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.

Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification.

Abstract: The genetic analysis of congenital skull malformations provides insight into normal mechanisms of calvarial osteogenesis1 Enlarged parietal foramina (PFM) are oval defects of the parietal bones caused by deficient ossification around the parietal notch, which is normally obliterated during the fifth fetal month2 PFM are usually asymptomatic, but may be associated with headache, scalp defects and structural or vascular malformations of the brain3,4 Inheritance is frequently autosomal dominant, but no causative mutations have been identified in non-syndromic cases We describe here heterozygous mutations of the homeobox gene MSX2 (located on 5q34–q35) in three unrelated families with PFM One is a deletion of approximately 206 kb including the entire gene and the others are intragenic mutations of the DNA-binding homeodomain (RK159-160del and R172H) that predict disruption of critical intramolecular and DNA contacts Mouse Msx2 protein with either of the homeodomain mutations exhibited more than 85% reduction in binding to an optimal Msx2 DNA-binding site Our findings contrast with the only described MSX2 homeodomain mutation5 (P148H), associated with craniosynostosis, that binds with enhanced affinity to the same target6 This demonstrates that MSX2 dosage is critical for human skull development and suggests that PFM and craniosynostosis result, respectively, from loss and gain of activity in an MSX2-mediated pathway of calvarial osteogenic differentiation

Polygenic control of autoimmune diabetes in nonobese diabetic mice

Abstract: Partial exclusion mapping of the nonobese (NOD) diabetic mouse genome has shown linkage of diabetes to at least five different chromosomes. We have now excluded almost all of the genome for the presence of susceptibility genes with fully recessive effects and have obtained evidence of linkage of ten distinct loci to diabetes or the pre–diabetic lesion, insulitis, indicative of a polygenic mode of inheritance. The relative importance of these loci and their interactions have been assessed using a new application of multiple polychotomous regression methods. A candidate disease gene, interleukin–2 (Il–2), which is closely linked to insulitis and diabetes, is shown to have a different sequence in NOD, including an insertion and a deletion of tandem repeat sequences which encode amino acid repeats in the mature protein.

Myocardial Tissue Characterization Using Magnetic Resonance Noncontrast T1 Mapping in Hypertrophic and Dilated Cardiomyopathy

Abstract: Background— Noncontrast magnetic resonance T1 mapping reflects a composite of both intra- and extracellular signal. We hypothesized that noncontrast T1 mapping can characterize the myocardium beyond that achieved by the well-established late gadolinium enhancement (LGE) technique (which detects focal fibrosis) in both hypertrophic (HCM) and dilated (DCM) cardiomyopathy, by detecting both diffuse and focal fibrosis. Methods and Results— Subjects underwent Cardiovascular Magnetic Resonance imaging at 3T (28 HCM, 18 DCM, and 12 normals). Matching short-axis slices were acquired for cine, T1 mapping, and LGE imaging (0.1 mmol/kg). Circumferential strain was measured in the midventricular slice, and 31P magnetic resonance spectroscopy was acquired for the septum of the midventricular slice. Mean T1 relaxation time was increased in HCM and DCM (HCM 1209±28 ms, DCM 1225±42 ms, normal 1178±13 ms, P <0.05). There was a weak correlation between mean T1 and LGE ( r =0.32, P <0.001). T1 values were higher in segments with LGE than in those without (HCM with LGE 1228±41 ms versus no LGE 1192±79 ms, P <0.01; DCM with LGE 1254±73 ms versus no LGE 1217±52 ms, P <0.01). However, in both HCM and DCM, even in segments unaffected by LGE, T1 values were significantly higher than normal ( P <0.01). T1 values correlated with disease severity, being increased as wall thickness increased in HCM; conversely, in DCM, T1 values were highest in the thinnest myocardial segments. T1 values also correlated significantly with circumferential strain ( r =0.42, P <0.01). Interestingly, this correlation remained statistically significant even for the slices without LGE ( r =0.56, P =0.04). Finally, there was also a statistically significant negative correlation between T1 values and phosphocreatine/adenosine triphosphate ratios ( r =−0.59, P <0.0001). Conclusions— In HCM and DCM, noncontrast T1 mapping detects underlying disease processes beyond those assessed by LGE in relatively low-risk individuals.