Effect of Blood Ammonia Elevation Following Oral Glutamine Load on the Psychometric Performance of Cirrhotic Patients

Oral glutamine challenge is a method to increase blood ammonia and may be used to study the ammonia lowering effect of drugs potentially useful in hepatic encephalopathy (HE). We tested its influence on the psychometric performance of 18 cirrhotic patients without HE. Twelve nonencephalopatic cirrhotic patients were studied before and after glutamine load (20 g in 100 mL tap water) and six patients before and after placebo (100 mL tap water) by using the Number Connection Test (NCT), the Covert Visual Attention Orienting Test (CVAOT), and the Scan Test (SCT). Blood ammonia increased significantly after glutamine (from 79 ± 34 to 211 ± 66 g/dL) but not after placebo (from 94 ± 41 to 88 ± 26). No difference in the NCT was found before and after glutamine load or placebo. The CVAOT was similar after glutamine challenge and placebo, nor any interaction between Loads (glutamine or placebo) × Cue position was found, suggesting that glutamine load did not influence attention-orienting. SCT results were also similar after glutamine and placebo, suggesting a lack of influence on the working memory. Glutamine challenge is a safe method to induce hyperammonemia in nonencephalopatic cirrhotic patients and, therefore, to study the efficacy of ammonia lowering treatments.     

Mosaic mice with teratocarcinoma-derived mutant cells deficient in hypoxanthine phosphoribosyltransferase

Mutagenized stem cells of a cultured mouse teratocarcinoma cell line were selected for resistance to the purine base analog 6-thioguanine. Cells of a resistant clone were completely deficient in activity of the enzyme hypoxanthine phosphoribosyltransferase (HPRT, IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8), the same X-linked lesion as occurs in human Lesch-Nyhan disease. After microinjection into blastocysts of another genetic strain, the previously malignant cells successfully participated in normal embryogenesis and tumor-free, viable mosaic mice were obtained. Cells of tumor lineage were identified by strain markers in virtually all tissues of some individuals. Mature function of those cells was evident from their tissue-specific products (e.g., melanins, liver proteins). These mutagenized teratocarcinoma cells are therefore developmentally totipotent. Retention of the severe HPRT deficiency in the differentiated state was documented in extracts of mosaic tissues by depressed specific activity of the enzyme, and also by presence of unlabeled clones in autoradiographs of explanted cells incubated in [(3)H]hypoxanthine. Some mosaic individuals had mutant-strain cells in only one or a few tissues. Such animals may provide unique opportunities to identify the tissue sources of particular aspects of the complex disease syndrome. The tissue distribution of HPRT-deficient cells suggests that selection against them is particularly strong in blood of the mosaic mice, as is already known to be the case in human heterozygotes. This phenotypic parallelism supports the expectation that afflicted F(1) male mice that might be obtained from mutant germ cells can serve as a model of the human disease.     

Usefulness of the dipyridamole-exercise echocardiography test for diagnosis of coronary artery disease

To test the hypothesis that a dipyridamole infusion might sensitize the myocardium to exercise-induced ischemia, 33 patients with effort chest pain syndrome--including 24 with and 9 without angiographically documented coronary artery disease (CAD)--and 10 control subjects were studied. As inclusion criterion, all enrolled subjects had a negative resting high-dose dipyridamole-echocardiography test result for both mechanical (development of a transient asynergy) and electrocardiographic (greater than 0.1 mV ST-segment shift) changes. All performed 2 supine exercises during 2-dimensional echocardiography and 12-lead electrocardiography monitoring, immediately after high-dose (0.84 mg/kg over 10 minutes) dipyridamole (dipyridamole-exercise stress test) or placebo (exercise stress test) infusion. The overall sensitivity (by electrocardiographic, echocardiographic or combined criteria) for CAD detection was 10 of 24 for exercise stress test and 21 of 24 for dipyridamole-exercise stress test (42 vs 88%, p less than 0.01). The specificity was 19 of 19 for exercise stress test and 18 of 19 for dipyridamole-exercise stress test (100 vs 95%, difference not significant). Both exercise stress test and dipyridamole-exercise stress test yielded negative results in the 10 control subjects, with a similar peak rate-pressure product (X 1/100) reached in the 2 tests (287 +/- 55 vs 274 +/- 42, difference not significant). Eight patients (all with significant CAD) had positive results of their exercise stress test and all 8 had also positive dipyridamole-exercise stress test results, at a significantly lower rate-pressure product with respect to the exercise stress test (253 +/- 49 vs 204 +/- 35, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bcl-2 protein expression is the strongest independent prognostic factor of survival in primary cutaneous large B-cell lymphomas

Bcl-2 protein expression has been associated with poor prognosis in patients with noncutaneous diffuse large B-cell lymphomas. In primary cutaneous large B-cell lymphomas, the location on the leg, the round-cell morphology defined as the predominance of centroblasts and immunoblasts over large centrocytes, and multiple skin lesions were identified as adverse prognostic factors. The prognostic value of bcl-2 protein expression has not been studied in large series of patients. We evaluated 80 primary cutaneous large B-cell lymphomas collected by the French Study Group on Cutaneous Lymphomas. The prognostic value of age, sex, number of lesions, cutaneous extent, location, serum lactate dehydrogenase (LDH) level, B symptoms, morphology, and bcl-2 protein expression was studied. The overall 5-year specific survival rate was 65%. In univariate analysis, advanced age, multiple skin lesions (n = 48), location on the leg (n = 25), round-cell morphology (n = 32), and bcl-2 expression (n = 39) were significantly related to death from lymphoma. In multivariate analysis, bcl-2 expression (P =.0003), multiple skin lesions (P =.004), and age remained independent prognostic factors. The 5-year specific survival rates in bcl-2-positive and bcl-2-negative patients were 41% and 89%, respectively (P <.0001). A new prognostic classification of primary cutaneous B-cell lymphoma should be based primarily on bcl-2 protein expression rather than the location of skin lesions.     

Interleukin‐6 limits influenza‐induced inflammation and protects against fatal lung pathology

Balancing the generation of immune responses capable of controlling virus replication with those causing immunopathology is critical for the survival of the host and resolution of influenza‐induced inflammation. Based on the capacity of interleukin‐6 (IL‐6) to govern both optimal T‐cell responses and inflammatory resolution, we hypothesised that IL‐6 plays an important role in maintaining this balance. Comparison of innate and adaptive immune responses in influenza‐infected wild‐type control and IL‐6‐deficient mice revealed striking differences in virus clearance, lung immunopathology and generation of heterosubtypic immunity. Mice lacking IL?6 displayed a profound defect in their ability to mount an anti‐viral T‐cell response. Failure to adequately control virus was further associated with an enhanced infiltration of inflammatory monocytes into the lung and an elevated production of the pro‐inflammatory cytokines, IFN‐α and TNF‐α. These events were associated with severe lung damage, characterised by profound vascular leakage and death. Our data highlight an essential role for IL‐6 in orchestrating anti‐viral immunity through an ability to limit inflammation, promote protective adaptive immune responses and prevent fatal immunopathology.