inhibits lymphocyte activation and affects other elements of the immune system, such as cytokine and immunoglobulin production, as well as major histocompatibility complex (MHC) class II and cluster of differentiation (CD)-4 expression (1). In NOD mice, the development of diabetes can be prevented by administration of 1,25(OH) 2 D 3 ( 2 ) , which inhibits lymphocyte activation and restores the altered ratio of CD4/CD8 cells.Vitamin D exerts its genomic action via the nuclear vitamin D receptor (VDR), which shows an extensive polymorphism. The VDR belongs to the steroid receptor super-family and is widely expressed in many cell types, including lymphocytes, macrophages, and pancreatic -cells (3). Four major polymorphic sites have been described within the VDR gene. A polymorphic F o kI site in exon 2 results in an alternative transcription initiation site, leading to a protein variant with three additional amino acids at the amino terminus (4). Polymorphic B s mI and A p aI sites are present in intron 8, and a silent T to C substitution creates a Ta qI restriction site in exon 9. R e c e n t l y, an association of VDR alleles with type 1 diabetes in Indian Asians has been reported (5). We therefore examined the VDR locus on chromosome 12q12-14 as a candidate gene for type 1 diabetes susceptibility in German families using extended transmission disequilibrium testing (ETDT).P a i r-wise transmission distortion testing revealed a strong linkage disequilibrium between "B" and "A" (0.1514 ± 0.0145), between "B" and "T" (-0.1953 ± 0.0148), and between "A" and "T" (-0.1322 ± 0.0144). No significant linkage disequilibrium between F o kI and any of the other sites was detectable. The allele combinations "b aT " (35.3%), "B A t" (29.5%), and "b AT " (16.8%) were most frequent in the analyzed population ( Ta b l e 1 ) .Based on the linkage disequilibrium data, ETDT analysis of the 3 -haplotypes (B s mI /A p aI /Ta qI) showed a signific a n t transmission distortion ( 2 = 18.886, df = 7, P = 0.0086). These observations (Ta b l e 2) were confirmed when looking at the two-locus haplotypes that are part of the B s mI /A p aI /Ta qI

Treatment of lean and obese diabetic patients with LA prevents hyperglycemia-induced increments of serum lactate and pyruvate levels and increases SG.

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We investigated microcirculatory changes in sodium taurocholate (ST)-induced pancreatitis. Groups of rats received as tracer either fluorescein isothiocyanate-dextran or acridine orange intravenously. The microcirculation of the exposed pancreas was observed by use of a video camera attached to an epi-illumination microscope. Vessel diameters and plaques of adherent leukocytes were measured with a digital image-analyzing system. In contrast to 0.4 ml of saline, intraductal infusion of ST (4%, 0.4 ml) induced a constriction of interlobular pancreatic arteries of 79 +/- 2% (P < 0.01) within 2 min. This constriction could not be antagonized by the leukotriene antagonist CGP-35949B. The radical scavengers superoxide dismutase (SOD) and N-(2-mercaptopropionyl)glycine (MPG) prevented the arterial constriction. Constriction of pancreatic arteries was accompanied by a decrease of erythrocyte velocity in the pancreatic capillaries. Flux in the head of the pancreas measured by laser-Doppler velocimetry decreased from 300 +/- 69 to 74 +/- 23 perfusion units (P < 0.01) after 446 +/- 159 s. Subsequently an increase of perfusion values was observed indicating reperfusion phenomena. ST induced leukocyte adherence to the walls of interlobular veins forming plaques constituting 39% of the observed venular cross section within 6 min. The leukotriene antagonist, SOD, or MPG prevented leukocyte adherence. Arterial constriction followed by ischemia-reperfusion and leukocyte adherence to venular endothelium during the reperfusion period represented the sequence of microcirculatory changes in ST-induced pancreatitis. The radical scavengers SOD and MPG prevented arterial constriction and leukocyte adherence to venular endothelium, indicating the involvement of free radicals in the pathogenesis of ST-induced pancreatitis in the rat.

Studies in animal models of spontaneous Hashimoto's autoimmune thyroiditis (HT) show that prophylactic treatment with levothyroxine (LT4) can reduce incidence and degree of lymphocytic infiltration in HT. The aim of the present study was to clarify whether there is a benefit of prophylactic treatment with LT4 in patients with euthyroid HT with respect to the progression of the autoimmune process. Twenty-one patients with euthyroid HT were checked for thyroid function (thyrotropin [TSH], free triiodothyronine [FT3], free thyroxine [FT4]), thyroid volume, antibodies (thyroglobulin [Tg-Ab], thyroid peroxidase [TPO-Ab]), and lymphocyte subsets. Peripheral (PBL) and thyroid-derived lymphocytes (TL) were analyzed by triple color flow cytometry. One-half of the patients with euthyroid HT were treated with LT4 for 1 year (n = 10). The other half (n = 11) were never treated with LT4. TL were obtained by fine-needle aspiration biopsy (FNAB). Thirteen healthy subjects (C) without medical history of thyroid disease served as controls concerning PBL, and patients with non-toxic nodular goiter (NG; n = 10) served as controls concerning TL. Thyroid-derived T-helper cells were found more frequently in euthyroid patients with HT compared to patients with NG (p < 0.01). After 1 year of therapy with LT4, TPO-Abs and B lymphocytes decreased significantly only in the treated group of euthyroid patients with HT (p < 0.05). In contrast, TPO-Abs levels did not change or even increased in untreated euthyroid patients with HT. Thyroid volume did not differ before and after therapy. Prophylactic treatment of euthyroid patients with HT reduced both serological and cellular markers of autoimmune thyroiditis. Therefore, prophylactic LT4 treatment might be useful to stop the progression or even manifestation of the disease. However, the long-term clinical benefit of prophylactic LT4 therapy in euthyroid patients with HT is yet to be established.