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Recent evidence implicates epigenetic mechanisms in drug-associated memory processes. However, a possible role for one major epigenetic mechanism, nucleosome remodelling, in drug-associated memories remains largely unexplored. Here we examine mice with genetic manipulations targeting a neuron-specific nucleosome remodelling complex subunit, BAF53b. These mice display deficits in cocaine-associated memory that are more severe in BAF53b transgenic mice compared with BAF53b heterozygous mice. Similar to the memory deficits, theta-induced long-term potentiation (theta-LTP) in the nucleus accumbens (NAc) is significantly impaired in slices taken from BAF53b transgenic mice but not heterozygous mice. Further experiments indicate that theta-LTP in the NAc is dependent on TrkB receptor activation, and that BDNF rescues theta-LTP and cocaine-associated memory deficits in BAF53b transgenic mice. Together, these results suggest a role for BAF53b in NAc neuronal function required for cocaine-associated memories, and also that BDNF/TrkB activation in the NAc may overcome memory and plasticity deficits linked to BAF53b mutations.

Introduction Nonessential central venous catheters (CVCs) should be removed promptly to prevent adverse events. Little is known about effective strategies to achieve this goal. The present study evaluates the effectiveness of a quality improvement (QI) initiative to remove nonessential CVCs in the intensive care unit (ICU).Methods A prospective observational study was performed in two ICUs following a QI intervention that included a daily checklist, education, and reminders. During 28 consecutive days, all CVCs were identified and the presence of ongoing indications for CVC placement was recorded. The proportions of nonessential CVCs and CVC days were compared with pre-intervention proportions and between the participating units. Rates of central line-associated bloodstream infections (CLABSI) were measured separately through Ontario's Critical Care Information System. Results One hundred and ten patients and 159 CVCs were reviewed. Eighty-eight (11%) of 820 catheter days showed no apparent indication for CVC placement, and compared with the pre-intervention period, the proportion of patients with any number of nonessential CVC days decreased from 51% to 26% (relative risk 0.51; 95% confidence interval 0.34 to 0.74; P \ 0.001). There was no significant difference in the proportion of nonessential catheter days between participating units. Reported rates of CLABSI decreased substantially during the intervention. Discussion A checklist tool supported by a multifaceted QI intervention effectively ensured prompt removal of nonessential CVCs in two ICUs. RésuméIntroduction Les cathe´ters veineux centraux (CVC) non essentiels doivent eˆtre retire´s rapidement afin de pre´venir les effets inde´sirables. On ne sait que peu de choses sur les strate´gies efficaces permettant d'atteindre cet objectif. La pre´sente e´tude e´value l'efficacite´d'une initiative d'ame´lioration de la qualite´pour supprimer les CVC non essentiels dans une unite´de soins intensifs (USI). Méthode Une e´tude observationnelle prospective a e´te´mene´e dans deux USI suite a`une intervention

The enzyme aminopeptidase N (APN, also known as CD13) is known to play an important role in tumor proliferation, attachment, angiogenesis, and tumor invasion. In this study, we hypothesized that a radiolabeled high affinity APN inhibitor could be potentially useful for imaging APN expression in vivo. Here we report synthesis, radiolabeling, and biological evaluation of new probestin conjugates containing a tripeptide, N,N-dimethylglycyl-L-lysinyl-L-cysteinylamide (N3S), chelator. New probestin conjugates were synthesized by solid-phase peptide synthesis method, purified by reversed-phase HPLC, and characterized by electrospray mass spectrometry. The conjugates were complexed with Re(V) and 99mTc(V) by transmetallation using corresponding Re(V) or 99mTc(V) gluconate synthon. The mass spectral analyses of ReO-N3S-Probestin conjugates were consistent with the formation of neutral Re(V)O-N3S complexes. Initial biological activity of ReO-N3S-Probestin conjugates determined by performing an in vitro APN enzyme assay using intact HT-1080 cells demonstrated higher inhibition of APN enzyme activity than bestatin. In vivo biodistribution and whole body planar imaging studies of 99mTcO-N3S-PEG2-Probestin performed in nude mice xenografted with human fibrosarcoma tumors derived from HT-1080 cells demonstrated a tumor uptake value of 2.88 ± 0.64 %ID/g with tumor-to-blood and tumor-to-muscle ratios of 4.8 and 5.3 respectively at 1 hr post-injection (p.i.). Tumors were clearly visible in whole-body planar image obtained at 1 hr p.i., but not when the APN was competitively blocked with a co-injection of excess non-radioactive ReO-N3S-PEG2-Probestin conjugate. These results demonstrate the feasibility of using high affinity APN inhibitor conjugates as targeting vectors for in vivo targeting of APN.

Adequate first-line supplementation with vitamin D and phosphate appeared to improve biochemical markers of MBD, but given the observational nature of this study, further longitudinal/prospective studies are required to confirm these findings.

Reproducible methods for [(18)F]radiolabeling of biological vectors are essential for the development of new [(18)F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi-step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [(18)F]radiolabeling of such molecules, our group has synthesized ethynyl-4-[(18)F]fluorobenzene ([(18)F]2, [(18)F]EYFB) in a single step (14 ± 2% non-decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne-functionalized synthon [(18)F]2 was then conjugated to two azido-functionalized vector molecules via CuAAC reactions. The first 'proof of principle' conjugation of [(18)F]2 to 1-azido-1-deoxy-β-D-glucopyranoside (3) gave the desired radiolabeled product [(18)F]4 in excellent radiochemical yield (76 ± 4% ndc RCY (11% overall)). As a second example, the conjugation of [(18)F]2 to matrix-metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [(18)F]6 in very good radiochemical yield (56 ± 12% ndc RCY (8% overall)). Total preparation time for [(18)F]4 and [(18)F]6 including [(18)F]F(-) drying, two-step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [(18)F]2 and the conjugated products, [(18)F]4 and [(18)F]6, were all greater than 98%. The specific activities of [(18)F]2 and [(18)F]6 were low, 5.97 and 0.17 MBq nmol(-1), respectively.

Color Vision Changes Associated with Cataracts 2 Abstract Purpose: The cone contrast threshold (CCT) test quantified color vision changes in subjects of all ages and those undergoing cataract surgery. Methods: Twenty-four healthy volunteers from two cohort studies performed CCT using best corrected visual acuity, filters, mydriasis, and pinhole correction. Retrospective cross-sectional study of patients seen in eye clinics evaluated the relationship between age and color vision, and age and lens status in 355 eyes. Lastly, 25 subjects performed CCT before and after cataract surgery. Results: CCT scores were most reliable in the non-mydriatic condition without pinhole correction. Progressively dense brown filters produced small but significant reductions in S-cone sensitivity. Linear regression analysis of phakic subjects showed a decline for all cone classes with age. Rate of decline was greater for S-cones (slope (95% CI) = -1.09 (-1.23, 0.94)) than Mcones (slope (95% CI) = -0.80 (-0.95, -0.66)) and L-cones (slope (95% CI) = -0.66 (-0.81, -0.52)). CCT scores increased for S-cones but reduced for L-and M-cones in pseudophakic subjects compared to phakic patients. CCT scores after cataract surgery increased for S-cones, M-cones, and L-cones by 33.0 (p<0.001), 24.9 (p=0.001), and 22.0 (p=0.008). Conclusions: CCT assessment allows for clinically practical quantitation of color and contrast vision improvement after cataract surgery and aging patients who note poor vision despite good visual acuity. Translational Relevance: CCT testing, historically used in research, is now a clinically practical tool to evaluate age and cataract related changes in color and contrast vision and routinely quantify vision beyond black and white visual acuity testing.

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