Forensic psychiatric issues in intellectual disability.

Forensic psychiatrists and neuropsychiatrists are likely to encounter individuals with intellectual disability as they are over-represented in the judicial system. These individuals may have the full range of mental illnesses and comorbid conditions, including physical infirmity, sensory deficits, language impairment, and maladaptive behaviors. They are frequently disadvantaged in the judicial system due to lack of comprehension, lack of accommodations, and stigmatization. Decision making capacity may need to be assessed for health care, sexual autonomy, marriage, financial management, making a will, and need for guardianship. The usual approach to conducting an evaluation needs adaptation to fit the unique characteristics and circumstances of the individual with intellectual disability. The forensic consultant can assist attorneys, defendants, and victims in recommending accommodations and the expert witness can provide education to juries.

Geographic Disparities in Re-triage Destinations Among Seriously Injured Californians.

Objective: To quantify geographic disparities in sub-optimal re-triage of seriously injured patients in California. Summary of Background Data: Re-triage is the emergent transfer of seriously injured patients from the emergency departments of non-trauma and low-level trauma centers to, ideally, high-level trauma centers. Some patients are re-triaged to a second non-trauma or low-level trauma center (sub-optimal) instead of a high-level trauma center (optimal). Methods: This was a retrospective observational cohort study of seriously injured patients, defined by an Injury Severity Score > 15, re-triaged in California (2009-2018). Re-triages within one day of presentation to the sending center were considered. The sub-optimal re-triage rate was quantified at the state, regional trauma coordinating committees (RTCC), local emergency medical service agencies, and sending center level. A generalized linear mixed-effects regression quantified the association of sub-optimality with the RTCC of the sending center. Geospatial analyses demonstrated geographic variations in sub-optimal re-triage rates and calculated alternative re-triage destinations. Results: There were 8,882 re-triages of seriously injured patients and 2,680 (30.2 %) were sub-optimal. Sub-optimally re-triaged patients had 1.5 higher odds of transfer to a third short-term acute care hospital and 1.25 increased odds of re-admission within 60 days from discharge. The sub-optimal re-triage rates increased from 29.3 % in 2009 to 38.6 % in 2018. 56.0 % of non-trauma and low-level trauma centers had at least one sub-optimal re-triage. The Southwest RTCC accounted for the largest proportion (39.8 %) of all sub-optimal re-triages in California. Conclusion: High population density geographic areas experienced higher sub-optimal re-triage rates.

Chemokine Receptor CCR7 Triggers an Endomembrane Signaling Complex for Spatial Rac Activation.

Chemokine-guided cell migration is pivotal for many immunological and developmental processes. How chemokine receptor signaling persists to guarantee sustained directional migration despite receptor desensitization and internalization remains poorly understood. Here, we uncover a function for an intracellular pool of the chemokine receptor CCR7 present in human dendritic cells and cellular model systems. We find that CCR7 signaling, initiated at the plasma membrane, is translocated by joint trafficking of ß-arrestin and Src kinase to endomembrane-residing CCR7. There, Src tyrosine phosphorylates CCR7, required for the recruitment of Vav1 to form an endomembrane-residing multi-protein signaling complex comprising CCR7, the RhoGEF Vav1, and its effector, Rac1. Interfering with vesicular trafficking affects CCR7-driven cell migration, whereas CCR7:Vav1 interaction at endomembranes is essential for local Rac1 recruitment to CCR7. Photoactivation of Rac1 at endomembranes leads to lamellipodia formation at the cell's leading edge, supporting the role of sustained endomembrane signaling in guiding cell migration.

Macrophage Superoxide Anion Production in Essential Hypertension: Associations With Biological and Psychological Cardiovascular Risk Factors.

OBJECTIVE: Essential hypertension is an important risk factor for coronary artery disease and its underlying process atherosclerosis, but involved mechanisms are not fully understood. Both macrophages and superoxide anions have been proposed to play a major role in the pathogenesis of atherosclerosis. In the present study, we investigated whether macrophages of individuals with hypertension show higher nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide anion production compared with normotensive individuals. Furthermore, we examined associations between macrophage superoxide anion production and the psychological factors depression and chronic stress independent from hypertension status. METHODS: We studied 30 hypertensive (mean [standard deviation] = 48.7 [2.4] years) and 30 age-matched normotensive men (mean [standard deviation] = 48.6 [2.4] years). We assessed macrophage superoxide anion production using the WST-1 assay. The assay is based on the chemical reduction of the cell-impermeative tetrazolium salt WST-1 by superoxide anions that are produced by activated human ex vivo isolated monocyte-derived macrophages. We further evaluated whether chronic stress or depressive symptom severity was associated with macrophage superoxide anion production. All analyses were adjusted for potential confounders. RESULTS: Individuals with hypertension showed higher superoxide anion production compared with normotensive individuals (F(1,58) = 11.56, p = .001). Complementary analyses using mean arterial blood pressure as a continuous measure revealed that higher mean arterial pressure correlated significantly with higher WST-1 reduction (ß = .38, p = .003, ΔR = .145). These results remained significant when controlling for potential confounding influences. Chronic stress was related to higher WST-1 reduction scores, but this association was not statistically significant (ß = .24, p = .067, ΔR = .053); depression levels were not significantly associated with WST-1 reduction scores (p = .24). CONCLUSIONS: Our results indicate higher macrophage superoxide anion production in individuals with hypertension compared with normotensive individuals. This may suggest a mechanism underlying cardiovascular risk with hypertension.

Distinct CCR7 glycosylation pattern shapes receptor signaling and endocytosis to modulate chemotactic responses.

The homeostatic chemokines CCL19 and CCL21 and their common cognate chemokine receptor CCR7 orchestrate immune cell trafficking by eliciting distinct signaling pathways. Here, we demonstrate that human CCR7 is N-glycosylated on 2 specific residues in the N terminus and the third extracellular loop. Conceptually, CCR7 glycosylation adds steric hindrance to the receptor N terminus and extracellular loop 3, acting as a "swinging door" to regulate receptor sensitivity and cell migration. We found that freshly isolated human B cells, as well as expanded T cells, but not naïve T cells, express highly sialylated CCR7. Moreover, we identified that human dendritic cells imprint T cell migration toward CCR7 ligands by secreting enzymes that deglycosylate CCR7, thereby boosting CCR7 signaling on T cells, permitting enhanced T cell locomotion, while simultaneously decreasing receptor endocytosis. In addition, dendritic cells proteolytically convert immobilized CCL21 to a soluble form that is more potent in triggering chemotactic movement and does not desensitize the receptor. Furthermore, we demonstrate that soluble CCL21 functionally resembles neither the CCL19 nor the CCL21 phenotype but acts as a chemokine with unique features. Thus, we advance the concept of dendritic cell-dependent generation of micromilieus and lymph node conditioning by demonstrating a novel layer of CCR7 regulation through CCR7 sialylation. In summary, we demonstrate that leukocyte subsets express distinct patterns of CCR7 sialylation that contribute to receptor signaling and fine-tuning chemotactic responses.

Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes.

Chemokines are pivotal regulators of cell migration during continuous immune surveillance, inflammation, homeostasis, and development. Chemokine binding to their 7-transmembrane domain, G-protein-coupled receptors causes conformational changes that elicit intracellular signaling pathways to acquire and maintain an asymmetric architectural organization and a polarized distribution of signaling molecules necessary for directional cell migration. Leukocytes rely on the interplay of chemokine-triggered migration modules to promote amoeboid-like locomotion. One of the most important chemokine receptors for adaptive immune cell migration is the CC-chemokine receptor CCR7. CCR7 and its ligands CCL19 and CCL21 control homing of T cells and dendritic cells to areas of the lymph nodes where T cell priming and the initiation of the adaptive immune response occur. Moreover, CCR7 signaling also contributes to T cell development in the thymus and to lymphorganogenesis. Although the CCR7-CCL19/CCL21 axis evolved to benefit the host, inappropriate regulation or use of these proteins can contribute or cause pathobiology of chronic inflammation, tumorigenesis, and metastasis, as well as autoimmune diseases. Therefore, it appears as the CCR7-CCL19/CCL21 axis is tightly regulated at numerous intersections. Here, we discuss the multiple regulatory mechanism of CCR7 signaling and its influence on CCR7 function. In particular, we focus on the functional diversity of the 2 CCR7 ligands, CCL19 and CCL21, as well as on their impact on biased signaling. The understanding of the molecular determinants of biased signaling and the multiple layers of CCR7 regulation holds the promise for potential future therapeutic intervention.

Inflammation-Induced CCR7 Oligomers Form Scaffolds to Integrate Distinct Signaling Pathways for Efficient Cell Migration.

Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways.

In vivo TCR Signaling in CD4(+) T Cells Imprints a Cell-Intrinsic, Transient Low-Motility Pattern Independent of Chemokine Receptor Expression Levels, or Microtubular Network, Integrin, and Protein Kinase C Activity.

Intravital imaging has revealed that T cells change their migratory behavior during physiological activation inside lymphoid tissue. Yet, it remains less well investigated how the intrinsic migratory capacity of activated T cells is regulated by chemokine receptor levels or other regulatory elements. Here, we used an adjuvant-driven inflammation model to examine how motility patterns corresponded with CCR7, CXCR4, and CXCR5 expression levels on ovalbumin-specific DO11.10 CD4(+) T cells in draining lymph nodes. We found that while CCR7 and CXCR4 surface levels remained essentially unaltered during the first 48-72 h after activation of CD4(+) T cells, their in vitro chemokinetic and directed migratory capacity to the respective ligands, CCL19, CCL21, and CXCL12, was substantially reduced during this time window. Activated T cells recovered from this temporary decrease in motility on day 6 post immunization, coinciding with increased migration to the CXCR5 ligand CXCL13. The transiently impaired CD4(+) T cell motility pattern correlated with increased LFA-1 expression and augmented phosphorylation of the microtubule regulator Stathmin on day 3 post immunization, yet neither microtubule destabilization nor integrin blocking could reverse TCR-imprinted unresponsiveness. Furthermore, protein kinase C (PKC) inhibition did not restore chemotactic activity, ruling out PKC-mediated receptor desensitization as mechanism for reduced migration in activated T cells. Thus, we identify a cell-intrinsic, chemokine receptor level-uncoupled decrease in motility in CD4(+) T cells shortly after activation, coinciding with clonal expansion. The transiently reduced ability to react to chemokinetic and chemotactic stimuli may contribute to the sequestering of activated CD4(+) T cells in reactive peripheral lymph nodes, allowing for integration of costimulatory signals required for full activation.

Regulation of Sec16 levels and dynamics links proliferation and secretion.

We currently lack a broader mechanistic understanding of the integration of the early secretory pathway with other homeostatic processes such as cell growth. Here, we explore the possibility that Sec16A, a major constituent of endoplasmic reticulum exit sites (ERES), acts as an integrator of growth factor signaling. Surprisingly, we find that Sec16A is a short-lived protein that is regulated by growth factors in a manner dependent on Egr family transcription factors. We hypothesize that Sec16A acts as a central node in a coherent feed-forward loop that detects persistent growth factor stimuli to increase ERES number. Consistent with this notion, Sec16A is also regulated by short-term growth factor treatment that leads to increased turnover of Sec16A at ERES. Finally, we demonstrate that Sec16A depletion reduces proliferation, whereas its overexpression increases proliferation. Together with our finding that growth factors regulate Sec16A levels and its dynamics on ERES, we propose that this protein acts as an integrator linking growth factor signaling and secretion. This provides a mechanistic basis for the previously proposed link between secretion and proliferation.

CCR7: roles in cancer cell dissemination, migration and metastasis formation.

The CC-chemokine receptor 7 (CCR7) coordinates the migration of cancer cells as well as immune cells towards lymphatic organs where its two ligands CCL19 and CCL21 are constitutively expressed. Here we provide a topological model of CCR7, which belongs to the class A of G-protein coupled, seven-transmembrane spanning receptors, and describe how CCR7 expression is regulated. We focus on its role in cancer cell migration and metastasis formation and discuss how cancer cells can utilize CCR7 or its ligands to escape from immune surveillance.

Psychiatric disorders in people with intellectual disability (intellectual developmental disorder): forensic aspects.

PURPOSE OF THE REVIEW: Persons with intellectual disability come into frequent and underreported contact with the legal system. Advances in forensic psychiatry help better identify persons with intellectual disability in forensic contexts, inform evaluation and treatment, and elucidate unique characteristics of this population. With the release of Diagnostic and Statistical Manual of Mental Disorders (DSM-5), forensic psychiatrists must adjust to changes in the diagnostic process. RECENT FINDINGS: This review examines the past year's contributions to the literature, including predictors among offenders with intellectual disability, concurrent diagnoses, efficacy of competence restoration, means of studying individuals with intellectual disability, and impact of DSM-5. SUMMARY: Impoverished personal relationships are found to be an important predictor of offense among persons with intellectual disability. A Personality Disorder Characteristics Checklist allows screening for personality disorders (indicative of increased risk of violence) among intellectual disability offenders. Referrals to specialists for treatment more often occur for violent and sexual offenses than for other offenses. Competence restoration is historically low among those with intellectual disability, specially compared with those referred for substance abuse and personality disorders. However, the Slater Method results in higher rates of restoration than traditional training methods. DSM-5 alters the definition of intellectual disability, moving from an IQ-oriented diagnosis system to a multifaceted approach, introducing more flexibility and nuance.

Do forensic practitioners distinguish between testifying and consulting experts? A pilot study.

Forensic mental health professionals (n=44) reviewed a series of statements that an attorney might make to a consulting or testifying expert. Each statement was rated for its degree of appropriateness to either the consulting or the testifying role. In light of increasing attention paid to this topic in the forensic practice literature, as well as long-standing distinctions recognized by the legal profession, it was originally hypothesized that participants would differentiate clearly between these roles; however, results of this pilot study indicate that forensic practitioners do not possess a consistent sense of which activities rest most comfortably within testimonial as opposed to consulting duties.

Ubiquitylation of the chemokine receptor CCR7 enables efficient receptor recycling and cell migration.

The chemokine receptor CCR7 is essential for lymphocyte and dendritic cell homing to secondary lymphoid organs. Owing to the ability to induce directional migration, CCR7 and its ligands CCL19 and CCL21 are pivotal for the regulation of the immune system. Here, we identify a novel function for receptor ubiquitylation in the regulation of the trafficking process of this G-protein-coupled seven transmembrane receptor. We discovered that CCR7 is ubiquitylated in a constitutive, ligand-independent manner and that receptor ubiquitylation regulates the basal trafficking of CCR7 in the absence of chemokine. Upon CCL19 binding, we show that internalized CCR7 recycles back to the plasma membrane via the trans-Golgi network. An ubiquitylation-deficient CCR7 mutant internalized normally after ligand binding, but inefficiently recycled in immune cells and was transiently retarded in the trans-Golgi network compartment of HEK293 transfectants. Finally, we demonstrate that the lack of CCR7 ubiquitylation profoundly impairs immune cell migration. Our results provide evidence for a novel function of receptor ubiquitylation in the regulation of CCR7 recycling and immune cell migration.

Cross-talk between TCR and CCR7 signaling sets a temporal threshold for enhanced T lymphocyte migration.

Lymphocyte homing to, and motility within, lymph nodes is regulated by the chemokine receptor CCR7 and its two ligands CCL19 and CCL21. There, lymphocytes are exposed to a number of extracellular stimuli that influence cellular functions and determine the cell fate. In this study, we assessed the effect of TCR engagement on CCR7-mediated cell migration. We found that long-term TCR triggering of freshly isolated human T cells through CD3/CD28 attenuated CCR7-driven chemotaxis, whereas short-term activation significantly enhanced CCR7-mediated, but not CXCR4-mediated, migration efficiency. Short-term activation most prominently enhanced the migratory response of naive T cells of both CD4 and CD8 subsets. We identified distinct roles for Src family kinases in modulating CCR7-mediated T cell migration. We provide evidence that Fyn, together with Ca(2+)-independent protein kinase C isoforms, kept the migratory response of naive T cells toward CCL21 at a low level. In nonactivated T cells, CCR7 triggering induced a Fyn-dependent phosphorylation of the inhibitory Tyr505 of Lck. Inhibiting Fyn in these nonactivated T cells prevented the negative regulation of Lck and facilitated high CCR7-driven T cell chemotaxis. Moreover, we found that the enhanced migration of short-term activated T cells was accompanied by a synergistic, Src-dependent activation of the adaptor molecule linker for activation of T cells. Collectively, we characterize a cross-talk between the TCR and CCR7 and provide mechanistic evidence that the activation status of T cells controls lymphocyte motility and sets a threshold for their migratory response.

Clinicians imagine a patient's view: Rating disclosures of confidential information.

Consent to disclosure of confidential information is a cornerstone of the clinician-patient relationship; however, changes in the legal, regulatory, and technological landscape affecting patient confidentiality have brought increasing conflict between ethics-based commitments and the realities of practice. In this pilot study, 119 mental-health clinicians completed a questionnaire that measured levels of disapproval of disclosures of confidential information to various third parties. Clinicians were asked to respond as though they were patients whose information was to be disclosed. Clinicians, taking a patient's perspective, most disapproved of disclosures to anyone who wanted the information and to entities that marketed pharmaceutical, medical, or other products. They were progressively less uncomfortable with disclosures to family members, for educational use without consent but with de-identification, to insurance companies, to pharmacists, to journals, for educational purposes in training other clinicians, and for research. They were least disapproving of disclosures to other clinicians. Based on this initial study of clinicians taking a patient's perspective, clinicians will do well to inform patients about disclosure practices at least as fully as they themselves would want to be informed.

"The whole truth" versus "the admissible truth": an ethics dilemma for expert witnesses.

The expert witness testifies under oath to tell "the whole truth," yet certain aspects of the legal system itself make this ideal difficult or impossible. The authors present both a philosophical and a practical discussion of the challenges for the expert in attaining this goal. After review of oaths in general and truth-telling in particular, real-life examples are provided to examine the vicissitudes of the whole truth in court. Recommendations are provided for experts, to preserve the truth in the adversary system.