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M Somerville

Publications and source records attributed to M Somerville.

At least 19 recordsLinked to original sources
PubMed2006

Low-dose infliximab treatment for ankylosing spondylitis--clinically- and cost-effective.

OBJECTIVES: Infliximab has been shown to be effective in the treatment of ankylosing spondylitis (AS) when treated in a dose of 5 mg/kg at 6 weekly intervals. This dose of infliximab has not been determined by any structured randomized trials and has significant cost implications. We describe our experience of treating AS with low-dose infliximab (3mg/kg at 8 weekly intervals). The efficacy and cost implications are discussed. METHODS: Patients who had active AS [Bath AS Disease Activity Index (BASDAI) > or = 4] were treated with infliximab 3 mg/kg at 0, 2, 6 weeks and thereafter at 8 weekly intervals. Response to treatment was defined as 50% improvement in BASDAI. Other response criteria such as ASAS 20, 40 and five of the six criteria were also assessed. Direct drug costs for infliximab were determined. RESULTS: Twenty-two consecutive AS patients received infliximab. All 22 completed treatment for 3 months, 15 patients for 6 months and 14 for 12 months. Mean age was 45 years (range 21-62) and mean disease duration 14.5 years (range 2-43). Of the patients, 54% achieved a 50% BASDAI response at 3 months and the benefit was sustained at 12 months in 63%. Similar response rate was seen with the other assessment criteria. Direct drug costs were significantly lower when low-dose infliximab regimen was used. CONCLUSIONS: Low-dose infliximab (3 mg/kg at 8 weekly infusions) is effective in the treatment of AS. Higher doses are required in a small proportion of patients when treatment is only partially effective. Titrating the dose and frequency of infusions may be required in individual patients to achieve optimal response. Using low-dose infliximab has significant economic implications.

Adult↗
PubMed2006

Surveillance of Barrett's oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

OBJECTIVES: To assess what is known about the effectiveness, safety, affordability, cost-effectiveness and organisational impact of endoscopic surveillance in preventing morbidity and mortality from adenocarcinoma in patients with Barrett's oesophagus. In addition, to identify important areas of uncertainty in current knowledge for these programmes and to identify areas for further research. DATA SOURCES: Electronic databases up to March 2004. Experts in Barrett's oesophagus from the UK. REVIEW METHODS: A systematic review of the effectiveness of endoscopic surveillance of Barrett's oesophagus was carried out following methodological guidelines. Experts in Barrett's oesophagus from the UK were invited to contribute to a workshop held in London in May 2004 on surveillance of Barrett's oesophagus. Small group discussion, using a modified nominal group technique, identified key areas of uncertainty and ranked them for importance. A Markov model was developed to assess the cost-effectiveness of a surveillance programme for patients with Barrett's oesophagus compared with no surveillance and to quantify important areas of uncertainty. The model estimates incremental cost--utility and expected value of perfect information for an endoscopic surveillance programme compared with no surveillance. A cohort of 1000 55-year-old men with a diagnosis of Barrett's oesophagus was modelled for 20 years. The base case used costs in 2004 and took the perspective of the UK NHS. Estimates of expected value of information were included. RESULTS: No randomised controlled trials (RCTs) or well-designed non-randomised controlled studies were identified, although two comparative studies and numerous case series were found. Reaching clear conclusions from these studies was impossible owing to lack of RCT evidence. In addition, there was incomplete reporting of data particularly about cause of death, and changes in surveillance practice over time were mentioned but not explained in several studies. Three cost--utility analyses of surveillance of Barrett's oesophagus were identified, of which one was a further development of a previous study by the same group. Both sets of authors used Markov modelling and confined their analysis to 50- or 55-year-old white men with gastro-oesophageal reflux disease (GORD) symptoms. The models were run either for 30 years or to age 75 years. As these models are American, there are almost certainly differences in practice from the UK and possible underlying differences in the epidemiology and natural history of the disease. The costs of the procedures involved are also likely to be very different. The expert workshop identified the following key areas of uncertainty that needed to be addressed: the contribution of risk factors for the progression of Barrett's oesophagus to the development of high-grade dysplasia (HGD) and adenocarcinoma of the oesophagus; possible techniques for use in the general population to identify patients with high risk of adenocarcinoma; effectiveness of treatments for Barrett's oesophagus in altering cancer incidence; how best to identify those at risk in order to target treatment; whether surveillance programmes should take place at all; and whether there are clinical subgroups at higher risk of adenocarcinoma. Our Markov model suggests that the base case scenario of endoscopic surveillance of Barrett's oesophagus at 3-yearly intervals, with low-grade dysplasia surveyed yearly and HGD 3-monthly, does more harm than good when compared with no surveillance. Surveillance produces fewer quality-adjusted life-years (QALYs) for higher cost than no surveillance, therefore it is dominated by no surveillance. The cost per cancer identified approaches pound 45,000 in the surveillance arm and there is no apparent survival advantage owing to high recurrence rates and increased mortality due to more oesophagectomies in this arm. Non-surveillance continues to cost less and result in better quality of life whatever the surveillance intervals for Barrett's oesophagus and dysplastic states and whatever the costs (including none) attached to endoscopy and biopsy as the surveillance test. The probabilistic analyses assess the overall uncertainty in the model. According to this, it is very unlikely that surveillance will be cost-effective even at relatively high levels of willingness to pay. The simulation showed that, in the majority of model runs, non-surveillance continued to cost less and result in better quality of life than surveillance. At the population level (i.e. people with Barrett's oesophagus in England and Wales), a value of pound 6.5 million is placed on acquiring perfect information about surveillance for Barrett's oesophagus using expected value of perfect information (EVPI) analyses, if the surveillance is assumed to be relevant over 10 years. As with the one-way sensitivity analyses, the partial EVPI highlighted recurrence of adenocarcinoma of the oesophagus (ACO) after surgery and time taken for ACO to become symptomatic as particularly important parameters in the model. CONCLUSIONS: The systematic review concludes that there is insufficient evidence available to assess the clinical effectiveness of surveillance programmes of Barrett's oesophagus. There are numerous gaps in the evidence, of which the lack of RCT data is the major one. The expert workshop reflected these gaps in the range of topics raised as important in answering the question of the effectiveness of surveillance. Previous models of cost-effectiveness have most recently shown that surveillance programmes either do more harm than good compared with no surveillance or are unlikely to be cost-effective at usual levels of willingness to pay. Our cost--utility model has shown that, across a range of values for the various parameters that have been chosen to reflect uncertainty in the inputs, it is likely that surveillance programmes do more harm than good -- costing more and conferring lower quality of life than no surveillance. Probabilistic analysis shows that, in most cases, surveillance does more harm and costs more than no surveillance. It is unlikely, but still possible, that surveillance may prove to be cost-effective. The cost-effectiveness acceptability curve, however, shows that surveillance is unlikely to be cost-effective at either the 'usual' level of willingness to pay ( pound 20,000-30,000 per QALY) or at much higher levels. The expected value of perfect information at the population level is pound 6.5 million. Future research should target both the overall effectiveness of surveillance and the individual elements that contribute to a surveillance programme, particularly the performance of the test and the effectiveness of treatment for both Barrett's oesophagus and ACO. In addition, of particular importance is the clarification of the natural history of Barrett's oesophagus.

Adenocarcinoma↗
PubMed2005

Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH.

Intellectual disability (ID) affects about 3% of the population (IQ < 70), and in about 40% of moderate (IQ 35-49) to severe ID (IQ < 34), and 70% of cases of mild ID (IQ 50-70), the etiology of the disease remains unknown. It has long been suspected that chromosomal gains and losses undetectable by routine cytogenetic analysis (i.e., less than 5-10 Mb in size) are implicated in ID of unknown etiology. Array CGH has recently been used to perform a genome-wide screen for submicroscopic gains and losses in individuals with a normal karyotype but with features suggestive of a chromosome abnormality. In two recent studies, the technique has demonstrated a approximately 15% detection rate for de novo copy number changes of individual clones or groups of clones. Here, we describe a study of 22 individuals with mild to moderate ID and nonsyndromic pattern of dysmorphic features suspicious of an underlying chromosome abnormality, using the 3 Mb and 1 Mb commercial arrays (Spectral Genomics). Deletions and duplications of 16 clones, previously described to show copy number variability in normal individuals [Iafrate et al., 2004; Lapierre et al., 2004; Schoumans et al., 2004; Vermeesch et al., 2005] were seen in 21/22 subjects and were considered polymorphisms. In addition, three subjects showed submicroscopic deletions and duplications not previously reported as normal variants. Two of these submicroscopic changes were of de novo origin (microdeletions at 7q36.3 and a microduplication at 11q12.3-13.1) and one was of unknown origin as parental testing of origin could not be performed (microduplication of Xp22.3). The clinical description of the three subjects with submicroscopic chromosomal changes at 7q36.3, 11q12.3-13.1, Xp22.3 is provided.

Chromosome Aberrations↗
PubMed2004

Effect of dutasteride on the detection of prostate cancer in men with benign prostatic hyperplasia.

OBJECTIVES: To examine the rate of prostate cancer detection in three large randomized placebo-controlled benign prostatic hyperplasia trials of dutasteride. Dutasteride, which lowers serum dihydrotestosterone more than 93% by inhibiting type 1 and type 2 5-alpha-reductase, is effective in the treatment of benign prostatic hyperplasia. However, its effect on the development of prostate cancer is unknown. METHODS: A total of 4325 men with benign prostatic hyperplasia but without a history, or evidence, of prostate cancer, and a serum prostate-specific antigen level of 1.5 to 10 ng/mL, were randomized to 0.5 mg/day dutasteride or placebo for 24 months. The prostate cancer detection rates for subjects were determined by non-protocol-mandated biopsies, either during the double-blind phase of the study or during the first 3 months of the open-label extension. A follow-up questionnaire was administered to a subset of consenting subjects to ascertain the number, outcomes, and reasons for the prostate biopsies. RESULTS: The cumulative incidence of prostate cancer as an adverse event was significantly lower in the dutasteride versus placebo group at 24 months (1.1% versus 1.9%, P = 0.025) and 27 months (1.2% versus 2.5%, P = 0.002). There were no differences in the diagnosis rates of prostate cancer during the first 15 months, after which time the detection rate of prostate cancer increased in the placebo group and remained low in the dutasteride group. CONCLUSIONS: Prostate cancer detection was significantly lower in subjects randomized to dutasteride compared with the placebo group. These results have prompted the initiation of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, which was designed and powered to test the hypothesis that treatment with dutasteride decreases the incidence and progression of prostate cancer.

5-alpha Reductase Inhibitors↗
PubMed2000

Housing and health: does installing heating in their homes improve the health of children with asthma?

The objective of this study was to evaluate the use of NHS money to improve health by improving housing conditions. A pilot study assessing health outcomes before and after improving housing conditions was conducted, studying 72 children with previously diagnosed asthma living in 59 damp houses in Cornwall. The intervention was the installation of central heating. This improved the energy efficiency of the housing. The children's health was a symptom-based outcome measure for asthma and time lost from school. Improvements comprised installation of gas central heating in 28/59 (47%) houses, electric storage heaters in 22/59 (37%), solid fuel central heating in 7/59 (12%) and oil-fired central heating in 2/59 (4%) houses. Energy efficiency improved by a mean of 2.1 on the National Home Energy Rating scale (95% CI 1.68-2.47, P<0.001) in the 37/59 (62%) houses for which two readings were available. Initially, 69/72 (92%) children's bedrooms were unheated and 44/72 (61%) were damp; following improvements, the proportions were 10/72 (14%) and 15/72 (21%) respectively. All respiratory symptoms were significantly reduced after intervention; the greatest reduction was seen in nocturnal cough from a median score of 3 (most nights) to 1 (on one or several nights) (P<0.001) in the previous month. School-age children lost significantly less time from school for asthma in the previous 3 months (9.3 days per 100 school days before intervention and 2.1 days afterwards, P<0.01) but not for other reasons (1.4 days per 100 school days before and 3.2 after, P>0.05). In conclusion, this study provides the first evaluation of health outcomes following housing improvements. Lack of a comparison group means that effects of age, season and biased reporting cannot be eliminated. More work is needed to substantiate these results.

Asthma↗
PubMed1995

Mucus glycoconjugate complexes released from feline trachea by a bacterial toxin.

This paper describes low-density mucus glycoconjugates released from feline trachea by dirhamnolipid (DRL), a toxin from Pseudomonas aeruginosa. Mucus glycoconjugates in feline tracheas were radiolabeled in vivo with 3H-proline and 14C-glucose. Control mucus and that released by 200 micrograms/ml DRL were dissolved in guanidine hydrochloride buffer (GuHCl) and chromatographed on Sepharose CL-2B. Molecules eluting in the void volume (V0) of the column were isolated by isopycnic density gradient centrifugation in CsCl/GuHCl. All samples gave peaks of radiolabeled and periodic acid/Schiff (PAS)-reactive material at rho = approximately 1.50 and approximately 1.60 g/ml, but DRL-stimulated samples contained low-density material (rho < 1.32 g/ml), also PAS-reactive and radiolabeled. Control secretions incubated with DRL in vitro did not form low-density material. In Triton X-100 (1% vol/vol), a nonionic detergent, low-density material behaved as smaller molecules, running in the partially included volume (Vi) of the column of Sepharose CL-2B, but still in the V0 of Sephacryl S-300. Incubation with chondroitinase ABC, heparinase II and III, and keratanase failed to change its elution profile on S-300, evidence against glycosaminoglycans; but proteolysis with trypsin or proteinase K gave two peaks, peptide fragments near the totally included volume of the column and glycopeptides in V0. The V0 glycopeptides banded between 1.50 and 1.55 g/ml in a CsCl gradient and eluted as a single peak in the Vi of Sephacryl S-400, suggesting a distinct homogeneous glycopeptide, smaller than those from normal mucins. The main 14C-labeled sugars in this glycopeptide were fucose, glucosamine, galactosamine, and galactose, consistent with a mucin. Thus, DRL releases stable but noncovalent complexes containing one or more distinct mucinlike glycoconjugates, probably combined with lipids and peptides. We discuss their possible relevance to airway diseases, including cystic fibrosis.

Animals↗
PubMed1995

Asthma deaths in Mersey region 1989-1990.

BACKGROUND: We examined the circumstances surrounding death from asthma in Mersey Region and the feasibility of conducting a regional confidential enquiry, as suggested by the British Thoracic Society in response to the proposal in the Green Paper the health of the nation that asthma should be a key area for action. METHOD: Sixty-three Mersey residents, aged 16-65 years, died in Mersey Region in 1989 and 1990 with ICD code 493. Diagnostic criteria for asthma were applied to each case. Anonymized case-note summaries were assessed by a chest physician (M.P.) for (1) severity of symptoms/disease, (2) risk of a respiratory death and (3)avoidable factors in the circumstances surrounding death. RESULTS: Some written information was available on every patients. In 43/63 (68 percent) cases asthma was the true cause of death; 41/43 had had asthma diagnosed in life. Mean age (47 years) and median age of onset of asthma (10 years) were similar to those found in previous studies, but the proportion of men (58 percent) was higher. Only 6 (14 percent) deaths occurred after more than a few hours in hospital; for the rest, hospital contact was either too late (19 percent) or did not occur (67 percent). Of 22/43 (51 percent) patients considered at high risk of a respiratory death, 15 had poorly controlled symptoms for at least a year before their deaths. Avoidable factors were present in 29/43 (67 percent) cases; most commonly lack of assessment, inadequate doses of steroids and over-reliance on bronchodilators. CONCLUSION: These findings resemble those of previous studies, showing that little has changed. Asthma deaths occur mostly outside hospital; thus to replace deaths, resources should be directed at the community to improve the recognition of asthma by patients, their families and the primary care team. A regional confidential enquiry is feasible and could be an effective mechanism for proving management.

Adolescent↗
PubMed1992

Release of mucus glycoconjugates by Pseudomonas aeruginosa rhamnolipid into feline trachea in vivo and human bronchus in vitro.

Pseudomonas aeruginosa colonizes the lower respiratory tracts of patients with severe bronchiectasis, including cystic fibrosis, a condition associated with increased airway mucus output. We have shown that an extract containing chloroform-soluble extracellular products of P. aeruginosa releases glycoconjugates into the cat trachea in vivo. This activity was not related to pyocyanin, a major component of the extract, but was associated with the rhamnolipids. Purified monorhamnolipid (100 micrograms/ml) released radiolabeled and periodic acid-Schiff (PAS)-reactive glycoconjugates (delta 3H = +490 +/- 70%, delta 35S = +170 +/- 40%, delta PAS = +8.6 +/- 1.7 micrograms/min; n = 6, P less than 0.02 for each). Dirhamnolipid (200 micrograms/ml) was also effective (delta 3H = +640 +/- 70%, delta 35S = +130 +/- 20%, delta PAS = +9.3 +/- 1.5 micrograms/min; n = 6, P less than 0.02 for each). Monorhamnolipid (100 micrograms/ml) also released 35S-labeled and PAS-reactive glycoconjugates from human bronchial tissue in vitro (delta 35S = +189 +/- 47%, delta PAS = +26.3 +/- 8.5 micrograms/min; n = 7, P less than 0.001 versus control tissues in which no stimulus was given). The cat tracheal glycoconjugates released by the rhamnolipids differed from those released by pilocarpine 50 microM, in having a higher 3H:35S ratio (P less than 0.001). After gel chromatography on a Sepharose CL-4B column, the void volume fractions of the glycoconjugates also had different profiles in a cesium chloride density gradient. Those released by rhamnolipid banded at 1.62 g/ml, while those released by pilocarpine banded mainly at 1.50 g/ml, with some of the higher density material also present.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Stimulation of secretion into human and feline airways by Pseudomonas aeruginosa proteases.

We have investigated the effect of elastase and alkaline protease from Pseudomonas aeruginosa on airway secretion into the trachea of anesthetized cats and from human bronchial mucosa in vitro. Secretory macromolecules were radiolabeled biosynthetically with two precursors in the cat, [3H]glucose and [35S]sulfate, and with [35S]-sulfate only in human tissue. Both enzymes (2.6 x 10(-9) to 1.3 x 10(-6)M elastase and 8 x 10(-9) to 2.4 x 10(-6)M alkaline protease) released radiolabeled macromolecules in a concentration-dependent manner from the two preparations. Purified elastase, 1.3 x 10(-6)M, released radiolabeled macromolecules (delta 3H = +397 +/- 72%, delta 35S 225 +/- 40% over control, P less than 0.001) and periodic acid-Schiff- (PAS) reactive glycoconjugates (delta PAS = +4.1 +/- 0.96 micrograms/min or +102 +/- 20%; P less than 0.01) from cat trachea, as did alkaline protease, 2.4 x 10(-6)M (delta 3H = +356 +/- 57%, delta 35S = +176 +/- 25%, delta PAS = +7.5 +/- 1.3 micrograms/min or 194 +/- 36%, P less than 0.001). Increases in 3H exceeded those of 35S, suggesting surface epithelium as the main source of secretion. Inhibition of enzyme activity abolished secretory effects. Both enzymes also stimulated secretion from human bronchus (e.g., with elastase, 1.3 x 10(-6)M: delta 35S = +331 +/- 67%, delta PAS = +4.3 +/- 0.92 micrograms/min or +131 +/- 24%, P less than 0.001; with alkaline protease, 2.4 x 10(-6)M: delta 35S = +220 +/- 67%, delta PAS = +12.7 +/- 3.2 micrograms/min or +575 +/- 245%, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Mucin structure. The structure and heterogeneity of respiratory mucus glycoproteins.

Respiratory mucus glycoproteins purified from both "normal" respiratory secretions and sputa of patients with a variety of hypersecretory conditions are high Mr linear molecules adopting a random coil configuration in solution. Studies on their polydispersity show them to have an Mr in the range 3 to 32 x 10(6) and a distribution of length from 200 nm to beyond 10 microns. These macromolecules are fragmented by reduction of intermolecular disulfide bonds into subunits, with Mr approximately 2 x 10(6) and length from 200 to 600 nm. Reduction not only cleaves the mucin molecule but opens, presumably by breaking intramolecular disulfide bonds, cryptic "naked" protein regions. Trypsin digestion of subunits yields high Mr glycopeptides (Mr, 300 to 500,000), presumably by cleavage of the peptide core within the unfolded "naked" protein domains. Respiratory mucus glycoproteins from infected sputum samples are usually heterogeneous in CsCl density gradients, in contrast to those from "normal" tracheobronchial secretions. The former are characterized by the presence of a number of different mucin species, and the basis for the separation of these mucins appears to be the variable presence of sialic acid and sulfate moieties in the oligosaccharide clusters. This heterogeneity may reflect a difference in cellular origin of the mucins and also may be clinically significant.

Glycoproteins↗
PubMed1990

Characterisation of Pseudomonas rhamnolipids.

The Gram negative organism, Pseudomonas aeruginosa, is often found in the lungs of patients with cystic fibrosis and other forms of severe bronchiectasis, where it secretes a number of extracellular toxins including the mono- and dirhamnolipids. The principal monorhamnolipid from P. aeruginosa has previously been identified as rhamnosyl-3-hydroxydecanoyl-3-hydroxydecanoate (Rh-C10.C10). A number of related mono- and dirhamnolipids have been purified from cultures of a clinical isolate of P. aeruginosa and identified by fast atom bombardment and electron impact mass spectrometry: these contain the 3-hydroxyoctanoyl-3-hydroxydecanoate (C8.C10) and 3-hydroxydecanoyl-3-hydroxydodecanoate (C10.C12) homologues. Structural isomers were also present where the order of the lipid linkage was transposed (Rh-C10.C8 and Rh-C12.C10). Unsaturated mono- and dirhamnolipids containing the 3-hydroxydecanoyl-3-hydroxydodec-5-enoate (C10.C12:1) lipid were also present.

Glycolipids↗
PubMed1990

The effects of local anaesthetic agents upon mucus secretion in the feline trachea in vivo.

The actions of lignocaine and tetrodotoxin (TTX) in a tracheal segment of the cat were tested on secretion of mucus macromolecules radiolabelled with 35S and 3H. Lignocaine, 4.3-43 mM, given into the segment, caused a concentration dependent increase of secretion of 3H-and 35S-labelled macromolecules. At 43 mM, lignocaine increased secretion: delta 3H = +433 +/- 191%, delta 35S = +327 +/- 34.5% (n = 8). This effect lessened over 15-45 min. Atropine (1 mg/kg) had little effect on these responses. All concentrations of lignocaine tested (4.3-43 mM) abolished the effect of vagus nerve stimulation on secretion and diminished the effect of a submaximal concentration of pilocarpine (5 microM) in the segment in a dose-dependent manner. TTX in the segment did not alter the resting secretion. At 50 microM it abolished, and at 10 microM diminished, vagal control of secretion without affecting the secretory response to pilocarpine. The study shows that lignocaine, in concentrations which block vagal control of secretion (greater than or equal to 4.3 mM), stimulates the release of mucus macromolecules. Resting secretion is unaltered by TTX, and so does not appear to be under neurogenic inhibition. Larger concentrations of lignocaine (greater than or equal to 13 mM) also diminish pilocarpine-induced secretion, whereas TTX may inhibit nervous control of mucus secretion selectively. The results suggest that clinical anaesthesia of the airways with lignocaine may stimulate mucus secretion.

Animals↗