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Williams G.P.,University of Birmingham | Radford C.,University College London | Nightingale P.,Wellcome Trust Clinical Research Facility | Dart J.K.G.,University College London | Rauz S.,University of Birmingham
Eye | Year: 2011

Purpose: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom. Patients and Methods: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3years, n=26, 51 eyes) and (ii) established disease (EstD:>5years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed. Results: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation. Conclusions: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage. © 2011 Macmillan Publishers Limited All rights reserved.

Fewtrell M.S.,University College London | Kennedy K.,University College London | Murgatroyd P.R.,Wellcome Trust Clinical Research Facility | Williams J.E.,University College London | And 2 more authors.
British Journal of Nutrition | Year: 2013

Few studies have investigated the effects of infant nutrition on later bone health in term infants, although low sn-2 palmitate in infant formulas has been shown to result in the formation of stool fatty acid soaps, reduced Ca absorption and lower bone mass in the short term. To investigate the effect of (1) breast-feeding (BF) and (2) the type of infant formula (standard fat blend v. high-sn-2 fat blend) on bone mass at age 10 years, anthropometry and bone mass (from dual-energy X-ray absorptiometry (GE Lunar Prodigy); lumbar spine (LS) and total body less head; adjusted for size (bone mineral apparent density standard deviation score (SDS) and regression)) were measured in 10-year-old subjects born at term and either breast-fed (n 34) or randomised to a standard control formula (n 27) or a high-sn-2 palmitate formula (n 30) for the first 12 weeks of life. At follow-up, previously BF children were older but lighter (by 0·5 SDS, P=Â 0·03) than formula-fed children with a lower LS bone mineral density SDS (by 0·44, P=Â 0·03), but size-adjusted bone mass did not differ. There were no significant differences in bone mass between the formula-fed groups. These findings suggest that there is no significant effect of BF or high-sn-2 infant formula on size-adjusted bone mass in mid-childhood, and that the effects of infant nutrition on bone mass previously reported may be confined to the short term. A larger study would be required to exclude smaller effects. Copyright © The Authors 2013.

Hazlehurst J.M.,University of Birmingham | Gathercole L.L.,University of Birmingham | Nasiri M.,University of Birmingham | Armstrong M.J.,University of Birmingham | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: It is widely believed that glucocorticoids cause insulin resistance in all tissues. We have previously demonstrated that glucocorticoids cause insulin sensitization in human adipose tissue in vitro and induce insulin resistance in skeletal muscle. Objective: Our aim wastodetermine whether glucocorticoids have tissue-specific effectsoninsulin sensitivity in vivo. Design: Fifteen healthy volunteers were recruited into a double-blind, randomized, placebo-controlled, crossover study, receiving bothanovernight hydrocortisoneand saline infusion. Thetissue-specific actions of insulin were determined using paired 2-step hyperinsulinemiceuglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis. Setting: The study was performedinthe Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom. Main Outcome Measures: The sensitivity of sc adipose tissue to insulin action was measured. Results: Hydrocortisone induced systemic insulin resistance but failed to cause sc adipose tissue insulin resistance as measured by suppression of adipose tissue lipolysis and enhanced insulin-stimulated pyruvate generation. In primary cultures of human hepatocytes, glucocorticoids increased insulin-stimulated p-ser473akt/protein kinase B. Similarly, glucocorticoids enhanced insulin-stimulated p-ser473akt/protein kinase B and increased Insulin receptor substrate 2 mRNA expression in sc, but not omental, intact human adipocytes, suggesting a depot-specificity of action. Conclusions: This study represents the first description of sc adipose insulin sensitization by glucocorticoids in vivo and demonstrates tissue-specific actions of glucocorticoids to modify insulin action. It defines an important advance in our understanding of the actions of both endogenous and exogenous glucocorticoids and may have implications for the development and targeting of future glucocorticoid therapies. Copyright © 2013 by The Endocrine Society.

Rahman I.A.,University of Birmingham | Mascaro J.G.,University of Birmingham | Steeds R.P.,University of Birmingham | Frenneaux M.P.,University of Birmingham | And 5 more authors.
Circulation | Year: 2010

Background-: We assessed whether remote ischemic preconditioning (RIPC) improves myocardial, renal, and lung protection after on-pump coronary surgery. Methods and results-: This was a single-center, prospective, randomized (1:1), placebo-controlled trial. Patients, investigators, anesthetists, surgeons, and critical care teams were blinded to group allocation. Subjects received RIPC (or placebo) stimuli (×3 upper limb (or dummy arm), 5-minute cycles of 200 mm Hg cuff inflation/deflation) before aortic clamping. Anesthesia, perfusion, cardioplegia, and surgical techniques were standardized. The primary end point was 48-hour area under the curve (AUC) troponin T (cTnT) release. Secondary end points were 6-hour and peak cTnT, ECG changes, cardiac index, inotrope and vasoconstrictor use, renal dysfunction, and lung injury. Hospital survival was 99.4%. Comparing placebo and RIPC, median (interquartile range) AUC 48-hour cTnT (ng/mL-1/48 h-1); 28 (19, 39) versus 30 (22, 38), 6-hour cTnT (ng/mL-1); 0.93(0.59, 1.35) versus 1.01(0.72, 1.43), peak cTnT (ng/mL-1); 1.02 (0.74, 1.44) versus 1.04 (0.78, 1.51), de novo left bundle-branch block (4% versus 0%) and Q waves (5.3% versus 5.5%), serial cardiac indices, intraaortic balloon pump usage (8.5% versus 7.5%), inotrope (39% versus 50%) and vasoconstrictor usage (66% versus 64%) were not different. Dialysis requirement (1.2% versus 3.8%), peak creatinine (median [interquartile range], 1.2 mg/dL-1 (1.1, 1.4) versus 1.2 (1.0, 1.4)), and AUC urinary albumin-creatinine ratios 69 (40, 112) versus 58 (32, 85) were not different. Intubation times; median (interquartile range), 937 minutes(766, 1402) versus 895(675, 1180), 6-hour; 278 (210, 338) versus 270 (218, 323) and 12-hour pO2:FiO2 ratios 255 (195, 323) versus 263 (210, 308) were similar. Conclusions-: In contrast to prior smaller studies, RIPC did not reduce troponin release, improve hemodynamics, or enhance renal or lung protection. © 2010 American Heart Association, Inc.

Das I.,University of Birmingham | Nightingale P.,Wellcome Trust Clinical Research Facility | Patel M.,University of Birmingham | Jumaa P.,University of Birmingham
International Journal of Infectious Diseases | Year: 2011

Objectives: To review the epidemiology of candidemia in a UK tertiary referral center. Methods: Clinical and laboratory data from patients with candidemia were collected prospectively from October 1, 2005 to June 30, 2008 (a 33-month period). Results: A total of 107 episodes were identified. The incidence was 10.9 episodes/100 000 bed-days. The most common predisposing factors were the use of broad-spectrum antibiotics (92%), the presence of an intravascular device (IVD) (82%), admission to an intensive care unit (ICU) (51%), and recent surgery (50%). Non-Candida albicans species accounted for 58% of the episodes, which is higher than the percentage reported from other UK centers. C. albicans was the most common species, accounting for 43% of episodes, followed by C. glabrata (31%) and C. parapsilosis (20%). Overall C. tropicalis, C. krusei, C. norvegensis, and C. lusitaniae caused 7% of episodes. The crude 30-day mortality rate was 37%. Advanced age (p = 0.003) and the presence of septic shock (p = 0.038) were associated with mortality. Conclusions: Candidemia continues to be associated with a high mortality. Preventative measures should be targeted against high-risk hospitalized patients, especially those in ICUs, the elderly, and those undergoing major surgery. Local surveillance of candidemia is important to optimize management. © 2011 International Society for Infectious Diseases.

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