62 research outputs found
Whole exome sequence analysis reveals a homozygous mutation in PNPLA2 as the cause of severe dilated cardiomyopathy secondary to neutral lipid storage disease.
Accepted manuscript 12 month embargo, pre-print immediately
Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis
The functional impact of altered drug transport protein expression on the systemic pharmacokinetics of morphine, hepatically-derived morphine glucuronide (morphine-3- and morphine-6-glucuronide), and fasting bile acids was evaluated in patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) compared to healthy subjects. The maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) of morphine glucuronide in serum were increased in NASH patients (343 vs. 225nM and 58.8 vs. 37.2μM*min, respectively; P≤0.005); morphine pharmacokinetics did not differ between groups. Linear regression analyses detected an association of NASH severity with increased morphine glucuronide Cmax and AUC0-last (P<0.001). Fasting serum glycocholate, taurocholate and total bile acid concentrations were associated with NASH severity (P<0.006). Increased hepatic basolateral efflux of morphine glucuronide and bile acids is consistent with altered hepatic transport protein expression in patients with NASH and may partially explain differences in efficacy and/or toxicity of some highly transported anionic drugs/metabolites in this patient population
A SLUGGS and Gemini/GMOS combined study of the elliptical galaxy M60: wide-field photometry and kinematics of the globular cluster system
We present new wide-field photometry and spectroscopy of the globular clusters (GCs) around NGC 4649 (M60), the third brightest galaxy in the Virgo cluster. Imaging of NGC 4649 was assembled from a recently obtained Hubble Space Telescope/Advanced Camera for Surveys mosaic, and new Subaru/Suprime-Cam and archival Canada–France–Hawaii Telescope/MegaCam data. About 1200 sources were followed up spectroscopically using combined observations from three multi-object spectrographs: Keck/Deep Imaging Multi-Object Spectrograph, Gemini/Gemini Multi-Object Spectrograph and Multiple Mirror Telescope/Hectospec. We confirm 431 unique GCs belonging to NGC 4649, a factor of 3.5 larger than previous data sets and with a factor of 3 improvement in velocity precision. We confirm significant GC colour bimodality and find that the red GCs are more centrally concentrated, while the blue GCs are more spatially extended. We infer negative GC colour gradients in the innermost 20 kpc and flat gradients out to large radii. Rotation is detected along the galaxy major axis for all tracers: blue GCs, red GCs, galaxy stars and planetary nebulae. We compare the observed properties of NGC 4649 with galaxy formation models. We find that formation via a major merger between two gas-poor galaxies, followed by satellite accretion, can consistently reproduce the observations of NGC 4649 at different radii. We find no strong evidence to support an interaction between NGC 4649 and the neighbouring spiral galaxy NGC 4647. We identify interesting GC kinematic features in our data, such as counter-rotating subgroups and bumpy kinematic profiles, which encode more clues about the formation history of NGC 4649
Cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics in patients with glomerulonephritis secondary to lupus and small vessel vasculitis
Cyclophosphamide, the precursor to the active 4-hydroxycyclophosphamide, is used in active glomerulonephritis despite limited pharmacokinetics data. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were evaluated. The influence of laboratory and pharmacogenomic covariates on pharmacokinetics was evaluated as a secondary aim
B cell activity is impaired in human and mouse obesity and is responsive to an essential fatty acid upon murine influenza infection
Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming theWestern diet had diminished Ab titers whereas theWestern diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism
Tau, β-amyloid and β-amyloid precursor protein distribution in the entorhinal-hippocampal alvear and perforant pathways in the Alzheimer's brain
It has been suggested that the pathological lesions of Alzheimer's disease (AD) spread along neuronal connections. This study was designed to examine this hypothesis in the alvear and perforant pathways, two well-defined neuroanatomical pathways that project from the entorhinal cortex to the hippocampus. Paraffin-sections of hippocampal-entorhinal cortex from 25 AD cases were immunolabelled for tau, β-amyloid (Aβ) and β-amyloid precursor protein (βAPP). We used image-analysis to quantify immunolabelling at both ends of the alvear and perforant pathways. At the beginning and the end of the alvear pathway, area of immunolabelling in µm2 per area of field (72000 µm2) were as follows: tau 349 and 821 (P<0.01), Aβ 349 and 61 (P<0.05) and βAPP 18 and 73 (P<0.01). Corresponding values for the perforant pathway were tau 421 and 387, Aβ382 and 115 (P<0.05) and βAPP 55 and 83. Tau was significantly greater at the end than at the beginning of the alvear pathway, but similar at both ends of the perforant pathway. There was significantly more Aβ at the beginning than at the end of the alvear and perforant pathway. These results at least in part reinforce previous work [19] that tau-rich areas may be neuronally connected to Aβ-rich areas
Primary diffuse leptomeningeal gliomatosis predominantly affecting the spinal cord: case report and review of the literature
Primary leptomeningeal gliomatosis is a rare, fatal neoplastic syndrome. A 71 year old man is reported on, who after a 2 month history of back stiffness, epigastric pain, and weight loss developed visual blurring. Cranial CT and MRI studies showed no leptomeningeal enhancement. Examination of CSF 10 weeks premortem showed an increase in protein and decrease in glucose but no malignant cells. He became increasingly confused and repeated CSF examination showed inflammation and a few suspicious cells but no definitive evidence of neoplasia. He died 7 months after onset of his initial symptoms. At postmortem meningeal whitening was seen at the base of the brain and over the spinal cord. Histology disclosed diffuse leptomeningeal gliomatosis (GFAP positive, cytokeratin negative) over the brain, optic nerves, and spinal cord without parenchymal involvement. No tumour was found in internal organs. The diagnosis of primary leptomeningeal gliomatosis was not evident after cranial CT and MRI and CSF examination premortem. Suspected cases need MRI scanning of the entire neuraxis and meningeal biopsy
Vision loss due to coincident ocular and central causes in a patient with Heidenhain variant Creutzfeldt-Jakob disease
Creutzfeldt-Jakob disease (CJD) is a degenerative disease of the brain associated with a rapidly progressive spongiform encephalopathy. Visual symptoms and neuro-ophthalmological signs are not infrequent, and presentation to an ophthalmologist may result. A case is reported of an 89-years-old gentleman who presented with a short history of isolated deterioration in vision. He underwent ocular intervention but subsequently developed progressive dementia, asterixis, myoclonus, cerebellar and extrapyramidal signs, and cortical blindness. An electroencephalogram was consistent with CJD. The patient progressively deteriorated and died 9 weeks after symptom onset. Limited post-mortem examination confirmed CJ
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