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Biomedical subjects

H Clark

Publications and source records attributed to H Clark.

At least 19 recordsLinked to original sources
PubMed2006

The associations of birthweight, gestational age and childhood BMI with type 2 diabetes: findings from the Aberdeen Children of the 1950s cohort.

AIMS/HYPOTHESIS: The aim of this study was to examine the associations of birthweight, gestational age and childhood BMI (assessed at a mean age of 5 years) with a self-report of a doctor diagnosis of diabetes in middle age. METHODS: We studied a birth cohort of 5,793 individuals who were born between 1950 and 1956 in Aberdeen, Scotland, and who responded to a questionnaire administered in 2000. RESULTS: Birthweight and gestational age were inversely associated with diabetes. These associations remained with additional adjustment for indicators of childhood and adult socioeconomic position, maternal complications of pregnancy, adult smoking, adult BMI and simultaneous adjustment for each other: the adjusted odds ratio per unit increase in birthweight z score was 0.73 (95% CI 0.60-0.88), the odds ratio per week increase in gestational age was 0.91 (95% CI 0.82-1.00) and odds ratio for preterm birth was 2.04 (94% CI 1.18-3.53). The positive association of childhood BMI with diabetes was attenuated on adjustment for adult BMI. CONCLUSIONS/INTERPRETATION: In this population, who were born in the 1950s, poor intrauterine growth and preterm birth are associated with an increased risk of diabetes.

Birth Weight↗
PubMed2006

Childhood intelligence, educational attainment and adult body mass index: findings from a prospective cohort and within sibling-pairs analysis.

BACKGROUND: The mechanisms underlying the observed association of childhood intelligence with body mass index (BMI) are unclear and few studies of this association have been prospective in design. METHODS: Prospective study in a birth cohort of 5467 individuals who were born in Aberdeen, Scotland between 1950 and 1956 and who responded to a follow-up survey in 2001. Comparison of associations within sibling pairs of the same family to associations between different families in 643 sibling pairs (1286 individuals) who are participants in the main cohort. RESULTS: Childhood intelligence (age 7 years) and educational attainment were both inversely associated with adult BMI (mean age 48 years): the sex- and age-adjusted mean change in adult BMI per s.d. of intelligence was -0.35 kg/m(2) (95% CI: -0.49, -0.21 kg/m(2)) and per unit increase in educational category (seven categories) was -0.28 kg/m(2) (95% CI: -0.34, -0.22). On adjustment for education the association between childhood intelligence and adult BMI attenuated to the null (-0.03 kg/m(2) (-0.19, 0.13 kg/m(2))); other potential confounding or mediating factors had little or only modest effects on this association. The association between education and adult BMI was not affected by adjustment for childhood intelligence or other potential covariates. The within sibling-pair effect of education on adult BMI (-0.06 kg/m(2) (95% CI: -0.26, 0.14)) was weaker than the effect between different families (-0.37 kg/m(2) (95%CI: -0.58, -0.17)), P-value for difference of within sibling and between family effect=0.03. CONCLUSIONS: The association of childhood intelligence with adult BMI is attenuated to the null on adjustment for educational attainment, whereas the association of educational attainment with adult BMI appears to be independent of childhood intelligence and other measured covariates. However, our family analyses suggest that fixed family and neighbourhood factors, which are closely matched in siblings of a similar age, explain much of the association between greater educational attainment and lower adult BMI.

Body Mass Index↗
PubMed2006

Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria.

Novel recombinant adeno-associated virus vectors pseudotyped with serotype 8 capsid (rAAV2/8) have recently shown exciting promise as effective liver-directed gene transfer reagents. We have produced a novel liver-specific rAAV2/8 vector expressing the mouse phenylalanine hydroxylase (Pah) cDNA and have administered this vector to hyperphenylalaninemic PAH-deficient Pah(enu2) mice, a model of human phenylketonuria (PKU). Our hypothesis was that this vector would produce sufficient hepatocyte transduction frequency and PAH activity to correct blood phenylalanine levels in murine PKU. Portal vein injection of recombinant AAV2/8 vector into five adult Pah(enu2) mice yielded complete and stable (up to 17 weeks) correction of serum phenylalanine levels. Liver PAH activity was corrected to 11.5+/-2.4% of wild type liver activity and was associated with a significant increase in phenylalanine clearance following parenteral phenylalanine challenge. Although questions of long-term safety and stability of expression remain, recombinant AAV2/8-mediated, liver-directed gene therapy is a promising novel treatment approach for PKU and allied inborn errors of metabolism.

Animals↗
PubMed2005

A critical review of foot orthoses in the rheumatoid arthritic foot.

Foot orthoses are commonly prescribed by health professionals as a form of intervention for the symptomatic foot in rheumatoid arthritis. However, there is a limited evidence base to support the use of foot orthoses in this patient group. This article provides a critical review of the use of foot orthoses in the management of rheumatoid arthritic foot pathologies. A search was conducted in the Cochrane Controlled Trials Register (current issue of the Cochrane Library), Physiotherapy evidence database (PEDro), Medline, The Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Allied and Complementary Medicine (AMED) and from reference lists in journal articles. The language was restricted to English. Searching of the databases was undertaken between December 2004 and March 2005. The results indicated there is no consensus of opinion on the choice of foot orthoses used for the management of pathology in the rheumatoid foot, although there is strong evidence that foot orthoses do reduce pain and improve functional ability. The type of foot orthoses used ranged from simple cushioned insoles to custom-made rigid cast devices. Methodological issues raised included small sample size and poor use of valid and reliable outcome measures. There is limited evidence pertaining to cost-effectiveness. The results indicated a need for further investigation into the most clinically and cost-effective foot orthoses to prescribe in the management of the rheumatoid arthritic foot. This review highlights the need to identify the various types of foot orthoses that are most effective in the management of the established rheumatoid arthritic foot.

Arthritis, Rheumatoid↗
PubMed2005

The role of surfactant protein D in the colonisation of the respiratory tract and onset of bacteraemia during pneumococcal pneumonia.

We have shown previously that surfactant protein D (SP-D) binds and agglutinates Streptococcus pneumoniae in vitro. In this study, the role of SP-D in innate immunity against S. pneumoniae was investigated in vivo, by comparing the outcome of intranasal infection in surfactant protein D deficient (SP-D-/-) to wildtype mice (SP-D+/+). Deficiency of SP-D was associated with enhanced colonisation and infection of the upper and lower respiratory tract and earlier onset and longer persistence of bacteraemia. Recruitment of neutrophils to inflammatory sites in the lung was similar in both strains mice in the first 24 hrs post-infection, but different by 48 hrs. T cell influx was greatly enhanced in SP-D-/- mice as compared to SP-D+/+ mice. Our data provides evidence that SP-D has a significant role to play in the clearance of pneumococci during the early stages of infection in both pulmonary sites and blood.

Animals↗
PubMed2005

A comparison of computerised strain gauge plethysmography with D-dimer testing in screening for deep-vein thrombosis.

There has been a significant increase in the amount of diagnostic testing performed to confirm or refute a diagnosis of deep-vein thrombosis (DVT), often in low-risk patients. D-dimer testing and computer-assisted strain gauge plethysmography (SGP) are rapid, inexpensive methods of excluding DVT and, in combination with a clinical probability score for DVT, both have been used to accurately exclude DVT. D-dimer testing, SGP and a combination of both in excluding DVT were compared in 243 ambulant outpatients who followed a prespecified investigation protocol. The negative-predictive value of D-dimer testing alone was 100%, 93.9% (95% CI 93.6-94.1) and 80% (95% CI 73.7-86.3) in patients with a low, moderate and high pretest probability (PTP) score for DVT respectively. The corresponding results for SGP were 95.6% (95% CI 95.5-95.7), 86.1% (95% CI 85.9-86.4) and 77.8% (95% CI 75.9-79.7) in patients with a low, moderate and high PTP score for DVT respectively. D-dimer testing provided a rapid, cost-effective method for excluding DVT in low-risk ambulant patients, which was superior to SGP. Combined use of the modalities did not improve any aspect of clinical decision making.

Biomarkers↗
PubMed2004

Water relations in grassland and desert ecosystems exposed to elevated atmospheric CO2.

Atmospheric CO2 enrichment may stimulate plant growth directly through (1) enhanced photosynthesis or indirectly, through (2) reduced plant water consumption and hence slower soil moisture depletion, or the combination of both. Herein we describe gas exchange, plant biomass and species responses of five native or semi-native temperate and Mediterranean grasslands and three semi-arid systems to CO2 enrichment, with an emphasis on water relations. Increasing CO2 led to decreased leaf conductance for water vapor, improved plant water status, altered seasonal evapotranspiration dynamics, and in most cases, periodic increases in soil water content. The extent, timing and duration of these responses varied among ecosystems, species and years. Across the grasslands of the Kansas tallgrass prairie, Colorado shortgrass steppe and Swiss calcareous grassland, increases in aboveground biomass from CO2 enrichment were relatively greater in dry years. In contrast, CO2-induced aboveground biomass increases in the Texas C3/C4 grassland and the New Zealand pasture seemed little or only marginally influenced by yearly variation in soil water, while plant growth in the Mojave Desert was stimulated by CO2 in a relatively wet year. Mediterranean grasslands sometimes failed to respond to CO2-related increased late-season water, whereas semiarid Negev grassland assemblages profited. Vegetative and reproductive responses to CO2 were highly varied among species and ecosystems, and did not generally follow any predictable pattern in regard to functional groups. Results suggest that the indirect effects of CO2 on plant and soil water relations may contribute substantially to experimentally induced CO2-effects, and also reflect local humidity conditions. For landscape scale predictions, this analysis calls for a clear distinction between biomass responses due to direct CO2 effects on photosynthesis and those indirect CO2 effects via soil moisture as documented here.

Air↗
PubMed2003

Collectins and their role in lung immunity.

The collectins are a small family of secreted glycoproteins that contain C-type lectin domains and collagenous regions. They have an important function in innate immunity, recognizing and binding to microorganisms via sugar arrays on the microbial surface. Their function is to enhance adhesion and phagocytosis of microorganisms by agglutination and opsonization. In the lung, two members of the collectin family, surfactant proteins A and D, are major protein constituents of surfactant. Another collectin, mannan-binding lectin, is also present in the upper airways and buccal cavity and may protect against respiratory infections. Recent work has shown that collectins have roles in resistance to allergy and in the control of apoptosis and clearance of apoptotic macrophage in the lung.

Cell Adhesion↗
PubMed2003

The potential of recombinant surfactant protein D therapy to reduce inflammation in neonatal chronic lung disease, cystic fibrosis, and emphysema.

By lowering surface tension at the air-water interface in the surfactant deficient premature lung, exogenous surfactant replacement therapy for neonatal respiratory distress syndrome has been highly successful in decreasing mortality after preterm birth. It has emerged in recent years that surfactant components not present in current surfactant formulations--particularly surfactant associated proteins A and D (SP-A and SP-D)-have additional roles in host defence distinct from the surface tension lowering effects of surfactant. SP-A and SP-D are calcium dependent carbohydrate binding proteins of the innate immune system important in the first line defence of the lung against microorganisms and in the control of lung inflammation. This review addresses the possibility that recently developed recombinant forms of SP-D could be useful therapeutically in attenuating inflammatory processes in neonatal chronic lung disease, cystic fibrosis, and emphysema.

Cystic Fibrosis↗
PubMed2002

Intranasal application of chitin microparticles down-regulates symptoms of allergic hypersensitivity to Dermatophagoides pteronyssinus and Aspergillus fumigatus in murine models of allergy.

BACKGROUND: Previous studies have demonstrated that chitin in the form of microparticles that can be phagocytosed is a potent macrophage stimulator and promotes a Th1 cytokine response and it has been shown that oral administration of chitin microparticles is effective in down-regulating serum IgE and lung eosinophilia in a mouse model of ragweed allergy. To date there have been no studies on the effectivness of directly applying chitin microparticles to the respiratory tract as a treatment for allergic symptoms. OBJECTIVE: To test the effectivness of chitin microparticles when given intranasally as a treatment for the symptoms of respiratory allergy and allergic asthma and to compare its effectivness in two different mouse models of allergy, namely to Dermatophagoides pteronyssinus and Aspergilhus fumigatus. RESULTS: The intranasal application of microgram doses of chitin microparticles is an effective treatment for reducing serum IgE and peripheral blood eosinophilia, airway hyper-responsiveness and lung inflammation in both allergy models results in elevation in Th1 cytokines IL-12, IFN-gamma and TNF-alpha and reduction in IL-4 production during allergen challenge. CONCLUSION: Chitin microparticle suspensions have Th1 immunostimulatory properties and are effective when administered intranasally in mice. The stimulation of the nasal associated lymphoid tissue with chitin microparticles could offer a novel and natural approach to treating allergic disease in humans.

Administration, Intranasal↗
PubMed2002

Intranasal delivery of a truncated recombinant human SP-D is effective at down-regulating allergic hypersensitivity in mice sensitized to allergens of Aspergillus fumigatus.

C57BL/6 mice were sensitized to Aspergillus fumigatus 1-week culture filtrate, which is rich in the non-glycosylated allergen Asp f1, a major allergen in allergic bronchopulmonary aspergillosis (ABPA). A comparison of the effect of treatment of allergen challenged mice by intranasal administration of a 60-kDa truncated recombinant form of human SP-D (rfhSP-D) or recombinant full length SP-A (rhSP-A) was undertaken. Treatment with rfhSP-D produced significant reduction in IgE, IgG1 and peripheral blood eosinophilia and treatment with rfhSP-D, but not rhSP-A resulted in a significant reduction in airway hyperresponsiveness as measured by whole body plethysmography. Lung histology revealed less peribronchial lymphocytic infiltration in mice treated with rfhSP-D. Intracellular cytokine staining of spleen homogenates showed increases in IL-12 and IFN-gamma and decrease in IL-4. The level of endogenous mouse SP-D was elevated sixfold in the lungs of sensitized mice and was not affected by treatment with rfhSP-D. Taken with our previous studies, with a BALB/c mouse model of ABPA using a 3-week A. fumigatus culture filtrate, the present results show that rfhSP-D can suppress the development of allergic symptoms in sensitized mice independent of genetic background and using a different preparation of A. fumigatus allergens.

Administration, Intranasal↗
PubMed2001

c-myc box II mutations in Burkitt's lymphoma-derived alleles reduce cell-transformation activity and lower response to broad apoptotic stimuli.

In addition to c-myc rearrangement, over 50% of Burkitt's lymphoma cases present clustered mutations in exon 2, where many of the functional activities of c-Myc protein are based. This report describes the functional consequences induced by tumour-derived c-myc mutations located in c-myc box II. Two mutated alleles were studied, focusing on the P138C mutation, and compared to wild-type c-myc. The c-Myc transformation, transactivation and apoptosis activities were explored based on cells over-expressing c-Myc. While the transcriptional activation activity was not affected, our experiments exploring the anchorage-independent growth capacity of c-Myc-transfected Rat1a cells showed that c-Myc box II mutants were less potent than wild-type c-Myc in promoting cell transformation. Considering the possibility that these mutations could be interfering with the ability of c-Myc to promote apoptosis, we tested c-Myc-transfected Rat1a fibroblasts under several conditions: serum deprivation-, staurosporine- and TNFalpha-induced cell death. Interestingly, the mutated alleles were characterized by an overall decrease in ability to mediate apoptosis. Our study indicates that point mutations located in c-Myc box II can decrease the ability of the protein to promote both transformation and apoptosis without modifying its transactivating activity.

Alleles↗
PubMed2001

Automation of mouse micronucleus genotoxicity assay by laser scanning cytometry.

BACKGROUND: The evaluation of the safety of drugs and other chemicals is an important aspect of toxicology work. The mouse micronucleus assay is a standard in vivo genotoxicity assay. Chromosomal damage is an indicator of genotoxicity, which manifests in the formation of micronuclei in polychromatic erythrocytes from bone marrow and in peripheral blood erythrocytes. The assay is laborious to perform by manual counting. The laser scanning cytometer allows automated and rapid quantitation of cellular and subcellular fluorescence in monodisperse cell samples on a microscope slide. The object of this study was to evaluate the application of this new technology in the mouse micronucleus genotoxicity assay. Materials and Methods One hundred forty-four mice of various strains were dosed with combinations of carcinogens and antioxidants. Duplicate blood films were prepared 3 days later. One set of slides was stained with acridine orange, and the proportion of micronucleated erythrocytes was counted in 5,000 cells per slide. The duplicates were stained with propidium iodide (40 microg/ml). Five thousand cells per sample were examined using a laser scanning cytometer. The proportion of micronucleated erythrocytes was measured. RESULTS: A coefficient of correlation of 0.96 was found between the data from the two assays. The automation of the assay on the LSC produced a considerable time saving and efficiency gain. CONCLUSIONS: We conclude that with further development, laser scanning cytometry is likely to become the preferred modality for the performance of standard genotoxicity assays.

Animals↗
PubMed2001

Angiotensin-converting enzyme inhibition is associated with reduced troponin release in non-ST-elevation acute coronary syndromes.

OBJECTIVES: This study was done to determine the effects of angiotensin-converting enzyme (ACE) inhibition and other clinical factors on troponin release in non-ST-elevation acute coronary syndrome (ACS). BACKGROUND: Troponin is now widely used as a marker of risk in ACS, but determinants of its release have not been defined. METHODS: This was a prospective cohort study of 301 consecutive patients admitted with non-ST-elevation ACS. Baseline clinical data were recorded, ACE gene polymorphism was determined and serial blood samples were obtained for troponin-I assay. RESULTS: Significant troponin-I release (>0.1 microg/l) was detected in 93 (31%) patients. Pretreatment with ACE inhibitors, recorded in 53 patients (17.6%), independently reduced the odds of troponin-I release (odds ratio 0.25; 95% confidence intervals 0.10 to 0.64) and was associated with lower maximum troponin-I concentrations (median [interquartile range]) compared with patients not pretreated with ACE inhibitors (0.44 microg/l [0.19 to 2.65 microg/l] vs. 4.18 microg/l [0.91 to 12.41 microg/l], p = 0.01). Pretreatment with aspirin, recorded in 173 patients (57.5%), did not significantly reduce the odds of troponin-I release after adjustment but was associated with lower maximum troponin-I concentrations compared with patients not pretreated with aspirin (2.31 microg/l [0.72 to 8.02 microg/l] vs. 5.85 microg/l [1.19 to 12.79 microg/l], p = 0.05). The ACE genotyping (n = 268) showed 81 patients (30%) DD homozygous and 77 (29%) II homozygous. There was no association between ACE genotype and troponin release. CONCLUSIONS: We conclude that ACE inhibition reduces troponin release in non-ST-elevation ACS. This is likely to be mediated by the beneficial effects of treatment on vascular reactivity and the coagulation system.

Aged↗
PubMed2001

Prehospital resuscitative thoracotomy for cardiac arrest after penetrating trauma: rationale and case series.

OBJECTIVE: The purpose of this study is to present the rationale for an algorithm that describes the place of resuscitative thoracotomy in the prehospital management of a patient with penetrating chest injury, and to review a 6-year experience using this algorithm. METHODS: This study was a retrospective review of all cases where a prehospital thoracotomy was performed by the medical teams of the London Helicopter Emergency Medical Service. RESULTS: Thirty-nine prehospital thoracotomies were performed. Four (10%) patients survived, one with long-term disability. Factors associated with survival were stab wound, single cardiac wound, cardiac tamponade, and loss of pulse in the presence of an experienced prehospital doctor. CONCLUSION: Current evidence suggests that patients who suffer a cardiac arrest more than 10 minutes away from emergency room thoracotomy are very unlikely to survive. Prehospital thoracotomy is associated with a small number of survivors. This intervention should be considered if there is an appropriately experienced, trained, and equipped doctor present, who is acting within a trauma system with ongoing training and quality assurance.

Adolescent↗