Cytokine response in patients with chronic infections caused by Staphylococcus aureus strains and diversification of their Agr system classes.

This study aimed to describe the levels of circulating cytokine levels produced by Th lymphocytes (IFN-γ, IL-4, IL-10, IL-17A), as well as the levels of cytokines produced by monocytes/macrophages (TNF-α, IL-1ß, IL-12), in patients with chronic infections caused by Staphylococcus aureus strains, particularly in the context of the diversification of their Agr system classes. The studies were conducted on adult patients, including 50 patients with chronic suppurative dermatitis, 40 patients with chronic infections of the upper respiratory tract and 25 healthy individuals (control group). Blood serum cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). S. aureus was detected in cultures of suppurative dermal exudates or of pharyngeal smears. Classes of Agr systems in the S. aureus strains were identified using polymerase chain reaction (PCR). In both groups of patients, on average, levels of IFN-γ were doubled, while levels of IL-17A were increased by 2.5-fold, which, however, was not accompanied by increased levels of TNF-α or IL-12. The data indicate that the development of S. aureus infection among the studied patients was linked to an impoverished cytokine response of monocytes/macrophages, while that induced by the pathogen lymphocytes Th17/Th1 may be responsible for promotion of the chronic inflammatory response. In parallel, no quantitative or qualitative differences were disclosed between cytokine responses manifested by subgroups of patients infected with S. aureus strains belonging to class IV Agr, as compared to patients infected with strains of classes I to III Agr. Nevertheless, in the patients, strains belonging to class IV Agr prevailed, which points to the preferential relationship between the class and the pathogenicity of S. aureus.

Protective effect of oral Lactobacilli in pathogenesis of chronic periodontitis.

UNLABELLED: The study aimed at evaluation of IL-17 and TNF-α levels and at analysis of oral lactobacilli in patients with chronic periodontitis (CP) in the context of their protective effect on a course of the disease. The study was conducted on 14 patients with moderate CP (group 1) and 14 patients with severe CP (group 2). Control group (group 3) included 15 individuals with gingivitis. Levels of IL-17 and TNF-α were estimated using an ELISA. Strains of Lactobacillus were isolated in Rogosa agar, H(2)O(2)-production was determined in TMB-Plus agar. In group 1, the mean content of IL-17 was 19.66±6.1 pg/ml, and that of TNF-α was 4.95±0.91 pg/ml, in group 2 IL-17 content was 34.7±6.65 pg/ml, and that of TNF-α was 6.94±0.78pg/ml, in group 3 content of IL-17 was 0.65±0.58pg/ml, content of TNF-α was 0.17±0.14pg/ml. Analysis of lactobacilli manifestation in the control group and in the group with moderate CP in most of the persons demonstrated presence of H(2)O(2)-producing Lactobacillus, while in the group with severe CP presence of Lactobacillus was demonstrated in only 5 patients. CONCLUSIONS: development of CP is linked to persistent excessive cytokine response of Th17 cells, the intensity of which may affect clinical course of the disease; in parallel, H(2)O(2)-producing oral lactobacilli may prevent against progression of CP, most probably reducing secretory activity of Th17 cells and restricting growth of periodontopathogens.

Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33.

Polymorphic markers within the CTLA4 gene on chromosome 2q33 have been shown to be associated with type 1 diabetes. Therefore, a gene responsible for the disease (IDDM12) most likely lies within a region of <1-2 cM of CTLA4. To define more precisely the IDDM12 interval, we genotyped a multiethnic (U.S. Caucasian, Mexican-American, French, Spanish, Korean, and Chinese) collection of 178 simplex and 350 multiplex families for 10 polymorphic markers within a genomic interval of approximately 300 kb, which contains the candidate genes CTLA4 and CD28. The order of these markers (D2S346, CD28, GGAA19E07, D2S307, D2S72, CTLA4, D2S105, and GATA52A04) was determined by sequence tagged site content mapping of bacterial artificial chromosome (BAC) and yeast artificial chromosome (YAC) clones. The transmission disequilibrium test (TDT) analyses of our data revealed significant association/linkage with three markers within CTLA4 and two immediate flanking markers (D2S72 and D2S105) on each side of CTLA4 but not with more distant markers including the candidate gene CD28. Tsp analyses revealed significant association only with the three polymorphic markers within the CTLA4 gene. The markers linked and associated with type 1 diabetes are contained within a phagemid artificial chromosome clone of 100 kb, suggesting that the IDDM12 locus is either CTLA4 or an unknown gene in very close proximity.

Giant cell arteritis is more prevalent in urban than in rural populations: results of an epidemiological study of primary systemic vasculitides in Germany.

OBJECTIVE: To investigate the period prevalences of primary systemic vasculitides (PSV) in urban and rural populations in northern and southern Germany in 1994. METHODS: Questionnaires were sent to all hospital departments, all physicians, health insurance providers and pension funds, reference laboratories for autoimmune diseases, and death registries in two catchment areas in northern and southern Germany (combined population 875 983) to identify patients with PSV between 1 January and 31 December 1994. Each catchment area encompassed both an urban and a rural area. Each case was re-evaluated by the authors by applying the definitions of the 1992 Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis. RESULTS: A total of 180 PSV patients were identified. The overall prevalence of PSV was 216 cases per 1 000 000 inhabitants (95% confidence interval (CI) 173-259) in northern Germany vs 195 (95% CI 153-236) in southern Germany. The prevalence of PSV was two-fold higher in women than in men, and five-fold higher in people aged > or =50 yr than in people aged <50 yr. The most frequent type of PSV was giant cell arteritis (GCA), with 87 cases per 1 000 000 in northern and 94 in southern Germany, followed by Wegener's granulomatosis, with 58 and 42 cases respectively. In the population aged > or =50 yr the prevalence of GCA was 240 per 1 000 000 in northern and 300 in southern Germany. In both northern and southern Germany the prevalence of GCA in this older population was significantly higher in urban than in rural populations (355 per 1 000 000 vs 115 in northern Germany (P<0.01) and 395 vs 220 (P<0.05) in southern Germany). The relative risk for the older urban population having GCA was 2.25-fold higher (95% CI 1.4-3.6) than in the rural population, and for the female population it was 4.7-fold higher in the urban than in the rural areas (95% CI 2.4-9.3). CONCLUSION: In both northern and southern Germany, GCA was significantly more prevalent in urban than in rural populations, especially among people aged > or =50 yr and in women. It remains unclear whether this disparity was due to underdiagnosis of GCA in the rural regions associated with differences in the German health-care system in cities vs rural areas. Further studies must examine the role of (chronic) exposure to the environmental factors characteristic of cities.

Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups.

Linkage disequilibrium (association) analysis was used to evaluate a candidate region near the CTLA4/CD28 genes using a multi-ethnic collection of families with one or more children affected by IDDM. In the data set unique to this study (Spanish, French, Mexican-American, Chinese and Korean), the transmission/disequilibrium test (TDT) revealed a highly significant deviation for transmission of alleles at the (AT)n microsatellite marker in the 3' untranslated region (P = 0.002) and the A/G polymorphism in the first exon (P = 0.00002) of the CTLA4 gene. The overall evidence for transmission deviation of the CTLA4 A/G alleles is also highly significant (P = 0.00005) in the combined data set (669 multiplex and 357 simplex families) from this study and a previous report on families from USA, Italy, UK, Spain and Sardinia. Significant heterogeneity was observed in these data sets. The British, Sardinian and Chinese data sets did not show any deviation for the A/G polymorphism, while the Caucasian-American data set showed a weak transmission deviation. Strong deviation for transmission was seen in the three Mediterranean-European populations (Italian, Spanish and French) (P = 10(-5)), the Mexican-American population (P = 0.002) and the Korean population (P = 0.03). These results suggest that a true IDDM susceptibility locus (designated IDDM12) is located near CTLA4.

Impaired exocrine pancreatic function in diabetics with diarrhea and peripheral neuropathy.

Exocrine pancreatic insufficiency has been observed in some diabetics with peripheral neuropathy and diarrhea. Several mechanisms may be responsible for this insufficiency: (1) pancreatic atrophy, (2) disruption of the cholinergic enteropancreatic reflexes, or (3) elevated serum levels of peptides such as glucagon and pancreatic polypeptide which are known to inhibit pancreatic exocrine secretion. To clarify the mechanism(s) involved in this exocrine pancreatic impairment, we studied 10 diabetics with diarrhea and peripheral neuropathy. Their results were compared to those of eight normal volunteers. Each subject underwent a standardized pancreatic function study which assessed nonstimulated secretion, the response to intrajejunal infusion of a mixture of amino acids, and the output following intravenous administration of secretin and cholecystokinin (CCK). In separate studies, the effect of a background infusion of bethanechol and secretin on the pancreatic response to CCK was assessed in six patients and six normal controls. Compared to normals, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli. This reduction was not corrected by administering bethanechol. Plasma glucagon and pancreatic polypeptide levels in diabetics were not significantly higher than those in controls. We conclude that diabetics with diarrhea and peripheral neuropathy exhibit impairment of their exocrine pancreatic secretion and possible mechanisms for this are discussed.

Pituitary gonadal function in diabetic male patients with and without impotence.

Assessment of pituitary function was undertaken in diabetic male patients with and without impotence, and in normal subjects, using a combined gonadotropin releasing hormone (GnRH) and thyrotropin releasing hormone (TRH) test. Basal plasma levels of testosterone, gonadotropins, PRL and TSH were similar in the diabetic patients and controls. Following the administration of I.V. GnRH 150 microgram and TRH 500 microgram, diabetic patients with impotence demonstrated a lower LH response at 30 and 150 minutes and an increased PRL response at 20 minutes, which was statistically significant when compared to controls. FSH and TSH were similar in the diabetic patients and controls. The GnRH and TRH test was repeated in impotent diabetic patients while receiving 0.8-1 mU/kg/hr of insulin through an infusion pump. No difference in LH and PRL response could be demonstrated. These results demonstrate that following GnRH and TRH test, diabetic patients with impotence have a significantly different LH and PRL response than controls. In these patients acute control of hyperglycemia using an insulin infusion pump did not reverse the abnormal response.

A prospective study of glucose tolerance, insulin, C-peptide, and glucagon responses in patients with pancreatic carcinoma.

Ninety-nine patients suspected of having pancreatic carcinoma were studied prospectively for carbohydrate tolerance. Thirty-two patients were proven subsequently to have pancreatic carcinoma; the remainder served as a control group. There was an increased incidence of carbohydrate intolerance in patients with pancreatic carcinoma compared to the control group. Insulin and C-peptide measurements during glucose tolerance tests suggest abnormal beta cell function and possibly insulin resistance as causes for this abnormality. Although factors related to malignancy in general could partly account for the results, a specific factor occurring in patients with pancreatic carcinoma must also be considered as it could serve as a marker for the early detection of this disease.