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Biomedical subjects

J Richardson

Publications and source records attributed to J Richardson.

At least 109 records · Page 6Linked to original sources
PubMed1999

Randomized trial of informed consent and recruitment for clinical trials in the immediate preoperative period.

BACKGROUND: The standard process of obtaining informed consent sometimes prevents physicians or patients from participating in clinical trials, partly because they are concerned about eventual treatment allocation or the physician is concerned the patient might harbor some uncertainty about the best treatment. Alternative randomization methods have been advocated that may address these and other concerns. METHODS: After institutional ethics committee gave its approval, the authors interviewed 770 patients before operation and asked them to consider enrolling in a mock anesthesia trial. Patients were allocated randomly to one of five methods of randomization and consent: one-sided informed consent (the most common approach), prerandomized consent to experimental treatment, prerandomized consent to standard treatment, one-sided physician-modified informed consent, or one-sided patient-modified informed consent. Recruitment rates were compared and sociodemographic and perioperative predictors of recruitment were identified. RESULTS: The randomization method did not result in any significant difference in recruitment rates: one-sided informed consent, 55.6%; prerandomized consent to experimental treatment, 53.3%; prerandomized consent to standard treatment, 53%; one-sided physician-modified informed consent, 60.7%; and one-sided patient-modified informed consent, 56.7% (P = 0.66). Multivariate predictors of recruitment were patient age >45 yr (odds ratio, 1.44; 95% confidence interval [CI], 1.08 to 1.93), English-speaking at home (1.49; 1.0 to 2.21), and male researcher-male patient interaction (1.37; 1.20 to 1.57). CONCLUSIONS: No evidence emerged that alternative randomization and consent designs resulted in increased recruitment rates compared with simple one-sided informed consent for a sham anesthesia trial in patients awaiting elective surgery. Older, male patients were more likely to provide consent.

Adolescent↗
PubMed1999

Shared usage of the chemokine receptor CXCR4 by primary and laboratory-adapted strains of feline immunodeficiency virus.

Strains of the feline immunodeficiency virus (FIV) presently under investigation exhibit distinct patterns of in vitro tropism. In particular, the adaptation of FIV for propagation in Crandell feline kidney (CrFK) cells results in the selection of strains capable of forming syncytia with cell lines of diverse species origin. The infection of CrFK cells by CrFK-adapted strains appears to require the chemokine receptor CXCR4 and is inhibited by its natural ligand, stromal cell-derived factor 1alpha (SDF-1alpha). Here we found that inhibitors of CXCR4-mediated infection by human immunodeficiency virus type I (HIV-1), such as the bicyclam AMD3100 and short peptides derived from the amino-terminal region of SDF-1alpha, also blocked infection of CrFK by FIV. Nevertheless, we observed differences in the ranking order of the peptides as inhibitors of FIV and HIV-1 and showed that such differences are related to the species origin of CXCR4 and not that of the viral envelope. These results suggest that, although the envelope glycoproteins of FIV and HIV-1 are substantially divergent, FIV and HIV-1 interact with CXCR4 in a highly similar manner. We have also addressed the role of CXCR4 in the life cycle of primary isolates of FIV. Various CXCR4 ligands inhibited infection of feline peripheral blood mononuclear cells (PBMC) by primary FIV isolates in a concentration-dependent manner. These ligands also blocked the viral transduction of feline PBMC by pseudotyped viral particles when infection was mediated by the envelope glycoprotein of a primary FIV isolate but not by the G protein of vesicular stomatitis virus, indicating that they act at an envelope-mediated step and presumably at viral entry. These findings strongly suggest that primary and CrFK-adapted strains of FIV, despite disparate in vitro tropisms, share usage of CXCR4.

Adaptation, Biological↗
PubMed1999

Cyclic adenosine-3',5'-monophosphate-mediated activation of a glutamine synthetase composite glucocorticoid response element.

The glutamate synthetase gene (GS) contains a composite glucocorticoid response element (cGRE) comprised of a GRE and an adjacent element with features of both a cAMP-response element (CRE) and a 12-O-tetradecanoylphorbol 13-acetate (TPA) response element (TRE). The CRE/TRE element of the cGRE contributed to two modes of transcriptional activation: 1) enhancement of the response to cortisol and 2) a synergistic response to cortisol and increased cAMP. COS-7 cells transfected with a cGRE-luciferase construct show minimal expression under basal conditions or forskolin treatment. After cortisol treatment, luciferase activity from the cGRE is enhanced 4- to 8-fold greater than the GRE portion of the cGRE or a GRE from the tyrosine aminotransferase gene. Treatment with both forskolin and cortisol produced a 2- to 4-fold synergistic response over cortisol alone. Synergy is also seen with 8-bromo-cAMP, is specific for the cGRE, and occurs in a number of established cell lines. Elimination of the GRE or CRE/TRE reduces the synergy by 70-100%. Altering the CRE/TRE to GRE spacing changed both enhancement and synergy. Moving the elements 3 bp closer or extending 15 bp reduced enhancement. Synergy was markedly reduced when elements were one half of a helical turn out of phase. Western blots verified that CREB (cAMP-responsive binding protein) and ATF-1 (activating transcription factor-1) binds to the cGRE sequence. A specific dominant negative inhibitor of the CREB family, A-CREB, reduced synergy by 50%. These results suggest that the GS cGRE can potentially integrate signaling from both the cAMP and glucocorticoid receptor transduction pathways and that CREB/ATF-1 may play an important role in this process.

Activating Transcription Factor 1↗
PubMed1999

Oesophagogastrectomy in the elderly high risk patients: role of effective regional analgesia and early mobilisation.

BACKGROUND: Oesophagogastrectomy is the best available treatment for patients with carcinoma of the oesophagus or cardia. However, surgical resection may lead to increased mortality, morbidity and longer hospital stays in elderly (aged over 70 years) high risk patients. METHODS: To assess the impact of balanced pre-emptive and postoperative analgesia combined with early mobilisation in elderly patients undergoing oesophagogastrectomy we consecutively studied 52 patients (30 male, 22 female) of 75+/-4.2 years of age (mean+/-SD). Pre-emptive analgesia was by pre-incisional percutaneous paravertebral block combined with an opiate and a nonsteroidal anti-inflammatory drug (NSAID) premedication. Postoperative maintenance analgesia was by NSAID and continuous extrapleural intercostal nerve block. Following surgery all but three patients were returned to the ward. RESULTS: The hospital mortality rate was 7.6%. Morbidity caused by cardiovascular (27%), respiratory (23%) and cerebrovascular (19%) complications occurred in 19 patients, with two patients requiring ventilatory support. The mean hospital stay for the survivors was 10 days (range 8 to 30 days). All the survivors had their swallowing restored to normal and returned to their accustomed environment. CONCLUSIONS: These data suggests that surgical treatment can be achieved in the elderly high risk patients with acceptable mortality and morbidity. This is achieved by early mobilisation enabled by balanced pre-emptive and postoperative analgesia.

Aged↗
PubMed1999

Post-thoracotomy spirometric lung function: the effect of analgesia. A review.

BACKGROUND: The effects of postthoracotomy pain management on pulmonary function has been assessed. METHODS: All English language publications involving prospective, randomised, controlled studies of patients undergoing postero-lateral thoracotomy incisions where perioperative spirometry had been studied were included. The mean postoperative percentage preservation of preoperative lung function was recorded or determined for each analgesic regimen. RESULTS: 55 studies were reviewed with a total of 1762 patients. The most effective analgesic method in terms of preservation of spirometric function was paravertebral analgesia, patients having approximately 75% of their preoperative values in the first 48 hours after surgery. Most other techniques e.g. intercostal nerve blocks, epidural local anaesthetics or local anaesthetic-opiate combinations produced approximately a 55% preservation by 48 hours. Interpleural analgesia was the least effective, with a mean of 35% preservation by 48 hours, less even than TENS or cryoanalgesia. CONCLUSIONS: A thoracotomy potentially produces a marked reduction in postoperative pulmonary function and the choice of pain management has major implications. Attenuation of postthoracotomy pulmonary dysfunction by effective analgesia should be provided for all patients undergoing chest surgery. Simply providing effective analgesia on its own without regard to pulmonary function is inadequate. Spirometric monitoring should be standard in all thoracic units and is essential for objective comparisons of the efficacy of different methods of pain management.

Analgesia↗
PubMed1999

Life-saving treatments and disabilities. Are all QALYs created equal?

OBJECTIVES: Decision-makers and the general public are often reluctant to adopt policy recommendations based exclusively upon cost-utility analyses. One possible reason explored here is that patients' previous health state before experiencing the onset of an acute life-threatening illness may influence the value of saving those patients' lives. METHODS: We surveyed members of the general public to see the relative importance of saving patients' lives when some patients could be returned to perfect health and others would live the remainder of their years with paraplegia. Among this latter group, some were described as having pre-existing paraplegia. Others were described as having as having the onset of paraplegia. The relative importance of saving each of these lives was measured using the person trade-off method. RESULTS: Six hundred five subjects completed questionnaires, and 250 met pre-established consistency criteria and were included in the final analysis. Overall, subjects placed equal importance on saving the lives of people with pre-existing paraplegia versus those who could be returned to perfect health because they did not have pre-existing paraplegia. In contrast, respondents gave lower priority to patients who would experience the onset of paraplegia after having their lives saved, especially if their paraplegia was avoidable with an alternative treatment. CONCLUSION: People do not think that all quality-adjusted life-years are created equal. Instead, the value that people place on treatment programs depends on patients' state of health before developing life-threatening illnesses, and on whether alternative treatments are available that provide better health outcomes for the patients. These results may explain, in part, public discomfort over basing health care priorities on cost-utility analysis.

Adult↗
PubMed1998

A calcineurin-dependent transcriptional pathway for cardiac hypertrophy.

In response to numerous pathologic stimuli, the myocardium undergoes a hypertrophic response characterized by increased myocardial cell size and activation of fetal cardiac genes. We show that cardiac hypertrophy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to translocate to the nucleus. NF-AT3 interacts with the cardiac zinc finger transcription factor GATA4, resulting in synergistic activation of cardiac transcription. Transgenic mice that express activated forms of calcineurin or NF-AT3 in the heart develop cardiac hypertrophy and heart failure that mimic human heart disease. Pharmacologic inhibition of calcineurin activity blocks hypertrophy in vivo and in vitro. These results define a novel hypertrophic signaling pathway and suggest pharmacologic approaches to prevent cardiac hypertrophy and heart failure.

Angiotensin II↗
PubMed1998

Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that has been detected in several human cardiac-related conditions, including congestive heart failure and septic cardiomyopathy. In these conditions, the origin of TNF-alpha secretion is, at least in part, cardiac myocytes. METHODS AND RESULTS: To determine the consequences of TNF-alpha production by cardiac myocytes in vivo, we developed transgenic mice in which expression of a murine TNF-alpha coding sequence was driven by the murine alpha-myosin heavy chain promoter. Four transgenic founders developed an identical illness consisting of tachypnea, decreased activity, and hunched posture. In vivo, ECG-gated MRI of symptomatic transgenic mice documented a severe impairment of cardiac function evidenced by biventricular dilatation and depressed ejection fractions. All transgenic mice died prematurely. Pathological examination of affected animals revealed a globular dilated heart, bilateral pleural effusions, myocyte apoptosis, and transmural myocarditis in both the right and left ventricular free walls, septum, and atrial chambers. In all terminally ill animals, there was significant biventricular fibrosis and atrial thrombosis. CONCLUSIONS: This is the first report detailing the effects of tissue-specific production of TNF-alpha by cardiac myocytes in vivo. These findings indicate that production of TNF-alpha by cardiac myocytes is sufficient to cause severe cardiac disease and support a causal role for this cytokine in the pathogenesis of human cardiac disease.

Animals↗
PubMed1998

Postthoracotomy pain.

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Analgesia, Patient-Controlled↗
PubMed1998

The effects of age, apolipoprotein E phenotype and gender on the concentration of amyloid-beta (A beta) 40, A beta 4242, apolipoprotein E and transthyretin in human cerebrospinal fluid.

OBJECTIVE: To test whether the concentrations of amyloid-beta (A beta) 40, A beta 42, apolipoprotein E (apoE) and transthyretin in the CSF of normal individuals, are linked to three factors which modulate the risk of Alzheimer's disease (AD): chronological age, gender, and the presence of the apoE4 allele. METHODS AND RESULTS: Proteins were measured by enzyme-linked immunosorbent assays except for transthyretin, which was assayed by radial immunodiffusion. The apoE phenotype was determined by isoelectric focusing. While the CSF levels of A beta 42, apoE, and transthyretin are reported to be reduced in AD, we found no relationship between age, gene, or apoE phenotype and the level of any of these proteins in the CSF of nondemented individuals. The concentration of A beta 40 was not modulated by gender or apoE phenotype, but did decline significantly with age. CONCLUSION: These results indicate that the changes observed in the CSF of AD patients are specific to the disease itself rather than the known risk factors.

Adult↗
PubMed1998

Pleural bupivacaine placement for optimal postthoracotomy pulmonary function: a prospective, randomized study.

OBJECTIVE: To determine dependent chest tube losses of bupivacaine with paravertebral versus interpleural administration, thereby helping to explain the significant differences in pulmonary function that exist between these two techniques. DESIGN: A prospective, randomized study. SETTING: A single hospital. PARTICIPANTS: Twelve adult patients undergoing posterolateral thoracotomies. INTERVENTIONS: Paravertebral or interpleural administration of bupivacaine. MEASUREMENTS AND MAIN RESULTS: Analgesia, as assessed by visual analog pain scores and patient-controlled morphine requirements, was similar in both groups. Postoperative spirometric values were significantly better at most times with the paravertebral route of administration. Dependent chest tube bupivacaine losses were approximately four times higher in the interpleural group. CONCLUSION: Local anesthetic on the diaphragm might actively impair respiratory function through diaphragmatic and abdominal muscle weakness, while failing to contribute to pain relief.

Aged↗
PubMed1998

Ethnicity and cancer outcomes: behavioral and psychosocial considerations.

Cancer has been the subject of thousands of behavioral and psychosocial studies. The literature has focused largely on non-Hispanic Whites, despite the fact that cancer outcomes vary by ethnicity. This article provides a review of those studies that do consider the relations between ethnicity and cancer-related adherence behaviors, survival, and quality of life. The authors propose a mediational framework that links ethnicity and cancer outcomes through socioeconomic status, knowledge and attitudes, and access to medical care. They use this framework to organize the literature and to develop recommendations for future research.

Ethnicity↗
PubMed1998

Downregulation of Escherichia coli yfiD expression by FNR occupying a site at -93.5 involves the AR1-containing face of FNR.

The promoter of the FNR-activated yfiD gene of Escherichia coli has an unusual architecture because it contains two FNR sites, an arrangement usually associated with FNR-mediated repression. Investigation of yfiD promoter derivatives with altered FNR sites revealed that occupation of the far upstream FNR site (FNR II) downregulated expression, despite the presence of a FNR dimer activating expression from the promoter proximal site (FNR I). Transcript mapping by primer extension, and mutagenesis of potential -10 elements, indicated that yfiD expression is driven from a single FNR-dependent promoter with FNR sites at -40.5 (FNR I) and -93.5 (FNR II). However, yfiD mRNA is processed in stationary-phase cultures independently of rne, rpoS, ihfA and fis to yield transcripts lacking 12 and 21 bases from their respective 5' ends. Single amino acid substitutions (G74-->C, F92-->S, A95-->P, R184-->P, P188-->A or L193-->P) in the surface of FNR that contains activating region 1 (AR1 contacts the alpha-subunit of RNA polymerase to promote transcription activation) reduced the inhibitory effect of FNR at FNR II, indicating that this region of the protein may have a role in repression as well as activation. The FNR variant F92-->S was notable because, although it activated transcription of yfiD (two FNR sites), it was unable to activate transcription from model Class I and II promoters, which contain only a single FNR site.

Amino Acid Substitution↗
PubMed1998

Enhancing the usability of a task analysis method: a notation and environment for requirements specification.

This paper presents a notation and computer-based tool for the Sub-Goal Template (SGT) method, a task-analytic approach to specifying information requirements. In particular, it focuses upon the ergonomic redesign of a notation used in the SGT method for specifying contingent sequences in operators' tasks. Two experiments are reported in which two notations for redescribing sequences that involve making a choice between task alternatives are compared: a disjunctive form (Either ... or ...)-used in the original SGT scheme, and a conditional form with a redundant negative (If ... then ... if not ...), which has been promoted as a notation for capturing procedural sequences in computer programming. In experiment 1, performance with the conditional notation was better than with the disjunctive notation for redescribing simple and moderately complex task plans, although there was no difference for the most complex task plans. In experiment 2, a computer environment for specifying task plans using the SGT method was compared with a paper-based equivalent. In general, the computer environment was found to be easier to use and led to greater accuracy in plan redescription, although it was slower perhaps as a result of the constraints that it placed on participants. This paper argues for the necessity of ergonomic design in developing notations and tools to support task analysis methods.

Computers↗
PubMed1998

Functional expression of the MHC class I-related receptor, FcRn, in endothelial cells of mice.

Our recent data indicate that the MHC class I-related receptor, FcRn, plays a role in regulating serum IgG levels, in addition to its known role in transferring IgG from mother to young. In the current study, the distribution of FcRn in adult mice has been investigated using several approaches. First, tissue distribution of anti-FcRn F(ab')2, murine IgG1 and recombinant, IgG1-derived Fc-hinge fragments has been analyzed, and these FcRn binding proteins localize predominantly in skin and muscle with lesser amounts in liver and adipose tissue. Second, histochemical analyses of muscle and liver with anti-FcRn F(ab')2 indicate that FcRn is expressed in the endothelium of small arterioles and capillaries, but not in larger vessels such as the central vein and portal vasculature. Third, immunoprecipitation and immunofluorescence studies of cultured murine endothelial cells show that functional FcRn is expressed in these cells, and is located within vesicular structures in the cytosol and not on the membrane. Taken together the data demonstrate that FcRn is expressed in functionally active form in endothelial cells, indicating that these cells are a possible site at which serum IgG homeostasis is maintained.

Amino Acid Sequence↗
PubMed1998

The effect of thoracic paravertebral blockade on intercostal somatosensory evoked potentials.

UNLABELLED: The paravertebral nerve blocks used in upper abdominal or thoracic surgery provide excellent pain relief and can inhibit some aspects of the neuroendocrine stress response to surgical trauma, which suggests that a very high-quality afferent block can be effected. To confirm this, we evaluated intercostal somatosensory evoked potentials (SSEPs) in 10 patients undergoing paravertebral nerve blocks as a treatment for chronic pain. SSEPs were recorded before and after ipsilateral thoracic paravertebral deposition of 1.5 mg/kg bupivacaine 0.5%. Sensory loss to temperature was demonstrated in all patients at the level of injection and had a mean superior spread of 1.4 (range 0-4) dermatomes and a mean inferior spread of 2.8 (range 0-7) dermatomes. SSEPs were abolished (the normal waveform was rendered unrecognizable with unmeasurable latencies and a mean amplitude of zero) in all patients at the level of injection. In addition, a two-dermatome SSEP abolition was found in four patients and a three-dermatome abolition was found in two patients. SSEPs were modified, but not significantly, at all other test points. We conclude that cortical responses to thoracic dermatomal stimulation can be abolished at the block level and adjacent dermatomes by thoracic paravertebral nerve blockade. Equivalent results have not been demonstrated with more central forms of afferent blockade, which suggests that thoracic paravertebral nerve blocks may be uniquely effective. IMPLICATIONS: To improve outcomes after major surgery, as much nociceptive information as possible should be prevented from entering the central nervous and neuroendocrine systems. We have shown that local anesthetics alongside the vertebral column can abolish the usual brain recordings that follow intercostal nerve stimulation, which suggests that paravertebral nerve blocks may be uniquely effective.

Chronic Disease↗
PubMed1998

Economic evaluation of health promotion: friend or foe?

It is commonly believed that economic evaluation is hostile to health promotion and that the requirement for health programs to be cost effective will result in a biased allocation of funds in favour of programs that can demonstrate short-run benefits as defined by inadequate outcome measures. The paper is concerned with the validity of this perception. It is argued that economic evaluation has the potential for treating health promotion activities on an equal basis with other health interventions. The major obstacle to this does not arise from the theory of economic evaluation, which is discussed, but from a lack of information about outcomes. Without this information any evaluation--economic or otherwise--is flawed. Three problems relating to the economic evaluation of health promotion activities are considered. These are: the discounting of future health benefits; the potential for economic evaluation to be counter-productive if applied to 'immature' projects; and the practical problems encountered in the measurement of the outcomes of health promotion programs. A four-fold classification which is based upon a distinction between disease cure, individual health promotion, community welfare and systemic change designed to promote either individual health or social well-being. The capacity of economics to incorporate these objectives is discussed.

Cost-Benefit Analysis↗