Is Gatekeeper Training Enough for Suicide Prevention?

While schools have the capacity to reach youth at-risk for suicide, there remains a gap between the number of youth with mental health issues and those who     

A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

Cocaine functions, in part, through agonist actions at sigma‐1 (σ₁) receptors, while roles played by sigma‐2 (σ₂) receptors are less established. Attempts to discriminate σ₂ receptor‐mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ₂ receptor affinity, and excellent selectivity for binding to σ₂ over σ₁ receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5‐bromo‐N‐[4‐(6,7‐dimethoxy‐3,4‐dihydro‐1H‐isoquinolin‐2‐yl)‐butyl)]‐2,3‐dimethoxy‐benzamide, 1 , a ligand shown by others to bind preferentially to σ₂ over σ₁ receptors, as well as dopamine D₂ and D₃ sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57‐fold selectivity for σ₂ receptors over the serotonin transporter, and >800‐fold selectivity for σ₂ receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD‐1® mice, and saw no alteration of basal activity at doses up to 31.6 µmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 µmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ₁ receptors or the dopamine transporter by 1 , or its possible metabolites, at the 31.6 µmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ₂ receptor‐selective antagonist that is able to counteract cocaine's motor stimulatory effects. Synapse 68:73–84, 2014 . © 2013 Wiley Periodicals, Inc.     

BMP2 Regulation of CXCL12 Cellular,Temporal, and Spatial Expression Is Essential During Fracture Repair

The cellular and humoral responses that orchestrate fracture healing are still elusive. Here we report that bone morphogenic protein 2 (BMP2)‐dependent fracture healing occurs through a tight control of chemokine C‐X‐C motif‐ligand‐12 (CXCL12) cellular, spatial, and temporal expression. We found that the fracture repair process elicited an early site‐specific response of CXCL12⁺‐BMP2⁺ endosteal cells and osteocytes that was not present in unfractured bones and gradually decreased as healing progressed. Absence of a full complement of BMP2 in mesenchyme osteoprogenitors (BMP2^cKO/+) prevented healing and led to a dysregulated temporal and cellular upregulation of CXCL12 expression associated with a deranged angiogenic response. Healing was rescued when BMP2^cKO/+ mice were systemically treated with AMD3100, an antagonist of CXCR4 and agonist for CXCR7 both receptors for CXCL12. We further found that mesenchymal stromal cells (MSCs), capable of delivering BMP2 at the endosteal site, restored fracture healing when transplanted into BMP2^cKO/+ mice by rectifying the CXCL12 expression pattern. Our in vitro studies showed that in isolated endosteal cells, BMP2, while inducing osteoblastic differentiation, stimulated expression of pericyte markers that was coupled with a decrease in CXCL12. Furthermore, in isolated BMP2^cKO/cKO endosteal cells, high expression levels of CXCL12 inhibited osteoblastic differentiation that was restored by AMD3100 treatment or coculture with BMP2‐expressing MSCs that led to an upregulation of pericyte markers while decreasing platelet endothelial cell adhesion molecule (PECAM). Taken together, our studies show that following fracture, a CXCL12⁺‐BMP2⁺ perivascular cell population is recruited along the endosteum, then a timely increase of BMP2 leads to downregulation of CXCL12 that is essential to determine the fate of the CXCL12⁺‐BMP2⁺ to osteogenesis while departing their supportive role to angiogenesis. Our findings have far‐reaching implications for understanding mechanisms regulating the selective recruitment of distinct cells into the repairing niches and the development of novel pharmacological (by targeting BMP2/CXCL12) and cellular (MSCs, endosteal cells) interventions to promote fracture healing. © 2015 American Society for Bone and Mineral Research.     

Inhibition of HIV-1 replication by oligonucleotide analogues directed to the packaging signal and trans-activating response region

HIV possesses a remarkable capacity for mutational escape from therapeutics that target the viral proteins and enzymes. Inhibitory strategies aimed at highly conserved nucleic acid sequences within the genome are an attractive alternative. However, it has proven difficult to achieve an effective level of therapeutic at the appropriate site within the cell. Oligonucleotide delivery is a rapidly advancing field. We have investigated oligonucleotide analogues as steric-block therapeutics against two highly conserved regions of the HIV-1 genome. In the study we show that 2'0-methyl/locked nucleic acid oligonucleotides against the packaging signal and trans-activating response regions of HIV can inhibit replication of the virus.     

The impact of behavioral signs of intoxication on bartender service

Objective: The present study was designed to assess whether the serving practices of a sample of bartenders in an American university town would vary as a function of the number of behavioral cues of intoxication displayed by apparently real patrons (who were actually experimental confederates).

Method: We trained two male and three female confederates to role-play three different conditions (three ambiguous signs, eight apparently obvious signs, or no signs of intoxication) and assessed whether they would be served a second beer after ‘accidentally’ knocking over a first beer.

Results: Service of another beer was denied in only 10% of episodes when a confederate displayed no signs or three signs indicative of intoxication; however, confederates were denied service during 50% of episodes when multiple, obvious signs were displayed. Furthermore, neither the type of the establishment, gender of the bartender or gender of the confederate was associated with likelihood of being served the second drink.

Conclusion: Although some bartenders are attentive to multiple behavioral signs of intoxication, we recommend additional research on the most effective combinations of server training and legal measures to reduce further the proportion of intoxicated customers served alcohol, both for their own benefit and the public health.