Elucidating the nature of the proton radioactivity and branching ratio on the first proton emitter discovered 53mCo.

The observation of a weak proton-emission branch in the decay of the 3174-keV 53mCo isomeric state marked the discovery of proton radioactivity in atomic nuclei in 1970. Here we show, based on the partial half-lives and the decay energies of the possible proton-emission branches, that the exceptionally high angular momentum barriers, [Formula: see text] and [Formula: see text], play a key role in hindering the proton radioactivity from 53mCo, making them very challenging to observe and calculate. Indeed, experiments had to wait decades for significant advances in accelerator facilities and multi-faceted state-of-the-art decay stations to gain full access to all observables. Combining data taken with the TASISpec decay station at the Accelerator Laboratory of the University of Jyväskylä, Finland, and the ACTAR TPC device on LISE3 at GANIL, France, we measured their branching ratios as bp1 = 1.3(1)% and bp2 = 0.025(4)%. These results were compared to cutting-edge shell-model and barrier penetration calculations. This description reproduces the order of magnitude of the branching ratios and partial half-lives, despite their very small spectroscopic factors.

A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'.

End-stage renal disease (ESRD) presenting in a familial autosomal dominant pattern points to an underlying monogenic cause. Nail-patella syndrome (NPS) is an autosomal dominant disorder that may lead to ESRD caused by mutations in the transcription factor LMX1B. Renal-limited forms of this disease, termed nail-patella-like renal disease (NPLRD), and LMX1B nephropathy have recently been described. We report a large family, from the North East of England, with seven affected members with varying phenotypes of renal disease, ranging from ESRD at 28 years of age to microscopic haematuria and proteinuria and relatively preserved renal function. In this family, there were no extra-renal manifestations to suggest NPS. Genome-wide linkage studies and inheritance by descent (IBD) suggested disease loci on Chromosome 1 and 9. Whole exome sequencing (WES) analysis identified a novel sequence variant (p.R249Q) in the LMX1B gene in each of the three samples submitted, which was confirmed using Sanger sequencing. The variant segregated with the disease in all affected individuals. In silico modelling revealed that R249 is putatively located in close proximity to the DNA phosphoskeleton, supporting a role for this residue in the interaction between the LMX1B homeodomain and its target DNA. WES and analysis of potential target genes, including CD2AP, NPHS2, COL4A3, COL4A4 and COL4A5, did not reveal any co-inherited pathogenic variants. In conclusion, we confirm a novel LMX1B mutation in a large family with an autosomal dominant pattern of nephropathy. This report confirms that LMX1B mutations may cause a glomerulopathy without extra-renal manifestations. A molecular genetic diagnosis of LMX1B nephropathy thus provides a definitive diagnosis, prevents the need for renal biopsies and allows at risk family members to be screened.

Determining the population frequency of the CFHR3/CFHR1 deletion at 1q32.

In this study we have used multiplex ligation-dependent probe amplification (MLPA) to measure the copy number of CFHR3 and CFHR1 in DNA samples from 238 individuals from the UK and 439 individuals from the HGDP-CEPH Human Genome Diversity Cell Line Panel. We have then calculated the allele frequency and frequency of homozygosity for the copy number polymorphism represented by the CFHR3/CFHR1 deletion. There was a highly significant difference between geographical locations in both the allele frequency (X(2)  = 127.7, DF = 11, P-value = 4.97x10(-22)) and frequency of homozygosity (X(2)  = 142.3, DF = 22, P-value = 1.33x10(-19)). The highest frequency for the deleted allele (54.7%) was seen in DNA samples from Nigeria and the lowest (0%) in samples from South America and Japan. The observed frequencies in conjunction with the known association of the deletion with AMD, SLE and IgA nephropathy is in keeping with differences in the prevalence of these diseases in African and European Americans. This emphasises the importance of identifying copy number polymorphism in disease.

Factor H autoantibodies in membranoproliferative glomerulonephritis.

Factor H autoantibodies are found in ~10% of aHUS patients. Most are associated with complete deficiency of factor H related proteins 1/3 and bind to the C terminal recognition domain. MPGN, like aHUS, is characterised by complement activation. In this study we, therefore, examined the hypothesis that factor H autoantibodies are associated with MPGN. We screened sera from 16 MPGN patients and 100 normal controls using ELISA and detected strongly positive IgG factor H autoantibodies in 2 patients. One patient had type II (DDD) MPGN (male aged 24 yrs) with C3NeF and the other type I (female aged 26 yrs) with no detectable C3NeF. We identified the binding site of the autoantibodies using small SCR domain fragments in the ELISA and showed that the autoantibodies in both patients bound predominately to the N terminal complement regulatory domain of factor H. We measured CFHR 1/3 copy number using MLPA and showed that both patients had 2 copies of CFHR1 and 3. Finally, we examined the functionality of detected factor H autoantibodies using purified patient IgG and observed increased haemolysis when purified IgG from both patients was added to normal human sera prior to incubation with rabbit red blood cells. Thus, in a cohort of MPGN patients we have found a high titre of functionally significant factor H autoantibodies in two patients with MPGN. Antibody depleting therapy may have a role in such patients and we suggest that screening for factor H autoantibodies should be undertaken in all patients with MPGN.

Factor I autoantibodies in patients with atypical hemolytic uremic syndrome: disease-associated or an epiphenomenon?

BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome is a disease associated with mutations in the genes encoding the complement regulators factors H and I. In addition, factor H autoantibodies have been reported in ∼10% of patients with atypical hemolytic uremic syndrome. This study searched for the presence of factor I autoantibodies in atypical hemolytic uremic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study screened 175 atypical hemolytic uremic syndrome patients for factor I autoantibodies using ELISA with confirmatory Western blotting. Functional studies using purified immunoglobulin from one patient were subsequently undertaken. RESULTS: Factor I autoantibodies were detected in three patients. In one patient with a high titer of autoantibody, the titer was tracked over time and was found to have no association with disease activity. This study found evidence of an immune complex of antibody and factor I in this patient, but purified IgG, isolated from current serum samples, had only a minor effect on fluid phase and cell surface complement regulation. Genetic analysis of the three patients with factor I autoantibodies revealed that they had two copies of the genes encoding factor H-related proteins 1 and 3 and therefore, did not have a deletion commonly associated with factor H autoantibodies in atypical hemolytic uremic syndrome. Two patients, however, had functionally significant mutations in complement factor H. CONCLUSIONS: These findings reinforce the concept of multiple concurrent risk factors being associated with atypical hemolytic uremic syndrome but question whether autoantibodies per se predispose to atypical hemolytic uremic syndrome.

Complement factor h autoantibodies and age-related macular degeneration.

PURPOSE: In this case-control study, the hypothesis that factor H autoantibodies are associated with age-related macular degeneration (AMD) was examined. METHODS: One hundred AMD patients (median age, 78 years), 98 age-matched control subjects (median age, 78 years) known not to have AMD, and 100 healthy blood donors (median age, 43 years) were enrolled. An enzyme-linked immunosorbent assay (ELISA) was used to screen for complement factor H autoantibodies and either quantitative polymerase chain reaction (qPCR) or multiplex ligation-dependent probe amplification (MLPA) were performed to measure the copy number of the gene encoding complement factor H-related protein 3 (CFHR3). RESULTS: There was a significant difference in the median complement factor H autoantibody titer between the three groups (AMD patients, 196 reference units [RU]]; age-match control subjects, 316 RU; and blood donor control subjects, 121 RU; Kruskal-Wallis test, P < 0.001). Pair-wise comparison (Mann-Whitney test) showed that all three groups were significantly different from each other. Two different thresholds were used in the healthy blood donors to identify individuals with complement factor H autoantibodies. Both suggested that the prevalence of factor H autoantibodies was decreased in AMD patients. The CFHR3 copy number was measured as a surrogate for the deletion of the genes encoding complement factor H-related proteins 3 and 1 (CFHR3/1). The allele frequency of the deletion was significantly higher in the age-matched control subjects than in the AMD patients (22.2% vs. 8.2%). CONCLUSIONS: The level of factor H autoantibodies is lower in AMD patients than in age-matched control subjects.

Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome.

Factor H autoantibodies have been reported in approximately 10% of patients with atypical hemolytic uremic syndrome (aHUS) and are associated with deficiency of factor H-related proteins 1 and 3. In this study we examined the prevalence of factor H autoantibodies in the Newcastle cohort of aHUS patients, determined whether the presence of such autoantibodies is always associated with deficiency of factor H-related proteins 1 and 3, and examined whether such patients have additional susceptibility factors and/or mutations in the genes encoding complement regulator/activators. We screened 142 patients with aHUS and found factor H autoantibodies in 13 individuals (age 1-11 years). The presence of the autoantibodies was confirmed by Western blotting. By using multiplex ligation-dependent probe amplification we measured complement factor H-related (CFHR)1 and CFHR3 copy number. In 10 of the 13 patients there were 0 copies of CFHR1, and in 3 patients there were 2. In 3 of the patients with 0 copies of CFHR1 there was 1 copy of CFHR3, and these individuals exhibited a novel deletion incorporating CFHR1 and CFHR4. In 5 patients mutations were identified: 1 in CFH, 1 in CFI, 1 in CD46, and 2 in C3. The latter observation emphasizes that multiple concurrent factors may be necessary in individual patients for disease manifestation.

A microbiological survey of bicarbonate-based replacement circuits in continuous veno-venous hemofiltration.

OBJECTIVE: The potential for clinically significant transfer of pyrogen-inducing material in dialysate and substitution fluids is well recognized in the setting of chronic hemodialysis and hemodiafiltration and has led to the establishment of strict standards for microbiological purity. Preliminary evidence has indicated the potential for fluid contamination in continuous renal replacement therapy, and although the scale of the problem in contemporary, industry-standard equipment is unclear. We aimed to define the microbial integrity of modern continuous veno-venous hemofiltration (CVVH) replacement fluid circuitry. DESIGN: Twenty-four CVVH replacement fluid circuits (mean lifespan, 34.2 hours; range, 4-86) were studied at completion of therapy. SETTING: The integrated critical care unit and cardiothoracic intensive care unit of the Freeman Hospital, Newcastle upon Tyne, United Kingdom, between January and August 2007. SUBJECTS: Patients with renal failure receiving treatment with CVVH. INTERVENTIONS: Nil. MEASUREMENTS: Culture and endotoxin assays of replacement fluid, culture of endoluminal swabs, and electron microscopy of harvested tubing. MAIN RESULTS: Of the 24 replacement fluid cultures, nine (mean lifespan 32.8 hours, range 5-79) breached European Pharmacopoeia standards for ultrapure water (<0.1 colony-forming units/mL). One of 24 endotoxin measurements breached European Pharmacopoeia standards (<0.03 endotoxin units/mL). Internal tubing cultures were negative, but electron microscopy revealed 13 of the 24 collected tubing samples to be contaminated with biofilm. Only seven of the 24 studied circuits proved to be free from microbial contamination. CONCLUSIONS: We have confirmed frequent breaches of microbial integrity in industry-standard, bicarbonate-based CVVH, indicating the potential for added risk to the vulnerable, critically ill patient. These findings are of particular concern given the need for systemic infusion of replacement fluid. Measures to reduce the levels of contamination and their impact are discussed.

Pantoprazole-induced acute interstitial nephritis.

Pantoprazole is a proton-pump inhibitor (PPI) that is commonly prescribed for the treatment of gastroesophageal reflux-related disorders. There are many documented side effects of PPIs. Here we report a case of acute interstitial nephritis, which developed after 6 weeks of treatment with pantoprazole. A 23-year-old man presented with acute renal failure requiring renal replacement therapy. Acute interstitial nephritis was diagnosed by renal biopsy and was successfully treated with corticosteroids and withdrawal of pantoprazole. Drug-induced acute interstitial nephritis can occur with PPIs such as pantoprazole and vigilance needs to be maintained.