SummaryUsing a series of phenotypic markers that include immunoglobulin (Ig)D, IgM, IgG, CD23, CD44, Bcl-2, CD38, CD10, CD77, and Ki67, human tonsillar B cells were separated into five fractions representing different stages of B cell differentiation that included slgD + (Bin1 and Bm2), germinal center (Bin3 and Bin4), and memory (BinS) B cells. To establish whether the initiation of somatic mutation correlated with this phenotypic characterization, we performed polymerase chain reaction and subsequent sequence analysis of the Ig heavy chain variable region genes from each of the B cell subsets. We studied the genes from the smallest V. families (VH4, V.5, and VH6) in order to facilitate the mutational analysis. In agreement with previous reports, we found that the somatic mutation machinery is activated only after B cells reach the germinal center and become centroblasts (Bm3). Whereas 47 independently rearranged IgM transcripts from the Bml and Bm2 subsets were nearly germline encoded, 57 Bm3-, and Bm4-, and BmSderived IgM transcripts had accumulated an average of 5.7 point mutations within the V. gene segment. 3' transcripts corresponding to the same V. gene families were isolated from subsets Bm3, Bin4, and Bm5, and had accumulated an average of 9.5 somatic mutations. We conclude that the molecular events underlying the process of somatic mutation takes place during the transition from IgD +, CD23 + B cells (Bm2) to the IgD-, CD23-, germinal center centroblast (Bm3). Furthermore, the analysis of Ig variable region transcripts from the different subpopulations confirms that the pathway of B cell differentiation from virgin B cell throughout the germinal center up to the memory compartment can be traced with phenotypic markers. The availability of these subpopulations should permit the identification of the functional molecules relevant to each stage of 13 cell differentiation.T he variable regions of the two critical antigen receptors of the immune system, the T cell receptor and the immunoglobulin molecule, are encoded by five different genetic elements that, in the germline, are separated by thousands of base pairs (1, 2). A recombination machinery shared by T and B cells brings these elements together into functional TCR V~/V~ and Ig V./V~ chains (3). Availability of a broad array of germline genes, generation of random amino acids during the process of rearrangement, and combinatorial association of Vo/V~ and VH/V~ chains are essential steps in the generation of diversity within the T and B cell repertoires. B cells display the unique property of accumulating somatic mutations in their Ig variable region genes, further contributing to increase the almost limitless number of antigenic specificities (1).Although a large body of information has accumulated in recent years concerning the repertoire of human Ig variable region genes, both at the level of genomic organization and expression, our current knowledge about the mechanism of somatic mutation remains elementary. Mutations are introduced only into rear...

A routine of regular exercise is highly effective for prevention and treatment of many common chronic diseases and improves cardiovascular (CV) health and longevity. However, long-term excessive endurance exercise may induce pathologic structural remodeling of the heart and large arteries. Emerging data suggest that chronic training for and competing in extreme endurance events such as marathons, ultramarathons, ironman distance triathlons, and very long distance bicycle races, can cause transient acute volume overload of the atria and right ventricle, with transient reductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which return to normal within 1 week. Over months to years of repetitive injury, this process, in some individuals, may lead to patchy myocardial fibrosis, particularly in the atria, interventricular septum, and right ventricle, creating a substrate for atrial and ventricular arrhythmias. Additionally, long-term excessive sustained exercise may be associated with coronary artery calcification, diastolic dysfunction, and large-artery wall stiffening. However, this concept is still hypothetical and there is some inconsistency in the reported findings. Furthermore, lifelong vigorous exercisers generally have low mortality rates and excellent functional capacity. Notwithstanding, the hypothesis that long-term excessive endurance exercise may induce adverse CV remodeling warrants further investigation to identify at-risk individuals and formulate physical fitness regimens for conferring optimal CV health and longevity.

The implantable continuous hemodynamic monitor-guided care did not significantly reduce total HF-related events compared with optimal medical management. Additional trials will be necessary to establish the clinical benefit of implantable continuous hemodynamic monitor-guided care in patients with advanced HF.

Background-Omega-3 fatty acids (FAs) appear to reduce the risk of sudden death from myocardial infarction. This reduction is believed to occur via the incorporation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the myocardium itself, altering the dynamics of sodium and calcium channel function. The extent of incorporation has not been determined in humans. Methods and Results-We first determined the correlation between red blood cell (RBC) and cardiac omega-3 FA levels in 20 heart transplant recipients. We then examined the effects of 6 months of omega-3 FA supplementation (1 g responses among tissues were not significantly different). Conclusions-Although any of the tissues examined could serve as a surrogate for cardiac omega-3 FA content, RBC EPAϩDHA was highly correlated with cardiac EPAϩDHA; the RBC omega-3 response to supplementation was similar to that of the heart; RBCs are easily collected and analyzed; and they have a less variable FA composition than plasma. Therefore, RBC EPAϩDHA (also called the Omega-3 Index) may be the preferred surrogate for cardiac omega-3 FA status.