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Biomedical subjects

R Simon

Publications and source records attributed to R Simon.

At least 37 records · Page 2Linked to original sources
PubMed1995

Investigating a sequence of randomized phase II trials to discover promising treatments.

We consider clinical trial strategies to study diseases in which there is rapidly developing technology. We assume the availability of a limited number of patients for screening treatments over a time horizon, and that availability of new treatments for test is staggered over time. We assume further that patient response is binary and rapidly observable. We consider the strategy of conducting a sequence of two-armed randomized clinical trials. We carry over the treatment with the larger number of observed successes on the current trial to the next trial for comparison with a new treatment, with this process repeated at each step. For a fixed total number of patients (N), the number of trials one may conduct in sequence (k) is inversely related to the sample size per trial (2n), N = 2nk. We investigate how k and n influence (a) the expected success probability for the treatment selected at the end, and (b) the expected number of total successes for the N patients. The ultimate objective is to select one treatment, the winner at stage k, to test against a standard regimen in a randomized comparative phase III trial.

Clinical Trials, Phase II as Topic↗
PubMed1995

Human ciliary neurotrophic factor: a structure-function analysis.

Ciliary neurotrophic factor (CNTF) promotes survival in vitro and in vivo of several neuronal cell types including sensory and motor neurons. The primary structure of CNTF suggests it to be a cytosolic protein with strong similarity to the alpha-helical cytokine family which is characterized by a bundle of four anti-parallel helices. CNTF exerts its activity via complexation with CNTF receptor (CNTF-R). This complex consists of a CNTF-binding protein (CNTF-R) and two proteins important for signal transduction [gp130 and leukaemia inhibitory factor receptor (LIF-R)]. We have shortened the cDNA coding for CNTF at both the 5' and the 3' end and expressed the truncated proteins in bacteria. Biological activities of the protein preparations were determined by their ability to induce proliferation of BAF/3 cells that were stably transfected with CNTF-R, gp130 and LIF-R cDNAs. CNTF proteins with 14 amino acid residues removed from the N-terminus were biologically active whereas the removal of 23 amino acids resulted in an inactive protein. In addition, 18 amino acid residues could be removed from the C-terminus of the CNTF protein without apparent loss of bioactivity, but further truncation at the C-terminus yielded biologically inactive proteins. The introduction of two point mutations into the CNTF protein at a site that presumably interacts with one of the two signal-transducing proteins resulted in a CNTF mutant with no measurable bioactivity. In addition, a model of the three-dimensional structure of human CNTF was constructed using the recently established structural co-ordinates of the related cytokine, granulocyte colony-stimulating factor. CD spectra of CNTF together with our mutational analysis and our three-dimensional model fully support the view that CNTF belongs to the family of alpha-helical cytokines. It is expected that our results will facilitate the rational design of CNTF mutants with agonistic or antagonistic properties.

Amino Acid Sequence↗
PubMed1995

[Fatal Aspergillus sepsis following orthotopic heart transplantation].

In a 64-year-old man heart transplantation had been performed for ischaemic heart disease. 7 months later severe vascular disease in the transplant necessitated a second transplantation. Both procedures had been performed under immunosuppression (cyclosporine, azathioprine, prednisolone, antithymocyte globulin), with a subsequent prednisolone maintenance dose of 10 mg daily. At first there were no complications, but 31 days after the re-transplantation atrial flutter developed. Although this was quickly terminated by drugs, circulatory failure set in. Because of signs of infection (white blood cell count 29,800/microliters, 17% stab cells, C-reactive protein 24 mg/l) broad-spectrum antibiotics were administered, but without response. As a trial anti-rejection treatment was started (prednisolone 250 mg daily: antithymocyte globulin 100 mg daily for 4 days). When cytomegalovirus (CMV) infection was demonstrated, ganciclovir and CMV hyperimmunoglobulin were administered and slow improvement was noted. The finding of Aspergillus in tracheal secretion was interpreted as apathogenic colonization. The patient died from cardiorespiratory failure 57 days after the second transplantation. Autopsy revealed Aspergillus sepsis.

Aspergillosis↗
PubMed1995

Site-directed mutagenesis of human CNTF: functional analysis of recombinant variants.

Ciliary neurotrophic factor (CNTF), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and oncostatin M (OSM) share functional properties, a predicted common helical framework, and partially identical receptor components. CNTF is a survival promoting factor for various types of neurons in vitro and in vivo. In the present study, structural features essential for the biological function of human CNTF were investigated. Several recombinant CNTF variants were constructed by PCR and expressed in E. coli. Their survival promoting activities were determined using cultures of embryonic chick and newborn rat dorsal root ganglion cells. Deletion of 14 N-terminal and 18 C-terminal amino acids significantly increased bioactivity compared to wild-type (wt) CNTF. Further truncation of the CNTF molecule at the N- or C-terminus resulted in a significant reduction or complete loss of activity. Substitution of two amino acids (Lys154Glu and Trp157Pro) abolished the survival promoting effect. Recently described analogous substitutions in IL-6 had resulted in a partial IL-6 receptor antagonist. However, the double substitution variant had no significant inhibitory effect on wtCNTF activity in assays with both wt and mutant factor. The CNTF variants constructed had almost identical effects on both chick and rat neurons indicating a close similarity of the avian and the mammalian CNTF receptor complex. The present results also demonstrate that a core segment of the CNTF molecule is indispensable for biological function. Analogous segments important for activity have already been identified in the related molecules IL-6, LIF, and OSM. Thus, our data confirm the close structural relationship of CNTF to these "neuropoietic" cytokines. In addition, they demonstrate that site-directed mutagenesis of recombinant human CNTF can yield molecules which show increased survival promoting activity on mammalian neurons.

Animals↗
PubMed1995

The CONSTANS gene of Arabidopsis promotes flowering and encodes a protein showing similarities to zinc finger transcription factors.

The vegetative and reproductive (flowering) phases of Arabidopsis development are clearly separated. The onset of flowering is promoted by long photoperiods, but the constans (co) mutant flowers later than wild type under these conditions. The CO gene was isolated, and two zinc fingers that show a similar spacing of cysteines, but little direct homology, to members of the GATA1 family were identified in the amino acid sequence. co mutations were shown to affect amino acids that are conserved in both fingers. Some transgenic plants containing extra copies of CO flowered earlier than wild type, suggesting that CO activity is limiting on flowering time. Double mutants were constructed containing co and mutations affecting gibberellic acid responses, meristem identity, or phytochrome function, and their phenotypes suggested a model for the role of CO in promoting flowering.

Alleles↗
PubMed1995

A neural network model for survival data.

Neural networks have received considerable attention recently, mostly by non-statisticians. They are considered by many to be very promising tools for classification and prediction. In this paper we present an approach to modelling censored survival data using the input-output relationship associated with a simple feed-forward neural network as the basis for a non-linear proportional hazards model. This approach can be extended to other models used with censored survival data. The proportional hazards neural network parameters are estimated using the method of maximum likelihood. These maximum likelihood based models can be compared, using readily available techniques such as the likelihood ratio test and the Akaike criterion. The neural network models are illustrated using data on the survival of men with prostatic carcinoma. A method of interpreting the neural network predictions based on the factorial contrasts is presented.

Diethylstilbestrol↗
PubMed1995

Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels.

PURPOSE: In patients with septic shock, to (1) determine the incidence of adrenal insufficiency (AI), (2) observe the effects of glucocorticoid therapy on outcome in those with impaired adrenal function, and (3) investigate a possible correlation between adrenal function and peripheral cytokine levels. PATIENTS AND METHODS: Twenty-one patients admitted to the medical and surgical intensive care unit with septic shock and 11 healthy volunteers were studied. Cortisol, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) levels were measured before and after infusion of low (1 microgram) and standard doses (250 micrograms) of adrenocorticotropic hormone (ACTH) within 24 hours of the diagnosis of septic shock. Patients with subnormal adrenal responses to ACTH were treated with stress doses of steroids. Hormone, cytokine, and survival data in patients with normal response were compared to those with subnormal adrenal function. RESULTS: Five patients (23.8%) exhibited AI by ACTH stimulation testing. Three of them received steroid supplementation with rapid improvement in hemodynamic parameters. Autopsies of 2 patients with AI revealed intact adrenal cortices. Sixteen patients had adequate adrenal responses (AAR) to the standard-dose ACTH infusion. TNF-alpha levels were inversely correlated with mean arterial pressure (MAP) (r = -.52, P = 0.038) in AAR but not AI. There was no difference in mean peripheral TNF-alpha levels between AAR and AI. There was no correlation between TNF-alpha levels and mortality or adrenal function in those with septic shock. A trend toward lower IL-6 levels in AI suggests a link between reduced IL-6 levels and understimulation of the pituitary-adrenal axis in this group. Mortality in patients with AI was 80% at 4 weeks as compared with 43.8% in the group with normal adrenal response. CONCLUSIONS: Adrenal hyporesponsiveness is a feature of septic shock in some patients. Its etiology is probably complex. Steroid supplementation appeared to improve short-term survival when AI occurred, although these patients' overall mortality was worse than that of patients with septic shock and AAR. The standard-dose (250 micrograms) rapid ACTH infusion test was adequate for detecting AI. Adrenal insufficiency should be suspected in patients with septic shock who do not respond to conventional treatment. Performing the ACTH infusion test and initiating a trial of stress doses of glucocorticoids pending the results is a reasonable strategy in this situation.

Adrenal Insufficiency↗
PubMed1995

Evaluation of recombinant hirudin (CGP 39,393/TMREVASC) in the prevention of restenosis after percutaneous transluminal coronary angioplasty. Rationale and design of the HELVETICA trial, a multicentre randomized double blind heparin controlled study.

One of the main areas of interest in interventional cardiology is the understanding, and ultimate prevention of restenosis after an initially successful percutaneous transluminal coronary angioplasty. Restenosis is the recurrence of luminal narrowing following angioplasty, and still frustrates the late results in the treatment of angina pectoris. Experimental, pathological and clinical studies suggest that restenosis may occur via activation of the coagulation cascade, platelet activation and thrombus formation. Thrombin itself is identified as the most potent platelet activator, and has a pivotal role in the coagulation system. Furthermore, thrombin directly mediates smooth muscle cell proliferation by stimulating thrombin receptors at the smooth muscle cell surface. Thrombus indirectly induces excessive intimal smooth muscle cell proliferation by means of released mitogens (growth factors), which may contribute to late restenosis. Therefore direct and irreversible thrombin blockade by hirudin is deemed to be effective in the prevention of restenosis following angioplasty. The HELVETICA trial is a multicentre, randomized, double-blind heparin-controlled study, designed to compare the effects of two dose regimens of recombinant-hirudin (CGP 39,393/TMRevasc) with those of heparin on event-free survival, safety, tolerability and luminal renarrowing using quantitative coronary angiography no later than 26 weeks after the coronary angioplasty procedure.

Adult↗
PubMed1995

Automated laser fluorescence analysis of randomly amplified polymorphic DNA: a rapid method for investigating nosocomial transmission of Acinetobacter baumannii.

A rapid method for genotyping Acinetobacter baumannii based on PCR-fingerprinting with fluorescent primers was evaluated. Automated laser fluorescence analysis (ALFA) enabled on-line generation of high resolution DNA-fingerprints during polyacrylamide gel electrophoresis of randomly amplified polymorphic DNA (RAPD) products. The results were in concordance with macro-restriction fragment patterns produced by pulse-field gel electrophoresis (PFGE) of ApaI digests of chromosomal DNA. RAPD-ALFA was able to identify homologous strains suggestive of horizontal transmission in < 8 h after colonies were obtained on solid media, whereas PFGE analysis took c. 90 h. Speed and digitised data format renders RAPD-ALFA attractive for routine in-house epidemiological screening of isolates from intensive care and other hospital units.

Acinetobacter↗
PubMed1995

Parallels between UNUSUAL FLORAL ORGANS and FIMBRIATA, genes controlling flower development in Arabidopsis and Antirrhinum.

The unusual floral organs (ufo) mutant of Arabidopsis has flowers with variable homeotic organ transformations and inflorescence-like characteristics. To determine the relationship between UFO and previously characterized meristem and organ identity genes, we cloned UFO and determined its expression pattern. The UFO gene shows extensive homology with FIMBRIATA (FIM), a gene mediating between meristem and organ identity genes in Antirrhinum. All three UFO mutant alleles that we sequenced are predicted to produce truncated proteins. UFO transcripts were first detected in early floral meristems, before organ identity genes had been activated. At later developmental stages, UFO expression is restricted to the junction between sepal and petal primordia. Phenotypic, genetic, and expression pattern comparisons between UFO and FIM suggest that they are cognate homologs and play a similar role in mediating between meristem and organ identity genes. However, some differences in the functions and genetic interactions of UFO and FIM were apparent, indicating that changes in partially redundant pathways have occurred during the evolutionary divergence of Arabidopsis and Antirrhinum.

Alleles↗
PubMed1995

Cross-reactivity of alternate plant sources of latex in subjects with systemic IgE-mediated sensitivity to Hevea brasiliensis latex.

BACKGROUND: Previous studies have suggested that there is cross-reactivity in subjects sensitive to natural rubber proteins with other plant proteins such as banana, chestnut, and avocado. There are numerous other plants known to produce rubber including Parthenium argentatum and Ficus elastica. It is not known whether patients with IgE-mediated systemic reactions caused by the common source of natural rubber Hevea brasiliensis are also sensitive to the rubber-containing material from these other plant sources of latex. It is also not certain how much the allergenicity of latex made from Hevea brasiliensis can be reduced by extracting proteins from the sap since some proteins are tightly associated with the cis-1,4-polyisoprene. OBJECTIVE: In this study we investigated whether there would be cross-reactivity to other natural sources of latex in these patients. METHODS: Seven patients with histories of systemic type I hypersensitivity to latex products had strongly positive skin tests to Hevea brasiliensis latex from two different sources. These subjects were tested by the prick method for sensitivity to three other natural sources of latex. These included latex-containing material from Parthenium-argentatum and Ficus elastica as well as washed and centrifuged rubber particles from Hevea brasiliensis sap. RESULTS: All subjects had negative skin tests to all dilutions of the rubber samples from these other natural sources of latex. CONCLUSION: These results suggest several potential sources of natural hypoallergenic latex that might be tolerated by latex-sensitive individuals.

Adult↗
PubMed1995

[Pseudo-stenosis caused by vessel wall invagination during interventional treatment of 2 coronary vessels in a patient].

We report on a 59-year-old man who underwent a combined procedure of directional coronary atherectomy (DCA) and PTCA of significant lesions of the right coronary artery (RCA) and the left circumflex artery (LCX). Already after positioning of a standard guide wire in the right coronary artery a new excentric "pseudo-stenosis" was observed in the proximal part of the right coronary artery. Since the patient remained symptom free, a 7F DCA catheter was introduced to the stenotic area in the mid RCA, which led to an extension of the narrowing, involving the total segment proximal to the DCA catheter. Directional coronary atherectomy was performed without complications. Removal of the catheter, after successful DCA, and administration of intracoronary nitroglycerin did not relieve the proximal narrowing, which disappeared spontaneously after the guide wire was pulled out. During PTCA of the left circumflex using a standard guide wire and a 3.0 mm Monorail balloon catheter, a similar tight narrowing of the origin of the LCX was observed, which could also not be influenced by vasodilator drugs, but relieved after wire removal. Until now, this phenomenon has only been described for the right coronary artery. The reason underlying intimal folding is a shifting of the intimal layer against the medial layer of the vessel wall. Our observation firstly describes this phenomenon of "pseudo narrowing" in two different vessels in one patient. We, like other authors before, recommend that interventional therapy of these pseudo-lesions should be avoided.

Angioplasty, Balloon, Coronary↗
PubMed1994

Randomized clinical trials in oncology. Principles and obstacles.

Cancer clinical trials have two broad objectives: To identify promising treatments and to determine whether such treatments really do reduce morbidity and mortality. These two objectives generally require different types of clinical trials. The guiding principle of clinical trials is to ask an important question and get a reliable answer. Asking an important question generally means asking a question that has the potential for influencing medical practice, using a control treatment that is widely accepted, using an experimental treatment that is widely applicable, using an endpoint that is a direct measure of patient benefit, and studying a group of patients who are broadly representative. Getting a reliable answer also has many components, including randomized treatment assignment, adequate sample size, intent-to-treat analysis, and testing of prestated hypotheses on mature data. These components are discussed. Several recent developments in clinical trials methodology: interim monitoring boundaries, large simple trials, and metaanalysis, are highlighted here. Major obstacles to conducting randomized clinical trials are also described.

Humans↗
PubMed1994

[Hypocalcemic cardiomyopathy as the cause of severe left heart failure].

A 25-year-old man was hospitalized because of dyspnoea and retrosternal pain. There were clinical and radiological signs of severe left ventricular failure which within a few hours necessitated artificial ventilation. A year before he had been diagnosed as having pseudohyperparathyroidism and disseminated encephalomyelitis. Administration of calcium and vitamin D was only partially efficacious. On admission the calcium concentration was 1.5 mmol/l. The severe left ventricular failure did not respond adequately to the usual therapeutic measures including artificial ventilation and catecholamines. A cumulative dose of about 50 mmol calcium was administered intravenously over 10 days, but marked improvement in myocardial function already became apparent at a calcium concentration of about 1.8 mmol/l. Lasting correction of the hypocalcaemia was achieved with 0.5 g calcium three times daily by mouth and 0.5 mg/d dihydrotachysterol. After transfer to a special neurological department because of an acute attack of multiple sclerosis there was no detectable impairment of cardiac function. This case demonstrates that hypocalcaemic cardiomyopathy should be considered in the differential diagnosis of heart failure in previously well young persons who do not respond adequately to the usual treatment. Myocardial impairment is fully reversible after administration of calcium.

Adult↗