Ischemic tolerance in the brain.
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Apoptosis↗
Biomedical subjects
R Simon
Publications and source records attributed to R Simon.
Preparing the next generation of clinicians to manage information.
Curriculum development in informatics must be underpinned by knowledge of the information environment new recruits encounter after qualification. A pilot study was carried out to identify the type of information handling tasks newly qualified healthcare professionals are expected to undertake. This data was related to the skills junior staff possess at the point of entry to hospital posts. Data was collected on the opportunities these recently qualified individuals had to acquire IT skills and generic competence in information handling in their prequalification courses. Self-report data was supplemented by direct observation of junior staff on the wards. In addition to investigating the perspective of the junior staff, the study also explored the attitudes and expectations of senior clinicians, educationalists and NHS trust staff. The purpose of the study was to provide guidance to those involved in developing informatics curricula for clinical students at the prequalification stage. This paper reports some of our preliminary findings.
Adult↗
Exaggerated lithotomy position-related rhabdomyolysis.
A case report and review of the exaggerated lithotomy position, in particular, and other position-related rhabdomyolysis is presented. The objective is to emphasize that the exaggerated lithotomy position, although providing good exposure for urethral and prostatic surgery, is associated with a low but definite risk of rhabdomyolysis and acute renal failure. Certain risk factors for the complication have been outlined. Close perioperative monitoring, including the use of pulmonary artery pressure and lower-extremity compartment pressure measurements in high-risk cases, is suggested for the prevention and the early detection of these cases. Prompt volume replacement and diuresis is the cornerstone of therapy in preventing acute renal failure in patients who develop rhabdomyolysis and myoglobinuria.
Acute Kidney Injury↗
Bayesian design and analysis of two x two factorial clinical trials.
The 2 x 2 factorial design has been advocated for improving the efficiency of clinical trials. Most such trials are designed on the assumption that there is no interaction between the levels of the factors and outcome. This assumption is often problematic, however, because interactions are usually possible in clinical trials and the sample sizes often used provide little power in testing for interactions. We consider the use of Bayesian methods for the design and analysis of 2 x 2 factorial clinical trials. This approach avoids the need to dichotomize one's assumptions that interactions either do or do not exist and provides a flexible approach to the design and analysis of such clinical trials. Exact results are developed for balanced factorial designs with normal response. Approximations are then presented for factorial designs based on the logistic model for binary response or the proportional hazards model for time-to-event data. The resulting approximate posterior distributions are normal and hence no extensive computations are required. Suggestions for specification of prior distributions are presented.
Antineoplastic Agents, Phytogenic↗
Condyloma accuminata.
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Administration, Topical↗
Assessing whether to perform a confirmatory randomized clinical trial.
BACKGROUND: A confirmatory randomized clinical trial is a trial that is aimed at assessing whether a treatment effect observed in a previous randomized trial (or trials) is real and important. There is often considerable disagreement about the need for such confirmatory trials. PURPOSE: Our aim is to provide a general statistical framework for evaluating whether a confirmatory trial is warranted in a particular situation. METHODS AND RESULTS: The results of two clinical trials are considered: 1) a Cancer and Leukemia Group B trial comparing induction chemotherapy plus radiotherapy with radiotherapy alone in the treatment of patients with locally advanced non-small-cell lung cancer and 2) a North Central Cancer Treatment Group trial comparing surgery plus adjuvant chemotherapy with surgery alone in the treatment of patients with advanced colon cancer. In our analysis, we argue that differences in the interpretation of results from a randomized trial are based on differences in prior beliefs about the efficacy of the treatment(s) under study. We believe that a major factor in the decision to perform a confirmatory trial is prior skepticism about the clinical worth of the treatment in question. Both the level of prior skepticism and the minimum treatment effect deemed clinically worthwhile require subjective judgment. We develop a Bayesian framework to allow differences in interpretation to be examined systematically and the need for a confirmatory trial to be assessed. Our model allows the addition of prior belief (specified in the form of a prior distribution of treatment effect) to the results of a trial to yield a posterior distribution. The interpretation of trial results is based on the posterior distribution and will vary as the prior distribution (i.e., the prior belief) varies. To aid in the interpretation of trial results, we also advocate the specification of a minimum clinically worthwhile treatment effect at the start of a trial. CONCLUSIONS AND IMPLICATIONS: Our approach acknowledges that a number of different prior beliefs are possible, giving rise to a range of interpretations of results from a clinical trial. This approach provides a formal and systematic basis for considering both the range of likely opinions and the subsequent decision to be made with regard to the need for a confirmatory trial. We recommend that this approach be considered in the discussion of future confirmatory randomized clinical trials.
Adjuvants, Immunologic↗
Activation of floral meristem identity genes in Arabidopsis.
The Arabidopsis floral meristem-identity genes APETALA1 (AP1) and LEAFY (LFY) confer floral identity on developing floral primordia, whereas TERMINAL FLOWER (TFL) is required to repress their expression within shoot and inflorescence meristems. LFY and AP1 are expressed in floral primordia in response to environmental conditions, such as day length, which regulate the onset of flowering, and presumably also in response to the action of genes that influence flowering time. However, the relationship between these flowering-time genes and the floral meristem-identity genes has been difficult to assess because flowering time is determined by several interacting genetic pathways. Here we describe a method to regulate expression of the flowering-time gene CONSTANS (CO) and demonstrate that CO expression is sufficient to trigger flowering, irrespective of day length. In response to CO expression, transcription of LFY and TFL is initiated rapidly, whereas transcription of AP1 occurs much later. We propose that CO acts within a genetic pathway that is sufficient to activate LFY and TFL transcription, but that rapid activation of AP1 requires an additional pathway.
Arabidopsis↗
A simulation study of cross-validation for selecting an optimal cutpoint in univariate survival analysis.
Continuous measurements are often dichotomized for classification of subjects. This paper evaluates two procedures for determining a best cutpoint for a continuous prognostic factor with right censored outcome data. One procedure selects the cutpoint that minimizes the significance level of a logrank test with comparison of the two groups defined by the cutpoint. This procedure adjusts the significance level for maximal selection. The other procedure uses a cross-validation approach. The latter easily extends to accommodate multiple other prognostic factors. We compare the methods in terms of statistical power and bias in estimation of the true relative risk associated with the prognostic factor. Both procedures produce approximately the correct type I error rate. Use of a maximally selected cutpoint without adjustment of the significance level, however, results in a substantially elevated type I error rate. The cross-validation procedure unbiasedly estimated the relative risk under the null hypothesis while the procedure based on the maximally selected test resulted in an upward bias. When the relative risk for the two groups defined by the covariate and true changepoint was small, the cross-validation procedure provided greater power than the maximally selected test. The cross-validation based estimate of relative risk was unbiased while the procedure based on the maximally selected test produced a biased estimate. As the true relative risk increased, the power of the maximally selected test was about 10 per cent greater than the power obtained using cross-validation. The maximally selected test overestimated the relative risk by about 10 per cent. The cross-validation procedure produced at most 5 per cent underestimation of the true relative risk. Finally, we report the effect of dichotomizing a continuous non-linear relationship between covariate and risk. We compare using a linear proportional hazard model to using models based on optimally selected cutpoints. Our simulation study indicates that we can have a substantial loss of statistical power when we use cutpoint models in cases where there is a continuous relationship between covariate and risk.
Humans↗
Cytoplasmic polyadenylation of activin receptor mRNA and the control of pattern formation in Xenopus development.
The activin receptor, a transmembrane serine-threonine kinase, is a key component necessary for pattern formation in early Xenopus development. This protein interacts with members of the transforming growth factor beta family and stimulates cells of the marginal zone to differentiate along the mesodermal pathway. In large part, this function of the activin receptor has been inferred from observations of phenotypes induced by injected mRNA encoding wild-type or mutant forms of the protein. Naturally occurring activin receptor mRNA is maternally inherited and contains within its 3' untranslated region an embryonic-type cytoplasmic polyadenylation element (CPE), an oligouridylic acid sequence that promotes cytoplasmic polyadenylation and resultant translational activation. Based on the presence of this element, we predicted in a previous report that activin receptor mRNA expression in embryos might be regulated by cytoplasmic polyadenylation (Simon and Richter, Mol. Cell. Biol. 14, 7867-7875, 1994). In this study, we have tested this hypothesis and show that not only do endogenous and injected activin receptor mRNAs undergo cytoplasmic polyadenylation during embryogenesis, but also that this process is necessary for stimulating translation and inducing the morphological defects observed by mRNA overexpression. The activin receptor CPE is bound by a Mr 36 x 10(3) protein in vitro, and competition for this factor between mRNAs in vivo inhibits activin receptor mRNA polyadenylation. This competition may be responsible for the lack of mesoderm formation observed in such injected embryos. These data suggest that cytoplasmic polyadenylation controls differentiation and pattern formation in early Xenopus development.
Activin Receptors↗
Herbage density of third-stage larvae of goat strongyles during the dry season in Guadeloupe.
The objective of this study was to determine the main sources of variation in herbage densities of infective third stage larvae of goat strongyles during the marked dry season of 1994 in Guadeloupe (FWI). Herbage samples were collected for L3 density (LD) determination by an accurate method, 4 times at 4-week intervals in 58 paddocks of 21 farms spread out in five regions of the archipel of Guadeloupe. At the same time, FEC of each grazing animal and fecal culture for parasite genus determination according to sex and age were carried out. Stocking rate, dry matter content of soil, and daily climatic data were also recorded. An index of egg development in larvae (IEDL) was calculated as the ratio of LD to the eggs deposed during the 4th, 3rd, and 2nd weeks before sampling. Medians of LD in herbage were 3397, 1853, 1410, and 324 L3/kg DM for all parasites, Haemonchus, Trichostrongylus, and Oesophagostomum, respectively. Date of sampling, region, and irrigation practice in the northern windward region were the main sources of variation in LD and in frequency of each parasite. LD decreased as the dryness lasted, but it remained important (500 L3/kg DM) despite the drought. LD in windward regions were higher than in other regions. The region, the farm, and the paddock were the main sources of variation of IEDL. LD of each parasites were inversely correlated to global radiation recorded 1 to 3 weeks before herbage sampling, but no relation was found with rainfall data. Trichostrongylus frequency in L3 population increased as the dryness lasted. A dryness axis was extracted from environmental variables (climatic data, dry matter of soil, duration of dryness) by a multiple factorial procedure. LD and Haemonchus frequency in L3 population were inversely correlated to dryness axis (p < 0.01). In contrast, Trichostrongylus frequency was positively correlated to the dryness component.
Animal Feed↗
Microbiological contamination of drinking water in a commercial household water filter system.
The microbiological quality of filtered water in a commercial water filter system (Brita) was tested in households and in two laboratories. In 24 of 34 filters used in households, bacterial counts increased in the filtered water up to 6,000 cfu/ml. In 4 of 6 filters tested in the laboratory, bacterial counts in the fresh filtrate were higher than in tap water after approximately one week of use both at room temperature and at 4 degrees C, suggesting growth or biofilm formation in the filter material. In some cases colony counts in the filtered water were 10,000 times those in tap water. The filter material of 5 of 13 new commercial filters was contaminated with bacteria or moulds. National or international regulatory agencies should ensure that water filters marketed for domestic use do not allow deterioration in the microbiological quality of drinking water.
Bacteria↗
[Comparative genomic hybridization in pathology. A new molecular cytogenetic method].
Comparative genomic hybridisation (CGH) is a new cytogenetic method, which is based on a combination of fluorescence microscopy and digital image analysis. The molecular genetic basis is the hybridization of a mixture of fluorescein labeled test-DNA and reference-DNA on normal metaphase chromosomes. Comparative analysis allows the identification of all unbalanced chromosomal aberrations of the test-DNA in a single experimental step. The resulting DNA gains or DNA losses on the chromosomal or subchromosomal level mirror possible amplifications of oncogenes or losses of suppress orgenes. As CGH can be performed with genomic DNA of formalin-fixed and fresh-frozen tissue or cells, this new method is a very effective tool for pathologists and cytologists in the extended genomic screening of tumors and genetically altered tissues. Despite CGH analysis at present is restricted to research applications; its widespread dissemination as a routine method in diagnostic pathology can be expected in the near future.
Animals↗
[Synopsis of unbalanced chromosome aberrations in neuroblastoma by comparative genomic hybridization].
Neuroblastoma is the most frequent extracranial solid tumor of early childhood. Histologically and genetically, neuroblastoma represents a heterogeneous group of tumors with significant differences in clinical behavior. In the past, several different characteristic chromosomal aberrations of neuroblastoma have been described, of which a deletion on chromosome 1p and N-myc amplification have been shown to be of major prognostic significance. However, the role of various other nonrandom DNA imbalances in tumor development and progression needs to be clarified. Taking advantage of the recently established comparative genomic hybridization (CGH), we show that this method is able to accurately detect chromosomal imbalances of known prognostic impact. As CGH gives a comprehensive picture of genetic imbalances in just one experiment, it additionally sheds light on other abnormalities of possible prognostic relevance. We therefore recommend further use of this method not only in the field of research but also for the purpose of genetic routine diagnostics in neuroblastoma.
Child↗
A novel class of 5-HT2A receptor antagonists: aryl aminoguanidines.
Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report the effects of a new class of aminoguanidine 5-HT2 antagonists, with relative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding studies with 125I DOI on human 5-HT2A and 5-HT2C receptors and with 3H-5-HT on human 5-HT2B receptors demonstrated that, LY314228, and LY320954 displayed some selectivity for the 5-HT2A receptor. When compared to binding at other 5-HT2 receptor subtypes, LY314228 had an 18.6-fold greater affinity for the 5-HT2A site over the 5-HT2B site, and 2.6 fold greater at the 5-HT2C site. LY320954 displayed similar preference for 5-HT2A sites. Both compounds also inhibited 5-HT-induced paw swelling in rats, with ED50's of 6.4 and 4.8 mg/kg (for LY314228 and LY320954, respectively). These studies offer evidence for a novel class of pharmacophores for the 5-HT2 receptor family which show greater relative affinities for the 5-HT2A receptor subclass.
Animals↗
Comparison of methods for counting third stage larvae of gastrointestinal nematodes of small ruminants in tropical pastures.
The accuracy and the precision of a simple and reliable technique for the extraction and the counting of third stage larvae densities of gastro-intestinal strongyles of ruminants from pasture samples are assessed in tropical conditions, i.e. for pangola pastures and for the genera of Haemonchus and Trichostrongylus. To separate the larvae from herbage samples, water washings obtained by a centrifuge spin-dryer were put to sediment in disposable plastic bags. The extraction and counting of larvae from sediments were achieved by exhaustion of sediments with repeated sucrose/water interface procedures. The recovery rate of third stage infective larvae (L3) added to the sediment was 79.1% (+/- 9.49%). The accuracy, estimated as recovery rate of L3 added to herbage samples, was 76.5 (+/- 11.31%). The recovery by the sedimentation method was 3.5 times higher than that of a filtering method through a 20 microns sieve. The detection limit was estimated to be 130 L3 kg-1 dry matter. Precision, estimated as the residual standard deviation of duplicate assays, was 1857 L3 kg-1 dry matter (mean 9164 L3 kg-1 dry matter). Results obtained in routine epidemiological surveys of gastro-intestinal strongylosis of small ruminants in West Africa and in the West Indies demonstrated the usefulness of the technique.
Animal Feed↗
Continued benefit of coronary stenting versus balloon angioplasty: one-year clinical follow-up of Benestent trial. Benestent Study Group.
OBJECTIVES: This study sought to determine the 1-year clinical follow-up of patients included in the Benestent trial. BACKGROUND: The Benestent trial is a randomized study comparing elective Palmaz-Schatz stent implantation with balloon angioplasty in patients with stable angina and a de novo coronary artery lesion. Seven-month follow-up data have shown a decreased rate of restenosis and fewer clinical events in the stent group. It is not established whether this favorable clinical outcome is maintained for longer periods or whether coronary stenting defers restenosis and its subsequent clinical manifestations. METHODS: To clarify this uncertainty, we updated clinical information on all but 1 of 516 patients enrolled in the Benestent trial (257 in balloon group, 259 in stent group) at least 12 months after the intervention. Major clinical events (primary clinical end point) were tabulated according to the intention to treat principle and included death, the occurrence of a cerebrovascular accident, myocardial infarction, the need for bypass surgery or a further percutaneous intervention in the previously treated lesion. RESULTS: After 1 year, no significant differences in mortality (1.2% vs. 0.8%), stroke (0.0% vs. 0.8%), myocardial infarction (5.0% vs. 4.2%) or coronary bypass graft surgery (6.9% vs. 5.1%) were found between the stent and balloon angioplasty groups, respectively. However, the requirement for a repeat angioplasty procedure was significantly lower in the stent group (10%) than the balloon angioplasty group (21%, relative risk [RR] 0.49, 95% confidence interval [CI] 0.31 to 0.75, p = 0.001), and overall primary end points were less frequently reached by stent group patients (23.2%) than those in the balloon group (31.5%, RR 0.74, 95% CI 0.55 to 0.98, p = 0.04). No differences were found between groups with respect to functional class angina and prescribed medication at the time of follow-up. CONCLUSIONS: These clinical follow-up data show that the benefit of elective native coronary artery stenting in patients with stable angina is maintained to at least 1 year after the procedure and results in a significantly reduced requirement for repeat intervention.
Angina Pectoris↗
Data monitoring committees and problems of lower-than-expected accrual or events rates.
Data monitoring committees for randomized clinical trials must frequently decide what action, if any, is required for trials whose accrual has been slower than expected, or whose event rates have been less than expected. We discuss in this article some of the practical issues concerning modifying or closing such trials, including what data and analyses could be helpful to the data monitoring committee in their deliberations.
Decision Making↗
Vasodilator provocation of occult urinary tract hemorrhage.
This case demonstrates the use of vasodilators to reactivate an intermittent urinary tract hemorrhage. The site of bleeding was demonstrated and treated with subselective embolization.
Abdominal Injuries↗