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.

No abstract

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.

In rats, the hemorrhagic gastric erosions produced by ethanol, and the fatal hemorrhagic hepatic necrosis induced by phalloidin, were significantly reduced by regular somatostatin, but not by derivatives devoid of -SH containing cysteines. These effects of the hormone were abolished in animals which received, in addition, the sulfhydryl blocker n-ethylmaleimide before the toxic chemicals. Thus, somatostatin exhibits organoprotection dependent on endogenous sulfhydryls.

The genetic susceptibility to rheumatoid arthritis is conferred by genes in the human leukocyte antigen (HLA) region on chromosome 6, but additional genes may be involved to determine disease susceptibility. We have studied the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in rheumatoid arthritis. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, SSCP and RFLP in 258 Caucasian rheumatoid arthritis patients and 456 controls. Rheumatoid arthritis patients were characterized by a decreased frequency of homozygotes for the Thr-17 substitution (32% versus 39%) and an overrepresentation of patients heterozygous for the Thr/Ala substitution (54% versus 46%). Gene frequencies for the Ala/Thr substitution differed only marginally from controls. In contrast, analyses of the CTLA4 exon 1 polymorphism with respect to HLA-DRB1*04 revealed significantly more patients with Ala in the homozygous (19% versus 15% controls) or heterozygous state (54% versus 39% controls) and less homozygous for Thr (27% versus 46% controls), with a particular increase of Ala/Ala genotypes among rheumatoid arthritis patients carrying the HLA-DRB1*0401 subtype. Among HLA-DRB1*04 negative rheumatoid arthritis patients, we observed no difference between the allele frequencies of the Ala-17 or Thr-17 substitution.

The presence of fetal cells in a maternal compartment is defined as fetal-maternal microchimerism, which has been detected in thyroids of mothers suffering from autoimmunity. We analyzed the immunohistology of paraffin-embedded thyroid specimen taken at surgery from 49 women with Hashimoto's thyroiditis (n = 25), Graves' disease (n = 15), or nodular or diffuse follicular adenomas (n = 9), whose childbirth history was positive for sons. By fluorescence in situ hybridization we screened for X-chromosome- and Y-chromosome-specific staining and compared the finding with human leukocyte antigen (HLA) DQ types of the mothers and, where available, their offspring. In 23 thyroids we found Y-chromosome-specific staining, which was more frequent in thyroid autoimmune disease (60% Hashimoto's thyroiditis and 40% Graves' disease) than in follicular adenomas (22.2%). There was no significant difference for HLA DQ alleles among women whose thyroids showed Y-chromosome staining and those without. However, a subgroup of all investigated microchimerism-positive mother-child pairs and women with Hashimoto's thyroiditis and Graves' disease more often had the susceptibility alleles HLA DQA1*0501-DQB1*0201 or DQB1*0301. In conclusion, fetal microchimerism is observed in thyroids of mothers with sons, and this is found more frequently in thyroid autoimmune diseases.