The use of peptides as therapeutics & vaccines.
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Aging↗
Biomedical subjects
J Michaelis
Publications and source records attributed to J Michaelis.
Hydrochlorothiazide and verapamil in the treatment of hypertension. The Verapamil Versus Diuretic (VERDI) Trial Research Group.
The efficacy and tolerability of hydrochlorothiazide, sustained-release verapamil, and their combination was compared in patients with mild to moderate hypertension. The design was a multicenter, randomized, double-blind clinical trial with a single-blind placebo baseline period of 2 weeks. Three hundred sixty-nine patients with a diastolic blood pressure of 95-120 mm Hg were included. Treatment consisted of 12.5 mg of hydrochlorothiazide once daily, then 25 mg once daily, and finally 25 mg twice daily; the other group received verapamil at a dose of 120 mg once daily, then 240 mg once daily, and finally 240 mg twice daily. Patients not achieving target blood pressure (less than 90 mm Hg diastolic) were given the combination of hydrochlorothiazide and verapamil, that is, 25 and 240 mg once daily and twice daily. During all time points during the study patients receiving verapamil achieved target blood pressure more often than patients receiving hydrochlorothiazide (after 8 weeks, 57.7 and 42.7%; after 24 weeks, 46.8 and 26.4%; and after 48 weeks, 44.8 and 24.7%, respectively). Adding verapamil to hydrochlorothiazide was more effective in lowering blood pressure than adding hydrochlorothiazide to verapamil. The number of treatment withdrawals was essentially the same with the two drugs. Therefore, in the doses currently used in antihypertensive treatment, verapamil was more effective than hydrochlorothiazide as a single agent and in combination in mild to moderate hypertension.
Adult↗
Elements of significance testing with equivalence problems.
The paper outlines an approach to the general methodological problem of equivalence assessment which is based on the classical theory of testing statistical hypotheses. Within this frame of reference it is natural to search for decision rules satisfying the same criteria of optimality which are customarily applied in deriving solutions to one- and two-sided testing problems. For three standard situations very frequently encountered in medical applications of statistics, a concise account of such an optimal test for equivalence is presented. It is pointed out that tests based on the well-known principle of confidence interval inclusion are valid in the sense of guaranteeing the prespecified level of significance, but tend to have an unnecessarily low efficiency.
Confidence Intervals↗
Human neutrophil collagenase cleaves alpha 1-antitrypsin.
Inactivation of the plasma serine-proteinase inhibitor alpha 1-antitrypsin (alpha 1-AT) by neutrophil metalloproteinases has been reported [Vissers, George, Bathurst, Brennan & Winterbourn (1987) Fed. Proc. Fed. Am. Soc. Exp. Biol. 46, 1390a; (1988) J. Clin. Invest. 82, 706-711; Desrochers & Weiss (1988) J. Clin. Invest. 81, 1646-1650]. To identify the enzyme responsible, supernatant from neutrophils stimulated with phorbol 12-myristate 13-acetate was subjected to preparative SDS/PAGE, both with and without activation of latent metalloproteinases with HgCl2. The lanes were subsequently sliced into pieces, the slices incubated with equimolar amounts of type I collagen and alpha 1-AT in the presence of HgCl2, and the reaction products separated by SDS/PAGE. With the latent supernatant, the characteristic collagen-cleavage products and cleaved alpha 1-AT were present in the same slices, corresponding to an Mr of 80,000-85,000. On treatment with HgCl2 both degradative activities underwent the same molecular-mass shift to a position corresponding to Mr 60,000-65,000. Western blots of neutrophil supernatants, using a polyclonal antibody to purified collagenase, showed Mr values of 83,000 for the latent enzyme and 63,000 for the HgCl2-activated enzyme. Neutrophil collagenase was purified to homogeneity and shown also to exist in a second latent form with Mr 70,000. When activated to the Mr-63,000 form by HgCl2 and incubated with equimolar amounts of collagen and alpha 1-AT, collagenase cleaved alpha 1-AT at almost twice the rate at which collagen was cleaved. alpha 1-AT cleavage was inhibited by 1,10-phenanthroline and by high concentrations of collagen. That the purified collagenase did not contain a contaminant proteinase such as stromelysin was indicated by inability of the preparation to cleave casein. Taken together these results lead us to conclude that neutrophil collagenase is capable of degrading alpha 1-AT. Neutrophil gelatinase also cleaved alpha 1-AT, but cleavage was slow when compared with its activity against gelatin.
Caseins↗
[The importance of preoperative chemotherapy and radiotherapy in 373 children with Wilms' tumor].
Between 1980 and 1988, in a prospective study of 373 children with Wilms' tumour throughout the Federal Republic of Germany, the results of various pre- and postoperative treatment schedules were analysed. There were 184 boys and 189 girls, mean age 3 11/12 (0-27) years. One third each was in group I, II or III-V, respectively. In 52% of cases the tumour volume, measured by ultrasound, was more than 400 ml. 218 of the children were called protocol patients, the remaining 155 served as observation patients, because the latter had histological variants or there had been marked treatment deviations. The stage-adapted treatment always included operation, in 30% of children after pre-operative chemo- or radiotherapy. Radiotherapy was given in selected patients in stage II and always to those in stages III, IV or V. Chemotherapy consisted of Actinomycin D and vincristine, adriamycin was added for stages III-V and cyclophosphamide or ifosfamide for histologically highly malignant variants. Of the 218 protocol patients 196 (90%) were alive without recurrence, after a mean observation time of more than 7 years. Radiotherapy was given to only 105 of the 218 protocol patients. The prognosis of the 155 observation patients differed according to the histology: those with clear-cell type had a better prognosis than previously reported. Among the total group of 373 patients 305 (81.8%) have remained without recurrence after more than 6 years.
Adolescent↗
The activation of human neutrophil gelatinase.
To study the mechanisms of activation of human neutrophil gelatinase, the enzyme has been purified using a combination of chromatography on a DEAE-Sephacel and a gelatin-peptide-Sepharose column. On reducing SDS-polyacrylamide-gel electrophoresis the purified gelatinase ran as a single band of about 94,000 Da, and had a specific activity of 5624.4 units/mg of enzyme protein. When latent gelatinase was treated with trypsin, cathepsin G, neutrophil elastase, HgCl2 or urea, its activity was enhanced and the enzyme was processed and converted into species of the lower molecular mass. Upon activation, the protein band of 94,000 Da of reduced latent gelatinase underwent a decrease of about 6,000-12,000 Da. Formation of the species of lower molecular mass during urea activation could be blocked by the addition of EDTA.
Chromatography, Affinity↗
Use of information from clinical trials for an integrated cancer registry.
The registry of childhood malignancies in the F.R.G. is a combination of a population-based and hospital-based cancer registry. A large amount of the collected data originates from multicenter clinical trials which are integrated into the documentation system of the cancer registry. The paper describes the information flow and the system of data storage which consists of a central database on a departmental system at the registry and of several coordinated peripheral databases on microcomputers at the trial centers. Practical experience shows an increased availability and validity of the data in the registry since the implementation of the system. Aspects of data integrity and security are discussed. Although the system was designed according to specific demands of the registry, it may serve as a model for similar tasks of cooperative documentation and information exchange.
Child↗
Reference standards for software evaluation.
The field of automated ECG analysis was one of the earliest topics in Medical Informatics and may be regarded as a model both for computer-assisted medical diagnosis and for evaluating medical diagnostic programs. The CSE project has set reference standards of two kinds: In a broad sense, a standard how to perform a comprehensive evaluation study, in a narrow sense, standards as specific references for evaluating computer ECG programs. The evaluation methodology used within the CSE project is described as a basis for presentation of results which are published elsewhere in this issue.
Diagnosis, Computer-Assisted↗
Evaluation of ECG interpretation results obtained by computer and cardiologists.
In an international project investigators from 25 institutes are trying to establish a common reference library and evaluation methods for testing the diagnostic performance of various ECG computer programs and of cardiologists, based on ECG-independent clinical information. A first set of 500 validated ECGs was collected and analyzed by fifteen different computer programs and nine cardiologists, seven of who analysed the ECG and five the VCG. A coding scheme was used to map individual diagnostic statements onto a common set. Combined program and referee results were obtained by weighted averaging. Preliminary results indicate that the classification accuracy of several programs can still be improved. However, it was also apparent that the results of the best 12-lead ECG computer programs proved to be almost as accurate as the best of seven cardiologists in classifying seven main disease categories, i.e., normal, left, right and biventricular hypertrophy, anterior, inferior and combined myocardial infarction. Evaluation of rhythm statements and conduction disturbances was not included in the study. The data collection is still being pursued in order to reach over 1,000 cases. In this way a common diagnostic database is being established for comparative testing of diagnostic computer programs. This should lead to consumer protection and improve the accuracy and reliability of computerized electrocardiography.
Cardiovascular Diseases↗
Verapamil versus hydrochlorothiazide in the treatment of hypertension: results of long term double blind comparative trial. Verapamil versus Diuretic (VERDI) Trial Research Group.
OBJECTIVE: To compare the efficacy and tolerability of hydrochlorothiazide, sustained release verapamil, and their combination in patients with mild to moderate hypertension. DESIGN: Randomised multicentre trial of 48 weeks' duration with a double blind comparison of hydrochlorothiazide and verapamil followed by an open trial of combined treatment for patients not achieving the target diastolic blood pressure (less than 90 mm Hg) during treatment with a single drug. SETTING: Outpatient departments in 10 clinics and 10 private practices of general practitioners or internists. PATIENTS: 369 Hypertensive patients with a diastolic blood pressure of 95-120 mm Hg during a placebo run in period of two weeks. INTERVENTIONS: Initial treatment consisted of 12.5 mg hydrochlorothiazide (n = 187) or 120 mg sustained release verapamil (n = 182) once daily (regimen I). If the target diastolic blood pressure of less than 90 mm Hg was not achieved within four weeks doses were increased to 25 mg hydrochlorothiazide or 240 mg verapamil once (regimen II) and twice daily (regimen III). Patients not achieving target blood pressure were given the combination of hydrochlorothiazide and verapamil--that is, 25 and 240 mg once (regimen IV) and twice daily (regimen V). MAIN OUTCOME MEASURE: Blood pressure determined with a device permitting automatic repeated measurements with printouts. RESULTS: After eight weeks of treatment with a single drug 76 out of 178 (43%) and 101 out of 175 (58%) patients achieved the target blood pressure with hydrochlorothiazide and verapamil, respectively. During follow up until 48 weeks patients treated with verapamil reached the target blood pressure more often and at lower doses and were less likely to switch to combination treatment than patients randomised to hydrochlorothiazide treatment. Adding verapamil to hydrochlorothiazide was more effective than the addition of hydrochlorothiazide to verapamil. At the end of the study 42 out of 169 (25%) and 73 out of 163 (45%) patients initially randomised to hydrochlorothiazide and verapamil, respectively, were at target blood pressure without combination treatment. After adding verapamil to hydrochlorothiazide or hydrochlorothiazide to verapamil an additional 58 (34%) and 29 (18%) patients reached the target blood pressure, respectively. Altogether 92 out of 332 (28%) patients failed to achieve target blood pressure with regimen V. There were four, 10, seven, and seven withdrawals due to possible adverse effects to treatment with hydrochlorothiazide, verapamil, combining verapamil with hydrochlorothiazide, and combining hydrochlorothiazide with verapamil, respectively. CONCLUSIONS: In doses currently used in antihypertensive treatment verapamil was more effective than hydrochlorothiazide as a single agent and in combination in mild to moderate hypertension, whereas withdrawal rates caused by side effects possibly related to treatment were similar.
Adult↗
Attitudes to early retirement and the possible connection with subsequent mortality from cardiovascular diseases after 15 years of follow-up.
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Attitude↗
Tissue kallikrein effectively activates latent matrix degrading metalloenzymes.
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Animals↗
Enzyme linked immunosorbent assays (ELISA) for the quantitative determination of human leukocyte collagenase and gelatinase.
A competitive and a sandwich enzyme linked immunosorbent assay (ELISA) were developed for human leukocyte collagenase and gelatinase. The competitive assay could detect 0.5 ng collagenase and 0.05 ng gelatinase. The detection limit of the sandwich ELISA was 0.05 ng for collagenase and 0.02 ng for gelatinase. No cross reactivity between human leukocyte collagenase and gelatinase was detected. The sandwich ELISA was used to determine plasma levels of these enzymes. The 90% range for collagenase was between 0 and 50 micrograms/l; the 90% range for gelatinase was between 27 and 94 micrograms/l.
Blotting, Western↗
Teaching medical informatics to medical students in the Federal Republic of Germany.
The medical curriculum in the Federal Republic of Germany (FRG) is regulated by federal legislation. Medical informatics is part of this curriculum and is therefore taught by all 27 medical faculties in the FRG, 24 of which have related departments. The teaching situation in general and the specific approach at the author's department are described.
Attitude to Computers↗
Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial.
The German Society of Pediatric Oncology in 1981 initiated the Cooperative Ewing's Sarcoma Study (CESS 81) using a four-drug combination of chemotherapy prior to definitive local control with surgery and/or radiation. From January 1, 1981 until February 28, 1985, 93 patients were registered at the trial office from 54 participating institutions in West Germany, Austria, Switzerland, and the Netherlands. On February 1, 1987, 54 of 93 patients were disease-free. Using the Kaplan-Meier life table analysis, the estimated disease-free survival (DFS) rate was 60% at 36 months and 55% at 69 months. The median period of observation was 29 months, ranging from 22 months to 69 months. Twenty-one of 93 patients (23%) had local failure, 18 of 93 patients (19%) developed systemic metastases. The local failure rate was particularly high in patients treated with radiation and was reduced when radiation planning was centralized within the study based upon the extent of disease at diagnosis. Cox regression analysis of prognostic factors showed that tumor volume was a significant factor influencing prognosis. The estimated 3-year DFS rate was 80% for patients with small tumors (volume less than 100 ml) compared to 31% for patients with large tumors (volume greater than or equal to 100 ml). In patients who had surgery for local control, the histologic response to chemotherapy was analyzed on the surgical specimen and had a strong influence on survival: 79% DFS at 3 years for patients with less than 10% viable tumor (good responders) compared to 31% DFS for patients with more than 10% viable tumor (poor responders). Tumor load and responsiveness to chemotherapy are the two major factors influencing prognosis in patients with primary Ewing's sarcoma of bone.
Adolescent↗
Prognostic factors in the treatment of Ewing's sarcoma. The Ewing's Sarcoma Study Group of the German Society of Paediatric Oncology CESS 81.
From 1981 up to February 1985, a total of 93 protocol patients entered the study CESS 81. The protocol recommended an initial 18-week period of polychemotherapy (VACA) followed by local therapy and two additional cycles of chemotherapy. Local therapy consisted either of radical surgery or of incomplete resection plus postoperative irradiation with 36 Gy or of radiotherapy alone (46 and 60 Gy). Centrally located lesions were always irradiated with 60 Gy. This article summarizes the data after 5 years. Data of 93 patients were analysed in October 1986 after a median follow-up of 37 months. The projected 5-year survival is 50%. The relapse rate was 42%, distant relapses occurred in 19%, local (plus distant) relapses in 23%. Most of the relapses occurred during the first 3 years of observation. Failure rate was high in patients undergoing irradiation alone (44%). Initial tumour mass (greater than 100 ml) and histopathologic response to initial chemotherapy were identified as major prognostic factors. Tumour site and type of local therapy were not significant if patients were categorised by tumour volume. In small lesions, surgery and radiotherapy were equally effective. In large lesions greater than 100 ml volume, a trend towards a better prognosis in surgically treated patients was observed. The results of CESS 81 emphasize the importance of permanent local control in Ewing's sarcoma even in the presence of systemic control by an effective multi-drug chemotherapy.
Adolescent↗
[Cooperative documentation of neoplasms in childhood. Assessment of over 6,000 new illnesses in West Germany since 1980].
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Adolescent↗