Identification of atherosclerosis-modifying genes: pathogenic insights and therapeutic potential

Atherosclerosis is a common, complex trait, with genetic variation in many genes and the environment contributing to risk for this condition, which has multiple and highly variable phenotypic manifestations. Progress has been made in the identification of atherosclerosis-modifying genes in both human studies and through the use of animal models. In the future, it may be possible to administer a genetic test for variation in a handful of the most common atherosclerosis-modifier genes, and thus predict if a patient is likely to develop atherosclerosis and ischemic heart disease. These patients could then be treated aggressively to lower their low-density lipoprotein cholesterol levels and other risk factors, including counseling to make adjustments in their lifestyle. This review will summarize the methods and results thus far in the identification of atherosclerosis-modifier genes.     

How does fast track affect quality of care in the emergency department?

STUDY OBJECTIVES: Use of fast track has been shown to improve the emergency department flow of less urgent patients. It has been speculated, however, that this could negatively affect the care of urgent patients. The objective of this study was to determine whether a dedicated fast track for less urgent patients [Canadian Triage and Acuity scale category 4/5 (CTAS 4/5)] affected (1) the time to assessment for urgent patients (CTAS 3), (2) the length of stay for less urgent patients (CTAS 4 and 5), and (3) the left-without-being-seen rate. METHODS: In June 2003, fast track was opened in our emergency department from 13:00 to 19:00 h. A before-after intervention comparison analysis was completed for 1 week in Aug 2002 and the same week in Aug 2003. Data collected included (1) time to assessment of CTAS 3 patients, (2) the length of stay for CTAS 4/5 patients, and (3) percentage of patients who left without being seen. RESULTS: A total of 368 patients were reviewed for 2002 and 380 patients were reviewed for 2003. Median time to assessment of CTAS 3 patients presenting from 13:00 to 19:00 h was reduced from 66 min (Interquartile range: 40, 94 min) in 2002 to 60 min (IQR: 38, 108 min) after fast track was open in 2003 (P = 0.95). Median length of stay of CTAS 4 and 5 patients was reduced from 170 min (IQR: 111, 256 min) to 110 min (IQR: 69, 185 min) (P < 0.001). The overall left-without-being-seen rate decreased from 5% (20/368) to 2% (9/380). CONCLUSION: A dedicated fast track for CTAS 4/5 patients can reduce the length of stay and the left-without-being-seen rate with no impact on CTAS 3 patients seen in the main emergency department.     

Falls in hospitalized children

PURPOSE: To identify risk factors in hospitalized children using two validated adult fall risk scales. METHODS: For each fall patient identified, a non-fall patient was matched for chronological age and year of hospitalization. The retrospective chart review coded the presence or absence of risk factors and completed both the Morse Fall Scale and Hendrich II Fall Risk Model. FINDINGS: Overall, a significant difference was detected between pediatric fallers and non-fallers on the Morse Fall Scale. The Morse Fall Scale's sensitivity, specificity and false positive rate suggested that the scale does little better than chance at detecting true fallers and may inaccurately identify non-fallers as high risk. CONCLUSIONS: Episodes of disorientation and fall history were the best predictors of pediatric falls for this sample.     

Magnet hospital characteristics and northern Canadian nurses' job satisfaction

Retention of health professionals is a serious problem in northern and rural Canada. Magnet hospital factors are known to increase job satisfaction, which contributes to retention. The purpose of this paper is to examine the extent to which magnet hospital characteristics (management support, nurse-doctor and nurse-manager relationships, professional autonomy and responsibility) contribute to northwestern Canadian hospital nurses' job satisfaction. Participants were 123 nurses from 13 hospitals in western Canada. They completed a survey and structured interview that provided data on their attitudes and perspectives about their hospital jobs. We found that some magnet hospital characteristics apply in northern and rural western Canadian hospitals. Our findings indicate that management support and nurse-manager relations are important to nurses' job satisfaction, but participants' views of management were fairly negative, an issue that management needs to address. Nurses' ability to work professionally and autonomously is also important to their satisfaction. There are indications that nursing supervisory skill sets need to be upgraded in some instances.     

Molecular Analysis of Fiji Disease Fijivirus Genome Segments 1 and 3

Fiji disease fijivirus (FDV) genomic segments 1 (S1) and 3 (S3) were completely sequenced. FDV S1 comprised 4532nt and was predicted to encode a 170.6kDa protein. FDV S3 comprised 3623nt and was predicted to encode a 135.5kDa protein. The terminal sequences of S1 and S3 were 5 AAGUUUUU......CAGCUAGCGUC 3 and 5 AAGUUUUU......CAGCAGAUGUC 3, respectively, and located immediately adjacent to these sequences were 12bp imperfect inverted repeats. The predicted translation product of FDV S1 showed highest similarity to Rice black-streaked dwarf virus (RBSDV) S1 and is thought to encode the viral RNA-dependent RNA polymerase (RdRp). The predicted translation product of FDV S3 was found to be most similar to RBSDV S4 which is thought to encode the 'B-spike' protein. The FDV sequence contained an ATP/GTP binding motif and a leucine zipper motif, but these motifs were not found in the RBSDV sequence. Phylogenetic analysis based on the amino acid sequences of the RdRp of FDV S1 and other reoviruses revealed that the fijiviruses form a cluster close to the oryzaviruses. The RdRp sequences were grouped into genera that were consistent with the current reovirus classification scheme that is based on physico-chemical and biological properties.     

When should patients begin ambulating following lower limb split skin graft surgery? A systematic review

Pretibial lacerations and lower limb wounds are referred to plastic surgery teams for split skin graft surgery. Traditionally, these patients have been immobilised on bedrest following surgery. More recently, patients have commenced ambulation earlier to avoid medical complications and facilitate discharge. The objective of this literature review was to determine when such patients should begin walking. A literature search was undertaken using the electronic databases AMED, Cinahl, Embase, Medline (via Ovid), PEDro and Pubmed. Clinical trials using human subjects, written in English, were included. Seventeen (of 1137) papers met the inclusion criteria and were reviewed. The literature suggested that patients should begin walking immediately or at the earliest possible opportunity after lower limb skin graft surgery. Although the literature advocated early ambulation, the evidence base presented with a number of recurrent methodological limitations, including small sample sizes, lack of a control sample, and limited follow-up. Accordingly, further research employing large, well-designed, randomised controlled trials is recommended. It will then be possible to understand with greater certainty when patients should begin walking after lower extremity split skin graft surgery.     

TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres

Mammalian telomeres are coated by the sequence-specific, DNA-binding protein, TRF1, a negative regulator of telomere length. Previous results showed that ADP-ribosylation of TRF1 by tankyrase 1 released TRF1 from telomeres and promoted telomere elongation. We now show that loss of TRF1 from telomeres results in ubiquitination and degradation of TRF1 by the proteasome and that degradation is required to keep TRF1 off telomeres. Ubiquitination of TRF1 is regulated by its telomere-binding status; only the telomere-unbound form of TRF1 is ubiquitinated. Our findings suggest a novel mechanism of sequential post translational modification of TRF1 (ADP-ribosylation and ubiquitination) for regulating access of telomerase to telomeres.     

Aberrant actin cytoskeleton leads to accelerated proliferation of corneal epithelial cells in mice deficient for destrin (actin depolymerizing factor)

Corneal disease is the most common cause of bilateral blindness in the world. Visual loss in this condition is often due to changes in morphology and function of the corneal epithelial surface. Corneal disease-1 (corn1) and corn1(2J) are spontaneous mouse mutants that develop irregular thickening of the corneal epithelium, similar to that observed in human corneal surface disease. These autosomal-recessive mutations cause an increase in the rate of proliferation of the corneal epithelial cells. Here, we report that the phenotypes in both mutants are caused by mutations within the destrin gene (also known as actin-depolymerizing factor). By positional cloning, we identified a deletion encompassing the entire coding sequence of the destrin gene in corn1 mice, and a point mutation (Pro106Ser) in the coding sequence of destrin in corn1(2J) mice. In situ analysis showed that destrin is highly expressed in the corneal epithelium. Consistent with the cellular roles for destrin, an essential regulator of actin filament turnover that acts by severing and enhancing depolymerization of actin filament, we observed that the corn1 mutations increased the content of filamentous actin in corneal epithelial cells. Our results suggest an in vivo connection between remodeling of the actin cytoskeleton and the control of cell proliferation, and a new pathway through which an aberrant actin cytoskeleton can cause epithelial hyperproliferation.     

The mitochondria‐targeted anti‐oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients

Background: Increased oxidative stress and subsequent mitochondrial damage are important pathways for liver damage in chronic hepatitis C virus (HCV) infection; consequently, therapies that decrease mitochondrial oxidative damage may improve outcome. The mitochondria‐targeted anti‐oxidant mitoquinone combines a potent anti‐oxidant with a lipophilic cation that causes it to accumulate several‐hundred fold within mitochondria in vivo. Aims: In this phase II study, we investigated the effect of oral mitoquinone on serum aminotransferases and HCV RNA levels in HCV‐infected patients. Methods: Thirty HCV patients who were either non‐responders or unsuitable candidates for standard‐of‐care (pegylated interferon plus ribavirin) were randomized to receive mitoquinone (40 or 80 mg) or placebo once daily for 28 days, and serum aminotransferases and HCV RNA levels were measured. Results: Both treatment groups showed significant decreases in absolute and percentage changes in serum alanine transaminase (ALT) from baseline to treatment day 28 (P<0.05). There was also a significant difference between incremental area under the curve for ALT between baseline and day 28 for the 40 mg treatment group against placebo (P<0.05). The differences in plasma ALT activity from baseline to day 28 in both mitoquinone groups compared with placebo did not reach significance (P>0.05). There was no change in HCV load on mitoquinone treatment. Conclusions: Administration of the mitochondria‐targeted anti‐oxidant mitoquinone significantly decreased plasma ALT and aspartate aminotransferase in patients with chronic HCV infection, and this suggests that mitoquinone may decrease necroinflammation in the liver in these patients. As mitochondrial oxidative damage contributes to many other chronic liver diseases, such as steatohepatitis, further studies using mitochondria‐targeted anti‐oxidants in HCV and other liver diseases are warranted.