Summary Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this novel relationship between transcription, chromatin state and DNA repair, revealing a new, personalized determinant of cancer risk.

In vitro and in vivo studies have suggested that human complement component C5a plays a key role in neutrophil injury in the adult respiratory distress syndrome (ARDS). First, using leukocyte aggregometry, we demonstrated that the addition of a recently developed rabbit anti-human polyclonal antibody to C5a des arg to endotoxin-activated plasma prevented leukocyte aggregation in vitro. We then administered the anti-C5a des arg antibody to septic primates (Macaca fascicularis). Three groups of primates, coiltrol, septic, and anti-C5a antibody treated septic, were studied (n = 4 in each group). A 30-min infusion of Escherichia coii (1 X 101/kg) resulted in severe sepsis and ARDS. Primates were killed 4 h after completion of the E. coli infusion. Septic animals not treated with anti-C5a antibody had 75% mortality (3/4), decreased oxygenation, severe pulmonary edema, and profound hypotension. Septic primates treated with antiC5a antibodies did not die and did not develop decreased oxygenation (P < 0.05) or increased extravascular lung water (P < 0.05). They also had a marked recovery in their mean arterial blood pressure (P < 0.05). This study demonstrates that treatment with rabbit anti-human C5a des arg antibodies attenuates ARDS and some of the systemic manifestations of sepsis in nonhuman primates.

Summary This study examines the incidence and site of tracheal tube impingement during nasotracheal fibreoptic intubation, and the efficacy of anticlockwise tube rotation to overcome the problem. Forty‐three patients underwent fibreoptic‐assisted nasotracheal intubation using a preformed nasal tube, and a second fibrescope was used to observe any obstruction to passage of the tracheal tube. Impingement occurred in 10 cases, with the most common site being the right arytenoid cartilage. Rotation resulted in successful intubation in all 10 cases, but proximal rotation did not always result in an equal degree of rotation at the tube tip. We conclude that the site of impingement for nasotracheal intubation with preformed nasal tubes is located at the posterior structures of the laryngeal inlet and that anticlockwise rotation is a simple and effective solution.

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Catecholamine-secreting paragangliomas (CSPs) present challenges for the managing team of surgeons and anesthesiologists. Without proper preoperative management and planning, the patient is at high risk for complications and significant morbidity. A review of the literature looking at all aspects of the care of patients with CSP was performed to provide a consensus on the comprehensive care of these difficult patients. A case study is also provided to illustrate the management algorithm. Specific recommendations are made with regards to preoperative workup, including serum and urine testing, tumor localization, angiography, and embolization. Preoperative and intraoperative management techniques by the surgical and anesthesiology teams are discussed, including pharmaceutical interventions and fluid management. Aspects of postoperative care are also discussed. Management of patients with CSP requires significant attention to detail by a multidisciplinary team of surgeons and anesthesiologists. By following the recommendations included within this article, the morbidity associated with removal of these tumors can be significantly reduced or eliminated.