Late-onset Bartter syndrome type II

Mutations in the ROMK1 potassium channel gene (KCNJ1) cause antenatal/neonatal Bartter syndrome type II (aBS II), a renal disorder that begins in utero, accounting for the polyhydramnios and premature delivery that is typical in affected infants, who develop massive renal salt wasting, hypokalaemic metabolic alkalosis, secondary hyperreninaemic hyperaldosteronism, hypercalciuria and nephrocalcinosis. This BS type is believed to represent a disorder of the infancy, but not in adulthood. We herein describe a female patient with a remarkably late-onset and mild clinical manifestation of BS II with compound heterozygous KCNJ1 missense mutations, consisting of a novel c.197T > A (p.I66N) and a previously reported c.875G > A (p.R292Q) KCNJ1 mutation. We implemented and evaluated the performance of two different bioinformatics-based approaches of targeted massively parallel sequencing [next generation sequencing (NGS)] in defining the molecular diagnosis. Our results demonstrate that aBS II may be suspected in patients with a late-onset phenotype. Our experimental approach of NGS-based mutation screening combined with Sanger sequencing proved to be a reliable molecular approach for defining the clinical diagnosis in our patient, and results in important differential diagnostic and therapeutic implications for patients with BS. Our results could have a significant impact on the diagnosis and methodological approaches of genetic testing in other patients with clinical unclassified phenotypes of nephrocalcinosis and congenital renal electrolyte abnormalities

Conceptual Variability Management in Software Families with Multiple Contributors

To offer customisable software, there are two main concepts yet: software product lines that allow the product customisation based on a fixed set of variability and software ecosystems, allowing an open product customisation based on a common platform. Offering a software family that enables external developers to supply software artefacts means to offer a common platform as part of an ecosystem and to sacrifice variability control. Keeping full variability control means to offer a customisable product as a product line, but without the support for external contributors. This thesis proposes a third concept of variable software: partly open software families. They combine a customisable platform similar to product lines with controlled openness similar to ecosystems. As a major contribution of this thesis a variability modelling concept is proposed which is part of a variability management for these partly open software families. This modelling concept is based on feature models and extends them to support open variability modelling by means of interfaces, structural interface specifications and the inclusion of semantic information. Additionally, the introduction of a rights management allows multiple contributors to work with the model. This is required to enable external developers to use the model for the concrete extension development. The feasibility of the proposed model is evaluated using a prototypically developed modelling tool and by means of a case study based on a car infotainment system

Pathophysiological Role of Caveolae in Hypertension

Caveolae, flask-shaped cholesterol-, and glycosphingolipid-rich membrane microdomains, contain caveolin 1, 2, 3 and several structural proteins, in particular Cavin 1-4, EHD2, pacsin2, and dynamin 2. Caveolae participate in several physiological processes like lipid uptake, mechanosensitivity, or signaling events and are involved in pathophysiological changes in the cardiovascular system. They serve as a specific membrane platform for a diverse set of signaling molecules like endothelial nitric oxide synthase (eNOS), and further maintain vascular homeostasis. Lack of caveolins causes the complete loss of caveolae; induces vascular disorders, endothelial dysfunction, and impaired myogenic tone; and alters numerous cellular processes, which all contribute to an increased risk for hypertension. This brief review describes our current knowledge on caveolae in vasculature, with special focus on their pathophysiological role in hypertension

Role of Ryanodine Receptor Subtypes in Initiation and Formation of Calcium Sparks in Arterial Smooth Muscle: Comparison with Striated Muscle

Calcium sparks represent local, rapid, and transient calcium release events from a cluster of ryanodine receptors (RyRs) in the sarcoplasmic reticulum. In arterial smooth muscle cells (SMCs), calcium sparks activate calcium-dependent potassium channels causing decrease in the global intracellular [Ca2+] and oppose vasoconstriction. This is in contrast to cardiac and skeletal muscle, where spatial and temporal summation of calcium sparks leads to global increases in intracellular [Ca2+] and myocyte contraction. We summarize the present data on local RyR calcium signaling in arterial SMCs in comparison to striated muscle and muscle-specific differences in coupling between L-type calcium channels and RyRs. Accordingly, arterial SMC Cav1.2 L-type channels regulate intracellular calcium stores content, which in turn modulates calcium efflux though RyRs. Downregulation of RyR2 up to a certain degree is compensated by increased SR calcium content to normalize calcium sparks. This indirect coupling between Cav1.2 and RyR in arterial SMCs is opposite to striated muscle, where triggering of calcium sparks is controlled by rapid and direct cross-talk between Cav1.1/Cav1.2 L-type channels and RyRs. We discuss the role of RyR isoforms in initiation and formation of calcium sparks in SMCs and their possible molecular binding partners and regulators, which differ compared to striated muscle

The case: chronic kidney disease unmasked by single-subject research

We present a 42-year-old man with a BMI of 32, who was referred because of proteinuria and decreased renal function. We were impressed by his markedly muscular physique. A renal biopsy was performed, which showed focal segmental glomerular sclerosis (FSGS). Is this patient merely an obese person with FSGS or is something else going on here? We performed extensive clinical and laboratory examinations, genetic testing, and anthropometric data monitoring over time. We transferred our methodology for routine FSGS mutation screening (Sanger sequencing) to the Ion Torrent PGM platform with a new custom-targeted NGS gene panel (Ion Ampliseq FSGS panel) and tested the performance of the system in two cohorts of patients with FSGS. We discuss FSGS in bodybuilders, including possible mechanisms, and review the literature

Effects of hemodialysis on plasma oxylipins

Chronic kidney disease (CKD) is an important risk factor for cardiovascular and all-cause mortality. Survival rates among end-stage renal disease (ESRD) hemodialysis patients are poor and most deaths are related to cardiovascular disease. Oxylipins constitute a family of oxygenated natural products, formed from fatty acid by pathways involving at least one step of dioxygen-dependent oxidation. They are derived from polyunsaturated fatty acids (PUFAs) by cyclooxygenase (COX) enzymes, by lipoxygenases (LOX) enzymes, or by cytochrome P450 epoxygenase. Oxylipins have physiological significance and some could be of regulatory importance. The effects of decreased renal function and dialysis treatment on oxylipin metabolism are unknown. We studied 15 healthy persons and 15 CKD patients undergoing regular hemodialysis treatments and measured oxylipins (HPLC-MS lipidomics) derived from cytochrome P450 (CYP) monooxygenase and lipoxygenase (LOX)/CYP omega/(omega-1)-hydroxylase pathways in circulating blood. We found that all four subclasses of CYP epoxy metabolites were increased after the dialysis treatment. Rather than resulting from altered soluble epoxide hydrolase (sEH) activity, the oxylipins were released and accumulated in the circulation. Furthermore, hemodialysis did not change the majority of LOX/CYP omega/(omega-1)-hydroxylase metabolites. Our data support the idea that oxylipin profiles discriminate ESRD patients from normal controls and are influenced by renal replacement therapies

Electrostatic actuators for misalignment compensation in multi-layered microsystem devices

AbstractElectrostatic actuation is a promising approach to compensate for misalignment of bonded, multi-layered microsystem devices. The present work discusses the performance of electrostatic actuators used for in-plane misalignment compensation in an atom chip comprising an optical cavity. Experimental investigation revealed that the central frame suspending the mirrors can be moved between 3-5 m in the in-plane direction for the applied DC voltage of 90 volts. Future work involves characterizing the mirror displacement for optical tuning function

A three-dimensional electrostatic actuator with a locking mechanism for a new generation of atom chips

A micromachined three-dimensional electrostatic actuator that is optimized for aligning and tuning optical microcavities on atom chips is presented. The design of the 3D actuator is outlined in detail, and its characteristics are verified by analytical calculations and finite element modelling. Furthermore, the fabrication process of the actuation device is described and preliminary fabrication results are shown. The actuation in the chip plane which is used for mirror positioning has a working envelope of 17.5 ?m. The design incorporates a unique locking mechanism which allows the out-of-plane actuation that is used for cavity tuning to be carried out once the in-plane actuation is completed. A maximum translation of 7 ?m can be achieved in the out-of-plane direction

The effect of self-affine fractal roughness of wires on atom chips

Atom chips use current flowing in lithographically patterned wires to produce microscopic magnetic traps for atoms. The density distribution of a trapped cold atom cloud reveals disorder in the trapping potential, which results from meandering current flow in the wire. Roughness in the edges of the wire is usually the main cause of this behaviour. Here, we point out that the edges of microfabricated wires normally exhibit self-affine roughness. We investigate the consequences of this for disorder in atom traps. In particular, we consider how closely the trap can approach the wire when there is a maximum allowable strength of the disorder. We comment on the role of roughness in future atom--surface interaction experiments.Comment: 7 pages, 7 figure