Immunoglobulin heavy-chain class-switch recombination (CSR) occurs between highly repetitive switch sequences located upstream of the constant region genes. However, the role of these sequences remains unclear. Mutant mice were generated in which most of the I-C intron was deleted, including all the repeats. Late B-cell development was characterized by a severe impairment, but not a complete block, in class switching to all isotypes despite normal germ line transcription. Sequence analysis of the I-C intron in in vitro activatedmutant splenocytes did not reveal any significant increase in activation-induced cytidine deaminase (AID)-induced somatic mutations. Analysis of switch junctions showed that, in the absence of any S repeat, the I exon was readily used as a substrate for CSR. In contrast to the sequence alterations downstream of the switch junctions, very few, if any, mutations were found upstream of the junction sites. Our data suggest that the core E enhancer could be the boundary for CSRassociated somatic mutations. We propose that the core E enhancer plays a central role in the temporal dissociation of somatic hypermutation from class switching. ( IntroductionDuring B-cell development, the immunoglobulin (Ig) locus is the site of 2 types of rearrangements: V(D)J assembly that generates the variable (V) region exons at the heavy-and light-chain loci and class-switch recombination (CSR) at the heavy-chain (IgH) locus. Upon antigen challenge, mature B cells expressing IgM and/or IgD undergo diversification processes that affect both the V and the constant (C) genes. Point mutations and occasional insertions and deletions are introduced in the V regions during somatic hypermutation (SHM) and gene conversion eventually resulting in higheraffinity receptors. CSR specifically affects C genes through a deletional process whereby a downstream C-region gene is brought to proximity of a rearranged VDJ gene, allowing expression of one of the downstream isotypes (IgG, IgE, or IgA). 1,2 CSR generally occurs between highly repetitive, G-rich switch (S) sequences located upstream of all the C genes except C␦. S sequences differ both in size and in the nature of the repeats. In the mouse, S, S⑀, and S␣ are composed of pentameric tandem repeats such as GGGGT, GGGCT, and GAGCT, while S␥ sequences, which also contain these elements, consist of repeats of a 49-base pair (bp) sequence. 3 In addition, S sequences bind several protein complexes but the physiologic consequences of this binding are poorly understood. 2 CSR involves DNA breaks within partner S sequences followed by repair and ligation through a nonhomologous end-joining (NHEJ) mechanism with looped-out deletion of the intervening DNA. The final steps of CSR involve components of the general DNA repair machinery as well as mismatch-repair mechanisms. In contrast, the early steps requiring recognition and cleavage of S DNAs are still unclear. Both double-strand breaks and staggered single-strand breaks have been involved in the early steps of CSR. 4,5 Frequent mu...

BackgroundThe number of elderly (≥75 years) patients with end-stage renal disease (ESRD) has increased markedly, including in the Limousin region, which has the oldest population in France. We retrospectively compared outcomes in elderly and non-elderly ESRD patients who started dialysis during two time periods.MethodsBaseline clinical characteristics, care, and survival rates were assessed in 557 ESRD patients aged ≥75 and <75 years who started dialysis in 2002–2004 and 2005–2007. Survival curves and Cox proportional hazards model were used to assess survival and factors associated with survival.ResultsOf the 557 patients, 343 and 214 were <75 years and ≥75 years, respectively. Dialysis was started in 2002–2004 and 2005–2007 by 197 and 146 patients <75 years, respectively, and by 96 and 118 patients ≥75 years, respectively. Median age (73.4 years [interquartile range [IQR] 61.7-79.5 years] vs 69.5 years [IQR 57.4-77.4 years] p = 0.001) and the proportion aged ≥75 years (44.7% vs 32.8%, p = 0.004) were significantly higher in 2005–2007 than in 2002–2004. Improved initial status during 2005–2007 was observed only in patients ≥75 years, with a decrease in some co-morbidities, improved walking and better preparation for dialysis. Mortality rates were significantly lower in 2005–2007 than in 2002–2004 (hazard ratio 0.81, 95% confidence interval 0.69-0.95; p = 0.008), with the difference due to factors associated with clinical status and care.ConclusionsImproved initial clinical status and better preparation for dialysis, accompanied by increased survival, were observed for patients ≥75 years who started dialysis more recently, perhaps because of early referral to a nephrologist.

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