Advances in the therapeutic use of mammalian target of rapamycin (mTOR) inhibitors in dermatology.

Significant developments in the use of mammalian target of rapamycin (mTOR) inhibitors (mTORIs) as immunosuppressant and antiproliferative agents have been made. Recent advances in the understanding of the mTOR signaling pathway and its downstream effects on tumorigenesis and vascular proliferation have broadened the clinical applications of mTORIs in many challenging disorders such as tuberous sclerosis complex, pachyonychia congenita, complex vascular anomalies, and inflammatory dermatoses. Systemic mTORI therapy has shown benefits in these areas, but is associated with significant side effects that sometimes necessitate drug holidays. To mitigate the side effects of systemic mTORIs for dermatologic applications, preliminary work to assess the potential of percutaneous therapy has been performed, and the evidence suggests that percutaneous delivery of mTORIs may allow for effective long-term therapy while avoiding systemic toxicities. Additional large placebo-controlled, double-blinded, randomized studies are needed to assess the efficacy, safety, duration, and tolerability of topical treatments. The objective of this review is to provide updated information on the novel use of mTORIs in the management of many cutaneous disorders.

The utility of the additive EuroSCORE, RIFLE and AKIN staging scores in the prediction and diagnosis of acute kidney injury after cardiac surgery.

BACKGROUND/AIMS: Acute kidney injury (AKI) following cardiac surgery is a complication associated with high rates of morbidity and mortality. We compared staging systems for the diagnosis of AKI after cardiac surgery, and assessed pre-operative factors predictive of post-operative AKI. METHODS: Clinical data, surgical risk scores, procedure and clinical outcome were obtained on all 4,651 patients undergoing cardiac surgery to the Royal Infirmary of Edinburgh between April 2006 and March 2011, of whom 4,572 had sufficient measurements of creatinine before and after surgery to permit inclusion and analysis. The presence of AKI was assessed using the AKIN and RIFLE criteria. RESULTS: By AKIN criteria, 12.4% of the studied population developed AKI versus 6.5% by RIFLE criteria. Any post-operation AKI was associated with increased mortality from 2.2 to 13.5% (relative risk 7.0, p < 0.001), and increased inpatient stay from a median of 7 (IQR 4) to 9 (IQR 11) days (p < 0.05). Patients identified by AKIN, but not RIFLE, had a mean peak creatinine rise of 34% from baseline and had a significantly lower mortality compared to RIFLE-'Risk' AKI (mortality 6.1 vs. 9.7%; p < 0.05). Pre-operative creatinine, diabetes, NYHA Class IV dyspnoea and EuroSCORE-1 (a surgical risk score) all predicted subsequent AKI on multivariate analysis. EuroSCORE-1 outperformed any single demographic factor in predicting post-operative AKI risk, equating to an 8% increase in relative risk for each additional point. CONCLUSION: AKI after cardiac surgery is associated with delayed discharge and high mortality rates. The AKIN and RIFLE criteria identify patients at a range of AKI severity levels suitable for trial recruitment. The utility of EuroSCORE as a risk stratification tool to identify high AKI-risk subjects for prospective intervention merits further study.

A silent cause of sudden cardiac death especially in sport: congenital coronary artery anomalies.

AIM: To raise awareness of congenital coronary artery anomalies (CCAAs) as an important cause of sudden cardiac death (SCD) in athletes, we describe a cohort of the malignant subset. Defining the key anatomical features for the cardiologist and pathologist to be aware of and detailing a systematic approach to examining the coronary arteries at autopsy. METHODS: Retrospective non-case-controlled analysis of 2304 cases of SCD referred by pathologists between 1994 and January 2012. RESULTS: 31 (1.3%) of the 2304 cases of SCD had CCAAs; 24 men (77%) and 7 women (23%), mean age 28 years (range 16 months-63 years). In 15 cases (48%), SCD occurred during or immediately after physical exertion. Cardiac symptoms were documented to have occurred in only seven patients (23%) prior to SCD. The anomaly had been identified by the referring pathologist in only 11 of the 31 cases (35%). CONCLUSIONS: CCAAs are a rare and mostly benign entity, but a subset has the potential to be fatal without any forewarning. In a significant proportion of cases identified in this large cohort, the victim was under exertion at the time of death, highlighting the relevance of this anomaly to the sports and exercise medicine community.

Non-atherosclerotic coronary artery disease associated with sudden cardiac death.

BACKGROUND: The concept of non-atherosclerotic coronary artery pathology in sudden cardiac death (SCD) has not been given the attention it deserves. OBJECTIVE: To determine the incidence of non-atherosclerotic coronary artery pathology in SCD and raise awareness among cardiologists and pathologists alike. DESIGN: Retrospective non-case-controlled analysis. Setting Cardiac pathology centre at the National Heart and Lung Institute and Royal Brompton Hospital. SUBJECTS: Between 1994 and 2008, the hearts of 1647 people undergoing SCD were referred for pathological assessment to ascertain the precise aetiology of SCD. RESULTS: Fifty (3.0%) of the 1647 cases of SCD were associated with non-atherosclerotic coronary pathology (31 male subjects (62%) and 19 female subjects (38%, age range (8 weeks-71 years)). Twenty four of the 50 cases had anomalous coronary arteries (48%); eight cases had coronary artery dissection (16%); six cases had coronary artery vasculitis (12%); six cases had coronary artery spasm (12%); three cases had idiopathic arterial calcification of infancy (6%); two cases had fibromuscular dysplasia (4%) and one case had a benign tumour occluding the left coronary ostium (2%). Only 20 of the 50 patients (40%) were documented to have experienced cardiac symptoms such as syncope, chest pain on exertion or breathlessness before their SCD. Twelve of the patients (24%) died during or immediately after physical exertion. CONCLUSION: Non-atherosclerotic coronary disease is associated with sudden death in all age groups, particularly younger, male patients. Cardiologists need to be aware of these entities and investigate any patient who has cardiac symptoms especially with exertion.