Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men.

In contrast to conventional dual-energy X-ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single-nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment

Viral Endomyocardial Infection Is an Independent Predictor and Potentially Treatable Risk Factor for Graft Loss and Coronary Vasculopathy in Pediatric Cardiac Transplant Recipients

ObjectivesThis study sought to evaluate the outcome and prevalence of viral endomyocardial infection after cardiac transplantation.BackgroundViral myocardial infection causes heart failure, but its role after cardiac transplantation is unclear. We hypothesized that viral infection of the cardiac allograft reduces graft survival.MethodsBetween June 1999 and November 2004, 94 pediatric cardiac transplant patients were screened for the presence of viral genome in serial endomyocardial biopsies (EMBs) using polymerase chain reaction (PCR) assays. Graft loss, advanced transplant coronary artery disease (TCAD), and acute rejection (AR) were compared in the PCR-positive (n = 37) and PCR-negative (n = 57) groups, using time-dependent Kaplan-Meier and Cox regression analyses. From November 2002 to November 2004, intravenous immunoglobulin therapy (IVIG) was administered to patients with PCR-positive EMBs. The outcomes of the IVIG-treated, PCR-positive patients (n = 20) were compared with IVIG-untreated, PCR-positive patients (n = 17).ResultsViral genomes were detected in EMBs from 37 (39%) patients; parvovirus B19, adenovirus, and Epstein-Barr virus (EBV) were the most common. The PCR-positive group (n = 37, 25% graft loss at 2.4 years) had decreased graft survival (p < 0.001) compared with the PCR-negative group (n = 57, 25% graft loss at 8.7 years) and developed advanced TCAD prematurely (p = 0.001). The number of AR episodes was similar in both groups. On multivariate analysis, presence of viral genome was an independent risk factor for graft loss (relative risk: 4.2, p = 0.015). The time to advanced TCAD after becoming PCR-positive was longer in the IVIG-treated patients (p = 0.03) with a trend toward improved graft survival (p = 0.06).ConclusionsViral endomyocardial infection is an independent predictor of graft loss in pediatric cardiac transplant recipients. This effect appears to be mediated through premature development of advanced TCAD. IVIG therapy in this subgroup may improve survival and merits further investigation

Galaxy and Mass Assembly (GAMA): Variation in galaxy structure across the green valley

Using a sample of 472 local Universe (z \u3c 0.06) galaxies in the stellar mass range 10.25 \u3c logM*/M⊙ \u3c 10.75, we explore the variation in galaxy structure as a function of morphology and galaxy colour. Our sample of galaxies is subdivided into red, green, and blue colour groups and into elliptical and non-elliptical (disk-type) morphologies. Using Kilo- Degree Survey (KiDS) and Visible and Infrared Survey Telescope for Astronomy (VISTA) Kilo-Degree Infrared Galaxy Survey (VIKING) derived postage stamp images, a group of eight volunteers visually classified bars, rings, morphological lenses, tidal streams, shells, and signs of merger activity for all systems. We find a significant surplus of rings (2.3s) and lenses (2.9s) in disk-type galaxies as they transition across the green valley. Combined, this implies a joint ring/lens green valley surplus significance of 3.3s relative to equivalent disk-types within either the blue cloud or the red sequence. We recover a bar fraction of ~44 per cent which remains flat with colour, however, we find that the presence of a bar acts to modulate the incidence of rings and (to a lesser extent) lenses, with rings in barred disk-type galaxies more common by ~20-30 percentage points relative to their unbarred counterparts, regardless of colour. Additionally, green valley disk-type galaxies with a bar exhibit a significant 3.0s surplus of lenses relative to their blue/red analogues. The existence of such structures rules out violent transformative events as the primary end-of-life evolutionary mechanism, with a more passive scenario the favoured candidate for the majority of galaxies rapidly transitioning across the green valley

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes

Candidate Gene Analysis of Femoral Neck Trabecular and Cortical Volumetric Bone Mineral Density in Older Men

In contrast to conventional dual-energy X-ray absorptiometry, quantitative computed tomography separately measures trabecular and cortical volumetric bone mineral density (vBMD). Little is known about the genetic variants associated with trabecular and cortical vBMD in humans, although both may be important for determining bone strength and osteoporotic risk. In the current analysis, we tested the hypothesis that there are genetic variants associated with trabecular and cortical vBMD at the femoral neck by genotyping 4608 tagging and potentially functional single-nucleotide polymorphisms (SNPs) in 383 bone metabolism candidate genes in 822 Caucasian men aged 65 years or older from the Osteoporotic Fractures in Men Study (MrOS). Promising SNP associations then were tested for replication in an additional 1155 men from the same study. We identified SNPs in five genes (IFNAR2, NFATC1, SMAD1, HOXA, and KLF10) that were robustly associated with cortical vBMD and SNPs in nine genes (APC, ATF2, BMP3, BMP7, FGF18, FLT1, TGFB3, THRB, and RUNX1) that were robustly associated with trabecular vBMD. There was no overlap between genes associated with cortical vBMD and trabecular vBMD. These findings identify novel genetic variants for cortical and trabecular vBMD and raise the possibility that some genetic loci may be unique for each bone compartment. © 2010 American Society for Bone and Mineral Researc

Galaxy and Mass Assembly (GAMA): Variation in Galaxy Structure Across the Green Valley

Using a sample of 472 local Universe (z < 0.06) galaxies in the stellar mass range 10.25 < log M*/MG < 10.75, we explore the variation in galaxy structure as a function of morphology and galaxy colour. Our sample of galaxies is sub-divided into red, green and blue colour groups and into elliptical and non-elliptical (disk-type) morphologies. Using KiDS and VIKING derived postage stamp images, a group of eight volunteers visually classified bars, rings, morphological lenses, tidal streams, shells and signs of merger activity for all systems. We find a significant surplus of rings (2.3σ) and lenses (2.9σ) in disk-type galaxies as they transition across the green valley. Combined, this implies a joint ring/lens green valley surplus significance of 3.3σ relative to equivalent disk-types within either the blue cloud or the red sequence. We recover a bar fraction of ∼ 44% which remains flat with colour, however, we find that the presence of a bar acts to modulate the incidence of rings and (to a lesser extent) lenses, with rings in barred disk-type galaxies more common by ∼ 20 − 30 percentage points relative to their unbarred counterparts, regardless of colour. Additionally, green valley disk-type galaxies with a bar exhibit a significant 3.0σ surplus of lenses relative to their blue/red analogues. The existence of such structures rules out violent transformative events as the primary end-of-life evolutionary mechanism, with a more passive scenario the favoured candidate for the majority of galaxies rapidly transitioning across the green valley. Key words: galaxies: elliptical and lenticular, cD – galaxies: spiral – galaxies: evo- lution – galaxies: star formation – galaxies: statistics – galaxies: structur

Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression

From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-β and Wnt/β-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer

Proton Magnetic Resonance Spectroscopy Reveals Neuroprotection by Oral Minocycline in a Nonhuman Primate Model of Accelerated NeuroAIDS

Background: Despite the advent of highly active anti-retroviral therapy (HAART), HIV-associated neurocognitive disorders continue to be a significant problem. In efforts to understand and alleviate neurocognitive deficits associated with HIV, we used an accelerated simian immunodeficiency virus (SIV) macaque model of NeuroAIDS to test whether minocycline is neuroprotective against lentiviral-induced neuronal injury. Methodology/Principal Findings: Eleven rhesus macaques were infected with SIV, depleted of CD8+ lymphocytes, and studied until eight weeks post inoculation (wpi). Seven animals received daily minocycline orally beginning at 4 wpi. Neuronal integrity was monitored in vivo by proton magnetic resonance spectroscopy and post-mortem by immunohistochemistry for synaptophysin (SYN), microtubule-associated protein 2 (MAP2), and neuronal counts. Astrogliosis and microglial activation were quantified by measuring glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (IBA-1), respectively. SIV infection followed by CD8+ cell depletion induced a progressive decline in neuronal integrity evidenced by declining N-acetylaspartate/creatine (NAA/Cr), which was arrested with minocycline treatment. The recovery of this ratio was due to increases in NAA, indicating neuronal recovery, and decreases in Cr, likely reflecting downregulation of glial cell activation. SYN, MAP2, and neuronal counts were found to be higher in minocycline-treated animals compared to untreated animals while GFAP and IBA-1 expression were decreased compared to controls. CSF and plasma viral loads were lower in MN-treated animals. Conclusions/Significance: In conclusion, oral minocycline alleviates neuronal damage induced by the AIDS virus

Paired dissolved and particulate phase Cu isotope distributions in the South Atlantic

© 2018 The Authors Copper (Cu) is both an essential micronutrient and toxic to photosynthesizing microorganisms at low concentrations. Its dissolved vertical distribution in the oceans is unusual, being neither a nutrient-type nor scavenged-type element. This distribution is attributed to biological uptake in the surface ocean with remineralisation at depth, combined with strong organic complexation by dissolved ligands, scavenging onto particles, and benthic sedimentary input. We present coupled dissolved and particulate phase Cu isotope data along the UK-GEOTRACES South Atlantic section, alongside higher resolution dissolved and particulate phase Cu concentration measurements. Our dissolved phase isotope data contribute to an emerging picture of homogeneous deep ocean δ65Cu, at about +0.65‰ (relative to NIST SRM 976). We identify two pools of Cu in the particulate phase: a refractory, lithogenic pool, at about 0‰, and a labile pool accessed via a weak acidic leach, at about +0.4‰. These two pools are comparable to those previously observed in sediments. We observe deviations towards lighter δ65Cu values in the dissolved phase associated with local enrichments in particulate Cu concentrations along the continental slopes, and in the surface ocean. Copper isotopes are thus a sensitive indicator of localised particle-associated benthic or estuarine Cu inputs. The measurement of Cu isotopes in seawater is analytically challenging, and we call for an intercalibration exercise to better evaluate the potential impacts of UV-irradiation, storage time, and different analytical procedures

Patient Satisfaction with Private Physiotherapy for Musculoskeletal Pain

Despite emphasis on patient centred healthcare, healthcare professionals have been slow to use validated measurements of patient satisfaction in physiotherapy practice. This cross sectional survey measured patient satisfaction with private physiotherapy in Ireland, for patients with musculoskeletal pain, using a multidimensional patient satisfaction questionnaire (PTOPS). The 'PTOPS' questionnaire categorised and scored satisfaction items under four domains, Enhancer, Detractor, Location and Cost. 55% (n = 131/240) of questionnaires were returned. The most common site of musculoskeletal pain was spinal (51.5% n = 66) and the mean (SD) number of treatments attended was 8.3 (8.3), at a mean total cost (SD) of €350.2 (€322.8). Overall satisfaction with physiotherapy experience was scored on a five-point scale "excellent to poor", with a modal response of "Very Good" (42%; n = 55). Results demonstrated high levels of satisfaction with all components of physiotherapy treatment, except cost, and provided valuable patient feedback regarding their physiotherapy treatment for musculoskeletal pain.Peer reviewedFinal Published versio