Distribution of T cells and signs of T-cell activation in the rheumatoid joint: implications for semiquantitative comparative histology

A prerequisite for comparative histology of synovial tissue by means of biopsies is insight into the distribution of a marker under study. This investigation focuses on the variation in the presence of T cells and signs of T-cell activation within the rheumatoid joint. For this purpose, multiple slides from several pieces of synovial tissue from different parts of a joint were stained and scored for the expression of CD3, CD25, HLA-DR, Ki67 and interferon-gamma. The variation in scores for the presence of T cells and markers of activation was more pronounced in slides prepared from different pieces of tissue than in slides from one piece of tissue. Based on multiple analysis of variance, methods are suggested to establish a reliable overall score for the expression of a certain marker within a joint. Following validation, such methods may prove to be useful by allowing semiquantitative histology of synovial tissue for studies on arthritis.      

HLA Class I and Genetic Susceptibility to Type 1 Diabetes: Results From the Type 1 Diabetes Genetics Consortium

OBJECTIVE

We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study.

RESEARCH DESIGN AND METHODS

Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients.

RESULTS

Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes–associated alleles were B*5701 (odds ratio 0.19; P = 4 × 10⁻¹¹) and B*3906 (10.31; P = 4 × 10⁻¹⁰). Other significantly type 1 diabetes–associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class II. Other class I type 1 diabetes associations appear to be specific to individual class II haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403).

CONCLUSIONS

These data indicate that HLA class I alleles, in addition to and independently from HLA class II alleles, are associated with type 1 diabetes.Type 1 diabetes is an autoimmune disease characterized by progressive T-cell–mediated destruction of the pancreatic β-cells. Both genetic and environmental factors are involved in disease susceptibility; the major genetic susceptibility determinants are the highly polymorphic HLA loci on chromosome 6p21—more specifically the class II loci, HLA-DRB1, HLA-DQB1/DQA1 (see the study by Erlich et al. [1] and references therein), and, to a lesser extent, HLA-DPB1/DPA1 (2–6). These genes, however, cannot completely explain the association between type 1 diabetes and the HLA region. Several studies have shown that HLA class I genes (A, B, and C) are associated with type 1 diabetes (7–11). Products of the HLA class I genes bind and present peptide antigens. The HLA class I/peptide antigen complexes function both in shaping the T-cell repertoire in the thymus and in initiating antigen-specific T-cell–mediated cytotoxicity, providing a plausible immunological rationale to explain the genetic association. The extremely high linkage disequilibrium (LD) within the HLA region, combined with the strong susceptibility effects of the HLA DR- and DQ-encoding loci, can confound association studies of any loci in the region. Thus, apparent susceptibility effects of HLA class I alleles may, in some cases, be attributable to their presence on highly protective or predisposing HLA DRB1-DQA1-DQB1 haplotypes.Compared with the hundreds of studies of HLA class II association with type 1 diabetes, only a handful of reports focus on HLA class I and type 1 diabetes (7–12), and only a subset of these include molecular genotyping and consideration of LD with class II in association analyses. Some alleles have appeared consistently associated with type 1 diabetes both at the serologic and allele level, including A*24(02) and B*39(06), with and without conditioning on DR-DQ. HLA class I loci are extremely polymorphic, with a total of 2,893 alleles assigned for the three loci as of October 2009. Thus, large sample sizes are crucial to generate sufficient class I data for adequately powered disease association studies. The Type 1 Diabetes Genetics Consortium (T1DGC) is an international collaborative project that has ascertained the largest set of multiplex type 1 diabetes families in existence for the study of the genetic basis of type 1 diabetes susceptibility. All samples collected by the T1DGC are genotyped at all classical HLA loci (DRB1, DQA1, DQB1, DPA1, DPB1, A, B, and C) as well as for single nucleotide polymorphisms (SNPs) in the insulin and CTLA4 genes that have repeatedly been shown to be associated with type 1 diabetes. Subsets of the T1DGC collection have been genotyped for candidate gene SNPs reported to be associated with type 1 diabetes (the “Rapid Response” project), genome-wide microsatellites, and genome-wide SNPs (www.T1DGC.org).     

Cost-effectiveness of continuous positive airway pressure therapy in patients with obstructive sleep apnea-hypopnea in British Columbia

BACKGROUND:

Obstructive sleep apnea-hypopnea (OSAH) is a common disorder characterized by recurrent collapse of the upper airway during sleep. Patients experience a reduced quality of life and an increased risk of motor vehicle crashes (MVCs). Continuous positive airway pressure (CPAP), which is the first-line therapy for OSAH, improves sleepiness, vigilance and quality of life.

OBJECTIVE:

To assess the cost-effectiveness of CPAP therapy versus no treatment for OSAH patients who are drivers.

METHODS:

A Markov decision analytical model with a five-year time horizon was used. The study population consisted of male and female patients, between 30 and 59 years of age, who were newly diagnosed with moderate to severe OSAH. The model evaluated the cost-effectiveness of CPAP therapy in reducing rates of MVCs and improving quality of life. Utility values were obtained from previously published studies. Rates of MVCs under the CPAP and no CPAP scenarios were calculated from Insurance Corporation of British Columbia data and a systematic review of published studies. MVCs, equipment and physician costs were obtained from the British Columbia Medical Association, published cost-of-illness studies and the price lists of established vendors of CPAP equipment in British Columbia. Findings were examined from the perspectives of a third-party payer and society.

RESULTS:

From the third-party payer perspective, CPAP therapy was more effective but more costly than no CPAP (incremental cost-effectiveness ratio [ICER] of $3,626 per quality-adjusted life year). From the societal perspective, the ICER was similar ($2,979 per quality-adjusted life year). The ICER was most dependent on preference elicitation method used to obtain utility values, varying almost sixfold under alternative assumptions from the base-case analysis.

CONCLUSION:

After considering costs and impact on quality of life, as well as the risk of MVCs in individuals with OSAH, CPAP therapy for OSAH patients is a highly efficient use of health care resources. Provincial governments who do not provide funding for CPAP therapy should reconsider.     

Factors strengthening and weakening vaccination competence

The purpose of this study was to describe factors strengthening and weakening vaccination competence. The data were collected by focus group and individual interviews with 40 participants, consisting of health-care professionals, students and clients, and were then analysed by content analysis. The results could be classified into four categories: vaccinator professional conduct, education, client conduct and the vaccination environment. Successful client encounters, comprehensive knowledge of vaccinating, adequate education, clients' positive attitude, suitable physical environment and centralization of vaccinations were considered strengthening factors, whereas their opposites weakened vaccination competence. The two most important factors were vaccinator professional conduct and education, and therefore these factors should be considered the most in education, clinical practice and administration. Further research is necessary to determine how well current education, clinical practice and administration support factors strengthening, and help alleviate factors weakening vaccination competence.     

Effects of betaine on etnanol-stimulated secretion of IGF-I and IGFBP-1 in rat primary hepatocytes: involvement of p42/44 MAPK activation

AIM: To evaluate the effects of betaine on the ethanol-induced secretion of IGF-I and IGFBP-1 using radioim-munoassay and Western blotting, respectively, in primary cultured rat hepatocytes. METHODS: Hepatocytes isolated from male Sprague-Dawley rats were incubated with various concentrations of ethanol and PD98059 procedures. The hepatocytes were also treated with different doses of betaine (10-5, 10-4, and 10-3 mol/L). We measured IGF-I and IGFBP-1 using radioimmunoassay and Western blotting, respectively. RESULTS: The ethanol-induced inhibition of IGF-I secretion was attenuated by betaine in a concentration-dependent manner in primary cultured rat hepatocytes. At 10?mol/L, betaine significantly increased IGF-I secretion but decreased IGFBP-1 secretion. In addition, p42/44 mitogen-activated protein kinase (MAPK) activity was accelerated significantly from 10 min to 5 h after treatment with 10-3 mol/L betaine. Furthermore, the changes in IGF-1 and IGFBP-1 secretion resulting from the increased betaine-induced p42/44 MAPK activity in primary cultured rat hepatocytes was blocked by treatment with the MAPK inhibitor PD98059. Betaine treatment blocked the ethanol-induced inhibition of IGF-I secretion and p42/44 MAPK activity, and the ethanol-induced increase in IGFBP-1 secretion. CONCLUSION: Betaine modulates the secretion of IGF-I and IGFBP-1 via the activation of p42/44 MAPK in primary cultured rat hepatocytes. Betaine also alters the MAPK activations induced by ethanol.