Determining the breast-feeding interruption schedule after administration of 123I-iodide.

Radioactivity after administration of 123I-sodium iodide was measured in breast milk samples obtained from a patient with postpartum thyroiditis. The breast milk was collected over 93 h during the infant's regular feeding times. The radioactivity in the breast milk was calculated with a 123I capsule of the same lot number as the standard source. 123I was excreted exponentially with an effective half-life of 5.5 h; 2.5% of the total radioactivity administered was excreted in the breast milk over the 93 h, 95% of which was excreted within the first 24 h, and 98.2% within 36 h. The first milk sample collected at 7 h after administration of the radiopharmaceutical contained 48.5% of the total radioactivity excreted. We estimated the potential absorption of radioactivity to an infant's thyroid in uninterrupted breast-feeding to be 30.3 mGy. With a 24-hour interruption, the absorbed radioactivity would be 1.25 mGy; with a 36-hour interruption, it would be 0.24 mGy. According to our calculations, breast feeding should be curtailed for 36 h to reduce the infant's exposure to 123I radioactivity. By using a correction factor based on maximum radioactivity from another 123I capsule of the same lot, we were able to ascertain the appropriate protocol for our patient and establish a measurement method that can be applied in similar clinical situations.

Unusual accumulation of glycogen in liver parenchymal cells in a patient with anorexia nervosa.

Anorexia nervosa is an eating disorder characterized by a fear of weight gain and a preoccupation with body image. Although hepatic involvement has been reported in patients with anorexia nervosa, the mechanism is not fully understood. We describe a patient with anorexia nervosa with liver function abnormalities. Light and electron microscopic observations revealed a remarkable accumulation of glycogen in hepatocytes. These results suggest that adaptive responses to starvation may alter carbohydrate metabolism in patients with anorexia nervosa.

Combined measurements of GAD65 and ICA512 antibodies in acute onset and slowly progressive IDDM.

Autoantibodies to 65 kD glutamic acid decarboxylase (GADAA) and ICA512 (ICA512AA) were measured by radioimmunoassays using as antigens in vitro transcribed and translated [35S]-methionine-labeled human GAD65 and ICA512 (IA-2). The prevalence of GADAA and ICA512AA in sera from 87 patients with IDDM was 39 and 23%, respectively. The frequency and titer of ICA512AA declined sharply within 5 years after the onset of IDDM. Among patients tested within 4 years after diagnosis, the prevalence of ICA512AA was significantly higher in acute onset IDDM than in slowly progressive IDDM (37 versus 6%, P < 0.025) irrespective of age, while there was no difference in GADAA frequency between acute onset and slowly progressive subtypes (51 versus 63%). A total of two patients out of 121 patients with NIDDM were positive for GADAA, and two other NIDDM patients, who were suffering from sarcoidosis, were positive for ICA512AA. Neither of the antibodies were positive in sera from four atypical NIDDM patients, aged < 20 years, who showed ketosis at onset and required insulin followed by excellent metabolic control with diet restriction alone. These observations suggest that ICA512AA are associated with rapid progression of beta cell damage in IDDM. ICA512 radioassay, in combination with GAD assay may provide a useful diagnostic marker for IDDM especially in youth.

Mouse islet cell lysis mediated by interleukin-1-induced Fas.

This study was conducted to investigate the possible involvement of Fas in beta-cell death in insulitis of Type 1 (insulin-dependent) diabetes mellitus. Although primary cultured Balb/c mouse islet cells did not express Fas mRNA, 4-12 hours of treatment with 10(2)-10(3) U/l of mouse interleukin-1 alpha (IL-1 alpha) induced the expression of Fas mRNA. Surface Fas expression was detected by immunofluorescence flow cytometry using a non-cytolytic anti-Fas monoclonal antibody after 6 or 12 h of incubation with 10(3) U/l of IL-1 alpha. Primary islet cells were resistant to an agonistic anti-Fas monoclonal antibody. However, 12 h pretreatment with IL-1 alpha sensitized islet cells to its cytolytic effect. Significant cell death was observed 24 h after the addition of anti-Fas, and progressively increased until 72 h, when specific 51Cr release was 72 +/- 6%. Agarose gel electrophoresis of DNA extracted from cells exposed to IL-1 alpha and agonistic anti-Fas showed internucleosomal DNA fragmentation, a hallmark of apoptotic cell death. Since the Fas antibody showed no cross-reactive activity of tumour necrosis factor (TNF), the cytotoxic effect was not mediated by TNF receptors. A protein synthesis inhibitor cycloheximide augmented Fas-mediated islet cell death. The Fas-mediated killing of islet cells was not L-arginine-dependent, or blocked by N(G)-monomethyl-L-arginine. beta-TC1 cells also expressed Fas mRNA when exposed to IL-1 alpha or IL-1 alpha plus interferon-gamma. These observations suggest that Fas-mediated apoptosis may be a mechanism of islet cell death in autoimmune insulitis.

Endogenous tumor necrosis factor-alpha production by a pancreatic beta-cell line: inhibitory effects of hydrocortisone and nicotinamide.

The purpose of this study was to examine regulation of interleukin-1(IL-1)-induced tumor necrosis factor-alpha (TNF-alpha) production by a mouse beta-cell line (beta TC1). Three-hour incubation of beta TC1 cells with 5 U/ml of IL-1 beta results in the expression of TNF-alpha mRNA and intracellular accumulation of TNF-alpha. It has been shown that glucocorticoids and immunosuppressive agents such as cyclosporin and FK-506 inhibit TNF-alpha generation by T-lymphocytes and monocytes. Hydrocortisone of 1 and 10 mumol/l suppressed TNF-alpha mRNA levels and the TNF-alpha content of beta TC1 cells exposed to IL-1 beta, whereas neither cyclosporin nor FK-506 altered the TNF-alpha content. Nicotinamide of 5-10 mmol/l also reduced TNF-alpha mRNA and TNF-alpha protein levels in beta TC1 cells. Addition of exogenous TNF-alpha did not inhibit IL-1-induced transcription of TNF-alpha gene. These observations support the potential therapeutic role of glucocorticoids and nicotinamide in protecting beta-cells against cytokine-mediated damage, although glucocorticoid agonists have hyperglycemic metabolic effects.

Poly(ADP-ribose) synthesis induced by nitric oxide in a mouse beta-cell line.

Nitric oxide (NO) has been implicated as an immunological effector molecule that mediates beta-cell dysfunction associated with Type 1 diabetes. To assess whether NO induces poly(ADP-ribose) synthesis in islet cells, we examined the effect of nitroprusside on islet cells. The exposure of mouse islet cells and a beta-cell line (beta TC1) to 0.05-0.2 mM nitroprusside resulted in the reduction of intracellular nicotinamide adenine dinucleotide (NAD) levels. Nitroprusside stimulated poly(ADP-ribose) synthetase activity in beta TC1 cells. An inhibitor of poly(ADP-ribose) synthetase, 3-aminobenzamide, prevented both NAD decrease and poly ADP-ribosylation. These observations suggest that NO-induced pancreatic beta-cell damage may be ascribable to the activation of poly(ADP-ribose) synthetase that results in the decrease of NAD content.

Nitric oxide and nitric oxide synthase mRNA induction in mouse islet cells by interferon-gamma plus tumor necrosis factor-alpha.

It has been shown that nitric oxide (NO) is involved in islet cell damage induced by interleukin-1 (IL-1). Here we show that interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) synergistically induced NO production and inducible NO synthase (iNOS) mRNA expression in mouse islet cells. Cycloheximide (CXH) did not prevent the iNOS mRNA expressions. The combination of IFN-gamma and TNF-alpha, which is highly cytotoxic to mouse islet cells, failed to destruct islet cells in the absence of L-arginine or in the presence of NG-monomethyl-L-arginine (NMMA). These observations suggest that NO is a primary effector in islet cell damage caused by IFN-gamma plus TNF-alpha.

Effects of the carbohydrate composition of a low-protein meal on the postprandial responses of plasma glucose and insulin in diabetic patients.

We determined whether, in 15 diabetic patients, a conventional low-protein diet containing a high proportion of mono- and disaccharides would lead to a deterioration of postprandial glucose metabolism. Three different test meals were given on 3 different days. We found that a high proportion of simple carbohydrates, when consumed as a low-protein meal, aggravated the postprandial hyperglycemia in diabetic patients. The substitution of complex carbohydrates for simple sugars in the meal suppressed postprandial hyperglycemia in diabetic patients.

Pancreatic beta-cell-selective production of tumor necrosis factor-alpha induced by interleukin-1.

Cytokines have been regarded as effector molecules responsible for beta-cell death and major histocompatibility complex hyperexpression in endocrine pancreas of type I diabetes. However, the mechanism that results in beta-cell-selective destruction has not been elucidated. We demonstrated in this study, using cell lines of transformed mouse beta-cells and alpha-cells, that only pancreatic beta-cells but not alpha-cells produced tumor necrosis factor-alpha when exposed to interleukin-1 beta. Northern blot analysis confirmed the beta-cell-selective expression of tumor necrosis factor-alpha mRNA. Interleukin-1 beta also provoked tumor necrosis factor-alpha mRNA expression in vitro by normal mouse islet cells. Because tumor necrosis factor-alpha has been shown to potentiate beta-cell cytotoxicity of interleukin-1 and interferon-gamma, tumor necrosis factor-alpha produced in situ by beta-cells might be self-destructive. In fact, a low dose of interleukin-1 beta in combination with a low dose of interferon-gamma preferentially injured beta-cells. Hence endogenous tumor necrosis factor-alpha production by beta-cells may be involved in beta-cell-selective destruction in type 1 diabetes.

Effects of free radical scavengers on cytokine actions on islet cells.

We investigated the effect of free radical scavengers on the actions of cytokines on islet cells. Interferon-gamma and tumor necrosis factor-alpha reduced the nicotinamide adenine dinucleotide content of mouse islet cells; the combination of interferon-gamma (4 x 10(5) U/l) and tumor necrosis factor-alpha (4 x 10(5) U/l) caused nicotinamide adenine dinucleotide reduction by approximately 40%. Dimethyl urea and dimethyl sulfoxide prevented the decrease, whereas superoxide dismutase, catalase, and mannitol were not effective. Dimethyl urea and dimethyl sulfoxide protected islet cells from the synergistic cytotoxic action of interferon-gamma and tumor necrosis factor-alpha. Major histocompatibility complex class II antigen induction by interferon-gamma and tumor necrosis factor-alpha was also inhibited by dimethyl urea and dimethyl sulfoxide, but not by superoxide dismutase, catalase and mannitol. Since superoxide dismutase of a membrane-penetrable form attenuated the class II antigen induction, the inefficiency of superoxide dismutase, catalase and mannitol may be attributable to their inability to penetrate islet cells. These results suggest that the intracellular generation of free oxygen radicals is involved in islet cell cytotoxicity and class II molecule expression by interferon-gamma and tumor necrosis factor-alpha, and that nicotinamide adenine dinucleotide reduction may be associated with islet cell dysfunction caused by the cytokines.

A case of an undifferentiated small cell carcinoma of the esophagus with a primary abdominal mass.

This paper reports a case with an undifferentiated carcinoma of the esophagus which primarily developed symptoms due to metastatic lesions. The case was a 59-year-old woman with a primary manifestation of an abdominal mass and with subsequent dysphagia. A protruding lesion with ulceration was found at the lower third of the thoracic esophagus by endoscopic examination and was histologically proved to be an undifferentiated carcinoma by biopsy. The abdominal mass was initially thought to be due to metastasis to an abdominal lymph node based on the diagnosis image finding at admission, but it was consequently found by autopsy to be a metastatic tumor in the liver. Therefore, undifferentiated carcinoma of the esophagus should be take into account for differential diagnosis of an abdominal mass.

[A case of pituitary adenoma and hyperplasia with primary hypothyroidism].

A 23 year-old woman was admitted to our hospital, complaining of sterility and obesity. Her serum TSH and Prolactin were abnormally high, and her serum T3, T4 were low. Contrast-enhanced computerized tomographic (CT) scan revealed a round mass in the sella and suprasellar region. A transsphenoidal operation was then performed. The intrasellar mass was composed of a soft liquid-like part and a solid part. Only the soft liquid-like part of the mass was removed. Histological examination showed the typical appearance of chromophobe adenoma, Reticulin stain of the specimen revealed no reticular network. The remnant of the mass was considered to be hyperplasia because the size of the mass decreased on serial CT scan after thyroid hormonal replacement. Sometimes it may be difficult to distinguish between hyperplasia and adenoma. The application of reticulin stains is considered to be useful for differentiation between hyperplasia and adenoma.