Clinical Assessment of Judgment in Adults and the Elderly: Development and Validation of the Three Domains of Judgment Test-Clinical Version (3DJT-CV).

(1) Background: This article discusses the first two phases of development and validation of the Three Domains of Judgment Test (3DJT). This computer-based tool, co-constructed with users and capable of being administered remotely, aims to assess the three main domains of judgment (practical, moral, and social) and learn from the psychometric weaknesses of tests currently used in clinical practice. (2) Method: First, we presented the 3DJT to experts in cognition, who evaluated the tool as a whole as well as the content validity, relevance, and acceptability of 72 scenarios. Second, an improved version was administered to 70 subjects without cognitive impairment to select scenarios with the best psychometric properties in order to build a future clinically short version of the test. (3) Results: Fifty-six scenarios were retained following expert evaluation. Results support the idea that the improved version has good internal consistency, and the concurrent validity primer shows that 3DJT is a good measure of judgment. Furthermore, the improved version was found to have a significant number of scenarios with good psychometric properties to prepare a clinical version of the test. (4) Conclusion: The 3DJT is an interesting alternative tool for assessing judgment. However, more studies are needed for its implementation in a clinical context.

The defense of mental disorder and crimes against the person committed under the influence of cannabis: A Canadian perspective.

The legalization of cannabis raises many queries, one of which regards the criminal liability of users under the influence of cannabis when crimes against the person are committed. This perspective review consequently aims to examine the defense of mental disorder (also referred to as the insanity defense) in Canadian criminal law and revise court decisions involving cases with cannabis use rendered in the field between 1995 and 2021. The purpose was to specify the factors allowing Canadian criminal courts to grant or refuse the defense of mental disorder to help further operationalize the jurisprudential criteria for forensic practice. We noted that presence of a severe and persistent primary psychopathology was the most decisive factor when determining the verdict of the accused who consumed cannabis.

An in vitro reconstitution system to address the mechanism of the vascular expression of the bradykinin B1 receptor in response to angiotensin converting enzyme inhibition.

The expression of the bradykinin (BK) B1 receptor (B1R), lacking in normal vascular tissues, is induced following innate immune system activation and chronic blockade of angiotensin converting enzyme (ACE). To identify cytokine-dependent or -independent mechanisms for the latter phenomenon, the ACE inhibitor enalaprilat and several peptides potentiated in vivo by ACE blockade were applied either directly to human umbilical artery smooth muscle cells (hUA-SMCs) or to differentiated monoblastoid U937 cells to produce a conditioned medium (CM) that was later transferred to hUA-SMCs. A phagocyte stimulant, lipopolysaccharide, did not upregulate B1R, measured using [³H]Lys-des-Arg9-BK binding, or translocate NF-κB to the nuclei if applied directly to the hUA-SMCs. However, the CM of lipopolysaccharide-stimulated U937 cells was active in these respects (effects inhibited by etanercept and correlated to TNF-α presence in the CM). A peptidase-resistant B1R agonist had no significant direct or indirect acute effect (4h) on B1R expression, but repeated hUA-SMC stimulations over 40 h were stimulatory in the absence of NF-κB activation. Other peptides regulated by ACE or enalaprilat did not directly or indirectly stimulate B1R expression. The reconstitution system supports the rapid cytokine-dependent vascular induction of B1Rs and a slow "autoregulatory" one potentially relevant for the ACE blockade effect.

A ligand-based approach to investigate the expression and function of angiotensin converting enzyme in intact human umbilical vein endothelial cells.

Angiotensin converting enzyme (ACE) is a drug target and an effective bradykinin (BK)-inactivating ectopeptidase. We exploited a recently described [(3)H]enalaprilat binding assay to quantify the full dynamic range of ACE expression in intact human umbilical vein endothelial cells (HUVECs) stimulated with known or novel modulators of ACE expression. Further, the affinities for ACE of a set of physiological substrates were determined using the same assay. BK has the highest affinity (K(i) 525 nM) among known substrates to displace [(3)H]enalaprilat binding from ACE. Tumor necrosis factor (TNF)-alpha repressed the expression of ACE in HUVECs while phorbol 12-myristate 13-acetate (PMA) upregulated it in 24h (approximately 12-fold dynamic range by [(3)H]enalaprilat binding, corroborated by ACE immunoblotting). Intermediate levels of ACE expression were seen in cells stimulated with both PMA and a cytokine. In contrast, high glucose, insulin or EGF failed to affect ACE expression. The effect of TNF-alpha was abated by etanercept, the IKK2 inhibitor TPCA-1, or a p38 inhibitor while that of PMA was reduced by inhibitors of PKC isoforms sensitive to phorbol esters and calcium. The short-term PKC- and MEK1-dependent increase of c-Fos expression was best correlated to PMA-induced ACE upregulation. The [(3)H]enalaprilat binding assay applied to HUVECs supports that ACE is a particularly active kininase and that endothelial ACE expression is dynamically and specifically regulated. This has potential importance in inflammatory diseases and diabetes.