Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches

PMCID: PMC3668194SEP was directly funded by the National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts. SN acknowledges support from the Oxford NIHR Biomedical Research Centre and from the Oxford British Heart Foundation Centre of Research Excellence. SP and PL are funded by a BHF Senior Clinical Research fellowship. RC is supported by a BHF Research Chair and acknowledges the support of the Oxford BHF Centre for Research Excellence and the MRC and Wellcome Trust. PMM gratefully acknowledges training fellowships supporting his laboratory from the Wellcome Trust, GlaxoSmithKline and the Medical Research Council

Corticosteroid suppression of lipoxin A4 and leukotriene B4from alveolar macrophages in severe asthma

<p>Abstract</p> <p>Background</p> <p>An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B₄(LTB₄), and lipoxin A₄(LXA₄) production by alveolar macrophages (AMs) and studied the impact of corticosteroids.</p> <p>Methods</p> <p>AMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 μg/ml) with or without dexamethasone (10^-6M). LTB₄and LXA₄were measured by enzyme immunoassay.</p> <p>Results</p> <p>LXA₄biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA₄induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB₄were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB₄was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB₄and LXA₄, with lesser suppression of LTB₄in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA₄and FEV₁(% predicted) (r_s= 0.60; p < 0.01).</p> <p>Conclusions</p> <p>Decreased LXA₄and increased LTB₄generation plus impaired corticosteroid sensitivity of LPS-induced LTB₄but not of LXA₄support a role for AMs in establishing a pro-inflammatory balance in severe asthma.</p

Sex, sex chromosomes and gene expression

The X chromosome has fewer testis-specific genes than autosomes in many species. This bias is commonly attributed to X inactivation in spermatogenesis but a recent paper in BMC Biology provides evidence against X inactivation in Drosophila and proposes that somatic tissue- and testis- but not ovary-specific genes tend not to be located on the X chromosome. Here, we discuss possible mechanisms underlying this bias, including sexual antagonism and dosage compensation

RUNX2 mutations in Taiwanese patients with cleidocranial dysplasia

Cleidocranial dysplasia (CCD) is an autosomal dominant human skeletal disorder comprising hypoplastic clavicles, wide cranial sutures, supernumerary teeth, short stature, and other skeletal abnormalities. It is known that mutations in the human RUNX2 gene mapped at 6p21 are responsible for CCD. We analyzed the mutation patterns of the RUNX2 gene by direct sequencing in six Taiwanese index cases with typical CCD. One of the patients was a familial case and the others were sporadic cases. Sequencing identified four mutations. Three were caused by single nucleotide substitutions, which created a nonsense (p.R391X), two were missense mutations (p.R190W, p.R225Q), and the forth was a novel mutation (c.1119delC), a one-base deletion. Real time quantitative PCR adapted to determine copy numbers of the promoter, all exons and the 3’UTR region of the RUNX2 gene detected the deletion of a single allele in a sporadic case. The results extend the spectrum of RUNX2 mutations in CCD patients and indicate that complete deletions of the RUNX2 gene should be considered in those CCD patients lacking a point mutation detected by direct sequencing

Identification of hip fracture patients from radiographs using Fourier analysis of the trabecular structure: a cross-sectional study

Peer reviewedPublisher PD

KIDMAP, a web based system for gathering patients' feedback on their doctors

<p>Abstract</p> <p>Background</p> <p>The gathering of feedback on doctors from patients after consultations is an important part of patient involvement and participation. This study first assesses the 23-item Patient Feedback Questionnaire (PFQ) designed by the Picker Institute, Europe, to determine whether these items form a single latent trait. Then, an Internet module with visual representation is developed to gather patient views about their doctors; this program then distributes the individualized results by email.</p> <p>Methods</p> <p>A total of 450 patients were randomly recruited from a 1300-bed-size medical center in Taiwan. The Rasch rating scale model was used to examine the data-fit. Differential item functioning (DIF) analysis was conducted to verify construct equivalence across the groups. An Internet module with visual representation was developed to provide doctors with the patient's online feedback.</p> <p>Results</p> <p>Twenty-one of the 23 items met the model's expectation, namely that they constitute a single construct. The test reliability was 0.94. DIF was found between ages and different kinds of disease, but not between genders and education levels. The visual approach of the KIDMAP module on the WWW seemed to be an effective approach to the assessment of patient feedback in a clinical setting.</p> <p>Conclusion</p> <p>The revised 21-item PFQ measures a single construct. Our work supports the hypothesis that the revised PFQ online version is both valid and reliable, and that the KIDMAP module is good at its designated task. Further research is needed to confirm data congruence for patients with chronic diseases.</p

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

Comparison of SPECT bone scintigraphy with MRI for diagnosis of meniscal tears

BACKGROUND: Scintigraphy has been considered as competitive to MRI, but limited data are available on the accuracy of single photon emission tomography (SPECT) compared with MRI for the assessment of meniscal tears. Our objective was to assess the value of SPECT in comparison to MRI. METHODS: Between January 2003 and March 2004, sixteen patients were studied with both modalities and the accuracy rates of SPECT scan results, and MRI findings in the diagnosis of meniscal tears were compared. Arthroscopy was the gold standard. RESULTS: The respective sensitivity rate, specificity rate, and positive and negative predictive accuracies of MRI were 89%, 94%, 93%, and 79% and for SPECT those were 78%, 94%, 94%, and 88%. There was good agreement on the presence or absence of tears between two modalities (κ statistic = 0.699). CONCLUSION: SPECT and MRI are both valuable imaging techniques. SPECT is a useful alternative when MRI is unavailable or unsuitable and it is beneficial when more possible accuracy is desired (such as when MRI results are either inconclusive or conflict with other clinical data)