Citations

AbstractLight chain–associated amyloidosis (AL) is a plasma cell dyscrasia in which the secreted monoclonal immunoglobulin (Ig) light chains form amyloid fibrils. There is considerable heterogeneity in clinical presentation, and prognosis of the disease relates to the severity of organ dysfunction induced by amyloid deposits. The mechanisms by which the amyloid fibrils are deposited as well as the predilection for specific organ sites have not been clearly elucidated. This study characterizes the repertoire of immunoglobulin light chain variable genes used by the clonal B cell in AL amyloid patients, and the association of light chain variable region (VL) genes with clinical presentation and outcome is assessed in 58 (32 λ and 26 κ) patients. A preferential use of VL germ-line genes was noted for both AL κ and λ patients. There was a significant correlation between the use of the Vλ VI germ-line donor, 6a, and renal involvement as well as the Vλ III gene, 3r, with soft-tissue AL. The use of a biased VL gene repertoire also correlated with clinical outcome, revealing important trends for predicting prognosis. The use of Vλ II germ-line genes was associated with cardiac amyloidosis and affected survival adversely. The presence of multiple myeloma also correlated with a poor prognosis. The presence of renal disease, on the other hand, was associated with improved survival. Therefore, identification of the clonal VL gene in AL has important implications in determining clinical outcome.

Background— The gene encoding ACE exhibits an insertion/deletion polymorphism resulting in 3 genotypes (DD, ID, and II), which affects serum and tissue ACE activity as well as other vasoactive substances. Pulmonary function is frequently abnormal in patients with congestive heart failure (CHF), the mechanism of which has not been completely characterized. ACE inhibition has been shown to improve diffusion across the alveolar-capillary membrane and to improve exercise capacity and gas exchange in CHF. The aim of the current study was to determine if ACE genotype is associated with altered pulmonary function and exercise intolerance in patients with treated CHF. Methods and Results— Fifty-seven patients (stratified according to ACE genotype as17 DD, 28 ID, 12 II) with ischemic and dilated cardiomyopathy, left ventricular ejection fraction (LVEF) <35%, and <10 pack-years of smoking history were studied. All patients were receiving standard therapy for left ventricular systolic dysfunction. Pulmonary function, LVEF, serum ACE, plasma angiotensin II, atrial natriuretic peptide, and brain natriuretic peptide were measured at baseline. Peak V̇ o 2 and gas exchange measurements were assessed with graded exercise. Resting LVEF was similar among the genotype groups (25% to 28%), and no differences were observed in diastolic function or pulmonary artery pressures ( P >0.05). Mean peak V̇ o 2 and forced vital capacity (% Pred) were significantly reduced ( P <0.05), whereas mean serum ACE activity and plasma angiotensin II concentration were highest in DD homozygotes. Subjects homozygous for the D-allele also demonstrated higher mean ventilatory equivalents for carbon dioxide (V̇ e /V̇ co 2 ) during exercise ( P <0.05). Conclusions— ACE DD genotype is associated with decreased exercise tolerance in CHF, possibly mediated by altered pulmonary function. Pharmacological strategies effecting more complete inhibition of serum and tissue ACE and/or potentiation of bradykinin may improve exercise capacity in patients with CHF and ACE DD genotype.

Background — Regional myocardial function assessment is essential in the management of coronary artery disease (CAD). Tissue Doppler imaging (TDI) by depicting local myocardial motion can potentially quantify regional myocardial function. Strain rate imaging (SRI) that depicts regional deformation is less susceptible to cardiac translation and tethering and may be superior to TDI for regional function analysis. We examined regional myocardial function using TDI and SRI in a unique clinical model of a small, discrete myocardial infarction. Method and Results — Ten patients with severely symptomatic septal hypertrophy underwent basal septal ablation via intracoronary alcohol injection and had TDI and SRI pre- and postablation. Invasive hemodynamics showed no appreciable change in global function. Peak systolic strain rate was significantly lower postablation versus preablation (−0.5 versus −1.2 s −1 , P <0.001) and when comparing infarct and noninfarct areas (−0.5 versus −1.5 s −1 , P <0.001). In contrast, peak systolic tissue velocities were similar pre- and postablation (3.9 versus 2.9 cm/s, P =0.16) and between infarct and noninfarct areas (2.9 versus 2.2 cm/s, P =0.13). SRI analysis demonstrated reduced systolic function in the peri-infarct zone and preserved systolic function in the remote nonischemic zone. Conclusion — In the clinical setting of a small, discrete infarct unaccompanied by changes in global function, SRI accurately depicted changes in regional function. These data suggest that SRI may be the optimal method for objective, quantitative assessment of regional myocardial dysfunction.

Mice lacking the membrane tyrosine kinase c-mer have been shown to have altered macro-phage cytokine production and defective phagocytosis of apoptotic cells despite normal phagocytosis of other particles. We show here that c-mer–deficient mice have impaired clearance of infused apoptotic cells and that they develop progressive lupus-like autoimmunity, with antibodies to chromatin, DNA, and IgG. The autoimmunity appears to be driven by endogenous antigens, with little polyclonal B cell activation. These mice should be an excellent model for studying the role of apoptotic debris as an immunogenic stimulus for systemic autoimmunity.

▪ Abstract The potent immunosuppressive drugs FK506 and rapamycin interfere with signal transduction pathways required for T cell activation and growth. The distinct inhibitory effects of these drugs on the T cell activation program are mediated through the formation of pharmacologically active complexes with members of a family of intracellular receptors termed the FK506 binding proteins (FKBPs). The FKBP12 · FK506 complex specifically binds to and inhibits calcineurin, a signaling protein required for transcriptional activation of the interleukin (IL)-2 gene in response to T cell antigen receptor engagement. The FKBP12 · rapamycin complex interacts with a recently defined target protein termed the mammalian target of rapamycin (mTOR). Accumulating data suggest that mTOR functions in a previously unrecognized signal transduction pathway required for the progression of IL-2-stimulated T cells from G1into the S phase of the cell cycle. Here we review the immunopharmacology of rapamycin, with particular emphasis on the characterization of mTOR.

The immunosuppressant rapamycin interferes with G 1 -phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E–binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G 1 -phase progression in mammalian cells.

The apolipoprotein E ( APOE ) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.

ABSTRACT ATP‐sensitive K + (K ATP ) channels are unique metabolic sensors formed by association of Kir6.2, an inwardly rectifying K + channel, and the sulfonylurea receptor SUR, an ATP binding cassette protein. We identified an ATPase activity in immunoprecipitates of cardiac K ATP channels and in purified fusion proteins containing nucleotide binding domains NBD1 and NBD2 of the cardiac SUR2A isoform. NBD2 hydrolyzed ATP with a twofold higher rate compared to NBD1. The ATPase required Mg 2+ and was insensitive to ouabain, oligomycin, thapsigargin, or levamisole. K1348A and D1469N mutations in NBD2 reduced ATPase activity and produced channels with increased sensitivity to ATP. K ATP channel openers, which bind to SUR, promoted ATPase activity in purified sarcolemma. At higher concentrations, openers reduced ATPase activity, possibly through stabilization of MgADP at the channel site. K1348A and D1469N mutations attenuated the effect of openers on K ATP channel activity. Opener‐induced channel activation was also inhibited by the creatine kinase/creatine phosphate system that removes ADP from the channel complex. Thus, the K ATP channel complex functions not only as a K + conductance, but also as an enzyme regulating nucleotide‐dependent channel gating through an intrinsic ATPase activity of the SUR subunit. Modulation of the channel ATPase activity and/or scavenging the product of the ATPase reaction provide novel means to regulate cellular functions associated with K ATP channel opening.—Bienengraeber, M., Alekseev, A. E., Abraham, M. R., Carrasco, A. J., Moreau, C., Vivaudou, M., Dzeja, P. P., Terzic, A. ATPase activity of the sulfonylurea receptor: a catalytic function for the K ATP channel complex. FASEB J. 14, 1943–1952 (2000)