John Radcliffe Hospital

About: John Radcliffe Hospital is a healthcare organization based out in Oxford, Oxfordshire, United Kingdom. It is known for research contribution in the topics: Population & Antigen. The organization has 14491 authors who have published 23670 publications receiving 1459015 citations.

Glucocorticoid corticosteroids for Duchenne muscular dystrophy

Abstract: Background Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood. This incurable disease is characterised by muscle wasting and loss of walking ability leading to complete wheelchair dependence by 13 years of age. Prolongation of walking is one of the major aims of treatment. Objectives The aim of this review was to assess whether glucocorticoid corticosteroids stabilize or improve muscle strength and walking in boys with DMD. Search methods This is an update of the Cochrane systematic review first published in 2004 (Manzur 2004). We searched the Cochrane Neuromuscular Disease Group Trials Register (August 2006) using the term 'Duchenne muscular dystrophy'. We also searched MEDLINE (January 1966 to July 2007), EMBASE (January 1980 to August 2006), CINAHL and LILACS (January 1982 to August 2006). We wrote to authors of published studies and other experts in this disease to help identify other trials, checked the references in the identified trials and hand searched the abstracts of relevant journals. Selection criteria Types of studies: randomised or quasi-randomised trials. Types of participants: all patients with a definite diagnosis of Duchenne muscular dystrophy. Types of interventions: glucocorticoids such as prednisone, prednisolone, deflazacort or others, with a minimum treatment period of three months. Primary outcome measure: prolongation of walking (independent walking without long leg calipers). Secondary outcome measures: strength outcome measures, manual muscle strength testing using Medical Research Council strength scores, functional outcome measures and adverse events. Data collection and analysis We identified six randomised controlled trials that met the inclusion criteria for our review, and one of these (Beenakker 2005) is a new addition to this update, as it was published subsequent to our first review (Manzur 2004). Two review authors independently selected the trials for the review and assessed methodological quality. Data extraction and inputting were double-checked. Main results Primary outcome measure: data from one small study used prolongation of walking as an outcome measure and did not show significant benefit. Secondary outcome measures: The meta-analysis of the results from four randomised controlled trials with altogether 249 participants showed that glucocorticoid corticosteroids improved muscle strength and function over six months. Improvements were seen in time taken to rise from the floor (Gowers' time), nine metres walking time, four-stair climbing time, ability to lift weights, leg function grade and forced vital capacity. One randomised controlled trial with altogether 28 participants showed that glucocorticoid corticosteroids stabilize muscle strength and function for up to two years. The most effective prednisolone regime appears to be 0.75 mg/kg/day, given in a daily dose regime. Not enough data were available to compare efficacy of prednisone with deflazacort. Adverse effects: Excessive weight gain, behavioural abnormalities, cushingoid appearance and excessive hair growth were all more common with glucocorticoid corticosteroids than placebo. Long-term adverse effects of glucocorticoid therapy could not be evaluated because of the short-term duration of the randomised studies. Non-randomised studies: A number of non-randomised studies with important efficacy and adverse effects data are tabulated and discussed. Authors' conclusions There is evidence from randomised controlled studies that glucocorticoid corticosteroid therapy in Duchenne muscular dystrophy improves muscle strength and function in the short-term (six months to two years). The most effective prednisolone regime appears to be 0.75 mg/kg/day, given daily. In the short term, adverse effects were significantly more common but not clinically severe. Long-term benefits and hazards of glucocorticoid treatment cannot be evaluated from the currently published randomised studies. Non-randomised studies support the conclusions of functional benefits but also identify clinically significant adverse effects of long-term treatment. These benefits and adverse effects have implications for future research studies and clinical practice.

Craniosynostosis: Genes and Mechanisms

Abstract: Enlargement of the skull vault occurs by appositional growth at the fibrous joints between the bones, termed cranial sutures. Relatively little is known about the developmental biology of this process, but genetically determined disorders of premature cranial suture fusion (craniosynostosis) provide one route to the identification of some of the key molecules involved. Mutations of the MSX2, FGFR1, FGFR2, FGFR3 and TWIST genes yield new insights, both into normal and abnormal cranial suture biogenesis and into problems of broad interest, such as the conservation of molecular pathways in development, and mechanisms of mutation and dominance.

Genetic analysis of autoimmune type 1 diabetes mellitus in mice.

Abstract: Two genes, Idd-3 and Idd-4, that influence the onset of autoimmune type 1 diabetes in the nonobese diabetic mouse have been located on chromosomes 3 and 11, outside the chromosome 17 major histocompatibility complex. A genetic map of the mouse genome, analysed using the polymerase chain reaction, has been assembled specifically for the study. On the basis of comparative maps of the mouse and human genomes, the homologue of Idd-3 may reside on human chromosomes 1 or 4 and Idd-4 on chromosome 17.

The Bloom's syndrome gene product promotes branch migration of Holliday junctions

Abstract: Bloom's syndrome (BS) is an autosomal recessive disorder associated with dwarfism, immunodeficiency, reduced fertility, and elevated levels of many types of cancer. BS cells show marked genomic instability; in particular, hyperrecombination between sister chromatids and homologous chromosomes. This instability is thought to result from defective processing of DNA replication intermediates. The gene mutated in BS, BLM, encodes a member of the RecQ family of DExH box DNA helicases, which also includes the Werner's syndrome gene product. We have investigated the mechanism by which BLM suppresses hyperrecombination. Here, we show that BLM selectively binds Holliday junctions in vitro and acts on recombination intermediates containing a Holliday junction to promote ATP-dependent branch migration. We present a model in which BLM disrupts potentially recombinogenic molecules that arise at sites of stalled replication forks. Our results have implications for the role of BLM as an anti-recombinase in the suppression of tumorigenesis.

Craniopharyngiomas in children and adults: systematic analysis of 121 cases with long‐term follow‐up

Abstract: Summary Background Craniopharyngiomas account for 2–5% of all primary intracranial tumours. Despite their benign histological appearance, they are often associated with an unfavourable prognosis and their optimal treatment remains controversial. Aim To analyse the natural history and treatment outcome of children and adults presenting to the Departments of Paediatrics and Endocrinology with craniopharyngioma between 1964 and 2003. Patients and methods The records of 121 patients (age range 2·5–83 years, 42 aged < 16 and 79 aged ≥ 16) were identified. The mean follow-up period since presentation was 103 months (8·6 years) (range 0·3–468 months). Sixteen patients underwent gross total removal (A), 3 gross total removal + radiotherapy (B), 51 partial removal (C), 33 partial removal + radiotherapy (D), 6 cyst evacuation alone (E) and 3 cyst evacuation + radiotherapy (F). The clinical, imaging and endocrinological data at presentation and during follow-up were analysed. Results Headache and visual field defects were the most common presenting clinical features (64% and 55%, respectively). Ninety-four per cent of the tumours had an extrasellar component and 23% of them were associated with hydrocephalus. There was a significant difference in the recurrence-free survival rates between groups A–D [at 10 years: 100% (A), 100% (B), 38% (C) and 77% (D), P < 0·01], which persisted even when analysing patients operated after 1980. The median time of first recurrence was 2·5 years (range 0·5–36). The peri-operative mortality of the patients who had any type of neurosurgical intervention due to recurrence was higher than that observed after primary surgery (24%vs. 1·8%) (P < 0·01). The rate of re-accumulation of the cyst fluid was 58% during the first year in patients of group E, whereas none of the subjects of group F experienced such an event during their follow-up period. There was no reversal of pre-existing pituitary hormone deficits after any surgical intervention. The probabilities of GH, FSH/LH, ACTH, TSH deficiency and diabetes insipidus at the 10-year follow-up were 88%, 90%, 86%, 80% and 65%, respectively. After excluding the non-tumour-related deaths, the 10-year survival rate following presentation was 90%. Patients with recurrence had a significantly lower probability for survival compared with those without it (at 10 years: 70%vs. 99%, P < 0·01). At the 10-year follow-up the probability of the presence of major visual field defects was 48%, hyperphagia/obesity 39%, epilepsy 12% and hemi-/monoparesis 11%. In this large series no substantial differences in the outcome of tumours diagnosed during childhood or adult life were found. Conclusions Craniopharyngiomas remain tumours associated with significant morbidity. Gross total removal provides favourable results in terms of recurrences. If this cannot be achieved safely, adjuvant radiotherapy is beneficial in preventing tumour re-growth. Childhood- and adult-onset lesions generally behave similarly.