Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.

Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD

Determination of the Mechanical Properties of Hot Stamped Parts from Numerical Simulations

AbstractHot stamping is a well-established process in car manufacturing today. However, the resulting mechanical properties of a hot stamped part and its behaviour during a crash are still open questions. The usual procedure includes destructive experiments to determine the mechanical properties resulting from the forming and quenching process. The gained information is then used for crash simulation. Using images from micrographs to determine the proportion of bainite and martensite resulting from the hot stamping process has proved to be difficult, as these structures are fairly similar and hard to distinguish.Sophisticated numerical simulations of the hot stamping process are available. The hardness resulting from the hot stamping process can be predicted fairly well from these process simulations. However, information like the tensile strength that is more relevant for the crash behaviour cannot be predicted that easily. It is not yet state of the art to map the results from the hot stamping simulation directly into the crash simulation. The approach to be presented in detail in this contribution uses the forming speed and the quenching velocity to predict the relevant mechanical properties of the hot stamped parts. Both input parameters, the forming speed and the quenching velocity, can be derived from the numerical hot stamping simulation. By means of experiments using a thermomechanical test system Gleeble well defined process parameters were used. Micro tensile test specimens were manufactured out of the Gleeble specimens to eliminate the effect of the Gaussian temperature profile created during the Gleeble experiments. Afterwards, tensile tests were carried out to derive a response surface for 22MnB5. The validated results allow the determination of the tensile strength of hot stamped parts from the numerical simulation of the hot stamping process with good accuracy

Endovascular Intervention for Critical Lower Limb Ischemia; a Review of Outcomes after Percutaneous Transluminal Angioplasty using Balloon Catheter

Peripheral Arterial Disease (PAD) of lower limb with variable morbidity can be manifested as an asymptomatic, sever or life threatening disease. It is also a major cause of disability in many cases. The management of patients with PAD can be defined from a number of different treatment options in the terms of conservative-, interventional- and surgical therapies.Percutaneous Transluminal Angioplasty (PTA) using balloon catheter as a revascularization procedure has been used with acceptable outcomes. The method results are highlighted with comparable success—and patency rates, low complications, improving the quality of life and survival. We reviewed published studies and found that PTA is an appropriate alternative in the management of patient with Critical Limb Ischemia (CLI). Better outcomes have been achieved using Drug Coated Balloons (DCB) as well as Drug Eluting Stents (DES). Atherectomy remains with controversial results. Patient characteristics, the presence of associated risk factors, characteristics of lesions and accompanied cardiopulmonary disease may be the main challenges to use of these treatment options in the future

a pilot study

Background Parents caring for a child with Cystic Fibrosis (CF) are at high risk for psychological distress and have limited access to psychological care. Therefore, a web-based psychological support program for severely distressed parents of children with CF (WEP-CARE) was developed and evaluated for its feasibility and efficacy. Methods A clinical expert panel developed WEP-CARE based on principles of cognitive-behavioral therapy. This web-based writing therapy comprises nine sessions, tailored for the specific needs of caregivers. The pilot study was conducted as a single-group intervention with pre-post-follow-up design. Out of 31 participants, 23 parents completed the intervention (21 female; mean age 37 years; SD = 6.2 years, range 25 – 48 years). Psychological symptoms and quality of life were assessed online by self-report measures at pre- and post-treatment and were followed up three months later. Results On average, the caregivers’ symptoms of anxiety decreased statistically significant and clinical relevant about five points from an elevated (M = 11.4; SD =2.6) to a normal level (M = 6.7; SD = 2.6; p < .001) between pre and post treatment. Fear of disease progression (p < .001) and symptoms of depression (p = .02) significantly decreased as well. Quality of life significantly improved (p = .01). The effects were maintained at the 3-months follow-up assessment. Conclusions WEP-CARE is feasible and promising regarding its efficacy to improve parental mental health and quality of life

Active Cytomegalovirus Infection in Patients with Septic Shock

Cytomegalovirus reactivation occurred in one third of patients and was associated with prolonged ventilation and stay in an intensive care unit

An RNA-sequencing transcriptome of the rodent Schwann cell response to peripheral nerve injury.

BACKGROUND The important contribution of glia to mechanisms of injury and repair of the nervous system is increasingly recognized. In stark contrast to the central nervous system (CNS), the peripheral nervous system (PNS) has a remarkable capacity for regeneration after injury. Schwann cells are recognized as key contributors to PNS regeneration, but the molecular underpinnings of the Schwann cell response to injury and how they interact with the inflammatory response remain incompletely understood. METHODS We completed bulk RNA-sequencing of Schwann cells purified acutely using immunopanning from the naïve and injured rodent sciatic nerve at 3, 5, and 7 days post-injury. We used qRT-PCR and in situ hybridization to assess cell purity and probe dataset integrity. Finally, we used bioinformatic analysis to probe Schwann cell-specific injury-induced modulation of cellular pathways. RESULTS Our data confirm Schwann cell purity and validate RNAseq dataset integrity. Bioinformatic analysis identifies discrete modules of genes that follow distinct patterns of regulation in the 1st days after injury and their corresponding molecular pathways. These findings enable improved differentiation of myeloid and glial components of neuroinflammation after peripheral nerve injury and highlight novel molecular aspects of the Schwann cell injury response such as acute downregulation of the AGE/RAGE pathway and of secreted molecules Sparcl1 and Sema5a. CONCLUSIONS We provide a helpful resource for further deciphering the Schwann cell injury response and a depth of transcriptional data that can complement the findings of recent single cell sequencing approaches. As more data become available on the response of CNS glia to injury, we anticipate that this dataset will provide a valuable platform for understanding key differences in the PNS and CNS glial responses to injury and for designing approaches to ameliorate CNS regeneration

Piloted Simulation of the Rotorcraft Wind Turbine Wake Interaction during Hover and Transit Flights

Helicopters are used for offshore wind farms for maintenance and support flights. The number of helicopter operations is increasing with the expansion of offshore wind energy, which stresses the point that the current German regulations have not yet been validated through scientific analysis. A collaborative research project between DLR, the Technical University of Munich, the University of Stuttgart and the University of T&uuml;bingen has been conducted to examine the sizes of the flight corridors on offshore wind farms and the lateral safety clearance for helicopter hoist operations at offshore wind turbines. This paper details the results of piloted helicopter simulations in a realistic offshore wind farm scenario. The far-wake of rotating wind turbines and the near-wake of non-rotating wind turbines have been simulated with high-fidelity computational fluid dynamics under realistic turbulent inflow conditions. The resulting flow fields have been processed by superposition during piloted simulations in the research flight simulator AVES to examine the flight corridors in transit flights and the lateral safety clearance in hovering flights. The results suggest a sufficient size for the flight corridor and sufficient lateral safety clearance at the offshore wind turbines in the considered scenarios

Implicit complexity for coinductive data: a characterization of corecurrence

We propose a framework for reasoning about programs that manipulate coinductive data as well as inductive data. Our approach is based on using equational programs, which support a seamless combination of computation and reasoning, and using productivity (fairness) as the fundamental assertion, rather than bi-simulation. The latter is expressible in terms of the former. As an application to this framework, we give an implicit characterization of corecurrence: a function is definable using corecurrence iff its productivity is provable using coinduction for formulas in which data-predicates do not occur negatively. This is an analog, albeit in weaker form, of a characterization of recurrence (i.e. primitive recursion) in [Leivant, Unipolar induction, TCS 318, 2004].Comment: In Proceedings DICE 2011, arXiv:1201.034

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway–modulating therapeutics