The Dkk1 dose is critical for eye development

During mammalian ocular development, several signaling pathways control the spatiotemporal highly defined realization of the three-dimensional eye architecture. Given the complexity of these inductive signals, the developing eye is a sensitive organ for several diseases. In this study, we investigated a Dkk1+/- haploinsufficiency during eye development, resulting in coloboma and anterior eye defects, two common developmental eye disorders. Dkk1 impacts eye development from a defined developmental time point on, and is critical for lens separation from the surface ectoderm via beta-catenin mediated Pdgfr alpha and E-cadherin expression. Dkk1 does not impact the dorso ventral retina patterning in general but is critical for Shh dependent Pax2 extension into the midline region. The described results also indicate that the retinal Dkk1 dose is critical for important steps during eye development, such as optic fissure closure and cornea formation. Further analysis of the relationship between Dkk1 and Shh signaling revealed that Dkk1 and Shh coordinatively control anterior head formation and eye induction. During eye development itself, retinal Dkk1 activation is depending on cilia mediated Gli3 regulation. Therefore, our data essentially improve the knowledge of coloboma and anterior eye defects, which are common human eye developmental defects. (C) 2011 Elsevier Inc. All rights reserved

Meta-analysis of randomized controlled comparisons of psychopharmacological and psychological treatments for anxiety disorders

Background. A number of meta-analyses have led to contradictory results regarding the efficacy of the psychological and pharmacological treatment of anxiety disorders. The main reasons for these inconsistent results seem to be the inclusion of heterogeneous studies and influences of selection biases. We performed a meta-analysis, which only included studies using a direct comparison of pharmacological, psychological, or combined treatments. Method. Sixteen studies on panic disorder, six studies on social anxiety disorder, and two studies on generalized anxiety disorder have been analyzed. Effect sizes for differences between the different treatment modalities were calculated. Also, the effect sizes of the pre-post differences were calculated. Results. Pharmacological treatment, cognitive-behavioural treatment, and the combination of both treatment modalities all led to substantial improvement between pre- and post-treatment. Combined pharmacological and psychological treatment was superior to the monotherapies for panic disorder. For social anxiety disorder, there is only preliminary support for combined treatment. Due to lack of sufficient data, no final conclusions can be drawn for generalized anxiety disorder. Conclusions. While drug treatment and CBT showed equal efficacy, only in panic disorder the combination of pharmacological and psychological treatment was superior to either treatment alone. For the other anxiety disorders, the evidence for greater efficacy of combination treatment is still not sufficient due to lack of studies

Impact of eNOS-Dependent Oxidative Stress on Endothelial Function and Neointima Formation

Aims: Vascular oxidative stress generated by endothelial NO synthase (eNOS) was observed in experimental and clinical cardiovascular disease, but its relative importance for vascular pathologies is unclear. We investigated the impact of eNOS-dependent vascular oxidative stress on endothelial function and on neointimal hyperplasia. Results: A dimer-destabilized mutant of bovine eNOS where cysteine 101 was replaced by alanine was cloned and introduced into an eNOS-deficient mouse strain (eNOS-KO) in an endothelial-specific manner. Destabilization of mutant eNOS in cells and eNOS-KO was confirmed by the reduced dimer/monomer ratio. Purified mutant eNOS and transfected cells generated less citrulline and NO, respectively, while superoxide generation was enhanced. In eNOS-KO, introduction of mutant eNOS caused a 2.3–3.7-fold increase in superoxide and peroxynitrite formation in the aorta and myocardium. This was completely blunted by an NOS inhibitor. Nevertheless, expression of mutant eNOS in eNOS-KO completely restored maximal aortic endothelium-dependent relaxation to acetylcholine. Neointimal hyperplasia induced by carotid binding was much larger in eNOS-KO than in mutant eNOS-KO and C57BL/6, while the latter strains showed comparable hyperplasia. Likewise, vascular remodeling was blunted in eNOS-KO only. Innovation: Our results provide the first in vivo evidence that eNOS-dependent oxidative stress is unlikely to be an initial cause of impaired endothelium-dependent vasodilation and/or a pathologic factor promoting intimal hyperplasia. These findings highlight the importance of other sources of vascular oxidative stress in cardiovascular disease. Conclusion: eNOS-dependent oxidative stress is unlikely to induce functional vascular damage as long as concomitant generation of NO is preserved. This underlines the importance of current and new therapeutic strategies in improving endothelial NO generation. Antioxid. Redox Signal. 23, 711–723

S3 Guideline Smoking and Tobacco Dependence: Screening, Diagnosis, and Treatment - Short Version

Introduction: In addition to the prevention of tobacco consumption, the establishment and assurance of high-quality treatment for harmful use and dependence on tobacco products remains an important health-related task in Germany. Regular updating of the Association of the Scientific Medical Societies (AWMF) S3 guideline Smoking and Tobacco Dependence: Screening, Diagnosis, and Treatment (Tobacco Guideline) offers a sustainable and reputable source of knowledge on smoking cessation. Methods: Under the auspices of the German Society for Psychiatry, Psychotherapy, Psychosomatics, and Neurology (DGPPN) and the German Society for Addiction Research and Addiction Therapy (DG-Sucht), the Tobacco Guideline was revised in 2019-2020 by 63 experts, who were involved in the development process of the text, in 11 working groups. Undue influence of conflicts of interest on the guideline could be minimized through careful conflict of interest management. Delegates from 50 professional societies discussed the 80 guideline recommendations and voted online. Results: In addition to recommendations for screening and diagnostics, the Tobacco Guideline takes a positive stance towards the use of low-threshold counseling and support services. If, due to the severity of the tobacco-related disorder, brief counseling, telephone counseling, or internet- or smartphone-based methods are not sufficiently effective, individual or group behavioral therapy, possibly in combination with medication, is indicated. If nicotine replacement therapy is not effective, varenicline or bupropion should be offered. Alternative strategies with a lower level of recommendation are hypnotherapy, mindfulness-based treatments, or medication with cytisine. In adolescents and pregnant women, the use of medication should be limited to well-specified exceptions and nicotine replacement. The mean agreement with the recommendations reached a value of 98%. A general overview of the treatment recommendations of the Tobacco Guideline is provided by three clinical algorithms. (C) 2022 S. Karger AG, Basel

German Guideline for Smoking and Tobacco Dependence: Screening, Diagnosis and Treatment, Update 2021 - Short Version

Introduction: In addition to the prevention of tobacco consumption, the establishment and assurance of high-quality treatment for harmful use and dependance on tobacco products remains an important health-related task in Germany. Regular updating of the AWMF-S3Guideline,Smoking and Tobacco Dependence: Screening, Diagnosis and Treatment (Tobacco Guideline) offers a sustainable and reputable source of knowledge on smoking cessation. Methods: Under the auspices of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Neurology (DGPPN) and the German Society for Addiction Research and Addiction Therapy (DG-Sucht), the Tobacco Guideline was revised in 2019-2020 by 63 people, who were involved in the development process of the text, in 11 working groups. Through careful COI management, the influence of conflicts of interest could be minimised. Delegates from 50 professional societies discussed the 80 guideline recommendations and voted online. Results: In addition to recommendations for screening and diagnostics, the Tobacco Guideline takes a positive stance towards the use of low-threshold counselling and support services. If, due to the severity of the tobacco-related disorder, brief counselling, telephone counselling or internet- or smartphone-based methods are not sufficiently effective, individual or group behavioural therapy, possibly in combination with medication, is indicated. If nicotine replacement therapy is not effective, varenicline or bupropion should be offered. Alternative strategies with a lower level of recommendation are hypnotherapy, mindfulness-based treatments or cytisine. In adolescents and pregnant women, the use of medication should be limited to well-specified exceptions and nicotine replacement. The mean agreement with the recommendations reaches a value of 98 %. A general overview of the treatment recommendations of the Tobacco Guideline is provided by three clinical algorithms

A common variant on chromosome 11q13 is associated with atopic dermatitis.

We conducted a genome-wide association study in 939 individuals with atopic dermatitis and 975 controls as well as 270 complete nuclear families with two affected siblings. SNPs consistently associated with atopic dermatitis in both discovery sets were then investigated in two additional independent replication sets totalling 2,637 cases and 3,957 controls. Highly significant association was found with allele A of rs7927894 on chromosome 11q13.5, located 38 kb downstream of C11orf30 (P-combined = 7.6 x 10(-10)). Approximately 13% of individuals of European origin are homozygous for rs7927894[A], and their risk of developing atopic dermatitis is 1.47 times that of noncarriers