178 research outputs found
High Glucose Attenuates Shear-Induced Changes in Endothelial Hydraulic Conductivity by Degrading the Glycocalyx
Diabetes mellitus is a risk factor for cardiovascular disease; however, the mechanisms through which diabetes impairs homeostasis of the vasculature have not been completely elucidated. The endothelium interacts with circulating blood through the surface glycocalyx layer, which serves as a mechanosensor/transducer of fluid shear forces leading to biomolecular responses. Atherosclerosis localizes typically in regions of low or disturbed shear stress, but in diabetics, the distribution is more diffuse, suggesting that there is a fundamental difference in the way cells sense shear forces. In the present study, we examined the effect of hyperglycemia on mechanotranduction in bovine aortic endothelial cells (BAEC). After six days in high glucose media, we observed a decrease in heparan sulfate content coincident with a significant attenuation of the shear-induced hydraulic conductivity response, lower activation of eNOS after exposure to shear, and reduced cell alignment with shear stress. These studies are consistent with a diabetes-induced change to the glycocalyx altering endothelial response to shear stress that could affect the distribution of atherosclerotic plaques
Atypical mycobacterial infection mimicking metastatic cholangiocarcinoma
Mycobacterial infections are rare in developed countries. Isolated involvement of the liver and biliary tree by mycobacterial infection is extremely rare. We report a case of a 45-year-old Caucasian female presenting with obstructive jaundice with a common bile duct stricture and multiple hypodense liver lesions raising suspicion of a metastatic cholangiocarcinoma. Percutaneous core biopsies of the liver lesions however suggested granulomatous process and histology at surgical excision confirmed this finding. Atypical mycobacteria (M. abcessus) sensitive to Amikacin were cultured from the surgical specimen proving the diagnosis. With the resurgence of tubercular and atypical mycobacterial infections in the developed world, it is important not to overlook these in differential diagnosis of various malignancies.Harsh A. Kanhere, Markus I. Trochsler, John Pierides, and Guy J. Madder
COL4A5 and LAMA5 variants co-inherited in familial hematuria: Digenic inheritance or genetic modifier effect?
Background: About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). Methods: Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. Results: In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. Conclusions: A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts. 2018 The Author(s).The work was supported from the Cyprus Research Promotion Foundation through the grant NEW INFRASTRUCTURE/STRATEGIC/0308/24 to CD (co-funded by the European Regional Development Fund and the Republic of Cyprus). The funding body did not contribute to the design of study, collection, analysis and interpretation of data, or in manuscript writing.Scopu
An Ethnographer Lured into Darkness
No matter the combination of methods ethnographers bring to their research design and to participant observation, our pursuit to log, interpret, analyse and present the lives of those we meet is never an entirely intellectual or objective one. Ethnographic fieldwork is intimately sensory (Pink, Doing sensory ethnography, Sage, London, 2015), invokes our imagination (Sparkes, Qualitative research in sport and exercise, 1:21â35, 2009) and requires us to actively navigate social landscapes (Hammersley and Atkinson, Field relations. Ethnography: Principles in practice, Routledge, Stoodleigh, 2007). There is a tendency for these elements to fade in terms of visibility and immediacy within the research process. For those in accord with (Davies, Reflexive ethnography: A guide to researching selves and others, Routledge, New York, 2008), continuous reflexive labour becomes a core praxis to monitor the ways we observe and participate in this textured environment. Without this, we are left in the dark and are less able to see how we can (or should) respond to the nittyâgritty qualitative nature of ethnography. In this Chapter, two of methodological vignettes will act as entry points to unpack a set of tensions that commanded my attention during an eighteen months ethnography in Higher Education. âYou Look Like an Ivory Tower Studentâ, for example, begins to troubleshoot ethnographic participation within educational environments. âGoing Darkâ, on the other hand, problematises the prioritisation of visual observations that are implicit in ethnographic tradition. Throughout these discussions a metaphor of being lured into darkness is offered as a productive orientation for ethnography
The role of molecular genetics in diagnosing familial hematuria(s)
Familial microscopic hematuria (MH) of glomerular origin represents a heterogeneous group of monogenic conditions involving several genes, some of which remain unknown. Recent advances have increased our understanding and our ability to use molecular genetics for diagnosing such patients, enabling us to study their clinical characteristics over time. Three collagen IV genes, COL4A3, COL4A4, and COL4A5 explain the autosomal and X-linked forms of Alport syndrome (AS), and a subset of thin basement membrane nephropathy (TBMN). A number of X-linked AS patients follow a milder course reminiscent of that of patients with heterozygous COL4A3/COL4A4 mutations and TBMN, while at the same time a significant subset of patients with TBMN and familial MH progress to chronic kidney disease (CKD) or end-stage kidney disease (ESKD). A mutation in CFHR5, a member of the complement factor H family of genes that regulate complement activation, was recently shown to cause isolated C3 glomerulopathy, presenting with MH in childhood and demonstrating a significant risk for CKD/ESKD after 40Â years old. Through these results molecular genetics emerges as a powerful tool for a definite diagnosis when all the above conditions enter the differential diagnosis, while in many at-risk related family members, a molecular diagnosis may obviate the need for another renal biopsy
Forced Solid-State Interactions for the Selective âTurn-Onâ Fluorescence Sensing of Aluminum Ions in Water Using a Sensory Polymer Substrate
Selective and sensitive solid sensory substrates for detecting Al(III) in pure
water are reported. The material is a flexible polymer film that can be handled and exhibits gel
behavior and membrane performance. The film features a chemically anchored salicylaldehyde
benzoylhydrazone derivative as an aluminum ion fluorescence sensor. A novel procedure for
measuring Al(III) at the ppb level using a single solution drop in 20 min was developed. In this
procedure, a drop was allowed to enter the hydrophilic material for 15 min before a 5 min
drying period. The process forced the Al(III) to interact with the sensory motifs within the
membrane before measuring the fluorescence of the system. The limit of detection of Al(III)
was 22 ppm. Furthermore, a water-soluble sensory polymer containing the same sensory
motifs was developed with a limit of detection of Al(III) of 1.5 ppb, which was significantly
lower than the Environmental Protection Agency recommendations for drinking water.Spanish Ministerio de EconomiÌa
y Competitividad-Feder
(MAT2011-22544) and by the ConsejeriÌa
de EducacioÌn - Junta
de Castilla y LeoÌn (BU232U13)
Epistatic Role of the MYH9/APOL1 Region on Familial Hematuria Genes.
Familial hematuria (FH) is explained by at least four different genes (see below). About 50% of patients develop late proteinuria and chronic kidney disease (CKD). We hypothesized that MYH9/APOL1, two closely linked genes associated with CKD, may be associated with adverse progression in FH. Our study included 102 thin basement membrane nephropathy (TBMN) patients with three known COL4A3/COL4A4 mutations (cohort A), 83 CFHR5/C3 glomerulopathy patients (cohort B) with a single CFHR5 mutation and 15 Alport syndrome patients (cohort C) with two known COL4A5 mild mutations, who were categorized as "Mild" (controls) or "Severe" (cases), based on renal manifestations. E1 and S1 MYH9 haplotypes and variant rs11089788 were analyzed for association with disease phenotype. Evidence for association with "Severe" progression in CFHR5 nephropathy was found with MYH9 variant rs11089788 and was confirmed in an independent FH cohort, D (cumulative p valueâ=â0.001, odds ratioâ=â3.06, recessive model). No association was found with APOL1 gene. Quantitative Real time PCR did not reveal any functional significance for the rs11089788 risk allele. Our results derive additional evidence supporting previous reports according to which MYH9 is an important gene per se, predisposing to CKD, suggesting its usefulness as a prognostic marker for young hematuric patients
Medical student self-reported confidence in obstetrics and gynaecology: development of a core clinical competencies document
Background: Clinical competencies in obstetrics and gynaecology have not been clearly defined for Australian medical students, the growing numbers of which may impact clinical teaching. Our aim was to administer and validate a competencies list, for self-evaluation by medical students of their confidence to manage common clinical tasks in obstetrics and gynaecology; to evaluate studentsâ views on course changes that may result from increasing class sizes. Methods: A draft list of competencies was peer-reviewed, and discussed at two student focus groups. The resultant list was administered as part of an 81 item online survey. Results: Sixty-eight percent (Nâ=â172) of those eligible completed the survey. Most respondents (75.8%) agreed or strongly agreed that they felt confident and well equipped to recognise and manage most common and important obstetric and gynaecological conditions. Confidence was greater for women, and for those who received a higher assessment grade. Free-text data highlight reasons for lack of clinical experience that may impact perceived confidence. Conclusions: The document listing competencies for medical students and educators is useful for discussions around a national curriculum in obstetrics and gynaecology in medical schools, including the best methods of delivery, particularly in the context of increasing student numbers.Kristen Pierides, Paul Duggan, Anna Chur-Hansen and Amaya Gilso
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