Research ethics committee audit: differences between committees.

The same research proposal was submitted to 24 district health authority (DHA) research ethics committees in different parts of the country. The objective was to obtain permission for a multi-centre research project. The study of neonatal care in different types of unit (regional, subregional and district), required that four health authorities were approached in each of six widely separated health regions in England. Data were collected and compared concerning aspects of processing, including application forms, information required, timing and decision-making. The key finding was that ethics committees received and processed the applications variably, reflecting individual factors and local problems. To improve consensus and facilitate multicentre studies, standard forms and instructions are suggested and the establishment of a national committee or advisory group advocated.     

Intensivtherapie und Prognose des akuten Kreislaufstillstandes

Zusammenfassung Anhand von 115 im Zeitraum von 2 1/2 Jahren beobachteten Episoden von akutem Kreislaufstillstand bei 90 Patienten werden die Kriterien und Behandlungserfolge der Intensivtherapie des akuten Kreislaufstillstandes dargelegt. Während die Basis-Therapie mit externer Herzmassage, künstlicher Beatmung, Natriumbicarbonatinfusionen und elektrischer Defibrillation eindeutig feststeht, bietet die medikamentöse Führung noch immer Probleme. Zehn eigene Verlaufsbeobachtungen zeigen, daß betaadrenergische Sympathomimetica auch bei bestimmten Fällen tachysystolischer Herzrhythmusstörungen günstig wirken. Der Versuch der elektrischen Stimulation des Herzens mit einer extern angelegten epikardialen Schrittmachersonde bei akutem Kreislaufstillstand durch Asystolie oder Bradykardie führte in keinem von 8 Fällen zum Erfolg. Für die Früh- und Spätprognose sind bei adäquater Therapie in erster Linie Art und Schwere des Grundleidens sowie der morphologisch funktionelle Zustand lebenswichtiger Organe bei Einsetzen des plötzlichen Kreislaufstillstandes verantwortlich. Bei Kammerflimmern und Kammerflattern waren deutlich bessere Resultate zu erzielen, als beim akuten Kreislaufstillstand durch Asystolie. Von den 90 Patienten überlebten 12 länger als 4 Wochen (13%), 9 (10%) konnten entlassen werden und sind zum Zeitpunkt der Publikation ohne Nachwirkungen des akuten Kreislaufstillstandes. Es wird auf die Bedeutung einer lückenlosen Beobachtung Schwerstkranker und die Beachtung prämonitorischer Zeichen zur Verhütung des akuten Kreislaufstillstandes hingewiesen.

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Summary Criteria and therapeutic success of intensive therapy of cardiac arrests are evaluated in 115 episodes observed in 90 patients over a period of 2 1/22 years. While basic therapy with external cardiac massage, artificial ventilation, infusion of sodium bicarbonate and electrical defibrillation is generally agreed upon, the choice of further drugs is still problematic. It is shown in 10 cases that under certain conditions even in ventricular fibrillation and ventricular tachycardia beta-receptor stimulating drugs are indicated. Electrical stimulation of the heart by an external epicardial pacemaker was unsuccessful in all of eight cases with complete asystoly or bradycardia. Immediate and long term results of cardiac arrests with adequate treatment primarely depends on the extend of the underlying disease as well as on the condition of all vital organs at the time of onset of the arrest. Ventricular fibrillation and -flutter had a better prognosis than asystoly. Twelve out of the ninety patients lived longer than four weeks after the arrest (13%). Nine of these are still living at the time of publication with an observation time from three months to two years. The chance of improving therapeutic results with intensive care lie mainly in preventing rather than curing complications such as cardiac arrests.

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Professor Dr.H. E. Bock zum 65. Geburtstag.     

Gene therapy for sarcoma

Soft tissue sarcomas are mesenchymal tumors which respond poorly to systemic therapy. Recent studies suggest a higher response rate with an increased doxorubicin dosage. However, this was parallel with a profound hematotoxicity in 75% of patients. Transfer of the human multidrug resistance 1 (MDR1) gene to normal hematopoietic stem cells and transplantation may significantly reduce the hematotoxicity of anthracyclin-based chemotherapy. To test this concept of supportive gene therapy in advance of a clinical study, we transduced mobilized peripheral blood progenitor cells (PBPC) with the retroviral vector SF91m3 containing the human MDR1 gene, transplanted these cells to immune-deficient mice, allowed 6 weeks for engraftment to occur and treated the animals with MDR1-based chemotherapy. In the MDR1-transduced group the human leukocytes were significantly protected from the toxicity of chemotherapy (p < 0.05). While the gene transfer rate was in the range of 10% and thus comparable to recent clinical trials, the gene expression was 59% of transduced cells and thus significantly higher than previously reported for less-advanced vectors. On the other hand, ifosfamide, a drug which has been used successfully for stem cell mobilization, is active in soft tissue sarcoma. Due to these favorable characteristics sarcoma is an attractive target to test the efficacy of MDR1 gene therapy in a clinical setting. Gene therapeutic strategies may also be used to directly target sarcoma cells, e.g. by transfer of suicide genes. We found that adenoassociated virus 2 (AAV-2) vectors efficiently transduce human HS-1 and HT1080 sarcoma cells (>90%) while other tumor cell lines and primary human PBPC were less susceptible. The thymidine kinase (TK) suicide gene was cloned into an AAV-2 vector and a complete kill of TK-transduced HS-1 and HT1080 cells was observed following exposure to aciclovir or ganciclovir (GCV), while >90% of mock-transduced HS-1 cells survived at these dosages. Transplantation of those sarcoma cells to nonobese diabetic (NOD)/LtSz-severe-combined immunodeficient (scid)/scid (NOD/SCID) mice resulted in a survival of >5 months in the AAV-TK-transduced/GCV-treated group, while the mice in the mock-transduced/GCV-treated group had died after 3 weeks. These data show that soft tissue sarcomas are a particularly suitable model system for the development and clinical testing of new gene therapeutic concepts.     

Impact of selenium status on the pathogenesis of mycobacterial disease in HIV-1-infected drug users during the era of highly active antiretroviral therapy

The risk of mycobacterial disease is significantly increased in drug abusers as well as in immunocompromised HIV-1-infected individuals. The essential trace element selenium has an important function in maintaining immune processes and may, thus, have a critical role in clearance of mycobacteria. The impact of selenium status on the development of mycobacterial diseases in HIV-1-seropositive drug users was investigated over a 2-year period (1999-2001). Twelve cases of mycobacterial disease (tuberculosis, 9; infection due to atypical Mycobacterium species, 3) occurred; these 12 cases were compared with 32 controls with no history of respiratory infections who were matched on age, sex, and HIV status. Significant risk for development of mycobacterial disease was associated with a CD4 cell count of <200/mm 3, malnutrition, and selenium levels of 相似文献   

Frequent allelic loss of 21q11.1 approximately q21.1 region in advanced stage oral squamous cell carcinoma

A fine mapping of loss of heterozygosity (LOH) was performed in oral squamous cell carcinoma (OSCC), using 12 markers on 21q11.1 approximately q21.1. We studied 43 resected primary invasive tumors and their paired normal tissues, concurrent dysplasia or carcinoma in situ in separate areas from 8 of the specimens, and 6 local recurrent carcinomas. LOH status was compared between lesions of different phases of progression within the same patient. A high frequency of LOH was observed for D21S1410, D21S120, and D21S1433 (60% each) in the primary lesions, constituting two interstitial deleted regions encompassing eight known genes. Cases showing LOH of D21S120 were significantly associated with advanced clinical stages (III and IV; P=0.02). Consistent allelic loss was observed in 64.2% of the informative cases between the precursor lesions and their corresponding invasive tumors, and in 59.5% of those between the primary lesions and their recurrent counterparts. Fewer than half of the different lesions within a given patient showed discordant allelic loss for tested markers. Our results suggest that 21q11.1 approximately q21.1 harbors tumor suppressor genes in OSCC. Genetic divergence may develop during tumor clone evolution.     

Autosensitization by Sperm in Guinea Pigs

Guinea pigs injected intradermally with homologous sperm or testis in Freund's adjuvant developed the following manifestations of hypersensitivity: (a) histamine release from lung after treatment with antigen in vitro; (b) Schultz-Dale reactions (occasionally); (c) antibodies capable of passive sensitization in vitro (passive sensitization demonstrated by histamine release); (d) antibodies immobilizing sperm in presence of complement; (e) skin reactions with an immediate and a delayed component.

Autologous and homologous guinea-pig sperm or testis were equally active as antigens in producing histamine release from sensitized lung. Boar and rat sperm and guinea-pig kidney and brain were inactive. Although living sperm acted as an effective antigen its activity increased after freezing and thawing, when most of the activity was present in the supernatant. The antigen in sperm is stable at 56° but appreciable inactivation, increasing with time, occurs at 100°.

Attempts to transmit the hypersensitivity by transference of lymph node cells into the skin of normal recipients have been unsuccessful. Some evidence was obtained that testis sensitized cells per se produce local reactions which are greater than those of normal cells.

Fixation of antibody on the acrosomal portions of sperm was demonstrated by means of fluorescein tagged anti-globulin serum. The possibility is discussed that the antigenic activity of sperm may be due to a mucopolysaccharide.

     

Serotypes of beta-hemolytic Treponema hyodysenteriae.

Cultures form 13 isolates of pathogenic, beta-hemolytic Treponema hyodysenteriae from 11 geographically separate outbreaks and 2 experimentally induced cases of swine dysentery were lyophilized and extracted with hot phenol-water. The resulting water phases were examined serologically with antisera produced in rabbits against whole-cell bacterins of the 13 isolates for evidence of antigenic classes within the species. Water-phase antigens gave precipitin reactions with homologous antisera. Results from cross-testing of each water phase with each antiserum showed four serologically distinct groups among the isolants examined. Based on precipitin reactions in agarose gel, four serotypes of pathogenic, beta-hemolytic T. hyodysenteriae are proposed.     

Specific and nonspecific immune factors in dental plaque fluid and saliva from young and old populations.

Separate samples of supragingival dental plaque overtly free of blood were centrifuged to obtain the free fluid phase (plaque fluid). Bound protein was eluted from the plaque bacteria and matrix by washing the plaque with a low-pH buffer. The plaque fluid, low pH eluate, and whole saliva were assayed for immunoglobulins A, G, and M, the third component of complement, lysozyme, lactoferrin, and lactoperoxidase. Concentrations of total protein and albumin were also determined. Antibody reactive with specific plaque bacteria was detected by indirect immunofluorescent microscopy. Specific and nonspecific immune proteins were present in plaque fluid from adult subjects at significantly greater concentrations than in their saliva, which suggests that these proteins are concentrated in dental plaque. The results indicate that both saliva and gingival exudate contribute to the immunological proteins found in the free fluid phase of dental plaque. The observation that immunoglobulin A antibody reactive with plaque bacteria could be detected in plaque fluid suggests that a wide variety of immunological reactions may occur in the dental plaque. These potential interactions between host, plaque bacteria, and their products could serve to influence the plaque flora and its ability to induce disease.     

Antimicrobial resistance of Escherichia coli and therapeutic implications

Widespread antibiotic resistance has been recognized in Escherichia coli isolates from human, animal and environmental sources. Although prevalence rates for resistant E. coli strains are significantly distinct for various populations and environments, the impact of resistance to antimicrobial drugs is ubiquitous. This article provides information about the epidemiology, mechanisms and molecular principles of resistance, shows consequences for the antiinfective treatment of selected infections and describes measures to control the spread of antibiotic-resistant E. coli.     

Treatment simulation approaches for the estimation of the distributions of treatment quality parameters generated by geometrical uncertainties

Geometric uncertainties arise during treatment planning and treatment and mean that dose-dependent parameters such as EUD are random variables with a patient specific probability distribution. Treatment planning with highly conformal treatment techniques such as intensity modulated radiation therapy requires new evaluation tools which allow us to estimate this influence of geometrical uncertainties on the probable treatment dose for a planned dose distribution. Monte Carlo simulations of treatment courses with recalculation of the dose according to the daily geometric errors are a gold standard for such an evaluation. Distribution histograms which show the relative frequency of a treatment quality parameter in the treatment simulations can be used to evaluate the potential risks and chances of a planned dose distribution. As treatment simulations with dose recalculation are very time consuming for sufficient statistical accuracy, it is proposed to do treatment simulations in the dose parameter space where the result is mainly determined by the systematic and random component of the geometrical uncertainties. Comparison of the parameter space simulation method with the gold standard for prostate cases and a head and neck case shows good agreement as long as the number of fractions is high enough and the influence of tissue inhomogeneities and surface curvature on the dose is small.