HLA antigens A, B, C, DR and BF were determined in 14 sibling pairs with type I diabetes and in 61 patients without familial risks. Significantly positive associations of the disease with HLA DR3 and DR4 and a negative association with DR2 were found. Positive and negative associations with the various HLA A, B and C antigens (A1, A2, B8, B15, B18, Cw3) are of a secondary nature due to strong genetic coupling with primarily associated DR alleles. Localisation of diabetes-associated genes in the HLA DR region could be demonstrated in two families with HLA recombinations. In both cases the hypothetic disease gene segregated with the HLA DR segment. Joint evaluation of these data in an international series involving 1200 type I diabetics showed furthermore that around 90% of all patients are DR3 and/or DR4 positive, that the highest morbidity risk exists in DR3/4 heterozygosity and that DR4 positive persons usually fall ill before their 20th year of life and frequently in the last 3 months of the year. Allotment of clinical, epidemiological, virological and immunological criteria of type I diabetes to only one of the both risk factors indicates heterogeneous immunopathogenesis of the disease. HLA DR3 predisposes particularly to endocrine autoimmune disease and DR4 to increased virus susceptibility.

Disturbed immune regulation has been postulated to be crucial in the pathogenesis of IDDM and other autoimmune or allergic diseases. We therefore tested the hypothesis of a general bias in the peripheral immune system in patients with recent-onset IDDM or Graves' disease in comparison to healthy control subjects by studying whole blood cultures stimulated with phytohemagglutinin. Cells from IDDM patients (n = 53) produced significantly higher amounts of Thl cytokines γ-interferon (IFN-γ) (P = 0.028) and tumor necrosis factor α (TNF-α) (P = 0.007) than normal control subjects (n = 56), while Th2 cytokine levels (interleukin [IL]-4, IL-10) were similar. Low levels of islet cell antibodies (ICAs) in IDDM patients were associated with high levels of Thl and Th2 cytokines. Antibodies to GAD, ICA512, or insulin did not correlate with individual cytokine profiles. Also, HLA-DQ types did not significantly correlate with either Thl or Th2 cytokine production. Conversely, whole blood cultures from patients with Graves' disease (n = 18) produced significantly less TNF-α and IL-4 than normal subjects (P = 0.001–0.006). However, when the balance between Thl and Th2 cytokine production was analyzed in individuals, the ratio between IFN-γ or TNF-α and IL-4 or IL-10 was clearly biased toward Thl reactivity in patients with IDDM (P = 0.0001), while a dominance of Th2 cytokine production was seen in Graves' disease (P = 0.0001). The ratio of counterregulatory cytokines appeared to be the most reliable marker of the individual disease process. This study provides first evidence of a systemic bias in the immune regulation of humans, which might be either toward cell-mediated immunity (Thl) in IDDM or humoral immunity (Th2) in Graves' disease.

The intercellular adhesion molecule-3 (ICAM-3) has been identified as the third LFA-1 ligand in addition to ICAM-1 and ICAM-2. In this report we have identified circulating forms of ICAM-3 (cICAM-3) in human serum. Using a sandwich ELISA with two monoclonal anti-ICAM-3 Abs, we detected cICAM-3 in concentrations between 40 and 360 ng/ml in all of 112 healthy controls. An analysis of patient sera from 10 different immune-mediated diseases revealed a distinct pattern of expression. Significantly elevated cICAM-3 levels were found in rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barré syndrome, and multiple sclerosis, but not in type I diabetes, Grave's disease, chronic autoimmune thyroiditis, ulcerative colitis, or Crohn's disease. cICAM-3 levels were significantly higher in systemic lupus erythematosus patients with active compared with nonactive disease. Despite their binding to the same integrin receptor, serum levels of cICAM-3 did not correlate with cICAM-1 concentrations in either normal persons or in patients. The majority of patients had either elevated cICAM-3 or cICAM-1 levels but not both. In conclusion, a circulating form of ICAM-3 is present in human sera. cICAM-3 expression is elevated in certain immune-mediated diseases but occurs independently of cICAM-1.

Islet cell antigen (ICA) 69 is a newly-recognized islet cell antigen to which autoantibodies have been observed in prediabetic relatives of patients with insulin-dependent-diabetes mellitus (IDDM). Here we extend the earlier analysis of ICA 69 antibodies to patients with recent-onset IDDM and to patients with other immune-mediated diseases. ICA 69 antibodies were determined by Western blot using an affinity purified recombinant fusion protein of ICA 69 and maltose binding protein. ICA 69 antibody quantities were determined as titres using a titration curve of a standard serum as reference. Mean logarithmic ICA 69 antibody titres were 3.4 (±1.4) in 99 patients with acute IDDM compared to 2.8 (±0.9) in 49 healthy blood donors (p<0.001). A higher mean ICA 69 antibody titre of 4.1 (±0.8) was observed in 16 patients with rheumatoid arthritis in comparison to acute IDDM (p<0.01) and healthy control subjects (p<0.001). The percentage of sera with ICA 69 antibody titres above the 2 SD level of normal subjects was 21% in IDDM, 31% in rheumatoid arthritis and 6% in healthy blood donors. None of the patients with autoimmune thyroid disease (n=20), inflammatory bowel disease (n=9) or multiple sclerosis (n=7) had elevated ICA 69 antibodies. In IDDM, presence of ICA 69 antibodies persisted and the titre remained the same over 18 months of follow-up. The relationship of ICA 69 antibodies to islet cell antibodies (ICA) or insulin autoantibodies (IAA) was tested. The production of ICA 69 antibodies was not associated in diabetic patients with the presence of any of the two other autoantibodies. In conclusion, this study describes ICA 69 antibodies in acute IDDM and finds them to be independent of other islet autoantibodies. In addition ICA 69 is a target of humoural autoimmunity not only in IDDM but also in rheumatoid arthritis.

Treatment with omeprazole plus amoxicillin or clarithromycin resulted in encouraging Helicobacter pylori cure rates in pilot and controlled studies, The present prospective randomized study was designed to compare the efficacy and safety of amoxicillin and clarithromycin as constituents of omeprazole-enhanced antibiotic therapy of H. pylori infection. Fifty patients with active duodenal ulcer disease and histologically and/or culturally confirmed H. pylori colonization of the gastric mucosa were treated with omeprazole (day 1-14: 40 mg twice daily, day 15-42: 20 mg once in the morning). The patients were randomly assigned to receive either amoxicillin (1 g twice daily; group I: n 25) or clarithromycin (500 mg twice daily; group II: n = 25) during the first 2 weeks of treatment. The patients of group I and II had comparable demographic and clinical characteristics. One patient of group I was lost to followup. H. pylori infection was cured in 87.5% of group I and 84.0% of group II (p = 1.00). All ulcers had healed after 6 weeks of omeprazole treatment. Pain relief occurred within the first day of treatment in the majority of patients of both groups (p = 0.89). Minor side effects were recorded in 6 patients of group I and in 4 patients of group II(25 vs. 16%; p = 0.50). In 1 female patient amoxicillin had to be withdrawn after 3 days because of nausea and emesis. In conclusion, 2 weeks of treatment with omeprazole plus amoxicillin or clarithromycin are highly and equally effective regimens to cure H. pylori infection in patients with duodenal ulcer disease.

Omeprazole plus amoxicillin cures Helicobacter pylori infection. The hypothesis was tested that low acidity is a predictor of outcome. Fifty patients- with relapsing or complicated, or both H pylori positive duodenal (n=25) or gastric ulcer (n=25) were randomly treated with either omeprazole 20 mg twice daily plus amoxicillin 1 g twice daily or with omeprazole 40 mg twice daily plus amoxicillin 1 g twice daily over two weeks. After one week of combined treatment, a 24 hour gastric pH measurement was performed in all patients. H pylori cure rate was 67%. Patients who later turned out to be cured had higher pH values during night time and after meals (p<0.05). In an explorative analysis drug compliance, smoking, location of the ulcer (duodenum versus stomach), age, and grade of body gastritis were additional predictors of the outcome. Smoking (p=0.006), compliance (p=0.037), duodenal ulcer disease (p=0.065), and young age (p=0.021) were related to high acidity. In conclusion, the success of eradication treatment with omeprazole and amoxicillin in ulcer patients infected with H pylori depends on intragastric pH. Drug compliance, smoking habits, location of ulcer, age, and activity of body gastritis are other predictors and in part related to intragastric acidity.

METHODS:Fifty patients with relapsing or complicated Helicobacter pylori positive duodenal (n = 41) or gastric ulcer disease (n = 9) and failure of a combined treatment with omeprazole plus amoxycillin to eradicate H. pylori infection were re-treated with either oral triple therapy (bismuth subsalicylate, metronidazole, tetracycline) plus ranitidine [group I: n = 22] or high-dose omeprazole (40 mg b.d. to t.d.s.) plus amoxycillin (1 g t.d.s.) [group II: n = 28].RESULTS:Patients of group I and II had similar demographic and clinical characteristics. The overall proportion of eradication of H. pylori infection was 81.8% in group I and 78.6% in group II (P = N.S.) as judged from negative bacterial findings by means of an urease test, specific culture and histology after modified Giemsa stain. Ulcer healing was observed in all patients after a maximum duration of 10 weeks. Ten patients on triple therapy and only one patient on omeprazole plus amoxycillin (45.5% vs. 3.6%; P < 0.001) complained of side effects without necessity of discontinuation of the study medication in either group. Twenty patients (group I: n = 10; group II: n = 10) with relapsing duodenal ulcer disease and successful cure were prospectively followed for one year without any evidence of ulcer relapse or H. pylori re-infection.CONCLUSION:Oral triple therapy plus ranitidine or high-dose omeprazole plus amoxycillin remain highly effective in eradicating H. pylori infection in patients with peptic ulcer disease and treatment failure of omeprazole/amoxycillin, but the omeprazole enhanced antibiotic monotherapy seems to be superior with regard to side effects. Thus, high-dose omeprazole/amoxycillin is recommended as the treatment of first choice in these selected patients. Triple therapy should be reserved for patients intolerant of amoxycillin.

OBJECTIVE - To investigate the effect of an antiedematous therapy with the histamine antagonist ketotifen on beta-cell function in late prediabetes.RESEARCH DESIGN AND METHODS - in a randomized double-blind placebo-controlled study, ketotifen was administered for 3 months to 9 islet cell antibody positive (ICA+) prediabetic patients with a first-phase insulin response (FPIR) below the 2.5th percentile to preserve residual beta-cell function. Patients were followed by intravenous glucose tolerance tests (IVGTTs) every 4-6 weeks for determination of FPIR, HbA1, ICAs, and insulin autoantibodies. In 5 patients, the immune activation state was followed by determination of serum levels of tumor necrosis factor-alpha (TNF-alpha), beta2-microglobulin, and C-reactive protein (CRP).RESULTS - Seven of nine patients developed diabetes within one year of follow-up. Irrespective of treatment with ketotifen, a slow and linear decline (P < 0.05) of 1 + 3-min insulin values was observed in sequential IVGTTs in those 7 patients who developed insulin-dependent diabetes mellitus (IDDM) during follow-up. The 2 other patients showed wide fluctuations of the insulin response with a threefold increase of initial insulin levels. HbA, did not correlate with FPIR. Fasting blood glucose increased significantly during the study (P < 0.05). Individual levels of serum TNF-alpha, CRP, and beta2-microglobulin did not change during the study.CONCLUSIONS - The study could not demonstrate preservation of beta-cell function by ketotifen in the late stage before manifestation of clinical diabetes. Manifestation is preceded in the last 6 months by a steady loss of the FPIR without rapid deterioration immediately before diagnosis and without signs of increased immune activity.

The purpose of the present study was to investigate the Helicobacter pylori eradication potency of combined amoxicillin-omeprazole treatment in patients with duodenal ulcer disease and to compare the efficacy of two omeprazole and amoxicillin doses concerning H. pylori eradication, ulcer healing, pain relief, and safety. Ninety patients with active H. pylori-positive (culture and/or histology) duodenal ulcer disease were randomly treated with either omeprazole 20 mg twice a day plus amoxicillin 1 g twice a day (group I, N = 30), omeprazole 40 mg twice a day plus amoxicillin 1 g twice a day (group II, N = 30), or omeprazole 40 mg twice a day plus amoxicillin 1 g three times a day (group III, N = 30) over two weeks, followed by ranitidine at bedtime for another four weeks. The overall proportion of H. pylori eradication was 83% and of ulcer healing 92% without statistically significant differences between the study groups. Complete pain relief occurred after a median of one day in all groups. Six patients complained of side effects during the therapy phase, which led to therapy discontinuation in one female patient. In conclusion, omeprazole plus amoxicillin is a highly effective and well-tolerated therapy regimen to eradicate H. pylori in duodenal ulcer disease. In addition, the results suggest that there is no clear dose-response relation between the dosages of omeprazole and amoxicillin used in this study on the one hand and the H. pylori eradication rates on the other.

The hypothesis was tested that islet autoimmunity is induced by ongoing islet cell destruction in subjects with susceptibility genes HLA-DR 3 and/or DR 4. Sixty-one patients with confirmed chronic pancreatitis were analysed, 30 of whom expressed HLA-DR 3 and/or DR 4. Electron microscopy studies in 10 patients showed that the inflammatory process also affected islets, as recognisable from islet cell lysis, intrainsular fibrosis and immune cell infiltrates. None of the sera tested contained any of three markers of islet autoimmunity, ICA, IAA or GAD antibodies. A correlation was seen between the loss of exocrine function, as determined by the ALTAB-test, and of beta-cell function, as determined by the C-peptide response to i.v. glucagon. However, there was no preferential loss of beta-cell function in patients with HLA-DR 3 and/or DR 4. We conclude that islet cell destruction occurs during chronic pancreatitis, but does not trigger islet autoimmunity, even in the presence of HLA-DR 3 and/or DR 4.

Objective: To compare the medium-term clinical course of duodenal ulcer disease after attempting to cure Helicobacter pylori infection with either omeprazole (OME) plus amoxycillin (AMOX) or triple therapy plus ranitidine. Design: Patients treated with OME/AMOX or triple therapy plus ranitidine in a prospective, randomized and controlled study were followed for 1 year. Patients and methods: A total of 40 patients with active duodenal ulcer disease and H. pylori infection of the gastric mucosa were randomly treated with either OME 26 mg twice daily plus AMOX 500 mg four times daily for 2 weeks (group 1) or with bismuth subsalicylate 600 mg, metronidazole 400 mg, tetracycline 500 mg, all three times daily, and ranitidine 300 mg for 2 weeks (group 2). Study medication was followed in both groups by a 4-week treatment course of ranitidine 300 mg. After complete ulcer healing, patients were re-investigated clinically and with a C-13-urea breath test after 6 months. A clinical and endoscopic follow-up, including assessment of H. pylori infection by urease test, culture and histology, and a C-13-urea breath test, was carried out after 1 year, or earlier, if symptoms recurred during the follow-up period. Results: One patient from each group was lost to follow-up. H. pylori infection was cured in 15 out of 19 patients in group 1 (78.9%) and in 16 out of 19 patients in group 2 (84.2%). H. pylori reinfection was detected in one asymptomatic patient in group 2 after 1 year; 30 patients remained free of infection. Ulcer relapses were observed on endoscopy in three out of four patients with ongoing H. pylori infection following OME/AMOX treatment and in all three patients in whom triple therapy failed to cure the bacterial infection (P>0.1). Duodenal ulcer disease remained in remission in all patients with successful H. pylori eradication compared with a 1-year ulcer relapse rate of 85.7% (six out of seven) in H. pylori-positive patients (P<0.01). All patients with ulcer relapse were re-treated following crossover. H. pylori was eradicated in one out of three patients by triple therapy and by OME/AMOX in a further three patients. Conclusions: OME/AMOX seems to be equally as effective as triple therapy plus ranitidine in eradicating H. pylori and healing duodenal ulcer disease. The medium-term natural course of ulcer disease is strongly dependent on the presence or absence of H. pylori and is independent of the type of therapy used to eradicate the bacterial infection.

In this note is recommended a unified nomenclature for allotypes and variants of human complement factor B, which was approved by the Nomenclature Committee of the International Union of Immunological Societies (IUIS).

In 110 patients with unknown Helicobacter pylori status and without anti-bacterial treatment submitted for routine endoscopy of the upper gastrointestinal tract biopsies were taken from the antral and body mucosa, which were assessed for H. pylori colonisation and/or gastritis by an urease test (Jatrox H. p.-Test), microscopy after methylene-blue staining of a mucosal smear, specific culture and histology (stains: haematoxylin & eosin and Warthin-Starry). In addition, a simplified 13C-urea breath test was validated. A complete set of data was available from 104 patients (64 women - 40 men, median of age: 55 years [range: 17-92 years], H. pylori positive histologically and/or culturally [goldstandard]: n = 67). The test criteria sensitivity, specificity, positive and negative predictive value were calculated to be 100%/100%/100%/100% for the urease test, 76.1%/100%/100%/69.8% for microscopy of a mucosal smear, and 92.5%/97.3%/98.4%/88.1% for 13C-urea breath test (two-point measurement). Statistical analysis demonstrated highly significant (p < 0.0001) correlations between the reaction velocity of the urease test, the histologically visible degree of Helicobacter pylori colonisation and the differences of the delta-values of the 13C-urea breath test on the one hand and between grade and activity of gastritis as well as between the gastritis and activity scores, respectively, and the semi-quantitatively categorized results of the urease test, the histological degree of H. pylori colonisation and the 13C-urea breath test on the other hand.(ABSTRACT TRUNCATED AT 250 WORDS)

In this note is recommended a unified nomenclature for allotypes and variants of human complement factor B, which was approved by the Nomenclature Committee of the International Union of Immunological Societies (IUIS).

Insulin-dependent diabetes was observed in a woman, aged 29, 4 years after transplantation of bone marrow from her HLA-identical brother with insulin-dependent diabetes. Both had classic symptoms and insulin dependency from onset. At diagnosis of diabetes the recipient was positive for high-titre islet cell antibodies (ICA) whereas she had been ICA negative before transplantation. Chromosomal analyses verified that all circulating leucocytes were of male donor type. These findings suggest transfer of insulin-dependent diabetes by bone marrow cells and confirm the immune nature of the disease.

Serum levels of recently discovered circulating forms of adhesion molecules, ICAM-1 and L-selectin, were found to be elevated in IDDM patients and in subjects at risk for developing IDDM compared with 100 normal, nondiabetic blood donors. Both adhesion molecules were determined by sandwich ELISA. Serum concentrations of either clCAM-1 or cL-selectin were >2SD of normal mean in 10 of 14 recent-onset IDDM patients (P < 0.05). Serum levels of clCAM-1 and cL-selectin did not correlate. In first-degree relatives, elevated adhesion molecule levels were observed in the 6 ICA+ individuals and in the ICA- individuals all (n = 14) with a genetic risk of IDDM (sharing HLA-DR3 and/or -DR4 with the diabetic relative) but not in the HLA-DR3- and/or -DR4- relatives (n = 13). We conclude that elevated clCAM-1 and cL-selectin levels occur independently of ICA status and probably reflect ongoing immune processes in recent-onset IDDM patients and first-degree relatives at risk for IDDM.