Predictive Validity of the Suicide Trigger Scale (STS-3) for Post-Discharge Suicide Attempt in High-Risk Psychiatric Inpatients

Background

The greatly increased risk of suicide after psychiatric hospitalization is a critical problem, yet we are unable to identify individuals who would attempt suicide upon discharge. The Suicide Trigger Scale v.3 (STS-3), was designed to measure the construct of an affective ‘suicide trigger state’ hypothesized to precede a suicide attempt (SA). This study aims to test the predictive validity of the STS-3 for post-discharge SA on a high-risk psychiatric-inpatient sample.

Methods

The STS-3, and a psychological test battery measuring suicidality, mood, impulsivity, trauma history, and attachment style were administered to 161 adult psychiatric patients hospitalized following suicidal ideation (SI) or SA. Receiver Operator Characteristic and logistic regression analyses were used to assess prediction of SA in the 6-month period following discharge from hospitalization.

Results

STS-3 scores for the patients who made post-discharge SA followed a bimodal distribution skewed to high and low scores, thus a distance from median transform was applied to the scores. The transformed score was a significant predictor of post-discharge SA (AUC 0.731), and a subset of six STS-3 scale items was identified that produced improved prediction of post-discharge SA (AUC 0.814). Scores on C-SSRS and BSS were not predictive. Patients with ultra-high (90^th percentile) STS-3 scores differed significantly from ultra-low (10^th percentile) scorers on measures of affective intensity, depression, impulsiveness, abuse history, and attachment security.

Conclusion

STS-3 transformed scores at admission to the psychiatric hospital predict suicide attempts following discharge among the high-risk group of suicidal inpatients. Patients with high transformed scores appear to comprise two clinically distinct groups; an impulsive, affectively intense, fearfully attached group with high raw STS-3 scores and a low-impulsivity, low affect and low trauma-reporting group with low raw STS-3 scores. These groups may correspond to low-plan and planned suicide attempts, respectively, but this remains to be established by future research.     

Spatiotemporal dynamics of Spc105 regulates the assembly of the Drosophila kinetochore

The formation of kinetochores shortly before each cell division is a prerequisite for proper chromosome segregation. The synchronous mitoses of Drosophila syncytial embryos have provided an ideal in vivo system to follow kinetochore assembly kinetics and so address the question of how kinetochore formation is regulated. We found that the nuclear exclusion of the Spc105/KNL1 protein during interphase prevents precocious assembly of the Mis12 complex. The nuclear import of Spc105 in early prophase and its immediate association with the Mis12 complex on centromeres are thus the first steps in kinetochore assembly. The cumulative kinetochore levels of Spc105 and Mis12 complex then determine the rate of Ndc80 complex recruitment commencing only after nuclear envelope breakdown. The carboxy-terminal part of Spc105 directs its nuclear import and is sufficient for the assembly of all core kinetochore components and CENP-C, when localized ectopically to centrosomes. Super-resolution microscopy shows that carboxy-terminus of Spc105 lies at the junction of the Mis12 and Ndc80 complexes on stretched kinetochores. Our study thus indicates that physical accessibility of kinetochore components plays a crucial role in the regulation of Drosophila kinetochore assembly and leads us to a model in which Spc105 is a licensing factor for its onset.     

Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity

The liver is a target for toxic chemicals such as cadmium (Cd). When the liver is damaged, hepatic stellate cells (HSC) are activated and transformed into myofibroblast-like cells, which are responsible for liver fibrosis. Curcuma longa has been reported to exert a hepato-protective effect under various pathological conditions. We investigated the effects of C. longa administration on HSC activation in response to Cd induced hepatotoxicity. Forty adult male albino rats were divided into: group 1 (control), group 2 (Cd treated), group 3 (C. longa treated) and group 4 (Cd and C. longa treated). After 6 weeks, liver specimens were prepared for light and electron microscopy examination of histological changes and immunohistochemical localization of alpha smooth muscle actin (αSMA) as a specific marker for activated HSC. Activated HSC with a positive αSMA immune reaction were not detected in groups 1 and 3. Large numbers of activated HSC with αSMA immune reactions were observed in group 2 in addition to Cd induced hepatotoxic changes including excess collagen deposition in thickened portal triads, interlobular septa with hepatic lobulation, inflammatory cell infiltration, a significant increase in Kupffer cells and degenerated hepatocytes. In group 4, we observed a significant decrease in HSC that expressed αSMA with amelioration of the hepatotoxic changes. C. longa administration decreased HSC activation and ameliorated hepatotoxic changes caused by Cd in adult rats.     

Laser-induced heating of dextran-coated mesocapsules containing indocyanine green

Indocyanine green (ICG) is a photosensitive reagent with clinically relevant diagnostic and therapeutic applications. Recently, ICG has been investigated for its utility as an exogenous chromophore during laser-induced heating. However, ICG's effectiveness remains hindered by its molecular instability, rapid circulation kinetics, and nonspecific systemic distribution. To overcome these limitations, we have encapsulated ICG within dextran-coated mesocapsules (MCs). Our objective in this study was to explore the ability of MCs to induce thermal damage in response to laser irradiation. To simulate tumorous tissue targeted with MCs, cylindrical phantoms were prepared consisting of gelatin, intralipid emulsion, and various concentrations of MCs. The phantoms were embedded within fresh chicken breast tissue representing surrounding normal tissue. The tissue models were irradiated at lambda = 808 nm for 10 min at constant power (P = 4.2 W). Five hypodermic thermocouples were used to record the temperature at various depths below the tissue surface and transverse distances from the laser beam central axis during irradiation. Temperature profiles were processed to remove the baseline temperature and influence of light absorption by the thermocouple and subsequently used to calculate a damage index based on the Arrhenius damage integral. Tissue models containing MCs experienced a maximum temperature change of 18.5 degrees C. Damage index calculations showed that the heat generation from MCs at these parameters is sufficient to induce thermal damage, while no damage was predicted in the absence of MCs. ICG maintains its heat-generating capabilities in response to NIR laser irradiation when encapsulated within MCs. Such encapsulation provides a potentially useful methodology for laser-induced therapeutic strategies.     

Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice

Gene targeting techniques have led to the phenotypic characterization of numerous genes; however, many genes show minimal to no phenotypic consequences when disrupted, despite many having highly conserved sequences. The standard explanation for these findings is functional redundancy. A competing hypothesis is that these genes have important ecological functions in natural environments that are not needed under laboratory settings. Here we discriminate between these hypotheses by competing mice (Mus musculus) whose Hoxb1 gene has been replaced by Hoxa1, its highly conserved paralog, against matched wild-type controls in seminatural enclosures. This Hoxb1^A1 swap was reported as a genetic manipulation resulting in no discernible embryonic or physiological phenotype under standard laboratory tests. We observed a transient decline in first litter size for Hoxb1^A1 homozygous mice in breeding cages, but their fitness was consistently and more dramatically reduced when competing against controls within seminatural populations. Specifically, males homozygous for the Hoxb1^A1 swap acquired 10.6% fewer territories and the frequency of the Hoxb1^A1 allele decreased from 0.500 in population founders to 0.419 in their offspring. The decrease in Hoxb1^A1 frequency corresponded with a deficiency of both Hoxb1^A1 homozygous and heterozygous offspring. These data suggest that Hoxb1 and Hoxa1 are more phenotypically divergent than previously reported and support that sub- and/or neofunctionalization has occurred in these paralogous genes leading to a divergence of gene function and incomplete redundancy. Furthermore, this study highlights the importance of obtaining fitness measures of mutants in ecologically relevant conditions to better understand gene function and evolution.     

The Proapoptotic Protein tBid Forms Both Superficially Bound and Membrane-Inserted Oligomers

Bid is a proapopotic activator protein of the Bcl-2 family that plays a pivotal role in controlling mitochondrial outer membrane permeabilization during apoptosis. Here, we characterized the interaction of fluorescently labeled truncated Bid (tBid) with a mitochondria-like supported lipid bilayer at the single-molecule level. The proteins observed at the membrane exhibited a very wide range of mobility. Confocal images of the membrane displayed both diffraction-limited Gaussian spots and horizontal streaks, corresponding to immobile and mobile tBid species, respectively. We observed 1), fast-diffusing proteins corresponding to a loosely, probably electrostatically bound state; 2), slowly diffusing proteins, likely corresponding to a superficially inserted state; and 3), fully immobilized proteins, suggesting a fully inserted state. The stoichiometry of these proteins was determined by normalizing their fluorescence intensity by the brightness of a tBid monomer, measured separately using fluorescence fluctuation techniques. Strikingly, the immobile species were found to be mainly tetramers and higher, whereas the mobile species had on average a significantly lower stoichiometry. Taken together, these results show that as soluble Bid progresses toward a membrane-inserted state, it undergoes an oligomerization process similar to that observed for Bax.     

New inhibitors of VEGFR-2 targeting the extracellular domain dimerization process

We are reporting the discovery of small molecule inhibitors for vascular endothelial growth factor receptor type 2 (VEGFR-2) extracellular domain. The VEGFR-2 extracellular domain is responsible for the homo-dimerization process, which has been recently reported as a main step in VEGFR signal transduction cascade. This cascade is essential for the vascularization and survival of most types of cancers. Two main design strategies were used; Molecular docking-based Virtual Screening and Fragment Based Design (FBD). A virtual library of drug like compounds was screened using a cascade of docking techniques in order to discover an inhibitor that binds to this new binding site. Rapid docking methodology was used first to filter the large number of compounds followed by more accurate and slow ones. Fragment based molecular design was adopted afterwards due to unsatisfactory results of screening process. Screening and design process resulted in a group of inhibitors with superior binding energies exceeding that of the natural substrate. Molecular dynamics simulation was used to test the stability of binding of these inhibitors and finally the drug ability of these compounds was assisted using Lipinski rule of five. By this way the designed compounds have shown to possess high pharmacologic potential as novel anticancer agents.     

Synthesis and biological evaluation of some novel sulfamoylphenyl-pyridazinone as anti-inflammatory agents (Part-II * )

Seven novel 6-aryl-2-(p-sulfamoylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a-g) were synthesized by the condensation of appropriate aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Structure of all compounds have been elucidated by elemental analysis, IR, (1)H NMR, (13)C NMR, DEPT and MS spectrscopy. These compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Compound 2b exhibited anti-inflammatory activity comparable to that of celecoxib (at 5?h). Two other compounds 2d and 2g showed promising anti-inflammatory activity (edema reduction more than 80% at 5?h). These compounds (2b, 2d and 2g) did not produce any ulceration in gastric region.