Complement factor H and the haemolytic uraemic syndrome.
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Complement Factor H↗
Biomedical subjects
C M Taylor
Publications and source records attributed to C M Taylor.
Molecular characterization and ophthalmic investigation of a large family with type 2A Von Hippel-Lindau Disease.
BACKGROUND: Von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome. Since the identification of the VHL gene, at least 3 clinical-genetic subtypes of the disease have been recognized. OBJECTIVES: To identify the specific abnormality in the VHL gene and to correlate it with the prevalence and severity of ocular involvement in a large family with VHL disease. METHODS: A longitudinal clinical study and DNA analysis of 24 family members. RESULTS: All 14 affected family members exhibited a thymine-to-cysteine change at nucleotide 505 (T505C) in exon 1 of the VHL gene, consistent with the clinical diagnosis of VHL disease subtype 2A. Two asymptomatic gene carriers were also identified. Seventy-five percent (12/16) of the gene carriers had 1 or more ocular angiomas. The mean number of ocular angiomas per gene carrier was 3.3. Six eyes had optic disc angioma. Five gene carriers (31%) had lost vision because of angiomatosis. Cerebellar hemangioblastomas were present in 4 patients (25%) and pheochromocytomas in 11 (69%). No patient was found to have a renal cell carcinoma. CONCLUSIONS: The family shows a low susceptibility to renal carcinoma consistent with the clinical diagnosis of VHL disease type 2A. The prevalence and severity of ocular angiomatosis in this subtype do not significantly differ from those of the other more common subtypes of VHL. Recognition of the VHL disease 2A phenotype suggests the presence of a specific mutation (T505C) in the VHL gene. Confirmation of this genotype increases the clinician's ability to provide favorable prognostic information to affected family members.
Adrenal Gland Neoplasms↗
A novel dipolar dephasing method for the slow magic angle turning experiment.
Complete suppression of the resonances from protonated carbons in a slow magic angle spinning experiment can be achieved using five dipolar dephasing (Five-DD) periods distributed in one rotor period. This produces a spectrum containing only the spinning sidebands (SSB) from the nonprotonated carbons. It is shown that the SSB patterns corresponding to the nonprotonated carbons are not distorted over a wide range of dipolar dephasing times. Hence, this method can be used to obtain reliable principal values of the chemical shift tensors for each nonprotonated carbon. The Five-DD method can be readily incorporated into isotropic-anisotropic 2D experiments such as FIREMAT and 2D-PASS to facilitate the measurement of the (13)C chemical shift tensors in complex systems.
Carbon Isotopes↗
Congenital nephrotic syndrome.
A female infant born at 34 weeks' gestation after several days of ruptured membranes had a Potter-like face and compression-induced limb posture consistent with oligohydramnios. Oedema developed on day 2; initial investigations showed massive proteinuria, hypoalbuminaemia, hyponatraemia, acidosis and marked renal insufficiency. The infant was intubated and despite albumin infusion and intravenous antibiotics she became oligoanuric by day 8 and required haemofiltration. Renal biopsy at this stage showed cystic dilatation of tubules in the cortex and glomerular lesions consisting of shrunken tufts with sclerotic centres and a corona of epithelial cells at the periphery. Due to a very poor prognosis treatment was withdrawn. Postmortem examination of the kidneys confirmed the histological diagnosis of diffuse mesangial sclerosis. Genetic studies found no mutations in WT1 and NPHS1 genes although the entire genes could not be screened for mutations due to lack of DNA.
Fatal Outcome↗
Hemolytic-uremic syndrome and complement factor H deficiency: clinical aspects.
A subgroup of patients with hemolytic-uremic syndrome (HUS) has emerged with complement factor H deficiency. These have come to light because of persistent hypocomplementemia, although the molecular finding by Warwicker et al in one pedigree suggests that not all cases exhibit systemic hypocomplementemia. These patients have an atypical presentation in that they do not consistently have a prodrome of enterocolitis although precipitating factors may include infections of various kinds. Patients usually have severe hypertension early in the course of their illness, tend to relapse, and have a poor prognosis. The age of onset varies from neonates to adults. Plasma exchange and replacement with a plasma product containing factor H seem a reasonable option in the absence of better evidence. Kidney transplantation can meet with recurrence of HUS, but the risk of grafting has yet to be established, and a strategy to overcome graft recurrence is needed. Because of the great rarity of this disorder, a strong case can be made for international registries of atypical HUS cases so that clinical and laboratory investigation is promoted.
Complement Factor H↗
Visual and haptic perception of the horizontal-vertical illusion.
The horizontal-vertical illusion consists of two lines of the same length (one horizontal and the other vertical) at a 90 degree angle from one another forming either an inverted-T or an L-shape. The illusion occurs when the length of a vertical line is perceived as longer than the horizontal line even though they are the same physical length. The illusion has been shown both visually and haptically. The present purpose was to assess differences between the visual or haptic perception of the illusions and also whether differences occur between the inverted-T and the L-shape illusions. The current study showed a greater effect in the haptic perception of the horizontal-vertical illusion than in visual perception. There is also greater illusory susceptibility of the inverted-T than the L-shape.
Adult↗
Synthesis of the repeating decapeptide unit of Mefp1 in orthogonally protected form.
Mefp1 is a protein produced by the marine mussel, Mytilus edulis, which helps the organism to adhere to surfaces in turbulent waters. To better understand the nature of the adhesion process, we sought to synthesize homogeneous oligopeptides based on the repeating decapeptide unit of the protein. The fully protected decapeptide 10 has been synthesized from appropriately protected amino acid building blocks using a fragment condensation strategy. A key feature of the strategy is the late incorporation of the synthetically valuable dihydroxyproline residue. This synthesis of the orthogonally protected repeating decapeptide unit of Mefp1 represents an important first step toward producing useful quantities of homogeneous oligopeptides related to the protein.
Adhesiveness↗
1H dynamic nuclear polarization in supercritical ethylene at 1.4 T.
(1)H dynamic nuclear polarization (DNP) has been measured in supercritical ethylene in the pressure range 60-300 bar in an external field of 1.4 T. A single-cell sapphire tube was used as a high-pressure cell, and powdered 1,3-bisdiphenylene-2-phenyl allyl (BDPA) free radicals were added and distributed at the wall of the cell. At all pressures the dominant DNP mechanism was a positive Overhauser enhancement, caused by proton-electron contact interactions at the fluid/solid radical interface. The observed enhancements varied from 12 at 60 bar to 17 at 300 bar. Besides the Overhauser enhancement, small solid state and thermal mixing enhancements also were observed, indicating that part of the ethylene was adsorbed at the radical surface for a prolonged time. The impacts of the experimental conditions on the Overhauser enhancement factors are discussed, and enhancements of at least 40-60 are estimated when the EPR saturation factor and the leakage factor become maximal. These data indicate that DNP-enhanced NMR has the potential of extending the impact of NMR in research areas involving supercritical fluids.
Ethylenes↗
Role of nitric oxide in a toxin-induced model of haemolytic uraemic syndrome.
The role of nitric oxide in the pathogenesis of glomerular thrombotic microangiopathy was explored using an established rat model in which ricin with or without lipopolysaccharide induced glomerular thrombosis. Ricin alone caused a small rise in the plasma concentration of nitric oxide (control 9.2+/-0.7 microM, ricin 23.3+/-6.3 microM at 7 h). This increase occurred after the development of glomerular thrombosis. Nitric oxide synthase (NOS) activity in the kidney showed no significant change from control values (control 5.66+/-2.7 pmol/min per ml homogenate, ricin 7.52+/-1.8 pmol/min per ml homogenate, total activity). When ricin and lipopolysaccharide were administered together, calcium-independent NOS activity increased whereas calcium-dependent activity decreased (1.22+/-2.6 pmol/min per ml homogenate). The increase in calcium-independent NOS activity correlated with a high plasma concentration of interleukin-1beta in the ricin plus lipopolysaccharide group (4,036.83+/-1,001.5 pg/ml). These data indicate that thrombus formation in a rat model of haemolytic uraemic syndrome is independent of the effects of nitric oxide.
Animals↗
Microbiological testing of raw, boxed beef in the context of hazard analysis critical control point at a high-line-speed abattoir.
The efficacy of cold storage of raw, bagged, boxed beef was assessed microbiologically at a high-line-speed abattoir (270 carcasses per h). At the time of this study, plant management was in the process of creating a hazard analysis critical control point plan for all processes. Aerobic bacteria, coliforms, and type 1 Escherichia coli were enumerated (5 by 5-cm excision samples, hydrophobic grid membrane filter technology) before and after cold storage of this final product produced at six fabrication tables. In addition, the temperature-function integration technique (TFIT) was used to calculate the potential number of generations of E. coli during the first 24 or 48 h of storage of the boxed beef. Based on the temperature histories (total of 60 boxes, resulting from 12 product cuts, five boxes from each of two fabrication tables on each of 6 sampling days, and six types of fabrication tables), TFIT did not predict any growth of E. coli (with or without lag) for the test period. This was verified by E. coli mean log10 values of 0.65 to 0.42 cm2 (P > 0.05) determined by culture before and after the cooling process, respectively. Counts of aerobic bacteria and coliforms were significantly reduced (P < 0.001 and P < 0.05, respectively) during the initial period of the cooling process. There were significant microbiological differences (P < 0.05) between table-cut units.
Abattoirs↗
Factor V Leiden: a risk factor for renal vein thrombosis in renal transplantation.
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Child↗
Synthesis of a protected 3,4-dihydroxyproline from a pentose sugar.
[reaction: see text] D-Ribonolactone (6) was transformed into N-((fluorenylmethoxy)carbonyl)-3,4-bis-O-(tert-butyldimethylsilyl)-D-2,3-cis-3,4-cis-3,4-dihydroxyproline (13) in nine chemical steps. This represents a potentially general strategy for the synthesis of 3,4-dihydroxyprolines, utilizing the pentose sugar series as starting materials.
Aluminum Compounds↗
A comparison of the effects of verocytotoxin-1 on primary human renal cell cultures.
Infection with verocytotoxin-producing Escherichia coli causes haemolytic uraemic syndrome (HUS). Verocytotoxin-1 (VT1) is cytopathic to renal microvascular endothelial cells in culture, supporting the hypothesis that the vasculopathy of HUS is caused directly by the toxic action of VT1 on cells. We provide evidence that VT1 inhibits protein synthesis in primary cultures of glomerular epithelial cells (GE), cortical tubular epithelial cells (CTE) and mesangial cells (MC). Using 100 pg/ml of VT1 we saw a decrease in protein synthesis to 14.3+/-1.9% in vero cells (a primate cell line), 1.7+/-0.3% in GE, 0.9+/-0.4% in CTE and 74.8+/-1.3% in MC at 24 h. The human renal epithelial cells are at least as sensitive as vero cells to the protein synthesis inhibitory effects of VT1 if not more so. Cell viability decreased in all cultures as measured by MTT reduction, neutral red incorporation and lactate dehydrogenase release and followed the same pattern of susceptibility as for protein synthesis inhibition. However, unlike vero cells, death occurred without DNA fragmentation. Cell sensitivity was greatest in cells which bound more VT1.
Animals↗
Clinical characterization and linkage analysis of a family with congenital X-linked nystagmus and deuteranomaly.
OBJECTIVES: To identify a congenital nystagmus locus on the X chromosome and to characterize the phenotype of a 4-generation family affected with congenital nystagmus and color deficiency. METHODS: Sixty-five patients underwent an eye examination, including evaluation for the presence of nystagmus and color vision abnormalities. Affected patients and obligate carriers of the congenital nystagmus mutation were genotyped with short tandem repeat polymorphisms located on the X chromosome, and these data were subjected to linkage analysis. RESULTS: Fourteen patients were affected with a horizontal, conjugate, congenital nystagmus. All examined patients had a visual acuity of 20/60 or better. There were no associated ocular or systemic findings except that 18 of the family members had deficient red-green color vision, which was classified as deuteranomaly (the most common form of anomalous trichromacy). Five patients exhibited nystagmus and deuteranomaly. Significant linkage was demonstrated between the nystagmus phenotype and 11 markers from Xq. The maximum lod score was 4.84 (theta = 0) and was obtained with marker DXS8041. Analysis of recombinants defined the disease interval to lie between markers ATA59C05 and DXS1192 (a 5.4-centimorgan region). The proximity of this locus to the red-green opsin gene cluster (11 centimorgans more telomeric) explains the frequent coexistence of nystagmus and color vision deficiency in this family. CONCLUSIONS: We have identified the genetic locus of the X-linked congenital nystagmus gene in this family. The critical interval in this report is less than half the size of the previously described nystagmus locus. These findings will aid in identifying the gene responsible for this condition.
Chromosome Mapping↗
A laboratory model of toxin-induced hemolytic uremic syndrome.
BACKGROUND: Verocytotoxin-producing (Shiga-like toxin-producing) Escherichia coli infection is the principal cause of hemolytic uremic syndrome (HUS). The pathogenesis is unclear, and there is a need for animal models. These are impeded by the different distribution of verocytotoxin receptors between species. We have circumvented this restriction using ricin, which gains entry into cells via various galactose receptors. Like verocytotoxin, ricin specifically cleaves a single adenine from ribosomal RNA. METHODS: Rats were given ricin at a dose of 6.7 micrograms/100 g body wt, with or without lipopolysaccharide at 10 micrograms/100 g body wt. Lipopolysaccharide alone or saline were used as controls. Changes in glomerular filtration rate, hematological parameters, histology, and plasma cytokine concentrations were measured. RESULTS: Extensive glomerular thrombosis, pyknotic nuclei, and an infiltration of ED1-positive cells into glomeruli were observed eight hours after an injection of ricin. Other vascular beds were unaffected. Histologic changes were preceded by oliguric renal failure, hemolysis, and thrombocytopenia. Ricin produced a rise in plasma concentrations of monocyte chemotactic protein-1, > tumor necrosis factor-alpha, > interleukin-1 beta, > interleukin-6. Interferon-gamma showed a small increase at the end of the experiment. CONCLUSIONS: Ricin induces glomerular thrombotic microangiopathy, closely resembling that which occurs in verocytotoxin-producing E. coli-induced HUS. As in HUS, high concentrations of proinflammatory cytokines are present, which are probably a result of cytokine superinduction by the toxin.
Animals↗
Exclusion of AR-CHED from the chromosome 20 region containing the PPMD and AD-CHED loci.
Congenital hereditary endothelial dystrophy (CHED) is a disorder of the corneal endothelium and has been recognized to segregate in families with both autosomal dominant (AD) and autosomal recessive (AR) modes of transmission. AD-CHED has been previously linked to the pericentric region of chromosome 20. Posterior polymorphous dystrophy (PPMD), a corneal endothelial disorder showing phenotypic overlap with CHED, has also been previously genetically mapped to this region. The genetic interval containing AD-CHED is within the larger genetic interval containing the PPMD locus. This study sought to determine whether AR-CHED segregating in a consanguineous Saudi Arabian pedigree is linked to the previously mapped and overlapping loci for AD-CHED and PPMD on the pericentric region of chromosome 20. Forty members of a consanguineous Saudi Arabian pedigree segregating AR-CHED were ascertained. Short tandem-repeat polymorphic markers from the 20 cM interval on chromosome 20 containing both the PPMD and AD-CHED loci were used to genotype these individuals. LOD score analysis of the genotype data with the MENDEL software package utilizing a model of autosomal recessive inheritance with complete penetrance showed exclusion of CHED from the entire PPMD/AD-CHED interval by utilizing overlapping intervals of LOD scores of at least -2. The results obtained demonstrate that AR-CHED is not allelic to either AD-CHED or PPMD, although it has been proposed that AD-CHED may be allelic to PPMD. Thus, there are at least two genes responsible for CHED and PPMD.
Chromosome Mapping↗
No common final pathogenetic pathway in haemolytic uraemic syndromes.
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Adult↗
Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency.
BACKGROUND: In a recent study of three families we have found that inherited haemolytic uraemic syndrome (HUS) maps to a region of chromosome 1q containing the gene for complement factor H. In one of these families and also in a case of sporadic D-HUS, we have identified mutations in the factor H gene. A further family with inherited HUS has therefore been investigated. METHODS: DNA extracted from the family members and DNA extracted from archival post-mortem material from a deceased family member, was studied. Review of renal biopsies and study of complement components was also undertaken. RESULTS: This family demonstrates an inherited deficiency of complement factor H. Non-diarrhoeal HUS has affected at least two family members with half normal levels of factor H. CONCLUSION: These findings represent further evidence of the association between factor H dysfunction and HUS.
Adolescent↗