Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates T(H)2 differentiation and allergic airway disease.

BACKGROUND: IL-4 and signal transducer and activator of transcription 6 (STAT6) play an important role in the progression of allergic airway disease (AAD) or asthma. IL-4 and STAT6 mediate T(H)2 responses in T cells and immunoglobulin class-switching to IgE in B cells. Both T(H)2 responses and IgE promote the asthmatic condition. We have previously demonstrated that poly (ADP-ribose) polymerase (PARP) 14, a member of the PARP family of proteins, regulates the transcription function of STAT6. However, the role of PARP-14 in AAD is not known. OBJECTIVE: Here we investigate the role of PARP-14 and the enzyme activity associated with it in a model of AAD dependent on airway hyperresponsiveness and lung inflammation. We also elucidate the mechanism by which PARP-14 regulates AAD. METHODS: The role of PARP-14 and its enzyme activity in AAD and T(H)2 differentiation were examined by using a murine model of AAD and in vitro T(H) cell differentiation. RESULTS: PARP-14-deficient animals show reduced lung pathology and IgE levels when compared with control animals. Treating mice with a pharmacologic inhibitor for PARP activity reduced the severity of airway hyperresponsiveness and lung inflammation. Mechanistically, our data indicate that PARP-14 and its enzyme activity aid in the differentiation of T cells toward a T(H)2 phenotype by regulating the binding of STAT6 to the Gata3 promoter. CONCLUSION: PARP-14 and the catalytic activity associated with it promote T(H)2 differentiation and AAD in a murine model, and targeting PARP-14 might be a potential new therapy for allergic asthma.

Improved outcomes of bile duct injuries in the 21st century.

OBJECTIVE: The objectives of this analysis were to compare the outcomes of bile duct injuries by specialist over time and the role of management timing and biliary stents. BACKGROUND: Postoperative bile duct injuries require multidisciplinary management. In recent years, advancements have occurred in patient evaluation and in timing and type of therapy. METHODS: A multidisciplinary team managed 528 patients over 18 years. Mean age was 52 years; 69% were women and 95% had a cholecystectomy and/or bile duct exploration. Patients were classified by the Strasberg system as having bile leaks (type A, n = 239, 45%) or bile duct injuries (types B-E, n = 289, 55%). Injury outcomes from 1993 to 2003 (n = 132) were compared with those from 2004 to 2010 (n = 157). A successful outcome was defined as no need for further intervention after the initial 12 months of therapy. Standard statistical methods were employed. RESULTS: Patients with bile leaks were managed almost exclusively by endoscopists (96%) with a 96% success rate. Patients with bile duct injuries were managed most often by endoscopists (N = 115, 40%) followed by surgeons (N = 104, 36%) and interventional radiologists (N = 70, 24%). Overall success rates were best for surgery (88%, P < 0.05) followed by endoscopy (76%) and interventional radiology (50%) and improved over time (78% vs 69%). Outcomes were best for surgery in recent years (95% vs 80%, P < 0.05) and for patients stented for more than 6 months (P < 0.01). CONCLUSIONS: Almost all bile leaks and many bile duct injuries can be managed successfully by endoscopists. Selected proximal injuries can be treated by interventional radiologists with modest success. Outcomes of bile duct injuries are best with surgical management and in patients who are stented for more than 6 months.

Hydrogen-bonding catalysts based on fluorinated alcohol derivatives for living polymerization.

Recognize this! A hydrogen-bonding motif based on hexafluorinated alcohol derivatives (see picture; O red, F yellow) activates electrophilic substrates. The catalytic activity of the hydrogen-bonded systems was demonstrated for the ring-opening polymerization of a variety of strained heterocycles. Narrowly dispersed polymers with predictable molecular weights were obtained with end-group fidelity.