Search PubMed⌕ Search

Biomedical subjects

W A Scherbaum

Publications and source records attributed to W A Scherbaum.

At least 19 recordsLinked to original sources
PubMed1992

Human monoclonal islet cell antibodies from a patient with insulin-dependent diabetes mellitus reveal glutamate decarboxylase as the target antigen.

The autoimmune phenomena associated with destruction of the beta cell in pancreatic islets and development of type 1 (insulin-dependent) diabetes mellitus (IDDM) include circulating islet cell antibodies. We have immortalized peripheral blood lymphocytes from prediabetic individuals and patients with newly diagnosed IDDM by Epstein-Barr virus transformation. IgG-positive cells were selected by anti-human IgG-coupled magnetic beads and expanded in cell culture. Supernatants were screened for cytoplasmic islet cell antibodies using the conventional indirect immunofluorescence test on cryostat sections of human pancreas. Six islet cell-specific B-cell lines, originating from a patient with newly diagnosed IDDM, could be stabilized on a monoclonal level. All six monoclonal islet cell antibodies (MICA 1-6) were of the IgG class. None of the MICA reacted with human thyroid, adrenal gland, anterior pituitary, liver, lung, stomach, and intestine tissues but all six reacted with pancreatic islets of different mammalian species and, in addition, with neurons of rat cerebellar cortex. MICA 1-6 were shown to recognize four distinct antigenic epitopes in islets. Islet cell antibody-positive diabetic sera but not normal human sera blocked the binding of the monoclonal antibodies to their target epitopes. Immunoprecipitation of 35S-labeled human islet cell extracts revealed that a protein of identical size to the enzyme glutamate decarboxylase (EC 4.1.1.15) was a target of all MICA. Furthermore, antigen immunotrapped by the MICA from brain homogenates showed glutamate decarboxylase enzyme activity. MICA 1-6 therefore reveal glutamate decarboxylase as the predominant target antigen of cytoplasmic islet cell autoantibodies in a patient with newly diagnosed IDDM.

Adolescent↗
PubMed1992

Structure and dynamics of adrenal mitochondria following stimulation with corticotropin releasing hormone.

The mitochondria of rat adrenals were investigated qualitatively and quantitatively in different functional states of the adrenal cortex. Following stimulation of the animals with corticotropin releasing hormone (CRH), the corticosterone serum levels reached a maximum 1 hour after stimulation with CRH. The amount of inner mitochondrial membrane within the zona fasciculata increased showing a biphasic time course, with a first maximum 2 hours and a second maximum 8 hours after stimulation. In contrast, a significant rise of mitochondrial volume occurred only 24 hours after CRH stimulation. Therefore, the dense vesicularization of mitochondrial cristae may constitute an early process to enhance the steroidogenic capacity of these cells. Within cells of the transition zone between zona glomerulosa and zona fasciculata, we could depict a special type of mitochondria with characteristic crescent-like cristae only seen after stimulation with CRH. This type of mitochondria may represent an intermediate form between mitochondria of zona glomerulosa and zona fasciculata underlining the impressive transformational capacity of adrenocortical mitochondria. After hypophysectomy, zona fasciculata cells contained mitochondria with tubular inner membranes, representing a hypofunctional state. In contrast, the hypofunctional state after hypophysectomy and the hyperfunctional state after stimulation of the adrenal cortex via CRH injection did not appear to correlate with the morphology of mitochondria from the zona reticularis and adrenal medulla.

Adrenal Cortex↗
PubMed1992

Antibodies to the M(r) 64,000 (64K) protein in islet cell antibody positive non-diabetic individuals indicate high risk for impaired beta-cell function.

A prospective study of a normal childhood population identified 44 islet cell antibody positive individuals. These subjects were typed for HLA DR and DQ alleles and investigated for the presence of antibodies to the M(r) 64,000 (64K) islet cell antigen, complement-fixing islet cell antibodies and radiobinding insulin autoantibodies to determine their potency in detecting subjects with impaired Beta-cell function. At initial testing 64K antibodies were found in six of 44 islet cell antibody positive subjects (13.6%). The same sera were also positive for complement-fixing islet cell antibodies and five of them had insulin autoantibodies. During the follow-up at 18 months, islet cell antibodies remained detectable in 50% of the subjects studied. In all six cases who were originally positive, 64K antibodies were persistently detectable, whereas complement-fixing islet cell antibodies became negative in two of six and insulin autoantibodies in one of five individuals. HLA DR4 (p less than 0.005) and absence of asparic acid (Asp) at position 57 of the HLA DQ beta chain (p less than 0.05) were significantly increased in subjects with 64K antibodies compared with control subjects. Of 40 individuals tested in the intravenous glucose tolerance test, three had a first phase insulin response below the first percentile of normal control subjects. Two children developed Type 1 (insulin-dependent) diabetes mellitus after 18 and 26 months, respectively. Each of these subjects was non-Asp homozygous and had persistent islet cell and 64K antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Episodic thyrotropin (TSH) and prolactin (PRL) secretion during aging in postmenopausal women.

While aging is known to decrease episodic thyrotropin (TSH) secretion in men, no detailed information is available as to age-related alterations in the TSH and prolactin (PRL) release patterns in postmenopausal women (PMW). Accordingly, we compared the TSH and prolactin (PRL) secretory profiles of 6 euthyroid younger PMW (mean age: 53.0 years) with those of 7 euthyroid older PMW (mean age: 80.4 years). In all PMW, blood samples were obtained at 10 minute intervals for 10 hours for serial determinations of TSH and PRL by RIA. While thyroxine (T4) serum concentrations were not different in younger from older PMW, triiodothyronine (T3) levels markedly (p less than 0.05) decreased in older PMW. In both younger and older PMW, TSH and PRL were secreted episodically (by Cluster pulse algorithm), with considerable inter-individual variabilities in either study group. TSH and PRL pulse attributes (interpulse intervals, frequencies, amplitudes) were comparable in younger and older PMW, although a tendency of mean TSH to increase (p = 0.18) was noted for older PMW. Mean TSH and PRL serum concentrations were positively (r = 0.94, p less than 0.01) correlated in older, whereas not in younger PMW. These observations demonstrate that the pulse characteristics of episodic TSH and PRL secretion are preserved in PMW even of old age. However, in view of markedly decreased circulating T3 concentrations and of no substantial change in the TSH pulsatile secretion in older PMW, the negative feedback on the hypothalamic-pituitary unit may be impaired in elderly women.

Aged↗
PubMed1992

Endocrine function in multiple sclerosis.

In 31 patients with multiple sclerosis (MS) the endocrine functions of the hypothalamus, the pituitary and several peripheral endocrine glands were assessed with a combined pituitary test; 3/31 patients had an endocrine disease: one primary hypothyroidism, one primary amenorrhea and one primary male hypogonadism. We found no patient with endocrine disease of the hypothalamus, the pituitary or the adrenals. However, the poststimulatory secretion of cortisol, growth hormone or thyroid-stimulating hormone was impaired in 7/31 patients, suggesting a possible preclinical endocrine insufficiency in these patients.

Adult↗
PubMed1992

Prevalence of autoantibodies to endocrine organs in girls with Ullrich-Turner syndrome aged 5-14 years.

Endocrine function tests and a broad panel of autoantibodies to endocrine organs were assessed in 77 patients aged 5-14 years with Ullrich-Turner syndrome (UTS), who were included in the German UTS Multicenter Study. None of these patients had abnormal pituitary, thyroid or adrenocortical function, as assessed by the adequate hormone tests. Antibodies to thyroid microsomes were found in 3 of the 77 (3.9%), antibodies to thyroglobulin in 0/77, antibodies to adrenocortical cells in 1/77 (1.3%), gastric parietal cell antibodies in 2/77 (2.6%), and anterior pituitary cell antibodies in 3/77 (3.9%) probands. These prevalences were not significantly higher than those obtained in 154 age- and sex-matched normal control children when 2 control subjects were assigned to each patient with UTS. Our data do not show an increase in serological signs of endocrine autoimmunity in young patients with UTS suggesting that a putative association of these syndromes does not exist from birth and is not usually present in childhood. However, we cannot exclude the possibility that UTS is associated with factors that render these patients more susceptible to endocrine autoimmunity later in life.

Adolescent↗
PubMed1992

Role of ovarian sex steroids in the regulation of thyrotropin (TSH) secretion of hypogonadal women.

The exact role of ovarian sex steroids in the neuroendocrine regulation of thyrotropin (TSH) release in women can only be accurately assessed in the absence of any considerable ovarian sex steroid feedback upon the hypothalamic-pituitary unit. Consequently, the unstimulated episodic and thyrotropin-releasing hormone (TRH) stimulated TSH secretion was evaluated in postmenopausal women before and during sequential ovarian sex steroid replacements. Seven euthyroid women (mean age: 59.4 years) were studied initially without any sex steroid replacement (control studies), then on the last day of a 21-day course of oral estradiol-valeriate (E2) administration (2 mg daily) and finally, on the last day of a 21-day course of oral estradiol-progesterone (E2/P4) replacement (2 mg E2 and 200 mg micronized P4 daily). During all study occasions, blood was sampled at 10 min intervals for 10 h, while TRH (200 micrograms iv) was administered 8 h after initiation of blood collections. Compared to the control conditions, serum E2 and P4 concentrations markedly increased (p less than 0.001) following oral E2 or E2/P4 treatments. Total triiodothyronine (T3) and thyroxine (T4) concentrations and free T3 and T4 equivalents remained unchanged during E2 and E2/P4 regimens. In the unstimulated secretory profiles, TSH was found to be episodically released, with little interindividual variability for each study condition. Since the TSH pulse attributes (pulse amplitudes, frequencies, interpulse intervals, mean TSH concentrations, by Cluster pulse algorithm) did not significantly change during E2 and E2/P4 replacements, the episodic character of TSH secretion virtually remained unchanged by sex steroid replacements.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Regulation of adrenal steroidogenesis by adrenaline: expression of cytochrome P450 genes.

The effect of adrenaline on the secretion of cortisol and cyclic AMP (cAMP) and on the accumulation of four different mRNAs encoding cholesterol side-chain cleavage cytochrome P450 (P450scc), 17 alpha-hydroxylase cytochrome P450 (P450(17 alpha)), 21-hydroxylase cytochrome P450 (P450c21) and 11 beta-hydroxylase cytochrome P450 (P450(11 beta)) was studied in bovine adrenocortical cells in primary culture and compared with the effects of ACTH. Treatment of cultured cells with adrenaline (1-100 mumol/l) showed a biphasic response in cortisol release over 1-24 h. Concentration of cAMP in the culture media increased from a basal level of < 0.06 pmol/dish to a maximal level of 40.14 +/- 8.9 pmol/dish with a half-maximal release of 20.07 pmol cAMP/dish in the medium reached 1.2 h after treatment with 10 mumol adrenaline/l. This stimulation resulted in an uniform increase in the levels of all four P450 mRNAs as revealed by Northern blot analysis. Increasing doses of adrenaline produced a maximal mRNA accumulation at a concentration of 10 mumol adrenaline/l. Incubation of the cells with 10 mumol adrenaline/l for 1-24 h produced a biphasic time-course with a half-maximal stimulation after about 5-6 h. Maximal stimulation with ACTH (100 nmol/l) caused different accumulations of the four mRNAs: P450sec mRNA increased twice as much and P450(17 alpha) mRNA six times as much as the accumulation of P450c21 mRNA and P450(11 beta) mRNA, which was about ten-fold over basal values. Propranolol totally blocked the stimulatory effect of adrenaline but not the effect of ACTH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1992

Antineutrophil cytoplasmic autoantibodies (ANCA) in acute pancreatitis.

Antineutrophil cytoplasmic autoantibodies, which are now considered reliable serological markers of acute necrotizing vasculitic diseases, were measured in 11 patients with acute necrotizing pancreatitis and 12 patients with acute interstitial pancreatitis. When tested by indirect immunofluorescence, none of the sera was positive for diffuse cytoplasmic staining, and none was positive for perinuclear staining of antineutrophil cytoplasmic antibodies. Also by the sensitive enzyme-linked immunosorbent assay, none of the sera was positive when purified alpha-granule fraction of granulocytes was used as an antigen. We can therefore conclude that neither the diffuse cytoplasm-reacting, nor the perinuclear form of antineutrophil cytoplasmic antibodies, is involved in cases of acute pancreatitis.

Acute Disease↗
PubMed1992

Etiology and pathogenesis of type 1 diabetes.

An increasing bulk of evidence suggests that type 1 (insulin-dependent) diabetes mellitus is an autoimmune disease with a strong immunogenetic background. 1st-degree relatives of type 1 diabetic patients, especially HLA-identical individuals, bear an increased risk to develop the disease. The autoimmune reactions are pronounced at the onset of disease where an infiltration of islets with T and B lymphocytes, plasma cells and macrophages can be observed. Autoreactive T lymphocytes play a crucial role among effector mechanisms which finally lead to a selective destruction of pancreatic beta cells. Disease-specific autoantibodies (Ab) include cytoplasmic islet cell Ab (ICA), islet cell surface Ab (ICSA), Ab to the 64KD islet cell protein and Ab to insulin (IAA). As ICA can be detected months or years before the onset of clinical disease, testing of individuals at risk or population screening programs can help to recognize subclinical insulitis. High titers of ICA and high levels of IAA, as measured by radioimmunoassay, indicate a high risk for progression to type 1 diabetes. A blunted first phase insulin response in the i.v. glucose tolerance test is the most sensitive sign of an irreversible metabolic deterioration. It is likely that immunotherapy at a prediabetic state will be more efficacious than its initiation after the clinical manifestation of diabetes. However, the appropriate immunotherapeutical strategies are yet to be worked out.

Antibody Formation↗
PubMed1991

Insulin autoantibodies as determined by competitive radiobinding assay are positively correlated with impaired beta-cell function--the Ulm-Frankfurt Population Study.

Out of a random population of 4208 non-diabetic pupils without a family history of Type I diabetes 44 (1.05%) individuals had islet cell antibody (ICA) levels greater or equal to 5 Juvenile Diabetes Foundation (JDF) units. 39 of these ICA-positives could be repeatedly tested for circulating insulin autoantibodies (CIAA) using a competitive radiobinding assay. The results were compared with the insulin responses in the intravenous glucose tolerance tests (IVGTT) and with HLA types. Six pupils were positive for CIAA. All of them had complement-fixing ICA, and 5 of them were HLA-DR4 positive. Three of the 6 showed a first-phase insulin response below the first percentile of normal controls. Our data indicate that in population-based studies CIAA can be considered as a high risk marker for impaired beta-cell function in non-diabetic ICA-positive individuals.

Adolescent↗
PubMed1991

Prevalence of HLA-DQ beta chain non-Asp alleles in type I (insulin-dependent) diabetics with young and older ages of onset.

Particular HLA-DQ beta chain alleles were reported as immunogenetic markers of type I diabetes mellitus with young onset of the disease. In a homogeneous German population, we studied HLA-DR specificities and HLA-DQ beta chain alleles in young-onset (less than 21 years of age; n = 185) and adult-onset (greater than 40 years of age; n = 48) insulin-dependent diabetics. In both cohorts of type I diabetics, the HLA-DR3 and -DR4 specificities were significantly increased. The presence of an HLA haplotype with an amino acid other than aspartic acid at position 57 of the DQ beta chain was significantly associated with type I diabetes in both cohorts (etiologic fraction: 93% and 73%). We conclude that the presence of DNA sequences coding for an amino acid other than aspartic acid at the 57th position of the DQ beta chain provides a molecular risk marker for type I diabetes of both and adult onset.

Adolescent↗
PubMed1991

Morphological evidence for a close interaction of chromaffin cells with cortical cells within the adrenal gland.

The adrenal medulla appears to exert a regulatory influence on adrenocortical steroidogenesis. We have therefore studied the morphology of rat, porcine and bovine adrenals in order to characterize the contact zones of adrenomedullary and adrenocortical tissues. The distribution of chromaffin cells located within the adrenal cortex and of cortical cells located within the adrenal medulla was investigated. Chromaffin cells were characterized by immunostaining for synaptophysin and chromogranin A, both being considered specific for neuroendocrine cells. Cortical cells were characterized by immunostaining for 17 alpha-hydroxylase, an enzyme of the steroid pathway. Cellular contacts of chromaffin cells and cortical cells were examined at the electron microscopical level. In rat and porcine adrenals, rays of chromaffin cells, small cell clusters and single chromaffin cells or small invaginations from the medulla could be detected in all three zones of the cortex. Chromaffin cells often spread in the subcapsular space of the zona glomerulosa. In porcine and bovine adrenals, 17 alpha-hydroxylase immunoreactive cells were localized within the medulla. Single cortical cells and small accumulations of cells were spread throughout this region. At the ultrastructural level, the chromaffin cells located within the cortex in pig and rat adrenals formed close cellular contacts with cortical cells in all three zones. Our morphological data provide evidence for a possible paracrine role of chromaffin cells; this may be important for the neuroregulation of the adrenal cortex.

Adrenal Cortex↗
PubMed1991

No association between islet cell antibodies and Coxsackie B, mumps, rubella and cytomegalovirus antibodies in non-diabetic individuals aged 7-19 years.

Viral antibodies were tested in a cohort of 44 islet-cell antibody-positive individuals age 7-19 years, and 44 of their islet cell antibody-negative age and sex-matched classmates selected from a population study of 4208 pupils who had been screened for islet cell antibodies. Anti-coxsackie B1-5 IgM responses were detected in 14 of 44 (32%) of the islet cell antibody-positive subjects and in 7 of 44 (16%) control subjects. This difference did not reach the level of statistical significance. None of the islet cell antibody-positive subjects had specific IgM antibodies to mumps, rubella, or cytomegalovirus. There was also no increase in the prevalence or the mean titres of anti-mumps-IgG or IgA and anti-cytomegalovirus-IgG in islet cell antibody-positive subjects compared to control subjects. These results do not suggest any association between islet cell antibodies, and possibly insulitis, with recent mumps, rubella or cytomegalovirus infection. Further studies are required to clarify the relationship between islet cell antibodies and coxsackie B virus infections.

Adolescent↗
PubMed1991

Morphological and hormonal changes following vasectomy in rats, suggesting a functional role for Leydig-cell associated macrophages.

The effects of bilateral vasectomy on hormone serum levels as well as Leydig cell and associated macrophage structure were analysed in parallel in rats 36 weeks following the operation. Serum testosterone was decreased in vasectomized rats (1.96 +/- 0.11 ng/ml) compared with control animals (3.44 +/- 0.22 ng/ml, p less than 0.05). Vasectomy also resulted in an increase in serum luteinizing hormone (LH) to 0.299 +/- 0.02 ng/ml compared to the control group (0.175 +/- 0.01 ng/ml, p less than 0.05). Also serum follicle-stimulating hormone (FSH) was increased following vasectomy (350.88 +/- 15.5 ng/ml) compared to 132.0 +/- 4.8 ng/ml in control animals (p less than 0.01). Morphometric analysis of Leydig cells showed hypertrophy with a 19% increase of total cell area, p less than 0.01 (cytoplasm 28%, nucleus 8% increase). On the ultrastructural level, leydig cells demonstrated massively dilated smooth endoplasmic reticulum characteristic for stimulated cells. There was also a significant hypertrophy of the Leydig cell-associated macrophages. The macrophage cell area was enlarged by 22%, p less than 0.01 (cytoplasm 25%, nucleus 18%). Vasectomy also led to remarkable ultrastructural changes of macrophages with a marked dilated and extended rough endoplasmic reticulum. Macrophages were found in apposition to Leydig cells with close cellular contact zones, and they frequently formed cell extensions on Leydig cells. Our data obtained following vasectomy indicate that, by their close contacts to Leydig cells, as well as the known influence on Leydig-cell steroidogenesis, macrophages may form the basis of a local immunoendocrine regulation of the pituitary-gonadal axis.

Animals↗