Topical W-7 inhibits ultraviolet radiation-induced melanogenesis in Skh:HR2 pigmented hairless mice

We studied the effect of N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide (W-7) on ultraviolet radiation (UVR)-induced melanogenesis (tanning) in Skh:HR2 pigmented hairless mice. Topically pretreated mice were exposed to subminimal edematogenic as well as edematogenic UVR doses to establish whether W-7-UVR-induced edema prophylaxis allows increased melanogenesis while preventing edema. Ultraviolet light-irradiated vehicle control animals developed visible tans; however, both W-7-treated groups failed to tan. Topical W-7 before UVR exposure inhibited UVR induction of dopa oxidase activity in melanocytes by 49% (P=0.029) and inhibited UVR-induced deposition of melanin in the epidermis by 88% (P=0.006). Topical W-7 blocked 23% of the UVR but this blockage could not account for the inhibition of dopa oxidase and melanization. We conclude that, in addition to preventing edema, W-7 inhibits UVR-induced melanogenesis, possibly by affecting Ca²⁺-calmodulin and/or protein kinase C-dependent processes.     

Influence of protein transduction domains on intracellular delivery of macromolecules

As the plasma membrane and blood-brain barrier selectively restrict the entry of most compounds into cells to < 500 Da, delivering macromolecules into cells was, until recently, little more than a goal. However, with significant effort to capitalise on therapeutic targets available in the post-genomic era, novel approaches for delivering therapeutic macromolecules are being rapidly developed. The discovery of small cationic peptides, termed peptide/protein transduction domains or cell-penetrating peptides, which cross biological membranes, has emerged as a venerable Trojan horse to transport large, biologically active molecules, such as peptides, proteins and oligonucleotides, into mammalian cells in vitro, as well as in preclinical models and clinical trials in vivo. This review discusses the implications of peptide/protein transduction domain-mediated delivery of macromolecules and their possible uses as important primary drug delivery agents.     

Quality of life in adult survivors of critical illness: A systematic review of the literature

Objective: To determine how the quality of life (QOL) of intensive care unit (ICU) survivors compares with the general population, changes over time, and is predicted by baseline characteristics. Design: Systematic literature review including MEDLINE, EMBASE, CINAHL and Cochrane Library. Eligible studies measured QOL 30 days after ICU discharge using the Medical Outcomes Study 36-item Short Form (SF-36), EuroQol-5D, Sickness Impact Profile, or Nottingham Health Profile in representative populations of adult ICU survivors. Disease-specific studies were excluded. Measurements and results: Of 8,894 citations identified, 21 independent studies with 7,320 patients were reviewed. Three of three studies found that ICU survivors had significantly lower QOL prior to admission than did a matched general population. During post-discharge follow-up, ICU survivors had significantly lower QOL scores than the general population in each SF-36 domain (except bodily pain) in at least four of seven studies. Over 1–12 months of follow-up, at least two of four studies found clinically meaningful improvement in each SF-36 domain except mental health and general health perceptions. A majority of studies found that age and severity of illness predicted physical functioning. Conclusions: Compared with the general population, ICU survivors report lower QOL prior to ICU admission. After hospital discharge, QOL in ICU survivors improves but remains lower than general population levels. Age and severity of illness are predictors of physical functioning. This systematic review provides a general understanding of QOL following critical illness and can serve as a standard of comparison for QOL studies in specific ICU subpopulationsAn erratum to this article can be found at     

Studying outcomes of intensive care unit survivors: measuring exposures and outcomes

Background Measurement of long-term outcomes and the patient and intensive care unit (ICU) factors predicting them present investigators with unique challenges. There is little systematic guidance for measuring these outcomes and exposures within the ICU setting. As a result measurement methods are often variable and noncomparable across studies.Methods We use examples from the critical care literature to describe measurement as it relates to three key elements of clinical studies: subjects, outcomes and exposures, and time. Using this framework we review the principles and challenges of measurement and make recommendations for long-term outcomes research in the field of critical care medicine.Discussion Relevant challenges discussed include: (a) selection bias and heterogeneity of ICU research subjects, (b) appropriate selection and measurement of outcome and exposure variables, and (c) accounting for the effect of time in the exposure-outcome relationship, including measurement of baseline data and time-varying variables.Conclusions Addressing these methodological challenges will advance research aimed at improving the long-term outcomes of ICU survivors.Electronic Supplementary Material Electronic supplementary material to this paper can be obtained by using the Springer Link server located at .This research was supported by National Institutes of Health (ALI SCCOR Grant # P050 HL 73994-01). D.M.N. is supported by Clinician-Scientist Awards from the Canadian Institutes of Health Research and the University of Toronto, and a Detweiler Fellowship from the Royal College of Physicians and Surgeons of Canada.