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Biomedical subjects

I Klein

Publications and source records attributed to I Klein.

At least 109 records · Page 6Linked to original sources
PubMed1992

Hemodynamic regulation of myosin heavy chain gene expression. Studies in the transplanted rat heart.

Cardiac work is a major determinant of heart size and growth. Heterotopic cardiac isografts are hemodynamically unloaded and undergo atrophy. To determine the molecular changes that occur as a result of hemodynamic unloading, we have studied the rate of synthesis of total cardiac proteins and myosin heavy chain (MHC) and the expression of the myosin heavy chain gene as reflected in the messenger RNA levels for alpha- and beta-MHC isoforms. 72 h after transplantation there is a significant decrease in left ventricular size accompanied by a 27% decrease in the rate of total cardiac protein synthesis and a 53% decrease in the rate of myosin heavy chain synthesis. In contrast to isografts 14 d after transplantation which have a decrease in protein synthetic capacity, simultaneous measurements of 18S ribosomal RNA and myosin messenger RNA suggest that after 3 d the decrease in synthesis is due to a change in the efficiency of protein translation. While the working in situ heart expresses primarily alpha-MHC mRNA (97%) hemodynamic unloading leads to a 43% decrease in alpha-MHC mRNA concentration and the de novo expression of the beta-MHC mRNA. Total MHC mRNA (alpha plus beta) concentration analyzed by a quantitative S1 nuclease protection assay was similar in the two groups of hearts. Thus, in association with hemodynamic unloading there are changes in cardiac myosin heavy chain content as a result of both gene transcription and protein translation mechanisms.

Animals↗
PubMed1992

Time course of the in vivo effects of thyroid hormone on cardiac gene expression.

The rate of response to thyroid hormone on cardiac growth, heart rate, and the relative changes in messenger RNA (mRNA) coding for alpha- and beta-myosin heavy chain (MHC), slow sarcoplasmic reticulum calcium-adenosine triphosphatase, and thyroid hormone receptors in ventricular tissue of hypothyroid rats was investigated. Hypothyroid rats had significantly smaller hearts, with slower heart rates and expressed no alpha-MHC mRNA as analyzed by an S1 nuclease protection assay when compared to euthyroid animals that expressed 79% alpha-MHC. Twelve hours after treating hypothyroid rats with 20 micrograms of L-T4, detectable levels of alpha-MHC mRNA were present and the shift to alpha-MHC mRNA was complete by 72 h of treatment. Northern blot analysis showed that hypothyroidism resulted in a 60% decrease in the level of sarcoplasmic reticulum calcium-adenosine triphosphatase mRNA which increased after 12 h of T4 administration and was 2.5-fold (P less than 0.05) greater than euthyroid levels after 72 h. In contrast, thyroid hormone receptor mRNA levels measured in poly(A)+ RNA were elevated in hypothyroid rats and decreased to euthyroid levels within 24 h after thyroid hormone treatment. These changes in cardiac gene expression occurred simultaneously with changes in both cardiac size and heart rate. The current studies characterize the coordinated changes and the time course for gene expression that occur in the hypothyroid heart after acute T4 administration.

Animals↗
PubMed1992

Impact of starvation on hormone binding and hormonal imprinting in Tetrahymena.

Tetrahymena cells maintained (starved) in a physiological salt solution showed a considerable decrease in insulin binding capacity. The cells previously imprinted with insulin showed a comparable relative binding decrease after a similar exposure. This change was reversible by prolonged maintenance in plain nutrient medium after which the binding capacity of the imprinted cells increased appreciably over the control. The cells maintained (starved) in salt solution for 2 h were no longer imprintable with insulin; it follows that prolonged starvation not only reduced the recognition potential, but also extinguished the imprintability of Tetrahymena cells.

Animals↗
PubMed1991

The chemical reactivity of the modulating agent WR2721 (ethiofos) and its main metabolites with the antitumor agents cisplatin and carboplatin.

The antitumor agents cisplatin [cis-diamminedichloroplatinum(II), CDDP] and carboplatin [cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), CBDCA] can react with a nucleophilic agent by a direct ligand exchange of the (labile) anionic ligands or through hydrolysis of these ligands followed by a fast reaction of the hydration product with the nucleophile. At pH 7.4 and 37 degrees, CDDP and CBDCA were incubated with several molar excesses of the modulating agent WR2721, its active thiol metabolite WR1065 or the symmetrical disulphide WR33278. The reaction rate constants for the hydrolysis and the direct inactivation by the WR-compounds were obtained from the pseudo first-order disappearance of the intact Pt-drug, with or without the WR-compounds at molar ratios of 50, 100 and 200. The hydrolysis of carboplatin (kaq,CBDCA = 2 x 10(-8) M-1 sec-1) was 100-fold less rapid than that of cisplatin (kaq,CDDP = 2 x 10(-6) M-1 sec-1). However, direct inactivation by WR2721, WR1065 and WR33278 was only 4-, 4- and 22-fold less rapid for carboplatin than for cisplatin, respectively. This direct inactivation was slow compared to the strong nucleophiles thiosulphate (TS) and diethyldithiocarbamate (DDTC) and decreased for both Pt-drugs in the following order: WR1065 (kWR1065/CDDP = 49.1 x 10(-4) M-1 sec-1, kWR1065/CBDCA = 12.4 x 10(-4) M-1 sec-1) greater than WR2721 (kWR2721/CDDP = 25.3 x 10(-4) M-1 sec-1, kWR2721/CBDCA = 6.07 x 10(-4) M-1 sec-1) greater than WR33278 (kWR33278/CDDP = 8.60 x 10(-4) M-1 sec-1, kWR33278/CBDCA = 0.39 x 10(-4) M-1 sec-1. Thus for CDDP, the hydrolysis-mediated interaction with the WR-compounds contributed more to the disappearance of intact platinum antitumor agent than it did for CBDCA. Considering the relatively low reactivity of WR2721 and its main metabolites with the platinum antitumor agents, in addition to their pharmacokinetic behavior, a significant inactivation of the platinum antitumor drugs by WR2721 and its main metabolites is, in contrast to TS, not expected in the circulation.

Amifostine↗
PubMed1991

Thyroid hormone regulation of alpha-myosin heavy chain promoter activity assessed by in vivo DNA transfer in rat heart.

We have studied the thyroid-hormone responsiveness of the alpha-myosin heavy chain (MHC) gene in vivo by directly injecting an expression vector containing the alpha-MHC 5' regulatory sequences (-613 to +421 base pairs) into the rat heart. In the expression vector pAM1Luc the alpha-MHC promoter elements direct the synthesis of firefly luciferase. Although thyroxine administration of both euthyroid and thyroidectomized rats for 5 days increased alpha-MHC promoter activity, the pAM1Luc gene construct did not mimic expression of the endogenous gene. These studies of direct gene transfer into mammalian myocardium suggest that additional cis-acting elements necessary for the in vivo response to thyroid hormone reside outside the -613 to +421 region.

Animals↗
PubMed1991

Phase I study of spiroplatin.

Spiroplatin was investigated in a multicentre phase I study. 67 patients with advanced solid tumours received 151 cycles either by short-term or prolonged infusion, repeated every 3 weeks, at 2.5-40 mg/m2. Myelosuppression and renal toxicity were dose-limiting. Proteinuria, which was dose- and schedule-dependent, indicated glomerular and tubular damage. The maximum tolerated doses (MTD) for poor-risk and good-risk patients were 35 and 40 mg/m2, respectively. The area under the curve (AUC) at the MTD did not correspond with the AUC at the LD10 in mice with ratios of 0.3 for free platinum and 2.6 for total platinum; these were not suitable for predicting the MTD. 1 complete response was observed in a patient with breast cancer and lung metastases and 1 partial response in a patient with adenocarcinoma of the lung. The recommended dose for phase II studies was 30 mg/m2 by 4 h infusion every 3 weeks.

Adult↗
PubMed1991

Hyperthyroid myopathy and the response to treatment.

Hyperthyroidism is accompanied by significant dysfunction of both proximal and distal skeletal muscles. The purpose of this study was to quantitate the degree of muscle weakness in newly diagnosed patients with Graves' disease and to assess the response to treatment. Ten patients were prospectively studied with objective measures of strength and endurance of proximal and distal muscles while hyperthyroid (stage I), after 2 weeks of propranolol (stage II), and about 6 months later when euthyroid (stage III). Propranolol treatment for 2 weeks resulted in a subjective decrease in weakness, which was accompanied by a statistically significant improvement in grip strength (P less than 0.01), shoulder strength (P less than 0.02), and grip endurance (P less than 0.01) but not shoulder endurance. Muscle function further improved and attained control levels when the patients were chemically and clinically euthyroid. In contrast, a control group subjected to the same muscle testing protocol before and after 1 week of propranolol treatment showed no improvement in grip, shoulder strength, or shoulder endurance but had decreased grip endurance (P less than 0.01) and increased subjective weakness. These results confirm that muscle weakness commonly is associated with hyperthyroidism and can be quantitatively profound. In contrast to the effects of beta-blockade in normal controls, propranolol partially improves muscle weakness in thyrotoxic patients. We conclude that thyroid hormone and catecholamines in concert mediate the muscle dysfunction of hyperthyroidism.

Adrenergic beta-Antagonists↗
PubMed1991

Token reinforcement in the psychosocial rehabilitation of individuals with chronic mental illness: is it effective over time?

The main purpose of this project was to determine whether the addition of the token economy reinforcement to the regular treatment modalities (medication therapy and psychotherapy) improved the following outcome measures: re-hospitalization rate. NYPCC (agency) therapeutic goals, symptomatology, social integration activities and ADL skills. The research was carried out over a period of 18 months. Subjects were 617 individuals diagnosed as having chronic mental illness. They lived in three adult homes in New York, two of which were on a token economy programme, while the third served as a quasi-control group. The findings suggest that while medication therapy and psychotherapy have different effects in respect to the various outcome measures, the addition of the token economy programme resulted in positive, albeit marginal, gains to all outcome measures.

Activities of Daily Living↗
PubMed1991

Heterotopic cardiac transplantation decreases the capacity for rat myocardial protein synthesis.

Heterotopic cardiac isografts are vascularly perfused hearts that maintain structural and functional integrity for prolonged periods of time. When placed in an infrarenal location, the heart is hemodynamically unloaded and undergoes negative growth, leading to cardiac atrophy. At 7 and 14 days after transplantation, the transplanted heart was decreased in size compared with the in situ heart (p less than 0.001). To assess the possible mechanism(s) to account for this reduction in size we studied in vivo rates of total left ventricular (LV) protein synthesis, total LV RNA content, and 18S ribosomal RNA content by nucleic acid hybridization. The LV protein synthetic rate was 4.7 and 5.3 mg/day in the in situ heart and was significantly decreased to 2.9 and 2.7 mg/day in the transplanted hearts at 7 and 14 days, respectively. LV RNA content of the transplant declined to 53% and 48% of the in situ value at 7 and 14 days, respectively. Hybridization studies revealed that LV 18S ribosomal subunit content was reduced proportionately to total RNA in the heterotopic hearts. As a result of these changes, there was no significant difference in the efficiency of total LV protein synthesis between the in situ and transplanted hearts. The present studies demonstrate that the hemodynamic unloading and cardiac atrophy that is characteristic of heterotopic cardiac transplantation is accompanied by a decrease in LV total RNA content and 18S RNA, resulting in a decreased capacity for myocardial protein synthesis.

Animals↗
PubMed1991

Isovolumic loading prevents atrophy of the heterotopically transplanted rat heart.

Heterotopically (infrarenal) transplanted cardiac isografts are histologically normal, spontaneously beating, hemodynamically unloaded hearts that undergo rapid and predictable atrophy. To study the factors that regulate cardiac growth we examined the effect of left ventricular (LV) isovolumic balloon placement on the weight, in vitro protein synthesis rate, and LV RNA content of the transplanted heart. At day 0 the donor LV weight was 367 +/- 8 mg, which decreased to 226 +/- 14 mg (p less than 0.001) after transplantation. Isovolumic loading with a latex balloon (volume, 111 +/- 10 microliters) significantly increased the LV weight of the transplanted heart to 397 +/- 13 mg when compared with that of the unloaded heart 14 days after surgery and prevented the atrophy when compared with the LV weight at day 0. Sham-loaded transplants had LV weights of 256 +/- 17 mg, which did not differ from the LV weight of unloaded transplanted hearts. Protein synthesis rates (nmol lysine/LV/hr) and total LV RNA and LV 18S RNA content were significantly greater in the balloon-loaded hearts when compared with the unloaded isografts and returned to levels similar to those measured in the in situ hearts. The ability of isovolumic loading of the LV to prevent atrophy via increased protein synthesis and the maintenance of LV RNA in the heterotopically transplanted heart further supports the important role of cardiac work in the regulation of cardiac growth.

Animals↗
PubMed1991

Enhanced left ventricular diastolic function in hyperthyroidism: noninvasive assessment and response to treatment.

Hyperthyroidism is associated with a marked effect on the cardiovascular system. Despite enhanced resting ventricular systolic performance, thyrotoxicosis has been implicated as a primary cause of cardiomegaly, congestive heart failure, and decreased exercise tolerance. To further assess potential alterations in ventricular function we have noninvasively studied diastolic performance in nine newly diagnosed and untreated hyperthyroid patients. Parameters including diastolic flow velocities, isovolumic relaxation time (IVRT), and the rate of diastolic flow deceleration were compared to those of an age- and sex-matched control population, and then repeat determinations were made after beta-adrenergic blockade and again when the patients were chemically and clinically euthyroid. Before treatment the IVRT was 33.0 ms, which was significantly (P less than 0.005) shorter than the control value (57.9 ms) and in combination with other measures of diastolic function indicated enhanced left ventricular relaxation. beta-Adrenergic blockade slowed the resting heart rate from 97 to 80 beats/min (P less than 0.005) and partially normalized the rate of diastolic deceleration, but had no effect on the IVRT (33.8 ms). When patients were euthyroid, the IVRT was 51.7 ms, and other measures of diastolic performance were the same as those in controls. The current data assessing resting diastolic function in hyperthyroidism are similar to those previously reported for systolic function. Our findings of enhanced cardiac diastolic performance do not support the hypothesis that thyrotoxicosis is associated with compromised left ventricular function and suggest the possibility that the cardiac symptoms that accompany hyperthyroidism may be due to noncardiac mechanisms.

Adult↗
PubMed1990

Thyroid hormone and the cardiovascular system.

To understand the pathophysiology of thyroid heart disease, it is necessary to recognize that thyroid hormone has effects on both the peripheral circulation and the myocardium. One of the earliest responses to thyroid hormone administration is a decline in systemic vascular resistance and an increase in cardiac output and cardiac contractility. In many ways, this response is similar to the cardiovascular response to exercise and is associated with increased left ventricular work. The majority of cardiac adaptations to changes in thyroid function are physiologic; however, certain patients do demonstrate clinical evidence of cardiac disease. Atrial arrhythmias, limitations in exercise tolerance, and congestive heart failure are reported to occur as a result of hyperthyroidism and are more common in older patients. Thyroid hormone also plays an important role in the regulation of blood pressure. Diastolic hypertension is a common accompaniment of hypothyroidism. By understanding the mechanisms by which thyroid hormone affects both the peripheral circulation as well as the myocardium, it is possible to predict the clinical response to the treatment of various thyroid disease states.

Heart↗
PubMed1990

Catecholamine-thyroid hormone interactions and the cardiovascular manifestations of hyperthyroidism.

The spectrum of classic symptoms of hyperthyroidism suggests that in addition to the effects of increased thyroid hormone, affecting various organ systems, there is also a hyperadrenergic state. Despite this clinical impression, direct measures of serum levels of catecholamines and their urinary metabolites demonstrate values that are equal to or less than normal. In contrast, the hypothyroid patient who clinically manifests signs of decreased adrenergic stimulation can be expected to have increased levels of epinephrine, norepinephrine, and its metabolites. This review discusses possible mechanisms to explain this seeming paradox. Treatment of hyperthyroidism includes the rapid reversal of many of the adrenergic symptoms with use of beta-blocking drugs. Return to a clinically and chemically euthyroid state, however, requires antithyroid therapy accomplished over a longer period of time. A knowledge of the interaction of the cardiovascular and extracardiovascular manifestations of hyperthyroidism and the role of the adrenergic nervous system is important in the rational management of these patients.

Catecholamines↗
PubMed1990

Cardiac atrophy in the heterotopically transplanted rat heart: in vitro protein synthesis.

Heterotopic cardiac isografts are vasculary perfused organs that maintain structural and functional integrity. We have used this model to study the time course of change in total heart and left ventricular size which results from mechanical unloading of the myocardium. When compared to the in situ (working) heart there is a 19% decrease in the size of the heterotopic (non-working) heart (P less than 0.01) as early as 3 days post-transplantation. By 14 days there is 50% decrease in the size of the transplanted heart which is maintained at this atrophic size when measured after 4 weeks. Left ventricular protein synthesis was assayed by the simultaneous in vitro perfusion of the host and transplanted hearts under identical hemodynamic conditions. The hourly incorporation of 14C-lysine into total left ventricular protein was 21 nmol in the transplant compared to 50 nmol in the in situ heart (P less than 0.01). This incorporation remained significantly lower throughout the period of study. In contrast, both the total (mumol lysine/g protein nitrogen/h) and fractional rates of protein synthesis which were lower in the transplanted left ventricle at days 3 and 7 returned to control values by day 28. The present studies demonstrate that heterotropic cardiac transplantation leads to a prompt and reproducible decline in cardiac mass and in total protein synthesis. These studies further support the role of cardiac work as an important determinant in the regulation of cardiac protein synthesis.

Animals↗
PubMed1989

Pharmacokinetics of Brequinar sodium (NSC 368390) in patients with solid tumors during a phase I study.

The pharmacokinetics of the novel antipyrimidine agent Brequinar sodium (NSC 368390; DUP 785) was studied in 23 patients with solid tumors during the phase I study of this compound. The drug was administered by short-term (10-60 min) intravenous infusion every 3 weeks. The doses ranged from 15 to 2250 mg/m2. At doses higher than 1500 mg/m2 the areas under the plasma concentration vs. time curve (AUC) increased non-proportionally, while the total body clearance (Clt) dropped substantially, indicating non-linear pharmacokinetics of the drug. Brequinar sodium showed a triphasic decay of plasma concentrations with half-life ranges of 11.1-36.6 min, 1.7-6.9 h and 12.5-25.0 h, respectively. The volume of distribution (Vdss) ranged from 4.4 to 10.6 l/m2. The total body clearance (Clt) ranged from 6.9 to 22.1 ml/min with a small contribution of the renal clearance (0.04-0.4 ml/min). Up to 7 days, the cumulative urinary excretion (CUE) and the cumulative fecal excretion (CFE) ranged from 0.4 to 8.3% and from 7.7 to 18.3% of the dose, respectively. There was evidence for the presence of drug metabolites in urine and feces. There was no drug accumulation with repeated administration of Brequinar sodium by the above mentioned drug schedule. The ratio between the plasma AUC at the maximum tolerable dose (MTD) in man and that at the mouse LD10 was 0.8, while the ratio between the respective doses was 5.7. The ratios between the AUC in patients and that at the mouse LD10 were applied to guide dose escalation in the phase I study. The results of the above mentioned pharmacokinetic studies were useful for the choice of an optimal schedule for phase II trials of Brequinar sodium.

Adult↗
PubMed1989

Graves' disease: an analysis of thyroid hormone levels and hyperthyroid signs and symptoms.

PURPOSE: Assessment of disease severity for patients with hyperthyroidism involves clinical evaluation and laboratory testing. To determine if there is a correlation between symptoms and thyroid function test results, we prospectively studied hyperthyroid patients using a standardized symptom rating scale and serum thyroid function parameters. PATIENTS AND METHODS: We examined 25 patients with untreated, newly diagnosed Graves' disease using the Hyperthyroid Symptom Scale (HSS) and serum levels of thyroxine (T4), triiodothyronine (T3) relative insulin area (RIA), and estimates of free thyroxine index (FTI). In addition, we compared thyroid hormone levels with standard measures of depression and anxiety in these patients. RESULTS: When regression analyses controlling for age were performed, none of these symptom ratings were associated with FTI or T3 RIA. The HSS was correlated with goiter size and anxiety ratings and was inversely correlated with age. CONCLUSION: The present study suggests that there is no relationship between the clinical assessment of disease severity and serum levels of thyroid hormone in untreated Graves' disease.

Adult↗