21 research outputs found
Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom
No full textAtypical haemolytic uraemic syndrome (aHUS) is associated with a poor prognosis with regard to survival at presentation, recovery of renal function and transplantation. It is now established that aHUS is a disease of complement dysregulation with mutations in the genes encoding both complement regulators and activators, and autoantibodies against the complement regulator factor H. Identification of the underlying molecular abnormality in an individual patient can now help to guide their future management. In these guidelines we make recommendations for the investigation and management of aHUS patients both at presentation and in the long-term. We particularly address the role of renal transplantation alone and combined liver-kidney transplantation
Distribution and determinants of circulating complement factor H concentration determined by a high-throughput immunonephelometric assay
No full textBACKGROUND:
Research on complement factor H (fH) in human disease is hampered by lack of an assay suitable for use in large-scale epidemiological studies. We describe the development and validation of a high throughput nephelometric assay for fH.
METHODS:
Reagents from a commercial radial immunodiffusion (RID) assay (The Binding Site) were adapted for use on the Siemens BNII high throughput nephelometric instrument. The assay was calibrated with a highly purified human fH preparation with rigorously determined concentration, and assay performance was comprehensively evaluated using samples from healthy human volunteers, with the commercial RID assay as a comparator. The distribution and determinants of circulating fH concentration in humans were then investigated in a large representative population sample.
RESULTS:
The nephelometric assay had recovery close to 100%, was reproducible with intra- and inter-assay CV's of 11% and 5-15% respectively, and had a wider operating range than the RID assay. fH values were unaffected after multiple freeze-thaw cycles demonstrating that it is evidently a stable analyte for immunoassay. fH concentration was unaltered by an acute inflammatory stimulus. The population study showed that plasma fH concentration is associated with circulating lipids and indices of body fat.
CONCLUSION:
We present the first high throughput assay for circulating fH; the assay is accurate and reliable with reproducible measures from stored samples. It has established the distribution of fH values at a population level and demonstrated important associations with circulating lipids and indices of body fat, thus providing an important reference for future clinical and epidemiological investigations
Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation
No full textWhilst randomised control trials are undoubtedly the best way to demonstrate whether plasma exchange or infusion alone is the best first-line treatment for patients with atypical haemolytic uremic syndrome (aHUS), individual case reports can provide valuable information. To that effect, we have had the unique opportunity to follow over a 10-year period three sisters with aHUS associated with a factor H mutation (CFH). Two of the sisters are monozygotic twins. A similar natural evolution and response to treatment would be expected for the three patients, as they all presented with the same at-risk polymorphisms for CFH and CD46 and no identifiable mutation in either CD46 or CFI. Our report of different modalities of treatment of the initial episode and of three transplantations and relapses in the transplant in two of them, strongly suggest that intensive plasma exchange, both acutely and prophylactically, can maintain the long-term function of both native kidneys and allografts. In our experience, the success of plasma therapy is dependent on the use of plasma exchange as opposed to plasma infusion alone, the prolongation of daily plasma exchange after normalisation of haematological parameters followed by prophylactic plasma exchange, the use of prophylactic plasma exchange prior to transplantation and the use of prophylactic plasma exchange at least once a week posttransplant with immediate intensification of treatment if there are any signs of recurrenc
Plasma therapy for atypical haemolytic uraemic syndrome associated with heterozygous factor H mutations
No full textMutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis
No full textEllis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. The disease was mapped to chromosome 4p16 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil. Weyers acrodental dysostosis (MIM 193530), an autosomal dominant disorder with a similar but milder phenotype, has been mapped in a single pedigree to an area including the EvC critical region. We have identified a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in individuals with EvC. We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. The heterozygous carriers of these mutations did not manifest features of EvC. We found two heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis and another in a father and his daughter, who both have the heart defect characteristic of EvC and polydactyly, but not short stature. We suggest that EvC and Weyers acrodental dysostosis are allelic conditions
Association of Genetic Variants in Complement Factor H and Factor H-Related Genes with Systemic Lupus Erythematosus Susceptibility
No full textSystemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta) = 6.6x10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9x10(-7), OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a similar to 146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1 Delta), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1D (P(meta) = 3.2x10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5x10(-4), OR = 1.14). These results suggested that the CFHR3-1D deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.` Support for this work was obtained from the US National Institutes of Health grants: R01AR043814 (BP Tsao), R01AR043274 (KL Moser), R01AI063274 (PM Gaffney), N01AR62277 (JB Harley), R37AI024717 (JB Harley), R01AR042460 (JB Harley), P01AI083194 (JB Harley), P20RR020143 (JB Harley), P01AR049084 (RP Kimberly), R01AR33062 (RP Kimberly, EE Brown), K08AI083790 (TB Niewold), LRPAI071651 (TB Niewold), R01CA141700 (ME Alarcon-Riquelme), RC1AR058621 (ME Alarcon-Riquelme) and UL1RR024999 (TB Niewold), R01AR051545-01A2 (AM Stevens), P30AR053483 (JA James and JM Guthridge), AR43727 (MA Petri), UL1RR025005 (MA Petri), K24AR002138 (R Ramsey-Goldman), P602AR30692 (R Ramsey-Goldman), P01AR49084 (R Ramsey-Goldman), UL1RR025741 (R Ramsey-Goldman), P20RR015577 (JA James), RC1AR058554 (JA James), U19AI082714 (JA James), N01AI50026 (JA James and JM Guthridge), R21AI070304 (SA Boackle), P60AR053308 (LA Criswell), M01RR00079 (LA Criswell), UL1RR029882 (GS Gilkeson and DL Kamen), P60AR049459 (GS Gilkeson and DL Kamen), and R01AR054459 (C-Y Yu). The first author (J Zhao) is an Eng Tan Scholar supported by the Arthritis National Research Foundation. This study was also supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A080588; S-C Bae), Korean R&D Program of MKE/KEIT (10035615; YW Song), the Merit Award from the US Department of Veterans Affairs (JB Harley and GS Gilkeson), the US Department of Defense PR094002 (JB Harley), Lupus Research Institute (BP Tsao, AM Stevens, and TB Niewold), The Alliance for Lupus Research (KL Moser, TB Niewold, LA Criswell, and CO Jacob), the Arthritis National Research Foundation Eng Tan Scholar Award (TB Niewold), the Arthritis Foundation (AM Stevens and PM Gaffney), and the Lupus Foundation (AM Stevens). Additional funding awarded from the Swedish Research Council, Swedish Association Against Rheumatism, and the King Gustaf Vth 80th Jubilee. Foundation and the Fundacion Instituto de Salud Carlos III PS0900129 and the Consejeria de Salud de Andalucia PI-0012 (ME Alarcon-Riquelme), the Welcome Trust (TJ Vyse), Arthritis Research UK (TJ Vyse), UK Medical Research Council grant (G0701325; THJ Goodship), CTSA Grant Number I ULI RR025014-02 (AM Stevens) from the National Center for Research Resources (NCRR), Kirkland Scholar Award (LA Criswell and JA James), and Federico Wilhelm Agricola Foundation Research Grant (BA Pons-Estel). The work reported on in this publication has been in part financially supported by the ESF, in the framework of the Research Networking Programmers European Science Foundation - The Identification of Novel Genes and Biomarkers for Systemic Lupus Erythematosus (BIOLUPUS)-RNP-083. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Histopathologic features of distal tarsal joint cartilage and subchondral bone in ridden and pasture-exercised horses
No full textObjective-To determine whether histopathologic characteristics of the osteochondral unite of equine distal tarsal joints were associated with exercise history in horses without lameness Sample Population-30 cadaver tarsi from horses without lameness and with known exercise history were separated into 3 groups nonridden pasture exercise (group P) low-intensity ridden exercise (group L) and high intensity elite competition exercise (group E) Procedures-Standardized sites from the centrodistal and tarsometatarsal joints underwent histologic preparation A grading system was adapted to describe location depth and shape of lesions cellular arrangement organization at cartilage and subchondral bone (SOB) junctions and organization of SCB A high score signified a more severe pathological change than a low score Exercise groups were compared by calculation of Spearman rank correlations Results-In the centrodistal Joint lesions were present in groups L and E but only medially Cellular arrangement scores were higher at the dorsomedial location in group P than in groups L and E Groups L and E had higher scores than group P for the organization of the cartilage SCB junctions and SCB with higher scores at the dorsomedial location In the tarsometatarsal joint lesions were evident across the whole Joint surface with more severe lesions located laterally in all 3 groups Overall group E had higher scores for cellular arrangement and SOB organization than groups P and L Conclusions and Clinical Relevance-Ridden exercise may increase the risk of osteochondral lesions at distal tarsal sites predisposed to osteoarthritis relative to the risk with non ridden exercise (Am J Vet Res 2011 72 33-41
Sandwich injection moulding with thermoset materials
No full textThis project aimed to study the feasibility of making a thermoset sandwich injection
moulding from a novel thermoset co-injection moulding system. Two thermoset
polyesters, BMC and a powder coating, were used for all experiments. Flow and cure
of those materials in a newly designed manifold system were studied and some
thermoset sandwich injection mouldings have been produced. Despite producing
novel co-injection mouldings using two thermoset materials together, the results
showed that the existing system was not applicable for large-scale production of
sandwich parts and needed some improvements.
The experiments on the moulding materials and single injection of each material
gave temperature windows and settings for the co-injection moulding. The results
from all experiments indicated that temperature and the time of applying heat to a
thermoset material were very important to its flow ability and formation. Especially
when producing a sandwich moulding, adequate heat and time was necessary for the
skin material to form a sufficient layer to cover the core material. Investigation of the
sandwich moulding cross-sections showed that applying more core injection delay
time could help to increase the skin thickness. Surface assessmenitn dicated that the
surface quality was also improved when the skin layer was thicker. However, core
break-through at the position opposite to the mould gate was found in all sandwich
mouldings showing that the type of mould gate was also important. A central sprue
gated mould used in these experiments was found to be not suitable for producing a
sandwich component using this machine configuration.
A new manifold design was proposed and was compared to the existing manifold
designed by using a simulation software package from Moldflow. Thermoset single
injection moulding simulation was used to help to understand the flow and cure of a
thermoset material in both manifold designs. It was shown that the new manifold
system design was an improvement on the existing one
Prophylactic plasma exchange in CD46-associated atypical haemolytic uremic syndrome
No full textPatients with atypical haemolytic uremic syndrome (aHUS) with a mutation in the gene encoding membrane cofactor protein (CD46) are known to have a better prognosis than those with mutations in factor H (CFH) or factor I (CFI), but a small number of the former still proceed to end-stage renal failure. Plasma therapy (PE) is the recommended approach to treat both acute episodes and prevent recurrences in aHUS, but studies have yet to show PE efficacy in aHUS associated with a CD46 mutation. The factors determining failure to treatment are not clear and may be related to the mutation involved or to insufficient treatment. Our experience of PE in a family of three sisters with CFH-associated aHUS suggests that intensive and prophylactic PE allows renal function to be maintained in both native kidneys and allografts. The success of this strategy has led us to use it in all cases of aHUS. Here, we describe the effect of this strategy in a child with aHUS and a CD46 mutation. The initial episode was treated with daily PE, resulting in the recovery of renal function. However, over the next 4 years, there was a progressive decline in renal function to end-stage renal failure, with evidence of an on-going thrombotic microangiopathy despite continuous prophylactic PE. Prophylactic PE does not influence the natural course of aHUS and CD46 mutatio
Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language (Nature Communications, (2018), 9, 1, (4619), 10.1038/s41467-018-06014-6)
No full text\ua9 2019, The Author(s).The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1
