Tracheal agenesis versus tracheal atresia: anatomical conditions, pathomechanisms and causes with a possible link to a novel MAPK11 variant in one case.

BACKGROUND: In this study we aimed to describe the morphological and pathogenetic differences between tracheal agenesis and tracheal atresia, which are not clearly distinguished from each other in the literature, and to contribute thereby to the understanding and management of these conditions. Both tracheal agenesis and tracheal atresia represent rare disorders of still unknown aetiology that cannot be detected by prenatal ultrasound. If the affected foetuses survive until birth these conditions result in respiratory failure and in futile attempts to rescue the infant's life. RESULTS: Autopsies and genetic analyses, including singleton or trio exome sequencing, were performed on five neonates/foetuses with tracheal agenesis and three foetuses with tracheal atresia. Tracheal agenesis was characterized by absence of the sublaryngeal trachea and presence of a bronchooesophageal fistula and by pulmonary isomerism and occurred as an isolated malformation complex or as part of a VACTERL association. Special findings were an additional so-called 'pig bronchus' and a first case of tracheal agenesis with sirenomelia. Tracheal atresia presenting with partial obliteration of its lumen and persistence of a fibromuscular streak resulted in CHAOS. This condition was associated with normal lung lobulation and single, non-VACTERL type malformations. Trio ES revealed a novel variant of MAPK11 in one tracheal agenesis case. Its involvement in tracheooesophageal malformation is herein discussed, but remains hypothetical. CONCLUSION: Tracheal agenesis and tracheal atresia represent different disease entities in terms of morphology, pathogenesis and accompanying anomalies due to a primary developmental and secondary disruptive possibly vascular disturbance, respectively.

Outbreak of severe community-acquired bacterial infections among children in North Rhine-Westphalia (Germany), October to December 2022.

PURPOSE: In late 2022, a surge of severe S. pyogenes infections was reported in several European countries. This study assessed hospitalizations and disease severity of community-acquired bacterial infections with S. pyogenes, S. pneumoniae, N. meningitidis, and H. influenzae among children in North Rhine-Westphalia (NRW), Germany, during the last quarter of 2022 compared to long-term incidences. METHODS: Hospital cases due to bacterial infections between October and December 2022 were collected in a multicenter study (MC) from 59/62 (95%) children's hospitals in NRW and combined with surveillance data (2016-2023) from the national reference laboratories for streptococci, N. meningitidis, and H. influenzae. Overall and pathogen-specific incidence rates (IR) from January 2016 to March 2023 were estimated via capture-recapture analyses. Expected annual deaths from the studied pathogens were calculated from national death cause statistics. RESULTS: In the MC study, 153 cases with high overall disease severity were reported with pneumonia being most common (59%, n = 91). IRs of bacterial infections declined at the beginning of the COVID-19 pandemic and massively surged to unprecedented levels in late 2022 and early 2023 (overall hospitalizations 3.5-fold), with S. pyogenes and S. pneumoniae as main drivers (18-fold and threefold). Observed deaths during the study period exceeded the expected number for the entire year in NRW by far (7 vs. 0.9). DISCUSSION: The unprecedented peak of bacterial infections and deaths in late 2022 and early 2023 was caused mainly by S. pyogenes and S. pneumoniae. Improved precautionary measures are needed to attenuate future outbreaks.

Impact of the First COVID Lockdown on Accident- and Injury-Related Pediatric Intensive Care Admissions in Germany-A Multicenter Study.

Children's and adolescents' lives drastically changed during COVID lockdowns worldwide. To compare accident- and injury-related admissions to pediatric intensive care units (PICU) during the first German COVID lockdown with previous years, we conducted a retrospective multicenter study among 37 PICUs (21.5% of German PICU capacities). A total of 1444 admissions after accidents or injuries during the first lockdown period and matched periods of 2017-2019 were reported and standardized morbidity ratios (SMR) were calculated. Total PICU admissions due to accidents/injuries declined from an average of 366 to 346 (SMR 0.95 (CI 0.85-1.05)). Admissions with trauma increased from 196 to 212 (1.07 (0.93-1.23). Traffic accidents and school/kindergarten accidents decreased (0.77 (0.57-1.02 and 0.26 (0.05-0.75)), whereas household and leisure accidents increased (1.33 (1.06-1.66) and 1.34 (1.06-1.67)). Less neurosurgeries and more visceral surgeries were performed (0.69 (0.38-1.16) and 2.09 (1.19-3.39)). Non-accidental non-suicidal injuries declined (0.73 (0.42-1.17)). Suicide attempts increased in adolescent boys (1.38 (0.51-3.02)), but decreased in adolescent girls (0.56 (0.32-0.79)). In summary, changed trauma mechanisms entailed different surgeries compared to previous years. We found no evidence for an increase in child abuse cases requiring intensive care. The increase in suicide attempts among boys demands investigation.

Protein kinase C (PKC) dependent induction of tissue factor (TF) by mesangial cells in response to inflammatory mediators and release during apoptosis.

1. In inflammatory kidney diseases procoagulatory activity (PCA) becomes evident. Glomerular fibrin deposits and capillary microthrombi are histopathological hallmarks in most forms of glomerulonephritis. 2. Therefore in this study the expression of tissue factor (TF) as the main inducer of thrombogenesis was examined in cultured human mesangial cells (MC) in response to proinflammatory stimuli such as interleukin-1 (IL-1 beta), tumour necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS). Also main signalling pathways were investigated. 3. IL-1 beta, TNF-alpha and LPS induced TF in MC in a time and dose dependent manner on mRNA and protein levels. Highest activity was found after 12 h of stimulation. Induction of TF was completely blockable by BAPTA-AM, a chelator of intracellular [Ca(2+)](i) as well as calphostin, a protein kinase C (PKC) inhibitor. Activation of the protein kinase A (PKA) pathway had no influence on basal TF expression, but down-regulated cytokine-induced TF. The PKA blocker, KT5720, increased TF formation significantly. Since TF exerts its activity primarily on the surface of cells and after release of encrypted receptors we further tested TF activity in MC supernatants. IL-1 beta did not significantly increase TF activity in supernatants of intact cells. However, when MC were rendered apoptotic by oxidative metabolites, IL-1 beta treated MC released highly stimulated TF activity into the supernatants, suggesting that a paracrine activation of the coagulatory cascade can take place under such conditions. 4. Inflammatory mediators up-regulate TF expression in MC by a PKC dependent pathway whereas PKA can serve as a negative feed-back link. Apoptosis of inflammatory MC may trigger to spread PCA.

Down-regulation of monocyte apoptosis by phagocytosis of platelets: involvement of a caspase-9, caspase-3, and heat shock protein 70-dependent pathway.

Monocytes interact and cross-talk with platelets in many settings including inflammation, hemostasis, or vascular disorders. During inflammatory diseases, there is a rapid targeting of monocytes and platelets to points of inflammation and endothelial injury, where they lie side-by-side. In this in vitro study, we investigated different interactions between monocytes and platelets and elucidated whether platelets might affect monocyte apoptosis. Freshly isolated human monocytes were rendered apoptotic by serum deprivation or CD95 ligation and cocultured with platelets. Monocyte apoptosis was determined by flow cytometry, TUNEL staining, DNA electrophoresis, and transmission electron microscopy imaging. We could show that monocyte apoptosis was highly suppressed when platelets were added to the cultures. Transmission electron microscopy depicted that monocytes completely ingested thrombocytes by phagocytosis. Blocking thrombocyte uptake by the phagocytosis inhibitor cytochalasin D abrogated the enhanced monocyte survival and led to high apoptosis levels. Monocyte survival was paralleled by down-regulation of caspase-9 and -3 and up-regulation of heat shock protein 70 during uptake of platelets. Platelet supernatants and contents of platelet granules were ineffective in altering monocyte senescence. Also, ingestion of latex beads or zymosan by monocytes was ineffective to mimic platelet-dependent rescue from apoptosis. In conclusion, this study shows that platelets can suppress apoptosis of monocytes by a specific phagocytosis-dependent process with further consequences for atherosclerotic or inflammatory conditions.