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Biomedical subjects

W A Scherbaum

Publications and source records attributed to W A Scherbaum.

At least 55 records · Page 3Linked to original sources
PubMed2002

The short synacthen test in the evaluation of adrenal masses in patients with malignancies.

Adrenal computed tomography with determination of Hounsfield units has proved to be sensitive and specific in the differential diagnosis of benign vs. malign adrenal lesions. On the other hand, computed tomography may fail in patients with small adrenal masses of less than 1.0 cm. However, especially in patients with diagnosed malignancies and small adrenal masses which were discovered during the diagnostic staging procedure it is important to determine the origin of the adrenal lesion. An augmented increase in 17alpha-hydroxyprogesterone (17-OHP) levels following corticotropin (1-24) stimulation has been noted in incidentally discovered adrenal masses by several groups. Therefore, we tested the hypothesis that elevated ACTH-stimulated 17-OHP (delta > 2.6 ng/mL) can predict primary adrenal lesions. We evaluated the use of the ACTH test in 85 patients with adrenocortical tumors and in 16 patients who underwent abdominal imaging for staging of a carcinoma other than of adrenal origin. We found an augmented 17-OHP response in 70 (>82%) of patients with known adrenocortical tumors and in 10 (>62%) of patients with adrenal masses and diagnosed malignancies. Results in the latter group have been confirmed in histological studies after operation or puncture. In the group of patients who suffered from a solid malignant tumor and had an adrenal mass, it was thus possible to separate primary from secondary adrenal lesions in 100%. In the group of patients with known adrenocortical tumors, it failed to differentiate between benign and malignant adrenocortical lesion in one case. We therefore think that the ACTH test is a valuable biochemical tool to distinguish primary adrenal tumors from adrenal metastasis derived from other malignancies.

17-alpha-Hydroxyprogesterone↗
PubMed2001

Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA).

UNLABELLED: ABSTRACT AIMS/HYPOTHESIS: This study aimed to define the immunological parameters which could be used to identify patients with the distinct metabolic features of adult latent autoimmune diabetes. METHODS: Sera of 312 patients with short-term diabetes (duration < 5 years) over 35 years of age at diagnosis were screened for ICA, GAD- and IA2-Ab by antibody assays validated in workshops. The antibody status was correlated with age, BMI, residual beta-cell function, measured by fasting C-peptide, onset of diabetes-related complications and markers of the metabolic syndrome (hypertension and hyperlipidaemia). RESULTS: A total of 51 antibody positive patients were identified. These patients had lower fasting C-peptide and less neuropathy and hypertension compared with matched antibody-negative patients. However, only patients with two or more antibodies had reduced residual beta-cell function compared with antibody-negative or single antibody-positive (ICA or GAD-Ab only) patients. Patients with two or more antibodies were also leaner and had diabetes-related complications or hypertension less frequently than single antibody-positive or antibody negative-patients. IA2 antibody status did not substantially contribute to the diagnosis or differentiation of LADA patients. CONCLUSION/INTERPRETATION: We concluded that the combination of ICA and GAD antibodies and high titre of GAD antibodies are characteristic of patients with insulin deficiency with the clinical features of Type I (insulin-dependent) diabetes mellitus (LADA-type 1). Single antibody positivity and low titre antibodies are markers for LADA-type 2 associated with the clinical and metabolic phenotype of Type II (non-insulin-dependent) diabetes patients.

Adult↗
PubMed2001

Autoantibodies from patients with coeliac disease recognize distinct functional domains of the autoantigen tissue transglutaminase.

The enzyme tissue transglutaminase (tTG) has been recently identified to represent a highly sensitive and specific target of autoantibodies in coeliac disease. To characterize autoantigenic epitopes, we generated novel tTG deletion mutants by polymerase chain reaction, produced radiolabelled fragments by in vitro transcription/translation, immunoprecipitated the mutants using sera from patients with coeliac disease, and related the binding data with putative structural and functional domains of human tTG. We show that tTG antibody positive sera display a heterogeneous autoantibody response covering distinct regions of the molecule. The N-terminal and C-terminal third of tTG, comprising amino acid (aa) 1-281 and aa 473-687, harbour the dominant epitopes (67.4% and 69.4% positive), whereas the catalytic region is of minor antigenicity (22.5% positive). Autoantibodies directed to one, two and three domains were observed in 36.7%, 28.6% and 22.4% of patients, respectively. Comparative analysis revealed the presence of strictly conformational epitopes which were dependent on the N-terminus (aa 1-12) or the intact beta-barrel domains in the C-terminus (aa 473-497, aa 649-687). In conclusion, we here demonstrate for the first time that the humoral autoimmunity is directed against distinct functional tTG domains. The spectrum of autoantibodies indicates that the native folded protein may be the target of autoantibodies.

Adolescent↗
PubMed2001

Dendritic cell immunotherapy in a neuroendocrine pancreas carcinoma.

OBJECTIVE: Metastatic neuroendocrine carcinomas of the pancreas frequently fail to respond to conventional therapies, including radiation and chemotherapy. We therefore tested a dendritic cell-based immunotherapy in an attempt to eradicate residual tumour masses in a patient suffering from a metastatic insulin-producing pancreatic carcinoma. DESIGN: Autologous dendritic cells (DCs) were generated from peripheral blood monocytes in the presence of granulocyte/macrophage colony-stimulating factor, interleukin-4 and tumour necrosis factor alpha. DCs were loaded with tumour-derived lysate (TL), and were delivered by subcutaneous injections in 4-week intervals. RESULTS: Three weeks after first treatment, the patient developed a strong delayed-type hypersensitivity (DTH) skin reaction with an erythema and induration after the challenge with TL-pulsed DCs, which indicates the efficient generation of antigen-specific memory T-cells. Immunohistochemical analysis of skin biopsy demonstrated a strong perivascular and epidermal infiltration by T-helper (CD4 positive) and cytotoxic T cells (CD8 positive). Stimulation with TL revealed a dose-dependent T-cell proliferation with a stimulation index of 1.1-5.7 compared to 1.1-1.4 before vaccination (P < 0.01). Most strikingly, DC-based vaccination was accompanied by a steady decrease of the tumour marker chromogranin A from 2.93 umol/l initially to below the detection limit of 0.15 umol/l within 9 months of therapy. The ultrasound examination revealed a tumour regression of the metastasis in the right lobe of the liver. CONCLUSIONS: Our data indicate that vaccination with tumour lysate-pulsed DCs induced a significant antitumour immune response in a neuroendocrine carcinoma of the pancreas. This approach represents an alternative strategy for the treatment of advanced neuroendocrine carcinomas that are resistant to conventional therapy.

Adult↗
PubMed2001

Modern concepts for the prediction of type 1 diabetes.

Type 1 diabetes results from the destruction of the insulin-producing beta cells of the pancreas. The disease process is thought to be initiated by a complex interaction between genetic and environmental factors leading to a cellular and humoral autoimmune response against beta cell specific components. Over the past decade there has been important progress in identification of several diabetes specific autoantigens. The availability of recombinant antigens, most notably the enzyme glutamic acid decarboxylase (GAD) and the tyrosine phosphatase-like molecule IA-2, made it possible to develop simple, sensitive and specific radioimmunoassays for the detection of autoantibodies on a large scale. It has been shown that the combination of GAD antibodies (GADA) and IA-2 antibodies (IA-2-A) with insulin autoantibodies (IAA) can replace the conventional ICA test. This considerably facilitates screening programmes. Prospective studies in subjects with and without family history of type 1 diabetes conclusively demonstrate that the risk for type 1 diabetes is strongly correlated with the number of positive antibodies. The 5-10-years risk for type 1 diabetes varies from 0-1% in individuals with only one positive antibodies to 62-100% in subjects who were positive for three or more antibodies. Despite the identification of novel genetic markers associated with type 1 diabetes, the major histocompatibility complex, namely HLA-DQ alleles, still represents the strongest genetic risk factor. The analysis of HLA-DQ alleles may be important to discriminate between subjects at high or intermediate risk from antibody positive individuals carrying protective haplotypes. Assessment of the metabolic state using the first phase insulin response to intravenous glucose may provide additional information to predict rapid progression to diabetes. Screening for multiple antibodies is the most specific and sensitive strategy for identifying subject at risk for type 1 diabetes. Second-line genotyping or analysis of the first phase insulin response can serve as useful tool to improve the prediction of type 1 diabetes. The value of additional markers such as isotype specific autoantibodies or T-helper cells subsets measured by ELISPOT assays or FACS remains to be shown.

Autoantibodies↗
PubMed2001

Differential gene expression profile of glucocorticoids, testosterone, and dehydroepiandrosterone in human cells.

Glucocorticoids are the major immunomodulating hormones in the human body. Recently, increasing interest in androgens as immunomodulators has emerged. In particular, Dehydroepiandrosterone (DHEA) has been suggested as beneficial in the treatment of some autoimmune disorders. However, the action and role of testicular and adrenal androgens on human immune cells remains unclear. This is the first study to provide large-scale gene expression data on the action of different steroids (DHEA, glucocorticoids, and testosterone) on human peripheral blood mononuclear cells using the recently developed genomic-scale technology of microarrays. Novel computational tools and techniques such as Principal Component Analysis (PCA) were used for analysis, clustering and visualization. We have demonstrated that each steroid has its distinct gene expression profile, although DHEA and testosterone co-regulated most genes in a similar direction while glucocorticoids frequently regulated the same genes in an opposite direction. Our data suggest an important and a complex regulatory role for androgens on human immune cells that should be considered in androgen replacement or treatment strategies.

Dehydroepiandrosterone↗
PubMed2001

Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases.

UNLABELLED: High prevalence of autoantibodies against glutamic acid decarboxylase (GAD-Ab) in stiff man syndrome (SMS) not only helps diagnosis, but also suggests immune mediated impairment of GABAergic functions. However, the presence of GAD-Ab has also been reported in other neurological syndromes. Therefore the prevalence of GAD-Ab was investigated in SMS, progressive encephalomyelitis with rigidity and myoclonus (PERM), and in other neurological diseases (OND). Serum antibodies against the GAD isoforms, GAD65 and GAD67, were investigated with radioimmunoassays in 13 patients with SMS, nine with PERM, 279 consecutive patients with OND, and in 100 normal controls. RESULTS: Prevalence of GAD65Ab was around 80% in patients with SMS/PERM compared with 5% in patients with OND and 1% in normal controls. Prevalence of GAD67Ab was 60% in SMS/PERM, 2% in patients with OND, and 1% in normal controls. Raised GAD-Ab clustered in an OND subgroup with sporadic progressive ataxia, but not in OND subgroups with recognised neuroimmunological diseases. In conclusion, increased GAD-Ab is neither a non-specific epiphenomenon of neuronal damage nor a common feature of recognised neuroimmunological disorders. In neurological diseases, GAD-Ab may be a pathogenetic agent or a marker for an ongoing autoimmune process, or both.

Antibodies↗
PubMed2001

Osteoporosis screening in systemic lupus erythematosus: impact of disease duration and organ damage.

The aim of the present study was to assess the effects of disease severity and demonstrable organ damage as risk factors for the development of osteoporosis in systemic lupus erythematosus (SLE). Sixty-four SLE patients were included. Mean disease duration was 7.7 +/- 5.7 y. Thirty-two patients had persistent organ damage, defined as SLICC-ACR damage score > or = 1. Disease activity measured by SLAM-2 ranged from 3 to 27. Bone mineral density (BMD) measurements were performed with dual X-ray absorptiometry. In addition, biochemical markers of bone metabolism were studied. BMD was inversely correlated with disease duration, damage score and cumulative glucocorticoid intake, but no correlation was found for current glucocortioid use or with markers of bone metabolism. In a multivariate analysis, body weight, disease duration and damage index fitted best for the prediction of BMD at both lumbar spine and femoral neck. Seven out of 64 patients had osteoporosis according to WHO criteria. In conclusion, severe osteoporosis is uncommon in lupus patients. Disease activity and severity were no major risk factors for loss of BMD in this study, but persistent non-bone-related organ damage was significantly linked to the presence of osteoporosis measured as decreased BMD. Our data suggest that, in addition to patients receiving glucocorticoids, patients with an SLICC-ACR > or = 1 or a disease duration > or = 7 y might benefit from regular monitoring of BMD as secondary prevention of damage.

Adult↗
PubMed2001

Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination.

Recent studies suggest that immunization with autologeous dendritic cells (DCs) pulsed with tumor antigen result in protective immunity and rejection of established tumors in various human malignancies. The objective of this study was to develop a DC vaccination therapy in patients with metastasized medullary thyroid carcinoma (MTC). Mature DCs were generated from peripheral blood monocytes in the presence of granulocyte macrophage colony-stimulating factor, IL-4, and TNFalpha. After loading with calcitonin and carcinoembryonic antigen (CEA) peptide, 2-5 x 10(6) DCs were repeatedly delivered by sc injections. During follow-up (mean, 13.1 months) all patients developed a strong delayed-type hypersensitivity skin reaction caused by perivascular and epidermal infiltration with CD4+ memory T cells and CD8+ cytotoxic T cells. Clinical responses with a decrease of serum calcitonin and CEA were initially documented in three of seven patients. One of these patients had a complete regression of detectable liver metastases and a significant reduction of pulmonary lesions. T-cell response in this patient revealed a calcitonin- and CEA-specific immunreactivity. Our data indicate that vaccination with calcitonin and/or CEA peptide-pulsed DC results in the induction of a cellular, antigen-specific immune response in patients with MTC, leading to clinical response in some patients. Our approach may represent the basis for the development of new therapeutic strategies not only in MTC but also in other endocrine malignancies.

Adult↗
PubMed2001

Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function.

Adipocytes produce the inflammatory cytokine interleukin-6 (IL-6); however, it is not known whether these cells express the IL-6 receptor system, how the secretion of this cytokine is regulated, and whether it has a function within adipose tissue. Using cultured human breast adipocytes, we investigated the expression of IL-6 and its receptor system, the effects of IL-6 on main adipocyte functions, and the regulation of IL-6 secretion by catecholamines and glucocorticoids. In the culture system, immunohistochemistry demonstrated expression of IL-6 and its receptor system, consisting of the ligand-binding IL-6 receptor and the signal-transducing protein gp130, in mature adipocytes, but not in undifferentiated adipocyte precursor cells. In freshly isolated adipocytes, RT-PCR detected messenger ribonucleic acids encoding the above proteins. Chronic incubation of adipocytes with 1 nmol/L IL-6 during adipose differentiation reduced glycero-3-phosphate dehydrogenase (GPDH) activity, a marker of adipocyte differentiation, and triglyceride synthesis to 67 +/- 9% of the basal level (mean +/- SEM; P < 0.05) only on day 21. Incubation of differentiated adipocytes with 10 nmol/L IL-6 for 24 h also resulted in a reduction of GPDH activity to 81 +/- 5% (P < 0.05). On the other hand, 24-h exposure to 10 nmol/L IL-6 increased basal glycerol release by 42 +/- 12% (P < 0.01) and isoproterenol-induced glycerol release by 21 +/- 6% (P < 0.05). The same concentration of IL-6, however, did not alter basal or insulin-stimulated glucose transport. IL-6 secretion was acutely and chronically stimulated by 1 micromol/L isoproterenol (peak of 6.2-fold after 3 h; P < 0.001) and only moderately suppressed by 100 nmol/L cortisol (-36 +/- 10%; P < 0.001). In conclusion, human breast adipocytes release substantial amounts of IL-6 and express IL-6 receptor and gp130. The secretion of IL-6 by adipocytes is strongly stimulated by beta-adrenergic activation and is modestly suppressed by glucocorticoids. IL-6 reduces GPDH activity and stimulates lipolysis, suggesting an autocrine/paracrine role of this cytokine in human adipose breast tissue.

Adipocytes↗
PubMed2001

Soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.

In Hashimoto's thyroiditis, Fas-induced apoptosis is one of the mechanisms leading to cell destruction, whereas thyroid tissue in Graves' disease is prevented from it. The soluble form of the Fas molecule produced by alternative splicing prevents from apoptosis. We measured soluble Fas in the sera of 112 patients with Graves' disease, 21 patients with toxic goiter, and 24 patients with subclinical hyperthyroidism due to suppressive therapy with levothyroxine after near-total resection of the thyroid gland for nodular goiter. Soluble Fas was increased in thyrotoxic patients, toxic goiter, and patients with subclinical hyperthyroidism. Decreased levels of soluble Fas were found in euthyroid patients with Graves' disease after surgery, whereas soluble Fas was normal in euthyroid patients with Graves' disease receiving antithyroid drug treatment and in patients in stable remission. There was a good correlation between soluble Fas with free T(3) (r = 0.6) and free T(4) (r = 0.5). Our results show that soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.

Adult↗
PubMed2000

[Management of diabetic patients in inpatient nursing care facilities in the Heinsberg district].

BACKGROUND AND OBJECTIVE: Little information is available on the diabetes management of elderly people under institutional care. It was therefore aim of this study to assess the quality of diabetes care in this patient group. PATIENTS AND METHODS: In the county of Heinsberg, North Rhine-Westphalia, after agreement in the local public health conference, all 41 nursing homes were addressed and asked to fill out a structured, detailed questionnaire. Thirty-nine institutions participated in the study representing 99.6% of all patients under such care. RESULTS: Out of the 1936 residents 507 had known diabetes mellitus (prevalence 26.2%) with an age-dependent decrease. 37.0% of the diabetic subjects were treated with insulin, 46.7% received oral hypoglycemic agents. Advanced late complications were reported in a minority of patients (3.4% amputations, 13.6% blindness or severe visual impairment, 1.0% hemodialysis). In the majority of patients, the metabolic control was assessed by blood glucose measurement, but only in low frequency. Eye examination within the previous 12 months was reported for only 50.0% of the diabetic subjects. Although the diabetics were frequently seen by their doctors (48.1% > 2 consultations/month, 48.7% with 1 to 2 consultations/month), 30.8% had at least 1 hospital stay during the previous 12 months. Among the 834 nurses with the full dataset only 4 had a special training in diabetology. CONCLUSION: The results of this study indicate that the diabetes management of patients living in nursing homes only partially fulfills the current requirements for diabetes care. There appears to be a particular need to improve the nurses training in diabetes as well as the communication between nursing homes and doctors.

Aged↗
PubMed2000

Classically conditioned responses following repeated insulin and glucose administration in humans.

This paper describes the neural basis and the role of Pavlovian conditioning in the modification of blood glucose and related endocrine parameters after repeated insulin and glucose administration. Pavlovian conditioning requires that conditioned stimulus (CS) and unconditioned stimulus (US) are both detected in the central nervous system (CNS), where the CS-US association takes place. We will therefore elucidate the detectability of insulin and glucose in the CNS. Since current data focus almost exclusively on animals, we conducted a placebo-controlled insulin conditioning experiment in humans (Experiment 1). Compared with the control group with CS-placebo pairings throughout, the experimental group with previous CS-insulin pairings in the acquisition phase showed a conditioned decrease in blood glucose and a trend for a conditioned baseline insulin increase, and an increase in cortisol levels relative to baseline and cumulative number of neuroglycopenic symptoms in the CS-placebo test session. The conditionability of glucose administration also had to be examined; experiments using an arbitrary CS and glucose are extremely rare, even in animals. Glucose is the natural stimulus for endogenous insulin secretion, so studies on cephalic-phase insulin release (CPIR) will be reviewed in this paper. We implemented a placebo-controlled three-group design (Experiment 2): Subjects received either CS-insulin, CS-glucose or CS-placebo pairings during the acquisition. Together, our results demonstrate the conditionability mainly of insulin, but also of glucose effects in healthy humans. The clinical relevance and future research perspectives are outlined with an emphasis on insulin in the brain and its role in learning and memory.

Conditioning, Classical↗
PubMed2000

[Care of elderly diabetics by ambulatory nursing in the Heinsberg region].

OBJECTIVE: The number of elderly people with chronic diseases receiving ambulant nursing care in the German population is continually increasing. However, little information is available on the quality of care of elderly diabetic patients. The aim of this study was to investigate the pattern of care provided for this group by such ambulatory nursing services. PATIENTS AND METHODS: All ambulant nursing services in the county of Heinsberg, North-Rhine-Westphalia, were contacted and asked to answer a standardized questionnaire. 23 of the 24 services participated in the study and provided suitable answers. The study was conducted between October 1998 and March 1999. RESULTS: All services together took care of 337 persons with known diabetes mellitus, of whom 79.6% were female and 20.4% were male. The total diabetes prevalence among all patients was 27.2%. 231 diabetic persons (68.5%) were treated with insulin. Nurses administered insulin to 84.8% of the patients. As expected many diabetics had severe late complications (7.4% amputation, 20.8% blindness, 4.2% renal failure). In the majority of patients, blood glucose was monitored, but only occasionally, whereas urinary glucose was checked in only a few cases. Foot inspection and care were provided regularly. 115 diabetics (34.1%) had at least one hospital stay during the previous 12-months period. CONCLUSION: The results of this study indicate that ambulatory nursing services care mainly for insulin-treated diabetic patients in late stages of the disease. The current organisational structure not meet the requirements of modern diabetes management.

Aged↗