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Biomedical subjects

I P Hall

Publications and source records attributed to I P Hall.

At least 19 recordsLinked to original sources
PubMed2006

Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome.

BACKGROUND: Hyponatraemia is the most commonly identified electrolyte abnormality. Published data on severe hyponatraemia in general medical in-patients is lacking. AIM: To determine the aetiology, adequacy of assessment, and outcome of severe hyponatraemia in general medical in-patients. DESIGN: Retrospective case-note review. METHODS: All general medical in-patients (n = 108) with serum sodium < or =125 mmol/l were identified from the clinical chemistry database, over a six-month period. A full review of notes and computer records was undertaken at the index date and a pre-determined follow-up date. RESULTS: Follow-up data were available in 105 patients. There was a wide range of aetiologies: diuretic therapy (loop and thiazide), congestive cardiac failure and liver disease were the most common, and 75.3% of patients had multiple causes. None of the 48% of patients whose history suggested a possible diagnosis of the syndrome of inappropriate anti-diuretic hormone (SIADH) met the generally accepted diagnostic criteria. Overall mortality was 20% during the index admission and 44.6% at follow-up, vs. 7.1% and 22%, respectively, for other patients admitted to the same directorate over the same time period (p < 0.001). Mortality was linked to aetiology, but not to reduced absolute serum sodium concentration at admission. DISCUSSION: Severe hyponatraemia in general medical patients is associated with a complex, multifactoral aetiology and a very poor prognosis. Outlook is governed principally by aetiology, and not by serum sodium level. Assessment of patients with hyponatraemia requires a practical clinical algorithm for diagnosing SIADH.

Adult↗
PubMed2006

Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness.

There is increasing evidence that the assessment of eosinophilic airway inflammation using induced sputum and measurement of airway hyperresponsiveness provides additional, clinically important information concerning asthma control. The aim of this study was to directly compare the effects of different treatments on these markers in patients with asthma and persistent symptoms, despite the use of low-dose inhaled corticosteroids. A double-blind four-way crossover study was performed, which compared a 1-month treatment with budesonide 400 mug b.i.d., additional formoterol, additional montelukast and placebo in 49 patients with uncontrolled asthma despite budesonide 100 mug b.i.d., with each treatment separated by a 4-week washout period. The change in sputum eosinophil count with formoterol (2.4 to 3.8% change, 0.6-fold reduction, 95% confidence interval (CI) 0.5-0.9) differed significantly from placebo (2.8 to 2.5% change, 1.1-fold reduction, 95% CI 0.7-1.6) and high-dose budesonide (2.7 to 1.6% change, 1.6-fold reduction, 95% CI 1.2-2.2). The effects of montelukast did not differ from placebo. The changes in methacholine airway responsiveness were small and did not differ between treatments. High-dose budesonide had the broadest range of beneficial effects on other outcomes, including symptom scores, morning peak expiratory flow and forced expiratory volume in one second. In conclusion, treatment given in addition to low-dose inhaled corticosteroids results in modest benefits. Formoterol and high-dose budesonide have contrasting effects on eosinophilic airway inflammation.

Acetates↗
PubMed2006

Thiazide diuretic prescription and electrolyte abnormalities in primary care.

AIMS: Thiazide diuretics have a number of well-documented metabolic adverse effects. The aim of this study was to estimate the frequency of hyponatraemia and hypokalaemia amongst patients taking a thiazide diuretic in primary care. METHODS: A computerized search of the electronic prescribing and laboratory records of six UK general practices was performed. Of the 32 218 adult patients identified, 3773 had received at least one prescription for a thiazide between the years 1990 and 2002. RESULTS: Detailed prescribing data were available for 2942 patients of whom 951 (32.3%) had a recorded check of their electrolytes. One hundred and ninety-six (20.6%) had a sodium and/or potassium concentration below the normal range. The sodium distribution had a negative skew (-1.8) and in 130 (13.7%) patients was within the hyponatraemic range. Hypokalaemia was less common, occurring in 79 (8.5%) patients. Hyponatraemia was significantly associated with increased age; the odds ratio for developing hyponatraemia in patients over 70 years was 3.87 compared with those of < or = 70 years. Hypokalaemia was significantly associated with increased thiazide dose. CONCLUSIONS: Prescription of a thiazide diuretic in primary care is associated with a high frequency of hyponatraemia and hypokalaemia. Thiazides should be prescribed at low dose and the risk of hyponatraemia, especially in the elderly, should be considered and monitored for when prescribing these agents.

Adult↗
PubMed2006

The effect of beta2-adrenoceptor haplotypes on bronchial hyper-responsiveness in patients with asthma.

BACKGROUND: The beta2-adrenoceptor exhibits genetic polymorphism which may be clinically relevant in terms of treatment response or bronchial hyper-responsiveness (BHR). The combined effect of these genotypes, or the haplotype, has not been fully characterized in terms of BHR. METHODS: We performed a retrospective analysis of the effects of haplotypes of amino acid substitution at position 16 (Gly/Arg) and position 27 (Gln/Glu) on spirometry and BHR to methacholine and adenosine monophosphate (AMP) in 594 asthmatic patients. RESULTS: There was a significant (P < 0.05) overall effect for forced expiratory volume (FEV(1)) but not after correction for steroid dose and atopic status. There were no significant differences for BHR to methacholine or AMP between the different haplotypes and no difference between the numbers of patients with or without clinically relevant BHR. Methacholine PD20 geometric mean-fold difference was 1.63 (95% CI: 0.95-2.80) between Arg-Arg/Gln-Gln and Gly-Gly/Gln-Gln and 1.26 (95% CI: 0.75-2.11) between Gly-Gly/Gln-Gln and Gly-Gly/Glu-Glu. CONCLUSIONS: The degree of BHR to indirect and direct stimuli does not differ between beta2-adrenoceptor haplotypes, and haplotypes cannot be used to predict BHR in patients presenting with asthma. Although beta2-adrenoceptor haplotypes do not predict BHR they may be important in predicting response to bronchodilator therapy.

Adenosine Monophosphate↗
PubMed2005

Contribution of ADAM33 polymorphisms to the population risk of asthma.

BACKGROUND: ADAM 33 is the first gene identified as a candidate for asthma by positional cloning techniques, with association studies reaching impressive statistical significance. It has a postulated role in myogenesis, airway modelling, and signalling via protein shedding. Concerns over the methodology of the initial study have led to several attempts at replication, with inconsistent results. METHOD: To clarify the role of ADAM33 in determining the risk of asthma in the general population, new transmission disequilibrium and case-control studies were undertaken followed by a meta-analysis of all existing data. RESULTS: Studies in Icelandic and UK populations revealed no association when taken in isolation. The meta-analysis, however, showed that the F+1 and ST+7 variants were significantly associated with asthma in both types of study. CONCLUSIONS: The additional risk imparted by this variation would account for 50,000 excess asthma cases in the UK alone. This study also demonstrates the size of study required to investigate such hypotheses adequately.

ADAM Proteins↗
PubMed2004

Expression profiling: fishing and chips.

Expression profiling approaches are potentially valuable in helping to define novel gene products which may be important in disease pathogenesis or treatment response. However, there are many pitfalls which need to be considered in the design of experiments of this kind and in considering interpretation of data from such studies. Some of these are discussed.

Celiac Disease↗
PubMed2002

Asthma.

Asthma is one of the commonest chronic diseases of affluent societies. The striking increase in prevalence of asthma over recent decades and the rarity of this disease in less affluent populations confirms the importance of environmental factors in the cause of asthma--although which environmental factors are responsible is still not clear. Family studies show that genetic factors are also important in determining individual susceptibility to asthma, with results of genetic studies suggesting that there are many genes with moderate effects rather than a few major genes. Asthmatic airways show inflammation and remodelling, with CD4+ helper cells, mast cells, and eosinophils characterising the inflammatory response. Inhaled corticosteroids remain the cornerstone of treatment with the addition of long-acting beta agonists as the next step if symptoms continue. Leukotriene antagonists, the only new drugs to reach the market in the past decade, have modest effects. However, a better understanding of the mechanisms underlying asthma and the genetic and environmental factors that predispose individuals to asthma should lead to better preventative strategies and new therapeutic approaches.

Asthma↗
PubMed2002

The selective CXCR2 antagonist SB272844 blocks interleukin-8 and growth-related oncogene-alpha-mediated inhibition of spontaneous neutrophil apoptosis.

The aims of this study were to investigate the effects of Interleukin-8 (IL-8) and Growth related oncogene-alpha (Gro-alpha) on neutrophil apoptosis and determine the potential for a selective CXCR2 antagonist to inhibit these responses. IL-8 and Gro-alpha both produced dose dependent inhibition of spontaneous human neutrophil apoptosis after 16 hours incubation (59+/-3.5% and 27.5+/-3% respectively; EC50s 2.2+/-1.8 nM, and 0.5+/-0.2 nM respectively). The pro-survival effect of a fixed concentration of agonist (IL-8 or Gro-alpha) on cultured neutrophils was abrogated by a selective CXCR2 antagonist SB272844 (K(D)s 253 nM and 49.9 nM in the presence of IL-8 or Gro-alpha respectively). Our data suggests that the anti-apoptotic effect of Gro-alpha is mediated through CXCR2 as selective CXCR2 blockade with SB272844 can potently abrogate this response. The inhibitory effect of IL-8 may in addition partly be mediated through CXCR1 as SB272844 was less potent in its ability to abrogate the anti-apoptotic effects of IL-8 when this agent was used as an agonist. CXCR2 antagonists may have a therapeutic role in controlling neutrophil-driven inflammation by reducing neutrophil recruitment and restoring neutrophils to the tissue clearance pathway of apoptosis.

Apoptosis↗
PubMed2002

Beta2 adrenoceptor promoter polymorphisms: extended haplotypes and functional effects in peripheral blood mononuclear cells.

BACKGROUND: The beta2 adrenoceptor and its 5' untranslated region contain a number of genetic variants. The aim of this study was to investigate the potential for genetic variation at this locus to influence the expression of beta2 adrenoceptors on circulating peripheral blood mononuclear cells (PBMCs). METHODS: Genotype was determined in 96 individuals with asthma for four polymorphisms at the beta2 adrenoceptor locus. Beta2 adrenoceptor binding and cyclic AMP responses to isoprenaline in PBMCs were determined and the relationship between genotype/haplotype and beta2 adrenoceptor expression and response to isoprenaline examined. RESULTS: Beta2 adrenoceptor promoter polymorphisms were found to be common in white subjects. Strong linkage disequilibrium exists across this locus, resulting in the occurrence of several common haplotypes. No single polymorphism or haplotype was correlated with the level of beta2 adrenoceptor expression or cyclic AMP responses to isoprenaline in vitro. CONCLUSION: Beta2 adrenoceptor polymorphisms, when considered in isolation or by extended haplotypes, do not determine the basal level of expression or coupling of beta2 adrenoceptors in PBMCs from asthmatic subjects.

Adolescent↗
PubMed2001

Mutation screening of the muscarinic M(2) and M(3) receptor genes in normal and asthmatic subjects.

1. Muscarinic receptors are important in the development of airway hyperresponsiveness, and dysfunction of these receptors has been suggested to be present in asthma. 2. The human muscarinic M(2) and M(3) receptor genes were screened for polymorphic variation using single-stranded conformation polymorphism (SSCP) analysis, complemented by direct fluorescent sequencing. Forty-six random DNA samples and 46 respiratory physician diagnosed asthmatic samples were used as a template for analysis. 3. Within the muscarinic M(2) receptor gene, we identified two degenerate single base substitutions (1197T-->C, Thr-->Thr and 976A-->C, Arg-->Arg) in one random and one asthmatic sample respectively. Analysis of the 3' UTR region revealed an additional 'A' at bp 1793 (c.f. ATG). This was present in all of 49 samples analysed by sequencing or BsmI digest, suggesting that the published sequence (GenBank Accession NO: M16404) is incorrect. A common 3' UTR polymorphism (T-->A) was found at bp 1696 (c.f. ATG) (allelic frequency=65%, n=60), but this does not alter transcription factor recognition sites. 4. We were unable to identify any polymorphic variation within the muscarinic M(3) coding region or the flanking regions investigated, using the methods described. 5. The coding regions for the human muscarinic M(2) and M(3) receptor genes are both highly conserved. These data suggest that polymorphic variation within these coding sequences is unlikely to account for inter-individual variability in response to methacholine or anticholinergic therapy. The potential functional significance of the muscarinic M(2) receptor 3' UTR polymorphism (bp 1696) remains to be determined.

3' Untranslated Regions↗
PubMed2001

Linkage analysis of the 5q31-33 candidate region for asthma in 240 UK families.

Atopy and asthma are complex genetic diseases resulting from the interactions of a number of genetic and environmental factors. We had previously reported allelic association between the IL9 marker on chromosome 5q31-33 and atopy. In order to further investigate the role of susceptibility genes on 5q31-33 in the development of atopy and asthma we have studied 240 UK families comprising 131 families selected at random, 60 multiplex families with affected sib pairs, and 49 single proband nuclear families. Polymorphic markers on 5q31-33 were genotyped and both single and multipoint linkage analysis was undertaken using the BETA program. We have used both affection status and quantitative scores for atopy and asthma for phenotypic variables, combining data into scores for asthma and atopy. The strongest suggestion of linkage using multipoint analysis was centred around D5S410 with a maximum Lod of 1.946 at location 171.3 cM and a standard error of 3.3 for the asthma quantitative score. There was no evidence of linkage with atopy, the atopy quantitative score or total serum IgE.

Asthma↗
PubMed2001

Human airway smooth muscle expresses 7 isoforms of adenylyl cyclase: a dominant role for isoform V.

Adenylyl cyclases are a nine-member family of differentially regulated enzymes responsible for the synthesis of cAMP. cAMP is an important second messenger that contributes to the regulation of airway smooth muscle tone. However, little is known regarding the expression and regulation of adenylyl cyclase isoforms in airway smooth muscle cells. Nondegenerate specific primers were designed for all nine known isoforms of human adenylyl cyclase. RT-PCR experiments were performed using total RNA extracted from whole human brain (positive control), whole rat brain (negative control), whole human trachea, human airway smooth muscle, and primary cultures of human airway smooth muscle cells. Seven of the nine known isoforms of adenylyl cyclase (isoforms I, III-VII, and IX) were expressed at the mRNA level in both human airway smooth muscle and primary cultures of human airway smooth muscle cells. Immunoblot and adenylyl cyclase functional assay indicated that isoform V is likely among the functionally predominant isoforms of adenylyl cyclase in human airway smooth muscle. These results suggest that multiple isoforms of adenylyl cyclase enzymes are coexpressed in human airway smooth muscle cells and that isoform V is among the functionally important isoforms.

Adenylyl Cyclases↗
PubMed2001

Mechanisms of cytokine effects on G protein-coupled receptor-mediated signaling in airway smooth muscle.

Numerous in vitro and in vivo studies have implicated the cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) as mediators of airway inflammation and therefore potentially important substances in the pathogenesis of asthma. In this study, we examined the mechanisms by which IL-1 beta and TNF-alpha affect inhibition of cell growth, G protein-coupled receptor (GPCR) desensitization, and the recently reported adenylyl cyclase sensitization in human airway smooth muscle (HASM) cultures. Our findings demonstrate that adenylyl cyclase sensitization is independent of cytokine-mediated cyclooxygenase type 2 (COX-2) and prostaglandin E(2) (PGE(2)) induction, whereas COX-2 induction appears to be required for both growth inhibition and GPCR desensitization. However, GPCR desensitization was highly dependent on the presence of EGF during chronic treatment with cytokines, which could be explained by a synergistic effect of EGF on cytokine-mediated COX-2 and PGE(2) induction. Interestingly, various agents (including inhibitors of p42/p44 and p38 mitogen-activated protein kinase signaling) were significantly more effective in inhibiting cytokine-mediated PGE(2) induction, GPCR desensitization, and cell growth inhibition than in inhibiting COX-2 induction. These data demonstrate disparity in the requirement and sufficiency of COX-2 induction in promoting different functional effects of IL-1 beta and TNF-alpha in HASM.

Adenylyl Cyclases↗
PubMed2001

Interleukin-1beta and rhinovirus sensitize adenylyl cyclase in human airway smooth-muscle cells.

Rhinovirus (RV) is a major cause of wheezing in asthmatics and has been reported to cause beta2 adrenergic receptor hyporesponsiveness in human airway smooth muscle (HASM) via cellular secretion of interleukin (IL)-1beta. We studied the effects of IL-1beta and RV on cyclic adenosine monophosphate (cAMP) production in HASM cells. Chronic incubation with IL-1beta or RV caused a significant increase (approximately 3- and approximately 2-fold, respectively) in forskolin (FSK)-stimulated cAMP production, suggesting a sensitization of adenylyl cyclase (AC). The observed augmentation of FSK-stimulated cAMP formation by IL-1beta was completely abrogated by pretreatment with an IL-1 receptor antagonist or cycloheximide, demonstrating that the effect is mediated via the IL-1 receptor 1 (IL-1R1) and that de novo protein synthesis is required. In contrast, RV-induced AC sensitization was not mediated via the IL-1R1 but was observed to be protein kinase C-dependent. We suggest that the sensitization of AC observed after exposure to IL-1beta or RV infection is a cellular defense mechanism to promote pathways that induce relaxation in the inflamed airway.

Adenylate Cyclase Toxin↗
PubMed2001

Effects of growth factors and extracellular matrix on survival of human airway smooth muscle cells.

Airway remodeling complicates longstanding asthma. It is characterized by an increase in the number of airway smooth muscle cells (SMCs) as well as an increase in and alteration of the type of extra-cellular matrix (ECM) in the airways. Although the number of SMCs in the airways depends on the balance of cell proliferation and cell death, studies to date have concentrated on factors affecting SMC proliferation. Here we report the first study on airway SMC survival factors: these cells receive a strong survival signal, which is not dependent on the known growth factor mitogens. We identified the ECM factors fibronectin, laminin, and collagens I and IV as important anti-apoptotic elements, and characterized the expression of the ECM receptors (integrins) on cultured SMC. Functionally blocking antibody and peptide studies revealed the alpha(5)beta(1) integrin to be an important transducer of the ECM-derived survival signal in these cells. Confocal microscopy confirmed the striking effects that discrete ECM factors have on SMC phenotype, notably the cytoskeleton. In summary, our data improves the understanding of the mechanisms underlying airway remodeling by outlining the key survival factors for airway SMC and by highlighting the impact of the cell-matrix interactions on cell death and phenotype.

Apoptosis↗
PubMed2001

Peripheral blood neutrophils are hyperresponsive to IL-8 and Gro-alpha in cryptogenic fibrosing alveolitis.

Cryptogenic fibrosing alveolitis (CFA) is characterized by increased pulmonary recruitment of peripheral blood neutrophils (PBNs) by interleukin (IL)-8 and other chemotactic mediators. This study investigated whether, in CFA, the PBN motility response is primed by IL-8 and growth-related oncogene (Gro)-alpha, as demonstrated in other neutrophilic inflammatory diseases, and whether the motility response of PBNs to IL-8 and Gro-alpha can be abrogated using a selective antagonist for the neutrophil receptor for IL-8 and Gro-alpha, CXCR2. The percentage of PBNs to undergo shape change (%SC), spontaneously and in response to IL-8 and Gro-alpha, was measured in patients with CFA (n=10) and controls (n=10), and the effect of the CXCR2 antagonist SB272844 studied. Plasma levels of IL-8, and Gro-alpha were measured using an enzyme-linked immunosorbent assay (ELISA). The %SC of unstimulated PBNs and the potency of Gro-alpha and IL-8 to produce neutrophil polarization was greater in CFA than in controls; dose which produces 50% of maximal effect (EC50) of IL-8 was 3.6 +/- 0.7 nM for CFA versus 6.3 +/- 1.0 nM for controls; p<0.05. SB272844 inhibited Gro-alpha induced but not IL-8 induced neutrophil shape change (equilibrium constant (KD) 123 +/- 18 nM). Plasma concentrations of Gro-alpha were increased in patients with CFA. PBNs are spontaneously activated and undergo a greater motility response to IL-8 and Gro-alpha in CFA. Interleukin-8 and growth-related oncogene-alpha, circulating in substimulatory amounts in cryptogenic fibrosing alveolitis, may prime the peripheral blood neutrophils motility response, thus increasing their capacity for migration to the lung. Selective CXCR2 antagonists may be useful to block the Gro-alpha-induced priming response whilst preserving neutrophil functions mediated by CXCR1, the alternative neutrophil receptor for interleukin-8.

Aged↗