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Biomedical subjects

R Haigh

Publications and source records attributed to R Haigh.

At least 19 recordsLinked to original sources
PubMed2006

The effect of substance P on nitric oxide release in a rheumatoid arthritis model.

OBJECTIVE: The inflammatory mediator substance P (SP) acts principally through the neurokinin (NK1) receptor. We assessed the influence of SP on production of NO and its possible role in the pathogenesis of rheumatoid arthritis (RA). METHODS: The effect of SP (0.1-100 nM) on concentrations of the NO metabolite, nitrite, produced by synovial fibroblasts from RA patients was studied. For comparison, the effects of TNF-alpha (0.57 pM-5.7 nM) and IL-1beta (0.57 pM-5.7 nM) were also studied. In parallel studies, footpad inflammation was induced in NK1 receptor knock-out (KO) and wild-type (WT) mice, and swelling and NO metabolite levels were measured. RESULTS: In cultured synoviocytes, SP, TNF-alpha and IL-1beta induced significantly increased nitrite concentrations. Consistent with a role for NO in SP-mediated inflammatory reactions, the plasma NO metabolite level in WT mice was significantly increased at 3 days following an injection of 10 mg/ml Mycobacterium tuberculosis, but there was no significant change in NK1 KO mice. These results were paralleled by the changes in footpad swelling in WT mice compared to NK1 KO mice. CONCLUSION: SP, like TNF-alpha and IL-1beta, induces NO in both rheumatoid synoviocytes and experimental models of inflammation. Treatments directed against SP may have important and hitherto unrecognised anti-inflammatory effects.

Aged↗
PubMed2004

Combined family trio and case-control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa.

The high activity Val158 (H) allele of the dopamine-metabolizing enzyme catechol-O-methyltransferase (COMT) was associated with anorexia nervosa (AN) in a recent family trio-based study of patients from Israel. In an attempt to replicate this finding, we performed a combined family trio and case-control study in an European population from seven centers in six different countries (Austria, Germany, Great Britain, Italy [Milan], Italy [Florence], Slovenia, and Spain), together contributing a total of 372 family trios, 684 controls and 266 cases. TDT analyses of high (H) and low (L) alleles in family trios showed that H allele and L allele were each transmitted 101 times (chi(2) = 0, ns). Allele-wise case-control analysis using separate samples simply combined from the centers was also not significant, with the frequencies of the H allele 50% in cases and same in controls. Stratified analysis of data from all centers gave an odds ratio of 0.98 (Cornfield 95% confidence limits 0.78-1.24). Analysis by genotype was likewise not significant (overall chi(2) = 0.42). Because we were not able to support the primary hypothesis that Val158Met is a risk factor for AN, we did not perform secondary analysis of minimum body mass index (mBMI), age at onset or illness subtype (restricting or binge purging anorexia). Overall we found no support for the hypothesis that the Val158 allele of COMT gene is associated with AN in our combined European sample.

Alleles↗
PubMed2004

Symmetry, T cells and neurogenic arthritis.

Symmetry in clinical disease occurs more commonly than expected by chance and is unexplained. In this paper we focus on symmetry in arthritis and describe the neurogenic hypothesis. Neuropeptides are anatomically relevant to systemic arthritis and have been shown to have modulating effects on both the immune and circulatory systems. Neural networks project bilaterally and are involved in the development and propagation of inflammatory disease. These putative pathological neuro-feedback loops may derive from the existence of biologically protective symmetrical mechanisms.

Arthritis↗
PubMed2004

The European Community strategy against antimicrobial resistance.

In 2001 the European Commission presented a 'Community strategy against Antimicrobial Resistance'. In previous years, the problem was addressed through an increasing number of isolated measures, but in this strategy the Commission outlined a comprehensive European Community approach across all sectors. The strategy consists of fifteen actions in four key areas: surveillance, prevention, research and product development, and international cooperation. An important part of this strategy is the 'Council Recommendation on the prudent use of antimicrobial agents in human medicine'. The Recommendation provides a detailed set of public health actions to contain antimicrobial resistance. This paper presents the eleven points of action of the strategy that are directly related to human medicine, and discusses related European Community activities. Under the new public health programme as well as under the research programme of the European Union, antimicrobial resistance is a key priority.

Drug Resistance, Microbial↗
PubMed2002

Synthesis and properties of amphiphilic networks 2: a differential scanning calorimetric study of poly(dodecyl methacrylate-stat-2,3 propandiol-1-methacrylate-stat-ethandiol dimethacrylate) networks and adhesion and spreading of dermal fibroblasts on these materials.

A series of amphiphilic networks was prepared by radical copolymerisation of dodecyl methacrylate, 2,3-propandiol-1-methacrylate and ethandiol dimethacrylate. DSC studies on these materials, swollen in water. revealed that only materials containing more than 27 wt% of water displayed melting endotherms due to the melting of ice-like structures of water (freezing water). In materials that did produce a melting endotherm the peak was generally bimodal. Changing thermal history and heating rate did not effect the shape of the two peaks, nor the relative contribution of each peak to the total endothermic response. These observations and the narrow peak width of the low temperature endotherm suggested that the bimodality was an artefact of the DSC experiment and may be due to the promotion of the glass transition once a fraction of the water has frozen. The morphology of transformed human dermal fibroblasts grown on these materials was then examined by scanning electron microscopy. Compositions that contained only non-freezing water were found to allow cell adhesion and spreading. Cells with well-spread morphologies were obtained on materials containing small fractions of freezing water and dodecyl methacrylate. These fibroblasts displayed surface features such as microvilli and filapodia. However, all compositions of poly(2,3-propandiol-1-methacrylate-co-ethandiol dimethacrylate) (i.e. hydrogels that do not contain dodecyl methacrylate repeat units) were poor substrates for cell growth and examination of these materials showed that very few cells had adhered and those that did were highly rounded.

Biocompatible Materials↗
PubMed2001

An in vitro transposon system for highly regulated gene expression: construction of Escherichia coli strains with arabinose-dependent growth at low temperatures.

Placing a gene of interest under the control of an inducible promoter greatly aids the purification, localization and functional analysis of proteins but usually requires the sub-cloning of the gene of interest into an appropriate expression vector. Here, we describe an alternative approach employing in vitro transposition of Tn Omega P(BAD) to place the highly regulable, arabinose inducible P(BAD) promoter upstream of the gene to be expressed. The method is rapid, simple and facilitates the optimization of expression by producing constructs with variable distances between the P(BAD) promoter and the gene. To illustrate the use of this approach, we describe the construction of a strain of Escherichia coli in which growth at low temperatures on solid media is dependent on threshold levels of arabinose. Other uses of the transposable promoter are also discussed.

Arabinose↗
PubMed2001

GnRH antagonists: a new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6.

A series of antagonists of gonadotropin-releasing hormone (GnRH) of the general formula Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph/4Amf(P)-D4Aph/D4Amf(Q)-Leu-ILys-Pro-DAla-NH2 was synthesized, characterized, and screened for duration of inhibition of luteinizing hormone release in a castrated male rat assay. Selected analogues were tested in a reporter gene assay (IC50 and pA2) and an in vitro histamine release assay. P and Q contain urea/carbamoyl functionalities designed to increase potential intra- and intermolecular hydrogen bonding opportunities for structural stabilization and peptide/receptor interactions, respectively. These substitutions resulted in analogues with increased hydrophilicity and a lesser propensity to form gels in aqueous solution than azaline B [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Atz)-D4Aph(Atz)-Leu-ILys-Pro-DAla-NH2 with Atz = 3'-amino-1H-1',2',4'-triazol-5'-yl, 5], and in some cases they resulted in a significant increase in duration of action after subcutaneous (s.c.) administration. Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(L-hydroorotyl)-D4Aph(carbamoyl)-Leu-ILys-Pro-DAla-NH2 (acetate salt is FE200486) (31) and eight other congeners (20, 35, 37, 39, 41, 45-47) were identified that exhibited significantly longer duration of action than acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(Ac)-Leu-ILys-Pro-DAla-NH2] (6) when administered subcutaneously in castrated male rats at a dose of 50 microg in 100 microL of phosphate buffer. No correlation was found between retention times on a C18 reverse phase column using a triethylammonium phosphate buffer at pH 7.0 (a measure of hydrophilicity) or affinity in an in vitro human GnRH report gene assay (pA2) and duration of action. FE200486 was selected for preclinical studies, and some of its properties were compared to those of other clinical candidates. In the intact rat, ganirelix, abarelix, azaline B, and FE200486 inhibited plasma testosterone for 1, 1, 14, and 57 days, respectively, at 2 mg/kg s.c. in 5% mannitol (injection volume = 20 microL). Based on the information that 31, 33, 35 and 37 were significantly shorter acting than acyline or azaline B after intravenous administration (100 microg/rat), we surmised that the very long duration of action of the related FE200486 (for example) was likely due to unique physicochemical properties such as solubility in aqueous milieu, comparatively low propensity to form gels, and ability to diffuse at high concentrations in a manner similar to that described for slow release formulations of peptides. Indeed, in rats injected s.c. with FE200486 (2 mg/kg), plasmatic concentrations of FE200486 remained above 5 ng/mL until day 41, and the time after which they dropped below 3 ng/mL and plasma LH levels started rising until full recovery was reached at day 84 with levels of FE200486 hovering around 1 ng/mL. Additionally, FE200486 was less potent at releasing histamine from isolated rat mast cells than any of the GnRH antagonists presently described in preclinical reports.

Animals↗
PubMed2001

[Use of outcome measures in physical medicine/rheumatological rehabilitation. Results of a questionnaire study].

BACKGROUND: As part of the EU-project ProESOR (Project for the European Standardisation of Outcome Measurement in Rehabilitation), a survey was undertaken to investigate the use of Outcome Measures (OM) within rehabilitation across Europe. This paper presents some of the Danish results of this survey. AIM: Evaluate the extent of use of OMs in rehabilitation. MATERIAL: All 37 Rheumatology/Physical Medicine and Rehabilitation departments and institutions in Denmark. METHOD: A questionnaire was mailed to the institutions. This included questions about the institution and its personnel, and nine diagnostic groups: Low back pain, multiple sclerosis, neuromuscular disorders, rheumatoid arthritis, spinal cord lesions, stroke, traumatic brain injury, hip and knee replacement, and lower limb amputees, with estimation of the number of patients treated and the extent of use of OMs. RESULTS: The majority of the departments treated more than 200 in- and out-patients per year. Patients with low back pain and rheumatoid arthritis were the largest patient groups, followed by patients with hip and knee replacement and stroke. OMs were most frequently used with rheumatoid arthritis and, to a lesser extent, patients with low back pain. Although many departments used one or more OM, several did not use any at all. For each diagnostic group more OMs were used if the patient was treated in a department specialised for patients with the particular diagnosis. More OMs were used with patients who tended to have longer inpatient stays. CONCLUSION: There is little consensus regarding which OMs should be used. We recommend that this challenge be taken up.

Cerebrovascular Disorders↗
PubMed2001

The use of outcome measures in physical medicine and rehabilitation within Europe.

The aim of the study was to survey the use of outcome measures in rehabilitation within Europe. It was envisaged that this would provide the basis for further studies on the cross-cultural validity of outcome measures. A postal questionnaire was distributed in November 1998 to 866 units providing rehabilitation. In total, 418 questionnaires were returned, corresponding to a response rate of 48%. These 418 centres treated an estimated 113,000 patients annually, undertaking 360,000 assessments. The survey focused on nine diagnostic groups: hip and knee replacement, low back pain, lower limb amputees, multiple sclerosis, neuromuscular disorders, rheumatoid arthritis, spinal cord lesions, stroke and traumatic brain injury. It identified a relatively small number of dominant outcome assessments for each diagnostic group and some variation in the preference for measures across regions. A large number of measures, however, are being used in one or a small number of locations and with relatively few patients. For rehabilitation of orthopaedic patients the majority of assessments undertaken are at the impairment level. For patients with neurological disorders the emphasis is mostly upon measures of disability.

Amputees↗
PubMed2001

Do rheumatologists recognize their patients' work-related problems?

OBJECTIVE: The question addressed in this pilot study was 'Does the addition of an occupational health physiotherapist offering early vocational assessment influence the management of rheumatology patients (clinically and related to the workplace)?' METHOD: Sequential vocational assessments were offered to 78 subjects with rheumatological complaints of more than 1 yr duration experiencing difficulties in working. The findings from the vocational assessments were fed back to rheumatologists. Where necessary and acceptable, workplace interventions were made and the Employment Service's Access to Work scheme was utilized to address the employment problems found. RESULTS: The intervention vocational assessments trebled the number of subjects seeing a Disability Employment Adviser (17% before the study, a further 37% during it). High levels of satisfaction were reported for interventions made at work. Some important changes to the management of some patients by a few doctors were made, but information from the vocational assessments did not reach them reliably in a number of cases. CONCLUSION: An unmet need for advice and workplace aids and equipment was identified. Vocational assessment by a practitioner with clinical knowledge, ergonomic and workplace experience proved helpful to patients in this pilot study. Without vocational assessment, the hospital-based team rarely identified what were often remediable, work problems and appeared unaware of the appropriate referral route for this group of patients. Rheumatologists may need to expand their management to include consideration of work issues to ensure that their patients are referred early for appropriate ergonomic intervention when required. Further study is required to help facilitate easy identification in the clinical setting of patients with problems at work.

Adult↗
PubMed2001

Measuring the function of children with juvenile arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) can affect a child's performance across a range of activities necessary to normal childhood development. Although there are now several available measures of disability in JIA, none have been validated for use with children in the UK. Consequently, a study was undertaken to compare and validate four such measures, together with a locally developed function test. METHODS: Fifty-three children between the ages of 5 and 16 yr were recruited into the study. The mean age was 10.4 yr and mean duration of disease 4 yr. Seventy per cent were female. RESULTS: Internal consistency was adequate in three of five measures. Four of five measures showed the expected associations between disease activity and function (P<0.05). The level of reliability was poor for tests that involved direct assessment by therapists. Most showed poor levels of unidimensionality. CONCLUSION: Until new measures become available, the CHAQ appears to be the current 'best buy' for measuring function in children with arthritis.

Adolescent↗
PubMed2001

Developing a disease-specific quality of life measure for people with multiple sclerosis.

OBJECTIVES: To develop a patient-completed disease-specific measure of quality of life in multiple sclerosis and to validate the measure in a community-based population of people with multiple sclerosis. METHODS: The items in the scale were selected in focus group sessions of people with multiple sclerosis. The initial scale included 25 items and was tested in subgroups of 150 people from a population register of people with multiple sclerosis in Leeds. Following further developmental phases, a restructured 16-item scale was tested on a random sample of 200 people with multiple sclerosis from the population register, stratified according to disease course. This led to a final eight-item unidimensional scale, the Leeds Multiple Sclerosis Quality of Life (LMSQoL) scale. RESULTS: After initial development a 16-item scale was found to be both reliable and valid. Cronbach's alpha for the 16-item scale was 0.86. The test-retest correlation was 0.74, using a two-week retest interval. However, convergent validity with the General Well Being Index was 0.67 and with the SF-36 Physical Function Scale was 0.68. This suggested that the scale straddled these two concepts and was confirmed by fit of the data to the Rasch measurement model. This revealed the potential for a reduced eight-item version of the scale. The eight-item scale had a closer association to well-being (0.83) than to physical function (0.39), had good internal consistency (0.79) and test-retest reliability (0.85). There were virtually no floor or ceiling effects for the scale. CONCLUSIONS: The study presents a disease-specific measure of quality of life in multiple sclerosis, the Leeds Multiple Sclerosis Quality of Life (LMSQoL) scale. The instrument is brief, easy to use and practical to administer in clinic or as a postal questionnaire. It measures a construct related to well-being, and provides an important adjunct to the measurement of outcome in multiple sclerosis.

Adult↗
PubMed2001

Extrusion of actin-positive strands from Hep-2 and Int 407 cells caused by outer membrane preparations of enteropathogenic Escherichia coil and specific attachment of wild type bacteria to the strands.

Enteropathogenic Escherichia coli (EPEC) causes persistent infantile diarrhoea. This nontoxigenic E. coli exhibits a complicated pathogenic mechanism in which its outer membrane proteins and type III secretory proteins damage intestinal epithelium and cause diarrhoea. In accordance with this, our previous study using HEp-2 cells demonstrated cytopathic effects caused by cell-free outer membrane preparations of EPEC. In this study, we report the extrusion of actin-positive strands from HEp-2 and Int 407 cells when treated with outer membrane preparations. An interesting observation of this work, perhaps relevant to the characteristic localized three-dimensional colony formation of EPEC, is the attachment of a wild type EPEC strain to these actin-positive strands.

Actin Cytoskeleton↗
PubMed2000

Synthesis and properties of amphiphilic networks. 1: the effect of hydration and polymer composition on the adhesion of immunoglobulin-G to poly(laurylmethacrylate-stat-glycerolmonomethacrylate-stat-ethylene-gly col-dimethacrylate) networks.

A series of hydrogels composed of varying fractions of dodecyl methacrylate (DM) and 2,3-dihydroxypropyl methacrylate (GM) were prepared using ethylene glycol dimethacrylate (EGDMA) as the cross-linking agent. The study found that for a series of gels with the same monomer ratio, bulk hydration could be controlled by adjusting the cross-link density. The ability to control cross-link density allowed the preparation of gels with the same bulk hydration but different ratios of the two monomers. The adsorption of IgG to the gels was investigated using ELISA. The aim of the project was to investigate the effect of the bulk hydration and polymer composition on IgG adsorption. The results show that for a series of gels with the same monomer ratio, there is a clear trend towards a reduction in protein adsorption as the bulk hydration and accompanying chain mobility of the gel increases. Studies on gels of the same bulk hydration but differing ratios of monomer show higher protein adsorption as the proportion of GM increases.

Adsorption↗