The structure of galactic disks: Studying late-type spiral galaxies using SDSS

Using imaging data from the SDSS survey, we present the g' and r' radial stellar light distribution of a complete sample of ~90 face-on to intermediate inclined, nearby, late-type (Sb-Sdm) spiral galaxies. The surface brightness profiles are reliable (1sigma uncertainty less than 0.2 mag) down to mu=~27magsqarcsec. Only ~10% of all galaxies have a normal/standard purely exponential disk down to our noise limit. The surface brightness distribution of the rest of the galaxies is better described as a broken exponential. About 60% of the galaxies have a break in the exponential profile between ~1.5-4.5 times the scalelength followed by a downbending, steeper outer region. Another ~30% shows also a clear break between ~4.0-6.0 times the scalelength but followed by an upbending, shallower outer region. A few galaxies have even a more complex surface brightness distribution. The shape of the profiles correlates with Hubble type. Downbending breaks are more frequent in later Hubble types while the fraction of upbending breaks rises towards earlier types. No clear relation is found between the environment, as characterised by the number of neighbours, and the shape of the profiles of the galaxies.Comment: LaTeX, 69 pages, 213 (very low resolution) figures, A&A accepted. Second version to match the accepted one including all referee's comments. Version with full resolution figures (highly recommended, but with 7.6MB) available at http://www.astro.rug.nl/~pohlen/pohlenSDSS.pd

Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS)

Background. Recessive mutations in the NPHS1 gene encoding nephrin account for ∼40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons. Methods. We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS. Results. We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (∼51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin. Conclusions. Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatmen

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.ope

Prevention of pruritus with ethyl-chloride in skin prick test: a double-blind placebo-controlled prospective study

BACKGROUND: Ethyl-chloride (EC) spray was recently shown to be an effective antipruritic agent, when given 15 min after histamine skin-prick test (SPT), without changing the wheal and flare reaction. We aimed to investigate the antipruritic effect of EC on SPT, when given prior to SPT. METHODS: A double-blind placebo-controlled prospective study. Overall, 44 volunteers underwent histamine SPT on both arms to trigger local pruritus. Prior to test, they were randomly treated with EC spray on one arm and saline spray (placebo) on the other. Subjects as well as researchers were blinded to the type of applied sprays. The wheal and flare reaction was measured after the SPT and subjects reported the intensity of pruritus following EC/placebo using a validated pruritus questionnaire (indexes 1–3) and a visual analog scale (VAS). RESULTS: Significant improvement in pruritus was reported following treatment with EC compared with placebo for all four studied parameters. Index 1 in EC 3.7 ± 2.3 versus 5 ± 3.5 (p = 0.007) in placebo, index 2 in EC 2.6 ± 2.1 versus 3.8 ± 2.8 (p = 0.002) in placebo, index 3 of EC 6.3 ± 3.8 versus 8.8 ± 5.8 (p = 0.03) and VAS in EC 3.7 ± 1.9 versus 4.4 ± 2.3 (p = 0.003). There were no significant differences between EC and placebo in terms of the wheal and flare indurations area. CONCLUSIONS: Ethyl-chloride has an effective antipruritic agent, when given before histamine SPT. Its use did not change the wheal and flare reaction, making it ideal for prevention of pruritus, secondary to allergy skin test, without masking the results

When the chimney is blocked: malignant renovascular hypertension after endovascular repair of abdominal aortic aneurysm

Abstract Background The Chimney graft (CG) procedure is one of the novel modification techniques of the endovascular aneurysm repair (EVAR) surgery to treat suprarenal and juxtarenal abdominal aortic aneurysms. Other indications for the use of CG placement include thoracic and thoracoabdominal aneurysms with supraortic branches orifice involvement and cases of common iliac artery aneurysms with or without internal iliac artery involvement. The technique is used in patients who due to aortic-neck morphology and lack of adequate fixation and/or sealing zones are not eligible for standard EVAR. In this procedure, a parallel stent-graft is placed adjacent to the main body of the aortic endograft to maintain blood supply to renovisceral or supraortic branches, once the body of the aortic stent-graft is deployed. Symptomatic occlusions of the CG with novel renovascular hypertension were not described until now. Case presentation A-64-year-old male patient, presented with new-onset malignant hypertension, 13 months after an EVAR operation with CG placement to the left renal artery. The patient was on preventive clopidrogel therapy, which was withheld temporarily for several days, one month before presentation. Imaging studies revealed a novel form of iatrogenic renovascular hypertension, caused by occlusion of the CG. Any attempt to recanalize the covered stent or revascularize the left kidney was rejected and conservative treatment was chosen. Seven months after presentation, blood pressure was within normal ranges with little need for antihypertensive therapy. Conclusions Physicians should be aware that the novel emerging techniques of EVAR to overcome the limitations of the aortic-neck anatomy may still adversely influence the renal outcome with potential development of new-onset hypertension. </jats:sec

Comparative 3D analyses and palaeoecology of giant early amphibians (Temnospondyli: Stereospondyli)

Macroevolutionary, palaeoecological and biomechanical analyses in deep time offer the possibility to decipher the structural constraints, ecomorphological patterns and evolutionary history of extinct groups. Here, 3D comparative biomechanical analyses of the extinct giant early amphibian group of stereospondyls together with living lissamphibians and crocodiles, shows that: i) stereospondyls had peculiar palaeoecological niches with proper bites and stress patterns very different than those of giant salamanders and crocodiles; ii) their extinction may be correlated with the appearance of neosuchians, which display morphofunctional innovations. Stereospondyls weathered the end-Permian mass extinction, re-radiated, acquired gigantic sizes and dominated (semi) aquatic ecosystems during the Triassic. Because these ecosystems are today occupied by crocodilians, and stereospondyls are extinct amphibians, their palaeobiology is a matter of an intensive debate: stereospondyls were a priori compared with putative living analogous such as giant salamanders and/or crocodilians and our new results try to close this debate.Peer ReviewedPostprint (published version

Translating the efficacy of dapagliflozin in chronic kidney disease to lower healthcare resource utilization and costs: a medical care cost offset analysis

AIMS: Dapagliflozin was approved for use in patients with chronic kidney disease (CKD) based on results of the DAPA-CKD trial, demonstrating attenuation of CKD progression and reduced risk of cardio-renal outcomes and all-cause mortality (ACM) versus placebo, in addition to standard therapy. The study objective was to assess the potential medical care cost offsets associated with reduced rates of cardio-renal outcomes across 31 countries and regions. MATERIALS AND METHODS: A comparative cost-determination framework estimated outcome-related costs of dapagliflozin plus standard therapy versus standard therapy alone over a 3-year horizon based on the DAPA-CKD trial. Incidence rates of end-stage kidney disease (ESKD), hospitalizations for heart failure (HHF), acute kidney injury (AKI), and ACM were estimated for a treated population of 100,000 patients. Associated medical care costs for non-fatal events were calculated using sources from a review of publicly available data specific to each considered setting. RESULTS: Patients treated with dapagliflozin plus standard therapy experienced fewer incidents of ESKD (7,221 vs 10,767; number needed to treat, NNT: 28), HHF (2,370 vs 4,684; NNT: 43), AKI (4,110 vs. 5,819; NNT: 58), and ACM (6,383 vs 8,874; NNT: 40) per 100,000 treated patients versus those treated with standard therapy alone. Across 31 countries/regions, reductions in clinical events were associated with a 33% reduction in total costs, or a cumulative mean medical care cost offset of $264 million per 100,000 patients over 3 years. LIMITATIONS AND CONCLUSIONS: This analysis is limited by the quality of country/region-specific data available for medical care event costs. Based on the DAPA-CKD trial, we show that treatment with dapagliflozin may prevent cardio-renal event incidence at the population level, which could have positive effects upon healthcare service delivery worldwide. The analysis was restricted to outcome-associated costs and did not consider the cost of drug treatments and disease management

A systematic approach to mapping recessive disease genes in individuals from outbred populations

The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049