Is clinical research still too haphazard? Clark, Otavio; Clark, Luciana; Djulbegovic, Benjamin
The Lancet (British edition),
11/2001, Letnik:
358, Številka:
9293
Journal Article
Recenzirano
The world of research has not yet adopted principles that are widely accepted in clinical practice.5 The evidence-based medicine movement has highlighted the need for transparent and explicit methods ...in patients' care and clinical research.5 Questions should be clearly formulated, and potentially eligible studies defined and sought by explicit search strategies.5 We assessed how a systematic approach could have been used in a study such as the Johns Hopkin's study. The investigators wanted to study the effect of hexamethonium on bronchodilatation in healthy volunteers challenged with a bronchoconstrictive agent.3 The systematic search for relevant existing evidence before the study needed to focus on adverse events of hexamethonium. Since the drug has not been used since 1972,3 to learn about the toxic profile, evidence should have been searched from the period of clinical use. ...the UK Medical Research Council and the Danish National Research Ethics Committee System now require investigators proposing new research to provide references to relevant systematic reviews and to discuss the need of the trial in the context of review.4 If researchers believe that their proposed study is the first to address a particular question, they must provide details of the search strategy they have used to try to locate other relevant research. 4 We suggest that these principles be adopted more widely.
Electrostatic solitons in an unmagnetized pair-ion plasma comprising adiabatic fluid positive and negative ions and non-isothermal electrons are investigated using both arbitrary and small amplitude ...techniques. An energy integral equation involving the Sagdeev potential is derived, and the basic properties of large amplitude solitary structures are investigated. Various features of solitons differ in different existence domains. The effects of ion adiabaticity, particle concentration, and resonant electrons on the profiles of Sagdeev potential and corresponding solitary waves are investigated. The generalized Korteweg-de Vries equation with mixed-nonlinearity is derived by expanding the Sagdeev potential. Asymptotic solutions for different orders of nonlinearity are discussed for solitary waves. The present work is applicable to understanding the wave phenomena and associated nonlinear electrostatic perturbations in pair/bi-ion plasmas which may occur in space and laboratory plasmas.
The nucleosynthetic path of the astrophysical r-process and the resulting elemental abundances depend on neutron-separation energies which can be determined from the masses of the nuclei along the ...r-process reaction path. Due to the current lack of experimental data, mass models are often used. The mass values provided by the mass models are often too imprecise or disagree with each other. Therefore, direct high-precision mass measurements of neutron-rich nuclei are necessary to provide input parameters to the calculations and help refine the mass models. The Californium Rare Isotope Breeder Upgrade (CARIBU) facility of Argonne National Laboratory will provide experiments with beams of short-lived neutron-rich nuclei. The Canadian Penning Trap (CPT) mass spectrometer has been relocated to the CARIBU low-energy beam line to extend measurements of the neutron-rich nuclei into the mostly unexplored region along the r-process path. This will allow precise mass measurements (∼ 10 keV/c2) of more than a hundred very neutron-rich isotopes that have not previously been measured.
Geographic regions characterized by income inequality are associated with adverse mortality statistics, but the pathophysiologic mechanisms that mediate this ecologic relationship have not been ...elucidated. This study used a United States mail survey of 34 158 male and 42 741 female healthy-adult volunteers to test the association between residence in geographic regions with relative income inequality and the likelihood of weight gain at the waist. Respondents came from 21 states that were characterized by the household income inequality (HII) index, a measure reflecting the proportion of total income received by the more well off 50% of households in the state. The main outcome measure was self-reported weight gain mainly at the waist as opposed to weight gain at other anatomic sites. After controlling for age, other individual-level factors, and each state's median household income, men's likelihood of weight gain at the waist was positively associated (p=0.0008) with the HII index. Men from states with a high HII (households above the median receive 81.6% to 82.6% of the income) described weight gain at the waist more often than men from states with a low HII (households above the median receive 77.0% to 78.5% of the income) (odds ratio=1.12, 95% confidence interval 1.03 to 1.22). Women's results showed a non-significant trend in the same direction. An association between ecologically defined socio-environmental stress and abdominal obesity may help to clarify the pathophysiologic pathways leading to several major chronic diseases.
Various approaches to the calculation of medical risk are reviewed, including univariate analysis, additive methods, use of Bayes' theorem by The Society of Thoracic Surgeons, logistic regression, ...and neural networks. Strengths and weaknesses of the various approaches are evaluated. The use and importance of observed/expected ratios, the C statistic, and receiver operating curves are discussed. Specific requirements for the building of useful risk-calculation models are discussed, including the importance of the model set/test set method and the role of both numbers of patients and time frames in model building.
Studies in developing rodents indicate that nicotine is a neuroteratogen that disrupts brain development by stimulating nicotinic acetylcholine receptors (nAChRs) that control neural cell replication ...and differentiation. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers (30 ng/ml). Fetal brain regions and peripheral tissues were examined for nAChR subtypes, other neurotransmitter receptors, and indices of cell signaling and cell damage. Nicotine evoked nAChR upregulation, but with distinct regional disparities indicative of selective stimulatory responses. Similarly, indices of cell loss (reduced DNA), cell size and neuritic outgrowth (protein/DNA and membrane/total protein ratios) were distinct for each region and did not necessarily follow the rank order of nAChR upregulation, suggesting the involvement of additional mechanisms such as oxidative stress. We then attempted to offset the adverse effects of nicotine with standard dietary supplements known to interact with nicotine. By itself, choline elicited nicotine-like actions commensurate with its promotion of cholinergic neurotransmission. When given in combination with nicotine, choline protected some regions from damage but worsened nicotine's effects in other regions. Similarly, Vitamin C supplementation had mixed effects, increasing nAChR responses while providing protection from cell damage in the caudate, the brain region most susceptible to oxidative stress. Our results indicate that nicotine elicits neurodevelopmental damage that is highly selective for different brain regions, and that dietary supplements ordinarily thought to be neuroprotectant may actually worsen some of the adverse effects of nicotine on the fetal brain.
Twin studies indicate that dyscalculia (or mathematical disability) is caused partly by a genetic component, which is yet to be understood at the molecular level. Recently, a coding variant ...(rs133885) in the myosin‐18B gene was shown to be associated with mathematical abilities with a specific effect among children with dyslexia. This association represents one of the most significant genetic associations reported to date for mathematical abilities and the only one reaching genome‐wide statistical significance. We conducted a replication study in different cohorts to assess the effect of rs133885 maths‐related measures. The study was conducted primarily using the Avon Longitudinal Study of Parents and Children (ALSPAC), (N = 3819). We tested additional cohorts including the York Cohort, the Specific Language Impairment Consortium (SLIC) cohort and the Raine Cohort, and stratified them for a definition of dyslexia whenever possible. We did not observe any associations between rs133885 in myosin‐18B and mathematical abilities among individuals with dyslexia or in the general population. Our results suggest that the myosin‐18B variant is unlikely to be a main factor contributing to mathematical abilities.
We could not replicate the association of the myosin‐18B gene with mathematical ability.
Department of Haematology, Royal Liverpool University Hospital, Prescot St, Liverpool L7 8XP, United Kingdom.
BCR-ABL kinase mutations may confer resistance to imatinib in patients with chronic ...myeloid leukemia (CML), and may predict a poor outcome. We investigated whether rises in BCR-ABL transcript levels predicted mutation development in 82 CML patients receiving imatinib. Eleven mutations were detected in 10 patients. A single 2-fold or greater rise in BCR-ABL transcript did not predict mutations. However, a mutation was detectable in five of six cases with progressively rising levels of transcripts. In contrast, consecutive rises were not seen in any of 33 stable responders. Rising BCR-ABL transcript levels can identify patients who developBCR-ABLmutations. A serial rise is more reliable than a single rise.
Adoptively transferred dendritic cells presenting antigens derived from different pathogens have been shown to elicit specific T cell responses and to induce protective antibacterial immunity. We ...describe here the induction of high levels of protective immunity in mice using dendritic cells infected with auxotrophic mutants of
Mycobacterium tuberculosis. We provide evidence that protection is superior to BCG and that it is associated with increased priming of CD4
+ and CD8
+ T cells specific for mycobacterial antigens. This method for generating high levels of anti-bacterial protective immunity could be helpful in the design of novel vaccines against tuberculosis and other intracellular pathogens.
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