Molecular characteristics and gene segment usage in IGH gene rearrangements in multiple myeloma.

BACKGROUND AND OBJECTIVES: Analysis of IgH rearrangements in B-cell malignancies has provided clinical researchers with a wide range of information during the last few years. However, only a few studies have contributed to the characterization of these features in multiple myeloma (MM), and they have been focused on the analysis of the expressed IgH allele only. Comparison between the expressed and the non-functional IgH alleles allows further characterizion of the selection processes to which pre-myeloma cells are submitted. DESIGN AND METHODS: We analyzed a cohort of 84 untreated MM patients in order to characterize their functional VDJH and non-functional DJH rearrangements. The pattern of mutations and gene segment usage for both types of rearrangements was analyzed by polymerase chain reaction and sequencing. RESULTS: VH3 and VH1 family members were over- and under-represented, respectively. VH3-30 and VH3-15 segments were the most frequently used, whereas VH4-34 was found only in non-functional or heavily mutated VDJH rearrangements. DH2 and DH3 family members were over-represented in both VDJH and DJH repertoires, while the DH1 family was under-represented only in the productive VDJH rearrangements. Finally, DH3-22 and DH2-21 gene segments were found to be over-represented in the functional repertoire while segments commonly used by less mature B-cell malignancies, such as DH6-19 or DH3-3, were under-represented. INTERPRETATION AND CONCLUSIONS: Data reported here help to identify the clonogenic MM cell as a post-germinal center B cell that has undergone selection processes during the germinal center reaction.

Fixed-boundary constituencies and the principle of equal representation in Ireland

The process of constituency boundary revision in Ireland, designed to satisfy what is perceived as a rigid requirement that a uniform deputy-population ratio be maintained across constituencies, has traditionally consumed a great deal of the time of politicians and officials. For almost two decades after a High Court ruling in 1961, the process was a political one, was highly contentious, and was marked by serious allegations of ministerial gerrymandering. The introduction in 1979 of constituency commissions made up of officials neutralised, for the most part, charges that the system had become too politicised, but it continued the process of micro-management of constituency boundaries. This article suggests that the continuing problems caused by this system – notably, the permanently changing nature of constituency boundaries and resulting difficulties of geographical identification – could be resolved by reversion to the procedure that is normal in proportional representation systems: periodic post-census allocation of seats to constituencies whose boundaries are based on those of recognised local government units and which are stable over time. This reform, replacing the principle of redistricting by the principle of reapportionment, would result in more recognisable constituencies, more predictable boundary trajectories over time, and a more efficient, fairer, and speedier process of revision.