John Wright

BACKGROUND: Obstructive sleep apnoea is the periodic reduction (hypopnoea) or cessation (apnoea) of breathing due to narrowing or occlusion of the upper airway during sleep. The main symptom is daytime sleepiness and it has been suggested it is linked to premature death, hypertension, ischaemic heart disease, stroke and road traffic accidents. OBJECTIVES: The main treatment for sleep apnoea is with the use of continuous positive airways pressure (CPAP), which requires a flow generator and mask. These are used at night to prevent apnoea, hypoxia and sleep disturbance. The objective was to assess the effects of CPAP in the treatment of obstructive sleep apnoea in adults. SEARCH STRATEGY: We searched the Cochrane Airways Group Trials Register and reference lists of articles. We consulted experts in the field. Searches were current to July 2005. SELECTION CRITERIA: We included randomised trials comparing nocturnal CPAP with an inactive control or oral appliances in adults with obstructive sleep apnoea (an apnoea and hypopnoea index greater than five per hour). Trials had a minimum intervention period of two weeks. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and two review authors extracted data independently. Study authors were contacted for missing information. Parallel and crossover group trials were analysed separately. MAIN RESULTS: Thirty-six trials involving 1718 people met the inclusion criteria. Study quality was mixed. Compared with control, CPAP showed significant improvements in certain objective and subjective sleepiness, measures of quality of life and cognitive function (parallel-group studies: Epworth sleepiness scale (ESS) -3.83 units, 95% CI -4.57 to -3.09; crossover studies: ESS -1.84 units, 95% CI -2.57 to -1.11). Twenty-four hour systolic and diastolic blood pressures were lower with CPAP compared with control (parallel-group trials). Compared with oral appliances, CPAP significantly reduced the apnoea and hypopnoea index (crossover studies: -7.97 events/hr, 95% CI -9.56 to -6.38) and improved sleep efficiency (crossover studies: 2.31%, 95% CI 0.02 to 4.6) and minimum oxygen saturation (4.14%, 95% CI 3.25 to 5.03). Responders to both treatments expressed a strong preference for the oral appliance. However, participants were more likely to withdraw on OA than on CPAP therapy. AUTHORS' CONCLUSIONS: CPAP is effective in reducing symptoms of sleepiness and improving quality of life measures in people with moderate and severe obstructive sleep apnoea (OSA). It is more effective than oral appliances in reducing respiratory disturbances in these people but subjective outcomes are more equivocal. Certain people tend to prefer oral appliances to CPAP where both are effective. This could be because they offer a more convenient way of controlling OSA. Short-term data indicate that CPAP leads to lower blood pressure than control. Long-term data are required for all outcomes in order to determine whether the initial benefits seen in short-term clinical trials persist.

The acute effects of different macronutrients on the secretion of glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) and glucose-dependent insulinotropic polypeptide (GIP) were compared in healthy human subjects. Circulating levels of the two hormones were measured over a 24-h period during which subjects consumed a mixed diet. In the first study, eight subjects consumed three equicaloric (375 kcal) test meals of carbohydrate, fat and protein. Small increases in plasma GLP-1(7-36) amide were found after all meals. Levels reached a maximum 30 min after the carbohydrate and 150 min after the fat load. Ingestion of both carbohydrate and fat induced substantial rises in GIP secretion, but the protein meal had no effect. In a second study, eight subjects consumed 75 g glucose or the equivalent portion of complex carbohydrate as boiled brown rice or barley. Plasma GIP, insulin and glucose levels increased after all three meals, the largest increase being observed following glucose and the smallest following the barley meal. Plasma GLP-1(7-36)amide levels rose only following the glucose meal. In the 24-h study, plasma GLP-1(7-36)amide and GIP concentrations were increased following every meal and remained elevated throughout the day, only falling to fasting levels at night. The increases in circulating GLP-1(7-36)amide and GIP levels following carbohydrate or a mixed meal are consistent with their role as incretins. The more sustained rises observed in the daytime during the 24-h study are consistent with an anabolic role in lipid metabolism.

John Wright, Neil Small, Pauline Raynor, Derek Tuffnell, Raj Bhopal, Noel Cameron, Lesley Fairley, Debbie A Lawlor, Roger Parslow, Emily S Petherick Kate E Pickett, Dagmar Waiblinger, Jane West on behalf of the Born in Bradford Scientific Collaborators Group

Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.