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M M Kaplan

Publications and source records attributed to M M Kaplan.

At least 145 records · Page 8Linked to original sources
PubMed1984

Acute posttranscriptional regulation of cerebrocortical and pituitary iodothyronine 5'-deiodinases by thyroid hormone.

Cerebrocortical and pituitary iodothyronine 5'-deiodinases produce 50% or more of the T3 found in these tissues and show rapid 3- to 5-fold changes in response to changes in the thyroid status. Since many T3 responses are initiated in the cell nucleus and require protein synthesis, we studied the influence of cycloheximide and actinomycin D on the acute T3 suppression of cerebrocortical and pituitary 5'-deiodinase activities in hypothyroid rats. Cycloheximide inhibited protein synthesis by more than 95%, but did not prevent the rapid (4-h) T3-mediated decreases in 5'-deiodinase activity. In the presence of cycloheximide, T3 decreased enzyme activity by more than 85%, with a t1/2 of approximately 70 min in the cerebral cortex and about 110 min in the pituitary. In vitro, neither T3 nor cycloheximide in large excess had any effect on enzyme activity. In cycloheximide-treated rats, cerebrocortical 5'-deiodinase activity decreased with a fractional turnover rate (k) of 1.2 h-1 in euthyroid and 0.07 h-1 in hypothyroid rats, respectively, with corresponding steady state enzyme levels of 18 +/- 3 and 145 +/- 9 U/mg protein. The resulting production rates of cerebrocortical 5'-deiodinase were 22 and 10 U/mg protein X h. Actinomycin D failed to alter either the cerebrocortical 5'-deiodinase in euthyroid rats in 4 h or the inhibitory effect of T3, but inhibited RNA synthesis by more than 70%. These data indicate that the T3-dependent fall in cerebrocortical 5'-deiodinase is mediated by a posttranscriptional mechanism that ultimately increases the rate of degradation/inactivation of the enzyme.

Animals↗
PubMed1984

Iodothyronine deiodination reaction types in several rat tissues: effects of age, thyroid status, and glucocorticoid treatment.

Two types of iodothyronine 5'-deiodination have been characterized previously in rat tissues. They can be distinguished by inhibition of type I but not type II by 6-n-propylthiouracil, by the relative suitability of T4 and rT3 as substrates, rT3 much better than T4 for type I and T4 as good as, or better than, rT3 for type II, and by the concentration of T4 required to inhibit deiodination of rT3, 1-10 microM for type I and 1-10 nM for type II. Type I activity (6-n-propylthiouracil sensitive) is most abundant in liver and kidney. Type II activity has, to date, been identified only in the pituitary, central nervous system, and brown adipose tissue. Iodothyronine tyrosyl deiodination has also been identified in homogenates of rat brain, liver, and placenta. It is not clear how many different enzymes carry out this latter reaction. In the present studies, we have extended previous work by determining maturational patterns of the deiodinating pathways in several thyroid hormone-responsive rat tissues, possible modulation of those patterns by glucocorticoids, and the age of onset of responsivity of the deiodinases to hypothyroidism. Iodothyronine 5'-deiodinating activity was found in rat lung and eye, and the reaction was all or nearly all type I in both. Activity in the eye was virtually absent from the lens and vitreous humor. In immature rat cerebrum, pituitary, lung, and eye, between gestational day 17 and postnatal day 21, there was a uniform pattern of an increase in type I 5'-deiodination activity over time, until adult levels were attained. The ages at which adult activity levels were reached varied from tissue to tissue, however. Type II activity was present at the earliest ages tested in the cerebrum (gestational day 17), pituitary, and brown adipose tissue (day of birth). In cerebral cortex, type II activity was highest at day 21 postnatally and equal at birth and in adulthood, and in pituitary and brown adipose tissue it was higher in adulthood than at birth. T3 tyrosyl ring deiodinating activity was several times greater in homogenates of eye and placenta than in cerebral homogenates. In all three tissues, there was similar, dose-dependent inhibition of [125I]T3 tyrosyl deiodination by 5 nM and 20 nM nonradioactive T3. In the eye and brain, T3 tyrosyl deiodination rates decreased progressively with age from gestational day 17 to postnatal day 7.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue, Brown↗
PubMed1984

Type II iodothyronine 5'-deiodination by human and rat placenta in vitro.

T4 and rT3 5'-deiodination were measured in human and rat placental homogenates. rT3 5'-deiodination rates were reduced 5-40% by 1 mM 6-n-propylthiouracil (PTU), but T4 5'-deiodination was not affected by 1 mM PTU. In human tissue, homogenates of the chorionic membrane decidua had greater PTU-insensitive activity than homogenates of trophoblastic tissue or amnion. In the rat placenta, basal zone homogenates had greater activity than homogenates of placental labyrinth or amnion. The distribution of 5'-deiodinating activity in placental structures differed from that of T3 tyrosyl ring deiodinating activity in both species. PTU-insensitive rT3 5'-deiodinating activity was enriched in particulate subcellular fractions, but not in cytosol. Kinetic studies of T4 5'-deiodination using particulate fractions from human chorionic membrane decidua and rat basal zone showed a sequential kinetic pattern when the dithiothreitol concentration was varied, with apparent Michaelis constants (Km) and 50% inhibitory concentrations for T4 of 2.1-3.2 nM, and for rT3 of 9-15 nM. Thus, PTU-insensitive iodothyronine 5'-deiodination in rat and human placenta is very similar to, or the same as, that termed type II activity in rat anterior pituitary, central nervous system, and brown adipose tissue. These results extend the range of tissues in which type II iodothyronine 5'-deiodination has been identified, and strengthen the applicability to man of studies of iodothyronine deiodination in the rat.

Animals↗
PubMed1984

Lymphocyte subsets in primary biliary cirrhosis.

To ascertain whether abnormalities of circulating T-cell subsets are a cause or effect of primary cirrhosis, we analyzed peripheral blood lymphocytes from 44 patients at various stages of disease. The percentages of total T cells and helper/inducer cells were normal in early disease whereas the percentage of suppressor/inducer cells was increased. The percentage of all T-cell subsets fell steadily as the disease progressed histologically. The percentages in late (cirrhotic) disease were the same as those in patients with other types of cirrhosis. We conclude that most of the previously reported abnormalities of circulating T cells are secondary to the histologic progression of primary biliary cirrhosis.

Female↗
PubMed1984

Conversion of thyroxine to triiodothyronine in the anterior pituitary gland and the influence of this process on thyroid status.

There are two iodothyronine 5'-deiodinases in the rat anterior pituitary gland. The type II 5'-deiodinase is responsible for the observable T4 to T3 conversion in pituitary tissue, both in vivo and in vitro. This type II enzyme has kinetic characteristics which distinguish it from type I activity, and it is also insensitive to inhibition by propylthiouracil. Iopanoic acid is both a substrate for, and an inhibitor of, the pituitary type II 5'-deiodinase. Studies in the rat and in man using iopanoic acid as a probe indicate that conversion of T4 to T3 within the anterior pituitary is a necessary step in the expression of thyroid hormone effects on the thyrotrophic and somatotrophic cells after T4 administration. Amiodarone, which has effects on the human pituitary-thyroid axis similar to those of iopanoic acid, has little inhibitory activity on T4 5'-deiodination in rat pituitary homogenate. Phenytoin, which lowers the serum T4 after chronic administration without inducing an increase in thyrotropin, could theoretically act by enhancing intrapituitary T3 production. In actuality, phenytoin shows only inhibitory activity in vitro on type II 5'-deiodination in rat pituitary and brain homogenates and on type I activity in rat liver homogenates. Phenytoin treatment in vivo has no significant effect on T4 5'-deiodination in pituitary or liver homogenates either. Evidence is discussed regarding whether the increase in type II 5'-deiodinating activity in hypothyroidism, and the decrease in hyperthyroidism, are beneficial defense mechanisms; this is likely to be so in some parts of the body, but may ot be in the thyrotrophic cells of the anterior pituitary.

Animals↗
PubMed1983

Increased incidence of hypothyroidism in primary biliary cirrhosis.

We examined the thyroid status of 58 patients with primary biliary cirrhosis (PBC) using total serum thyroxin, thyroid hormone binding ratio, free thyroxin index, serum TSH, antithyroglobulin, and antimicrosomal antibodies. Seven patients were known to be hypothyroid prior to the diagnosis of PBC. Six additional patients were found to have biochemical evidence of hypothyroidism. The prevalence of hypothyroidism was 12% if we include only those six PBC patients with newly diagnosed hypothyroidism or 22% if we include all 13 patients. Five of the 58 patients had evidence for an elevation of thyroid hormone binding capacity. Three hypothyroid patients had normal total thyroxins with low thyroid hormone binding ratios. Two euthyroid patients had elevated total T4s with low thyroid hormone binding ratio and normal FTI. The prevalence of positive antimicrosomal antibodies was 34%, including 11 euthyroid PBC patients. The prevalence of positive antithyroglobulin antibodies was 20% including five euthyroid patients. There was no association between HLA DR3 or DR5 and the patients with hypothyroidism and/or antithyroid antibodies. Because fatigue, lethargy, and anorexia as well as hypercholesterolemia are common features of both hypothyroidism and PBC, patients with PBC should be screened for evidence of thyroid dysfunction. Thyroid disease may precede the diagnosis of PBC by several years. Therefore, the development of cholestatic liver disease in a patient with known autoimmune thyroiditis should arouse suspicion of PBC.

Autoantibodies↗
PubMed1983

Chronic erosive gastritis--a recently recognized disorder.

We have reviewed the clinical manifestations, endoscopic findings, pathology, and upper gastrointestinal x-rays in 10 patients with chronic erosive gastritis, a disorder that was rarely recognized before the use of double-contrast upper gastrointestinal radiology and endoscopy. The characteristic x-ray appearance is that of a series of 3 to 11-mm nodules, some with central collections of barium, that are distributed along rugal folds and usually extend into the antrum. The endoscopic appearance is similar: small erythematous nodules with shallow central erosions. The pathology differs from that seen in peptic ulcer disease. There are few polymorphonuclear leukocytes and a predominance of plasma cells in the inflammatory infiltrate. Seven of our patients presented with epigastric pain similar to that of peptic ulcer disease; four of these also had anorexia and weight loss. In two other patients anorexia and weight loss were the only symptoms. One patient was asymptomatic. All nine symptomatic patients responded to antacid treatment. However, repeat x-rays demonstrated persistence of the nodules, although the central erosions usually disappeared. The etiology is unknown. Chronic erosive gastritis appears to be a distinct entity different from peptic ulcer disease.

Adult↗
PubMed1983

Risk factors for thyroid abnormalities after neck irradiation for childhood cancer.

Thyroid evaluations were performed in 95 patients who received radiotherapy to the neck region for childhood cancer five to 34 years earlier. Fifty-six patients (61 percent) had at least one abnormality of serum free thyroxine index, serum thyroid-stimulating hormone (thyrotropin), or thyroid palpation. Seven had subnormal free thyroxine index and 40 had elevated thyrotropin concentrations. Thyroidal radiation doses of 3,000 or more rads and lymphangiography independently increased the risk (p less than or equal to 0.01) of an elevated serum thyrotropin concentration (present in 11 percent of patients with neither risk factor, 50 percent of those who underwent lymphangiography and received less than 3,000 rads, 46 percent of those who had 3,000 or more rads and no lymphangiography, and 76 percent of those with both), but duration of follow-up did not. Twenty-six patients had thyroid nodules and six others had diffuse thyroid enlargement. The frequency of palpable abnormalities increased with the follow-up time after radiation (30 percent of patients followed up less than 10 years had abnormalities versus 43 percent of those followed up 10 or more years, p = 0.03), but was not related to the serum thyrotropin level, radiation dose, or lymphangiography. Among 10 patients who had surgery for nodules, three had localized papillary thyroid carcinomas.

Adolescent↗
PubMed1983

Genetic abnormalities of immunoregulation in primary biliary cirrhosis.

Patients with primary biliary cirrhosis have an abnormality of lymphocyte suppressor cell function that could play a role in the pathogenesis of their disease. To investigate this possibility, suppressor cell function in patients with primary biliary cirrhosis, in their healthy first-degree relatives, in unrelated household contacts, in patients with other types of cirrhosis, and in normal control subjects was studied. The method used is based on the finding that the in vitro addition of concanavalin A to pokeweed mitogen-stimulated lymphocytes activates suppressor cells, which in turn inhibit immunoglobulin synthesis. Thirteen of 16 patients with primary biliary cirrhosis and six of 23 healthy relatives had significant impairment of IgG suppression. All six of these relatives were female. No abnormal suppression was found in unrelated household contacts of patients with primary biliary cirrhosis, in patients with other types of cirrhosis, or in healthy control subjects. There was no correlation between results of the IgG suppressor cell assay and the disease activity in patients with primary biliary cirrhosis. These data suggest that the abnormal suppressor cell function is not a direct cause of primary biliary cirrhosis; however, it may be a genetic marker for susceptibility to this disease.

Adult↗
PubMed1983

The spectrum of chronic active liver disease.

Much progress has been made in the classification of chronic hepatitis syndromes, based on correlation of specific histologic features with progressive liver destruction. Four etiologic subtypes have been defined--drug-induced, hepatitis B, non-A, non-B hepatitis, and autoimmune hepatitis. The last paradoxically is least understood etiologically and pathophysiologically but the most amenable to specific therapy.

Adrenal Cortex Hormones↗
PubMed1983

Evidence for two pathways of iodothyronine 5'-deiodination in rat pituitary that differ in kinetics, propylthiouracil sensitivity, and response to hypothyroidism.

We have studied 5'-deiodination of thyroxine (T(4)) and 3,3',5'-triiodothyronine (rT(3)) in rat pituitary tissue in vitro, with respect to substrate specificity, reaction kinetics, effects of 6-n-propyl-2-thiouracil (PTU), and the time course of effects of thyroid hormone depletion and repletion. Removal of one phenolic iodine or both tyrosyl iodines from the T(4) molecule resulted in compounds that were not deiodinated, but alterations in the alanine side chain had little effect.5'-Deiodination of 2 nM rT(3) by pituitary microsomes from euthyroid rats was inhibited >90% by 1 mM PTU, but was inhibited <10% by 100 nM T(4). The apparent Michaelis constant (K(m)) and maximum velocity (V(max)) for rT(3) at 20 mM dithiothreitol (DTT) were 33 nM and 84 pmol/mg protein per h. This reaction followed ping-pong type reaction kinetics when concentrations of DTT were varied. PTU inhibition was competitive with DTT and uncompetitive with rT(3). In contrast, when pituitary microsomes from hypothyroid rats (21 d postthyroidectomy) were used, deiodination of 2 nM rT(3) was inhibited only 20% by 1 mM PTU and up to 80% by 100 nM T(4). At 20 mM DTT, the apparent K(m) and V(max) in hypothyroid microsomes were 4.7 nM rT(3) and 16 pmol/mg protein per h. T(4) was a competitive inhibitor of PTU-insensitive rT(3) 5'-deiodination (K(i) = 1.3 nM). T(4) 5'-deiodination by hypothyroid microsomes was not affected by PTU, was competitively inhibited by rT(3) (K(i), 1.7 nM), and exhibited sequential type reaction kinetics with DTT as cosubstrate. When T(4) 5'-deiodination was measured in euthyroid and hypothyroid microsomes, respectively, the apparent K(m) and V(max) for T(4) at 20 mM DTT, were 0.9 nM and 0.55 pmol/mg protein per h (euthyroid), and 0.8 nM and 6.9 pmol/mg protein per h (hypothyroid). The T(4) 5'-deiodination rate and the PTU-insensitive, but not total, rT(3) 5'-deiodination rate (i.e. measured in the presence and the absence of 1 mM PTU, respectively) in pituitary homogenates were significantly elevated 24 h after thyroidectomy. PTU-insensitive activity continued to increase until at >/=30 d after thyroidectomy it was 11 times the PTU-insensitive activity in controls. At the latter time, PTU-sensitive rT(3) 5'-deiodinase activity appeared to be decreased. The increase in PTU-insensitive T(4) and rT(3) 5'-deiodination observed 48 h after thyroidectomy was prevented by replacement doses of T(4) or T(3). The PTU-insensitive activity of long term hypothyroid pituitaries was decreased by 71% and >/=84% 4 h after injection of 20 and 200 mug T(3), respectively, with no change in PTU-sensitive rT(3) deiodination. These data show that rat pituitary tissue contains two distinct iodothyronine 5'-deiodinating pathways that differ with respect to substrate specificity, PTU sensitivity, reaction kinetics, and regulation by thyroid hormone. One of these resembles the 5'-deiodinase of liver and kidney, and predominates in euthyroid pituitary tissue in vitro. The other, also found in rat brain, predominates in hypothyroid pituitary tissue, is rapidly responsive to changes in thyroid hormone availability, and, as judged by previous, in vivo studies, appears to account for all the T(3) produced locally in the pituitary and, thereby, 50% of the intracellular T(3) in this tissue.

Animals↗
PubMed1982

gamma-Glutamyl transpeptidase activity in liver disease: serum elevation is independent of hepatic GGTP activity.

gamma-Glutamyl transpeptidase activity was measured in liver and serum from 110 patients undergoing diagnostic liver biopsy, including patients with alcoholic liver disease, fatty liver not due to alcohol, primary biliary cirrhosis, persistent hepatic disease, chronic active hepatitis and normal livers. Serum gamma-glutamyl transpeptidase was markedly elevated in patients with alcoholic liver disease and primary biliary cirrhosis while mean hepatic gamma-glutamyl transpeptidase activity was significantly increased only in the alcoholic liver disease group. There was considerable overlap of individual enzyme values among the different disease groups. There was no inhibitors or activators of liver gamma-glutamyl transpeptidase in any of these disorders. The increased liver activity was not related to the degree of hepatic fibrosis or cirrhosis. There was no correlation between hepatic and serum gamma-glutamyl transpeptidase activity. Hepatic and serum gamma activities were equally increased in individuals with alcoholic liver disease whether or not they were drinking at the time of the study. The data suggest that increased hepatic gamma-glutamyl transpeptidase activity is neither specific for alcoholic liver disease nor essential for serum GGTP to be elevated.

Chronic Disease↗
PubMed1982

Subcellular distribution of iodothyronine 5'-deiodinase in cerebral cortex from hypothyroid rats.

We have examined iodothyronine deiodination in subcellular fractions of cerebral cortex obtained from hypothyroid rats. Enzymatic activities were measured at 37 degrees C in the presence of 20 mM dithiothreitol with 125I-labeled T4 and 125I-labeled rT3 as substrates for 5'-deiodination and 131I-labeled T3 as the substrate for the 5-deiodinase. Reaction products were separated by descending paper and/or ion-exchange chromatography. Cerebral cortex subcellular fractions were also characterized by marker enzyme analysis and electron microscopy. Under optimal reaction conditions more than 80% of the 5'-deiodinase was recovered after fractionation. Both 5'-deiodinase and (Na+ + K+)-ATPase showed similar subcellular distributions and were enriched approx. 3-fold in the easily sedimenting membrane fraction and nerve terminal plasma membranes. Crude microsomal membranes (6 X 10(6) g X min pellet) also showed 2-fold enrichment of these enzymes. Nuclei and isolated mitochondria were devoid of deiodinating activity. T4 and T3 5-deiodinating activity was absent in the easily sedimenting membranes and present but not enriched in particulate fractions containing microsomal membranes. These data suggest that iodothyronine 5'-deiodinase is associated with plasma membrane fractions in the cerebral cortex.

Animals↗
PubMed1982

A prospective trial of D-penicillamine in primary biliary cirrhosis.

We evaluated D-penicillamine in the treatment of primary biliary cirrhosis. In a prospective double-blind trial, 26 patients received D-penicillamine (250 mg four times a day), and 26 received an identical placebo. Although the desired urinary excretion of copper was achieved in patients taking D-penicillamine, there was no improvement in survival or symptoms after 28 months. Serum bilirubin and alkaline phosphatase increased equally in both groups. Alanine and aspartate aminotransferases were lower in the D-penicillamine group, but serum albumin was also lower in this group. Liver histology worsened equally in both groups. Major side effects, some appearing more than 24 months after the start of treatment, occurred in 31 per cent of the patients receiving D-penicillamine. Less serious side effects occurred in an additional 46 per cent. We conclude that D-penicillamine at the dosage we used is not effective in the treatment of primary biliary cirrhosis and is associated with a high incidence of serious side effects.

Alanine Transaminase↗
PubMed1982

Human influenza A viruses in pigs: isolation of a H3N2 strain antigenically related to A/England/42/72 and evidence for continuous circulation of human viruses in the pig population.

An influenza virus strain isolated in Northern Italy in 1977 was identified as belonging to the H3N2 subtype (A/swine/Italy/1850/77). A close antigenic relationship to the human strain A/England/42/72 was demonstrated. Serologic surveys of 548 pig sera from 53 farms in two provinces in Northern Italy demonstrated the existence of antibodies to the swine/Italy/1850/77 strain and to A/Hong Kong/1/68, A/Victoria/3/75 and H 1 N 1 (Hsw 1 N 1) strains in the pig population.

Animals↗