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Effects of dextropropoxyphene on the steady-state kinetics of oxcarbazepine and its metabolites

The effects of dextropropoxyphene on the steady-state kinetics of oxcarbazepine and its metabolites were investigated in eight patients with epilepsy or trigeminal neuralgia. One patient dropped out of the study, presumably due to side-effects of dextropropoxyphene. Dextropropoxyphene did not affect the plasma levels of the principal active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. Since dextropropoxyphene is known to increase the plasma levels of carbamazepine, leading to toxicity, the findings of this study suggest that oxcarbazepine is a useful alternative to carbamazepine when concomitant dextropropoxyphene therapy is required.     

Plasma lipids and lipoproteins and essential hypertension

In recent years there have been many studies demonstrating a correlation between increased arterial blood pressure and altered lipid profiles, and there has been an especially positive correlation between high cholesterol levels and blood pressure. There are differences between the various reports that are important. In our study the lipid distribution in 105 hypertensive patients with mild or moderate arterial hypertension according to WHO criteria without clinically or ultrasonographically apparent atherosclerosis was compared to the lipid distribution in 65 age-matched healthy persons. On the epidemiological level a significant, positive association was found between LDL serum levels (P 0.001), Apo B serum levels (P 0.001), serum triglyceride levels (P 0.05) and VLDL serum levels (P 0.01) and arterial hypertension. However, in contrast to recent reports, no significant difference was found between total serum cholesterol levels in normotensives and hypertensives, and there was no difference in HDL serum levels. No evidence could be found for a significant increase in lipoprotein (a) serum levels in hypertensives.Abbreviations LDL low density lipoprotein - VLDL very low density lipoprotein - HDL high density lipoprotein - Apo B 100 apolipoprotein B 100 - Apo A I apolipoprotein A I Correspondence to: H. Vetter     

The role of T cell — Macrophage interactions in tuberculosis

Acquired resistance against tuberculosis paradigmatically depends on specific T lymphocytes and mononuclear phagocytes. The etiological agent,Mycobacterium tuberculosis is capable of replicating in mononuclear phagocytes which act both as habitat and as effectors of protection. Upon interaction with antigen-specific T lymphocytes infected mononuclear phagocytes acquire tuberculosis activities. Here, data from experimental tuberculosis studies in mice are summarized which show that: interleukins produced by cloned T cells and recombinant interferon-γ are capable of activating tuberculostatic capacities in macrophages; both CD4 and CD8 T cells, after adequate stimulation, produce interferon-γ; CD8 T cells lyse macrophages in an antigen-specific way; not only CD8 but also CD4 T cells possess an antigen-specific cytolytic potential; lysis of infected macrophages results in mycobacterial growth inhibition. Evidence is also presented that tuberculostatic activities of activated macrophages depend on phagosome-lysosome fusion and are independent of reactive oxygen metabolites and that some strains ofM. tuberculosis are resistant against interferon-γ activated macrophages. These findings suggest that both helper and cytolytic T cells participate in the immune response to tuberculosis and that similar T cell mechanisms contribute to resistance as well as pathogenesis. Protection against tuberculosis, therefore, depends on subtle coordination of the immune response.     

Autologous bone marrow transplantation for acute leukemia using transplant chemopurified with metabolite of oxazaphosphorines (ASTA Z 7557, INN mafosfamide)

Summary The contamination of autologous marrow with clonogenic tumor cells has been the main argument against ABMT in acute leukemia.In a preclinical study we evaluated an active cyclophosphamide derivative named ASTA Z 7557. We observed that the toxic effect of this drug on CFU-GM growth was dependent on nucleated cell concentration as well as on red blood cell contamination. The potency of the drug was in close relationship with the incubation temperature.The growth of leukemic CFU was inhibited with an ASTA Z dose higher than 30 g/ml. In our system, beyond 40 g/ml more than 95% of committed stem cells are destroyed.Fifteen patients had autotransplant because of AML for 10 patients and because of ALL for 5 patients (4 patients were grafted in relapse and 11 patients in remission).We demonstrated that the marrow take was possible although the inoculum is CFU-GM depleted.Five of the 10 AML patients are alive and remain disease-free at 45 +, 65 +, 190 +, 345+ and 570 + days from ABMT without any maintenance treatment. Four of the 5 ALL patients are alive, three of them in complete remission (404+, 110+, 250+ days).The number of patients reported in this clinical study was relatively small and more cases should be evaluated to be conclusive. Nevertheless the feasibility of chemopurified ABMT was demonstrated.     

Evidence against a role of nitric oxide in the indirect negative inotropic-effect of M-cholinoceptor stimulation in human ventricular myocardium

Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with N^G-monomethyl-l-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37°C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 mol/l) was studied in the presence of the \-adrenoceptor agonist isoprenaline (0.03 mol/l).After stimulation with isoprenaline, carbachol significantly (P < 0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to \-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 mol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 mol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction. Basal force of contraction, as well as the positive inotropic effect of isoprenaline remained unaffected by NMMA or methylene blue.The present study provides evidence that the indirect negative inotropic effect of M-cholinoceptor agonists is not due to an effect of NO in the human myocardium. Furthermore, the well known enhancement of cGMP in response to M-cholinoceptor stimulation appears not to be involved in this antiadrenergic effect.     

Rflp analysis of the L-myc oncogene in head and neck-cancer - relationship study with susceptibility and disease progression

The L-myc DNA restriction fragment length polymorphism (RFLF), revealed by EcoRI digestion, has been evaluated in a case-control study including 161 head and neck cancer (HNSCC) patients and 160 normal healthy individuals with similar smoking and alcohol habits. No significant difference in the distribution of L-myc genotypes (LL, LS or SS) was found between the two populations implying thus no predisposition to head and neck tumour by either allele. There was no significant association between L-myc genotypes and the usual clinicopathological features such as T staging, differentiation status and lymph node involvement. Moreover, follow-up data from 154 patients was obtained and correlated with the L-myc pattern. No significant difference was observed in metastasis occurrence, multiple cancer incidence and survival data in the patients classified according to the L-myc genotypes; only a trend to preferentially develop metastasis in lung for patients with S allele was noted. In conclusion, our data shows that the L-myc typing does not contribute to HNSCC risk or prognosis assessment. A review of L-myc RFLP published studies shows contradictory results even on the same type of tumour and emphasizes the lacunae in understanding the biological role of L-myc for valid interpretation of L-myc allelic associations with cancer susceptibility or prognosis.     

Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial.

PURPOSE: This randomized, 2 x 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes' B2) and III (Dukes' C) colon cancer. PATIENTS AND METHODS: LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion. RESULTS: A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P =.74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P =.63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P =.18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P <.001). CONCLUSION: Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations.     

Sustained clinical response of large hepatocellular carcinoma after chemoembolization with pirarubicin, amiodarone and Lipiodol

Although chemoembolization is known to be an effective palliative treatment in hepatocellular carcinoma, it has a limited effect in large tumors. We report the case of a patient with a large hepatocellular carcinoma of the left liver who had a significant and sustained clinical response after six sessions of chemoembolization with a pirarubicin/amiodarone/lipiodol emulsion. Pirarubicin is an anthracycline which penetrates faster than doxorubicin into cancer cells. Amiodarone is a multidrug resistance inhibitor. Polysorbate 80, an excipient of injectable amiodarone stabilizes the anthracycline/lipiodol emulsion. The clinical efficacy of this new formulation could be evaluated in a phase II clinical trial.     

MIP-1alpha, MIP-1beta, RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines

We analyzed for the first time the expression of chemokines in subpopulations of the murine immune system at the single-cell level. We demonstrate in vitro and in a model of murine listeriosis that macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, regulated on activation normal T cell expressed and secreted (RANTES), and activation-induced, T cell-derived, and chemokine-related cytokine (ATAC)/lymphotactin are cosecreted to a high degree with IFN-gamma by activated individual natural killer (NK), CD8(+) T, and CD4(+) T helper 1 (Th1) cells. Functionally, ATAC and the CC chemokines cooperate with IFN-gamma in the up-regulation of CD40, IL-12, and tumor necrosis factor-alpha, molecules playing a central role in the effector phase of macrophages. Our data indicate that (i) MIP-1alpha, MIP-1beta, RANTES, and ATAC are not only chemoattractants but also coactivators of macrophages, (ii) MIP-1alpha, MIP-1beta, RANTES, and ATAC constitute together with IFN-gamma a group of "type 1 cytokines," and (iii) these cytokines act together as a functional unit that is used by NK cells in the innate phase and then "handed over" to CD8(+) T cells in the antigen-specific phase of the immune defense, thus bridging the two components of a Th1 immune reaction.