Plasma S1P Orchestrates the Reverse Transendothelial Migration of Aortic Intimal Myeloid Cells in Mice.

BACKGROUND: Myeloid cells (MCs) reside in the aortic intima at regions predisposed to atherosclerosis. Systemic inflammation triggers reverse transendothelial migration (RTM) of intimal MCs into the arterial blood, which orchestrates a protective immune response that clears intracellular pathogens from the arterial intima. Molecular pathways that regulate RTM remain poorly understood. S1P (sphingosine-1-phosphate) is a lipid mediator that regulates immune cell trafficking by signaling via 5 G-protein-coupled receptors (S1PRs [S1P receptors]). We investigated the role of S1P in the RTM of aortic intimal MCs. METHODS: Intravenous injection of lipopolysaccharide was used to model a systemic inflammatory stimulus that triggers RTM. CD11c+ intimal MCs in the lesser curvature of the ascending aortic arch were enumerated by en face confocal microscopy. Local gene expression was evaluated by transcriptomic analysis of microdissected intimal cells. RESULTS: In wild-type C57BL/6 mice, lipopolysaccharide induced intimal cell expression of S1pr1, S1pr3, and Sphk1 (a kinase responsible for S1P production). Pharmacological modulation of multiple S1PRs blocked lipopolysaccharide-induced RTM and modulation of S1PR1 and S1PR3 reduced RTM in an additive manner. Cre-mediated deletion of S1pr1 in MCs blocked lipopolysaccharide-induced RTM, confirming a role for myeloid-specific S1PR1 signaling. Global or hematopoietic deficiency of Sphk1 reduced plasma S1P levels, the abundance of CD11c+ MCs in the aortic intima, and blunted lipopolysaccharide-induced RTM. In contrast, plasma S1P levels, the abundance of intimal MCs, and lipopolysaccharide-induced RTM were rescued in Sphk1-/- mice transplanted with Sphk1+/+ or mixed Sphk1+/+ and Sphk1-/- bone marrow. Stimulation with lipopolysaccharide increased endothelial permeability and intimal MC exposure to circulating factors such as S1P. CONCLUSIONS: Functional and expression studies support a novel role for S1P signaling in the regulation of lipopolysaccharide-induced RTM and the homeostatic maintenance of aortic intimal MCs. Our data provide insight into how circulating plasma mediators help orchestrate intimal MC dynamics.

Radiation Impacts Early Atherosclerosis by Suppressing Intimal LDL Accumulation.

RATIONALE: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT. OBJECTIVE: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms. METHODS AND RESULTS: Ldlr-/- mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of Ldlr-/- relative to Ldlr+/+ mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT. CONCLUSIONS: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.

Speculations on the Future of Psychiatric Diagnosis.

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V), criterion symptom listings are frequently used in clinical practice as checklists to make diagnoses. However, most DSM-V conditions are, in fact, syndromes, that is, collections of signs and symptoms that commonly occur together in the clinic. This report discusses the value of syndromes in medicine and psychiatry. It is argued that a more precise future enumeration of brain circuits and the pathogenesis of psychiatric conditions will help us better understand and treat psychiatric syndromes, but they are unlikely to eliminate the need to categorize psychiatric conditions. We expect that biomarkers will play an increasingly critical role in psychiatric diagnosis. Beyond a better mechanistic understanding of the DSM-V syndromes, future diagnostic efforts will need to increase the focus on function and address risk factors for nonresponse and relapse. We suggest that new artificial intelligence advances will increase the efficiency and acceptability of psychiatric diagnosis and assist with treatment delivery.

Schizophrenia: treatment targets beyond monoamine systems.

We develop the proposal in this review that schizophrenia is a syndrome made up of component symptom complexes, each with distinctive clinical correlates, pathophysiology, and selective treatments. Psychosis is the necessary component of the syndrome; it has a young-adult onset and is sensitive to current antipsychotic drugs. Cognitive dysfunction often precedes psychosis onset, does not present an episodic course, and is poorly responsive to antipsychotic drugs. Treatments for cognition are being developed largely on the basis of animal pharmacology. Drugs for component symptom complexes will theoretically be coadministered to independent symptomatic end points. Animal models, some with genetic characteristics, can be more easily and directly developed to match an individual component than to match an illness definition as broad as schizophrenia.

Autorotation of the Mandible as Sequelae to Maxillary Intrusion: A Systematic Review.

BACKGROUND: Autorotation of the mandible is a normally anticipated phenomenon following a surgical superior repositioning of the maxilla in clinical situations where patients have an excessive gummy smile. Prediction of the surgical treatment outcome following a presurgical orthodontic treatment is a critical element in the surgical treatment planning. MATERIALS AND METHODS: The relevant articles were selected by hand search and electronic media (Google Scholar, PubMed, Science Direct, Medline, Embase, and Cochrane) from 1982 to 2020. All the relevant articles were properly screened, and findings were extracted from the articles. RESULTS: It was observed that, following maxillary intrusion, mandible would eventually autorotate to take a new occlusion. Mandibular autorotation as a result of maxillary intrusion would lead to minimal shortening of the lower lip in the vertical plane. It was observed that the amount of mandibular autorotation correlates with the extent of maxillary impaction. Studies have shown that there is a passive soft-tissue response which may be attributed to the fact that no muscular detachment had been affected in the lower lip and soft-tissue chin region during the maxillary surgery. CONCLUSION: It is observed that there is a definite influence on the mandibular and chin positions as a result of maxillary intrusion and autorotation of the mandible. Every 1 mm of maxillary superior impaction, the chin moved 0.6 mm vertically and 0.2 mm horizontally. There is an appreciable shortening of the lower lip length.

Comparison of self-report and clinician ratings on two inventories of depressive symptomatology.

OBJECTIVE: This study evaluated the concordance between the self-report and the clinician-rated versions of the Inventory of Depressive Symptomatology (IDS-30) and between the two versions of the briefer 16-item Quick Inventory of Depressive Symptomatology (QIDS-16). METHODS: Data were gathered for 544 adult outpatients with psychotic (N = 106) or nonpsychotic (N = 438) major depressive disorder at 14 public sector mental health clinics in the Texas Medication Algorithm Project. Data for the QIDS-16 were extracted from the IDS-30. Baseline scores and scores from the final study visit at or before month 12 were analyzed. The clinician-rated and the self-report versions of each scale were compared in their identification of response to treatment and remission. RESULTS: The average baseline IDS-SR-30 total score was 2.2 points higher (indicating greater severity) than the IDS-C-30 score; the average QIDS-SR-16 total score was only .3 points higher than the QIDS-C-16 score. The IDS-SR-30 and the IDS-C-30, as well as the QIDS-C-16 and QIDS-SR-16, agreed substantially in classifying response and remission for patients, regardless of whether the patients had psychotic features. None of a large number of clinical and demographic features accounted for differences between the QIDS-SR-16 and QIDS-C-16 total scores. CONCLUSIONS: Either the IDS-30 or the QIDS-16 self-report adequately assesses depressive symptom severity among public-sector outpatients with major depressive disorder. The briefer QIDS-16 may be preferred to save time and cost.

Dopaminergic abnormalities in select thalamic nuclei in schizophrenia: involvement of the intracellular signal integrating proteins calcyon and spinophilin.

OBJECTIVE: While both thalamic abnormalities and dopaminergic dysregulation have been separately implicated in the pathophysiology of schizophrenia, little is known about the possible dysfunction of molecules associated with dopaminergic neurotransmission in the thalamus in this illness. In this study, the authors studied this question by measuring in postmortem brain the expression of molecules associated with dopaminergic neurotransmission. METHOD: Using in situ hybridization and receptor autoradiography, the authors determined in schizophrenia and comparison subjects 1) thalamic expression of the transcripts encoding the five dopamine receptors; 2) binding to the dopamine D(1), D(2), and D(3) receptors; 3) monoaminergic innervation as assessed by binding to the vesicular monoamine transporter; and 4) transcripts encoding three dopamine receptor-associated intracellular proteins (calcyon, spinophilin, and DARPP-32) that mediate integration of dopaminergic signaling with other neurotransmitter systems. RESULTS: Both calcyon and spinophilin transcripts were significantly elevated in schizophrenia subjects. Monoaminergic innervation, as well as dopamine receptor transcripts and binding sites, were unaffected in this illness. CONCLUSIONS: These data indicate that there are dopaminergic abnormalities in the thalamus in schizophrenia but that they are at the level of intracellular integration of dopamine signaling with other neurotransmitter systems, likely including glutamate, in thalamic neurons.

Self-reported depressive symptom measures: sensitivity to detecting change in a randomized, controlled trial of chronically depressed, nonpsychotic outpatients.

This study evaluated and compared the performance of three self-report measures: (1) 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR30); (2) 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16); and (3) Patient Global Impression-Improvement (PGI-I) in assessing clinical outcomes in depressed patients during a 12-week, acute phase, randomized, controlled trial comparing nefazodone, cognitive-behavioral analysis system of psychotherapy (CBASP), and the combination in the treatment of chronic depression. The IDS-SR30, QIDS-SR16, PGI-I, and the 24-item Hamilton Depression Rating Scale (HDRS24) ratings were collected at baseline and at weeks 1-4, 6, 8, 10, and 12. Response was defined a priori as a > or =50% reduction in baseline total score for the IDS-SR30 or for the QIDS-SR16 or as a PGI-I score of 1 or 2 at exit. Overall response rates (LOCF) to nefazodone were 41% (IDS-SR30), 45% (QIDS-SR16), 53% (PCI-I), and 47% (HDRS17). For CBASP, response rates were 41% (IDS-SR30), 45% (QIDS-SR16), 48% (PGI-I), and 46% (HDRS17). For the combination, response rates were 68% (IDS-SR30 and QIDS-SR16), 73% (PGI-I), and 76% (HDRS17). Similarly, remission rates were comparable for nefazodone (IDS-SR30=32%, QIDS-SR16=28%, PGI-I=22%, HDRS17=30%), for CBASP (IDS-SR30=32%, QIDS-SR16=30%, PGI-I=21%, HDRS17=32%), and for the combination (IDS-SR30=52%, QIDS-SR16=50%, PGI-I=25%, HDRS17=49%). Both the IDS-SR30 and QIDS-SR16 closely mirrored and confirmed findings based on the HDRS24. These findings raise the possibility that these two self-reports could provide cost- and time-efficient substitutes for clinician ratings in treatment trials of outpatients with nonpsychotic MDD without cognitive impairment. Global patient ratings such as the PGI-I, as opposed to specific item-based ratings, provide less valid findings.