Biomedical subjects
Publications and source records attributed to S Goldfarb.
Urethral diverticulum is a correctable cause of lower urinary tract symptoms in women. It has been found to be present in from 1.85 to 4.7 per cent of all females. The postvoid film of the intravenous urogram (IVP) is the simplest and least invasive method available to diagnose urethral diverticula. It should be a routine part of the IVP in women with lower urinary tract symptoms.
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A marked heterogeneity of enzyme histochemical phenotypes was demonstrated in 48 primary hepatocellular carcinomas induced by feeding 2-acetylaminofluorene to rats. All eight possible combinations of three abnormal traits, gain of gamma-glutamyl transpeptidase activity, loss of adenosine-5'-triphosphatase activity, and loss of glucose-6-phosphatase activity, were represented among the hepatocellular carcinomas. The four combinations in which two or three traits occurred together were seen in 85% of the carcinomas, while those categories with a normal phenotype or containing only single marker changes contained the few remaining neoplasms. As expected, the carcinomas all showed greatly increased and variable [3H]thymidine labeling indices; however, neither the rates of cell replication or the degrees of differentiation of the carcinomas appeared to correlate in any meaningful way with the patterns of phenotypic diversity. The distribution of histochemical phenotypes in the carcinomas differs greatly from that reported for enzyme-altered hyperplastic islands induced by carcinogens, but the significance of the difference is not apparent at the present time.
We describe a patient with recurrent thrombotic thrombocytopenic purpura (TTP) manifested solely by aphasia after influenza infection. The clinical diagnosis was not made during acute episodes, and during the intercurrent period the patient had features of chronic glomerular disease, including hypertension, proteinuria, RBC casts, and a nonspecific renal histological appearance. A final episode of aphasia, acute renal failure, and microangiopathic anemia and thrombocytopenia made the diagnosis of TTP apparent. Chronic glomerular disease may in rare instances be a manifestation of occult TTP or the sequel of a prior acute episode of this disorder.
Intact, but sham-operated female rats had 2- to 3-fold higher levels of hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity than their male counterparts (15--21.5 vs. 6.7--8.7 nmol mevalonate/mg protein per h). The activity of the hepatic enzyme declined to about the same relative degree (40--60%) in male and female rats that were gonadectomized after puberty (53 days of age) and killed 5 weeks later. Implantation of silastic capsules containing 17 beta-estradiol increased the level of hepatic 3-hydroxy-3-methylglutaryl CoA reductase to levels found in sham-operated controls. In rats that were gonadectomized in infancy (12 h old) and killed 7--8 weeks later, the level of enzyme activity was not altered in females, but it was increased from 60--240% in males. Consequently, following neonatal gonadectomy, male-female differences in enzyme activity were no longer apparent. Implantation of silastic capsules containing estradiol in neonatally gonadectomized rats resulted in a doubling of enzyme activity in both males and females. Ovariectomy reduced plasma estrogen levels, but implantation of estradiol in gonadectomized males and females increased the hormone level to that found in sham-operated females. Thus, the results strongly suggest a role for physiologic levels of estrogen as a positive effector of 3-hydroxy-3-methylglutaryl CoA reductase activity. Neonatal sex imprinting also appears to modulate the enzyme activity since sex-mediated differences are effaced by gonadectomy in infancy, but not by gonadectomy following puberty.
Denonvillier's fascia ordinarily serves as an effective barrier to the posterior extension of carcinoma of the prostate. Consequently, it is generally unappreciated that cancer of the prostate can invade the rectum posteriorly and appear at diagnosis to be a rectal mass. Autopsy series show that this occurs in from 0.56% to 11.5% of all cases of prostatic carcinoma. When it does appear as a rectal mass, it can be confused with carcinoma of the rectum. Unless a biopsy confirms rectal carcinoma, such an error may even result in an inappropriate abdominoperineal resection of the rectum. Every surgeon must be aware of this entity, its presumed pathogenesis, and its three clinical types: rectal ulcer, stricture, and anterior rectal mass.
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Nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to cause sodium retention and to decrease glomerular filtration rate (GFR). We studied the effects of two such drugs, indomethacin and oxaprozin, a new propionic acid derivative, on renal function of awake, normal human subjects during sustained water diuresis. Although neither drug had a long-term effect on GFR or sodium clearance (CNa), indomethacin (six subjects) but not oxaprozin (seven subjects) transiently reduced GFR and CNa. Given over the short term, oxaprozin caused a reduction in GFR from 113.7 +/- 5.7 to 99.8 +/- 4.7 ml/min (p < 0.01) and CNa from 0.84 +/- 0.07 to 0.61 +/- 0.08 ml/min (p < 0.005). The results were much the same when an additional dose of indomethacin was given to subjects who had been receiving the drug for a week. Inference from clearance data at a time when urinary osmolality (Uosm) remained constant but urine flow per GFR (V/GFR) fell suggests that both drugs stimulated proximal tubular sodium and fluid resorption. Both suppressed renin and aldosterone levels comparably and reduced potassium excretion transiently, but only indomethacin caused a sustained change in serum potassium concentration; serum potassium rose from 4.32 +/- 0.10 to 4.56 +/- 0.11 mEq/l (p < 0.05) after 1 wk. These disparate findings suggest that prostaglandin synthesis inhibition may not be the sole mechanism of action of NSAIDs.
To determine the effects of methyldopa on renal function, clearance studies were performed on hypertensive subjects during sustained steady-state water diuresis. The data reveal an acute fall in glomerular filtration rate and sodium clearance, whereas renal blood flow was unchanged. The antinatriuresis was the result of decreased filtration of sodium and possibly enhanced proximal tubular sodium reabsorption. These changes occurred before any demonstrable fall in systemic blood pressure; thus a direct effect of the drug on arteriolar resistance within the renal circulation is suggested. Chronic administration of methyldopa for 1 wk induced sustained reduction in blood pressure and resulted in the same changes in renal hemodynamics and sodium excretion noted after acute administration. These data suggest that methyldopa, like other antihypertensives, reduces glomerular filtration rate and increases sodium retention.
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The cat kidney possesses discrete venous drainage systems for superficial and deep (juxtamedullary) portions of the renal cortex. Arteriovenous (A-V) extraction and micropuncture studies may thus be used to evaluate PO4 transport in the two nephron populations. Determinations of A-V extraction showed whole kidney percentage of fractional PO4 excretion (%FEPO4) was 29.04 +/- 2.01%, percentage of fractional delivery of PO4 (%FDPO4) from the superficial nephrons was 42.94 +/- 2.42%, and that from deep nephrons was 22.35 +/- 2.05%. The %FDPO4 from superficial nephrons was significantly greater than %FEPO, in urine (P < 0.001) and than %FDPO4 from deep nephrons (P < 0.001). Micropuncture studies showed %FDPO4 from late distal tubules was 41.63 +/- 3.61%, while %FEPO4 in urine was 30.24 +/- 2.22%. Infusion of acetazolamide increased both %FEPO4 in urine and %FDPO4 from deep nephrons (A-V extraction studies), but had no effect on %FDPO4 from either superficial nephrons (A-V extraction) or from late distal tubules (micropuncture), thus abolishing the differences between superficial and deep compartments. Nephron heterogeneity apparently exists for superficial and juxtamedullary PO4 reabsorption in the cat. Acetazolamide increase %FEPO4 in urine primarily by reducing deep nephron PO4 reabsorption.
We have recently seen a patient with tumoral calcinosis, a syndrome comprising hyperphosphatemia, normocalcemia, normal glomerular filtration rate (GFR), and extensive periarticular calcific masses. Parathyroid hormone (PTH) deficiency or target organ resistance was ruled out by demonstration of normal serum PTH and urinary 3'5'cyclic AMP excretion and normal response to exogenous PTH and to endogenous stimulation by ethylenediaminetetraacetate. An intrinsic proximal tubular defect allowing enhanced renal PO4 reabsorption was probably present because there was no phosphaturic response to acetazolamine and renal PO4 threshold remained abnormally elevated even after PTH infusion. We then studied the mechanism by which serum calcium level is maintained in the normal range despite hyperphosphatemia and absence of secondary hyperparathyroidism. Normal 1,25-(OH)2 vitamin D was found, suggesting normal gastrointestinal calcium absorption. This, combined with markedly reduced urinary calcium excretion, perhaps a direct effect of hyperphosphatemia, may maintain calcium balance and prevent secondary hyperparathyroidism. A rise in urinary cyclic AMP excretion after furosemide-induced calciuria supports this hypothesis.
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The effect of i.v. injection of mevalonate on the activity of microsomal 3-hydroxy-3-methylglutaryl Coenzyme A reductase was studied in livers from non-tumor-bearing rats and in host liver and hepatomas from rats bearing transplantable Morris hepatoma 7800. We confirmed that a single bolus injection of 100 mg of mevalonate in non-tumor-bearing male rats caused a 90% inhibition of hepatic 3-hydroxy-3-methylglutaryl Coenzyme A reductase activity within 2 hr. In two experiments mevalonate injection caused a 50 to 60% reduction in enzyme activity of hepatomas but no significant decline in the enzyme activity in host livers. Thirty in after injection of [14C]mevalonate in a similarly sized bolus, the ratio of specific activities of cholesterol in liver:hepatoma:kidney:blood was 13:5.6:0.5:1. Thus, both the liver and hepatoma efficiently utilized mevalonate for the synthesis of cholesterol. The precise cause of the inhibition of enzyme activity in the liver of non-tumor-bearing rats and in the transplantable hepatomas is not clear from this study. However, on the basis of other published reports, we suggest that it resulted from the accumulation of endogenous cholesterol in microsomal membrane. The activity of cholesterol 7 alpha-hydroxylase, the rate-controlling enzyme for bile acid synthesis, was also studied in the hepatoma, but, in general, it did not differ from that in the host liver or control liver.
Various biochemical properties of the adenine nucleotide translocase were compared with mitochondria prepared from control and host liver, and Morris hepatomas 7777, 7800 and 5123C. The transport of phosphoenolpyruvate on the adenine nucleotide translocase was found to be three to four times more active, and inhibition of the transporter by palmitoyl-CoA and atractylate considerably less in hepatoma the active transport of phosphoenolypyruvate was associated with a greater stimulation of calcium egress from the mitochondria matrix by the anion in the hepatoma. The diminished sensitivity of the adenine nucleotide translocase to palmitoyl-CoA in hepatoma mitochondria was associated with lower levels of long chain acyl-CoA esters in the whole tissue. A change in activation energy at 6 degrees C for the adenine nucleotide translocase was found in host liver mitochondria while no break point in the temperature curve was observed in hepatoma mitochondria. These results are most consistent with a change in the structure-function relationship of hepatoma mitochondria due to differences in lipid composition.
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Studies were performed on 12 patients with idiopathic hypercalciuria to evaluate the hypothesis that the acid load accompanying potassium acid phosphate would adversely affect renal calcium reabsorption and citrate excretion compared to the neutral form of the phosphate salt. During acute clearance studies, neutral phosphate (NP) led to a fall in FECa (2.2 +/- 0.6% to 0.8 +/- 0.1%, P less than 0.02) and no change in titratable acidity (TA) or net acid excretion (NAE). Acid phosphate (AP) did not reduce FECa acutely, and led to a rise in TA (22 +/- 4 to 62 +/- 6 muEq/min, P less than 0.02) and NAE (46 +/- 6 to 6 89 +/- 7 muEq/min, P less than 0.02). During chronic administration, AP resulted in higher urinary calcium excretion in both absorptive (187 +/- 29 vs. 141 +/- 18 mg/day, P less than 0.02) and renal hypercalciuric patients (233 +/- 24 vs. 173 +/- 190.02 mg/day, P less than 0.02). Also, TA and NAE were higher following AP, whereas citrate excretion was lower (375.4 +/- 64.6 vs. 633.4 +/- 28.8 mg/day, P less than 0.01). These data suggest that the reported ineffectiveness of AP in the therapy of nephrolithiasis may be related to the deleterious effects of the acid load on calcium and citrate metabolism.