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.     

Virological, biochemical and histological effects of human lymphoblastoid interferon in Swedish patients with chronic hepatitis C

Thirty-eight Swedish patients with chronic hepatitis C were randomly assigned to receive either 3 million units (MU) or 5MU of human lymphoblastoid interferon-α-n1 (Wellferon) three times per week for either 6 or 12 months. The patients were monitored biochemically, histologically and by quantitative polymerase chain reaction for circulating HCV RNA, during therapy and for the following year. Overall, 22 (58%) of the patients lost detectable hepatitis C virus (HCV) viraemia during therapy but eight of these patients relapsed during follow-up, leaving 14 (37%) sustained responders. Patients infected with HCV non-type 1 genotypes were significantly more likely to achieve a sustained response than were those infected with HCV type 1 (63% vs 10.5%, P =0.001). Sustained virological responses were also associated with lower pretreatment viraemia level, younger age, absence of cirrhosis and the higher interferon dosage regimens but these associations failed to reach statistical significance. In 97% of patients there was concordance between virological and biochemical responses, and a statistically significant ( P =0.005) improvement in the Knodell histological activity index was observed in the virological sustained responders.     

Burkitt''s Lymphoma in an Old Patient with Diarrhea: Ileoscopic Diagnosis

A 61-yr-old man with Burkitt's lymphoma who presented with 6 months of diarrhea was found, at ileoscopy, to have inflammation of the mucosal narrow lumen, deep linear ulcerations, and a "cobblestone" appearance of the terminal ileum. Endoscopic biopsies were diagnostic of Burkitt's lymphoma, and no laparotomy was necessary. Presentation with diarrhea and the age of the patient were unusual, and the endoscopic features and diagnosis of the disease in the terminal ileum made by ileoscopy have not been previously reported.     

Immunization of rabbits with a modified vaccinia Ankara recombinant virus bearing the HIV envelope antigen on its outer membrane

Modified vaccinia virus Ankara (MVA) is a highly attenuated strain of vaccinia virus, which propagates efficiently in chicken embryo fibroblasts but fails to complete its growth cycle in many types of mammalian cells. We constructed a recombinant virus MVA/EK5, which has a chimeric gene encoding for the extracellular domain of the HIV envelope protein fused to the cytoplasmic and transmembrane domain of the B5R protein of vaccinia virus. The fused HIV envelope antigen was expressed in the African green monkey kidney BS-C-1 cells infected with the recombinant virus. This virus, which had been grown in chicken embryo fibroblasts, induced in rabbits antibodies against the HIV envelope antigen, in addition to those against poxvirus.     

Iron overload in multiply transfused patients who are HIV seropositive.

AIMS--To assess histologically the amount of iron deposited in liver biopsy specimens from HIV positive patients; and to perform estimations of liver iron on tissue from patients with an increase in parenchymal stainable iron. To correlate the amount of blood transfused and the degree of iron overload. METHODS--Liver biopsy specimens (n = 120) from 109 HIV positive patients, 74 of whom had AIDS, were examined retrospectively and the amount of iron, as visualised with Perls's stain, was graded. Fibrosis was assessed using connective tissue stains. Estimations of liver iron were performed on tissue retrieved from paraffin wax blocks in cases with histological grade 3 or 4 iron overload. The amount of blood transfused before liver biopsy was determined from the notes for each patient. RESULTS--Fifteen of the 120 liver biopsy specimens had significantly increased amounts of iron in their hepatocytes, as assessed histologically, and this was confirmed in seven cases by measurement of liver iron. There was a close correlation between the amount of blood transfused and the degree of iron overload. In the initial biopsy specimens only one case showed portal tract expansion. Three of the five patients who had repeat biopsies, however, showed progressive fibrosis. CONCLUSION--Multiply transfused HIV positive patients may develop clinically important iron overload and are at risk of developing progressive fibrosis. Superimposed liver disease, especially viral hepatitis, in these high risk patients may exacerbate the effects of the iron overload.