Campomelic dysplasia is a malformation syndrome with multiple symptoms including characteristic shortness and bowing of the long bones (campomelia). CD, often lethal due to airway malformations, is caused by heterozygous mutations in SOX9, an SRY-related gene regulating testis and chondrocyte development including expression of many cartilage genes such as type II collagen. Male to female sex reversal occurs in the majority of affected individuals with an XY karyotype. A mild form without campomelia exists, in which sex-reversal may be also absent. We report here two novel SOX9 missense mutations in a male (c.495C>G; p.His165Gln) and a female (c.337A>G; p.Met113Val) within the DNA-binding domain leading to non-lethal acampomelic CD. Functional analyses of mutant proteins demonstrate residual DNA-binding and transactivation of SOX9-regulated genes. Combining our data and reports from the literature we postulate a genotype-phenotype correlation: SOX9 mutations allowing for residual function lead to a mild form of CD in which campomelia and sex reversal may be absent.

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Tissue-specific transcripts are likely to be of importance for the corresponding organ. While attempting to define the specific transcriptome of the human lung, we identified the transcript of a yet uncharacterized protein, SFTA2. In silico analyses, biochemical methods, fluorescence imaging and animal challenge experiments were employed to characterize SFTA2. Human SFTA2 is located on Chr. 6p21.33, a disease-susceptibility locus for diffuse panbronchiolitis. RT-PCR verified the abundance of SFTA2-specific transcripts in human and mouse lung. SFTA2 is synthesized as a hydrophilic precursor releasing a 59 amino acid mature peptide after cleavage of an N-terminal secretory signal. SFTA2 has no recognizable homology to other proteins while orthologues are present in all mammals. SFTA2 is a glycosylated protein and specifically expressed in nonciliated bronchiolar epithelium and type II pneumocytes. In accordance with other hydrophilic surfactant proteins, SFTA2 did not colocalize with lamellar bodies but colocalized with golgin97 and clathrin-labelled vesicles, suggesting a classical secretory pathway for its expression and secretion. In the mouse lung, Sfta2 was significantly downregulated after induction of an inflammatory reaction by intratracheal lipopolysaccharides paralleling surfactant proteins B and C but not D. Hyperoxia, however, did not alter SFTA2 mRNA levels. We have characterized SFTA2 and present it as a novel unique secretory peptide highly expressed in the lung.

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Background Superobesity and laparoscopic surgery promote negative end-expiratory transpulmonary pressure, which causes atelectasis formation and impaired respiratory mechanics. We hypothesized that end-expiratory transpulmonary pressure differs between fixed and individualized PEEP strategies, and mediates their effects on respiratory mechanics, end-expiratory lung volume, gas-exchange, and hemodynamic parameters in superobese patients. Methods In this prospective, non-randomized crossover study including 40 superobese patients (body mass index 57.3 ± 6.4 kg·m-2) undergoing laparoscopic bariatric surgery, PEEP was set according to A) a fixed level of 8 cmH2O (PEEPEmpirical), (B) the highest respiratory system compliance (PEEPCompliance) or (C) an end-expiratory transpulmonary pressure targeting 0 cmH2O (PEEPTranspul) at different surgical positioning. The primary endpoint was end-expiratory transpulmonary pressure at different surgical positioning, secondary endpoints were respiratory mechanics, end-expiratory lung volume, gas-exchange, and hemodynamic parameters. Results Individualized PEEPCompliance compared to fixed PEEPEmpirical resulted in higher PEEP (supine, 17.2 ± 2.4 vs. 8.0 ± 0.0 cmH2O; supine with pneumoperitoneum, 21.5 ± 2.5 vs. 8.0 ± 0.0 cmH2O; and beach chair with pneumoperitoneum; 15.8 ± 2.5 vs. 8.0 ± 0.0 cmH2O; P < 0.001 each) and less negative end-expiratory transpulmonary pressure (supine, −2.9 ± 2.0 vs. −10.6 ± 2.6 cmH2O; supine with pneumoperitoneum, −2.9 ± 2.0 vs. −14.1 ± 3.7 cmH2O; and beach chair with pneumoperitoneum, −2.8 ± 2.2 vs. −9.2 ± 3.7 cmH2O; P < 0.001 each). Titrated PEEP, end-expiratory transpulmonary pressure and lung volume were lower with PEEPCompliance compared to PEEPTranspul (P < 0.001 each). Respiratory system and transpulmonary driving pressure, and mechanical power normalized to respiratory system compliance were reduced using PEEPCompliance compared to PEEPTranspul. Conclusions In superobese patients undergoing laparoscopic surgery, individualized PEEPCompliance may provide a feasible compromise regarding end-expiratory transpulmonary pressures compared to PEEPEmpirical and PEEPTranspul, since PEEPCompliance with slightly negative end-expiratory transpulmonary pressures improved respiratory mechanics, lung volumes, and oxygenation while preserving cardiac output.