Rapid screening for suicide risk: An algorithmic approach.

INTRODUCTION: In the United States, primary medical care settings are the first accessed resource for both medical and behavioral health care. Thus, there is a clear need for accurate and efficient behavioral health screening in this setting, including routine surveillance screening for suicide risk. The Multidimensional Behavioral Health Screen (MBHS), a broadband but very brief screening tool developed specifically for primary care, has been updated to include an algorithm that classifies suicide risk based on the interpersonal-psychological theory of suicide, and associated interview and decision framework. This study aims to evaluate the predictive accuracy of the new MBHS 2.0 suicide risk algorithm, with actual risk determined by clinical suicide risk interview. METHOD: Data were collected as part of a larger study that, overall, included 551 college student participants. Of these, 309 completed the MBHS 2.0 and the clinical suicide risk interview, the two measures reported here. The final participant count was 299 following the removal of incomplete or invalid cases. Predicted suicide risk as determined by the MBHS 2.0 (Low, Mild, At least Moderate) was compared to actual risk as determined by clinical interview (Low, Moderate, Severe, Extreme). RESULTS: Utilizing chi-square analyses, data show a significant association between the predicted suicide risk category based on the MBHS 2.0 algorithm and the actual risk category based on the semi-structured clinical interview. Furthermore, classification analyses suggest that primary care providers will be able to confidently assess the suicide risk level for the majority of their patients when using the MBHS. CONCLUSION: Findings suggest that the MBHS 2.0 can be an accurate and efficient tool for use by primary care providers in classifying suicide risk. Future research will be useful to evaluate the utility of the suicide risk algorithm among primary care populations.

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels.

Drugs do not act solely by canonical ligand-receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure-activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT's membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported.

Stereochemically general approach to adjacent bis(tetrahydrofuran) cores of annonaceous acetogenins.

A series of six 2,5-disubstituted adjacent bis(tetrahydrofuran) stereoisomers with trans/erythro/cis, trans/threo/trans, or cis/threo/cis relative stereochemistry have been synthesized from known dihydroxycyclooctenes via ring opening/cross metathesis and Pd(0)-mediated asymmetric double cycloetherification. The stereochemistry of four of these isomers has been found in the biologically active annonaceous acetogenin natural products. [reaction: see text].

Localization and activity of multidrug resistance protein 1 in the secretory pathway of Leishmania parasites.

Upregulation of the multidrug resistance protein 1 (LeMDR1) in the protozoan parasite, Leishmania enriettii, confers resistance to hydrophobic drugs such as vinblastine, but increases the sensitivity of these parasites to the mitochondrial drug, rhodamine 123. In order to investigate the mechanism of action of LeMDR1, the subcellular localization of green fluorescent protein (GFP)-tagged versions of LeMDR1 and the fate of the traceable-fluorescent LeMDR1 substrate calcein AM were examined in both Leishmania mexicana and L. enriettii LeMDR1 -/- and overexpressing cell lines. The LeMDR1-GFP chimera was localized by fluorescence microscopy to a number of secretory and endocytic compartments, including the Golgi apparatus, endoplasmic reticulum (ER) and a multivesicular tubule (MVT)-lysosome. Pulse-chase labelling experiments with calcein AM suggested that the Golgi and ER pools, but not the MVT-lysosome pool, of LeMDR1 were active in pumping calcein AM out of the cell. Cells labelled with calcein AM under conditions that slow vesicular transport (low temperature and stationary growth) inhibited export and resulted in the accumulation of fluorescent calcein in both the Golgi and the mitochondria. We propose that LeMDR1 substrates are pumped into secretory compartments and exported from the parasite by exocytosis. Accumulation of MDR substrates in the ER can result in alternative transport to the mitochondrion, explaining the reciprocal sensitivity of drug-resistant Leishmania to vinblastine and rhodamine 123.

Identification of regulatory elements in the Plasmodium falciparum genome.

There is little information regarding regulatory sequences in the newly sequenced genome of the malaria parasite, Plasmodium falciparum. Thus, for the first time, a bioinformatic strategy was utilized to identify regulatory elements in this genome using the P. falciparum heat shock protein (hsp) gene family as a model system. Our analysis indicates that the P. falciparum hsp genes do not contain standard eukaryotic regulatory elements. However, a novel G-rich regulatory element named the G-box was identified upstream of several P. falciparum hsp genes and the P. yoelii yoelii, P. berghei, and P. vivax hsp86 genes. Remarkably, the Plasmodium sp. G-boxes were required for maximal reporter gene expression in transient transfection assays. The G-box is not homologous to known eukaryotic elements, and is the best-defined functional element elucidated from Plasmodium sp. Our analysis also revealed several other elements necessary for reporter gene expression including an upstream sequence element, the region surrounding the transcription start site, and the 5' and 3' untranslated regions. These data demonstrate that unique regulatory elements are conserved in the genomes of Plasmodium sp., and demonstrate the feasibility of bioinformatic approaches for their identification.