Search PubMed⌕ Search

Biomedical subjects

S Goldfarb

Publications and source records attributed to S Goldfarb.

At least 55 records · Page 3Linked to original sources
PubMed1990

Ovariectomy accelerates the growth of microscopic hepatocellular neoplasms in the mouse: possible association with whole body growth and fat deposition.

Ovariectomy (ovex) shortens the latency for development of hepatocellular neoplasms in mice, but the mechanism by which this occurs is not known. In the present study, B6C3F1 mice were given single i.p. injections of diethylnitrosamine (5 mg/kg) when they were 15 days old and either ovexed or sham operated 7 weeks later. Groups of 6 to 8 mice were killed after an additional 8, 14, 20, and 26 weeks. Four ovexed and four sham-operated mice were also killed after 56 weeks. By 8 weeks after surgery, the fractional volume of microscopic liver neoplasms in the ovexed mice was 4.3 times greater than in the shams and ablation had caused a 27% greater gain in body weight. During the following 18 weeks, tumor burdens were 3.9 to 10.6 times greater in ovexed than in the sham-operated mice and the rates of weight gain were similar in the two groups. Stereological analysis indicated that ovexed animals had more tumors than sham-operated animals, 575 versus 234/liver at 8 weeks and 952 versus 724/liver at 14 weeks after surgery. The ovex-induced increase in the number of neoplasms was spread throughout most of the size classes at both times; however, the impact on tumor burden of a small number of large tumors was only apparent at 14 weeks, when 8% of them accounted for more than two thirds of the aggregate tumor volume. The effect of the early emergence of these more rapidly growing tumors was also obvious at 1 year, when the livers of ovexed mice were more than twice the size of the shams (5.1 versus 1.8 g) and they contained 4 times as many tumors larger than 1 cm in diameter than the shams (2 versus 0.5/mouse). Since these very large tumors were invariably, at least partially, composed of trabecular hepatocellular carcinoma, ovariectomy appears to have also fostered tumor progression. The time course of ovex-stimulated weight gain and the manner in which it affected body composition were also analyzed. Eight days following ovex, the rate of weight gain abruptly increased. The acceleration persisted for only 14 days, after which it leveled off at body weights that were 24% higher than in sham-operated mice. The difference in weights resulted from 2.5 times more fat and 10% more protein in the carcasses of ovexed than sham-operated mice. This study identifies an early 8-week period in which hormonal changes resulting from ovex maximally stimulate the growth of liver tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue↗
PubMed1990

Morphology and anatomic localization of renal microneoplasms and proximal tubule dysplasias induced by four different estrogens in the hamster.

Estrogens are known to induce tumors in high frequency in orchiectomized Syrian golden hamsters, but the histogenesis of the tumors is controversial. In order to identify the earliest precursors of the tumors, animals were implanted with pellets of four different estrogens, sacrificed at times ranging up to 6.4 months, and the various neoplastic and nonneoplastic lesions were characterized. Infiltrating cancers were identified in 80% of animals exposed to diethylstilbestrol, 17 beta-estradiol, and hexestrol for periods of 5.3-6.4 months; however hamsters exposed to ethinyl estradiol for comparable times did not develop any tumors. Proximal tubule dysplasia, identified as focal collections of abnormal-appearing cells with increased [3H]thymidine-labeling indices (eight times higher than nondysplastic cells), was the only nonmalignant change that, for every agent, either preceded or accompanied the development of cancer. The dysplastic lesions were further subdivided into two types when it became apparent that they and carcinoma in situ, another lesion in the proximal tubules, might be part of a continuum of tumor progression that results in infiltrating cancer. Another dysplastic variant, classified as florid dysplasia because of its extensive involvement of tubules, showed well-differentiated features; it was seen only in the ethinyl estradiol-treated hamsters. In a quantitative study of the anatomic localization of dysplasias and microcancers (less than 0.5 mm in diameter) induced by diethylstilbestrol, both lesions showed highest incidence in the deep renal parenchyma. The dysplasias were at least eight times more prevalent in the proximal tubules of the innermost 10% of the cortex and subjacent medulla than in the rest of the cortex. We conclude that proximal tubule dysplasias developing in the deep renal parenchyma are the most likely precursors of the estrogen-induced cancers.

Animals↗
PubMed1990

High glucose induces cell hypertrophy and stimulates collagen gene transcription in proximal tubule.

Tubulointerstitial changes in the diabetic kidney correlate closely with the decline in glomerular filtration. In this study, we used a cell culture system of mouse proximal tubule epithelial cells to test the effects of glucose on cell growth, size, and matrix biosynthesis. [3H]thymidine incorporation was significantly inhibited in cells grown in 450 mg/dl glucose, compared with cells grown in 100 mg/dl glucose. The cells grown in the higher glucose concentration were slightly larger, their protein content and the total protein synthetic rate were significantly increased, and they secreted approximately twice as much procollagens type IV and type I. Concordantly, steady-state procollagen mRNA levels were also increased: 2.6-fold for the alpha 1(IV) and 2.2-fold for the alpha 2(I) procollagens. Additionally, nuclear run-off studies demonstrated that procollagen gene transcription rate was stimulated approximately 50%; beta-actin transcription rate was not altered. We used chloramphenicol acetyltransferase (CAT) reporter gene constructs to determine whether the increased transcription rate of alpha 2(I) gene was associated with activation of its enhancer sequence. Cells transfected with the enhancer demonstrated more than fivefold increase in CAT activity when cultured in the high-glucose medium. These studies demonstrate a multitude of effects of high ambient glucose concentrations on proximal tubule cell growth and collagen biosynthesis; cell proliferation is decreased although cell hypertrophy occurs. Procollagen gene transcription rate is stimulated and this response contributes to the observed increase in procollagen mRNA content. Activation of an enhancer sequence may be one possible mode through which high glucose levels increase the transcription of procollagen type I, presumably involving trans-acting factor(s).

Animals↗
PubMed1990

The role of diet in the pathogenesis and therapy of nephrolithiasis.

The epidemic of nephrolithiasis in the developed world in the twentieth century is in part the result of the diet consumed in these affluent nations. High protein intake is probably the most important factor. The patients who develop nephrolithiasis may have an increased calciuric response to diet protein and perhaps to diet sodium. The benefits of dietary modification include not only a tendency to reduce urinary calcium excretion but also increased urinary citrate and reduced urinary oxalate excretion. High fluid intake is also an important component of the therapeutic armamentarium of the physician treating patients with recurrent stone formation. The benefit of dietary therapy in patients with recurrent stone formation has not as yet been rigorously tested in controlled studies. Furthermore, there are few valid clinical studies of various pharmacologic agents such as thiazides, phosphates, allopurinol, and citrate. In the absence of clear-cut advantage of any specific pharmacologic agent, it appears that many patients may benefit from dietary modification rather than embarking on a life-long use of medications to prevent stone recurrences.

Calcium↗
PubMed1989

Focal impairment of growth in hepatocellular neoplasms of C57BL/6 mice: a possible explanation for the strain's resistance to hepatocarcinogenesis.

C57BL/6 mice are relatively more resistant to hepatocarcinogens than C3H and C57BL/6 x C3H F1 (hereafter called B6C3F1) mice; however, the basis for this strain-dependent difference is not clear. In order to address this issue, male C57BL/6 mice were treated i.p. with 5 mg/kg diethylnitrosamine when 15 days old and the histological features of induced hepatocellular neoplasms were assessed at intervals over the ensuing 80 weeks. In many respects the natural history of the tumors was similar to that previously reported for hepatic neoplasms in B6C3F1 mice; they invaded hepatic vein branches while still microscopic (18 weeks after diethylnitrosamine) and developed into metastasizing trabecular carcinomas by 80 weeks. However, the tumors in the C57BL/6 mice were unique in their early focal development of cells containing inclusions of secretory protein within the endoplasmic reticulum. At 12 weeks after diethylnitrosamine, more than 90% of the neoplasms contained inclusions. Over the ensuing months, the inclusions increased in size and number and the regions containing them became more sharply defined. In mice killed 48 weeks after carcinogen, the extent of inclusion formation was correlated with [3H]thymidine labeling indices. Mean labeling indices were higher in the inclusion-poor than in the inclusion-rich areas: 5.4% versus 1.5% for the 36 neoplasms smaller than 1 mm in diameter and 14% versus 6% for the 18 neoplasms larger than 1 mm. Thus, we suggest that the focal slowing of hepatocellular tumor growth in C57BL/6 mice contributes to the strain's apparent resistance to hepatocarcinogenicity. However, the impairment does not appear to block tumor progression and the ultimate development of trabecular carcinomas. In addition, the data indicate that, independent of the presence or absence of inclusions, larger tumors have higher labeling indices, and presumably higher growth rates, than smaller ones. While the reason for the association between cytoplasmic inclusions and the low labeling indices is not known at present, at the very least the inclusions serve as unique markers for the growth retardation.

Animals↗
PubMed1989

WR-2721 reduces bone loss after hindlimb tenotomy in rats.

WR-2721 is a thiophosphate analog of cysteamine that produces hypocalcemia in vivo. Previous studies suggest that WR-2721 produces hypocalcemia by independent inhibitory effects on parathyroid hormone (PTH) secretion, osteoclastic bone resorption, and tubular reabsorption of calcium. We sought to determine if WR-2721 would decrease bone loss in an animal model of disuse osteoporosis produced by unilateral knee tenotomy in the rat. Tenotomy significantly increased osteoclast number in tibias on the side of the procedure compared with tibias on the opposite side which had not undergone the procedure at 3 and 14 days. Femoral weight of tenotomized limbs were also reduced significantly compared with the contralateral limb at 3 and 14 days. WR-2721 treatment (240 mg/kg daily) prevented 26% of the loss of femoral dry weight and 29% of the loss of femoral ashed weight produced 14 days after tenotomy. In addition, WR-2721 treated (240 mg/kg daily) animals had fewer osteoclasts in tenotomized tibias than control animals at 3 days (6.6 +/- 0.7/mm versus 10.3 +/- 0.9/mm, p less than 0.02) and at 14 days (5.8 +/- 0.3/mm versus 8.7 +/- 0.4/mm, p less than 0.02). These data suggest that WR-2721 decreases bone loss in this model by decreasing osteoclastic bone resorption.

Amifostine↗
PubMed1989

Hyperfiltration and renal disease in glycogen storage disease, type I.

A prospective study of 14 patients (ages 6 months to 33 years) with glycogen storage disease, Type I (GSD-I) was carried out in order to define the character and frequency of renal dysfunction. A marked increase in the glomerular filtration rate (GFR) was documented in virtually all subjects, with the mean GFR raised by approximately 50%, to the range of 170 ml/min/1.73 m2. While this constituted the only renal abnormality found in the younger patients, a significant increase in urinary albumin excretion was seen in three teen-aged individuals; three patients over 20 years of age exhibited frank proteinuria (2 to 8 g/day). Renal biopsy on two of the proteinuric subjects revealed focal and global glomerulosclerosis and interstitial fibrosis. Evaluation of factors known to cause an increase in GFR did not define the precise etiology for its elevation in GSD-I. These studies suggest that: (1) glomerular damage and chronic renal disease are common in older patients with GSD-I; (2) the renal injury appears to be specifically related to GSD-I and is not secondary to the treatment of the disease; and (3) the natural history of the renal lesion in GSD-I may be analogous to that seen in insulin-dependent diabetes, with a "silent" period where hyperfiltration is the only demonstrable renal abnormality, followed by evidence of increasing glomerular damage progressing from microalbuminuria to frank proteinuria.

Adolescent↗
PubMed1989

Specific estrogen-induced cell proliferation of cultured Syrian hamster renal proximal tubular cells in serum-free chemically defined media.

It has long been recognized that the renal proximal tubular epithelium of the hamster is a bona fide estrogen target tissue. The effect of estrogens on the growth of proximal tubule cell explants and dissociated single cells derived from these explant outgrowths has been studied in culture. Renal tubular cells were grown on a PF-HR-9 basement membrane under serum-free chemically defined culture conditions. The cells of tissue explant outgrowths exhibited ultrastructural features typical of proximal tubules including junctional complexes, numerous mitochondria, peroxisomes, and microvilli. At 7-14 days in culture, cell number was enhanced 3-fold in the presence of either 17 beta-estradiol or diethylstilbestrol. Maximal proliferative response was observed at hormone concentrations of 0.6-1 nM. A similar 3-fold increase in cell number was also seen at 1 nM 17 beta-estradiol in subcultured dissociated single tubular cells derived from hamster renal tubular explant outgrowths at 21 days in culture. Neither progesterone, 5 alpha-dihydrotestosterone, nor the inactive diethylstilbestrol metabolite beta-dienestrol elicited this mitogenic effect. Concomitant exposure of tamoxifen at 3-fold molar excess in culture completely abolished the increase in cell number seen with 17 beta-estradiol. Tubular cells obtained from hamster medulla did not exhibit this proliferative response when exposed similarly to 17 beta-estradiol or diethylstilbestrol. The proliferative effect of estrogens on proximal tubular cell growth appears to be species specific since 17 beta-estradiol did not alter the growth of either rat or guinea pig proximal tubules in culture. In addition, at 7-10 days in culture in the presence of 17 beta-estradiol, [3H]thymidine labeling of hamster tubular cells was enhanced 3-fold. A similar increase in mitoses was also observed in cultures containing these potent estrogens during the same time interval of estrogen exposure. These results clearly indicate that estrogens can directly induce primary epithelial cell proliferation at physiologic concentrations and provide strong additional evidence for an important hormonal role in the neoplastic transformation of the hamster kidney.

Animals↗
PubMed1989

Autoradiographic evidence of estrogen binding sites in nuclei of diethylstilbesterol induced hamster renal carcinomas.

Estrogen binding sites were demonstrated by autoradiography in one transplantable and five primary diethylstilbesterol induced renal carcinomas in three hamsters. Radiolabelling, following the in vivo injection of 3H-17 beta estradiol, was increased only over the nuclei of tumor cells; stereologic analysis revealed a 4.5- to 6.7-times higher concentration of reduced silver grains over nuclei than cytoplasm of these cells. Despite rapid tubular excretion of estradiol which peaked in less than 1 h, the normal cells did not appear to bind the ligand. This is the first published report documenting the preferential in vivo binding of estrogen to nuclei of cells in estrogen induced hamster renal carcinomas.

Animals↗
PubMed1988

Immunohistochemical demonstration of estrophilin in mouse tissues using a biotinylated monoclonal antibody.

We have developed a direct avidin-biotin-peroxidase complex (ABC) immunohistochemical method for localization of estrophilin in mouse tissues. The method has been found especially useful for microscopic demonstration of the receptor in mouse liver, since the indirect alternative, autoradiography after injection of radiolabeled estrogens, is of no value in this organ. The ABC technique employs a biotinylated monoclonal antibody to human estrophilin (Abbot H222) which was previously shown to crossreact with the murine receptor. Cryostat-cut tissue sections which were briefly fixed were incubated with the modified antibody, and the estrophilin was revealed by subsequent exposure to ABC followed by H2O2/diaminobenzidine.

Animals↗
PubMed1987

Performance of a dangerous answer subtest within a subspecialty certifying examination.

Previous studies have been reported suggesting that a population of candidates for specialty board certification can be identified who pass the certification examination but who give an unduly high number of 'dangerous' responses, indicating their acceptance of actively harmful actions. To confirm these results, a retrospective analysis was undertaken of a Subspecialty Board of Nephrology certification examination. Experts identified a subtest of 75 dangerous answers. The performance of candidates on this subtest was compared with their performance on the total examination. The subtest was moderately reliable, ranked criterion groups appropriately, had a correlation with the total test of 0.71, and using the standard used for the total examination, identified the certification status of 84% of candidates. However, when the correlation was corrected for unreliability, the correlation became 1.0, indicating that a dangerous answer subtest, at least in this examination and population, does not identify a unique population of certified but 'dangerous' doctors.

Certification↗
PubMed1987

WR-2721 inhibits parathyroid adenylate cyclase.

WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] is a chemoprotective and radioprotective agent that has been shown to lower serum calcium in dogs and in humans. This is secondary both to impaired release of Ca2+ from bone and diminished secretion of parathyroid hormone (PTH) from parathyroid glands. Because cAMP plays a role in the regulation of PTH secretion and WR-2721 has been shown to lower cAMP levels in radiated mouse spleen, we investigated the effects of WR-2721 on cAMP production in dispersed bovine parathyroid cells. Additionally, we studied the adenylate cyclase in plasma membranes from normal bovine parathyroid glands after exposure to WR-2721. With parathyroid cells incubated at 0.5 mM Ca2+, addition of WR-2721 in concentrations ranging from 0.02 to 2.0 mM resulted in a progressive decrease in intracellular cAMP (42-50%, respectively). In plasma membranes of bovine parathyroid cells a dose-dependent decrease in adenylate cyclase activity was noted. Inhibition of the cyclase was seen over a wide range of Mg2+ concentrations (2.5-40 mM). WR-2721 inhibited both basal and NaF, Gpp(NH)p, forskolin, and pertussin toxin-stimulated adenylate cyclase. These data suggest that WR-2721 inhibits the activity of parathyroid adenylate cyclase.

Adenylyl Cyclase Inhibitors↗
PubMed1987

Case-control study of risk factors for idiopathic calcium nephrolithiasis.

We compared epidemiological risk factors and urine excretion of calcium, phosphate, uric acid, urea nitrogen, sodium, potassium, and fluid volume in recurrent idiopathic calcium stone-formers and in a control group of age- and sex-matched normal volunteers. Stone-formers were less likely than normal subjects to have followed a low-calorie diet, but body weight did not differ between the two groups. Daily urine calcium excretion was a graded risk factor for stone formation throughout its range. Daily urine urea nitrogen and potassium excretion were lower in stone-formers than in controls, but excretion of uric acid, sodium, phosphate, and creatinine did not differ. However, there were positive associations between urine calcium excretion and the urine excretion of sodium, urea nitrogen, uric acid, phosphate, and creatinine in stone-formers; and these associations were significantly stronger than in normal subjects. We conclude that urine calcium excretion is a major risk factor for idiopathic calcium stone formation, but cannot confirm such a role for urine uric acid excretion. Total dietary protein intake may be lower in stone-formers than in controls. However, stone-formers may be more sensitive than normal subjects to the calciuric effects of protein and sodium. A strong association of urine calcium excretion with urine phosphate excretion in stone-formers is probably independent of dietary protein intake.

Adolescent↗
PubMed1986

Characterization of estrogen binding proteins in mouse liver cytosol: absence of sexual dimorphism.

Estrogen binding proteins in mouse liver cytosol were characterized by separation on Sephadex G-75 columns, by Scatchard plot analysis, and by hormonal competition studies. A high affinity receptor (56-70 fmol/mg cytosolic protein) with a mol. wt greater than 75,000, Kd of 5.7-8.4 X 10(-10) M was identified in male and female C3H liver. A second high capacity low affinity (HCLA) binder (200-300 fmol/mg cytosolic protein) with a mol. wt of about 50,000, Kd of 1.7-7.2 X 10(-8) was also identified. Following partial purification of the estrogen binders by ammonium sulfate precipitation, Scatchard plot analysis revealed selective removal of HCLA. On Sephadex G-75 filtration, the purification also resulted in selective removal of the 17 beta-estradiol binding component with a mol. wt of 50,000. Comparison with rat cytosol separations show that the sexual dimorphism in HCLA binding proteins (5 times higher in male than female rat liver) was absent in the mouse liver. These studies document the presence of a specific high affinity estrogen binding protein in mouse liver and indicate that the sexual dimorphism in HCLA proteins is not a universal feature of all rodent species.

Animals↗
PubMed1986

Phase II clinical evaluation of AZQ in renal cell carcinoma.

Twenty-two patients with advanced measurable renal cell carcinoma were treated with AZQ 20 mg/m2 weekly for 4 weeks, followed by a 2-week rest. No complete or partial responses were observed among 15 fully evaluable patients. Stabilization was observed in eight individuals (range 8-27 weeks with a median of 12.5 weeks). Toxicity was primarily reversible myelosuppression. We conclude that AZQ administered at this dose and schedule has no significant activity against advanced renal cell carcinoma.

Adenocarcinoma↗