Untersuchung von nierentransplantierten Patienten unter Berücksichtigung der HLA-Kompatibilität und der Dynamik der HLA-Antikörperbildung

In dieser Arbeit wurde die Überlebenszeit von Nierentransplantaten untersucht und deren Abhängigkeit von zwei Faktoren: der HLA-Kompatibilität und der Antikörperdynamik. Hierzu konnten Daten von 327 Patienten gesammelt werden, die zwischen 1991 und 1996 eine postmortale Spenderniere erhielten. Eine konventionelle Gewebetypisierung erfolgte mittels serologischer und molekularbiologischer Untersuchungen. Eine neue Matchingmethode wurde durchgeführt auf Ebene von Aminosäuren. Ein Antikörperscreening erfolgte vor und nach Transplantation mittels Lymphozytotoxtest und ELISA. Zur statistischen Bewertung benutzten wir die Kaplan-Meier-Methode zur Berechnung der Überlebenszeit und eine Cox Regression zur Berechnung des relativen Risikos. Bezüglich der Gewebeübereinstimmung konnten wir beim konventionellen Matching eine Tendenz feststellen, daß Patienten mit einer guten Übereinstimmung eine längere Transplantatüberlebenszeit zeigten, als Patienten mit einer schlechten Übereinstimmung. Beim Matching auf Aminosäureebene konnten keine Unterschiede in der Transplantatfunktion nachgewiesen werden. Bei Betrachtung des Antikörperverhaltens der Empfänger konnten wir signifikante Unterschiede nachweisen dahingehend, daß Nierentransplantierte mit einer Antikörperbildung eine schlechtere Transplantatüberlebenszeit besaßen als Patienten ohne Antikörpernachweis. Außerdem konnte gezeigt werden, daß Patienten mit vielen Transfusionen vor Transplantation eine signifikant kürzere Transplantatüberlebenszeit zeigten, als Patienten mit wenigen Transfusionen. Anhand unserer Ergebnisse empfehlen wir ein konventionelles Matching als Grundlage der Nierentransplantation. Ein Matching auf Ebene von Aminosäuren könnte zukünftig das konventionelle Match ergänzen oder ablösen. Außerdem empfehlen wir ein generelles Antikörperscreening der Empfänger vor und nach Transplantation, da Aussagen möglich werden zum Verlauf nach Transplantation und die immunsuppressive Therapie angepaßt werden kann.In this study we examined the survival of kidney transplants and the influence of two factors: the hla-compatibility and the dynamics of antibodies. For this we collected full data of 327 Patients, who were transplanted with a postmortal kidney transplant between the years 1991-1996. A conventional tissue typing was done with serological and molecular biological tests. A new matching method was done at the level of amino acids. A screening for antibodies was done before and after transplantation using lymphocytotoxtest and ELISA. For statistical valuation we used the Kaplan-Meier-method for the calculation of the transplant survival time and a cox regression for the calculation of the relative risk. Regarding the tissue similarities at the conventional match we saw the trend of a longer transplant survival time at patients with a good match compared to patients with more missmatches. At matching at amino acid-level we couldn´t show any differences in the transplant survival time. By observing the dynamics of antibodies of the receiver we could show a significant difference: kidney transplant receivers developing antibodies show a shorter transplant survival time than patients, who didn´t develop antibodies. Additionally we could show that patients with many transfusions before transplantation have a significantly worser transplant function than patients with less transfusions. Resulting from our examinations we recommend a conventional matching as a basic for kidney transplantation. In future a matching at amino acid-level could supplement or replace the conventional match. Additionally we recommend an antibodyscreening of the transplant receivers before and after transplantation. A prediction for the posttransplant course will be possible and an individual adjustment of the immunsuppressive therapy

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III

Contains fulltext : 153818.pdf (publisher's version ) (Open Access)A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy

Multifractal Scaling in Sinai Diffusion

We consider the mean first passage time of random walks to go from one end of a segment of a Sinai lattice to the other. We show that the distribution of the mean first passage time over Sinai disorder obeys a finite-size-multiscaling form

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

International audienc

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo