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Background Congenital Central Hypoventilation Syndrome (CCHS) is a rare condition characterized by an alveolar hypoventilation due to a deficient autonomic central control of ventilation and a global autonomic dysfunction. Paired-like homeobox 2B (PHOX2B) mutations are found in most of the patients with CCHS. In recent years, the condition has evolved from a life-threatening neonatal onset disorder to include broader and milder clinical presentations, affecting children, adults and families. Genes other than PHOX2B have been found responsible for CCHS in rare cases and there are as yet other unknown genes that may account for the disease. At present, management relies on lifelong ventilatory support and close follow up of dysautonomic progression. Body This paper provides a state-of-the-art comprehensive description of CCHS and of the components of diagnostic evaluation and multi-disciplinary management, as well as considerations for future research. Conclusion Awareness and knowledge of the diagnosis and management of this rare disease should be brought to a large health community including adult physicians and health carers.

The aim of this study was to analyze the exhaled volatile organic compounds (VOCs) profile, airway microbiome, lung function and exercise performance in congenital diaphragmatic hernia (CDH) patients compared to healthy age and sex-matched controls. A total of nine patients (median age 9 years, range 6–13 years) treated for CDH were included. Exhaled VOCs were measured by GC–MS. Airway microbiome was determined from deep induced sputum by 16S rRNA gene sequencing. Patients underwent conventional spirometry and exhausting bicycle spiroergometry. The exhaled VOC profile showed significantly higher levels of cyclohexane and significantly lower levels of acetone and 2-methylbutane in CDH patients. Microbiome analysis revealed no significant differences for alpha-diversity, beta-diversity and LefSe analysis. CDH patients had significantly lower relative abundances of Pasteurellales and Pasteurellaceae. CDH patients exhibited a significantly reduced Tiffeneau Index. Spiroergometry showed no significant differences. This is the first study to report the VOCs profile and airway microbiome in patients with CDH. Elevations of cyclohexane observed in the CDH group have also been reported in cases of lung cancer and pneumonia. CDH patients had no signs of impaired physical performance capacity, fueling controversial reports in the literature.

Serum eosinophil cationic protein (ECP) has been promoted as a marker of inflammatory activity in bronchial asthma. Bronchial responsiveness, measured either by inhaling pharmacologically active substances such as histamine or methacholine, or by applying physical stimuli such as the hyperventilation of cold dry air, is also considered to be an indirect marker of bronchial inflammation. In this study, we investigated the possible relationship between serum ECP and bronchial responsiveness to both cold dry air and histamine in presently symptom- and medication-free pediatric and adolescent asthma patients. Thirty-six children and adolescents with atopic asthma were studied. On 2 consecutive days, bronchial responsiveness was assessed nonpharmacologically by cold dry air and pharmacologically by histamine in random order. Blood samples for determination of ECP were collected before each challenge. Serum ECP levels correlated with neither cold dry air-induced changes in FEV1 nor the provocation concentrations of histamine causing a 20% fall in FEV1. Subjects with bronchial hyperresponsiveness to cold dry air and histamine had somewhat higher levels of serum ECP than subjects with normal responses, but these differences were insignificant. Our results indicate a lack of relationship both between serum ECP and bronchial responsiveness to cold dry air and between serum ECP and bronchial responsiveness to histamine.

Vaskuläre Anomalien werden nach der Klassifikation der International Society for the Study of Vascular Anomalies in vaskuläre Tumoren, die als häufigste Entitäten kaposiforme Hämangioendotheliome und Hämangiome umfassen, und vaskuläre Malformationen unterteilt. Die Behandlung vaskulärer Anomalien erfolgt interdisziplinär und basiert, abhängig von der Entität auf Resektion, Sklero‑/Kryotherapie, Embolisation und medikamentöser (antiangiogenetischer und/oder zytostatischer) Therapie. Eine komplette Entfernung ist aufgrund von Ausdehnung und meist diffus infiltrativem Wachstum nur in sehr wenigen Fällen möglich. Seit der Erstbeschreibung der Wirksamkeit in dieser Indikation 2008 gilt Propranolol als etablierte Erstlinienbehandlung für komplizierte infantile Hämangiome. Sirolimus ist ein in der Organtransplantation verbreitet eingesetztes Immunsuppressivum, das den Mammalian/mechanistic-target-of-rapamycin(mTOR)-Signalübertragungsweg inhibiert, auch antiangiogenetisch wirksam ist und daher zunehmend für die Behandlung von vaskulären Tumoren und Malformationen eingesetzt wird. Drei Säuglinge mit vaskulären Anomalien (kaposiformes Hämangioendotheliom, gemischt makro‑/mikrozystische lymphatische Malformation, diffuses infantiles Leberhämangiom) erhielten eine Propranolol‑/Sirolimus-basierte medikamentöse Therapie, ohne klinisch relevante Nebenwirkungen entwickelt zu haben. Obwohl die Verträglichkeit von Propranolol und Sirolimus meist ausgezeichnet ist, erfordern schwere, mitunter lebensbedrohliche Nebenwirkungen (Propranolol: kardiovaskulär; Sirolimus: infektiös), die in Einzelfällen berichtet sind, besondere Beachtung.

This case report describes a 13-year-old boy with diffuse microvascular pulmonary arteriovenous malformations, in whom total anomalous pulmonary venous drainage had been corrected surgically in the newborn period. Contrast transesophageal echocardiography, cardiac catheterization and a lung perfusion scan suggested, and lung biopsy confirmed the diagnosis in our patient. Treatment with nifedipin was commenced. Conclusion: This case illustrates the diagnostic difficulties with this rare malformation.

We report on two Turkish children who presented with progressive airway obstruction. Open lung biopsy revealed follicular bronchiolitis. The children were treated with systemic steroids and various topical medications. Whereas the respiratory situation of patient 1 required immunosuppressive therapy, the condition of patient 2 stabilised without systemic medication. Diagnosis of follicular bronchiolitis should be considered when children present with recurrent respiratory tract infections, progressive dyspnoea, and chronic bronchial obstruction. Children in whom follicular bronchiolitis is suspected should undergo open lung biopsy for confirmation of diagnosis.

We report on the clinical, laboratory, and molecular genetic findings in a 15-month-old boy who initially presented with disseminated cytomegalovirus and concomitant para-influenza virus infection. Hyper-IgM syndrome, suspected on clinical grounds, was confirmed by immunological investigations. In addition, a previously unreported potentially disease-causing mutation in the CD40 ligand gene was detected in this patient. The present case illustrates that disseminated cytomegalovirus infection with atypical clinical features should be included in the spectrum of the hyper-IgM syndrome.

Hippo signaling acts as a master regulatory pathway controlling growth, proliferation, and apoptosis and also ensures that variations in proliferation do not alter organ size. How the pathway coordinates restricting proliferation with organ size control remains a major unanswered question. Here we identify Rae1 as a highly-conserved target of the Hippo Pathway integrating proliferation and organ size. Genetic and biochemical studies in Drosophila cells and tissues and in mammalian cells indicate that Hippo signaling promotes Rae1 degradation downstream of Warts/Lats. In proliferating cells, Rae1 loss restricts cyclin B levels and organ size while Rae1 over-expression increases cyclin B levels and organ size, similar to Hippo Pathway over-activation or loss-of-function, respectively. Importantly, Rae1 regulation by the Hippo Pathway is crucial for its regulation of cyclin B and organ size; reducing Rae1 blocks cyclin B accumulation and suppresses overgrowth caused by Hippo Pathway loss. Surprisingly, in addition to suppressing overgrowth, reducing Rae1 also compromises survival of epithelial tissue overgrowing due to loss of Hippo signaling leading to a tissue \"synthetic lethality\" phenotype. Excitingly, Rae1 plays a highly conserved role to reduce the levels and activity of the Yki/YAP oncogene. Rae1 increases activation of the core kinases Hippo and Warts and plays a post-transcriptional role to increase the protein levels of the Merlin, Hippo, and Warts components of the pathway; therefore, in addition to Rae1 coordinating organ size regulation with proliferative control, we propose that Rae1 also acts in a feedback circuit to regulate pathway homeostasis.

Background The transition to a climate-neutral energy system requires industrial demand-side flexibility to complement renewable energy sources. Energy-intensive industries, such as iron and steel or food industries, play a pivotal role in this transformation by adopting demand-side management strategies. However, challenges remain in terms of aligning production scheduling without compromising operational constraints. Results This study presents two use cases that employ integer linear programming to optimize scheduling and investigate industrial flexibility, focusing on baking ovens in an industrial-scale bakery and a rolling mill in an electric steel plant. In the bakery, optimized schedules could reduce energy consumption during the nightshift (dayshift) by 30% (43%) and total runtime by 43% (55%). The rolling mill model achieves cost savings of up to 7% by aligning production schedules with volatile electricity prices over the medium term. There is a correlation observed between electricity price volatility and cost savings, with greater fluctuations yielding higher savings. The potential for load-shifting potential is demonstrated, with weekly shifts reaching nearly 40% of original energy consumption in favorable periods. Conclusions The results highlight the importance of tailored scheduling models in unlocking the potential for demand-side flexibility in industrial processes. While optimized bakery schedules improve energy efficiency, optimized rolling mill schedules demonstrate the feasibility of minimizing costs in the medium term through implicit demand response. The findings demonstrate the challenges through low automation levels, which can be overcome by combining optimization approaches with manual ‘what-if’ tools. Additionally, the need for more accurate energy price forecasts or intermediate electricity markets to bridge the gap between short-term spot market and the long-term futures markets is demonstrated. Overcoming computational constraints, ensuring user acceptance, and addressing market barriers are essential for scaling these strategies across industries.

The polarization of cells is essential for the proper functioning of most organs. Planar Cell Polarity (PCP), the polarization within the plane of an epithelium, is perpendicular to apical-basal polarity and established by the non-canonical Wnt/Fz-PCP signaling pathway. Within each tissue, downstream PCP effectors link the signal to tissue specific readouts such as stereocilia orientation in the inner ear and hair follicle orientation in vertebrates or the polarization of ommatidia and wing hairs in Drosophila melanogaster. Specific PCP effectors in the wing such as Multiple wing hairs (Mwh) and Rho Kinase (Rok) are required to position the hair at the correct position and to prevent ectopic actin hairs. In a genome-wide screen in vitro, we identified Combover (Cmb)/CG10732 as a novel Rho kinase substrate. Overexpression of Cmb causes the formation of a multiple hair cell phenotype (MHC), similar to loss of rok and mwh. This MHC phenotype is dominantly enhanced by removal of rok or of other members of the PCP effector gene family. Furthermore, we show that Cmb physically interacts with Mwh, and cmb null mutants suppress the MHC phenotype of mwh alleles. Our data indicate that Cmb is a novel PCP effector that promotes to wing hair formation, a function that is antagonized by Mwh.