Ultrasound-Guided Nerve Blocks: Suggested Procedural Guidelines for Emergency Physicians.

Acute pain is one of the most frequent, and yet one of the most challenging, complaints physicians encounter in the emergency department (ED). Currently, opioids are one of several pain medications given for acute pain, but given the long-term side effects and potential for abuse, alternative pain regimens are sought. Ultrasound-guided nerve blocks (UGNB) can provide quick and sufficient pain control and therefore can be considered a component of a physician's multimodal pain plan in the ED. As UGNB are more widely implemented at the point of care, guidelines are needed to assist emergency providers to acquire the skill necessary to incorporate them into their acute pain management.

High throughput screening for inhibitors of the HECT ubiquitin E3 ligase ITCH identifies antidepressant drugs as regulators of autophagy.

Inhibition of distinct ubiquitin E3 ligases might represent a powerful therapeutic tool. ITCH is a HECT domain-containing E3 ligase that promotes the ubiquitylation and degradation of several proteins, including p73, p63, c-Jun, JunB, Notch and c-FLIP, thus affecting cell fate. Accordingly, ITCH depletion potentiates the effect of chemotherapeutic drugs, revealing ITCH as a potential pharmacological target in cancer therapy. Using high throughput screening of ITCH auto-ubiquitylation, we identified several putative ITCH inhibitors, one of which is clomipramine--a clinically useful antidepressant drug. Previously, we have shown that clomipramine inhibits autophagy by blocking autophagolysosomal fluxes and thus could potentiate chemotherapy in vitro. Here, we found that clomipramine specifically blocks ITCH auto-ubiquitylation, as well as p73 ubiquitylation. By screening structural homologs of clomipramine, we identified several ITCH inhibitors and putative molecular moieties that are essential for ITCH inhibition. Treating a panel of breast, prostate and bladder cancer cell lines with clomipramine, or its homologs, we found that they reduce cancer cell growth, and synergize with gemcitabine or mitomycin in killing cancer cells by blocking autophagy. We also discuss a potential mechanism of inhibition. Together, our study (i) demonstrates the feasibility of using high throughput screening to identify E3 ligase inhibitors and (ii) provides insight into how clomipramine and its structural homologs might interfere with ITCH and other HECT E3 ligase catalytic activity in (iii) potentiating chemotherapy by regulating autophagic fluxes. These results may have direct clinical applications.

Inter-American investigation of mortality in childhood: 1968-1970 organization and some preliminary results - abstract

The Inter-American Investigation of Mortality in Childhood was inaugurated by PAHO/WHO in 1967 following a successful inter-American study of adult urban mortality. The study, an exercise in international and interdisciplinary co-operation, is being conducted in fifteen centres in the Western hemisphere, including Kingston and St. Andrew, Jamaica, and is being coordinated by the Health Statistics Department of PAHO/WHO under Dr. Ruth Puffer. A team including physicians, social workers, nurses, and a medical statistician is studying the deaths of all children under five years in the Kingston and St. Andrew area during the years 1968-1970. To enable valid conclusion to be drawn, similar data on social, economic and environmental factors are being collected for a representative sample of living children from the same area and in the same age group. The aim of the study is to elucidate the various factors contributing to death so as to make more accurate data available for those responsible planning the health services and for appropriate preventive measures. Preliminary analysis of the first year's data on approximately 1,000 deaths has shown that the principal underlying causes of death in the age group studied are perinatal causes (38 percent), gastroenteritis (18.4 percent) congenital anomalies (7.9 percent), respiratory tract infections (7.3 percent), malnutrition (7.1 percent), and accidents (3.4 percent) AU