TNFα Induces Choroid Plexus Epithelial Cell Barrier Alterations by Apoptotic and Nonapoptotic Mechanisms

The choroid plexus epithelium constitutes the structural basis of the blood-cerebrospinal fluid barrier. Since the cytokine TNFα is markedly increased during inflammatory diseases in the blood and the central nervous system, we investigated by which mechanisms TNFα induces barrier alteration in porcine choroid plexus epithelial cells. We found a dose-dependent decrease of transepithelial electrical resistance, increase of paracellular inulin-flux, and induction of histone-associated DNA fragmentation and caspase-3 activation after TNFα stimulation. This response was strongly aggravated by the addition of cycloheximide and could partially be inhibited by the NF-κB inhibitor CAPE, but most effectively by the pan-caspase-inhibitor zVAD-fmk and not by the JNK inhibitor SP600125. Partial loss of cell viability could also be attenuated by CAPE. Immunostaining showed cell condensation and nuclear binding of high-mobility group box 1 protein as a sign of apoptosis after TNFα stimulation. Taken together our findings indicate that TNFα compromises PCPEC barrier function by caspase and NF-κB dependent mechanisms

ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations; however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESCs), including a knockout and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-sequencing analyses in Zscan10−/− mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10

Information sources influencing urban Mexican-American women\u27s cancer screening participation

Breast and cervical cancer, though less common in Mexican-American than in Anglo women, are more likely to go undetected in Mexican-American women, leaving them more vulnerable to advanced disease and death. Although highly effective screening tests--the Pap smear and the mammogram--can detect these cancers early, many Mexican-American women do not regularly undergo these preventive screening tests. To explore the differential influence of encouraging sources of health information, this investigation examined the relationship between encouragement from a peer --husband or partner, child or children, other family members, or close friends--and a health professional --a doctor, a nurse, or another health professional--on Mexican-American women\u27s cancer screening intentions and behaviors. Furthermore, this research explored whether the sources\u27 influence on cancer screening intentions and behaviors differed depending on level of acculturation. One thousand seven hundred eleven surveys of Mexican-American women were analyzed to identify the source that most effectively encourages these women to participate in cancer screening. The data provided evidence that health professionals strongly influenced this population\u27s cancer screening intentions and behaviors. Evidence for peer influence was also found; however, it was usually weaker, and, in some cases, negligible. Peer encouragement was related to Pap test behaviors and mammogram intentions, but not to Pap test intentions or mammogram behaviors. Consistently, women reported greater intentions and screening behaviors when encouraged from a health professional than from a peer. Acculturation was not found to be a modifying variable related to the relationship between sources of information and Pap test or mammogram intentions and behaviors. Because health professionals were identified as strongly influencing both intentions and behaviors for Pap tests and mammograms, further efforts should be undertaken to urge them to encourage their clients to obtain cancer screening. Failure to provide this encouragement leads to missed opportunities. Enlisting support from peers also may help to increase cancer screening participation in urban Mexican-American women; however, the consistently greater intentions and behaviors related to a health professional\u27s encouragement indicated the greater power of the latter

Erklärungs- und Veränderungsmodelle 1: Einstellungs- und Verhaltensänderung

Finne E, Gohres H, Seibt AC. Erklärungs- und Veränderungsmodelle 1: Einstellungs- und Verhaltensänderung. In: Bundeszentrale für gesundheitliche Aufklärung (BZgA), ed. Leitbegriffe der Gesundheitsförderung und Prävention. Glossar zu Konzepten, Strategien und Methoden. Köln: BZgA; 2021

Erklärungs- und Veränderungsmodelle 3: Persuasion, Diffusion, Marketing und Medienanwaltschaft

Reifegerste D, Franzkowiak P, Seibt AC. Erklärungs- und Veränderungsmodelle 3: Persuasion, Diffusion, Marketing und Medienanwaltschaft. In: Bundeszentrale für gesundheitliche Aufklärung (BZgA), ed. Leitbegriffe der Gesundheitsförderung und Prävention. Glossar zu Konzepten, Strategien und Methoden. Köln: BZgA; 2021.In diesem Leitbegriff werden vier Modelle vorgestellt, die vorrangig für die kommunikative Umsetzung von Interventionen und Kampagnen von Bedeutung sind. Sie entstammen der Psychologie, der Soziologie, der Werbeforschung sowie der Kommunikationswissenschaft und Betriebswirtschaft. Im Gegensatz zu den Erklärungs- und Veränderungsmodellen I und II sind die hier vorgestellten Modelle weniger individuumsbezogen und berücksichtigen stärker das soziale Umfeld und die strukturellen Rahmenbedingungen der Zielgruppen. Ausgehend von den zentralen Einflussfaktoren und den Mechanismen, werden Konsequenzen für die Gesundheitsprogramme formuliert

Erklärungs- und Veränderungsmodelle 2: Theoriebasierte Interventionsplanung

Gohres H, Finne E, Seibt AC. Erklärungs- und Veränderungsmodelle 2: Theoriebasierte Interventionsplanung. In: Bundeszentrale für gesundheitliche Aufklärung (BZgA), ed. Leitbegriffe der Gesundheitsförderung und Prävention. Glossar zu Konzepten, Strategien und Methoden. Köln: BZgA; 2021