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CD40-CD40L interaction is necessary for the activation of both humoral and cellular immune response and has been suggested to play a role in the pathogenesis of multiple sclerosis (MS). Therefore, we analyzed the combined influence of the CD40 and CD40L variants on MS susceptibility and progression on well-defined Polish population. Our investigation revealed that CT individuals in rs1883832 locus of CD40 possessed almost 1.5-fold higher risk for MS than CC individuals (OR=1.44; 95%CI=1.03-2.1; p=0.032), while this risk for TT individuals was almost 2.5-fold higher (OR=2.36; 95%CI=1.19-4.78; p=0.014). Moreover, for the first time, we observed the association of CD40 gene with MS development and progression. We observed that for the rs1883832CC individuals the age at diagnosis was on average 2years lower than for the rs1883832CT and rs1883832TT individuals (CI95%=−3.69−(−0.29); p=0.023). Additionally, we detected that individuals with TT and CT genotypes showed lower risk of developing secondary progressive course in comparison to those with CC genotype. For rs1883832TT individuals this risk was 4-fold lower (HR=0.24; CI95%=0.10-0.53; p=0.00062). Despite the fact that CD40-CD40L pathway plays a key role in development of autoimmune diseases, we were not able to detect gene-gene interactions between CD40 and CD40L polymorphisms associated with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Abstract Introduction Staphylococcus aureus infection, and health care-associated-methicillin resistant S aureus (HA-MRSA) in particular, is a serious risk for patients treated with organ transplantation. The frequent combined resistance of these bacteria to macrolides, lincosamides, and streptogramin-B (MLS-B) limits the use of these drugs in therapy. Aim Evaluation of the mechanism of MLS-B resistance among HA-MRSA strains derived from patients treated in surgical-transplantation wards, over a 24-year period, and assessment of correlation of clindamycin use and resistance phenotype. Materials and methods One hundred and twelve HA-MRSA strains from patients in surgical-transplantation wards (clinical hospital, Warsaw), hospitalized in the period from 1991 to 2014. Methicillin-resistance was determined using phenotypic and genetic methods by detecting the mecA gene. Erythromycin/clindamycin resistance was determined by E-test, the iMLS-B (inductive) and cMLS-B (constitutive) phenotypes by the D-test method. The number of defined daily doses (DDD), statistically per 1000 person-days, was calculated in accordance with the WHO guidelines. Results Resistance to erythromycin/clindamycin in MRSA strains increased from 1991 to 2004–2007 from 64.7/11.8% to 100/76.9%, respectively. The frequency of the cMLS-B phenotype in the years 1991/2010–2011/2012 was 5.9%/76.9%/69.7%, respectively, and correlated with the increased use of clindamycin in the examined wards. In 2012, the percentage of MLS-B-sensitive isolates increased from 3.9 to 21.7%, while constitutive resistance decreased to 69.7%, which correlated with a decrease in the use of clindamycin. Conclusions The proportion of cMLS-B to iMLS-B phenotypes in HA-MRSA is related to the amount of clindamycin used in hospital wards. Limiting the selection pressure of antibiotics can lead to complete loss of resistance or return to the inductive mechanism of its regulation. Highlights • cMLS-B MRSA were selected under the pressure of clindamycin from previous iMLS-B. • Spontaneous mutations caused an increase in the incidence of cMLS-B variants. • A 14-fold increase in the occurrence of cMLS-B was noted between 1991 and 2014. • Limiting clindamycin use may lead to restoration of the inducible phenotype. [ABSTRACT FROM AUTHOR]