Timing of Parathyroidectomy Does Not Influence Renal Function After Kidney Transplantation

Background Parathyroidectomy (PTx) is the treatment of choice for end-stage renal disease (ESRD) patients with therapy-resistant hyperparathyroidism (HPT). The optimal timing of PTx for ESRD-related HPT—before or after kidney transplantation (KTx)—is subject of debate. Methods Patients with ESRD-related HPT who underwent both PTx and KTx between 1994 and 2015 were included in a multicenter retrospective study in four university hospitals. Two groups were formed according to treatment sequence: PTx before KTx (PTxKTx) and PTx after KTx (KTxPTx). Primary endpoint was renal function (eGFR, CKD-EPI) between both groups at several time points post-transplantation. Correlation between the timing of PTx and KTx and the course of eGFR was assessed using generalized estimating equations (GEE). Results The PTxKTx group consisted of 102 (55.1%) and the KTxPTx group of 83 (44.9%) patients. Recipient age, donor type, PTx type, and pre-KTx PTH levels were significantly different between groups. At 5 years after transplantation, eGFR was similar in the PTxKTx group (eGFR 44.5 ± 4.0 ml/min/1.73 m2 ) and KTxPTx group (40.0 ± 6.4 ml/min/1.73 m2 , p = 0.43). The unadjusted GEE model showed that timing of PTx was not correlated with graft function over time (mean difference -1.0 ml/min/1.73 m2 , 95% confidence interval -8.4 to 6.4, p = 0.79). Adjustment for potential confounders including recipient age and sex, various donor characteristics, PTx type, and PTH levels did not materially influence the results. Conclusions In this multicenter cohort study, timing of PTx before or after KTx does not independently impact graft function over time

Mineralogical and geochemical analysis of Fe-phases in drill-cores from the Triassic Stuttgart Formation at Ketzin CO₂ storage site before CO₂ arrival

Reactive iron (Fe) oxides and sheet silicate-bound Fe in reservoir rocks may affect the subsurface storage of CO2 through several processes by changing the capacity to buffer the acidification by CO2 and the permeability of the reservoir rock: (1) the reduction of three-valent Fe in anoxic environments can lead to an increase in pH, (2) under sulphidic conditions, Fe may drive sulphur cycling and lead to the formation of pyrite, and (3) the leaching of Fe from sheet silicates may affect silicate diagenesis. In order to evaluate the importance of Fe-reduction on the CO2 reservoir, we analysed the Fe geochemistry in drill-cores from the Triassic Stuttgart Formation (Schilfsandstein) recovered from the monitoring well at the CO2 test injection site near Ketzin, Germany. The reservoir rock is a porous, poorly to moderately cohesive fluvial sandstone containing up to 2–4 wt% reactive Fe. Based on a sequential extraction, most Fe falls into the dithionite-extractable Fe-fraction and Fe bound to sheet silicates, whereby some Fe in the dithionite-extractable Fe-fraction may have been leached from illite and smectite. Illite and smectite were detected in core samples by X-ray diffraction and confirmed as the main Fe-containing mineral phases by X-ray absorption spectroscopy. Chlorite is also present, but likely does not contribute much to the high amount of Fe in the silicate-bound fraction. The organic carbon content of the reservoir rock is extremely low (<0.3 wt%), thus likely limiting microbial Fe-reduction or sulphate reduction despite relatively high concentrations of reactive Fe-mineral phases in the reservoir rock and sulphate in the reservoir fluid. Both processes could, however, be fuelled by organic matter that is mobilized by the flow of supercritical CO2 or introduced with the drilling fluid. Over long time periods, a potential way of liberating additional reactive Fe could occur through weathering of silicates due to acidification by CO2

The design, construction, and commissioning of the KATRIN experiment

The KArlsruhe TRItium Neutrino (KATRIN) experiment, which aims to make a direct and model-independent determination of the absolute neutrino mass scale, is a complex experiment with many components. More than 15 years ago, we published a technical design report (TDR) [1] to describe the hardware design and requirements to achieve our sensitivity goal of 0.2 eV at 90% C.L. on the neutrino mass. Since then there has been considerable progress, culminating in the publication of first neutrino mass results with the entire beamline operating [2]. In this paper, we document the current state of all completed beamline components (as of the first neutrino mass measurement campaign), demonstrate our ability to reliably and stably control them over long times, and present details on their respective commissioning campaigns

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Activated PI3K Delta Syndrome-1 mutations cause neutrophilia in zebrafish larvae

People with Activated PI3 Kinase Delta Syndrome 1 (APDS1) suffer from immune deficiency and severe bronchiectasis. APDS1 is caused by dominant activating mutations of the PIK3CD gene that encodes the PI3 kinase delta (PI3Kδ) catalytic subunit. Despite the importance of innate immunity defects in bronchiectasis, there has been limited investigation of neutrophils or macrophages in APDS1 patients or mouse models. Zebrafish embryos provide an ideal system to study neutrophils and macrophages. Previous studies of zebrafish with strongly hyperactivated PI3 kinase activity due to Pten deficiency, revealed excessive production of immature neutrophils that fail to mature. We used CRISPR-Cas9 and CRISPR-Cpf1, with oligo-nucleotide directed homologous repair, to engineer zebrafish equivalents of the two most prevalent human APDS1 disease mutations. These zebrafish pik3cd alleles dominantly cause excessive neutrophilic inflammation in a tail-fin injury model. They also exhibit total body neutrophilia in the absence of any inflammatory stimulus but have normal numbers of macrophages. Exposure to the PI3Kδ inhibitor CAL-101 reverses the total body neutrophilia. There is no apparent defect in neutrophil maturation or migration and tail-fin regeneration is unimpaired

Résultats cliniques et angiographiques immédiats et à moyen terme après l'implantation de microprothèses endocoronaires AVE chez 140 patients consécutifs. Expérience lausannoise [Immediate and mid-term clinical and angiographic results after implantation of AVE intracoronary micro-stents in 140 consecutive cases. An experience in Lausanne].

Two hundred AVE (Arterial Vascular Engineering) microstents measuring 4 to 30 mm were implanted in 140 patients aged 62 +/- 10 years with Class II to IV angina of the Canadian Cardiovascular Society Classification. The indications were: de novo lesions (30%), suboptimal angioplasty results (54%), acute occlusion (8%) or restenosis (8%). The stents of 3.0 to 4.0 mm diameter were implanted in the left main coronary artery (1%) the left anterior descending artery (20%), the left circumflex artery (19%), the right coronary artery (44%) or a venous bypass graft (7%) after intravenous injection of 15,000 IU of heparin. Daily treatment with aspirin 100 mg and ticlopidine 500 mg was instituted from the day of the procedure. The success rate was 98.5% with only 3 technical failures. The minimal luminal diameter and percentage stenosis ranged from 0.80 +/- 0.2 mm and 74 +/- 13% before to 2.66 +/- 0.38 mm and 15 +/- 7% after the procedure in vessels with an average reference diameter of 3.05 +/- 0.35 mm. There were 3% of stent-related immediate clinical complications. In February 1996, 97 patients had survived 6 months. With a 97% follow-up rate, the clinical event rate was 18%. The angiographic follow-up rate was 70% and the restenosis rate was 27%. The authors conclude that the AVE microstents are easy to implant and provide excellent immediate angiographic results with a low complication rate

Intracoronary Stenting for Restenosis: Long-Term Follow-up: A Single Center Experience.

One-hundred thirteen stents (78 Wallstents, 29 Palmaz-Schatz and 6 Wiktor) were implanted in 106 patients aged 63 +/- 5 years to treat a restenosis following previous angioplasty in a native coronary artery (86 cases) and in a venous graft (20 cases). Implantation was technically possible in all cases. The native vessels had a mean reference diameter of 3.3 +/- 0.3 mm and their mean minimal lumen diameter increased from 1.2 +/- 0.3 mm before angioplasty to 2.8 +/- 0.8 after stent implantation. The venous grafts mean reference diameter was 4.4 +/- 0.7 mm and their mean minimal lumen diameter increased from 1.3 +/- 0.4 mm before angioplasty to 4.0 +/- 0.7 mm after implantation. Percentage stenosis in the native arteries and in the venous grafts were respectively 78 +/- 13% and 69 +/- 14% before angioplasty and 24 +/- 8% and 22 +/- 8% after stent implantation. Complications at 6 months, presented as a ranking scale with 100% follow-up rate were, overall, of 20% clinical events (4% deaths, 6% myocardial infractions, 2% coronary artery bypass grafting and 8% re-angioplasty). Angiographic complications were of 8% subacute thrombosis and 19% restenosis and chronic occlusions. Long-term, at 65 +/- 9 months, clinical (86% follow-up) and angiographic (74% follow-up) showed that only a further 9% clinical events and 14% restenosis (12% of them between 6 and 12 months) occurred after 6 months. At an estimated follow-up time of 104 months, 70% patients remain event-free and the survival rate is 95%. In conclusion, stent implantation in the treatment of restenosis following conventional balloon angioplasty is a valid strategy with good long-term results