Evaluation of the IL2/IL21, IL2RA and IL2RB genetic variants influence on the endogenous non-anterior uveitis genetic predisposition.

BACKGROUND Recently, different genetic variants located within the IL2/IL21 genetic region as well as within both IL2RA and IL2RB loci have been associated to multiple autoimmune disorders. We aimed to investigate for the first time the potential influence of the IL2/IL21, IL2RA and IL2RB most associated polymorphisms with autoimmunity on the endogenous non-anterior uveitis genetic predisposition. METHODS A total of 196 patients with endogenous non-anterior uveitis and 760 healthy controls, all of them from Caucasian population, were included in the current study. The IL2/IL21 (rs2069762, rs6822844 and rs907715), IL2RA (2104286, rs11594656 and rs12722495) and IL2RB (rs743777) genetic variants were genotyped using TaqMan® allelic discrimination assays. RESULTS A statistically significant difference was found for the rs6822844 (IL2/IL21 region) minor allele frequency in the group of uveitis patients compared with controls (P(-value)=0.02, OR=0.64 CI 95%=0.43-0.94) although the significance was lost after multiple testing correction. Furthermore, no evidence of association with uveitis was detected for the analyzed genetic variants of the IL2RA or IL2RB loci. CONCLUSION Our results indicate that analyzed IL2/IL21, IL2RA and IL2RB polymorphisms do not seem to play a significant role on the non-anterior uveitis genetic predisposition although further studies are needed in order to clear up the influence of these loci on the non-anterior uveitis susceptibility.

Optimization of treatment with interferon beta in multiple sclerosis. Usefulness of automatic system application criteria

Background. A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation. METHODS: Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN beta1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years. RESULTS: We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m - last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m - last visit; CH: 0.29, NCH: 0.13). CONCLUSION: Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression.

Bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli in the CTX-M era: a new clinical challenge.

Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, particularly those producing CTX-M types of ESBL, are emerging pathogens. Bacteremia caused by these organisms represents a clinical challenge, because the organisms are frequently resistant to the antimicrobials recommended for treatment of patients with suspected E. coli sepsis. METHODS:A cohort study was performed that included all episodes of bloodstream infection due to ESBL-producing E. coli during the period from January 2001 through March 2005. Data on predisposing factors, clinical presentation, and outcome were collected. ESBLs were characterized using isoelectric focusing, polymerase chain reaction, and sequencing. RESULTS: Forty-three episodes (8.8% of cases of bacteremia due to E. coli) were included; 70% of the isolates produced a CTX-M type of ESBL. The most frequent origins of infection were the urinary (46%) and biliary tracts (21%). Acquisition was nosocomial in 21 cases (49%), health care associated in 14 cases (32%), and strictly community acquired in 8 cases (19%). Thirty-eight percent and 25% of patients had obstructive diseases of the urinary and biliary tracts, respectively, and 38% had recently received antimicrobials. Nine patients (21%) died. Compared with beta-lactam/beta-lactamase-inhibitor and carbapenem-based regimens, empirical therapy with cephalosporins or fluoroquinolones was associated with a higher mortality rate (9% vs. 35%; P=.05) and needed to be changed more frequently (24% vs. 78%; P=.001). CONCLUSIONS: ESBL-producing E. coli is a significant cause of bloodstream infection in hospitalized and nonhospitalized patients in the context of the emergence of CTX-M enzymes. Empirical treatment of sepsis potentially caused by E. coli may need to be reconsidered in areas where such ESBL-producing isolates are present.

Clinical and molecular epidemiology of extended-spectrum beta-lactamase-producing Escherichia coli as a cause of nosocomial infection or colonization: implications for control.

BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing members of the Enterobacteriaceae family are important nosocomial pathogens. Escherichia coli producing a specific family of ESBL (the CTX-M enzymes) are emerging worldwide. The epidemiology of these organisms as causes of nosocomial infection is poorly understood. The aims of this study were to investigate the clinical and molecular epidemiology of nosocomial infection or colonization due to ESBL-producing E. coli in hospitalized patients, consider the specific types of ESBLs produced, and identify the risk factors for infection and colonization with these organisms. METHODS: All patients with nosocomial colonization and/or infection due to ESBL-producing E. coli in 2 centers (a tertiary care hospital and a geriatric care center) identified between January 2001 and May 2002 were included. A double case-control study was performed. The clonal relatedness of the isolates was studied by repetitive extragenic palindromic-polymerase chain reaction and pulsed-field gel electrophoresis. ESBLs were characterized by isoelectric focusing, polymerase chain reaction, and sequencing. RESULTS: Forty-seven case patients were included. CTX-M-producing E. coli were clonally unrelated and more frequently susceptible to nonoxyimino-beta-lactams. Alternately, isolates producing SHV- and TEM-type ESBL were epidemic and multidrug resistant. Urinary catheterization was a risk factor for both CTX-M-producing and SHV-TEM-producing isolates. Previous oxyimino-beta-lactam use, diabetes, and ultimately fatal or nonfatal underlying diseases were independent risk factors for infection or colonization with CTX-M-producing isolates, whereas previous fluoroquinolone use was associated with infection or colonization with SHV-TEM-producing isolates. CONCLUSIONS: The epidemiology of ESBL-producing E. coli as a cause of nosocomial infection is complex. Sporadic CTX-M-producing isolates coexisted with epidemic multidrug-resistant SHV-TEM-producing isolates. These data should be taken into account for the design of control measures.

Candidate gene study of TRAIL and TRAIL receptors: association with response to interferon beta therapy in multiple sclerosis patients.

TRAIL and TRAIL Receptor genes have been implicated in Multiple Sclerosis pathology as well as in the response to IFN beta therapy. The objective of our study was to evaluate the association of these genes in relation to the age at disease onset (AAO) and to the clinical response upon IFN beta treatment in Spanish MS patients. We carried out a candidate gene study of TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 genes. A total of 54 SNPs were analysed in 509 MS patients under IFN beta treatment, and an additional cohort of 226 MS patients was used to validate the results. Associations of rs1047275 in TRAILR-2 and rs7011559 in TRAILR-4 genes with AAO under an additive model did not withstand Bonferroni correction. In contrast, patients with the TRAILR-1 rs20576-CC genotype showed a better clinical response to IFN beta therapy compared with patients carrying the A-allele (recessive model: p = 8.88×10(-4), pc = 0.048, OR = 0.30). This SNP resulted in a non synonymous substitution of Glutamic acid to Alanine in position 228 (E228A), a change previously associated with susceptibility to different cancer types and risk of metastases, suggesting a lack of functionality of TRAILR-1. In order to unravel how this amino acid change in TRAILR-1 would affect to death signal, we performed a molecular modelling with both alleles. Neither TRAIL binding sites in the receptor nor the expression levels of TRAILR-1 in peripheral blood mononuclear cell subsets (monocytes, CD4+ and CD8+ T cells) were modified, suggesting that this SNP may be altering the death signal by some other mechanism. These findings show a role for TRAILR-1 gene variations in the clinical outcome of IFN beta therapy that might have relevance as a biomarker to predict the response to IFN beta in MS.