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Biomedical subjects

Chris Smith

Publications and source records attributed to Chris Smith.

At least 19 recordsLinked to original sources
PubMed2006

H3+: the driver of giant planet atmospheres.

We present a review of recent developments in the use of H3+ molecular ion as a probe of physics and chemistry of the upper atmospheres of giant planets. This ion is shown to be a good tracer of energy inputs into Jupiter (J), Saturn (S) and Uranus (U). It also acts as a 'thermostat', offsetting increases in the energy inputs owing to particle precipitation via cooling to space (J and U). Computer models have established that H3+ is also the main contributor to ionospheric conductivity. The coupling of electric and magnetic fields in the auroral polar regions leads to ion winds, which, in turn, drive neutral circulation systems (J and S). These latter two effects, dependent on H3+, also result in very large heating terms, approximately 5 x 10(12) W for Saturn and greater than 10(14) W for Jupiter, planet-wide; these terms compare with approximately 2.5 x 10(11) W of solar extreme UV absorbed at Saturn and 10(12) W at Jupiter. Thus, H3+ is shown to play a major role in explaining why the temperatures of the giant planets are much greater (by hundreds of kelvin) at the top of the atmosphere than solar inputs alone can account for.

Journal Article↗
PubMed2006

Change for Life/Cambia tu vida: A health promotion program based on the stages of change model for African descendent and Latino adults in New Hampshire.

Studies have shown that diabetes and cardiovascular disease can be controlled and prevented through the modification of behavioral risk factors. The transtheoretical model of behavior change, also known as the stages of change model, offers promise for designing behavior change interventions. However, this model has rarely been applied in group settings with minority communities. To address racial and ethnic disparities related to the risk for diabetes and cardiovascular disease, the New Hampshire REACH 2010 Initiative has designed and implemented Change for Life/Cambia tu vida, a health promotion program based on the stages of change model for African descendent and Latino residents of southern New Hampshire. The program guides participants through the five stages of change and provides resources to support healthy behavior change. We also sponsor periodic class reunions that help program graduates to maintain these healthy habits. This article describes curriculum development, participant feedback, and early pretest and posttest evaluation results from a standardized assessment.

Black People↗
PubMed2006

Large-scale trends in the evolution of gene structures within 11 animal genomes.

We have used the annotations of six animal genomes (Homo sapiens, Mus musculus, Ciona intestinalis, Drosophila melanogaster, Anopheles gambiae, and Caenorhabditis elegans) together with the sequences of five unannotated Drosophila genomes to survey changes in protein sequence and gene structure over a variety of timescales--from the less than 5 million years since the divergence of D. simulans and D. melanogaster to the more than 500 million years that have elapsed since the Cambrian explosion. To do so, we have developed a new open-source software library called CGL (for "Comparative Genomics Library"). Our results demonstrate that change in intron-exon structure is gradual, clock-like, and largely independent of coding-sequence evolution. This means that genome annotations can be used in new ways to inform, corroborate, and test conclusions drawn from comparative genomics analyses that are based upon protein and nucleotide sequence similarities.

Animals↗
PubMed2006

Use of inhaled corticosteroids and the risk of fracture.

BACKGROUND: Previous studies have found an association between the use of inhaled corticosteroids and fracture, but the extent to which this association is due to inhaled corticosteroids or to related factors, such as the severity of airflow obstruction, is disputed. We report a new approach in which we combine data on people with airflow obstruction from a large Medical Research Council study of the assessment and management of older people in the community with longitudinal data from their computerized general practice records. METHODS: Our cohort includes 1,671 study participants with a diagnosis of asthma or COPD (mean age, 80.6 years). We determined the dose-response relationship between inhaled corticosteroid exposure and time to first fracture using Cox regression, allowing for a wide range of potential confounding factors. RESULTS: During a mean follow-up period of 9.4 years, 982 patients (59%) received a prescription for an inhaled corticosteroid and 187 patients had a fracture. After adjusting for the effects of age and gender, we found a dose-related increase in fracture risk with exposure to inhaled corticosteroids (rate ratio for mean daily dose > 601 mug, 2.53; 95% confidence interval [CI], 1.65 to 3.89; overall trend p < 0.0001). The results were similar after adjusting for oral corticosteroid exposure, airflow obstruction diagnosis, historical fracture, and bronchodilator use (rate ratio, 4.21; 95% CI, 2.19 to 8.13), and also in the subset of people with no exposure to oral corticosteroids (rate ratio, 4.54; 95% CI, 1.23 to 16.74). CONCLUSIONS: Our findings provide further evidence that inhaled corticosteroid use is an independent risk factor for fracture.

Administration, Inhalation↗
PubMed2006

Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour-stroma interactions.

Our previous investigations using cell models of tamoxifen resistance have shown that the acquisition of an endocrine-insensitive state is accompanied by an invasive in vitro phenotype. In this study, we wished to determine whether this was specifically related to partial oestrogen receptor agonists or whether similar phenomena arise with the newer 'pure' anti-oestrogens, exemplified by fulvestrant. Our data demonstrate that the development of fulvestrant resistance in two breast cancer cell lines, MCF7 and T47D, is accompanied by an augmented migratory and invasive phenotype in vitro and overexpression of the HGF/SF receptor, c-Met. Importantly, upregulated c-Met expression in these cells facilitates their stimulation by HGF/SF-secreting stromal fibroblasts, leading to the activation of Src, Akt and ERK1/2 and a profound enhancement of their aggressive phenotype in vitro. These effects could be specifically attributable to activation of the c-Met receptor since the inclusion of neutralising antibodies to c-Met, or siRNA-mediated knockdown of c-Met expression, suppressed both invasion and migration stimulated by either exogenous HGF/SF, fibroblast-conditioned medium or following co-culture with fibroblast cells. Together, these in vitro data suggest that the development of fulvestrant resistance in vivo may confer a metastatic advantage to the cells by allowing their migratory and invasive behaviour to be augmented by surrounding stromal cells.

Antineoplastic Agents, Hormonal↗
PubMed2004

HSV vector-delivery of GDNF in a rat model of PD: partial efficacy obscured by vector toxicity.

Herpes simplex virus (HSV)-derived vectors have been suggested for potential use in gene therapy for Parkinson's disease (PD). HSV naturally infects adult neuronal cells and possesses a large genome for the insertion of transgenes. In the present study, we have used two different HSV constructs to deliver glial cell line-derived neurotrophic factor (GDNF) to the striatum, and to assess the neuroprotective effects of the GDNF product in an intrastriatal 6-hydroxydopamine lesion model. One construct is blocked for IE gene expression whereas the other is deleted in the thymidine kinase gene. Both constructs induced a significant protection of the dopaminergic neurons in the substantia nigra from the lesions, whereas only one induced a transient behavioural recovery in amphetamine-induced rotation. Unexpectedly, the more deleted virus caused the greater toxicity. This was found to be due to the way the vector was purified. The issue of toxicity, which might account for the variable functional effects, needs resolving prior to therapeutic application of these vectors.

Animals↗
PubMed2004

Mining biomarkers in human sera using proteomic tools.

One of the major difficulties in mining low abundance biomarkers from serum or plasma is due to the fact that a small number of proteins such as albumin, alpha2-macroglobulin, transferrin, and immunoglobulins, may represent as much as 80% of the total serum protein. The large quantity of these proteins makes it difficult to identify low abundance proteins in serum using traditional 2-dimensional electrophoresis. We recently used a combination of multidimensional liquid chromatography and gel electrophoresis coupled to matrix-assisted laser desorption/ionization-quadrupole-time of flight and Ion Trap liquid chromatography-tandem mass spectrometry to identify protein markers in sera of Alzheimer's disease (AD), insulin resistance/type-2 diabetes (IR/D2), and congestive heart failure (CHF) patients. We identified 8 proteins that exhibit higher levels in control sera and 36 proteins that exhibit higher levels in disease sera. For example, haptoglobin and hemoglobin are elevated in sera of AD, IR/D2, and CHF patients. The levels of several other proteins including fibrinogen and its fragments, alpha 2-macroglobulin, transthyretin, pro-platelet basic protein, protease inhibitors clade A and C, as well as proteins involved in the classical complement pathway such as complement C3, C4, and C1 inhibitor, were found to differ between IR/D2 and control sera. The sera levels of proteins, such as the 10 kDa subunit of vitronectin, alpha 1-acid glycoprotein, apolipoprotein B100, fragment of factor H, and histidine-rich glycoprotein were observed to be different between AD and controls. The differences observed in these biomarker candidates were confirmed by Western blot and the enzyme-linked immunosorbent assay. The biological meaning of the proteomic changes in the disease states and the potential use of these changes as diagnostic tools or for therapeutic intervention will be discussed.

Biomarkers↗
PubMed2004

Vaccination and allergic disease: a birth cohort study.

OBJECTIVES: We examined the effect of vaccination for diphtheria; polio; pertussis and tetanus; or measles, mumps, and rubella on the incidence of physician-diagnosed asthma and eczema. METHODS: We used a previously established birth cohort in the West Midlands General Practice research database. RESULTS: We found an association between vaccination and the development of allergic disease; however, this association was present only among children with the fewest physician visits and can be explained by this factor. CONCLUSIONS: Our data suggest that currently recommended routine vaccinations are not a risk factor for asthma or eczema.

Asthma↗
PubMed2003

Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture.

The use of tricyclic antidepressants is associated with an increased risk of hip fracture. Despite a better side effect profile, this adverse effect has also been reported for selective serotonin reuptake inhibitors. To determine whether these findings result from bias arising from the case-control method, the authors have performed a case-control analysis and a self-controlled case-series analysis using 1987-1999 diagnosis data for 16,341 cases of hip fracture and 29,889 controls drawn from the United Kingdom General Practice Research Database. Both analyses showed an association between hip fracture and antidepressant treatment, and this was most marked during the first 15 days of treatment. The estimates from the case-control study were larger than those from the case-series analysis: The odds ratios for fracture within the first 15 days of a prescription for tricyclic antidepressants and serotonin reuptake inhibitors were 4.76 (95% confidence interval (CI): 3.06, 7.41) and 6.30 (95% CI: 2.65, 14.97), whereas the equivalent incidence ratios were 2.30 (95% CI: 1.82, 2.90) and 1.96 (95% CI: 1.35, 2.83). Tricyclic antidepressants and serotonin reuptake inhibitors are both associated with an independent increase in hip fracture incidence during the first weeks of treatment. The estimates from the case-series analyses were smaller than those from the case-control analyses, suggesting that the case-control method is subject to bias.

Aged↗
PubMed2003

Oxidised lipoproteins may promote inflammation through the selective delay of engulfment but not binding of apoptotic cells by macrophages.

During normal tissue homeostasis apoptotic cells (AC) are rapidly recognised and engulfed by neighbouring cells or macrophages (Mphi), thus preventing an inflammatory response. Conversely, in chronically inflamed tissues, including the atherosclerotic artery and rheumatoid joint, removal of AC is defective despite the co-localisation of seemingly adequate numbers of Mphi. Mechanisms preventing removal of AC in vivo remain obscure, but might include oxidised low-density lipoprotein (ox-LDL), which is abundant in chronic inflammatory lesions. Although implicated in their pathogenesis, defining the role of ox-LDL on inflammatory processes has proved complicated. In fact, seemingly contradictory results have previously been described, though these may in part reflect the heterogeneous nature of ox-LDL applied in these studies. We wished to investigate the effect of physiologically representative ox-LDL on the binding and engulfment of apoptotic vascular smooth muscle cells (VSMC) and fibroblasts, as these have previously been shown to co-localise with Mphi in chronically inflamed tissues in vivo. We show that Mphi recognition of AC in vitro is not affected at physiological levels of ox-LDL. However, engulfment of intact AC is dramatically reduced/delayed. Importantly, in the absence of ox-LDL rapid phagocytosis of intact AC suppresses Mphi inflammatory cytokine release. In striking contrast, in the presence of ox-LDL, despite binding of AC to Mphi, release of IL-6 and MCP-1 is no longer suppressed. We propose that ox-LDL could maintain an inflammatory response by inhibiting the engulfment of AC, required for Mphi de-activation. This mechanism may contribute to chronic persisting inflammation in the atherosclerotic artery and rheumatoid joint.

Apoptosis↗
PubMed2003

Fracture risk in people with celiac disease: a population-based cohort study.

BACKGROUND & AIMS: People with celiac disease are at risk of developing osteoporosis, but the extent of any increased fracture risk is unclear. We performed a population-based cohort study by using the General Practice Research Database to quantify the fracture risk in people with celiac disease compared with the general population. METHODS: We identified 4732 people with celiac disease, of whom 1589 were "incident" cases, and 23,620 age- and sex-matched control subjects. We used Cox regression to estimate the hazard ratios for any fracture, hip fracture, and ulna or radius fracture in the celiac disease cohort compared with the general population. RESULTS: In the incident subjects with celiac disease, the mean age at diagnosis was 44 years, and 67% were women. The overall hazard ratio for any fracture was 1.30 (95% confidence interval, 1.16-1.46), for hip fracture was 1.90 (95% confidence interval, 1.20-3.02), and for ulna or radius fracture was 1.77 (95% confidence interval, 1.35-2.34). The absolute difference in the overall fracture rate was 3.20 per 1000 person-years and for hip fracture it was 0.97 per 1000 person-years in those older than 45 years. In 1589 incident subjects, the excess fracture risk was slightly lower compared with the "prevalent" subjects (hazard ratio for any fracture, 1.19 vs. 1.40, respectively). CONCLUSIONS: There were small increases in both the absolute and relative fracture risks in people with celiac disease; the excess risks were slightly lower in those with a more recent diagnosis. Our data indicate that concerns regarding a markedly increased fracture risk in celiac disease are unwarranted.

Adolescent↗
PubMed2002

The importance of prenatal exposures on the development of allergic disease: a birth cohort study using the West Midlands General Practice Database.

The etiology of allergic disease is not understood, but a decreased exposure to infection may play an important role. There are few published data on the impact of change in microbial exposure during pregnancy on the child's risk of developing allergic disease. Using a birth cohort of 24,690 children, derived from the West Midlands General Practice Research Database, we investigated a number of perinatal exposures on the incidence of asthma, eczema, and hay fever. Our findings suggest that exposure to antibiotics in utero is associated with an increased risk of asthma in a dose-related manner (more than two courses of antibiotics compared with none adjusted hazard ratio [HR] 1.68; 95% confidence interval [CI], 1.51-1.87), and similar associations are present for eczema (adjusted HR 1.17; 95% CI, 1.06-1.29) and hay fever (adjusted HR 1.56; 95% CI, 1.22-2.01). Exposure to a range of infections in utero was also associated with a small increased risk of developing allergic disease. Strong protective effects of older siblings on the incidence of allergy are present within this cohort, but previous pregnancies that did not result in a live birth were not protective. Our findings suggest that exposure to antibiotics and to infections in utero is a potentially important risk factor in the development of allergic disease.

Age Factors↗
PubMed2002

Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database.

BACKGROUND: It has been suggested that the rise in prevalence of allergic disease in westernized countries is due in part to a decrease in exposure to infections and an increase in the use of antibiotics early in life. OBJECTIVE: The purpose of this investigation was to quantify the relationships between (1) exposure to personal infections, infections in siblings, and use of antibiotics in early life and (2) the incidence of allergic disease. METHODS: Using the West Midlands section of the UK General Practice Research Database, we established a historical birth cohort of children (N = 29,238). For each child, we identified all personal infections and infections in siblings and determined the use of antibiotics in early life; we also noted incident diagnoses of asthma, eczema, and hay fever. The data were analyzed through use of Cox regression. RESULTS: There was no clear protective effect of exposure to either personal infections or infections in siblings with respect to the incidence of allergic disease. Antibiotic exposure was associated with an increased risk of developing allergic disease in a dose-related manner: having 4 or more courses of antibiotics in the first year of life was associated with an increased incidence of asthma (hazard ratio [HR], 3.13; 95% CI, 2.75-3.57), eczema (HR, 1.48; 95% CI, 1.31-1.68), and hay fever (HR, 2.12; 95% CI, 1.68-2.66). However, adjusting for consulting behavior reduced these effects (adjusted HR [95% CI]: asthma, 1.99 [1.72-2.31]; eczema, 1.01 [0.88-1.17]; hay fever, 1.14 [0.88-1.47]). CONCLUSIONS: We found no evidence that exposure to infections reduced the incidence of allergic disease, and infections did not explain the previous findings of a strong birth order effect in this cohort. The use of antibiotics might be associated with early diagnoses of allergic disease.

Anti-Bacterial Agents↗
PubMed2002

Mode of delivery and risk of developing allergic disease.

The aim of this study was to quantify the relationship between mode of delivery and subsequent incidence of allergic disease. The analysis is based on data derived from a birth cohort of 24,690 children who contributed data to the West Midlands General Practice Research Database. We found no convincing evidence to suggest that babies born by caesarean, forceps, or breech delivery had an increased risk of developing allergic disease.

Asthma↗