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Biomedical subjects

M M Kaplan

Publications and source records attributed to M M Kaplan.

At least 109 records · Page 6Linked to original sources
PubMed1988

Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells.

The development of a goiter and hypothyroidism in a 28-year-old man in whom metastatic melanoma had been treated with interleukin-2 and lymphokine-activated killer cells (LAK cells) prompted us to assess thyroid function in patients undergoing this therapy. Thirty-four patients with advanced neoplasms who had received interleukin-2 and LAK cells were followed for at least four weeks after treatment. Seven patients (21 percent) had laboratory evidence of hypothyroidism, with a decline in the serum thyroxine concentration to below normal (less than or equal to 35 nmol per liter; normal, 65 to 148), a decline in the serum free thyroxine index, and a rise in the serum thyrotropin concentration (peak values, 7.2 to 166 mU per liter; normal, 0.5 to 5.5) 6 to 11 weeks after treatment. Two patients had elevated serum thyrotropin levels before treatment, which increased further after treatment. In two patients, these abnormal values returned to normal within 10 months. All five symptomatic patients had borderline or elevated serum antimicrosomal antibody titers after treatment; two had serum antibodies to thyroglobulin. Five of the seven patients with hypothyroidism (71 percent) but only 5 of the 27 euthyroid patients (19 percent) had evidence of tumor regression (P less than 0.02). None of 11 patients treated with interleukin-2 but not LAK cells had hypothyroidism. We conclude that treatment with interleukin-2 and LAK cells can cause hypothyroidism, possibly by exacerbating preexisting autoimmune thyroiditis, and that it may be associated with a favorable tumor response.

Adult↗
PubMed1988

The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience.

An important question facing physicians who care for families with multiple endocrine neoplasia type 2a is whether prospective screening to detect early abnormalities of the thyroid, parathyroid, or adrenal glands favorably influences the ultimate course of the disease. An 18-year study of a large family has allowed us to examine the effect of early treatment on the clinical course of the disease. Of 22 patients who underwent thyroidectomy for early C-cell abnormalities, 19 remained free of detectable medullary thyroid carcinoma according to all criteria, at a mean of 11 years after thyroidectomy. None of the 22 patients had evidence of parathyroid disease either at the time of surgery or after a mean follow-up of 10 years. Prospective screening for adrenal medullary abnormalities by means of measurement of 24-hour urinary epinephrine excretion and the ratio of urinary epinephrine to norepinephrine was predictive of pheochromocytoma in 10 of 11 patients (with a false negative result in one patient) but was not useful in diagnosing adrenal medullary hyperplasia. We conclude that regular, prospective screening and early treatment of the manifestations of multiple endocrine neoplasia can prevent metastasis of medullary thyroid carcinoma and the morbidity and mortality caused by pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1988

Inhibition of human neutrophil and Pseudomonas elastases by the amyloid P-component: a constituent of elastic fibers and amyloid deposits.

The amyloid P-component (AP), a ubiquitous component of amyloid fibrils, is also a plasma protein and a connective tissue constituent. Its proximity to elastin, in particular, suggested that AP might serve to protect elastic tissue from hydrolytic enzymes. The inhibition of pancreatic elastase by AP has been reported. In the present study, the effects of AP on human neutrophil elastase and Pseudomonas elastase were investigated, and AP was shown to interfere with the cleavage of soluble elastin. As indicated by Michaelis-Menten analysis, AP is acting as a noncompetitive inhibitor. C-reactive protein, which is structurally similar to AP, had no effect on either elastase. AP was also found to inhibit the degradation of secondary amyloid fibrils by neutrophil elastase when these structures were first partially purified and then reexposed to AP. AP's ability to inhibit elastase was compared with alpha-1 antitrypsin in the presence and absence of oxidizing agents. These substances, which are released by inflammatory cells, are known to abrogate alpha-1 antitrypsin's anti-protease capacity. This contributes to elevated levels of free proteases in the circulation and extravascular spaces during severe inflammation. AP is not susceptible to oxidation and remains a functional inhibitor under these conditions. The potential role of AP as an elastase inhibitor is discussed.

Amyloid↗
PubMed1988

Clinical use of serum enzymes in liver disease.

Some of the many enzymes found in hepatocytes can be measured in the serum and are used as tests of liver function. We now review the current knowledge of their physiology and pathophysiology and outline their clinical usefulness. We divide them into two categories: enzymes that primarily reflect cholestasis, such as the alkaline phosphatase, the 5'-nucleotidase, and the gamma-glutamyl transpeptidase, and those that primarily reflect hepatocellular necrosis, such as the aminotransferases. We also briefly discuss several enzymes of more limited usefulness.

5'-Nucleotidase↗
PubMed1988

Inhibition of thyroxine 5'-deiodination type II in cultured human placental cells by cortisol, insulin, 3', 5'-cyclic adenosine monophosphate, and butyrate.

The regulation of conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) by the type II iodothyronine deiodinating pathway was studied in normal human placental cells cultured from the chorionic membrane. T4 5'-deiodination was measured in cell sonicates after intact cells were incubated with test agents for 24 to 48 hours. Stimulation of T4 5'-deiodination occurred to a similar degree after depriving cells of thyroid hormone in serum-free medium and in medium containing 10% calf serum. Cortisol at 10 to 100 nmol/L in serum-free medium inhibited T4 5'-deiodination up to 36%, and 1 to 100 nmol/L of insulin inhibited deiodination up to 50%. Dibutyryl-cyclic AMP (dbcAMP) inhibited deiodination, but this appeared to result from the inhibitory effects of butyrate. Addition to the culture media of 8-bromo-cAMP, cholera toxin, and theophylline each caused partial inhibition of T4 5'-deiodination, strongly suggesting an inhibitory effect of raised intracellular cAMP. Neither alpha- nor beta-adrenergic agonists had any effect when added to the culture medium, nor did glucagon or cysteamine. These results demonstrate a complex, multihormonal control of human placental type II iodothyronine deiodination, and suggest that changes in the activity of this pathway may result in altered intracellular, and conceivably circulating, T3 concentrations in states of cortisol excess and marked hyperinsulinism. The factor that regulates type II deiodination via cAMP remains to be identified.

Butyrates↗
PubMed1988

Fat-soluble vitamin nutriture in primary biliary cirrhosis.

We measured serum levels of vitamins A, E, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D, as well as levels of abnormal (des-gamma-carboxy) prothrombin, in 52 patients with primary biliary cirrhosis. Decreased serum levels of retinol (vitamin A) and 25-hydroxyvitamin D and elevated levels of abnormal prothrombin were common in these patients and correlated with the histologic stage of the disease and with the clinical severity of disease as judged by elevated serum bilirubin levels and decreased serum albumin levels. The increased levels of abnormal prothrombin were due primarily to vitamin K deficiency but also, in part, to the severity of the liver disease itself. Vitamin E deficiency was rare. Only 1 patient had clinical manifestations of fat-soluble vitamin deficiency, night blindness, and gastrointestinal bleeding related to a marked prolongation of the prothrombin time. Deficiencies of fat-soluble vitamins are most likely to be present in jaundiced patients with long-standing, severe cholestasis. We suggest that fat-soluble vitamin status be determined in all patients with primary biliary cirrhosis by appropriate blood tests and that vitamin supplements be given only to those patients who require them.

Biomarkers↗
PubMed1988

Triiodothyronine exerts direct cell-specific regulation of thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus.

Thyroid hormone administered systemically exerts negative feedback control of biosynthesis of the TRH pro-hormone in the hypothalamic paraventricular nucleus (PVN), the origin of neurons that regulate anterior pituitary TSH secretion, but not in any other group of TRH-synthesizing neurons in the brain. To determine whether this response is mediated by direct effects on PVN neurons, we studied the effect of unilateral stereotaxic implants of L-T3 into the anterior hypothalamus on the concentration of pro-TRH mRNA and pro-TRH in the PVN of hypothyroid rats. Because hypothalamic-pituitary-thyroid function is also regulated by central catecholamines, we also determined the effect of unilateral ablation of ascending catecholaminergic fibers to one side of the PVN by stereotaxic injection of 6-hydroxydopamine or transection of ascending catecholaminergic pathways. T3-implanted hypothyroid animals showed a marked reduction in pro-TRH mRNA and immunoreactive pro-TRH in medial parvocellular neurons of the PVN on the same side as the implant, but not in contralateral PVN neurons or TRH-synthesizing neurons in other hypothalamic regions. In contrast, hypothyroid animals implanted with pellets of hormonally inactive 3,5-diiodo-L-thyronine showed intense symmetric hybridization and immunoreaction product in both wings of the PVN. Despite marked unilateral reduction in the catecholamine innervation to the PVN, no reduction in pro-TRH mRNA or immunoreactive pro-TRH was observed in the PVN on the affected side compared to that on the unaffected side. These studies demonstrate that negative feedback regulation of thyroid hormone occurs directly on TRH neurons and is restricted only to those in the PVN tuberoinfundibular system.

Animals↗
PubMed1988

Thyroid, parathyroid, and salivary gland evaluations in patients exposed to multiple fluoroscopic examinations during tuberculosis therapy: a pilot study.

The prevalence of thyroid, parathyroid, and salivary abnormalities was determined in 91 women who received an average of 112 fluoroscopic chest examinations during pneumothorax treatment for tuberculosis more than 40 yr previously and in 72 women treated for tuberculosis by other modalities. Thyroid abnormalities were determined by physical examination, scintiscans, and measurements of serum free T4 index, TSH, and thyroid microsomal antibodies. Thyroid nodules were diagnosed in 7.7% of the exposed and 4.2% of the comparison group (prevalence ratio, 1.8; 90% confidence interval 0.6-5.7). Autoimmune thyroid disease was diagnosed in 15.2% of the exposed and 6.9% of the comparison group (prevalence ratio, 2.2; 95% confidence interval, 0.8-6.2). No salivary tumors were detected. Two exposed women and 1 comparison woman had primary hyperparathyroidism. Although absorbed dose to the thyroid could not be precisely determined, approximately 60 rads would be expected to yield the observed excess of thyroid nodules. While the prevalence ratios were not significantly increased in the exposed group, the results suggest that susceptibility of the thyroid to nodules from cumulative radiation doses of this magnitude could be increased even when the doses are accumulated over years and that such x-ray exposure of the thyroid gland may predispose the patient to the development of autoimmune disease.

Breast Neoplasms↗
PubMed1988

Human epidermal keratinocytes in culture convert thyroxine to 3,5,3'-triiodothyronine by type II iodothyronine deiodination: a novel endocrine function of the skin.

Cultured human keratinocytes converted T4 to T3 by type II iodothyronine deiodination. Homogenates of keratinocytes cultured from neonatal foreskin or adult arm skin had similar mean T4 5'-deiodinating activities. Conversion of T4 to T3 by intact cells was demonstrable in cultures from neonatal and adult donors. Only phenolic ring deiodination occurred in the cultured cells and their homogenates, the apparent Michaelis constant for T4 was 12 nmol/L, and T4 and rT3 each inhibited 5'-deiodination of the other. T4 5'-deiodination was unaffected by addition to the assay mixture of 1 mumol/L T3, but was inhibited less than 10% by 1 mmol/L 6-n-propyl-2-thiouracil, 50% by 270 nmol/L iopanoic acid, 50% by 9.4 mumol/L 3,5-diiodo- 3',5'-dimethyl-L-thyronine, and 33% by 42 mumol/L amiodarone. When keratinocytes were cultured for 3-4 days in medium containing iodothyronine-free fetal calf serum, the T4 5'-deiodination rates in homogenates doubled; this increase was prevented by restoring a physiological free T4 concentration, but not by a supraphysiological T3 concentration. Homogenates of fresh whole skin or fetal cadaveric epidermis did not convert T4 to T3 in measureable amounts, although one epidermal homogenate had low level T3 typrosyl-ring deiodinating activity. These results suggest that human epidermal type II iodothyronine deiodination in man might conceivably contribute to the intracellular T3 content of the skin and even to serum T3 concentrations, especially in hypothyroidism.

Cells, Cultured↗
PubMed1987

Anti-DNA antibody idiotypes in primary biliary cirrhosis.

A significant increase in 16/6 Id--a major cross-reactive idiotype of anti-DNA antibodies (Ab) derived from a patient with systemic lupus erythematosus (SLE) and hitherto identified in SLE patients and their relatives, was found in 16/17 patients with primary biliary cirrhosis (PBC). The increased serum level of Ab with the 16/6 idiotype (16/6 Id) in PBC patients (median 50 ng/ml) was not found in 6/7 of the patients' spouses nor among 27/28 healthy controls or most patients with other types of cirrhosis. The quantity of 16/6 Id was not correlated to either the stage of disease or the presence of antimitochondrial, antinuclear, or anti-dsDNA antibodies. However, 16/6 Id could be shown to be associated with anti-ssDNA antibodies. The high frequency of the lupus-derived 16/6 Id in PBC may accompany the polyclonal B-cell activation seen in that disease. Of 14 healthy first-degree relatives of the PBC patients, 4 (29%) also had elevated serum 16/6 Id (20-25 ng/ml) and the cluster of 3 of them in a single family may indicate a genetic predisposition to develop PBC.

Adult↗
PubMed1987

A randomized clinical trial comparing OKT3 and steroids for treatment of hepatic allograft rejection.

A multiinstitutional randomized trial was undertaken comparing OKT3 with steroids for treatment of hepatic allograft rejection. All patients received baseline immunosuppression with Cyclosporine (CsA) and steroids. At the time of biopsy-confirmed rejection, up to 2 intravenous boluses (250-1000 mg) of methylprednisolone were initially administered. Twenty-eight patients who failed to respond were then randomly assigned to OKT3 or continued steroid therapy. Rescue therapy with the opposite treatment arm was added after 6 days if the primarily allocated protocol failed. Three of 13 patients assigned to the steroid group responded promptly, and continue with good function 7-12 months later. OKT3 rescue was required in 10 patients who failed to improve despite receiving up to 6 g of methylprednisolone (mean: 3.3 g/patient). One patient died of sepsis and hepatic failure. Rejection was reversed in 9 OKT3-rescue patients, 7 of whom are well 1-17 months later. In the OKT3 group, improved allograft function was observed within 72 hr in 11 of 15 patients. Two patients with inadequate response were successfully rescued with steroids; 1 patient underwent retransplantation; and 1 patient developed a biliary fistula that eventually resulted in sepsis and death. In summary, 23 of 28 hepatic recipients (82%) are alive with the original allograft 1-17 (mean 7.8) months after treatment for acute rejection. Another patient is alive 14 months following retransplantation. Eighteen (78%) of the survivors required OKT3 as initial (11) or rescue (7) therapy, whereas only 5 were successfully managed with steroids. OKT3 is superior to steroids for reversing liver allograft rejection and has greatly reduced the need for retransplantation even in recipients selected on the basis of having failed initial steroid therapy.

Antibodies, Monoclonal↗
PubMed1987

Abnormal thyroid hormone deiodination in tissues of ob/ob and db/db obese mice.

To explore the relationships between thyroid hormone economy and defective thermogenesis in two genetically obese mouse strains, ob/ob and db/db, we measured iodothyronine deiodination in tissue homogenates and the T4 and T3 content of selected tissues. In lean mice acclimated at room temperature, type II 5'-deiodination in brown adipose tissue (BAT) homogenates rose 14.5-fold between 30 and 180 min of cold exposure at 4 C. In ob/ob mice kept at room temperature, type II 5'-deiodination rates in BAT homogenates were 2.29 times those in lean controls, but acute exposure to 4 C for 3 h caused a much smaller rise in 5'-deiodination in the ob/ob mice than in lean controls. Administration of 1 microgram/g norepinephrine caused similar elevations in BAT 5'-deiodination in ob/ob and lean mice. db/db mice had a defect in cold-stimulated BAT 5'-deiodination similar to that in the ob/ob mice in two of three experiments. In the obese animals of both strains, but not the lean mice, the magnitude of the rise in BAT type II deiodination after cold exposure was much greater in December than in warm months. Cerebrocortical homogenates from ob/ob mice had about 33% higher type II 5'-deiodination rates than those from lean controls, but showed normal type III T3 5'-deiodination. ob/ob liver homogenates had about 33% lower type I 5'-deiodination rates than controls. db/db, but not ob/ob, mice had lower serum T4 concentrations than controls. Both ob/ob and db/db mice had lower hepatic T4 concentrations than lean controls. The ob/ob animals had no alteration in brain T4 concentrations. Neither ob/ob or db/db mice had altered serum T3 concentrations, ob/ob mice had subnormal hepatic, but not brain, mean T3 concentrations. db/db mice also had reduced mean heptic T3 concentration. These results suggest that the subnormal cold-induced rise in ob/ob and db/db BAT type II 5'-deiodination is unrelated to thyroid status, perhaps being partly caused by defective sympathetic stimulation. This impaired deiodination response might result in subnormal intracellular T3 in BAT, thereby contributing to impaired thermogenesis. In contrast, the elevated cerebrocortical and unstimulated BAT type II deiodination and the decreased hepatic type I deiodination in the ob/ob mice are probably due to intracellular thyroid hormone deficiency.

Adipose Tissue, Brown↗
PubMed1987

Primary sclerosing cholangitis and low-dose oral pulse methotrexate therapy. Clinical and histologic response.

Two patients with sclerosing cholangitis responded to low-dose methotrexate treatment. A 40-year-old man who had previously undergone total colectomy for ulcerative colitis presented with refractory erythroderma and sclerosing cholangitis. Both disorders were alleviated and have remained in remission on methotrexate, 5 mg every 12 hours three times each week (15 mg/wk). Liver function improved, bile duct scarring did not worsen, and repeat liver biopsy samples have shown striking improvement. A 60-year-old man with long-standing ulcerative colitis and repeated exacerbations of sclerosing cholangitis had a similar response to low-dose methotrexate, 2.5 mg every 12 hours three times each week (7.5 mg/wk), during a 6-year period. Recurrent episodes of cholangitis have disappeared, liver function has become normal, bile duct scarring has not worsened, and liver histologic findings have become normal. Because of the potential hepatotoxicity of methotrexate, we suggest that a prospective, randomized trial be done.

Administration, Oral↗