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Abnormal serum immunoglobulin (Ig) free light chains (FLC) are established biomarkers of early disease in multiple B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Heavy chains have also been shown to be biomarkers in plasma cell disorders. An unanswered question is whether these Ig biomarkers are heritable, i.e., influenced by germline factors. CLL is heritable but highly heterogeneous. Heritable biomarkers could elucidate steps of disease pathogenesis that are affected by germline factors, and may help partition heterogeneity and identify genetic pleiotropies across malignancies. Relatives in CLL pedigrees present an opportunity to identify heritable biomarkers. We compared FLCs and heavy chains between relatives in 23 high-risk CLL pedigrees and population controls. Elevated IgM (eIgM) and abnormal FLC (aFLC) ratio was significantly increased in relatives, suggesting that these Ig biomarkers are heritable and could offer risk stratification in pedigree relatives. Within high-risk CLL pedigrees, B-cell lymphoid malignancies were five times more prevalent in close relatives of individuals with eIgM, prostate cancer was three times more prevalent in relatives of individuals with aFLC, and monoclonal B-cell lymphocytosis increased surrounding individuals with normal Ig levels. These different clustering patterns suggest Ig biomarkers have the potential to partition genetic heterogeneity in CLL and provide insight into distinct heritable pleiotropies associated with CLL.

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THE action of adrenaline and acetylcholine is known to be profoundly influenced by the ionic concentration of the medium in which they act. The literature on this subject contains many apparently conflicting statements, and a critical analysis suggests that the following facts may account for some of the discrepancies. (a) The bulk of the literature is concerned with the frog heart. Different species of frog were used by various authors, experimenting on different preparations at different seasons. There is evidence that the various species of frog do not react in the same way to a given drug-Krogh [1917] and Lanz [1928]-and that the ionic medium of cold-blooded animals alters with seasonBouckaert, Bouckaert and Noyons [1922]. (b) It is necessary to differentiate between results obtained with the whole heart and those with the isolated auricle, isolated ventricle, ventricular slips, and other modifications. (c) In assessing results, it is important to allow for the wide variety of perfusion fluids which has been used. To consider but one constituent, Ca", of frog heart Ringer's fluid, Sollman and Barlow [1926[ ] used 0-026 p.c., Clark [1913 used 0-012 p.c., while Burridge [1920] added Ca" till the heart was beating at a sufficient amplitude. (d) The pH was not always controlled, and (e) the concentrations of drug employed were often of very different orders.With these considerations in mind the experiments described below were performed, their principal object being to re-examine the effect of ionic changes on the heart and to determine to what extent these affect the action of adrenaline and acetylcholine. METHODS.Experiments were performed upon the isolated perfused frog heart, and repeated upon the isolated perfused rabbit heart'. Frog hearts were 1 Several guinea-pig hearts also were used; the results were parallel to those on the rabbit.

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