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2.
JAMA Psychiatry ; 78(3): 311-319, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33355626

ABSTRACT

Importance: Racial/ethnic disparities in health care use and clinical outcomes for behavioral health disorders, including psychosis, are well documented, but less is known about these disparities during the period leading up to first-episode psychosis (FEP). Objective: To describe the racial/ethnic disparities in behavioral health care use and prescription drug use of children and young adults before the diagnosis of FEP. Design, Setting, and Participants: An observational cohort study was conducted using medical and prescription drug claims from January 1, 2007, to September 30, 2015, obtained from Optum's deidentified Clinformatics Data Mart Database, a commercial claims database augmented with race/ethnicity and socioeconomic variables. Data analysis was performed from February 6, 2018, to October 10, 2020. First-episode psychosis was determined by the presence of psychosis diagnoses on claims for at least 1 hospitalization or 2 outpatient events, with a continuous enrollment requirement of at least 2 years before the first diagnosis. Participants included 3017 Black, Hispanic, or White patients who were continually enrolled in commercial insurance plans and received an FEP diagnosis between the ages of 10 and 21 years. Main Outcomes and Measures: Race/ethnicity was determined from a commercial claims database. Rates of inpatient admission, emergency department presentation, and outpatient visits (including psychotherapy), behavioral health disorder diagnoses, and antipsychotic/antidepressant prescription fills were determined for the year before FEP. Race/ethnicity was also obtained from Optum's claims database. With use of multivariable logistic regression, results were adjusted for covariates including estimated household income, age, sex, and geographic division in the US. Results: Of the 3017 patients with FEP, 643 Black or Hispanic patients (343 [53.3%] Black, 300 [46.7%] Hispanic, 324 [50.4%] male, mean [SD] age, 17.2 [2.76] years) were less likely than 2374 White patients (1210 [51.0%] male, mean age, 17.0 [2.72] years) to receive comorbid behavioral health disorder diagnoses in the year before the diagnosis of FEP (410 [63.8%] vs 1806 [76.1%], χ2 = 39.3; P < .001). Except for emergency care, behavioral health care use rates were lower in Black and Hispanic patients vs White patients (424 [65.9%] vs 1868 [78.7%]; χ2 = 45.0; P < .001), particularly for outpatient visits with behavioral health care professionals (232 [36.1%] vs 1236 [52.1%]; χ2 = 51.7; P < .001). After adjustment for socioeconomic covariates, behavioral health care use rates (68.9% vs 79.2%; P < .001), outpatient visits with behavioral health professionals (37.7% vs 51.2%; P < .001), and other outcomes remained significantly lower for Black and Hispanic patients vs White patients. Conclusions and Relevance: The results of this study extend existing research findings of well-known racial/ethnic disparities in the population of patients who are diagnosed with FEP. These differences were apparent in young patients with continuous commercial health insurance and after controlling for household income. Providing equal access to preventive outpatient behavioral health care may increase opportunities for timely detection of psychotic symptoms and early intervention and improve differential outcomes after FEP.


Subject(s)
Behavioral Symptoms/ethnology , Black or African American/ethnology , Facilities and Services Utilization/statistics & numerical data , Healthcare Disparities/ethnology , Hispanic or Latino/statistics & numerical data , Mental Health Services/statistics & numerical data , Psychotic Disorders/ethnology , White People/ethnology , Adolescent , Adult , Ambulatory Care/statistics & numerical data , Behavioral Symptoms/diagnosis , Behavioral Symptoms/therapy , Child , Cohort Studies , Female , Humans , Insurance, Health/statistics & numerical data , Male , Socioeconomic Factors , Young Adult
3.
Mamm Genome ; 30(9-10): 245-259, 2019 10.
Article in English | MEDLINE | ID: mdl-31673770

ABSTRACT

Genome-wide association studies (GWAS) and functional genomic analyses have implicated several ITGAM (CD11b) single-nucleotide polymorphisms (SNPs) in the development of SLE and other disorders. ITGAM encodes the αM chain of the ß2 integrin Mac-1, a receptor that plays important roles in myeloid cell functions. The ITGAM SNP rs1143679, which results in an arginine to histidine change at amino acid position 77 of the CD11b protein, has been shown to reduce binding to several ligands and to alter Mac-1-mediated cellular response in vitro. Importantly, however, the potential contribution of this SNP variant to the initiation and/or progression of immune and inflammatory processes in vivo remains unexplored. Herein, we describe for the first time the generation and characterization of a mouse line expressing the 77His variant of CD11b. Surprisingly, we found that 77His did not significantly affect Mac-1-mediated leukocyte migration and activation as assessed using thioglycollate-induced peritonitis and LPS/TNF-α-induced dermal inflammation models. In contrast, expression of this variant did alter T cell immunity, as evidenced by significantly reduced proliferation of ovalbumin (OVA)-specific transgenic T cells in 77His mice immunized with OVA. Reduced antigen-specific T cell proliferation was also observed when either 77His splenic dendritic cells (DCs) or bone marrow-derived DCs were used as antigen-presenting cells (APCs). Although more work is necessary to determine how this alteration might influence the development of SLE or other diseases, these in vivo findings suggest that the 77His variant of CD11b can compromise the ability of DCs to induce antigen-driven T cell proliferation.


Subject(s)
CD11b Antigen/genetics , Dendritic Cells/immunology , Polymorphism, Single Nucleotide , T-Lymphocytes/cytology , Alleles , Amino Acid Substitution , Animals , CD11b Antigen/immunology , Cell Proliferation , Female , Genome-Wide Association Study , Genotype , Male , Mice , Mice, Inbred C57BL , T-Lymphocytes/immunology
4.
Front Immunol ; 9: 372, 2018.
Article in English | MEDLINE | ID: mdl-29556231

ABSTRACT

C-reactive protein (CRP) is the prototypical acute phase reactant, increasing in blood concentration rapidly and several-fold in response to inflammation. Recent evidence indicates that CRP has an important physiological role even at low, baseline levels, or in the absence of overt inflammation. For example, we have shown that human CRP inhibits the progression of experimental autoimmune encephalomyelitis (EAE) in CRP transgenic mice by shifting CD4+ T cells away from the TH1 and toward the TH2 subset. Notably, this action required the inhibitory Fcγ receptor IIB (FcγRIIB), but did not require high levels of human CRP. Herein, we sought to determine if CRP's influence in EAE might be explained by CRP acting on dendritic cells (DC; antigen presenting cells known to express FcγRIIB). We found that CRP (50 µg/ml) reduced the yield of CD11c+ bone marrow-derived DCs (BMDCs) and CRP (≥5 µg/ml) prevented their full expression of major histocompatibility complex class II and the co-stimulatory molecules CD86 and CD40. CRP also decreased the ability of BMDCs to stimulate antigen-driven proliferation of T cells in vitro. Importantly, if the BMDCs were genetically deficient in mouse FcγRIIB then (i) the ability of CRP to alter BMDC surface phenotype and impair T cell proliferation was ablated and (ii) CD11c-driven expression of a human FCGR2B transgene rescued the CRP effect. Lastly, the protective influence of CRP in EAE was fully restored in mice with CD11c-driven human FcγRIIB expression. These findings add to the growing evidence that CRP has important biological effects even in the absence of an acute phase response, i.e., CRP acts as a tonic suppressor of the adaptive immune system. The ability of CRP to suppress development, maturation, and function of DCs implicates CRP in the maintenance of peripheral T cell tolerance.


Subject(s)
C-Reactive Protein/metabolism , Cell Differentiation , Dendritic Cells/physiology , Encephalomyelitis, Autoimmune, Experimental/immunology , Multiple Sclerosis/immunology , Animals , C-Reactive Protein/genetics , CD11c Antigen/metabolism , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Humans , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Peripheral Tolerance , Receptors, IgG/genetics
6.
Autoimmune Dis ; 2015: 640171, 2015.
Article in English | MEDLINE | ID: mdl-26421184

ABSTRACT

We recently demonstrated that human C-reactive protein (CRP), expressed hepatically in transgenic mice (CRPtg), improved the outcome of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). The liver is the primary site of CRP synthesis in humans and in CRPtg mice but is also expressed by both at low levels in the CNS. To determine if CNS expression of human CRP is sufficient to impact EAE, we generated neuronal CRP transgenic mice (nCRPtg) wherein human CRP expression is driven by the neuron-specific Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) gene promoter. We found that hepatically expressed/blood-borne CRP, but not CNS expressed CRP, lessened EAE severity. These outcomes indicate that the protective actions of human CRP in EAE are manifested in the periphery and not in the CNS and reveal a previously unappreciated site specificity for the beneficial actions of CRP in CNS disease.

7.
J Immunol ; 194(11): 5243-52, 2015 Jun 01.
Article in English | MEDLINE | ID: mdl-25917100

ABSTRACT

Human C-reactive protein (CRP) is a serum-soluble pattern recognition receptor that serves as a marker of inflammation and directly contributes to innate immunity. In this study, we show that human CRP also directly contributes to adaptive immunity, that is, native CRP binds specifically to human Jurkat T cells and to mouse naive CD4(+) T cells and modulates their Th1 and Th2 responses. In vitro both exogenously added (purified) and endogenously expressed (via transfection) human CRP inhibited Th1 differentiation and augmented Th2 differentiation of naive CD4(+) T cells. In vivo for human CRP transgenic compared with wild-type mice, a lesser proportion of the T cells recovered from the spleens of healthy animals were Th1 cells. Moreover, in both CRP transgenic mice and in wild-type mice treated with human CRP, during myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis both the Th1 cell response and disease severity were inhibited. These pattern recognition-independent actions of CRP directly on T cells highlights the potential for this soluble pattern recognition receptor to act as a tonic regulator of immunity, shaping global adaptive immune responses during both homeostasis and disease.


Subject(s)
Adaptive Immunity/immunology , C-Reactive Protein/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Th1 Cells/immunology , Animals , C-Reactive Protein/genetics , Cell Differentiation/immunology , Encephalomyelitis, Autoimmune, Experimental/genetics , Humans , Jurkat Cells , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myelin-Oligodendrocyte Glycoprotein , Protein Binding/immunology , Th1 Cells/cytology , Th2 Cells/cytology , Th2 Cells/immunology
8.
Invest Ophthalmol Vis Sci ; 55(8): 4776-89, 2014 May 22.
Article in English | MEDLINE | ID: mdl-24854857

ABSTRACT

PURPOSE: Delayed rod-mediated dark adaptation (DA) is characteristic of early age-related macular degeneration (AMD) and also can be observed in some older adults in normal macular health. We examine cross-sectional associations between rod-mediated DA and risk factors for AMD in older adults in normal macular health. METHODS: The sample consisted of adults aged ≥60 years old in normal macular health per grading of fundus photos using an established disease classification system. Rod-mediated DA was measured psychophysically following a photobleach using a computer-automated dark adaptometer with targets centered at 5° on the inferior vertical meridian. The speed of DA was characterized by the rod-intercept value, with abnormal DA defined as rod-intercept ≥ 12.3 minutes. We assessed several health and functional characteristics that the literature has suggested increase AMD risk (e.g., smoking, alcohol use, inflammatory markers, apolipoproteins, low luminance visual acuity, chronic medical conditions, body mass, family history). RESULTS: Among 381 participants (mean age, 68.5 years; SD, 5.5), 78% had normal and 22% had abnormal DA, with the prevalence of abnormal DA increasing with age. After age-adjustment, abnormal DA was associated with increased odds of elevated C-reactive protein (CRP), heavy use of or abstention from alcohol, high blood pressure, and drop in visual acuity under mesopic conditions. CONCLUSIONS: Despite having normal macular health according to accepted definitions of AMD presence, approximately one-quarter of older adults recruited from primary eye care clinics had abnormal DA, which was associated with known risk factors for AMD, including elevated CRP.


Subject(s)
Aging/physiology , Dark Adaptation/physiology , Macula Lutea/physiology , Macular Degeneration/physiopathology , Retinal Rod Photoreceptor Cells/physiology , Visual Acuity , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Photic Stimulation , Psychometrics/methods , Reference Values
9.
Autoimmune Dis ; 2011: 484936, 2010 Oct 12.
Article in English | MEDLINE | ID: mdl-21151582

ABSTRACT

We showed earlier that experimental autoimmune encephalomyelitis (EAE) in human C-reactive protein (CRP) transgenic mice (CRPtg) has delayed onset and reduced severity compared to wild-type mice. Since human CRP is known to engage Fc receptors and Fc receptors are known to play a role in EAE in the mouse, we sought to determine if FcγRI, FcγRIIb, or FcγRIII was needed to manifest human CRP-mediated protection of CRPtg. We report here that in CRPtg lacking either of the two activating receptors, FcγRI and FcγRIII, the beneficial effects of human CRP are still observed. In contrast, if CRPtg lack expression of the inhibitory receptor FcγRIIB, then the beneficial effect of human CRP is abrogated. Also, subcutaneous administration of purified human CRP stalled progression of ongoing EAE in wild-type mice, but similar treatment failed to impede EAE progression in mice lacking FcγRIIB. The results reveal that a CRP → FcγRIIB axis is responsible for protection against EAE in the CRPtg model.

10.
J Neurosci Res ; 86(3): 618-29, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18041089

ABSTRACT

Reactive astrogliosis is a prominent neuropathologic feature of manganism, a neurodegenerative disorder caused by excessive accumulation of manganese (Mn) in the basal ganglia. Activation of astrocytes has been linked to neuronal injury in manganism resulting from overproduction of inflammatory mediators, including tumor necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma), interleukin-1beta (IL-1beta), and nitric oxide (NO), but the signaling mechanisms by which Mn regulates these factors remain poorly understood. We previously reported that Mn enhances production of NO in activated astrocytes that promotes apoptosis in cocultured neuronal cells by a mechanism involving the transcription factor nuclear factor-kappaB (NF-kappaB) (Liu et al., 2005). Because NF-kappaB-dependent expression of inducible nitric oxide synthase (NOS2) can be antagonized by the nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPARgamma), we postulated that a novel agonist of this receptor, 1,1-bis(3'-indolyl)-1-(p-trifluoromethylphenyl)methane (cDIM1), would suppress expression of NOS2 in astrocytes and protect cocultured neuronal cells from apoptosis. Submicromolar concentrations of cDIM1 potently suppressed production of NO and expression of NOS2 in cultured astrocytes exposed to Mn and IFNgamma/TNFalpha and prevented apoptosis in cocultures of differentiated PC12 cells, but this neuroprotective effect was lost in the absence of astrocytes. By using fluorescence reporter and chromatin immunoprecipitation (ChIP) assays, we found that cDIM1 prevented activation of NF-kappaB in astrocytes by a mechanism involving stabilization of the nuclear corepressor 2 (NCoR2) on the proximal NF-kappaB binding site of the NOS2 promoter. These data suggest that PPARgamma may be an effective target for limiting inflammatory activation of astrocytes during neurologic injury.


Subject(s)
Apoptosis/drug effects , Astrocytes/metabolism , Indoles/pharmacology , Manganese/pharmacology , Neuroprotective Agents/pharmacology , Nitric Oxide/antagonists & inhibitors , PC12 Cells/physiology , PPAR gamma/agonists , Animals , Astrocytes/drug effects , Binding Sites , Coculture Techniques , DNA-Binding Proteins/metabolism , Interferon-gamma/pharmacology , NF-kappa B/antagonists & inhibitors , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/genetics , Nuclear Receptor Co-Repressor 2 , PC12 Cells/drug effects , Promoter Regions, Genetic , Rats , Repressor Proteins/metabolism , Tumor Necrosis Factor-alpha/pharmacology
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