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Biomedical subjects

S Lerner

Publications and source records attributed to S Lerner.

At least 55 records · Page 3Linked to original sources
PubMed1993

Nerve growth factor induces a succession of increases in isoprenylated methylated small GTP-binding proteins of PC-12 pheochromocytoma cells.

Pheochromocytoma (PC-12) cells exposed to nerve growth factor (NGF) acquire a sympathetic neuron-like phenotype. This NGF-response is blocked by methylation inhibitors and can be mimicked by the farnesylated methylated small GTP-binding protein p21ras. The implicated involvement of prenylation, methylation and a small GTP-binding protein in the NGF-response has been studied by directly measuring 3H-mevalonic acid (MVA)-metabolites incorporated into proteins, protein carboxy [methyl-3H]ester formation and levels of [alpha-32P]GTP-binding proteins in NGF-induced PC-12 cells. We demonstrate that NGF induces a 2-3-fold increase in 21-24 kDa methylated membrane proteins that incorporate 3H-MVA-metabolites, and bind GTP. Levels of [alpha-32P]GTP-binding in these proteins were increased by 2-3-fold. Methylation and membrane association of the small GTP-binding proteins were blocked by lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which also enhanced their labeling by 3H-MVA-metabolites. Cycloheximide reduced the levels of [methyl-3H] labeled 21-24 kDa proteins and of the overlapping [alpha-32P]GTP binding-proteins. About 70% of the [methyl-3H]-groups found in these proteins were recovered from two dimensional gel blots in nine distinct spots of [alpha-32P]GTP-binding proteins. Taken together these results strongly suggest that in PC-12 cells, NGF induces an increase in the synthesis of prenylated methylated small GTP-binding proteins. The efficacy of lovastatin blockage of protein methylation and enhancement of 3H-MVA-metabolites incorporation into GTP-binding proteins was lower in NGF-induced cells than in controls. This suggests that NGF also induces an increase in HMG-CoA reductase activity. At the early phase of the NGF response in PC-12 cells (15 min-1 h), the levels of two small GTP-binding proteins (molecular mass of 21-22 kDa and 23-24 kDa) were increased. Thus, at least two proteins, of which one but not the other may be p21ras, appear to be involved in the early response. After a lag period of 24 h with NGF, a second more robust phase of increase in methylated small GTP-binding proteins was apparent. This relatively late response, which was almost completed within 24 h, may reflect involvement of small GTP-binding proteins in neurite-outgrowth and in the functional activity of the differentiated cells. Many small GTP-binding proteins were increased during the second phase, precluding electrophoretic separation of all of them. 3 proteins, however, were well separated (one 23-24 kDa protein and two 21-22 kDa proteins).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Phase II clinical trial of fludarabine in chronic lymphocytic leukemia on a weekly low-dose schedule.

The major complication during therapy of chronic lymphocytic leukemia (CLL) with the purine nucleotide analogue fludarabine is infection, which is also the main cause of morbidity and mortality in the disease. As the incidence of infectious episodes during therapy correlated with severity of neutropenia, stage of disease, and response to therapy, an effort was made to reduce therapy-related myelosuppression and improve response by altering the conventional therapy regimen. The protocol which yielded a response rate of 57% in previously treated patients with CLL consisted of five consecutive daily doses of 25-30 mg/m2 fludarabine given every three to four weeks. Based on observations from intracellular pharmacology studies it was hypothesized that repetitive single weekly doses of fludarabine would allow normal bone marrow cells to recover while maintaining cytotoxic levels in the leukemic cells. The cumulative four-week dose of the once-weekly regimen was approximately 80% of the original protocol. Eleven out of 46 evaluable patients (24%) responded to the therapy. Seven patients (15%) achieved a complete remission, and four (9%) a partial remission. While myelosuppression was reduced by about 30% compared with the original protocol, the incidence of febrile episodes was increased by 17%. Pretreatment serum IgG levels below the normal range correlated significantly with a high incidence of infectious episodes and with a short median survival time. These observations suggest that in addition to myelosuppressive therapy, disease related depressed immune function causes morbidity and mortality due to infections. The results further show that changes in the scheduling of the therapy regimen, associated with a slightly lower dose, resulted in reduced efficacy as measured by the response rate.

Adult↗
PubMed1993

L-asparaginase and PEG asparaginase--past, present, and future.

L-asparaginase is an enzyme which hydrolyses asparagine. Since the 1960s it has been known that some leukemic cells are deficient in asparagine synthetase and therefore cannot manufacture sufficient quantities of this essential amino acid to maintain cell viability. L-asparaginase is predominantly useful in acute lymphocytic leukemia (ALL) although responses have been noted in patients with acute myeloid leukemia, lymphoma, and rarely other tumors. L-asparaginase has been used in conjunction with methotrexate and ara-C in combination programs in leukemia. The major side-effect limiting the usefulness of L-asparaginase is allergic reactions. In addition, it is probable that neutralizing antibodies develop which shorten the half life of the drug so that the goal of depletion of plasma levels of asparagine cannot be attained or maintained. Polyethylene glycol (M.W. 5000) can be conjugated to L-asparaginase at sites not involving the active site of the enzyme. This enables free access of a small molecule, asparagine, to the active site of the enzyme but prevents uptake by the reticuloendothelial system, greatly decreasing the probability of developing antibodies against the asparaginase and prolongs the circulating half life of the drug. In a phase I/II study conducted at the M.D. Anderson Cancer Center, 37 heavily pretreated patients with refractory hematologic malignancy were treated. The age range from 15 to 73 years, median 49 years. Nineteen patients had ALL, 15 lymphoma, two myeloma, and one Hodgkin's disease. The dose levels of PEG L-asparaginase varied from 250 IU/m2 up to 8000 IU/m2. The pharmacokinetic profile demonstrated a monophasic half life consistent with a one compartment model with a single elimination phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Pericardial tamponade in juvenile dermatomyositis.

Cardiac involvement in dermatomyositis has been well described; myocarditis and cardiac arrhythmias are the most frequent manifestations. An 8-year-old girl is presented, who developed pericardial tamponade in the course of the disease. It is the first time this association has been reported.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Isoprenylation and carboxylmethylation in small GTP-binding proteins of pheochromocytoma (PC-12) cells.

1. A group of 21 to 24-kDa proteins of pheochromocytoma (PC-12) cells was found in blot overlay assays to bind specifically [alpha-32P]GTP. Binding was inhibited by GTP analogues but not by ATP. Such small GTP-binding proteins were found in the cytosolic and in the particulate fraction of the cells, but they were unevenly distributed: about 75% of the small GTP-binding proteins were localized within the particulate fraction of the cells. Separation of these proteins by two-dimensional gel electrophoresis revealed the existence of seven distinct [alpha-32P]GTP-binding proteins. 2. Targeting of the small GTP-binding proteins to the particulate fraction of PC-12 cells requires modification by isoprenoids, since depleting the cells of the isoprenoid precursor mevalonic acid (MVA) by the use of lovastatin resulted in a 50% decrease in membrane-bound small GTP-binding proteins, with a proportionate increase in the cytosolic form. This blocking effect of lovastatin was reversed by exogenously added MVA. 3. In addition, metabolic labeling of PC-12 cells with [3H]MVA revealed incorporation of [3H]MVA metabolites into the cluster of 21 to 24-kDa proteins in a form typical of isoprenoids; the label was not removed from the proteins by hydroxylamine, and labeling was enhanced in cells incubated with lovastatin. The latter effect reflects a decrease in the isotopic dilution of the exogenously added [3H]MVA, as the addition of exogenous MVA reversed the effect of lovastatin on [3H]MVA-metabolite incorporation into the 21 to 24-kDa proteins. 4. Additional experiments demonstrated that isoprenylation is required not only for membrane association of small GTP-binding proteins, but also for their further modification by a methylation enzyme. This was evident in experiments in which the cells were metabolically labeled with [methyl-3H]methionine, a methylation precursor. The group of 21 to 24-kDa proteins was labeled with a methyl-3H group in a form typical of C-terminal-cysteinyl carboxylmethyl esters. Their methylation was blocked by the methylation inhibitors methylthioadenosine (MTA), 3-deazadenosine and homocysteine thiolactone as well as by lovastatin. MVA reversed the lovastatin block of methylation. 5. Two-dimensional gel analysis of the [3H]methylated proteins detected seven methylated small GTP-binding proteins that correspond to the isoprenylated proteins. Levels of the small GTP-binding proteins as well as isoprenylation and methylation were reduced by cycloheximide. 6. Distribution of the methylated proteins between particulate and cytosolic fractions was found to be similar to that of the small GTP-binding proteins (i.e., a 4:1 ratio).(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Gland Neoplasms↗
PubMed1992

Differing effects of cholesterol and taurocholate on steady state hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities and mRNA levels in the rat.

We investigated the effects of cholesterol, cholestyramine, and taurocholate feeding on steady state specific activities and mRNA levels of hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase and cholesterol 7 alpha-hydroxylase in the rat. Interruption of the enterohepatic circulation of bile acids (cholestyramine feeding) increased total HMG-CoA reductase activity 5-fold. Cholesterol and taurocholate administration suppressed total microsomal HMG-CoA reductase activities 87% and 65%, respectively. HMG-CoA reductase mRNA levels increased 3-fold with cholestyramine, did not decrease significantly with cholesterol feeding, but were markedly decreased after taurocholate treatment. Cholesterol 7 alpha-hydroxylase activity increased 4-fold with cholestyramine and 29% during cholesterol feeding, but decreased 64% with taurocholate. Cholesterol 7 alpha-hydroxylase mRNA levels rose 150% and 50% with cholestyramine and cholesterol feeding, respectively, but decreased 73% with taurocholate. The administration of cholesterol together with taurocholate prevented the decline in cholesterol 7 alpha-hydroxylase mRNA levels, but inhibition of enzyme activity persisted (-76%). Hepatic microsomal cholesterol concentrations increased 2-fold with cholesterol feeding but did not change with taurocholate or cholestyramine treatment. These results demonstrate that mRNA levels of HMG-CoA reductase are controlled by the hepatic taurocholate flux, whereas mRNA levels of cholesterol 7 alpha-hydroxylase are controlled by the cholesterol substrate supply. These end products, cholesterol and bile acids, exert post-transcriptional regulation on HMG-CoA reductase and cholesterol 7 alpha-hydroxylase, respectively.

Administration, Oral↗
PubMed1989

The role of transrectal ultrasonography in the diagnosis and management of prostatic and seminal vesicle cysts.

Cysts in the region of the prostate and seminal vesicles are interesting because of their differential diagnosis and embryological relevance. We present our experience with 5 cases that include a müllerian duct cyst, diverticulum of the spermatic tract, seminal vesicle cyst and 2 prostatic cysts. Transrectal ultrasonography had a significant role in the diagnostic evaluation of these cysts. Ultrasonographically guided transperineal needle aspiration added significant diagnostic information and might have a therapeutic value. After a review of the literature, we propose an algorithm for the evaluation and management of prostatic and seminal vesicle cysts.

Aged↗
PubMed1988

Duodenal instillation of pancreatin does not abolish steatorrhea in patients with pancreatic insufficiency.

Many believe that intragastric deactivation of lipase accounts for the frequent failure of orally ingested pancreatic enzymes to normalize fat absorption in patients with pancreatic insufficiency. To test this hypothesis, we measured fat absorption from a large test meal in six patients with pancreatic insufficiency after we had instilled Viokase directly into the postcibal duodenum in two doses, one to deliver lipase at about 10% of normal secretory rates and the other at four times this rate. Direct duodenal instillation of neither the low nor the high dose of Viokase, nor the low dose of Viokase plus sodium bicarbonate, normalized fat absorption from the test meal; none of these duodenal instillations significantly improved fat absorption over that after the test meal plus orally ingested Viokase. Despite these various treatments, the patients excreted an average of 25.5 g of dietary fat as opposed to 2.1 g excreted by six normal subjects after the same meal. We conclude that more than just intragastric destruction of lipase underlies the frequent failure of orally ingested pancreatin to normalize fat absorption in pancreatic insufficiency.

Celiac Disease↗
PubMed1985

Mechanism of the glucocorticoid regulation of growth of the androgen-sensitive prostate-derived R3327H-G8-A1 tumor cell line.

The R3327H-G8-A1 cell line derived from the Dunning rat prostate adenocarcinoma contains both androgen and glucocorticoid receptors. Following steroid deprivation, androgens specifically increase the concentration of their receptors in these cells by approximately 2-fold within 6 h and 3-4-fold in 24 h. In the presence of potent glucocorticoids, androgen receptor augmentation is reduced by 40-50% in the first 6 h and completely inhibited during the subsequent 24 h. This event, which is specific for glucocorticoids, appears to be due to an inhibition of androgen receptor synthesis. Furthermore, glucocorticoids inhibit proliferation of these cells by inhibiting the release of growth factors and arresting them in the G0 or A state of the cell cycle. This inhibition can be overcome by addition of low concentrations of either epidermal growth factor or platelet-derived growth factor; however, the inhibitory effect of the glucocorticoid on androgen receptor augmentation is not released. These results suggest that glucocorticoids arrest cellular proliferation by altering the autoregulation of growth and that this event is not dependent upon inhibition of androgen receptor augmentation.

Adenocarcinoma↗
PubMed1984

Histamine and slow reacting substance in acid-induced pneumonitis.

Acid pneumonitis was produced in 18 dogs by the tracheal instillation of 3 ml/kg 0.1 N hydrochloric acid. Arterial and mixed venous oxygen tension, static compliance and pulmonary capillary wedge pressure were measured during a 2-hour observation period. Plasma histamine (measured by the enzymatic isotopic assay) increased from 1.7 +/- 0.2 ng/ml (mean +/- SE) before acid injury to 13.5 +/- 1.9 ng/ml after injury (p less than 0.05). In one group of 7 control dogs, 3 ml/kg of normal saline produced no increase in plasma histamine. Pulmonary edema secretions from acid injured animals had a histamine level of 30.3 +/- 3.8 ng/ml and slow reacting substance was detected in 7 of 11 animals. The slow reacting substance was an antihistamine-resistant, ethanol extractable substance that contracted guinea pig ileum. Lung weight-body weight ratio PaO2, and static compliance were different with acid pneumonitis compared to controls. Total protein was not different in the tracheal secretions compared to plasma. We conclude that histamine and slow reacting substance are released in this animal model of acid pneumonitis and may be important in the pathogenesis of the lung injury.

Animals↗
PubMed1983

Biologic response to environmental toxins.

Biological response to environmental toxins results from the sum of natural, environmental, avocational, inapparent, and occupational exposures. These external exposures result in acceptable or unacceptable levels of absorption or internal exposure based on anticipated biological effects. There is no level of exposure which is in and of itself synonymous with intoxication. Biological effects may be classified as physiologic or pathologic, adaptive or nonadaptive, respectively. In each instance, the response may be acceptable or unacceptable. Intoxication requires the demonstration of a significant impairment of health. One may have an unacceptable pathologic response and still not have intoxication. Professional judgment is required.

Absorption↗
PubMed1983

A systemic approach to resistance: theoretical and technical considerations.

A systemic approach to resistance allows the individual therapist to appreciate the adaptive, protective, systems-maintaining aspects of "help-rejecting" behaviors which might otherwise elicit negatively toned interventions that serve to heighten or rigidify a resistant impasse. This article illustrates how a systemic perspective assists the psychodynamically oriented psychotherapist in adopting a neutral and respectful attitude toward a patient's resistant posture, and also explores implications for the theoretical understanding and technical management of resistance.

Adult↗
PubMed1982

Relationship of air lead and blood lead for workers at an automobile battery factory.

Air lead and blood lead data, recorded over a period of 3 years for 972 employees at an automobile battery factory as part of a lead control program, were summarized and statistically analyzed. The air lead values were measured by mobile area samplers for approximately 2 years and then by personal samplers for approximately 1 year. Blood lead analyses were usually performed once a month for most of the workers. The trend in air lead levels was significantly upward in the 1st year and significantly downward in the 2nd year while the trend in blood lead levels was significantly downward in the 1st year and in the 3rd year. There were no other significant trends. To assess the relationship between air lead and blood lead, data were used whenever an air lead obtained by personal sampler was followed within 1 month by a blood lead on the same worker. The variables age, job tenure, and department identity were included in an analysis of covariance. Only air lead and departments were significant, accounting for 9% and 13% of the variance in blood lead, respectively. From these data 95% confidence limits were calculated for predicting blood leads from given air leads for an individual worker. These were 30-68 micrograms/100 ml at 200 micrograms/m3, 25-62 micrograms/100 ml at 100 micrograms/m3, and 22-60 micrograms/100 ml at 50 micrograms/m3.

Adult↗
PubMed1982

Free erythrocyte protoporphyrin, zinc protoporphyrin and blood lead in newly re-exposed smelter workers: a prospective study.

The relationship between blood lead and free erythrocyte protoporphyrin (FEP) or zinc protoporphyrin (ZPP) was evaluated prospectively for 50 weeks in a group of workers who were removed from occupational lead exposure for 10 weeks. FEP or ZPP continued to fall in spite of a rising blood lead upon re-exposure. Although statistically significant relationships between square root FEP or ZPP and blood lead were found, wide confidence limits prevent meaningful predictions of blood lead from FEP or ZPP for an individual. Blood lead is a better index of exposure than FEP or ZPP, especially when exposure is not stable.

Environmental Exposure↗