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Biomedical subjects

A E Smith

Publications and source records attributed to A E Smith.

At least 37 records · Page 2Linked to original sources
PubMed2000

Genetic alterations in urinary bladder carcinosarcoma: evidence of a common clonal origin.

The cellular origin of carcinosarcoma of the bladder is unknown. We addressed this issue by using microsatellite analysis for loss of heterozygosity (LOH) in both the carcinomatous and sarcomatous components of 6 bladder tumors. We tested 40 microsatellite markers from 19 human chromosomes and compared the genetic alterations between the two separately isolated components. The potential relevance of the E-cadherin pathway was also evaluated by immunohistochemistry. All 6 cases revealed identical LOH on chromosomal arms 9p, 9q, 8p, and 8q, corresponding to relatively early events in bladder carcinogenesis. Discordant losses between two alleles in the remaining chromosomes, associated with progression, were seen in all tumors with a trend toward a higher incidence in the more advanced tumors (N1M1 and N1Mx). E-cadherin was strongly expressed in the carcinomatous components (5 of 6), whereas most of sarcomatous elements displayed absence of the protein product (4 of 6). These results indicate that both the carcinomatous and sarcomatous components of carcinosarcoma are derived from a common stem cell. Downregulation of E-cadherin may define one of the pathways responsible for conversion of epithelial cells to the sarcomatous phenotype.

Aged↗
PubMed2000

Domiciliary visits to the old and the mentally ill: how valuable?

In the early days of the British National Health Service, domiciliary visits were a continuation of the tradition whereby general practitioners (GPs) met consultants in the patient's home. The nature of domiciliary visits, which still attract a special fee, has since changed. We analysed the effectiveness of all domiciliary visits undertaken in a NHS trust providing primary care, mental health and elderly care services to a population of 470,000. Data were obtained from domiciliary visit claim forms and from questionnaires completed by the consultant, the referring GP and consultant peer reviewers. The largest number of visits (total 234) was in geriatric medicine 48.9%, followed by old-age psychiatry 44.9%. Geriatric medicine was more likely than psychiatry to admit patients to hospital (19%) after a visit. All domiciliary visits in old-age psychiatry were done during the day (9 am to 5 pm). Only 2% of GPs stated that they attended any of the domiciliary visits; almost all thought that the outcome of domiciliary visits was of value. Old-age-psychiatry peer reviewers believed that all visits in that specialty were appropriate; in geriatric medicine this figure was 77% and in other psychiatric specialties 65%. The findings indicate that domiciliary visits were not being used routinely as a pathway to hospital admission, though they were often used to expedite admission or gain a quick consultant opinion; the visits were valued by GPs. The practice of domiciliary visits differs greatly from the definition in NHS terms and conditions of service. One or other should be altered.

Aged↗
PubMed2000

Prevalence of home pregnancy testing among adolescents.

OBJECTIVES: This study estimated the prevalence of home pregnancy testing among adolescents. METHODS: A survey was administered in 11 urban clinics to 600 females aged 13 to 19 years. RESULTS: The prevalence of home pregnancy test use was 34% among 474 sexually experienced youths; 77% of the users had received at least 1 negative pregnancy test result, and 48% took no further action for confirmation. Compared with those who had never used such tests, users were older, younger at sexual debut, less likely to consistently use effective birth control, and more likely to have ever been pregnant. CONCLUSIONS: Health care clinics are important sources for pregnancy prevention, but clinics may have limited opportunity to intervene with some youths who use home pregnancy tests.

Adolescent↗
PubMed1999

PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo.

Replication-defective recombinant adenovirus (Ad) vectors are under development for a wide variety of gene therapy indications. A potential limiting factor associated with virus gene therapy requiring repeated treatment is the development of a humoral immune response to the vector by the host. In animal models, there is a dose-dependent rise in neutralizing antibodies after primary vector administration, which can preclude effective repeat administration. The strategy we have developed to circumvent the neutralization of adenovirus vectors by antibodies is to mask their surface by covalent attachment of the polymer polyethylene glycol (PEG). Covalent attachment of PEG to the surface of the adenovirus was achieved primarily by using activated PEG tresylmonomethoxypolyethylene glycol (TMPEG), which reacts preferentially with the epsilon-amino terminal of lysine residues. We show that the components of the capsid that elicit a neutralizing immune response, i.e., hexon, fiber, and penton base, are also the main targets for PEGylation. Several protocols for PEGylation of an adenovirus vector were evaluated with respect to retention of virus infectivity and masking from antibody neutralization. We show that covalent attachment of polymer to the surface of the adenovirus can be achieved with retention of infectivity. We show further that PEG-modified adenovirus can be protected from antibody neutralization in the lungs of mice with high antibody titers to adenovirus, suggesting that PEGylation will improve the ability to administer Ad vectors on a repeated basis.

Adenoviruses, Human↗
PubMed1999

Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis: a double-blind placebo-controlled trial.

BACKGROUND: We and others have previously reported significant changes in chloride transport after cationic-lipid-mediated transfer of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to the nasal epithelium of patients with cystic fibrosis. We studied the safety and efficacy of this gene transfer to the lungs and nose of patients with cystic fibrosis in a double-blind placebo-controlled trial. METHODS: Eight patients with cystic fibrosis were randomly assigned DNA-lipid complex (active) by nebulisation into the lungs followed 1 week later by administration to the nose. Eight control patients followed the same protocol but with the lipid alone (placebo). Safety was assessed clinically, by radiography, by pulmonary function, by induced sputum, and by histological analysis. Efficacy was assessed by analysis of vector-specific CFTR DNA and mRNA, in-vivo potential difference, epifluorescence assay of chloride efflux, and bacterial adherence. FINDINGS: Seven of the eight patients receiving the active complex reported mild influenza-like symptoms that resolved within 36 h. Six of eight patients in both the active and placebo groups reported mild airway symptoms over a period of 12 h following pulmonary administration. No specific treatment was required for either event. Pulmonary administration resulted in a significant (p<0.05) degree of correction of the chloride abnormality in the patients receiving active treatment but not in those on placebo when assessed by in-vivo potential difference and chloride efflux. Bacterial adherence was also reduced. We detected no alterations in the sodium transport abnormality. A similar pattern occurred following nasal administration. INTERPRETATION: Cationic-lipid-mediated CFTR gene transfer can significantly influence the underlying chloride defect in the lungs of patients with cystic fibrosis.

Adult↗
PubMed1999

An evaluation of intelligent prognostic systems for colorectal cancer.

In this paper we describe attempts at building a robust model for predicting the length of survival of patients with colorectal cancer. The aim of the research, reported in this paper, is to study the effective utilisation of artificial intelligence techniques in the medical domain. We suggest that an important research objective of proponents of intelligent prognostic systems must be to evaluate the additionality that AI techniques can bring to an already well-established field of medical prognosis. Towards this end, we compare a number of different AI techniques that lend themselves to the task of predicting survival in colorectal cancer patients. We describe the pros and cons of each of these methods using the usual metrics of accuracy and perspicuity. We then present the notion of intelligent hybrid systems and evaluate the role that they may potentially play in developing robust prognostic models. In particular we evaluate a hybrid system that utilises the k Nearest Neighbour technique in conjunction with Genetic Algorithms. We describe a number of innovations used within this hybrid paradigm used to build the prognostic model. We discuss the issue of censored patients and how this issue can be tackled within the various models used. In keeping with our objective of studying the additionality that AI techniques bring to building prognostic models, we use Cox's regression as a standard and compare each AI technique with it, attempting to discover their capabilities in enhancing prognostic methods in medicine. In doing so we address two main questions--which model fits the data best?, and are the results obtained by the various AI techniques significantly different from those of Cox's regression? We conclude this paper by discussing future enhancements to the work presented and lessons learned from the study to date.

Age Factors↗
PubMed1999

Do self-fulfilling prophecies accumulate, dissipate, or remain stable over time?

The authors examined whether self-fulfilling prophecies accumulate, dissipate, or remain stable over time by using data from more than 500 6th- through 12th-grade students in public school math classes. The authors used multiple regression analyses to assess the extent to which teacher perceptions predicted students' final math marks and standardized math-test scores from 6th through 12th grade. Control variables included 5 measures of student motivation and 2 measures of previous achievement. The results were consistent with both the dissipation and stability hypotheses. Implications for understanding the extent to which social perception creates social reality and the role of expectations in social problems are discussed.

Achievement↗
PubMed1999

Optimal design for a study of butadiene toxicokinetics in humans.

The derivation of the optimal design for an upcoming toxicokinetic study of butadiene in humans is presented. The specific goal of the planned study is to obtain a precise estimate of butadiene metabolic clearance for each study subject, together with a good characterization of its population variance. We used a two-compartment toxicokinetic model, imbedded in a hierarchical population model of variability, in conjunction with a preliminary set of butadiene kinetic data in humans, as a basis for design optimization. Optimization was performed using Monte Carlo simulations. Candidate designs differed in the number and timing of exhaled air samples to be collected. Simulations indicated that only 10 air samples should be necessary to obtain a coefficient of variation of 15% for the estimated clearance rate, if the timing of those samples is properly chosen. Optimal sampling times were found to closely bracket the end of exposure. This efficient design will allow the recruitment of more subjects in the study, in particular to match prescribed levels of accuracy in the estimate of the population variance of the butadiene metabolic rate constant. The techniques presented here have general applicability to the design of human and animal toxicology studies.

Administration, Inhalation↗
PubMed1999

Novel role for E4 region genes in protection of adenovirus vectors from lysis by cytotoxic T lymphocytes.

Target cells infected with adenovirus (Ad) vectors containing intact E3 and E4 regions were found to be relatively resistant to lysis by Ad-specific cytotoxic T lymphocytes. Elements from both the E3 and the E4 regions were required for this effect, leading to the identification of a previously undescribed role for E4 gene products in resistance to cytolysis.

Adenovirus E3 Proteins↗
PubMed1999

An integrated assessment framework for climate change and infectious diseases.

Many potential human health effects have been hypothesized to result either directly or indirectly from global climate change. Changes in the prevalence and spread of infectious diseases are some of the most widely cited potential effects of climate change, and could have significant consequences for human health as well as economic and societal impacts. These changes in disease incidence would be mediated through biologic, ecologic, sociologic, and epidemiologic processes that interact with each other and which may themselves be influenced by climate change. Although hypothesized infectious disease effects have been widely discussed, there have not yet been thorough quantitative studies addressing the many processes at work. In part this is because of the complexity of the many indirect and feedback interactions or mechanisms that bear on all aspects of the climate issue. It also results from the difficulty of including the multitude of always-changing determinants of these diseases. This paper proposes a framework for an integrated assessment of the impacts of climate change on infectious diseases. The framework allows identification of potentially important indirect interactions or mechanisms, identification of important research gaps, and a means of integrating targeted research from a variety of disciplines into an enhanced understanding of the whole system.

Climate↗
PubMed1998

Potentiation of gene transfer to the mouse lung by complexes of adenovirus vector and polycations improves therapeutic potential.

Recombinant adenovirus (Ad) vectors are being considered for in vivo delivery of various therapeutic genes. One limiting factor in the development of Ad-based gene therapy is the low efficiency of gene transfer to target tissues such as vascular endothelium, smooth muscle, and airway epithelium. Complexing Ad vector with various polycations has been shown to enhance transduction of cell lines otherwise resistant to Ad infection in vitro. On the basis of this observation, the activity of Ad/polycation complexes was tested in vivo in the mouse lung. The results indicated that several polycations were capable of enhancing transduction of mouse respiratory epithelium, leading to a 1-2 log increase in levels of transgene expression. Poly-L-lysine (PLL) and DEAE-dextran were examined further and were found to increase Ad-mediated gene transfer without any additional toxicity as assessed histologically or through the measurement of inflammatory cytokines in bronchoalveolar lavages. The two polycations also failed to affect the humoral response against Ad vector and were themselves nonimmunogenic under conditions leading to enhanced gene transfer. Moreover, the ability to use reduced doses of vector complexed with polycations resulted in lower levels of Ad-specific antibodies and, thereby, improved readministration of vector. These results suggest that complexing Ad vectors with polycations has the potential to improve the therapeutic index by increasing transgene expression while reducing unwanted responses associated with high doses of vector.

Adenoviridae↗
PubMed1998

Increasing speech intelligibility in children with autism.

Accumulating studies are documenting specific motivational variables that, when combined into a naturalistic teaching paradigm, reliably influence the effectiveness of language teaching interactions for children with autism. However, the effectiveness of this approach has not yet been assessed with respect to improving speech intelligibility. The purpose of this study was to systematically compare two intervention conditions, a Naturalistic approach (which incorporated motivational variables) vs. an Analog (more traditional, structured) approach, with developmentally similar speech sounds equated within and across conditions for each child. Data indicate that although both methods effectively increased correct production of the target sounds under some conditions, functional use of the target sounds in conversation occurred only when the naturalistic procedures were used during intervention. Results are discussed in terms of pivotal variables that may produce improvements in speech sounds during conversational speech.

Articulation Disorders↗