Summary This paper summarizes different theoretical and clinical approaches contributing to the concept of dose intensification. According to this concept, the amount of antineoplastic drug delivered per time predominantly determines the clinical outcome in patients with neoplastic disease. With the availability of recombinant haemopoietic growth factors haematotoxic side effects might be reduced, making this concept more feasible for clinical use. However, more prospective randomized studies, in which dose-intensity is the only treatment variable, are needed to prove that dose intensification will lead to higher survival rates.
Zusammenfassung In der vorliegenden Arbeit werden unterschiedliche theoretische und klinische Ansätze, die zu dem Konzept der Dosisintensivierung beigetragen haben, beschrieben. Dieses Konzept beinhaltet, daß die Dosierungen von verabreichten Zytostatika pro Zeiteinheit mitbestimmend für die erfolgreiche Behandlung von Patienten mit malignen Tumorerkrankungen sind. Durch den klinischen Einsatz von rekombinanten hämatopoetischen Wachstumsfaktoren können Nebenwirkungen auf das Knochenmark verringert werden, so daß das Konzept der Dosisintensivierung klinisch besser realisierbar wird. Prospektive randomisierte Studien, bei denen nur die Dosis-Intensität verändert wird, werden vermehrt erforderlich. Es wird sich dann erweisen, ob die Dosisintensivierung zu einer Lebensverlängerung beitragen kann.
Extrinsic denervation may be responsible for motor dysfunction after small bowel transplantation. The aim of this study was
to examine the role of extrinsic innervation of canine jejunum on contractile activity. An in vitro dose response of cholinergic
and adrenergic agonists was evaluated in canine jejunal strips of circular muscle at 0, 2, and 8 weeks in a control group
and after jejunoileal extrinsic denervation (EX DEN). Neurons in circular muscle were quantitated by means of immunohistochemical
techniques. Adrenergic and cholinergic responses did not differ at any time in the control group. However, at 2 and 8 weeks,
extrinsic denervation caused an increased sensitivity to the procontractile effects of the cholinergic agonist bethanechol
at the level of the smooth muscle cells, and increased sensitivity to the inhibitory effects of the adrenergic agent norepinephrine
mediated at the level of the enteric nervous system. Immunohistochemical analysis showed a reduction in all neurons and a
complete lack of adrenergic fibers in the EX DEN group after 2 and 8 weeks. Extrinsic denervation induces enteric neuronal
cholinergic and adrenergic smooth muscle hypersensitivity in canine jejunal circular muscle.
Presented in part at the annual meeting of the American Gastroenterological Association, Orlando, Florida, May 18, 1999 (poster
presentation), and published as an abstract in Gastroenterology 116:A1075, 1999.
Supported by United States Public Health Service grant DK39337 from the National Institutes of Health (M.G.S.); the Swiss
National Science Foundation; the Swiss Society of Gastroenterology and Hepatology; the Swiss Foundation for Medical and Biological
Science; the Novartis Foundation; Astra Zeneca Pharmaceuticals, Switzerland; and the Department of Visceral and Transplantation
Surgery, University of Bern, Switzerland. 相似文献
BACKGROUND: Genetic factors other than HLA have been reported to be associated with the outcome of organ transplantations. Because binding of FasL to its receptor Fas could play an important role in tubulitis and in the death of graft tubular epithelial cells during kidney allograft rejection, a gene polymorphism recently identified in position -671 in the promoter of the TNFRSF6 gene coding for Fas was investigated in donors. METHODS: A case-control study was performed within a cohort of non-hyperimmunized adult patients who had received cadaveric kidney transplants based on the occurrence or absence of acute cellular rejection in the first 6 months after renal transplantation. Each recipient from the acute rejection group (n = 35) was matched for age (+/- 5 years) and number of HLA-DR mismatches with two recipients within the non-acute rejection group (n = 70). RESULTS: The TNFRSF6-GG genotype was more frequent in donors in the group without rejection episodes. In contrast, patients who received a kidney from a TNFRSF6-A carrier were more likely to experience acute rejection episodes (relative risk nearly 2.1). CONCLUSION: This study suggests that donor TNFRSF6 polymorphism directly or indirectly influences acute kidney rejection episodes. 相似文献
Background: Percutaneous coronary intervention (PCI) is performed in patients with coronary artery disease who are undergoing major noncardiac procedures to reduce perioperative cardiac morbidity and mortality. However, the impact of this approach on postoperative outcome remains controversial.
Methods: The authors analyzed a cohort of 1,152 patients after abdominal aortic surgery in which 78 patients underwent PCI. A propensity score analysis was performed. Also, using a logistic regression model, the authors determined variables associated with a severe postoperative coronary event or a death in patients without PCI. Then, in patients with PCI, they compared the expected and observed outcome.
Results: Five variables (age > 75 yr, blood transfusion > 3 units, repeated surgery, preoperative hemodialysis, and previous cardiac failure) independently predicted (with 94% correctly classified) a severe postoperative coronary event, and five variables (age > 75 yr, repeated surgery, previously abnormal ST segment/T waves, previous hypertension, and previous cardiac failure) independently predicted (with 97% correctly classified) postoperative death. In the PCI group, the observed percentages of patients with a severe postoperative coronary event (9.0% [95% confidence interval, 4.4-17.4]) or death (5.1% [95% confidence interval, 2.0-12.5]) were not significantly different from the expected percentages (8.2 and 6.9%, respectively). When all patients were pooled together, the odds ratios of PCI were not significant. The propensity score analysis provided a similar conclusion. 相似文献
Alterations in protein synthesis following exposure to and recovery from hepatotoxic doses of acetaminophen (APAP) and its analogues, 3,5-dimethyl acetaminophen (3,5-DMA) and 2,6-dimethyl acetaminophen (2,6-DMA), were investigated in primary cultures of mouse hepatocytes. The rates of protein synthesis decreased within 4 hr after administration of 10 mM APAP and occurred after significant depletion of intracellular glutathione and covalent binding of APAP to proteins, but preceded the leakage of lactate dehydrogenase into the media. The inhibition of protein synthesis was reversible only if APAP exposure did not exceed 8 hr. Electrophoretic analysis of 35S-labeled proteins by one-dimensional SDS-PAGE revealed two consistent alterations in the patterns of newly synthesized proteins. First was a progressive diminution in the de novo synthesis of a protein migrating at approximately 58 kDa (p58). This was observed with APAP (10 mM) and 3,5-DMA (5 mM) but not with 2,6-DMA (10 mM). If exposure to APAP exceeded 8 hr, the biosynthesis of this protein was not only further decreased but was also no longer detectable during the recovery period. The second major alteration was an increase in the relative rate of biosynthesis of a 32-kDa protein (p32) following exposure and recovery from APAP and 3,5-DMA but not 2,6-DMA. Exposure to heme or arsenite induced the synthesis of a protein of similar molecular weight but did not result in the inhibition of p58 biosynthesis. The fact that the reactive metabolites of both APAP and 3,5-DMA, but not 2,6-DMA, possess oxidative properties suggests that the alterations in the synthesis of p32 and p58 may be related to an oxidative component induced by these compounds. 相似文献
Review of the current state of knowledge about Doppler diagnosis of pulmonary hypertension is presented. The authors compare the findings of numerous studies with their own data and analyse the causes of discrepancies and controversies that have remained to date. Doppler estimation of mean pulmonary artery pressure (PAP) using acceleration time (ACT) measurement in the right ventricular outflow tract or main pulmonary artery has been shown to correlate closely with simultaneously measured values of PAP both at rest and during exercise (r = -0.92 and -0.94, respectively). ACT values show sufficient sensitivity for the detection of pulmonary hypertension (89%), at maximum (100%) specificity. However, Doppler values not obtained simultaneously do not necessarily correlate with PAP in view of rapid physiological variations of PAP. For everyday diagnostic practice in cardiology, prediction based upon mere qualitative estimation of the type of velocity curve seems sufficient. Doppler diagnosis of pulmonary hypertension, little demanding on both technical skills and equipment, is gaining a priority status among the non-invasive methods available. 相似文献