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Biomedical subjects

M M Kaplan

Publications and source records attributed to M M Kaplan.

At least 127 records · Page 7Linked to original sources
PubMed1987

Histocompatibility antigens in primary biliary cirrhosis.

HLA-A, -B, and -DR antigens were examined in 71 patients with primary biliary cirrhosis (PBC) enrolled in a randomized, double-blind trial of colchicine versus placebo. All patients had typical laboratory and histological features of PBC, except that six had a negative test for antimitochondrial antibody. Frequencies of these antigens were compared with the international Caucasian panel of the Eighth International Workshop and with a local Caucasian panel. Antigen frequencies were compared using the chi 2 test, with a correction for the number of antigens tested. The PBC patients had a significant excess of DR4 (29 of 70 typed, or 41.1%) compared to the international (804 of 3811, or 21.1%, corrected p value less than 0.05) but not the local panel (47 or 129, or 36.4%). Of PBC patients, 52.9% had only one DR antigen identified, compared to 67.5% for the international panel and 49.6% for the local panel. In past studies, the HLA antigen most strongly correlated with PBC was DR8, but this was not included in our panel of antisera. However, no significant relationship between HLA and PBC was found among the antigens screened.

Colchicine↗
PubMed1986

A prospective trial of colchicine for primary biliary cirrhosis.

We entered 60 patients with primary biliary cirrhosis in a double-blind randomized controlled trial to determine whether colchicine is therapeutically effective. Thirty patients had early disease (Stages 1 and 2), and 30 had advanced disease (Stages 3 and 4). Fifteen patients with early disease and 15 with advanced disease received colchicine (0.6 mg twice daily), and the remainder received placebo. Patients were studied about every two months; those remaining in the blind phase at two years underwent repeat liver biopsy and were then placed on open-label colchicine (0.6 mg twice daily). With a few exceptions, the results in patients with early disease were similar to those in patients with advanced disease; hence, data on patients in all stages were combined in the main analysis. During the two-year study period the colchicine-treated patients, as compared with the placebo-treated patients, had improvement in levels of serum albumin, serum bilirubin, alkaline phosphatase, cholesterol, and aminotransferases. However, there was no such improvement in the severity of symptoms or physical findings; moreover, there was no significant difference in the histologic changes noted at liver biopsy in the two treatment groups. At four years after entry, the cumulative mortality from liver disease was 21 percent in patients given colchicine and 47 percent in those given placebo (P = 0.05). The only side effect of colchicine was diarrhea, noted in three patients. The consistent and significant improvement in a number of markers of liver disease and the apparent decreased mortality from liver disease suggest that colchicine may provide some long-term clinical benefit in patients with primary biliary cirrhosis. However, the failure of colchicine to reduce hepatic inflammation and fibrosis leaves uncertain the effect of the drug on the longterm outcome of this disease.

Alkaline Phosphatase↗
PubMed1986

In vitro anti-mitochondrial antibody synthesis in patients with primary biliary cirrhosis.

Suppressor cell function was studied in 31 patients with primary biliary cirrhosis. Blood mononuclear cells were activated in vitro with suboptimal or optimal concentrations of concanavalin A and suppression of mitogen-induced proliferation or synthesis of anti-mitochondrial antibodies was measured. At suboptimal concentrations of concanavalin A, mean (+/- SE) suppression of proliferation by patients' cells was significantly less than 14 controls (18.7 +/- 5% vs 34.3 +/- 5%; P less than 0.005). The degree of suppressor activity correlated with the clinical disease, i.e., suppression was greater in patients with early than advanced disease. Spontaneous anti-mitochondrial antibody synthesis was not detected in cultures of mononuclear cells from normal subjects nor from patients with negative serum antibody, nor could it be induced by pokeweed mitogen in either group. In contrast, spontaneous anti-mitochondrial antibody synthesis was detected in cultures of 18/23 patients with positive serum antibody and was significantly augmented by pokeweed in 12/18. Anti-mitochondrial antibody synthesis was augmented by 48% (+/- 19) in response to pokeweed and concanavalin A-induced suppression higher (39.4 +/- 7%) in patients with low titer antibody compared to 1.6% (+/- 8) pokeweed augmentation and 5.5 +/- 3% concanavalin A-induced suppression in patients with high titer antibody. These results suggest that some patients with primary biliary cirrhosis have an immunoregulatory defect which expresses itself in part as an inability to regulate autoantibody synthesis.

Antibody Formation↗
PubMed1986

Sustained rises in serum thyrotropin, thyroxine, and triiodothyronine during long term, continuous thyrotropin-releasing hormone treatment in patients with amyotrophic lateral sclerosis.

In a pilot therapeutic trial, four patients with amyotrophic lateral sclerosis (ALS) were treated with long term, continuous infusions of TRH, three intrathecally and one epidurally. They had prompt increases in serum TSH and thyroid hormone concentrations, averaging 120% for TSH, 49% for serum T4, 68% for the serum free T4 index, 49% for serum T3, and 67% for the serum free T3 index. These elevations were statistically significant for all but serum T3 and persisted for the duration of treatment (4-7 months). Mean values during treatment were near the upper limit of normal for each of these hormone measurements. After TRH withdrawal, serum TSH fell transiently below the normal range. A comparison group of four patients with ALS treated by twice weekly intrathecal bolus doses of TRH had no significant changes in serum TSH, T4, or T3. During continuous TRH treatment, the responsiveness of both TSH and PRL to a standard iv TRH stimulation test was blunted, but not abolished. Basal serum PRL was occasionally elevated in the two women during continuous TRH treatment, but was normal in the men, and serum GH was normal in all patients. In the patients receiving continuous TRH treatment, indexes of end-organ effects of thyroid hormone were inconclusive; none had a rise in serum ferritin, one of four had a rise in serum sex hormone-binding globulin, and three had increased creatinuria. These results provide direct evidence in man that chronic TRH administration can cause modest sustained increases in serum TSH and thyroid hormones, though the metabolic consequences of these changes are uncertain, and appears to raise the set-point of the pituitary-thyroid axis, i.e. the serum T4 and T3 concentrations needed for a given degree of suppression of basal TSH secretion.

Amyotrophic Lateral Sclerosis↗
PubMed1985

Isoenzyme studies in transient hyperphosphatasemia of infancy. Ten new cases and a review of the literature.

A literature review and ten new cases of benign transient hyperphosphatasemia of infancy are presented, with special attention paid to isoenzyme studies. Polyacrylamide gel electrophoresis, heat denaturation, and binding of alkaline phosphatase to anti-human alkaline phosphatases showed that the sources of the elevated alkaline phosphatase levels are normal bone and liver and not the small intestine. The data also suggest that the following criteria be present for a diagnosis of transient hyperphosphatasemia: (1) an age of less than 5 years, (2) variable symptoms, (3) no bone or liver disease noted on physical examination or (4) from laboratory investigations, (5) isoenzyme analysis showing elevations in both bone and liver activity, and (6) a return to normal serum alkaline phosphatase activity values within four months.

Alkaline Phosphatase↗
PubMed1985

Low incidence of hepatotoxicity associated with long-term, low-dose oral methotrexate in treatment of refractory psoriasis, psoriatic arthritis, and rheumatoid arthritis. An acceptable risk/benefit ratio.

Thirty patients with psoriasis or other nonmalignant diseases had liver biopsies done before treatment with low-dose methotrexate, 15 mg/week, and then at one- to two-year intervals as long as they continued the methotrexate. All patients were symptomatically improved on this regimen. The 15 patients who had normal liver biopsies at the start of the study had normal biopsies after methotrexate. Fifteen others had minor hepatic histologic abnormalities before treatment. Eleven patients had fatty infiltration. Ten showed no significant change after treatment while one had increased fat and portal fibrosis on a fourth liver biopsy done seven years after MTX was begun. This last patient, a former alcohol abuser, continued methotrexate and showed no further worsening at 8 years. The remaining four had portal fibrosis before treatment. One patient had less fibrosis after methotrexate, two patients slightly more fibrosis, and one a marked increase in portal fibrosis. No patient developed cirrhosis or clinical liver disease. Our results suggest that in the absence of alcohol consumption, low-dose weekly methotrexate treatment rarely causes clinically significant liver damage.

Adult↗
PubMed1985

Clinical and laboratory assessment of thyroid abnormalities.

Clinical assessment of the patient with suspected thyroid disease remains an important part of the workup. Available laboratory tests of thyroid function include measurements of serum thyroid hormones and thyroid-stimulating hormone, titers of autoantibodies involved with Graves' disease and thyroiditis, and thyroid imaging and uptake techniques. The usefulness and limitations of each of these tests are reviewed.

Autoantibodies↗
PubMed1985

Liver disease and the PI ElembergM phenotype of alpha 1-antitrypsin.

The purpose of this article is to document clinical and pathologic observations concerning liver disease associated with the PI ElembergM phenotype of alpha 1-antitrypsin. Deposits of alpha 1-antitrypsin that were periodic acid-Schiff positive and stained with an antiserum to alpha 1-antitrypsin were found in the liver of a markedly jaundiced, terminally ill patient with Stage IV primary biliary cirrhosis. A biopsy performed three years earlier failed to reveal alpha 1-antitrypsin deposits. The phenotype PI ElembergM was verified by both acid starch gel electrophoresis and isoelectric focusing in agarose. The deposits of alpha 1-antitrypsin in the liver appear to be a consequence of the patient's disease and age and not due to an association with the PI*Elemberg allele. Accumulation of alpha 1-antitrypsin in the liver of this patient may be due to an accelerated synthesis of this protease inhibitor exceeding the liver's capacity for glycosylation or other steps in its secretion.

Electrophoresis, Starch Gel↗
PubMed1985

Extrahepatic portal venous thrombosis: frequent recognition of associated diseases.

Twelve patients with obstruction of the extrahepatic portal venous system were seen at the Tufts-New England Medical Center between 1970 and 1979; a cause for the portal vein thrombosis was detected in 11. These included pancreatic disease (4); hematologic disorders (2); postoperative complications of laparotomy (3); transhepatic gelfoam embolization of the portal vein (1); and exchange transfusion via the umbilical vein (1). Clinical features included frequent self-limited episodes of bleeding from esophageal or gastric varices; and no characteristic or clinically helpful laboratory findings. The diagnosis was usually made in patients by identifying clots in the portal vein on selective angiography of the celiac and/or superior mesenteric arteries in which the venous phase was examined. Attempts at surgical correction were largely unsuccessful. Further thrombotic episodes occurred in three patients, and led to death in one. Two patients were given chronic anticoagulation with Coumadin and Persantin for 1 and 11/2 years, respectively without further thrombosis or gastrointestinal bleeding. However, it not yet possible to assess the risks and benefits of such therapy.

Adolescent↗
PubMed1985

Characteristics of thyroxine 5'-deiodination in cultured human placental cells. Regulation by iodothyronines.

Human and rat placental homogenates convert L-thyroxine (T4) to 3,5,3'-L-triiodothyronine (T3) via a pathway termed type II iodothyronine deiodination. To study regulation of this pathway, cell dispersions were prepared from human placental chorionic-decidual membrane. Dispersed cells deiodinated T4 and 3,3',5'-triiodothyronine (rT3), but not T3, at the 5' position. The reaction was only slightly inhibited by 1 mM 6-n-propylthiouracil, enhanced by dithiothreitol, and substantially inhibited by 50 nM iopanoic acid. Incubation of the cells in thyroid hormone-depleted medium induced a near doubling of T4 5'-deiodination in 36-48 h, with a significant rise seen as early as 12 h. Addition of T4, rT3, or T3 to hormone-depleted medium impaired the rise in type II deiodination in a dose-dependent fashion. T4 and rT3 were equipotent in this regard, and T3 was 2-3 times less potent. T4 was effective in physiological concentrations, 6.5-13 nM in medium containing 10% calf serum, and the effect of T4 was not due to its conversion to either T3 or rT3. In cells with deiodinase activity raised by 48 h incubation in thyroid hormone-depleted medium, addition of T4, T3, or rT3 reversed the increase in 8-24 h. Secretion of prolactin and beta hCG by the dispersed cells was not substantially affected by thyroid hormone deprivation. The increase in type II deiodination during thyroid hormone deprivation appears to depend on a signal from the thyroxine molecule, per se, and could potentially defend intracellular, and/or circulating, T3 pools in pathological states of mild-to-moderate hypothyroxinemia.

Cell Separation↗
PubMed1985

Optimized kinetics of reverse-triiodothyronine distribution and metabolism in the rat: dominance of large, slowly exchanging tissue pools for iodothyronines.

We have estimated numerous physiological parameters of production, interpool transport, distribution, and metabolism of rT3 in the major rT3 pools of the unanesthetized male Sprague-Dawley rat. These results also have been combined with similar results for T3 and T4, generating a composite model for all three iodothyronines. Three different approaches were used to analyze the rT3 data, determined from five optimally timed blood samples collected in new tracer kinetic studies and processed by Sephadex chromatography and RIA. A model-structure independent approach generated a plasma clearance rate of 2.82 (ml/min)/100 g BW, a plasma turnover rate of 1.05 min-1, a plasma-to-total tissue flux of 0.107 (ng/min)/100 g BW and a plasma appearance rate (PAR) of 0.061 (ng/min)/100 g BW, the latter being the product of the plasma clearance rate and the endogenous rT3 plasma concentration. Multicompartmental analysis resulted in additional parameters of physiological interest, many only as ranges or minimum and maximum possible values, owing to complex factors intrinsic in rT3 kinetics. Whole body rT3 production can be as low as 0.061 (=PAR), and as high as 0.377 (ng/min)/100 g BW, i.e. possibly as much as 5 times greater than the PAR, the conventional estimate of production rate. Plasma contains only 3-12% of total body rT3 (Qtot); slow tissue pools, that exchange rT3 slowly with plasma, possibly muscle, skin, and brain, contain 63-95% of Qtot, and produce more than 42% of total body rT3 from T4 locally; and fast tissues like liver and kidney contain 2-26% of Qtot, and produce more than 12% of total body rT3 from T4 locally. The plasma equivalent distribution volume (VD) of rT3 is 38-146 ml/100 g BW, and its whole body mean residence time is only 14-52 min, both of which are an order of magnitude smaller than corresponding T3 values; but VD for rT3 and T4 are roughly the same. Noncompartmental analysis underestimated VD and mean residence time by somewhere between a factor of 1.2 and 4.6. Overall, these results indicate that tissue pools that exchange rT3 slowly with the plasma pool contain the majority of rT3, T3, and T4 in steady state; and these tissues also are implicated as major sites of T4 monodeiodination, to both rT3 and T3.

Animals↗
PubMed1985

Abnormal thyroid hormone binding to serum proteins in ob/ob and db/db genetically obese mice.

Sera from ob/ob and db/db genetically obese mice exhibited abnormal nonspecific (no antibody present) binding measurements in T4 and T3 RIAs employing dextran-charcoal separations. They also showed decreased charcoal uptake compared to sera of lean controls in a conventional charcoal T4 uptake binding test. After correction for the abnormal nonspecific binding and after extraction of serum, mean serum T4 concentrations were similar in control and ob/ob mice. Mean serum T3 concentrations differed significantly (85 ng/dl in controls and 178 ng/dl in ob/ob) when a correction for altered binding in the T3 assay was made, but not when extracted serum was assayed (109 ng/dl in lean and 124 ng/dl in ob/ob). Dialyzable fractions of T4 and T3 were significantly reduced in both ob/ob and db/db mice. Free T4 concentrations were 0.82 +/- 0.05 (+/- SE) ng/dl in control and 0.61 +/- 0.05 ng/dl in ob/ob sera (P less than 0.01). Polyacrylamide gel electrophoresis showed increased binding of tracer T4 and T3 in ob/ob and db/db sera to a postalbumin with mobility similar to that of human T4-binding globulin. In ob/ob sera, this appeared to result from an increased binding capacity of the postalbumin. After in vivo iv injection of tracer T4 and T3 to ob/ob and lean control mice, analysis of tissue and plasma radioactivity showed that, except for T4 in cerebral cortex, tissue to plasma T4 and T3 ratios were lower in cerebral cortex, cerebellum, and liver of ob/ob mice. In summary, these data show increased binding of T4 and T3 to a postalbumin in two strains of genetically obese mice and, in the ob/ob strain, complex relationships between tissue and serum concentrations of thyroid hormones.

Animals↗
PubMed1984

The role of thyroid hormone deiodination in the regulation of hypothalamo-pituitary function.

There is extensive deiodinative metabolism of thyroxine (T4) in thyroid hormone target organs, including the pituitary and brain. In both rat and man, most of the 3,3',5-triiodothyronine (T3) in the body is produced outside the thyroid gland by deiodination of T4. T3 is the principal active form of thyroid hormone within cells. In the rat, there are at least three enzymatic iodothyronine-deiodinating pathways which can be distinguished by kinetics and substrate and inhibitor specificities. Two of these (types I and II) can convert T4 to T3. The third pathway (type III) converts T4 to the inactive reverse-T3 and T3 to an inactive diiodothyronine. Both the anterior pituitary and the brain produce most of their intracellular T3 locally, by the type-II pathway. Type-III activity is present throughout the brain, but not in the anterior pituitary. Studies in the rat, using the deiodination inhibitor iopanoic acid, show that the capacities of T4 to inhibit thyrotropin release and stimulate growth hormone synthesis require conversion of T4 to T3 in the pituitary. Studies in man strongly suggest that the same is true in the human adenohypophysis, and a syndrome in man of a deficiency in this process possibly exists. The hypothalamus exhibits some responses to thyroid hormone, including changes in somatostatin and substance P content and changes in activities of type-II and III deiodination. The mechanism(s) of action of thyroid hormone in the hypothalamus, and in the brain in general, are not yet well understood.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗