Autoimmunity in gestational diabetes mellitus in Sardinia: a preliminary case-control report

<p>Abstract</p> <p>Background</p> <p>We previously reported a high prevalence (22.3%) of gestational diabetes mellitus (GDM) in a large group of Sardinian women, in contrast with the prevalence of Type 2 diabetes. Sardinia has an unusual distribution of haplotypes and genotypes, with the highest population frequency of HLA DR3 in the world, and after Finland, the highest prevalence of Type 1 diabetes and Autoimmune-related Diseases. In this study we preliminarily tested the prevalence of serological markers of Type 1 diabetes in a group of Sardinian GDM patients.</p> <p>Methods</p> <p>We determined glutamic decarboxylase antibodies (anti-GAD65), protein tyrosine phosphatase ICA 512 (IA2) antibodies (anti-IA2), and IAA in 62 GDM patients, and in 56 controls with matching age, gestational age and parity.</p> <p>Results</p> <p>We found a high prevalence and very unusual distribution of antibodies in GDM patients (38.8%), the anti-IA2 being the most frequent antibody. Out of all our GDM patients, 38.8% (24 of 62) were positive for at least one antibody. Anti-IA2 was present in 29.0 % (18 out of 62) vs. 7.1% (4 out of 56) in the controls (P < 0.001). IAA was present in 14.5% (9 out of 62) of our GDM patients, and absent in the control subjects (P < 0.001). Anti-GAD65 was also present in GDM patients, with a prevalence of 3.2% (2 out of 62) while it was absent in the control group (P = NS). Pre-gestational weight was significantly lower (57.78 ± 9.8 vs 65.9 ± 17.3 <it>P </it>= 0.04) in auto-antibodies- positive GDM patients.</p> <p>Conclusion</p> <p>These results are in contrast with the very low prevalence of all antibodies reported in Italy. If confirmed, they could indicate that a large proportion of GDM patients in Sardinia have an autoimmune origin, in accordance with the high prevalence of Type 1 diabetes.</p

Genetic loci linked to Type 1 Diabetes and Multiple Sclerosis families in Sardinia

<p>Abstract</p> <p>Background</p> <p>The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis.</p> <p>Methods</p> <p>To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic.</p> <p>Results</p> <p>In T1D, aside from the HLA locus, we found four regions showing a lod-score ≥1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score ≥1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5).</p> <p>Conclusion</p> <p>This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.</p

Importanza della tecnica di trapianto recettoriale di ratto su oociti di Xenopus laevis per lo studio del recettore Gaba (a)

Dottorato di ricerca in neuroscienze. Coordinatore Gian Luigi Gessa. Tutore Giovanni BiggioConsiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7, Rome; Biblioteca Nazionale Centrale - P.za Cavalleggeri, 1, Florence / CNR - Consiglio Nazionale delle RichercheSIGLEITItal

Enhancement of acetylcholine release by flumazenil in the hippocampus of rats chronically treated with diazepam but not with imidazenil or abecarnil.

The effects of long-term treatment (three times a day for 3 weeks) with pharmacologically active doses of the novel anxiolytics and anticovulsants abecarnil (0.5 mg/kg, IF) and imidazenil (0.5 mg/kg, IF) on basal hippocampal acetylcholine release in freely moving rats were compared with those of diazepam (3 mg/kg, IF). Challenge doses of diazepam, abecarnil, and imidazenil decreased the extracellular acetylcholine concentration in the hippocampus by the same extent in animals chronically treated with the respective drug or vehicle. Moreover, the abrupt discontinuation of long-term treatment with diazepam, abecarnil, or imidazenil failed to affect hippocampal acetylcholine release during the first 5 days of withdrawal. In contrast, the acute administration of the benzodiazepine receptor antagonist flumazenil (1 mg/kg, IP) 2 days after diazepam withdrawal elicited a marked increase (65%) in acetylcholine release in the hippocampus. Flumazenil failed to induce the same effect 5 days after diazepam withdrawal or 2 or 5 days after discontinuation of long-term treatment with abecarnil or imidazenil. These results indicate that (i) the inhibitory effects of full (diazepam), partial (imidazenil), and selective (abecarnil) benzodiazepine receptor agonists on acetylcholine output in rat hippocampus are not affected by repeated drug administration; (ii) discontinuation of long-term treatment with each type of agonist does not affect hippocampal cholinergic mechanisms;; and (iii) flumazenil increases acetylcholine release only in the hippocampus of rats chronically treated with diazepam. Together, these data further differentiate the pharmacology of benzodiazepine receptor full agonists from that of partial and selective agonists

mtDNA control region and D-HPLC analysis: a method to evaluate the mating system in <i>Syngnathidae</i> (<i>Teleostei</i>)

Mitochondrial DNA (mtDNA) has been used extensively in animals for phylogenetic and population studies but it has been applied only occasionally to mating systems analysis, where nuclear markers are usually preferred. We used denaturing-high performance liquid chromatography (D-HPLC) to detect mitochondrial DNA polymorphisms to assess the genetic mating system in Syngnathus abaster. Our study of ten pregnant males, revealed polygyny in 30% of the males, who carried embryos originating from multiple females. In addition, 30% of the pregnant males carried embryos with the same mitochondrial haplotype. This is not sufficient to demonstrate polyandry but allows a rapid selection and a reduced sample size for further studies. In conclusion, the proposed technique is time- and cost-effective, allows the certain identification of polygyny and provides useful information to study polyandry

Inhibition of basal and stress-induced dopamine release in the cerebral cortex and nucleus accumbens of freely moving rats by the neurosteroid allopregnanolone

The neurosteroid allopregnanolone is a potent and efficacious modulator of gamma-aminobutyric acid (GABA) type A receptors. The effects of intracerebroventricular injection of allopregnanolone (5 to 15 mu g in 5 mu l) on basal and stress-induced changes in the extracellular concentrations of dopamine were investigated by microdialysis in various brain areas of freely moving rats and compared with those of the benzodiazepine midazolam (1 to 10 mu g in 5 mu l). Allopregnanolone reduced (by a maximum of 65 to 75%) basal dopamine content in the prefrontal cortex and nucleus accumbens in a dose-dependent manner, but had no effect on dopamine output in the striatum. Allopregnanolone (10 to 15 mu g) also completely prevented the increase in extracellular dopamine concentrations in the nucleus accumbens and cerebral cortex induced by foot-shock stress. Midazolam reduced basal dopamine content in all three brain regions studied as well as the stress-induced increase in dopamine content in the nucleus accumbens and cerebral cortex with a greater potency than allopregnanolone. These results suggest that endogenous neurosteroids may participate in the GABAergic modulation of dopaminergic transmission in the rat cerebral cortex and nucleus accumbens, two brain areas which are important in the regulation of emotional processes. These agents do not appear to affect striatal dopaminergic transmission which modulates motor function

Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes

There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (F = 2.4 × 10-4) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity