Genome scan in familial late‐onset Alzheimer's disease: A locus on chromosome 6 contributes to age‐at‐onset

Alzheimer's disease (AD) is a common, genetically complex, fatal neurodegenerative disorder of late life. Although several genes are known to play a role in early‐onset AD, identification of the genetic basis of late onset AD (LOAD) has been challenging, with only the APOE gene known to have a high contribution to both AD risk and age‐at‐onset. Here, we present the first genome‐scan analysis of the complete, well‐characterized University of Washington LOAD sample of 119 pedigrees, using age‐at‐onset as the trait of interest. The analysis approach used allows for a multilocus trait model while at the same time accommodating age censoring, effects of APOE as a known genetic covariate, and full pedigree and marker information. The results provide strong evidence for linkage of loci contributing to age‐at‐onset to genomic regions on chromosome 6q16.3, and to 19q13.42 in the region of the APOE locus. There was evidence for interaction between APOE and the locus on chromosome 6q and suggestive evidence for linkage to chromosomes 11p13, 15q12‐14, and 19p13.12. These results provide the first independent confirmation of an AD age‐at‐onset locus on chromosome 6 and suggest that further efforts towards identifying the underlying causal locus or loci are warranted. © 2013 Wiley Periodicals, Inc.     

A platelet target for venous thrombosis? P2Y1 deletion or antagonism protects mice from vena cava thrombosis

A role for platelets in the pathogenesis of venous thrombosis was suggested by clinical and preclinical studies. However, examination of the platelet receptor, P2Y1, in this area has been limited. The goal of the current study was to examine effects of P2Y1 deletion, or selective antagonism with MRS2500, in oxidative venous thrombosis in mice. The P2Y12 antagonist, clopidogrel, was included as a reference agent. Anesthetized C57BL/6 or genetically modified mice underwent 3.5 or 5 % FeCl(3)-induced vena cava thrombosis. Pharmacokinetic properties of MRS2500 were defined for dose selection. Platelet aggregation and renal or tail bleeding times (BT) were measured to put antithrombotic effects into perspective. P2Y1 deletion significantly reduced (p < 0.001) venous thrombus weight by 74 % in 3.5 % FeCl(3) injury compared to P2Y1(+/+) littermates. MRS2500 (2 mg/kg, i.v.) significantly decreased (p < 0.001) thrombus weight 64 % in C57BL/6 mice. In the more severe 5 % FeCl(3)-induced injury model, thrombus weight significantly (p < 0.001) decreased 68 % in P2Y1(-/-) mice versus P2Y1(+/+) mice, and MRS2500 (2 mg/kg) was also beneficial (54 % decrease, p < 0.01). Renal BT doubled in P2Y1(-/-) versus P2Y1(+/+) mice, and increased threefold with MRS2500 compared to vehicle. Tail BT was markedly prolonged in P2Y1(-/-) mice (7.9X) and in C57BL/6 mice given MRS2500. The current study demonstrates that P2Y1 deletion or antagonism significantly reduced venous thrombosis in mice, suggesting that P2Y1 receptors play a role in the pathogenesis of venous thrombosis, at least in this species. However as with many antithrombotic agents the benefit comes at the potential price of an increase in provoked bleeding times.     

Validity and reliability of measurements of aponeurosis dimensions from magnetic resonance images

Muscle performance is closely related to the structure and function of tendons and aponeuroses, the sheet‐like, intramuscular parts of tendons. The architecture of aponeuroses has been difficult to study with magnetic resonance imaging (MRI) because these thin, collagen‐rich connective tissues have very short transverse relaxation (T2) times and therefore provide a weak signal with conventional MRI sequences. Here, we validated measurements of aponeurosis dimensions from two MRI sequences commonly used in muscle‐tendon research (mDixon and T1‐weighted images), and an ultrashort echo time (UTE) sequence designed for imaging tissues with short T2 times. MRI‐based measurements of aponeurosis width, length, and area of 20 sheep leg muscles were compared to direct measurements made with three‐dimensional (3D) quantitative microdissection. The errors in measurement of aponeurosis width relative to the mean width were 1.8% for UTE, 3.7% for T1, and 18.8% for mDixon. For aponeurosis length, the errors were 7.6% for UTE, 1.9% for T1, and 21.0% for mDixon. Measurements from T1 and UTE scans were unbiased, but mDixon scans systematically underestimated widths, lengths, and areas of the aponeuroses. Using the same methods, we then found high inter‐rater reliability (intraclass correlation coefficients >0.92 for all measures) of measurements of the dimensions of the central aponeurosis of the human tibialis anterior muscle from T1‐weighted scans. We conclude that valid and reliable measurements of aponeurosis dimensions can be obtained from UTE and from T1‐weighted scans. When the goal is to study the macroscopic architecture of aponeuroses, UTE does not hold an advantage over T1‐weighted imaging.     

Development of Stabilizing Formulations of a Trivalent Inactivated Poliovirus Vaccine in a Dried State for Delivery in the Nanopatch™ Microprojection Array

The worldwide switch to inactivated polio vaccines (IPVs) is a key component of the overall strategy to achieve and maintain global polio eradication. To this end, new IPV vaccine delivery systems may enhance patient convenience and compliance. In this work, we examine Nanopatch? (a solid, polymer microprojection array) which offers potential advantages over standard needle/syringe administration including intradermal delivery and reduced antigen doses. Using trivalent IPV (tIPV) and a purpose-built evaporative dry-down system, candidate tIPV formulations were developed to stabilize tIPV during the drying process and on storage. Identifying conditions to minimize tIPV potency losses during rehydration and potency testing was a critical first step. Various classes and types of pharmaceutical excipients (～50 total) were then evaluated to mitigate potency losses (measured through D-antigen ELISAs for IPV1, IPV2, and IPV3) during drying and storage. Various concentrations and combinations of stabilizing additives were optimized in terms of tIPV potency retention, and 2 candidate tIPV formulations containing cyclodextrin and a reducing agent (e.g., glutathione), maintained ≥80% D-antigen potency during drying and subsequent storage for 4 weeks at 4°C, and ≥60% potency for 3 weeks at room temperature with the majority of losses occurring within the first day of storage.     

Supplemental peri-operative intravenous crystalloids for postoperative nausea and vomiting: an abridged Cochrane systematic review

We conducted a Cochrane systematic review on the effectiveness of supplemental intravenous crystalloid administration in preventing postoperative nausea and vomiting. We included randomised controlled trials of patients undergoing surgery under general anaesthesia and given supplemental peri-operative intravenous crystalloid. Our primary outcomes were the risk of postoperative nausea and the risk of postoperative vomiting. We assessed the risk of bias for each included study and applied the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework for the certainty of evidence. We included 41 studies. We found that the intervention probably reduces the overall risk of postoperative nausea, the risk ratio (95%CI) being 0.62 (0.51–0.75) (I² = 57%, p < 0.00001, 18 studies; 1766 participants; moderate-certainty evidence). It also probably reduces the risk of postoperative nausea within 6 h of surgery, with a risk ratio (95%CI) of 0.67 (0.58 to 0.78) (I² = 9%, p < 0.00001, 20 studies; 2310 participants; moderate-certainty evidence) and by around 24 h, the risk ratio (95%CI) being 0.47 (0.32–0.69) (I² = 38%, p = 0.0001, 17 studies; 1682 participants; moderate-certainty evidence). Supplemental intravenous crystalloid probably also reduces the overall risk of postoperative vomiting, with a risk ratio (95%CI) of 0.50 (0.40–0.63) (I² = 31%, p < 0.00001, 20 studies; 1970 participants; moderate-certainty evidence). The beneficial effect on vomiting was seen both within 6 h and by around 24 h postoperatively.