Risk-specific search for risk-defusing operators

According to the concept of “active risk-defusing behavior”, decision makers in risky situations look for additional actions that reduce risk and allow them to favor the more risky alternative. Our study demonstrates that risk-defusing behavior depends on the type of risk (normal, medium, catastrophic or global) as well as on the domain (health, economy or ecology). In total, 12 scenarios (four risk types from three risk domains each) were constructed. Using the interview techniques of active information search and thinking-aloud, 120 interviews about decision-making processes with these scenarios were conducted. They showed that the active search for different risk-defusing operators depends on the type of risk, but even more on the domain of the scenario. Results suggest a need for further research about a typology of risk situations in which, besides formal classification criteria, content issues are also explored

Animal models of cystic fibrosis

AbstractAnimal models of cystic fibrosis, in particular several different mutant mouse strains obtained by homologous recombination, have contributed considerably to our understanding of CF pathology. In this review, we describe and compare the main phenotypic features of these models. Recent and possible future developments in this field are discussed

Demografie

Die mit dem Begriff "demografischer Wandel" bezeichneten Entwicklungsprozesse in Bevölkerungszahl und Bevölkerungsstruktur werden Deutschland nachhaltig und weitreichend verändern. Deutschland wird schrumpfen, altern und aufgrund des zunehmenden Anteils der Bevölkerungsgruppen mit Migrationshintergrund "bunter" werden. Im Zentrum dieser Studie steht die Alterung unserer Gesellschaft. Die Studie gibt einen Überblick über die vergangene und zu erwartende demografische Entwicklung in Deutschland insgesamt und bettet diese in den internationalen Kontext ein. Weiterhin werden ausgewählte Aspekte der Bevölkerungsalterung aufgegriffen. Dabei werden die mit dieser Alterung einhergehenden Veränderungen und Auswirkungen auf drei verschiedenen Ebenen betrachtet: der individuellen Ebene, der Generationenebene sowie der gesellschaftlichen Ebene. Daneben stehen Branchentrends einer alternden Gesellschaft im Fokus der Studie. Er werden Chancen und Anlagemöglichkeiten aufgezeigt, um am demografischen Wandel teilzuhaben. Interessante Branchen dabei sind vor allem der Gesundheitsmarkt, Teile der Freizeitwirtschaft sowie die Medizintechnik und der Pflegebereich. Dabei gibt es im Bereich der Pflegeimmobilien diverse Anlagemöglichkeiten. Die absehbar längere Lebensarbeitszeit erfordert von jedem Einzelnen, sein Humankapital zu erhalten und durch gezielte Maßnahmen möglichst zu erhöhen. Dienstleister im Bereich der Aus- und Weiterbildung werden davon profitieren

Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

Objective: We aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.Methods: Whole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.Results: Brain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.Conclusions: We conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations

Rescue of Murine F508del CFTR Activity in Native Intestine by Low Temperature and Proteasome Inhibitors

Most patients with Cystic Fibrosis (CF) carry at least one allele with the F508del mutation, resulting in a CFTR chloride channel protein with a processing, gating and stability defect, but with substantial residual activity when correctly sorted to the apical membranes of epithelial cells. New therapies are therefore aimed at improving the folding and trafficking of F508del CFTR, (CFTR correctors) or at enhancing the open probability of the CFTR chloride channel (CFTR potentiators). Preventing premature breakdown of F508del CFTR is an alternative or additional strategy, which is investigated in this study. We established an ex vivo assay for murine F508del CFTR rescue in native intestinal epithelium that can be used as a pre-clinical test for candidate therapeutics. Overnight incubation of muscle stripped ileum in modified William's E medium at low temperature (26°C), and 4 h or 6 h incubation at 37°C with different proteasome inhibitors (PI: ALLN, MG-132, epoxomicin, PS341/bortezomib) resulted in fifty to hundred percent respectively of the wild type CFTR mediated chloride secretion (forskolin induced short-circuit current). The functional rescue was accompanied by enhanced expression of the murine F508del CFTR protein at the apical surface of intestinal crypts and a gain in the amount of complex-glycosylated CFTR (band C) up to 20% of WT levels. Sustained rescue in the presence of brefeldin A shows the involvement of a post-Golgi compartment in murine F508del CFTR degradation, as was shown earlier for its human counterpart. Our data show that proteasome inhibitors are promising candidate compounds for improving rescue of human F508del CFTR function, in combination with available correctors and potentiators

Spontaneous rescue from cystic fibrosis in a mouse model

BACKGROUND: From the original Cftr(TgH(neoim)Hgu )mutant mouse model with a divergent genetic background (129P2, C57BL/6, MF1) we have generated two inbred Cftr(TgH(neoim)Hgu )mutant strains named CF/1-Cftr(TgH(neoim)Hgu )and CF/3-Cftr(TgH(neoim)Hgu), which are fertile and show normal growth and lifespan. Initial genome wide scan analysis with microsatellite markers indicated that the two inbred strains differed on the genetic level. In order to further investigate whether these genetic differences have an impact on the disease phenotype of cystic fibrosis we characterised the phenotype of the two inbred strains. RESULTS: Reduced amounts, compared to wild type control animals, of correctly spliced Cftr mRNA were detected in the nasal epithelia, lungs and the intestine of both inbred Cftr(TgH(neoim)Hgu )strains, with higher residual amount observed for CF/1-Cftr(TgH(neoim)Hgu )than CF/3-Cftr(TgH(neoim)Hgu )for every investigated tissue. Accordingly the amounts of wild type Cftr protein in the intestine were 9% for CF/1-Cftr(TgH(neoim)Hgu )and 4% for CF/3-Cftr(TgH(neoim)Hgu). Unlike the apparent strain and/or tissue specific regulation of Cftr mRNA splicing, short circuit current measurements in the respiratory and intestinal epithelium revealed that both strains have ameliorated the basic defect of cystic fibrosis with a presentation of a normal electrophysiology in both tissues. CONCLUSION: Unlike the outbred Cftr(TgH(neoim)Hgu )insertional mouse model, which displayed the electrophysiological defect in the gastrointestinal and respiratory tracts characteristic of cystic fibrosis, both inbred Cftr(TgH(neoim)Hgu )strains have ameliorated the electrophysiological defect. On the basis of these findings both CF/1-Cftr(TgH(neoim)Hgu )and CF/3-Cftr(TgH(neoim)Hgu )offer an excellent model whereby determination of the minimal levels of protein required for the restoration of the basic defect of cystic fibrosis can be studied, along with the modulating factors which may affect this outcome

Very mild disease phenotype of congenic CftrTgH(neoim)Hgu cystic fibrosis mice

Background: A major boost to cystic fibrosis disease research was given by the generation of various mouse models using gene targeting in embryonal stem cells. Moreover, the introduction of the same mutation on different inbred strains generating congenic strains facilitated the search for modifier genes. From the original CftrTgH(neoim)Hgumouse model with a divergent genetic background (129/Sv, C57BL/6, HsdOla:MF1) two inbred mutant mouse strains CF/1-CftrTgH(neoim)Hguand CF/3-CftrTgH(neoim)Hguhad been generated using strict brother × sister mating. CF/1-CftrTgH(neoim)Hguand CF/3-CftrTgH(neoim)Hgumice were fertile and showed normal growth and lifespan. In this work the CftrTgH(neoim)Hguinsertional mutation was backcrossed from CF/3-CftrTgH(neoim)Hguonto the inbred backgrounds C57BL/6J and DBA/2J generating congenic animals in order to clarify the differential impact of the Cftr mutation and the genetic background on the disease phenotype of the cystic fibrosis mutant mice. Clinical and electrophysiological features of the two congenic strains were compared with those of CF/1-CftrTgH(neoim)Hguand CF/3-CftrTgH(neoim)Hguand wild type controls. Results: Under the standardized housing conditions of the animal facility, the four mouse strains CF/1-CftrTgH(neoim)Hgu, CF/3-CftrTgH(neoim)Hgu, D2.129P2(CF/3)-CftrTgH(neoim)Hguand B6.129P2(CF/3)-CftrTgH(neoim)Hguexhibited normal life expectancy. Growth of congenic cystic fibrosis mice was comparable with that of wild type controls. All mice but D2.129P2(CF/3)-CftrTgH(neoim)Hgufemales were fertile. Short circuit current measurements revealed characteristic response profiles of the HsdOla:MF1, DBA/2J and C57BL/6J backgrounds in nose, ileum and colon. All cystic fibrosis mouse lines showed the disease-typical hyperresponsiveness to amiloride in the respiratory epithelium. The mean chloride secretory responses to carbachol or forskolin were 15-100% of those of the cognate wild type control animals. Conclusion: The amelioration of the clinical features and of the basic defect that had emerged during the generation of CF/3-CftrTgH(neoim)Hgumice was retained in the congenic mice indicating that the Cftr linkage group or other loci shared between the inbred strains contain(s) the major modifier(s) of attenuation of cystic fibrosis symptoms

The Hematopoietic System–specific Minor Histocompatibility Antigen HA-1 Shows Aberrant Expression in Epithelial Cancer Cells

Allogeneic stem cell transplantation (SCT) can induce curative graft-versus-tumor reactions in patients with hematological malignancies and solid tumors. The graft-versus-tumor reaction after human histocompatibility leukocyte antigen (HLA)-identical SCT is mediated by alloimmune donor T cells specific for polymorphic minor histocompatibility antigens (mHags). Among these, the mHag HA-1 was found to be restricted to the hematopoietic system. Here, we report on the HA-1 ribonucleic acid expression by microdissected carcinoma tissues and by single disseminated tumor cells isolated from patients with various epithelial tumors. The HA-1 peptide is molecularly defined, as it forms an immunogenic peptide ligand with HLA-A2 on the cell membrane of carcinoma cell lines. HA-1–specific cytotoxic T cells lyse epithelial tumor cell lines in vitro, whereas normal epithelial cells are not recognized. Thus, HA-1–specific immunotherapy combined with HLA-identical allogeneic SCT may now be feasible for patients with HA-1+ carcinomas

Expert consensus on the contraindications and cautions of foam rolling: an international delphi study

Background: Foam rolling is a type of self-massage using tools such as foam or roller sticks. However, to date, there is no consensus on contraindications and cautions of foam rolling. A methodological approach to narrow that research gap is to obtain reliable opinions of expert groups. The aim of the study was to develop experts’ consensus on contraindications and cautions of foam rolling by means of a Delphi process. Methods: An international three-round Delphi study was conducted. Academic experts, defined as having (co-) authored at least one PubMed-listed paper on foam rolling, were invited to participate. Rounds 1 and 2 involved generation and rating of a list of possible contraindications and cautions of foam rolling. In round 3, participants indicated their agreement on contraindications and cautions for a final set of conditions. Consensus was evaluated using a priori defined criteria. Consensus on contraindications and cautions was considered as reached if more than 70% of participating experts labeled the respective item as contraindication and contraindication or caution, respectively, in round 3. Results: In the final Delphi process round, responses were received from 37 participants. Panel participants were predominantly sports scientists ( n = 21), physiotherapists ( n = 6), and medical professionals ( n = 5). Consensus on contraindications was reached for open wounds (73% agreement) and bone fractures (84%). Consensus on cautions was achieved for local tissue inflammation (97%), deep vein thrombosis (97%), osteomyelitis (94%), and myositis ossificans (92%). The highest impact/severity of an adverse event caused by contraindication/cautions was estimated for bone fractures, deep vein thrombosis, and osteomyelitis. Discussion: The mechanical forces applied through foam rolling can be considered as potential threats leading to adverse events in the context of the identified contraindications and cautions. Further evaluations by medical professionals as well as the collection of clinical data are needed to assess the risks of foam rolling and to generate guidance for different applications and professional backgrounds