Mitf dosage as a primary determinant of melanocyte survival after ultraviolet irradiation.

Microphthalmia-associated transcription factor (Mitf) is essential for melanocyte development and function and regulates anti-apoptotic Bcl2 expression. We hypothesized that cellular deficiency of Mitf can influence melanocyte survival in response to ultraviolet (UV) radiation. Primary melanocyte cultures were prepared from neonatal wild-type mice and congenic animals heterozygous for Mitf mutations Mitf (mi-vga9/+) and Mitf(Mi-wh/+) and exposed to UV irradiation. Wild-type melanocytes were more resistant to UV-induced apoptosis than melanocytes partially deficient in Mitf activity, as determined by relative levels of intracellular melanin and relative activation of Mitf target genes Tyr, Tyrp1, Dct, and Cdk2. Comparative experiments with wild-type cells and congenic albino melanocytes demonstrated that these differences are not due to differences in melanin content, implicating Mitf as a primary determinant of UV-dependent melanocyte survival. Mitf activity correlated directly with resistance to UV-induced apoptosis in melanocytes. Mitf was important not only for regulating the expression of anti-apoptotic Bcl-2 following UV irradiation, but also the expression of the pro-apoptotic BH3-only Bad protein and activation of the extrinsic apoptotic pathway. Hence, Mitf is a multifaceted regulator of UV-induced apoptosis in melanocytes.

Use of an impedance threshold device improves short-term outcomes following out-of-hospital cardiac arrest.

INTRODUCTION: An impedance threshold device (ITD) has been developed for the treatment of cardiac arrest to augment circulation to the heart and brain during cardiopulmonary resuscitation (CPR). The ITD has ventilation timing lights that flash at 12 min(-1) to discourage excessive ventilation rates. HYPOTHESIS: Implementation of the ITD during conventional manual CPR in a large emergency medical services (EMS) system (Staffordshire, UK) is safe, feasible and will improve short-term survival. METHODS: ITD use was implemented by the Staffordshire Ambulance Trust, which treats 1600 cardiac arrests per year with 90 advanced life support (ALS) units and an average response time of 6.3 min. During training, rescuers learned to use the ventilation timing lights to discourage hyperventilation. Rescuers applied the device after tracheal intubation. They were trained to allow the chest to recoil fully after each compression. Prospective ITD use in adults receiving conventional manual CPR for non-traumatic cardiac arrest was compared to matched historical controls receiving conventional manual CPR without inspiratory impedance. All received similar ALS care. The primary endpoint was admission to the emergency department (ED) alive following cardiac arrest. Chi-square, Fisher's exact and Kolmogorov-Smirnov tests were used for statistical analyses. RESULTS: Survival (alive upon ED admission) in all patients receiving an ITD (61/181 [34%]) improved by 50% compared to historical controls (180/808 [22%]) (P<0.01). Survival in patients presenting in asystole tripled in the group receiving an ITD (26/76 [34%]) compared with historical controls (39/351 [11%]) (P=0.001). There were no significant adverse events. CONCLUSIONS: The ITD was used safely and effectively in a large, diverse EMS system and markedly improved short-term survival for adult patients in non-traumatic cardiac arrest.