Cardiac magnetic resonance imaging for the detection of myocardial involvement in granulomatosis with polyangiitis

The prevalence of undiagnosed cardiac involvement in granulomatosis with polyangiitis (GPA) is unknown. In this prospective study we investigated the utility of cardiovascular magnetic resonance (CMR) to identify myocardial abnormalities in GPA and their correlation with disease phenotype. Twenty-six patients with GPA and no cardiovascular disease or diabetes mellitus underwent contrast-enhanced CMR, including late gadolinium-enhancement (LGE), T1-mapping for native T1 and extra-cellular volume (ECV) quantification for assessment of myocardial fibrosis, cine imaging and tissue tagging for assessment of left ventricular (LV) function. Twenty-five healthy volunteers (HV) with comparable age, sex, BMI and arterial blood pressure served as controls. Patients with GPA had similar cardiovascular risk profile to HV. A focal, non-ischaemic LGE pattern of fibrosis was detected in 24% of patients and no controls (p = 0.010). Patients with myocardial LGE were less frequently PR3 ANCA (7% vs 93%, p = 0.007), and had involvement of the lower respiratory tract and skin. LGE scar mass was higher in patients presenting with renal involvement. Native T1 and ECV were higher in patients with GPA than HV; ECV was higher in those with relapsing disease, and native T1 was inversely associated with PR3 ANCA (β = − 0.664, p = 0.001). Peak systolic strain was slightly reduced in GPA compared to controls; LV ejection function was inversely correlated with disease duration (β = − 0.454, p = 0.026). Patients with GPA have significant myocardial abnormalities on CMR. ANCA, systemic involvement and disease severity were associated with myocardial fibrosis. CMR could be a useful tool for risk stratification of myocardial involvement in GPA

Normal values and test–retest variability of stimulated-echo diffusion tensor imaging and fat fraction measurements in the muscle

OBJECTIVES: To assess the test–retest variability of both diffusion parameters and fat fraction (FF) estimates in normal muscle, and to assess differences in normal values between muscles in the thigh. METHODS: 29 healthy volunteers (mean age 37 years, range 20–60 years, 17/29 males) completed the study. Magnetic resonance images of the mid-thigh were acquired using a stimulated echo acquisition mode-echoplanar imaging (STEAM-EPI) imaging sequence, to assess diffusion, and 2-point Dixon imaging, to assess FF. Imaging was repeated in 19 participants after a 30 min interval in order to assess test–retest variability of the measurements. RESULTS: Intraclass correlation coefficients (ICCs) for test–retest variability were 0.99 [95% confidence interval, (CI): 0.98, 1] for FF, 0.94 (95% CI: 0.84, 0.97) for mean diffusivity and 0.89 (95% CI: 0.74, 0.96) for fractional anisotropy (FA). FF was higher in the hamstrings than the quadriceps by a mean difference of 1.81% (95% CI:1.63, 2.00)%, p < 0.001. Mean diffusivity was significantly lower in the hamstrings than the quadriceps (0.26 (0.13, 0.39) x10- 3 mm2s−1, p < 0.001) whereas fractional anisotropy was significantly higher in the hamstrings relative to the quadriceps with a mean difference of 0.063 (0.05, 0.07), p < 0.001. CONCLUSIONS: This study has shown excellent test-retest, variability in MR-based FF and diffusion measurements and demonstrated significant differences in these measures between hamstrings and quadriceps in the healthy thigh. ADVANCES IN KNOWLEDGE: Test–retest variability is excellent for STEAM-EPI diffusion and 2-point Dixon-based FF measurements in the healthy muscle. Inter- and intraobserver variability were excellent for region of interest placement for STEAM-EPI diffusion and 2-point Dixon-based FF measurements in the healthy muscle. There are significant differences in FF and diffusion measurements between the hamstrings and quadriceps in the normal muscle

Cardiovascular effects of biological versus conventional synthetic disease-modifying antirheumatic drug therapy in treatment-naïve, early rheumatoid arthritis

Objectives To determine whether patients with early rheumatoid arthritis (ERA) have cardiovascular disease (CVD) that is modifiable with disease-modifying antirheumatic drug (DMARD) therapy, comparing first-line etanercept (ETN) + methotrexate (MTX) with MTX strategy. Methods Patients from a phase IV ERA trial randomised to ETN+MTX or MTX strategy±month 6 escalation to ETN+MTX, and with no CVD and maximum one traditional risk factor underwent cardiovascular magnetic resonance (CMR) at baseline, years 1 and 2. Thirty matched controls underwent CMR. Primary outcome measure was aortic distensibility (AD) between controls and ERA, and baseline to year 1 AD change in ERA. Secondary analyses between and within ERA groups performed. Additional outcome measures included left ventricular (LV) mass and myocardial extracellular volume (ECV). Results Eighty-one patients recruited. In ERA versus controls, respectively, baseline (geometric mean, 95% CI) AD was significantly lower (3.0×10−3 mm Hg−1 (2.7–3.3) vs 4.4×10−3 mm Hg−1 (3.7–5.2), p<0.001); LV mass significantly lower (78.2 g (74.0–82.7), n=81 vs 92.9 g (84.8–101.7), n=30, p<0.01); and ECV increased (27.1% (26.4–27.9), n=78 vs 24.9% (23.8–26.1), n=30, p<0.01). Across all patients, AD improved significantly from baseline to year 1 (3.0×10−3 mm Hg−1 (2.7–3.4) to 3.6×10–3 mm Hg−1 (3.1–4.1), respectively, p<0.01), maintained at year 2. The improvement in AD did not differ between the two treatment arms and disease activity state (Disease Activity Score with 28 joint count)-erythrocyte sedimentation rate-defined responders versus non-responders. Conclusion We report the first evidence of vascular and myocardial abnormalities in an ERA randomised controlled trial cohort and show improvement with DMARD therapy. The type of DMARD (first-line tumour necrosis factor-inhibitors or MTX) and clinical response to therapy did not affect CVD markers. Trial registration number ISRCTN: ISRCTN89222125; ClinicalTrials.gov: NCT01295151

Cardiovascular MRI evidence of reduced systolic function and reduced LV mass in rheumatoid arthritis: impact of disease phenotype

The accelerated risk of cardiovascular disease (CVD) in Rheumatoid Arthritis (RA) requires further study of the underlying pathophysiology and determination of the at-risk RA phenotype. Our objectives were to describe the cardiac structure and function and arterial stiffness, and association with disease phenotype in patients with established) RA, in comparison to healthy controls, as measured by cardiovascular magnetic resonance imaging (CMR). 76 patients with established RA and no history of CVD/diabetes mellitus were assessed for RA and cardiovascular profile and underwent a non-contrast 3T-CMR, and compared to 26 healthy controls. A univariable analysis and multivariable linear regression model determined associations between baseline variables and CMR-measures. Ten-year cardiovascular risk scores were increased in RA compared with controls. Adjusting for age, sex and traditional cardiovascular risk factors, patients with RA had reduced left ventricular ejection fraction (mean difference − 2.86% (− 5.17, − 0.55) p = 0.016), reduced absolute values of mid systolic strain rate (p < 0.001) and lower late/active diastolic strain rate (p < 0.001) compared to controls. There was evidence of reduced LV mass index (LVMI) (− 4.56 g/m2 (− 8.92, − 0.20), p = 0.041). CMR-measures predominantly associated with traditional cardiovascular risk factors; male sex and systolic blood pressure independently with increasing LVMI. Patients with established RA and no history of CVD have evidence of reduced LV systolic function and LVMI after adjustment for traditional cardiovascular risk factors; the latter suggesting cardiac pathology other than atherosclerosis in RA. Traditional cardiovascular risk factors, rather than RA disease phenotype, appear to be key determinants of subclinical CVD in RA potentially warranting more effective cardiovascular risk reduction programs

Population transcriptomics of Drosophila melanogaster females

<p>Abstract</p> <p>Background</p> <p>Variation at the level of gene expression is abundant in natural populations and is thought to contribute to the adaptive divergence of populations and species. Gene expression also differs considerably between males and females. Here we report a microarray analysis of gene expression variation among females of 16 <it>Drosophila </it><it>melanogaster </it>strains derived from natural populations, including eight strains from the putative ancestral range in sub-Saharan Africa and eight strains from Europe. Gene expression variation among males of the same strains was reported previously.</p> <p>Results</p> <p>We detected relatively low levels of expression polymorphism within populations, but much higher expression divergence between populations. A total of 569 genes showed a significant expression difference between the African and European populations at a false discovery rate of 5%. Genes with significant over-expression in Europe included the insecticide resistance gene <it>Cyp6g1</it>, as well as genes involved in proteolysis and olfaction. Genes with functions in carbohydrate metabolism and vision were significantly over-expressed in the African population. There was little overlap between genes expressed differently between populations in females and males.</p> <p>Conclusions</p> <p>Our results suggest that adaptive changes in gene expression have accompanied the out-of-Africa migration of <it>D. melanogaster</it>. Comparison of female and male expression data indicates that the vast majority of genes differing in expression between populations do so in only one sex and suggests that most regulatory adaptation has been sex-specific.</p

Metabolic Impact of Adult-Onset, Isolated, Growth Hormone Deficiency (AOiGHD) Due to Destruction of Pituitary Somatotropes

Growth hormone (GH) inhibits fat accumulation and promotes protein accretion, therefore the fall in GH observed with weight gain and normal aging may contribute to metabolic dysfunction. To directly test this hypothesis a novel mouse model of adult onset-isolated GH deficiency (AOiGHD) was generated by cross breeding rat GH promoter-driven Cre recombinase mice (Cre) with inducible diphtheria toxin receptor mice (iDTR) and treating adult Cre+/−,iDTR+/− offspring with DT to selectively destroy the somatotrope population of the anterior pituitary gland, leading to a reduction in circulating GH and IGF-I levels. DT-treated Cre−/−,iDTR+/− mice were used as GH-intact controls. AOiGHD improved whole body insulin sensitivity in both low-fat and high-fat fed mice. Consistent with improved insulin sensitivity, indirect calorimetry revealed AOiGHD mice preferentially utilized carbohydrates for energy metabolism, as compared to GH-intact controls. In high-fat, but not low-fat fed AOiGHD mice, fat mass increased, hepatic lipids decreased and glucose clearance and insulin output were impaired. These results suggest the age-related decline in GH helps to preserve systemic insulin sensitivity, and in the context of moderate caloric intake, prevents the deterioration in metabolic function. However, in the context of excess caloric intake, low GH leads to impaired insulin output, and thereby could contribute to the development of diabetes

Quantitative susceptibility mapping: Report from the 2016 reconstruction challenge

PURPOSE: The aim of the 2016 quantitative susceptibility mapping (QSM) reconstruction challenge was to test the ability of various QSM algorithms to recover the underlying susceptibility from phase data faithfully. METHODS: Gradient-echo images of a healthy volunteer acquired at 3T in a single orientation with 1.06 mm isotropic resolution. A reference susceptibility map was provided, which was computed using the susceptibility tensor imaging algorithm on data acquired at 12 head orientations. Susceptibility maps calculated from the single orientation data were compared against the reference susceptibility map. Deviations were quantified using the following metrics: root mean squared error (RMSE), structure similarity index (SSIM), high-frequency error norm (HFEN), and the error in selected white and gray matter regions. RESULTS: Twenty-seven submissions were evaluated. Most of the best scoring approaches estimated the spatial frequency content in the ill-conditioned domain of the dipole kernel using compressed sensing strategies. The top 10 maps in each category had similar error metrics but substantially different visual appearance. CONCLUSION: Because QSM algorithms were optimized to minimize error metrics, the resulting susceptibility maps suffered from over-smoothing and conspicuity loss in fine features such as vessels. As such, the challenge highlighted the need for better numerical image quality criteria

Age-related changes to motor synergies in multi-joint and multi-finger manipulative skills: a meta-analysis

Purpose The aim of the current meta-analysis was to examine the extent to which there are differences in upper extremity motor synergies across different age groups in manipulative tasks. Methods The studies that used the uncontrolled manifold method to examine the effect of age on motor synergies in multijoint and multi-finger tasks were selected. Sixteen relevant studies from 1154 articles were selected for the meta-analysis—4 and 12 studies considered multi-joint kinematics and multi-finger kinetic tasks respectively. Results The results of the meta-analysis suggested reduced strength of synergies in multi-finger task in older adults, but this was not the case for synergies in multi-joint task. Part of this age-related difference in finger function is related to the increased variability in total force in grasping tasks. However, reductions in the strength of multi-finger synergies in hand functions following ageing appear to depend on the characteristics of the task. Conclusions These findings indicate that the cooperation among fingers to stabilise the total required force to apply for grasping and other fine motor skills is less efficient in older adults that might affect the quality of manipulative tasks

The IFN-γ-Inducible GTPase, Irga6, Protects Mice against Toxoplasma gondii but Not against Plasmodium berghei and Some Other Intracellular Pathogens

Clearance of infection with intracellular pathogens in mice involves interferon-regulated GTPases of the IRG protein family. Experiments with mice genetically deficient in members of this family such as Irgm1(LRG-47), Irgm3(IGTP), and Irgd(IRG-47) has revealed a critical role in microbial clearance, especially for Toxoplasma gondii. The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail. We investigated the susceptibility of two independently generated mouse strains deficient in Irga6 to in vivo infection with T. gondii, Mycobacterium tuberculosis, Leishmania mexicana, L. major, Listeria monocytogenes, Anaplasma phagocytophilum and Plasmodium berghei. Compared with wild-type mice, mice deficient in Irga6 showed increased susceptibility to oral and intraperitoneal infection with T. gondii but not to infection with the other organisms. Surprisingly, infection of Irga6-deficient mice with the related apicomplexan parasite, P. berghei, did not result in increased replication in the liver stage and no Irga6 (or any other IRG protein) was detected at the parasitophorous vacuole membrane in IFN-γ-induced wild-type cells infected with P. berghei in vitro. Susceptibility to infection with T. gondii was associated with increased mortality and reduced time to death, increased numbers of inflammatory foci in the brains and elevated parasite loads in brains of infected Irga6-deficient mice. In vitro, Irga6-deficient macrophages and fibroblasts stimulated with IFN-γ were defective in controlling parasite replication. Taken together, our results implicate Irga6 in the control of infection with T. gondii and further highlight the importance of the IRG system for resistance to this pathogen