for the years 1950 to 1987 in 27 countries by sex and ages 35 to 74 years from the World Health Organization statistical reports. Concordance of mortality trends was assessed for ages 35 to 74 between 1950 and 1983 through visual inspection and semiquantitative measurements of percentage change over time. The epidemic increase in heart disease mortality ended in the 1960s or 1970s in most industrialized countries; death rates often declined very steeply. Stroke mortality also changed from an increase to a decline or from a modest to a steep decline in the 1960s or 1970s. Lung cancer mortality slopes generally changed from a steep increase to either a modest increase, a flat trend, or a decline; the changes in slope are lagging behind those for heart disease and stroke. These improvements influenced trends for total mortality. Cancer other than lung cancer trends are less distinct than those for the three other causes of mortality. Yet, testing them for concordance with heart disease trends reveals that they are mostly concordant on a time-lag analysis that assumes that heart disease responds more rapidly to a change in lifestyle or environment than cancer. Trends for heart disease and lung cancer in men also tend to be concordant on time-lag analysis. Heart disease and stroke trends have become more concordant with time. CONCLUSIONS: Trends for mortality from heart disease, stroke, lung cancer, and, less distinctly, cancer other than lung cancer, tend to be similar in different countries, leading to a corresponding similarity in total mortality trends. An analysis of trends for pairs of diseases within countries indicates a tendency toward concordance of trends, suggesting the existence of common causes amenable to the same preventive measures. This analysis of international mortality trends is intended to stimulate further research along these lines, as a guide to preventive and therapeutic action.
Previous studies have shown that salt depletion enhances the susceptibility of the kidney to nephrotoxins (amphotericin, cyclosporine, and contrast). To study the renal response to salt depletion, Sprague-Dawley rats were fed a sodium-deficient diet (N = 12) with pair-fed controls (N = 13) for 4 wk. In addition, rats from each group underwent 24-h water deprivation studies (N = 9; four salt deprived, five normal). Plastic 1-micron horizontal sections of mid-inner stripe were examined, and cross-sectional areas of the medullary thick ascending limb (mTAL) were analyzed. The mTAL of the salt-deprived rats were smaller (P = 0.04) and showed greater variance in size (P = 0.02) than control (618 +/- 106 versus 693 +/- 50 microns2). However, mean glomerular and collecting duct cross-sectional areas were unaffected by salt intake. Cross-sectional areas of long- and short-loop mTAL were significantly different, regardless of group (518 +/- 78 versus 732 +/- 92 microns2). Maximal urinary concentrating ability was found to correlate with mTAL cross-sectional area (r = 0.85; P = 0.004) and with long-loop mTAL size (r = 0.77; P = 0.016). However, it did not significantly correlate with short loop mTAL size (r = 0.53; P = 0.14).(ABSTRACT TRUNCATED AT 250 WORDS)
Hyponatremia is a common cause of morbidity in the elderly, and thiazide diuretics are often implicated. Eleven healthy young volunteers, eight healthy old volunteers, and five elderly patients with a history of thiazide-induced hyponatremia were studied to determine susceptibility to thiazide-induced hypoosmolality in age. Each of the healthy subjects ingested a water load (20 mL/kg) after 3 days of hydrochlorothiazide (HCTZ) (100 mg/day) or placebo. Although there were no differences in minimum Uosm between young and old, the healthy old had lower hourly free water clearances (CH2O) as compared with the young and a greater decline in serum osmolality in response to water loading (P < 0.05). HCTZ impaired minimum urine osmolality and CH2O and delayed recovery of serum osmolality after the water load in both healthy young and old (P < 0.005, placebo versus HCTZ), but the impairment in the latter two parameters was greater in the healthy elderly (P < 0.05, young versus old). Vasopressin levels were not different between healthy young and old (1.9 +/- 0.3 versus 2.0 +/- 1.0 pm with placebo; 3.0 +/- 0.7 versus 4.4 +/- 1.0 with HCTZ). Five of the young subjects were restudied after the addition of ibuprofen (400 mg thrice daily) to the thiazide and placebo regimens. Creatinine clearance was not changed, but free water clearance and serum osmolality after water loading were significantly reduced to a degree similar to that seen in the elderly subjects on the thiazide regimen (P < 0.05), suggesting an important role for renal prostaglandins in the defense against hyponatremia.
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To determine the effects of hyperglycemia and hyperinsulinemia on atrial natriuretic peptide (ANP) levels in man, we studied normotensive nondiabetic volunteers (aged 25 to 63 years) during infusion of insulin and/or 20% dextrose (glucose clamp technique) to achieve three different states of "glycemia/hyperinsulinemia," as follows: (1) euglycemia for 2 hours during infusion of insulin (80 mU.m-2.min-1), resulting in plasma insulin levels of approximately 1,200 pmol/L (n = 9); (2) moderate stable hyperglycemia at a level of 11 mmol/L (198 mg/dL) for 2 hours, with infusion of glucagon-like peptide-1 (7-37) amide (GLP-1) during the second hour, which increased endogenous insulin responses to approximately 2,100 pmol/L (n = 9); and (3) marked stable hyperglycemia at a level of 18.5 mmol/L (330 mg/dL) for 2 hours, with endogenous insulin responses of approximately 720 pmol/L (n = 9). In addition, six patients with non-insulin-dependent diabetes mellitus were studied with the GLP-1 protocol at a hyperglycemic level of 14.5 mmol/L (261 mg/dL). In normal subjects, plasma ANP levels increased significantly from 3.0 +/- 0.4 to 4.6 +/- 0.8 pmol/L during marked hyperglycemia, but did not change during euglycemia or moderate hyperglycemia despite higher insulin levels (P < .01, ANOVA). Sodium excretion rates were also highest during the marked hyperglycemic study (125 +/- 14 v 91 +/- 7 v 74 +/- 10 mumol/min, P < .05, marked v moderate hyperglycemia v euglycemia). In diabetic subjects, ANP levels increased significantly from 12.5 +/- 4.1 to 21.1 +/- 5.0 pmol/L during hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)
1. Rectal glands secrete nitrate at 30% of their capacity to secrete chloride. 2. Nitrate secretion is directly related to its concentration at constant chloride concentrations. 3. Chloride has a biphasic effect on nitrate secretion. 4. Hill coefficients at chloride < 100 mM are equal to 1, while at 100 mM indicate inhibition of nitrate by chloride. 6. Lineweaver-Burk plots at chloride < 100 indicate a single site, while at 100 mM indicate inhibition of nitrate by chloride. 7. Bumetanide inhibits nitrate secretion. 8. The data suggest that nitrate interacts with one of the two chloride sites of the chloride transporter.
We evaluated the effect of glycine infusions on the early renal uptake of cisplatin, measured one hour after cisplatin was injected, as well as five days following cisplatin administration. Glycine (1.25 mmol per 100 g body wt) markedly attenuated the early uptake of platinum by the kidney, an effect not observed with control infusions of saline or of L-alanine. The kidney content of platinum at five days, on the other hand, was similar in glycine-treated animals and saline controls. Early inhibition of renal uptake of platinum may be responsible for glycine's protective action in experimental cisplatin nephrotoxicity.