Detection of linkage under heterogeneity: comparison of the two-locus vs. admixture models.

Linkage analysis under the two-locus model and the admixture model was compared on pedigree data for a common disease stimulated under a model of genetic heterogeneity. The ascertainment of families was designed so that the samples had a large proportion of families segregating for both disease loci. The two-locus linkage analysis model did not demonstrate increased power of detecting linkage or more accurate estimates of the recombination fraction, theta than did the admixture model linkage analysis. When a sample was purposely chosen so that all of the families were segregating for both loci, then the two-locus lod score analysis was better. However, the increased power depended on assuming the correct gene frequency for the linked locus. It can be concluded that under the conditions of genetic heterogeneity examined here, testing for linkage under the admixture model is the preferred method of analysis. However, this is not a general conclusion that can apply to all two-locus disease models.     

Nitric oxide production by monocytes in alcoholic liver disease

Nitric oxide, initially described as an endothelial-derived relaxing factor, has recently been recognised as a mediator of macrophage function. We have studied the production of nitric oxide by peripheral blood monocytes from both normal volunteers and alcoholics. This was measured indirectly by assessing nitrite formation. Normal monocytes were found to produce a basal level of nitrite, which could be stimulated more than 6-fold using endotoxin. This effect was abrogated by the addition of nitric oxide synthesis inhibitor, L-n-monomethyl-arginine. A striking difference was observed in the monocytes obtained from alcoholics with and without evidence of alcoholic hepatitis. Whereas the latter behaved in a similar manner to the controls, the former had markedly increased basal levels. In the hepatitis group there was also substantial inhibition of production by L-n-monomethyl-arginine. We believe that these results indicate that nitric oxide derived from monocytes may play a role in the pathogenesis of alcoholic liver disease, especially alcoholic hepatitis.     

The automatic implantable cardioverter-defibrillator. Clinical experience, complications, and follow-up in 25 patients

Twenty-five patients with recurrent ventricular tachyarrhythmias underwent implantation of an automatic implantable cardioverter-defibrillator. The mean length of follow-up was 11.9 +/- 10.8 months. Before the implantation, the patients had survived one or more cardiac arrests (mean, 1.7; range, 1 to 4) and episodes of syncope (mean, 2.2; range, 2 to 3) and had received 6.0 +/- 1.0 antiarrhythmic drug trials. The in-hospital complications included death (two patients), reoperation (one patient), intraoperative myocardial infarction (one patient), sensing-failure (one patient), infection (five patients), and pocket seroma (two patients). The posthospital complications included device failure (four patients), device deactivation (one patient), and inappropriate discharge (two patients). The device discharged appropriately in seven patients due to sustained ventricular tachycardia. During electrophysiologic measurements, the energy requirement for successful cardioversion-defibrillation was related to the type of ventricular arrhythmia induced (monomorphic or pleomorphic ventricular tachycardia or fibrillation). Ventricular tachycardia acceleration occurred in ten patients (40%). No significant changes were found in the size of the electrograms or in the cardioversion threshold during early and late follow-up measurements. Life table analysis showed a 12-month survival rate of 86% and an arrhythmic death survival rate of 100%. We confirm the improved rate of survival in this high-risk group of patients, despite significant complications.     

A novel 37-Kd adhesive membrane protein from cloned murine bone marrow stromal cells and cloned murine hematopoietic progenitor cells

The adhesion of hematopoietic progenitor cells to bone marrow stromal cells is critical to hematopoiesis and involves multiple effector molecules. Stromal cell molecules that participate in this interaction were sought by analyzing the detergent-soluble membrane proteins of GBI/6 stromal cells that could be adsorbed by intact FDCP-1 progenitor cells. A single-chain protein from GBI/6 cells having an apparent molecular weight of 37 Kd was selectively adsorbed by FDCP-1 cells. This protein, designated p37, could be surface-radiolabeled and thus appeared to be exposed on the cell membrane. An apparently identical 37- Kd protein was expressed by three stromal cell lines, by Swiss 3T3 fibroblastic cells, and by FDCP-1 and FDCP-2 progenitor cells. p37 was selectively adsorbed from membrane lysates by a variety of murine hematopoietic cells, including erythrocytes, but not by human erythrocytes. Binding of p37 to cells was calcium-dependent, and was not affected by inhibitors of the hematopoietic homing receptor or the cell-binding or heparin-binding functions of fibronectin. It is proposed that p37 may be a novel adhesive molecule expressed on the surface of a variety of hematopoietic cells that could participate in both homotypic and heterotypic interactions of stromal and progenitor cells.