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.
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