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Biomedical subjects

S Goldfarb

Publications and source records attributed to S Goldfarb.

At least 91 records · Page 5Linked to original sources
PubMed1983

Preneoplastic and neoplastic progression during hepatocarcinogenesis in mice injected with diethylnitrosamine in infancy.

Basophilic hepatic foci, nodules, and trabecular hepatocellular carcinomas, collectively referred to as focal hepatic lesions, were induced by single injections of 5.0 micrograms of diethylnitrosamine (DEN) per gram body weight in 15-day-old C57BL/6J X C3HeB/FeJ F1 (B6C3 F1) mice. Groups of eight experimental and eight control mice were killed at 3 days and at 1, 2, 4, 10, 20, 28, 36 and 41 weeks after injection. The only observable acute hepatic toxic effect of DEN, a mild steatosis, was noted at 3 days, but this had disappeared by 7 days following injection. Basophilic foci, composed entirely of altered hepatocytes, were first noted, when very small, at 10 weeks. At later times, some of the foci also contained small collections of proliferated ductules, apparently a result of secondary ingrowth from nearby interlobular bile ducts. The hepatocytes within basophilic foci were characterized by their abundant cytoplasmic RNA, a high nuclear to cytoplasmic ratio (two times greater than normal), which gave them a "crowded appearance," and decreased glucose-6-phosphatase activity. During the course of the study, basophilic foci appeared to increase in size and number. Cytologic anaplasia also became more evident, ultimately culminating in the development of typical trabecular hepatocellular carcinomas by 44 weeks. Invasion of hepatic veins by basophilic foci, first noted at 10 weeks, was prominent by 20 weeks and indicated that many of the lesions manifested this characteristic of malignancy well in advance of the anaplastic features that are also diagnostic of hepatocellular carcinoma. The high growth rates of basophilic foci were confirmed by their greatly increased 3H-thymidine labeling indices, which were 20 times greater than background hepatocytes at 20 weeks following DEN injection. Tumor progression during the course of the study was also suggested by a doubling of labeling indices of hepatocytes in the basophilic foci between 20 to 28 weeks. (The term tumor progression is used in a broad biological sense to encompass any or all of the qualitative and quantitative changes describing the stepwise development of initiated cells to highly malignant neoplasms. This definition differs from the more clinical usage which restricts the process to qualitative changes during the late stages in the development of fully autonomous neoplasms.) An analysis of the number and size of transections through basophilic foci and in some cases, actual reconstructions of the foci from serial sections, indicated that, in aggregate, they grew exponentially between 10 to 36 weeks, with a volume doubling time of 2.5 weeks. The combined morphologic and kinetic data support the view that trabecular hepatocellular carcinomas develop from basophilic foci. Because of their ease of quantitation on conventional H&E stained sections, their rather uniformly spherical shapes, and the high probability of their clonal origin, the induced focal hepatic lesions should provide a useful model for studying tumor growth kinetics during carcinogenesis.

Age Factors↗
PubMed1983

Idiopathic syndrome of inappropriate antidiuretic hormone secretion possibly related to advanced age.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) as a cause of hypotonic hyponatremia is well recognized. The syndrome is commonly associated with cranial and thoracic infectious disease or malignancy. An idiopathic form of the syndrome has been reported, but poorly documented. Our patient, an 88-year-old man without any associated disease, had SIADH confirmed by a standard water load test. The pattern of antidiuretic hormone release corresponded to the "vasopressin leak" pattern. A review of ten cases of "idiopathic" SIADH showed that each of these cases has been associated with neuropsychiatric or other medical disturbances. We conclude that idiopathic inappropriate antidiuresis does exist and is a discrete category of SIADH. Data suggest that advanced age may be a risk factor for this disease. This syndrome may account for the increased susceptibility to hyponatremia among older patients.

Adolescent↗
PubMed1983

Presence of alpha-fetoprotein-positive cells in hepatocellular foci and microcarcinomas induced by single injections of diethylnitrosamine in infant mice.

Single injections of diethylnitrosamine (5 and 50 micrograms/g body weight) in male C57BL/6J X C3HeB/FeJ F1 mice when they were 15 days old resulted in the induction of RNA-rich hepatocellular foci and nodules that contained alpha-fetoprotein (AFP)-positive hepatocytes after 20 and 28 weeks. The focal lesions were composed of 1- to 2-cell-thick plates of hepatocytes or closely packed clusters of cells, but they did not show the histological patterns that are diagnostic of trabecular hepatocellular carcinoma. AFP-positive hepatocytes were found in almost one-fourth (14 of 60) of the foci and nodules in a serially sectioned block of liver from a mouse given one injection of 50 micrograms/g body weight diethylnitrosamine and killed at 28 weeks. In general, the presence or absence of AFP-positive cells correlated with the size of the foci and nodules. All six nodules with diameters greater than 1.5 mm contained AFP-positive cells, while all 12 foci smaller than 0.24 mm in diameter were negative for AFP. However, among the 42 foci that were intermediate in size, there were 8 AFP-positive foci, the sizes of which appeared rather randomly distributed among the negative foci. Reactive changes in hepatocytes could be ruled out as a cause of the induction of AFP because the foci first appeared many weeks after the administration of diethylnitrosamine in these mice. Since bile ductules or oval cells, which occasionally appeared in these foci, were lacking entirely in AFP and since ductules are absent from the early-appearing and smallest foci, we believe that in this model the AFP-positive foci arise only from hepatocytes. The presence of AFP in the focal lesions and in tumor thrombi that extended from them into hepatic vein branches supports the hypothesis that some foci undergo progression to invasive microcarcinomas and that these in turn are precursors of late-appearing (after 1 year) metastasizing trabecular hepatocellular carcinomas.

Animals↗
PubMed1983

Hepatocarcinogenesis in the mouse. Combined morphologic-stereologic studies.

The histogenesis of trabecular hepatocellular carcinomas was studied in male B6C3 F1 mice that were given injections of 5 micrograms diethylnitrosamine (DENA)/g body wt when they were 15 days old. Fully developed trabecular carcinomas with characteristically thickened hepatic plates were not seen until 44 weeks after DENA injection. However, focal microscopic collections of RNA-rich hepatocytes, referred to as basophilic hepatic foci, were first noted at 10 weeks after DENA injection. Hepatocytes in the foci were characterized by a twofold increase in the nuclear to cytoplasmic ratios, which imparted an easily recognized crowded appearance to the lesions, and by a marked tendency to invade hepatic vein branches. Blocks of liver from 16 mice, killed at 10, 20, and 28 weeks, were serially sectioned; and all foci and nodules with a diameter greater than 80 mu were identified. At 20 weeks, only 6 of 51 foci (12%) with diameters between 160 and 224 mu showed venous invasion; whereas 15 of 20 (75%) in the range 320-450 mu showed this feature. Thus, the predisposition to invade hepatic vein branches correlated with an increase in the size of foci and preceded their development of thickened hepatic plates. Since other studies have documented the presence of alpha-fetoprotein, an oncofetal marker, in some invasive foci, and since the late-appearing trabecular carcinomas metastasize to the lungs, we have suggested that the tiny infiltrating lesions be classified as microcarcinomas that are predisposed to develop into trabecular hepatocellular carcinomas. Proliferated bile ductules were found in some of the larger foci and nodules. This feature also became more prevalent with an increase in the size of the lesions. The ductules were derived from bile ducts, which, in association with portal vein branches, entered the lesions at localized areas at their peripheries. Thus, the presence of ductules within foci appeared to result from an encroachment on bile ducts of the enlarging foci. Since the foci were generally spherical and did not disseminate within the liver, this single-dose carcinogen model should be particularly useful for further studies of tumor growth kinetics.

Animals↗
PubMed1983

Centrilobular distribution of diethylnitrosamine-induced hepatocellular foci in the mouse.

Hepatocellular foci, considered possible precursors of trabecular hepatocellular carcinomas, were induced after 10 weeks by injecting male B6C3 F1 mice with diethylnitrosamine, 5 mg/kg, when they were 15 days old. The locations of 41 of the foci with diameters between 80 and 112 microns were determined in serial sections of blocks of liver from five mice. The average distance between centers of foci and closest hepatic vein branches (143 microns) was 40% less than that between randomly selected points and veins (243 microns). The centrilobular distribution of the foci might have facilitated the infiltration of hepatic vein branches, which was a prominent feature in animals killed after 20 weeks. This is the first stereologic study documenting the nonrandom distribution of neoplastic or preneoplastic foci in the rodent liver.

Animals↗
PubMed1982

Disorders of calcium and magnesium homeostasis.

The components of calcium and magnesium balance and the factors responsible for the maintenance of the serum concentration of these cations are reviewed. Within this framework, the causes and treatment of disturbances of the serum concentration are discussed. Hypercalcemia is usually a reflection of increased bone resorption and/or gut absorption with the kidney playing a secondary role. Hypocalcemia is usually due to either a disturbance in the parathyroid hormone-adenylate cyclase system or a disturbance in vitamin D metabolism. As vitamin D is required for expression of the action of PTH at bone and as PTH is a prime regulator of vitamin D metabolism, the absence of either component results in important disturbances in calcium balance. In contrast to calcium homeostasis, the kidney plays a major role in the determination and regulation of serum magnesium. The major causes of hypermagnesemia therefore are associated with loss of renal function, and hypomagnesemia is frequently due to renal magnesium wasting.

Calcium Metabolism Disorders↗
PubMed1982

Effects of two models of hypercalcemia on renal acid base metabolism.

The effects of two models of chronic hypercalcemia on renal acid-base metabolism were studied in rats. In the first series of experiments, rats were rendered hyperparathyroid by the autologous grafting of 20 to 24 parathyroid glands into a single recipient. Hypercalcemia (5.48 +/- 0.03 mEq/liter in high PTH animals, 4.96 +/- 0.06 mEq/liter in pair-fed controls, P less than 0.001) occurred as did metabolic alkalosis (plasma total carbon dioxide 25.44 +/- 0.47 mEq/liter vs. 23.84 +/- 0.57 in controls, P less than 0.05). The rise in total carbon dioxide was in part a renal tubular effect since urine pH was lower (6.77 +/- 0.04 vs. 6.95 +/- 0.04, day 5, P less than 0.01) bicarbonaturia less (165 +/- 26 vs. 283 +/- 28 mumoles/24 hr, day 5, P less than 0.01) and titratable acid (TA) excretion increased (164 +/- 43.4 vs. 48.2 +/- 2.53 mEq/24 hr, day 5, P less than 0.01) in hyperparathyroid animals vs. pair-fed controls. To test the specific role of hypercalcemia versus PTH in this effect, normoparathyroid animals were treated with 1.25 (OH)2 vitamin D3 or SHAM injected, Urinary cAMP was reduced in these animals (0.030 +/- 0.004 mumoles/8 hr) compared to hyperparathyroid rats (0.055 +/- 0.01 mumoles/8 hr P less than 0.05) suggesting differences i PTH levels. Hypercalcemia occurred in 1,25(OH)2 vitamin D treated animals as did increased plasma total carbon dioxide and urinary TA while urinary bicarbonate excretion and urinary pH were reduced. Because hypercalcemia was associated with elevated total carbon dioxide in both models, it is proposed that chronic hypercalcemia stimulated renal acid excretion and in a sustained manner results in metabolic alkalosis, at least in part, on a renal basis.

Acid-Base Equilibrium↗
PubMed1982

Effects of calcium on ADH action in the cortical collecting tubule perfused in vitro.

To test the effects of calcium on ADH action in an in vitro mammalian system, the rabbit cortical collecting tubule was studied. After 25 microunits/ml ADH (n=8) in the presence of 1.25 mM calcium bath, water flow (Jv) rose to 1.56 +/- 0.34 nl.mm-1. min-1 and hydraulic conductivity (Lp, cm.s-1.atm-1 X 10(7)) rose to 123 +/- 22. After 25 microunits/ml ADH in the presence of 3.75 mM calcium bath (n=7), Jv rose to 2.96 +/- 0.6 nl.mm-1.min-1 (P less than 0.05 vs. control) and Lp rose to 286 +/- 62 cm.s-1.atm-1 X 10(7) (P less than 0.02 vs. 1.25 mM bath calcium control). Tubules (n=6) perfused with 3.75 mM Ca and bathed in 3.75 mM Ca also showed an Lp of 279 +/- 82 cm.s-1.atm-1 X 10 (7) following 25 microunits/ml ADH. Tubules similarly studied in 1.25 (n=6) or 3.75 mM Ca (n=6) bath but treated with 10(-4) M 8-[p-chlorophenylthio]cAMP demonstrated Lp of 222 +/- 26 and 235 +/- 37 cm.s-1.atm-1 X 10(7), respectively. These data suggest that increased bath Ca enhances ADH- but not cAMP-stimulated water flow in the rabbit cortical collecting tubule. High perfusate Ca2+ does not alter the stimulatory effect of elevated peritubular Ca2+.

Animals↗
PubMed1982

Effects of phosphate administration on tubular calcium transport.

To evaluate the mode and tubular sites of action of PO4 administration on renal Ca reabsorption, micropuncture and clearance experiments were performed on acutely parathyroidectomized rats: (1) control (n=7), 2.5% saline expansion + furosemide infusion (0.5 mg/kg/hr); (2) PO4 infusion (n=6), treated as were the controls plus intravenous neutral PO4 (25 mg/kg/hr). CaCI2 was infused to keep plasma UF Ca comparable in both groups [2.68 +/- 0.08 mEq/l (mean +/- S.E.) vs 2.52 +/- 0.10, N.S.]. Po4 infusion increased plasma PO4 (14.0 vs 8.4 mg/dl, p less than 0.001) and FE PO4 (9.03% vs. 0.09%, p less than 0.001) but decreased FE Ca (1.83% vs. 5.95%, p less than 0.02) while GFR and FE Na were similar. FD of Na, PO4 and Ca were similar in late proximal and ED tubule punctures. In the LD tubule, PO4 infusion increased FD PO4 (18.5% vs. 7.9%, p less than 0.005) and reduced FD Ca (3.51% vs. 6.66%, p less than 0.01) and (TF/UF) Ca/Na (0.69 vs. 1.40, p less than 0.001). LD tubule FD Ca (y) was inversely related to TF/P PO4 concentration (X) in LD tubules: (y=7.2 - 0.12x, r=0.68, p less than 0.02). Significant Ca reabsorption (1.68% of filtered load) was observed beyond the superficial LD tubule only during PO4 infusion. These data indicate that phosphate infusion enhances Ca reabsorption independently of PTH, plasma Ca, and renal Na handling at a site within and possible beyond the distal convoluted tubule of the superficial nephron. (J Lab Clin Med 99:317, 1982).

Animals↗
PubMed1982

Proximal tubular defects in idiopathic hypercalciuria: resistance to phosphate administration.

Of 100 consecutive patients with recurrent renal calculi, 43 had idiopathic hypercalciuria (IH) on outpatient evaluation. Hypercalciuria was classified as diet-dependent or fasting; all patients had normal serum iPTH and urinary cyclic AMP, and serum phosphate and TmPO4/GFR were reduced in IH compared to normocalciuric stone formers. In 16 patients with IH, clearance studies revealed an elevated urine flow are factored for GFR (V/GFR) as compared with normal controls (p less than 0.05). In 12 patients, serum PTH was normally suppressed by calcium infusion but TmPO4/GFR was persistently reduced. Acute and chronic phosphate administration significantly reduced urine calcium excretion but did not correct the abnormal V/GFR. We conclude that in IH of both the fasting and the diet-dependent type, there is a defect in the proximal tubular reabsorption of sodium and fluid as well as PTH-independent tubular phosphate wasting. The proximal tubular defect is not a consequence of hypercalciuria nor of phosphate depletion but may be a cause of these abnormalities.

Absorption↗
PubMed1981

Lymphocytic lymphoma simulating hairy cell leukemia: a consideration of reliable and unreliable diagnostic features.

Morphologic, immunologic and functional characteristics of an unusual poorly differentiated diffuse lymphocytic lymphoma closely resembling hairy cell leukemia are presented and the diagnostic features of the latter disease are reviewed. The malignant cells morphologically resembled hairy cells at the light as well as electron microscopic level. They had surface characteristics of both T and B lymphocytes, were phagocytic, and adhered to glass. The spleen was smooth and resembled that seen in hairy cell leukemia. Although there was a predilection for the red pulp of the spleen, there was a lack of characteristic pseudosinus formation, and areas of predominantly white pulp involvement considered characteristic of lymphocytic lymphoma were found after extensive examination.

Aged↗