Polymorphisms in chromosome region 12q13 and their influence on age at onset of type 1 diabetes.

AIMS/HYPOTHESIS: A complex region covering numerous genes in 12q13 was first associated with type 1 diabetes in the Wellcome Trust Case-Control Consortium (WTCCC) study. Two studies performed in a white population have tested the association of polymorphisms within this region with age at onset of the disease, with seemingly contradictory results. We aimed at replicating three of the strongest signals in a group of patients with early and late disease onset. METHODS: Polymorphisms rs773107, rs2292239 and rs10876864 were genotyped in 444 type 1 diabetic Spanish participants (age at onset 0-65 years) and 861 controls. The influence of single nucleotide polymorphisms (SNPs) on age at onset was tested through stratified and continuous analyses. RESULTS: rs773107 and rs2292239 were significantly associated with the disease, while rs10876864 showed a trend towards statistical significance in the whole population analyses. Comparison of early-onset patients to controls was significant for the three polymorphisms (allelic p < 0.006). Late-onset patients and controls did not reveal statistical differences. Analysis of age at onset in both rs773107 and rs2292239 showed differences between genotypes (p ≤ 0.002), alleles (p ≤ 0.013) and homozygotes for the risk genotype (p ≤ 4 × 10(-4)). Polymorphism rs10876864 showed trends towards statistical significance in the allelic frequencies (p = 0.051) and homozygotes for the risk genotype (p = 0.056). Subjects with risk genotypes had a disease onset between 2 and 5 years earlier than carriers of protective alleles. CONCLUSIONS/INTERPRETATION: We replicate two of the previously studied associations in a Spanish population and find new evidence of the influence of the 12q13 region on age at onset of type 1 diabetes.

Chromosomal region 16p13: further evidence of increased predisposition to immune diseases.

OBJECTIVE: Genome-wide studies have identified the chromosomal region 16p13 in the susceptibility to type 1 diabetes (T1D) and multiple sclerosis (MS). This region includes the CLEC16A/KIAA0350 gene and an adjacent gene, MHC2TA (MHC class II transactivator), previously associated with susceptibility to MS and rheumatoid arthritis (RA). The role of CLEC16A polymorphisms in the pathogenesis of T1D, MS and RA and its relationship with the association reported with a MHC2TA haplotype were investigated. METHODS: CLEC16A (rs2903692/rs6498169/rs11074956) polymorphisms were analysed in 435 patients with MS, 316 with T1D and 600 with RA and in 550 ethnically matched controls. The MHC2TA rs3087456G/rs4774C risk haplotype was studied in an independent RA cohort. RESULTS: rs2903692 conferred a protective effect on patients with T1D, MS and RA. The described association of rs6498169 with MS was replicated in MS and RA cohorts. The effect of the MHC2TA rs3087456G/rs4774C haplotype on RA susceptibility was confirmed, and the haplotype was found to be in negative linkage disequilibrium with the CLEC16A rs2903692A/rs6498169A haplotype. CONCLUSIONS: Associations of CLEC16A polymorphisms with T1D and MS were successfully replicated in a Spanish population. A novel association of rs6498169 with a predisposition to RA was described which is consistent with previous MHC2TA results. These data provide evidence for the influence of variants within this chromosomal region on the development of complex diseases.

Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases.

OBJECTIVE: The STAT4 gene encodes a transcription factor involved in the signaling pathways of several cytokines, including interleukin-12 (IL-12), the type I interferons, and IL-23. Recently, the association of a STAT4 haplotype marked by rs7574865 with rheumatoid arthritis (RA) and systemic lupus erythematosus was reported. The aim of this study was to investigate the role of this STAT4 tagging polymorphism in other immune-mediated diseases. METHODS: The study group comprised 2,776 consecutively recruited Spanish individuals: 575 with RA, 440 with multiple sclerosis, 700 with inflammatory bowel disease, 311 with type 1 diabetes, and 723 ethnically matched healthy control subjects. The STAT4 polymorphism rs7574865 was genotyped using a predesigned TaqMan assay. Allele and genotype frequencies in patients and control subjects were compared by chi-square test. RESULTS: The association of STAT4 polymorphism rs7574865 with RA was validated in patients of Spanish origin (for T versus G, P = 1.2 x 10(-6), odds ratio [OR] 1.59, 95% confidence interval [95% CI] 1.31-1.92), and the association was described for the first time in both clinical forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis (for T versus G, P = 0.006, OR 1.29, 95% CI 1.07-1.55), and in type 1 diabetes mellitus (for T versus G, P = 0.008, OR 1.36, 95% CI 1.07-1.71). In contrast, the genotypic distribution of this polymorphism showed no difference between patients with multiple sclerosis and healthy control subjects (for T versus G, P = 0.83, OR 1.02, 95% CI 0.82-1.28). CONCLUSION: The STAT4 gene is emerging as a novel common risk factor for diverse complex diseases.

Study of the association between the CAPSL-IL7R locus and type 1 diabetes.

AIMS/HYPOTHESIS: In the past few years, several genes outside the MHC region have been described as new susceptibility genetic factors to type 1 diabetes. An association between CAPSL-rs1445898 and type 1 diabetes was reported in a large white population and corroborated in a genome-wide analysis, which also found an association with IL7R, which is located adjacent to CAPSL. The aim of this study was to replicate the aforementioned associations in independent cohorts. METHODS: We analysed two CAPSL (rs1010601 and rs1445898) and three IL7R (rs6897932, rs987106 and rs3194051) polymorphisms. All these single nucleotide polymorphisms (SNPs) were genotyped using TaqMan minor groove binder chemistry in 301 unrelated Spanish type 1 diabetes patients and 646 healthy controls. Additionally, the associated CAPSL SNP rs1445898 was genotyped in a Dutch cohort consisting of 429 type 1 diabetes patients and 720 healthy controls. RESULTS: The homozygous mutant genotype of the CAPSL SNP rs1445898 showed a trend towards a protective effect in the overall Spanish cohort (OR [95% CI] 0.70 [0.44-1.09]; p = 0.09) and in the Dutch cohort (OR [95% CI] 0.74 [0.51-1.05]; p = 0.09). Pooling of both cohorts was performed, yielding a statistically significant difference (Mantel-Haenszel OR 0.71; p = 0.005). This protective effect was significantly different in early-onset vs late-onset Spanish patients (OR [95% CI] 0.26 [0.10-0.65]; p = 0.001). Similarly, in the early-onset subgroup, the homozygous mutant genotype of the IL7R SNP rs6897932 showed a similar protective effect (OR [95% CI] 0.18 [0.02-0.94]; p = 0.02). CONCLUSIONS/INTERPRETATION: In summary, we describe an independent replication of the association between the CAPSL-IL7R locus and type 1 diabetes, especially for early-onset type 1 diabetes patients.

Disfunción tiroidea autoinmunitaria de presentación variable en una paciente tratada con interferón-alfa / Variable presentation of autoimmune thyroid disorder in a patient treated with interferon-alpha?

El interferón-α es el principal agente terapéutico en los pacientes con hepatopatía crónica activa por el virus de la hepatitis C. Las alteraciones tiroideas autoinmunitarias constituyen un efecto secundario frecuente y bien conocido del tratamiento con interferón-α. Presentamos el caso de una paciente con hepatitis C crónica postrasfusional tratada con interferón-α en 2 ocasiones con un intervalo de 7 años. La paciente presentó, tras el primer ciclo de tratamiento con interferón-α, tirotoxicosis por enfermedad de Graves con recurrencia en 2 ocasiones. Después del segundo ciclo de tratamiento, la paciente presentó hipotiroidismo primario autoinmunitario

Interferon-α is the main therapeutic agent in patients with chronic active hepatitis C. Autoimmune thyroid disorders are a frequent and well-known adverse effect of interferon-α. We report the case of a patient with posttransfusion chronic hepatitis C treated with interferon-α on 2 occasions with an interval of 7 years. After the first cycle of interferon-α therapy she presented thyrotoxicosis due to Graves' disease with 2 relapses. After the second treatment, the patient showed hypothyroidism with positive thyroid antibodies

Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: results of the 5-nations trial.

AIMS: The goal of the study was to determine whether continuous subcutaneous insulin infusion (CSII) differs from a multiple daily injection (MDI) regimen based on neutral protamine hagedorn (NPH) as basal insulin with respect to glycaemic control and quality of life in people with Type 1 diabetes. METHODS: The 5-Nations trial was a randomized, controlled, crossover trial conducted in 11 European centres. Two hundred and seventy-two patients were treated with CSII or MDI during a 2-month run-in period followed by a 6-month treatment period, respectively. The quality of glycaemic control was assessed by HbA(1c), blood glucose values, and the frequency of hypoglycaemic events. For the evaluation of the quality of life, three different self-report questionnaires have been assessed. RESULTS: CSII treatment resulted in lower HbA(1c) (7.45 vs. 7.67%, P < 0.001), mean blood glucose level (8.6 vs. 9.4 mmol/l, P < 0.001) and less fluctuation in blood glucose levels than MDI (+/- 3.9 vs. +/- 4.3 mmol/l, P < 0.001). There was a marked reduction in the frequency of hypoglycaemic events using CSII compared with MDI, with an incidence ratio of 1.12 [95% confidence interval (CI): 1.08-1.17] and 2.61 (95% CI: 1.59-4.29) for mild and severe hypoglycaemia, respectively. The overall score of the diabetes quality of life questionnaire was higher for CSII (P < 0.001), and an improvement in pump users' perception of mental health was detected when using the SF-12 questionnaire (P < 0.05). CONCLUSION: CSII usage offers significant benefits over NPH-based MDI for individuals with Type 1 diabetes, with improvement in all significant metabolic parameters as well as in patients' quality of life. Additional studies are needed to compare CSII with glargine- and detemir-based MDI.

NFkappaB1 gene does not affect type 1 diabetes predisposition in a Spanish population.

The chromosomal location of the NFkappaB1 gene on 4q, a region linked to type 1 diabetes (T1D), together with the observed resistance to T1D of NFkappaB1-deficient mice, suggests its potential role as candidate gene increasing diabetes predisposition. Previous association studies in diverse populations yielded inconclusive results. Two polymorphisms in the promoter region of the NFkappaB1 gene have been studied: a functional -94ins/delATTG regulating the gene expression and a very informative CA-repeat microsatellite. A strong association with the latter was reported in British population but could not be replicated in Danish families. No evidence of association was detected for those genetic markers in 270 Spanish T1D patients and 484 healthy ethnically matched controls. Therefore, it seems that this gene plays no major role in T1D predisposition.

Interleukin-10 polymorphisms in Spanish type 1 diabetes patients.

The MHC accounts for half of the genetic susceptibility to type 1 diabetes (T1D). Evidence suggests that an imbalance in Th1/Th2 responses may play a key role in the development of autoimmune diabetes. Since interleukin-10 (IL-10) modulates immune and inflammatory responses and has been implicated in many autoimmune diseases, it seemed interesting to examine whether IL-10 polymorphisms participate in diabetes predisposition. In fact, this is the first association study investigating the role of the IL- 10 polymorphisms in susceptibility to T1D in a Caucasian population. Three promoter polymorphisms (-1082G/A, -819C/T, -592C/A) and two CA-repeat microsatellites (IL-10R and IL-10G at -4 and -1.1 kb) were tested in a case-control study with 294 T1D patients and 574 healthy controls. Our results prove a minor role of IL-10 in the autoimmune diabetes risk, although we found the same association trend with IL-10G(*)12 allele as was previously observed for multiple sclerosis and rheumatoid arthritis.

Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families.

The aims of this study were to estimate the prevalence of major maturity-onset diabetes of the young (MODY) subtypes in Spanish MODY families and to analyze genotype-phenotype correlations. Twenty-two unrelated pediatric MODY patients and 97 relatives were screened for mutations in the coding region of the glucokinase (GCK), hepatic nuclear factor- HNF-1alpha and HNF4alpha genes using PCR-single strand conformation polymorphism and/or direct sequencing. In families carrying GCK mutations, the influence of genetic defects on fetal growth was investigated by comparing the birth weights of 32 offspring discordant for the mutations. Mutations in MODY genes were identified in 64% of the families. GCK/MODY2 mutations were the most frequently found, in 41%: seven novel (R369P, S411F, M298K, C252Y, Y108C, A188E, and S383L) and 2 already described mutations. Four pedigrees (18%) harbored mutations in the HNF-1alpha/MODY3 gene, including a previously unreported change (R271G). One family (4%) carried a novel mutation in the HNF-4alpha gene (IVS5-2delA), representing the first report of a MODY1 pedigree in the Spanish population. The age at diagnosis was prepubertal in MODY2 index patients and pubertal in MODY3 patients. Overt diabetes was rare in MODY2 and was invariably present in MODY3 index patients. Chronic complications of diabetes were absent in the MODY2 population and were present in more than 40% of all relatives of MODY3. Birth weight was lower in the presence of a GCK fetal mutation when the mutation was of paternal origin. The MODY1 patient was diagnosed at 15 yr of age. She developed intermittent microalbuminuria despite good metabolic control, and severe late-onset complications were common within her family. Mutations in the GCK/MODY2 gene are the most common cause of MODY in our population as recruited from pediatric and adolescent index patients. The inheritance of GCK defects by the fetus results in a reduction of birth weight. Clinical expression of MODY3 and MODY1 mutations, the second and third groups of defects found, was more severe, including the frequent development of chronic complications.

Effect of the treatment of Helicobacter pylori infection on gastric emptying and its influence on the glycaemic control in type 1 diabetes mellitus.

Helicobacter pylori (Hp) infection plays a role in gastric emptying (GE) in type 1 diabetic patients and may have implications for glycaemic control. The aim of our study was to investigate this relationship. Gastric emptying was studied in 13 patients with type 1 diabetes and Hp infection. The Hp infection status was assessed by serology and urease breath test (UBT). In addition upper gastrointestinal endoscopy with gastric mucosal biopsy was performed to look for gastritis. A radionuclide-labeled solid meal was used to study GE before and after eradication therapy (amoxicillin, clarithromycin and omeprazole) for Hp infection. All patients were evaluated for autonomic and peripheral neuropathy and were asked for symptoms of gastrointestinal motor dysfunction. Blood glucose levels were determined before the meal and at 30,60,90 and 120 min after the start of the meal. Home blood glucose self-monitoring and HbA(1c) were performed to document glycaemic control during the study. Three months after treatment, five patients were free of Hp infection and were without gastritis (group I: no Hp infection, no gastritis); eight of the patients continued to have gastritis after treatment (group II) and of these eight patients, six had gastritis without Hp infection and two had gastritis plus persistent Hp infection. These last two patients were re-treated with eradication therapy. Patients with gastritis were re-evaluated 6 months after initial treatment; at which time four were now free of gastritis and were added to group I (n=9) while four continual to have gastritis although without Hp infection (group II, n=4). In group I, GE half-time showed an increase (30.6+/-10.3 min vs. 60.2+/-15.4 min; P<0.05) while no change (28.8+/-9.5 vs. 26.9+/-8.7 min; n.s.) was observed in group II. GE half-time was not altered by autonomic and peripheral neuropathy or blood glucose during solid meal test. HbA(1c) did not change significantly after treatment in either groups but the blood glucose levels were more stable in group I compared to group II. A delay in GE was observed with disappearance of gastritis associated to H. pylori infection after eradication treatment in patients with type 1 diabetes. This change in GE could help to stabilise the blood glucose levels in these patients treated with insulin before each meal.

High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus.

The current recommendation for strict metabolic control of type 1 diabetes mellitus requires the administration of supraphysiological doses of insulin, which might result in insulin-mediated stimulation of androgen synthesis, as occurs in insulin-resistant states. At present, the prevalence of hyperandrogenic disorders in women with type 1 diabetes mellitus is unknown. Eighty-five women with type 1 diabetes mellitus were evaluated for symptoms and signs of hyperandrogenism. In 68 of the patients, several serum androgen and hormone concentrations were measured. The polycystic ovary syndrome (PCOS) was defined by the presence of menstrual dysfunction, together with clinical and/or biochemical evidence of hyperandrogenism, and exclusion of other etiologies. Eighteen healthy women, menstruating regularly, served as controls for the androgenic profiles. Thirty-three patients (38.8%) presented hyperandrogenic disorders (16 had PCOS, and 17 had hirsutism without menstrual dysfunction). Type 1 diabetic patients with PCOS presented increased serum total and free testosterone concentrations, and serum androstenedione levels, but had normal serum sex hormone-binding globulin and dehydroepiandrosterone-sulfate levels. Hirsute type 1 diabetic women without menstrual dysfunction presented normal serum androgen levels. There were no significant differences between hyperandrogenic and nonhyperandrogenic type 1 diabetes mellitus women in clinical variables such as the duration of diabetes, age at diagnosis of diabetes, conventional or intensive insulin therapy, mean daily insulin dosage, or metabolic control. In conclusion, women with type 1 diabetes mellitus have a high prevalence of hyperandrogenic disorders, including PCOS and hirsutism.

Improvement in lipid and haemostasis patterns after Helicobacter pylori infection eradication in type 1 diabetic patients.

Helicobacter pylori has been implicated in the cardiovascular risk of diabetic patients. The aim of our study was to investigate whether the Helicobacter pylori infection plays a role in the lipid and haemostasis patterns of type 1 diabetic patients. Twenty nine patients with type 1 diabetes mellitus and H. pylori infection were enrolled (Chlamydia pneumoniae negative). The H. pylori infection status was assessed by serology and urease breath test. In all patients levels of total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, lipoprotein (a) (Lpa) C reactive protein (CRP), fibrinogen, thrombin/antithrombin III complex (TAT), plasminogen activator inhibitor type 1(PAI-1), tissue plasminogen activator (t-PA) and von Willebrand antigen were measured. All patients were evaluated before and after H. pylori eradicating treatment with amoxicillin, clarithromycin and omeprazole. Twenty two patients were eradicated and seven remained infected. In H. pylori eradicated patients, HDL cholesterol increased (59.7+/-18.9 mg/dl vs 65.2+/-15. 9 mg/dl, P << 0.05), after treatment. After H. pylori eradication, the levels of CRP and TAT decreased (48+/-0.7 ng/l vs 3.3+/-0.4 ng/l;P << 0.05), (27.7+/-44.7 microg/ml vs 2.1+/-1.4 microg/ml, P << 0.05), respectively. The decrease in TAT was higher in the group of H. pylori (+) patients with higher levels of TAT (TAT >> 20 ng/ml, 92.8+/-41.6 ng/ml vs 1.9+/-2.0 ng/ml, P << 0.005; TAT 4Eth 20 ng/ml; 10.1+/-5.2 ng/ml vs 2.2+/-0.6 ng/ml, P << 0.05). These changes did not occur in patients without H. pylori eradication. Eradication of H. pylori infection in type 1 diabetic patients modifies some parameters of lipid and haemostasis patterns, (increase of HDL-cholesterol, reduction of Lpa and decrease of CRP and TAT) and so contributes to improvement of cardiovascular risk factors in these patients.

Association of Helicobacter pylori infection with cardiovascular and cerebrovascular disease in diabetic patients.

OBJECTIVE: Infection by Helicobacter pylori has been epidemiologically linked to some extradigestive conditions, including ischemic heart disease. Diabetic patients are an at-risk population for cardiovascular and thrombo-occlusive cerebral disease. The aim of the study was to examine a possible relationship between H. pylori infection and cardiovascular or cerebrovascular disease in diabetic patients. RESEARCH DESIGN AND METHODS: This was a cross-sectional case-control study with 127 diabetic patients (both IDDM and NIDDM). Special emphasis was placed on the detection of clinical macro- and microvascular complications, cardiovascular risk factors, acute phase reactants, and serological markers of increased cardiovascular disease risk. H. pylori infection was assessed through the determination of specific Ig-G titers, measured by a commercial enzyme-linked immunosorbent assay. RESULTS: Coronary heart disease was more prevalent in diabetic patients with than without H. pylori (odds ratio [OR] 4.07; 95% CI 1.21-13.6; P < 0.05). A history of thrombo-occlusive cerebral disease was also more frequent in H. pylori-positive diabetic patients (OR 4.8; 95% CI 1.24-18.51; P < 0.05). Other complications such as peripheral arteriopathy, advanced nephropathy, neuropathy, or retinopathy were no differently distributed according to serological status. Alterations in the levels of the following acute-phase reactants and blood chemistry determinations were significantly more profound in H. pylori-positive diabetic patients: high fibrinogen (P < 0.05), high erythrocyte sedimentation rate (P < 0.001), high triglycerides (P < 0.001), and low HDL cholesterol (P < 0.001). There values were also more deeply altered in H. pylori-positive diabetic patients with a history of coronary heart disease, thrombo-occlusive cerebral disease, or both, when compared with H. pylori-positive diabetic patients without those complications. CONCLUSIONS: Our data indicate a possible association of H. pylori infection and the development of coronary heart disease, thrombo-occlusive cerebral disease, or both, in diabetic patients. The importance of this link is highlighted by the possibility of an effective intervention against H. pylori infection.

Helicobacter pylori infection is markedly increased in patients with autoimmune atrophic thyroiditis.

Infection by viral or bacterial pathogens has been suspected in playing a role in the development of autoimmune thyroid disease. Because Helicobacter pylori might be involved in the development of nongastrointestinal conditions such as rosacea, ischemic heart disease, and diabetes mellitus, we evaluated the prevalence of H. pylori infection in patients with autoimmune thyroid disease. Fifty-nine patients with autoimmune thyroid disease were included: autoimmune atrophic thyroiditis (n=21), Hashimoto's thyroiditis (n=18), and Graves' disease (n=20). Twenty patients with nontoxic multinodular goiter served as controls for nonautoimmune thyroid disease, and 11 patients with Addison's disease served as controls for nonthyroid endocrine autoimmune disease. The levels of anti-H. pylori immunoglobulin G (IgG) were determined, and a radiolabeled urea breath test were performed. The prevalence of H. pylori infection was markedly increased in the patients with autoimmune atrophic thyroiditis (85.7%), compared with the controls with nontoxic multinodular goiter (40%) and Addison's disease (45.4%). Infection by H. pylori resulted in increased levels of gastrin, pepsinogen I, and pepsinogen II in the H. pylori-positive groups, compared with the H. pylori-negative groups. A positive linear regression was found between the levels of microsomal autoantibodies and those of anti-H. pylori IgG in patients with autoimmune atrophic thyroiditis (n=21; r=0.79; p < 0.01). Finally, and although the overall prevalence of H. pylori infection was not increased, the anti-H. pylori IgG levels and the results from the breath test were higher in the patients with Graves' disease and Hashimoto's thyroiditis patients than in the controls. Clearly, the prevalence of H. pylori infection is increased in autoimmune atrophic thyroiditis and results in abnormalities of gastric secretory function. The strong relation between the levels of anti-H. pylori IgG and the levels of microsomal antibodies suggests that H. pylori antigens might be involved in the development of autoimmune atrophic thyroiditis or that autoimmune function in autoimmune atrophic thyroiditis may increase the likelihood of H. pylori infection.

Helicobacter pylori infection and insulin-dependent diabetes mellitus.

Helicobacter pylori is associated with different diseases: duodenal ulcer, rosacea, ischaemic heart disease and gastric cancer. Given the abnormal immunological response and the high prevalence of gastrointestinal symptoms in diabetic patients, we conducted a study on H. pylori prevalence among these patients. We designed a case control study of a population-based cohort. Eighty insulin-dependent diabetes mellitus (IDDM) patients with an average age (24.05 +/- 8.3 years), and 100 control subjects (25 +/- 7.1 years) were selected to verify the seroprevalence of Helicobacter pylori in these populations. One serum sample was obtained from each subject for evaluation of antibodies against Helicobacter pylori, parietal cells (APA) and pancreatic islets cells (ICA). The seroprevalence of H. pylori among IDDM patients aged less than 24 years was significantly higher than among control subjects; the corresponding rate among IDDM aged greater than 24 years was significantly lower than among control subjects. Antibodies against parietal cells (APA) and islet cells (ICA) among H. pylori positive diabetic patients were significantly higher than among H. pylori negative diabetic patients. IDDM patients were subdivided on the basis of the evolutive course of diabetes. Seroprevalence of H. pylori as well as prevalence of ICAs decreased with IDDM duration. Nevertheless, no variation in the prevalence of APAs during the course of diabetes was observed. We observed an association between the seroprevalence of Helicobacter pylori and the duration of IDDM. The seroprevalence of H. pylori and ICA decreased with the evolutive course of diabetes mellitus among IDDM. The prevalence of ICA and APA in IDDM H. pylori positive subjects was higher than among controls.

Massive glycation of protein HC, a low molecular weight lipocalin, in non-diabetic individuals.

Human protein HC is a member of the lipocalin superfamily with unique properties since it carries a covalently bound fluorescent chromophore mediating the linkage of the major part of protein HC to several plasma proteins, with IgA as the dominating complex partner. Native protein HC displays characteristic absorption and fluorescence spectra similar to those of glycated proteins with advanced glycosylation end products (AGEs). In vitro glycation of protein HC induces the formation of fibril aggregates with a corresponding increase of absorption in the visible region of the spectrum. Boronate-affinity chromatography and a novel galactosyltransferase assay indicate that protein HC is modified with residues of glucose exposed in a terminal non-reducing position which is typical of glycated proteins. The glycation level of several isolated batches of protein HC as measured by both assays was around 35%, which represents the highest level described for human plasma-derived proteins from healthy individuals.

Methimazole-induced severe aplastic anemia: unsuccessful treatment with recombinant human granulocyte-monocyte colony-stimulating factor.

Aplastic anemia is a rare but severe complication of thionamide therapy. Although colony-stimulating factors have been used extensively in thionamide-induced agranulocytosis with good results, the same might not apply to aplastic anemia. We present a case of a patient with methimazole-induced aplastic anemia in which, as administration of recombinant human granulocyte-monocyte colony-stimulating factor for a week did not result in an increase in peripheral blood cell count, standard immunosuppressive treatment was needed to restore normal hematopoiesis. The clinical characteristics of this patient are compared with those of previous cases of thionamide-induced aplastic anemia, especially with the only other reported patient in which colony-stimulating factors were used.

[Clinical effectiveness and tolerance of acarbose in the treatment of insulin-dependent diabetic patients (type I)]. / Eficacia clínica y tolerancia de la acarbosa en el tratamiento de pacientes diabéticos dependientes de la insulina (tipo I).

BACKGROUND: Acarbose is a reversible inhibitor of the intestinal alpha-glucosidases, the oral administration of which delays or diminishes the postprandial increase of glucose and insulin. METHODS: A multicentric double-blind clinical trial (11 centers), controlled versus placebo, crossed and randomized, was carried out with 137 insulin-dependent diabetic type I patients treated with diet and insulin. During the first 3 months of the trial the patients received placebo or acarbose randomly. Following one month of wash out with placebo the patients received the inverse medication for 3 more months. During the first month of each phase the patients were given 50 mg three times per day of acarbose or placebo and the two following moths received 100 mg x 3/day. RESULTS: Upon comparison of the two treatments significant statistical differences were found in HbA1 (p = 0.0005) and in postprandial glycemia (p = 0.007). There were differences, although not statistically significant, in the amounts of triglycerides, cholesterol and fasting glycemia. One hundred and two patients referred adverse events, most being gastrointestinal (flatulence, meteorism). CONCLUSIONS: Acarbose may be useful in the treatment of insulin-dependent diabetic type I patients treated with insulin and diet since it reduces the levels significantly of HbA1 and postprandial glucose.

Diabetic foot infections: scintigraphic evaluation with 99Tcm-labelled anti-granulocyte antibodies.

Thirty-eight lesions found by physical and/or radiological examination in 25 patients with long-term diabetes mellitus were studied in order to evaluate the clinical utility of immunoscintigraphy using 99Tcm-labelled anti-granulocyte monoclonal antibodies (MAb BW 250/183) for the diagnosis of infectious pathology in diabetic foot. All the patients underwent three-phase bone scintigraphy with 740 MBq 99Tcm-methylene disphosphonate. Immunoscintigraphy was performed 4 and 24 h after administration of 500 MBq of the labelled antibody by planar selective views. Uptake intensity was scored 0 to 4 (0 = normal, 1 = mildly increased, 2 = moderately increased, 3 = intense, 4 = very intense) when compared with adjacent or contralateral uninvolved bone marrow and soft tissue. Several projections were performed and anatomical references of bone scan were used to determine whether the lesion involved the bone or soft tissue. Definitive diagnoses were 15 osteomyelitis, 14 soft tissue lesions (nine cellulitis and five noninfected ischaemic or trophic wounds), and nine degenerative bone disease. 99Tcm-granulocyte scintigraphy showed increased uptake in seven soft tissue lesions, in four of which exclusively soft tissue involvement was demonstrated by scintigraphy. Only one false negative scintigraphic finding was observed (chronic osteomyelitis). No abnormal anti-granulocyte antibody uptake was observed in degenerative lesions. Based on our observations, immunoscintigraphy with 99Tcm-MAb BW250/183 has a sensitivity of 93% in the diagnosis of osteomyelitis involving diabetic patients' feet. Although it is feasible to distinguish exclusive soft tissue involvement, this is still the main cause of misdiagnosis in current clinical practice.