A lipid-based delivery system for antisense oligonucleotides derived from a hydrophobic complex.

Antisense oligodeoxynucleotides (ASOs) prevent expression of proteins by binding to specific regions of mRNA. This report investigates a potential lipid-based delivery system for ASO. A hydrophobic complex was recovered following addition of cationic lipids to ASOs in a Bligh and Dyer monophase [chloroform/methanol/water (1:2.1:1, v/v/v)]. The addition of monovalent cationic lipids (dioleyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dioleoyltrimethylammonium propane), resulted in > 95% recovery of the ASOs from the organic phase when ASO phosphate charge was neutralized. Cholesteryldimethylaminoethylcarbamate mediated efficient extraction at a charge ratio (+/-) > 5.2. ASOs could not be extracted into the organic phase by the polyvalent lipids, dioctadecylamidoglycyl spermine and 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propaminium trifluoroacetate, even at a charge ratio (+/-) > 5. Dioleoylphosphatidylethanolamine, but not dioleoylphosphatidylcholine, prevented formation and destabilized the hydrophobic complexes. The characterization of the hydrophobic complex led to the development of lipid-ASO particles containing dioleyldimethylammonium chloride, dioleoylphosphatidylethanolamine and poly(ethylene glycol)-conjugated phosphatidylethanolamine (LAPs). When FITC-labeled ASOs in LAPs were added to B-cell lymphoma cells (DoHH2) in vitro, cell-associated ASO decreased as poly(ethylene glycol)-conjugated phosphatidylethanolamine incorporation increased. Western Blot analysis demonstrated that no significant downregulation of Bcl-2 protein was observed when using LAPs. The results suggest that the use of stabilized PEG-conjugated lipids may be detrimental for cationic lipid-based ASO delivery.

Reporting and interpretation of the functional outcomes after the surgical treatment of disruptions of the pelvic ring: a systematic review.

We performed a systematic review of the literature to evaluate the use and interpretation of generic and disease-specific functional outcome instruments in the reporting of outcome after the surgical treatment of disruptions of the pelvic ring. A total of 28 papers met our inclusion criteria, with eight reporting only generic outcome instruments, 13 reporting only pelvis-specific outcome instruments, and six reporting both. The Short-Form 36 (SF-36) was by far the most commonly used generic outcome instrument, used in 12 papers, with widely variable reporting of scores. The pelvis-specific outcome instruments were used in 19 studies; the Majeed score in ten, Iowa pelvic score in six, Hannover pelvic score in two and the Orlando pelvic score in one. Four sets of authors, all testing construct validity based on correlation with the SF-36, performed psychometric testing of three pelvis-specific instruments (Majeed, IPS and Orlando scores). No testing of responsiveness, content validity, criterion validity, internal consistency or reproducibility was performed. The existing literature in this area is inadequate to inform surgeons or patients in a meaningful way about the functional outcomes of these fractures after fixation.

Length of stay, mortality, morbidity and delay to surgery in hip fractures.

Our aim was to determine the effect of delay to surgery on the time to discharge, in-hospital death, the presence of major and minor medical complications and the incidence of pressure sores in patients with a fracture of the hip. All patients admitted to Vancouver General Hospital with this injury between 1998 and 2001 inclusive were identified from our trauma registry. A review of the case notes was performed to determine the delay in time from admission to surgery, age, gender, type of fracture and medical comorbidities. A time-to-event analysis was performed for length of stay. Additionally, a Cox proportional hazards model was used to determine the effect of delay to surgery on the length of stay while controlling for other pertinent confounding factors. Using logistical regression we determined the effect of delay to surgery on in-hospital death, medical complications and the presence of pressure sores, while controlling for confounding factors. Delay to surgery (p = 0.0255), comorbidity (p < 0.0001), age (p < 0.0001) and type of fracture (p = 0.0004) were all significant in the Cox proportional hazards model for increased time to discharge. Delay to surgery was not a significant predictor of in-hospital mortality. However, a delay of more than 24 hours was a significant predictor of a minor medical complication (odds ratio (OR) 1.53, 95% confidence interval (CI) 1.05 to 2.22), while a delay of more than 48 hours was associated with an increased risk of a major medical complication (OR 2.21, 95% CI 1.01 to 4.34), a minor medical complication (OR 2.27, 95% CI 1.38 to 3.72) and of pressure sores (OR 2.29, 95% CI 1.19 to 4.40). Patients with a fracture of the hip should have surgery early to lessen the time to acute-care hospital discharge and to minimise the risk of complications.