Determinants of Kidney Failure in Primary Hyperoxaluria Type 1:Findings of the European Hyperoxaluria Consortium

INTRODUCTION: Primary hyperoxaluria type 1 (PH1) has a highly heterogeneous disease course. Apart from the c.508G&gt;A (p.Gly170Arg) AGXT variant, which imparts a relatively favorable outcome, little is known about determinants of kidney failure. Identifying these is crucial for disease management, especially in this era of new therapies. METHODS: In this retrospective study of 932 patients with PH1 included in the OxalEurope registry, we analyzed genotype-phenotype correlations as well as the impact of nephrocalcinosis, urolithiasis, and urinary oxalate and glycolate excretion on the development of kidney failure, using survival and mixed model analyses.RESULTS: The risk of developing kidney failure was the highest for 175 vitamin-B6 unresponsive ("null") homozygotes and lowest for 155 patients with c.508G&gt;A and c.454T&gt;A (p.Phe152Ile) variants, with a median age of onset of kidney failure of 7.8 and 31.8 years, respectively. Fifty patients with c.731T&gt;C (p.Ile244Thr) homozygote variants had better kidney survival than null homozygotes ( P = 0.003). Poor outcomes were found in patients with other potentially vitamin B6-responsive variants. Nephrocalcinosis increased the risk of kidney failure significantly (hazard ratio [HR] 3.17 [2.03-4.94], P &lt; 0.001). Urinary oxalate and glycolate measurements were available in 620 and 579 twenty-four-hour urine collections from 117 and 87 patients, respectively. Urinary oxalate excretion, unlike glycolate, was higher in patients who subsequently developed kidney failure ( P = 0.034). However, the 41% intraindividual variation of urinary oxalate resulted in wide confidence intervals. CONCLUSION: In conclusion, homozygosity for AGXT null variants and nephrocalcinosis were the strongest determinants for kidney failure in PH1. </p

The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort

Background: We aimed to expand the number of currently known pathogenic PNKP mutations, to study the phenotypic spectrum, including radiological characteristics and genotype-phenotype correlations, and to assess whether immunodeficiency and increased cancer risk are part of the DNA repair disorder caused by mutations in the PNKP gene. Methods: We evaluated nine patients with PNKP mutations. A neurological history and examination was obtained. All patients had undergone neuroimaging and genetic testing as part of the prior diagnostic process. Laboratory measurements included potential biomarkers, and, in the context of a DNA repair disorder, we performed a detailed immunologic evaluation, including B cell repertoire analysis. Results: We identified three new mutations in the PNKP gene and confirm the phenotypic spectrum of PNKP-associated disease, ranging from microcephaly, seizures, and developmental delay to ataxia with oculomotor apraxia type 4. Irrespective of the phenotype, alpha-fetoprotein is a biochemical marker and increases with age and progression of the disease. On neuroimaging, (progressive) cerebellar atrophy was a universal feature. No clinical signs of immunodeficiency were present, and immunologic assessment was unremarkable. One patient developed cancer, but this was attributed to a concurrent von HippelLindau mutation. Conclusions: Immunodeficiency and cancer predisposition do not appear to be part of PNKP-associated disease, contrasting many other DNA repair disorders. Furthermore, our study illustrates that the previously described syndromes microcephaly, seizures, and developmental delay, and ataxia with oculomotor apraxia type 4, represent the extremes of an overlapping spectrum of disease. Cerebellar atrophy and elevated serum alpha-fetoprotein levels are early diagnostic findings across the entire phenotypical spectrum

Selective microbial electrosynthesis of methane by a pure culture of a marine lithoautotrophic archaeon

Highlights • A lithoautotrophic archaeon selectively produces methane at − 0.4 V vs. SHE. • Methane production by strain IM1 proceeds with a coulomb efficiency of 80%. • CO2 reduction by strain IM1 features a low overpotential of only − 0.16 V vs. SHE. • Below − 0.4 V vs. SHE selectivity changes and H2 is evolved in a second pathway. • Strain IM 1 shows great promise for bioelectrical conversion of renewable energy

Selective microbial electrosynthesis of methane by a pure culture of a marine lithoautotrophic archaeon

Reduction of carbon dioxide to methane by microorganisms attached to electrodes is a promising process in terms of renewable energy storage strategies. However the efficient and specific electrosynthesis of methane by methanogenic archaea on cathodes needs fundamental investigations of the electron transfer mechanisms at the microbe–electrode interface without the addition of artificial electron mediators. Using well-defined electrochemical techniques directly coupled to gas chromatography and surface analysis by scanning electron microscopy, it is shown that a pure culture of the marine lithoautotrophic Methanobacterium-like archaeon strain IM1 is capable to utilize electrons from graphite cathodes for a highly selective production of methane, without hydrogen serving as a cathode-generated electron carrier. Microbial electrosynthesis of methane with cultures of strain IM1 is achieved at a set potential of − 0.4 V vs. SHE and is characterized by a coulomb efficiency of 80%, with rates reaching 350 nmol d− 1 cm− 2 after 23 days of incubation. Moreover, potential step measurements reveal a biologically catalyzed hydrogen production at potentials more positive than abiotic hydrogen evolution on graphite, indicating that an excessive supply of electrons to strain IM1 results in proton reduction rather than in a further increase of methane production

Monitoring of anaerobic microbially influenced corrosion via electrochemical frequency modulation

Electrochemical frequency modulation (EFM) is a rather novel technique to monitor corrosion rates in situ, providing direct access to Tafel slopes with only minor polarization. So far EFM has been applied mainly for electrochemical corrosion monitoring in purely chemical corrosion systems with predominant uniform corrosion, but it has also great potential for monitoring microbially influenced corrosion (MIC). Thus, in this study MIC induced by different cultures of sulfate-reducing bacteria (SRB) was monitored with EFM, and compared to results from linear polarization resistance (LPR) and measurements of the free corrosion potential E-corr. The electrochemical results obtained in small scale bioreactors with a three electrode setup were complemented by chemical analysis and SEM observations. SRB featuring high corrosion rates were compared to non-corrosive but still H-2-consuming control SRB, sterile controls and abiotic sulfide corrosion controls. Corrosion rates determined with EFM and LPR were accurate and precise in all cases as long as the system was based on uniform corrosion. However with the onset of localized corrosion both methods fail to predict accurate rates. Unlike other electrochemical corrosion rate measurements, EFM has the advantage to provide indicating ratios in the current response at different frequencies, so-called causality factors, which allow identifying changes in the corrosion system and therefore assessing the accurateness of the obtained results. As a consequence EFM is a promising electrochemical corrosion monitoring technique for MIC in fundamental and applied studies. (c) 2013 Elsevier Ltd. All rights reserved

Monitoring of anaerobic microbially influenced corrosion via electrochemical frequency modulation

Electrochemical frequency modulation (EFM) is a rather novel technique to monitor corrosion rates in situ, providing direct access to Tafel slopes with only minor polarization. So far EFM has been applied mainly for electrochemical corrosion monitoring in purely chemical corrosion systems with predominant uniform corrosion, but it has also great potential for monitoring microbially influenced corrosion (MIC). Thus, in this study MIC induced by different cultures of sulfate-reducing bacteria (SRB) was monitored with EFM, and compared to results from linear polarization resistance (LPR) and measurements of the free corrosion potential E-corr. The electrochemical results obtained in small scale bioreactors with a three electrode setup were complemented by chemical analysis and SEM observations. SRB featuring high corrosion rates were compared to non-corrosive but still H-2-consuming control SRB, sterile controls and abiotic sulfide corrosion controls. Corrosion rates determined with EFM and LPR were accurate and precise in all cases as long as the system was based on uniform corrosion. However with the onset of localized corrosion both methods fail to predict accurate rates. Unlike other electrochemical corrosion rate measurements, EFM has the advantage to provide indicating ratios in the current response at different frequencies, so-called causality factors, which allow identifying changes in the corrosion system and therefore assessing the accurateness of the obtained results. As a consequence EFM is a promising electrochemical corrosion monitoring technique for MIC in fundamental and applied studies. (c) 2013 Elsevier Ltd. All rights reserved