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Biomedical subjects

W A Scherbaum

Publications and source records attributed to W A Scherbaum.

At least 37 records · Page 2Linked to original sources
PubMed2004

Immunotherapy and gene therapy of thyroid cancer.

Most forms of thyroid cancer have a good prognosis. Some tumours, however, dedifferentiate and may finally develop into highly malignant anaplastic thyroid carcinomas with a low survival time. Due to their dedifferentiation these tumours are inaccessible to classical therapeutic options as radioiodide treatment or thyrotropin-suppression. Radical surgical revision of the tumour masses is the therapy of choice of patients with limited disease stages including patients with medullary thyroid carcinomas. Despite progress in radiation and chemotherapy regimes, many metastatic forms remain, however, incurable by conventional therapies. During the past few years new developments in immunology have revealed increasing information about the molecular basis of tumour-host interactions. The multitude of information resulting from basic science in cellular immunology, together with the availability of biologic reagents in pharmacological amounts, has opened new venues for the development of immunotherapy approaches for patients with different kind of cancers including thyroid malignancies. This review describes some most important developments in cellular immunotherapies e.g. dendritic cells-based protocols and gene therapy. It also provides a brief overview on the role of cytokines and antibodies in the treatment of advanced thyroid malignancies.

Antibodies, Neoplasm↗
PubMed2003

[Prerenal kidney failure in type 1 diabetes mellitus].

HISTORY AND ADMISSION FINDINGS: A 22-year-old man was admitted in a severely reduced condition. Type 1 diabetes mellitus had been diagnosed when he was 13 years old, hypothyroidism was treated with L-thyroxine for 2 years. For the past 3 years he suffered from repetitive hypoglycemia, combined with vertigo, weakness and low blood pressure. INVESTIGATIONS: He presented with hypotension and hyperpigmentation of the skin. Pathological laboratory results were: serum creatinine 2.5 mg/dl; urea 145 mg/dl; sodium 124 mmol/l; potassium 8.3 mmol/l, HbA (1c) 9.1%. The ECG showed large T waves. Additionally, plasma aldosterone was decreased (<10 ng/l), plasma renin was increased (2404 ng/l), basal serum cortisol was decreased (16.1 microg/l). No increase of plasma cortisol after i. v. stimulation with ACTH (1-24) occurred. Plasma ACTH was increased to 630 pg/ml. Test for adrenal autoantibodies were positive. DIAGNOSIS: Primary adrenal insufficiency with prerenal renal failure. Autoimmune polyglandular syndrome (APS) type II with Addison's disease, diabetes mellitus type 1 and hypothyroidism (Schmidt-Carpenter-Syndrome) were diagnosed. TREATMENT AND COURSE: Initially, the patient was treated with sodium chloride 0.9% i. v. and oral sodium 5 g 4 times/day. In addition, he was given hydrocortisone 100 mg i. v., and then switched to 40 mg per day (20-10-10 mg), fludrocortisone 0.05 mg/ day and L-thyroxine 75 microg/ day orally the clinical condition improved dramatically within 24 hours. Intensified conventional insulin therapy was continued. CONCLUSION: In patients with type 1 diabetes, especially in combination with associated organ-specific autoimmune diseases, autoimmune polyglandular syndrome should be considered and adequately treated with those hormones that are reduced.

Addison Disease↗
PubMed2003

Human adipocytes secrete mineralocorticoid-releasing factors.

Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension, and cardiovascular disease. Overweight and obesity are frequently associated with increased plasma levels of aldosterone. Recent evidence suggests that human fat is a highly active endocrine tissue. Therefore, we tested the hypothesis that adipocyte secretory products directly stimulate adrenocortical aldosterone secretion. Secretory products from isolated human adipocytes strongly stimulated steroidogenesis in human adrenocortical cells (NCI-H295R) with a predominant effect on mineralocorticoid secretion. Aldosterone secretion increased 7-fold during 24 h of incubation. This stimulation was comparable to maximal stimulation of these cells with forskolin (2 x 10(-5) M). On the molecular level, there was a 10-fold increase in the expression of steroid acute regulatory peptide mRNA. This effect was independent of adipose angiotensin II as revealed by the stimulatory effect of fat cell-conditioned medium even in the presence of the angiotensin type 1 receptor antagonist, valsartan. None of the recently defined adipocytokines accounted for the effect. Mineralocorticoid-stimulating activity was heat sensitive and could be blunted by heating fat cell-conditioned medium to 99 degrees C. Centrifugal filtration based on molecular mass revealed at least two releasing factors: a heat sensitive fraction (molecular mass >50 kDa) representing 60% of total activity, and an inactive fraction (molecular mass <50 kDa). However, the recovery rate increased to 92% when combining these two fractions, indicating the interaction of at least two factors. In conclusion, human adipocytes secrete potent mineralocorticoid-releasing factors, suggesting a direct link between obesity and hypertension.

Adipocytes↗
PubMed2003

Change in patients' body weight after 12 months of treatment with glimepiride or glibenclamide in Type 2 diabetes: a multicentre retrospective cohort study.

AIMS/HYPOTHESIS: Our study compared the effects of glimepiride or glibenclamide treatment on body weight over 12 months of treatment in patients with Type 2 diabetes in routine outpatient practice. METHODS: This new retrospective study design used data from physicians in a restricted manner (retrolective). Data from case report forms from 520 patients from 91 randomly selected centres were assessed and covariance analysis performed. RESULTS: The influence of practice and patient characteristics on treatment assignment was low, reflecting the design of randomised controlled trials. Mean weight loss and reduction in body mass index from baseline to study endpoint were greater with glimepiride than with glibenclamide (-2.04+/-3.99 kg vs -0.58+/-3.65 kg, p<0.001; -0.71+/-1.38 kg/m(2) vs -0.20+/-1.28 kg/m(2), p<0.001). Duration of treatment at baseline influenced treatment outcome, but propensity score, sex, age and fasting blood glucose at baseline did not. Both glimepiride and glibenclamide led to decreases in fasting blood glucose (-2.43+/-0.24 mmol/l vs -3.03+/-0.24 mmol/l; p<0.001 vs baseline) and HbA(1c) (-1.23+/-0.09% vs -1.26+/-0.09%; p<0.001 vs baseline). Both treatments were associated with a decrease in serum total cholesterol and low density lipoprotein cholesterol. Triglycerides were lower in the glibenclamide group and high density lipoprotein cholesterol was higher in the glimepiride group only. CONCLUSIONS/INTERPRETATION: Initial treatment of Type 2 diabetes with glimepiride was associated with a significantly greater decrease in body weight and body mass index than treatment with glibenclamide, while providing equivalent glycaemic control.

Blood Glucose↗
PubMed2003

Pancreatic NOD beta cells express MHC class II protein and the frequency of I-A(g7) mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes.

AIMS/HYPOTHESIS: In the NOD mouse model, attempts to show MHC class II expression by pancreatic beta cells were unsuccessful so far. We readdressed this question by analysing I-A(g7) expression in single pancreatic beta cells. METHODS: Single-cell multiplex RT PCR and single-cell immunofluorescence were used to study MHC class II expression in NOD and NOD/SCID beta cells. RESULTS: Pancreatic beta cells from NOD mice express the I-A(g7) protein as well as the corresponding mRNA. The frequency of MHC class II mRNA-expressing beta cells is drastically increased during the progression to overt diabetes. MHC class II protein is accumulated intracellularly, and invariant chain is co-expressed. Beta cells from 9- to 10-week-old NOD/SCID mice express MHC class II at the same low frequency as beta cells from 3-week-old NOD mice. CONCLUSION/INTERPRETATION: NOD beta cells express I-A(g7) and could be a direct target of autoreactive CD4+ T cells. This MHC class II expression is triggered by infiltrating lymphocytes.

Animals↗
PubMed2003

[Pilot study of controlled retrospective analysis (retrolective study design) of care for type 2 diabetics since 1990].

BACKGROUND AND OBJECTIVE: There are few data on the quality of care received by patients with type 2 diabetes under routine conditions and only a few long-term studies that investigated the influence of treatment strategies on the development of clinical endpoints. It was the aim of this study, using retrospectively obtained data, to determine whether it is possible to document over a 10 year period the treatment design and clinical end-points in type 2 diabetics under the care of general practitioners. PATIENTS AND METHODS: General practitioners were randomly selected and informed by independent collaborating monitors about the aim of the study and data documentation. At a second visit by a monitor the completed data forms were audited and entered into a database. Course of treatment was documented by 21 general practitioners, two of them diabetes specialists, for all patients in whom, between 1.1.1990 and 31.12.1993, type 2 diabetes had been diagnosed for the first time (n=455; 251 females, 204 males, mean age 61,5 years). Continuous complete documentation of the course of treatment in the given practice was obtained in 85% of patients over a mean observation period of 8,7 years. 45 myocardial infarcts in 40 patients (9%), 42 strokes in 37 patients (8%), blindness in seven eyes of five patients (1,5%) and 19 amputations (4,2%) were recorded; 72 patients died (15,8%). CONCLUSION: The data of this pilot study indicate that detailed analysis of treatment quality can be obtained in a sizeable cohort, using of a well controlled retrospective (retrolective) study design.

Adult↗
PubMed2003

[Diabetic complications. Micro and macroangiopathic end-organ damage].

Diabetes-associated sequelae lead to a considerable reduction in the quality of life and conspicuous increase in mortality. Subsequent damage becomes manifest in terms of macroangiopathy as coronary heart disease, peripheral arterial occlusive disease, and cerebrovascular insufficiency. Moreover, there is high risk of diabetic nephropathy, neuropathy, and retinopathy entailing the danger of developing chronic renal failure, loss of vision, or diabetic foot syndrome. Although chronic hyperglycemia constitutes a separate risk factor for macro- and microangiopathic complications, associated disorders such as arterial hypertension and hypercholesterinemia increase the mortality risk to a significant extent. Hence, in the past few years, new concepts have been developed for improving the diagnosis, therapy, and long-term care of people with diabetes to include diligent treatment of concomitant risk factors in addition to maintaining near-normal blood glucose levels. This optimized medical care can improve the quality of life and prognosis of patients with diabetes mellitus.

Arterial Occlusive Diseases↗
PubMed2002

[Diabetes mellitus type 2].

SUMMARY: Type 2 diabetes represents the most common form of carbohydrate disorders affecting at least 5% of the population in the industrialized world. In addition to genetic predisposition obesity and a sedentary lifestyle are the main promoters. Recent data clearly suggest that lifestyle intervention in people at increased risk can potently reduce the incidence of the disease. In overt type 2 diabetes, good glycaemic control and aggressive management of associated cardiovascular risk factors may prevent its multiple and costly complications.

Cardiovascular Diseases↗
PubMed2002

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice.

Corticotropin-releasing hormone (CRH) is both a main regulator of the hypothalamic-pituitary-adrenocortical axis and the autonomic nervous system. CRH receptor type 1 (CRHR1)-deficient mice demonstrate alterations in behavior, impaired stress responses with adrenocortical insufficiency and aberrant neuroendocrine development, but the adrenal medulla has not been analyzed in these animals. Therefore we studied the production of adrenal catecholamines, expression of the enzyme responsible for catecholamine biosynthesis neuropeptides and the ultrastructure of chromaffin cells in CRHR1 null mice. In addition we examined whether treatment of CRHR1 null mice with adrenocorticotropic hormone (ACTH) could restore function of the adrenal medulla. CRHR1 null mice received saline or ACTH, and wild-type or heterozygous mice injected with saline served as controls. Adrenal epinephrine levels in saline-treated CRHR1 null mice were 44% those of controls (P<0.001), and the phenylethanolamine N-methyltransferase (PNMT) mRNA levels in CRHR1 null mice were only 25% of controls (P <0.001). ACTH treatment increased epinephrine and PNMT mRNA level in CRHR1 null mice but failed to restore them to normal levels. Proenkephalin mRNA in both saline- and ACTH-treated CRHR1 null mice were higher than in control animals (215.8% P <0.05, 268.9% P <0.01) whereas expression of neuropeptide Y and chromogranin B did not differ. On the ultrastructural level, chromaffin cells in saline-treated CRHR1 null mice exhibited a marked depletion in epinephrine-storing secretory granules that was not completely normalized by ACTH-treatment. In conclusion, CRHR1 is required for a normal chromaffin cell structure and function and deletion of this gene is associated with a significant impairment of epinephrine biosynthesis.

Adrenal Glands↗
PubMed2002

Insulin Lispro in pregnancy--retrospective analysis of 33 cases and matched controls.

AIMS/HYPOTHESIS: To evaluate if the application of Lispro insulin in pregnancy increases the risk for malformations or unusual pregnancy courses. METHODS: Diabetes specialists were contacted in Germany and Austria and asked to report women with diabetes who had been treated with Lispro during pregnancy. Furthermore they were asked to report another pregnant diabetic woman treated with regular insulin with similar HbA1c and age for each Lispro case. Following data were requested: age, first HbA1c in pregnancy and time of analysis, start and duration of Lispro treatment, ultrasound examination, chorionic villi biopsy, amniocentesis, unusual pregnancy courses, standard examination of the new-born for any malformation. Two-sided 95% confidence limits (95%-CI) for risk differences of proportions of malformations or unusual pregnancy courses were calculated. RESULTS: 33 pregnant diabetic women with Lispro and 27 with regular insulin treatment were analysed (mean age 28.3 years (17-41)and 30.1 (19-40); mean HbA1c 6.9% (4.5-10.7) and 6.8% (4.7-9.8), respectively). There were four malformations or unusual pregnancy course (spontaneous abortion; elective interruption because of multiple malformations; heart malformations and hyaline membrane syndrom; premature birth) in the Lispro and one malformation (dyplastic hip) in the regular insulin group. Risk differences in proportions of malformation or unusual pregnancy courses were 8% (95%-CI: - 5% to 21%). CONCLUSIONS/INTERPRETATION: Risk differences for malformations or unusual pregnancy courses were not higher in the insulin Lispro group compared to the controls. However, we observed four malformations or unusual pregnancy courses in the Lispro group. A case-control study is suggested to get a precise risk estimate.

Abnormalities, Drug-Induced↗
PubMed2002

IA-2 autoantibodies restricted to the IgG4 subclass are associated with protection from type 1 diabetes.

The tyrosine phosphatase-like protein IA-2 is a major target antigen for autoantibodies in the preclinical period of type 1 diabetes. In this study, we examined whether immunoglobulin isotypes and IgG subclass specific autoantibodies directed at IA-2 discriminate between children at risk of type 1 diabetes who progressed to diabetes vs. those who remained diabetes-free. IgG1-4, IgA and the IgE-specific IA-2 antibody (IA-2A) were measured by radioligand assays in 50 patients with type 1 diabetes and 41 ICA-positive siblings of patients with type 1 diabetes who were followed for diabetes development. Of 41 siblings, 32 were positive for IA-2A; of these, 59 % had IA-2 IgG1, 59 % IgG4, 16 % IgG3, 9 % IgG2, 16 % IgA and 13 % IgE antibodies. IA-2 IgG1 was the dominant isotype in prediabetic children (n = 14, 86 % positive) and patients with type 1 diabetes (98 % positive) whereas only 7 of 18 (39 %) non-progressors had antibodies of this isotype. In subjects that remained diabetes-free, a significantly higher frequency of IA-2 IgG4 in the absence of IgG1 was observed (50 %) compared to progressors (7 %) and patients with type 1 diabetes (0 %). Life-table analysis revealed that IA-2A restricted to IgG4 correlated with protection from type 1 diabetes (p < 0.003). In contrast, IA-2 IgG2, IgG3, IgE and IgA did not differ significantly between study groups. Our findings suggest that the measurement of IA-2 IgG1 and IgG4 subclass antibodies can serve as surrogate marker to discriminate between antibody positive subjects at high or low risk for rapid development of diabetes.

Adolescent↗
PubMed2002

Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study.

Pioglitazone is a novel oral anti-diabetic agent belonging to the thiazolidinedione class. Pioglitazone has been shown to be effective and well tolerated in the treatment of patients with type 2 diabetes, as it reduces insulin resistance and improves glycaemic control and abnormal lipid profiles. This double-blind, randomised, placebo-controlled study was conducted for further evaluation of the efficacy and tolerability of once-daily administration of pioglitazone monotherapy alongside dietary measures in patients with type 2 diabetes. Following a 10-week washout period, 251 patients received one of three treatment regimens for 26 weeks: placebo + diet (n = 84), pioglitazone 15 mg once-daily + diet (n = 89), or pioglitazone 30 mg once-daily + diet (n = 78). Pioglitazone, both 15 and 30 mg/day, in addition to dietary control, was associated with significant reductions (vs. placebo) in mean levels of both glycosylated haemoglobin (HbA 1C ) and fasting blood glucose (FBG). HbA 1C was reduced by 0.92 % and 1.05 %, respectively, and FBG was reduced by 34.3 and 36.0 mg/dl, respectively, compared with the control group. Pioglitazone at 15 and 30 mg/day significantly reduced postprandial blood glucose levels at all visits (- 163 and - 165 mg/dl/hour, respectively) compared with an increase of 47.7 mg/dl/hour on placebo. The profile and frequency of adverse events were similar in all treatment groups. These results indicate that pioglitazone monotherapy together with dietary control is both effective and safe in patients with type 2 diabetes.

Adult↗
PubMed2002

Regulation of sodium-iodide-symporter gene expression in human thyrocytes measured by real-time polymerase chain reaction.

The sodium-iodide-symporter (NIS) plays a key role in iodination, the first step in the biosynthesis of the thyroid hormones, and is thought to be critically involved in several thyroid disorders associated with altered iodine up-take. To elucidate the pathogenic role of NIS in these diseases a sensitive technique is needed to measure human NIS gene expression. We established a real time RT-PCR for accurate quantification of hNIS mRNA levels based on fluorescence-labelled hybridisation probes in the LightCycler system. Human NIS expression was investigated in primary cultures of human thyrocytes. After optimisation of PCR conditions less than 10 molecules hNIS were detected with high sensitivity, specificity and reproducibility. Under basal conditions NIS expression varied from 83 to 593 copies per 10 6 GAPDH molecules. Stimulation of thyrocytes with TSH (0.1-10 U/ml) or forskolin (0.1-15 microM) results in a dose- and time-dependent up-regulation of NIS expression reaching a maximum at 10 mU/ml TSH (2211 +/- 761 copies) or 10 microM forskolin (1663 +/- 302 copies) after 24 h. In conclusion, we here established a real-time RT-PCR combining the advantages of rapid thermocycling and online detection of NIS mRNA amplification. The sensitive quantification of human NIS mRNA expression offered by this novel technique may improve analysis of hNIS regulation and measurement of NIS mRNA expression in small biopsies.

Biopsy↗