In this study, we used small interfering RNA (siRNA) directed against vascular endothelial growth factor receptor 1 (vegfr1) mRNA to investigate the role of VEGFR1 in ocular neovascularization (NV). After evaluating many siRNAs, Sirna-027 was identified; it cleaved vegfr1 mRNA at the predicted site and reduced its levels in cultured endothelial cells and in mouse models of retinal and choroidal neovascularization (CNV). Compared to injection of an inverted control sequence, quantitative reverse transcriptase-PCR demonstrated statistically significant reductions of 57 and 40% in vegfr1 mRNA after intravitreous or periocular injection of Sirna-027, respectively. Staining showed uptake of 5-bromodeoxyuridine-labeled Sirna-027 in retinal cells that lasted between 3 and 5 days after intravitreous injection and was still present 5 days after periocular injection. In a CNV model, intravitreous or periocular injections of Sirna-027 resulted in significant reductions in the area of NV ranging from 45 to 66%. In mice with ischemic retinopathy, intravitreous injection of 1.0 mg of Sirna-027 reduced retinal NV by 32% compared to fellow eyes treated with 1.0 mg of inverted control siRNA. These data suggest that VEGFR1 plays an important role in the development of retinal and CNV and that targeting vegfr1 mRNA with siRNA has therapeutic potential. Gene Therapy (2006) 13, 225-234.

Declarative memory encompasses representations of specific events as well as knowledge extracted by accumulation over multiple episodes. To investigate how these different sorts of memories are created, we developed a new behavioral task in rodents. The task consists of 3 distinct conditions (stable, overlapping, and random). Rodents are exposed to multiple sample trials, in which they explore objects in specific spatial arrangements, with object identity changing from trial to trial. In the stable condition, the locations are constant during all sample trials even though the objects themselves change; in the test trial, 1 object’s location is changed. In the random condition, object locations are presented in the sample phase without a specific spatial pattern. In the overlapping condition, 1 location is shared (overlapping) between all trials, while the other location changes during sample trials. We show that in the overlapping condition, instead of only remembering the last sample trial, rodents form a cumulative memory of the sample trials. Here, we could show that both mice and rats can accumulate information across multiple trials and express a long-term abstracted memory.

The role of extracorporeal membrane oxygenation (ECMO) as part of cardiopulmonary resuscitation (ECPR) among the elderly is not clearly defined. We sought to query the international Extracorporeal Life Support Organization (ELSO) registry database to investigate the use of ECMO support among the elderly. The objective of this study was to investigate survival to hospital discharge among the elderly supported on ECMO. The ELSO registry database was queried, identifying all elderly patients (>65 years of age) supported on ECMO for ECPR from 1998 to 2009. The primary outcome variable was survival to hospital discharge. Clinical characteristics between survivors and nonsurvivors were compared using univariate analysis. Ninety-nine elderly patients requiring ECPR were identified from the ELSO registry for the study period. The median age of the cohort was 70 years (range 65-86 years). The median admission to time on ECMO was 32 hours (range 1-998 hours), median time on ECMO was 69 hours (range 1-459 hours), and median time off to discharge for survivors was 587 hours (range 3-2,166 hours). Overall, survival at hospital discharge was 22.2% (22/99). No significant differences were noted between survivors and nonsurvivors for demographics, secondary diagnoses, pre-ECMO variables, complications on ECMO, as well as the type and duration of ECMO support. Among listed comorbidities, only the presence of pre-ECMO acute renal failure was significantly more frequent in nonsurvivors compared with survivors (14 vs. 0; p = 0.04). Survival to hospital discharge among the elderly supported on ECMO is lower than that for younger adult patients (28.7% vs. 40.0%). However, it is higher than that after conventional CPR (17%), suggesting that age should not be a bar against consideration for the use of ECMO in older patients but should be considered on a case-by-case basis.

Interindividual variability in analgesic response is at least partly due to well-characterized polymorphisms that are associated with opioid dosing and adverse outcomes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has put forward recommendations for the CYP2D6 phenotype, but the list of studied drug-gene pairs continues to grow. This clinical trial randomized chronic pain patients (n = 60), referred from primary care to pain unit care into two opioid prescribing arms, one guided by CYP2D6, μ-opioid receptor (OPRM1), and catechol-O-methyl transferase (COMT) genotypes vs. one with clinical routine. The genotype-guided treatment reduced pain intensity (76 vs. 59 mm, p < 0.01) by improving pain relief (28 vs. 48 mm, p < 0.05), increased quality of life (43 vs. 56 mm p < 0.001), and lowered the incidence of clinically relevant adverse events (3 [1–5] vs. 1 [0–2], p < 0.01) and 42% opioid dose (35 [22–61] vs. 60 [40–80] mg/day, p < 0.05) as opposed to usual prescribing arm. The final health utility score was significantly higher (0.71 [0.58–0.82] vs. 0.51 [0.13–0.67] controls, p < 0.05) by improving sleepiness and depression comorbidity, with a significant reduction of 30–34% for headache, dry mouth, nervousness, and constipation. A large-scale implementation analysis could help clinical translation, together with a pharmaco-economic evaluation.

An important aspect of a memory is whether it is representing a specific event or whether it is a representation of knowledge extracted over multiple episodes. To investigate this difference, we developed a new multi-trial behavioral task that can assess memory accumulation in rodents. It makes use of rodents' innate drive to explore novelty and allows for later recordings (e.g. electrophysiology) and interventions. The task consists of three distinct conditions (stable, overlapping, random) that can be repeated within animals. Rodents are exposed to multiple sample trials, in which they explore objects in specific spatial arrangements. In the stable condition, the locations are constant during all sample trials, and one object's location changes during test. In the random condition, object locations are presented without a specific spatial pattern. In the overlapping condition, one location is shared (overlapping) between all trials while the other location changes during sample trials. We show that in the overlapping condition, instead of only remembering the last sample trial, rodents form a cumulative memory of the sample trials. We adapted the task so that it can be learned by both rats and mice, making it suitable for investigating this aspect of memory across species and using a wide array of methods to measure and perturb the neural basis of memory.

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