ABSTRACT
OBJECTIVES: California features low smoking prevalence, cautionary electronic cigarette (e-cigarette) public messaging, and legal recreational cannabis: a unique landscape for dental professionals to navigate tobacco cessation promotion. This cross-sectional study assessed California dental professionals' self-reported tobacco patient counseling behaviors and the correlates of providing such assistance. METHODS: Statewide surveys of dental hygienists (n = 701) and dentists (n = 725) were distributed electronically. The dentist survey was weighted for sampling and nonresponse. Prevalence of asking patients about use was compared for cigarette and noncigarette products (e.g., e-cigarettes, cannabis). Multivariable models identified independent correlates of providing cessation assistance to tobacco-using patients. RESULTS: Respondents reported frequently (often/always) documenting patient tobacco use (hygienists: 80%; dentists: 73%) but less commonly provided forms of assistance (hygienists: 27%-49%; dentists: 10%-31%). Most respondents asked patients about cigarette smoking, but noncigarette product use (cigar, hookah, pipe, e-cigarette, or cannabis) was not commonly assessed. Greater confidence and willingness to assist were positively associated with providing assistance in multivariable models, but perceived barriers (e.g., lack of time and remuneration) were not. Results were robust to model specifications. CONCLUSIONS: California dental professionals often ask about smoking but lag in providing cessation assistance and inquiring about noncigarette products. Successful efforts to encourage dental professionals' engagement in tobacco prevention and cessation must enhance providers' self-efficacy and motivation and likely will require system and organizational change. KNOWLEDGE TRANSFER STATEMENT: Study findings identify substantial gaps in dental professionals' engagement in patient tobacco cessation. The results identify correlates of providing assistance and of dental professionals' willingness and confidence to do so, which could serve to inform interventions to support and enhance engagement.
Subject(s)
Cannabis , Electronic Nicotine Delivery Systems , Tobacco Products , Counseling , Cross-Sectional Studies , Dentists , Humans , NicotianaABSTRACT
BACKGROUND: The popularity of cognitive remediation (CR) interventions for individuals with psychosis is in part based on the well-established link between cognition and functioning and the assumption that by targeting cognition, function can improve. While numerous trials have reported CR's efficacy, it is still not considered an evidence-based treatment. Importantly, little is known about the mechanisms through which it may affect functioning. METHOD: In this study, we evaluated CR's proximal and distal effects, and examined potential mechanisms. A total of 75 individuals with psychotic disorders were randomized to a combination of strategy-based and drill-and-practice CR or wait-list control, with assessments of training task performance, neurocognition, functional capacity, symptoms and functioning conducted at baseline, end of the 2-month intervention, and 2-month follow-up. RESULTS: Compared with treatment as usual, CR was associated with large post-training improvements on training tasks targeting attention, visuospatial memory, and verbal learning and memory, with persisting group differences at the 2-month follow-up. These generalized to mostly large improvements on neuropsychological measures targeting visuospatial memory, verbal learning and memory, delayed verbal memory and verbal working memory. While there were no CR-associated improvements on measures of functional capacity, symptoms, or a self-report measure of independent living skills, there was an effect on an interviewer-rated measure of functioning (Quality of Life Scale), which appeared primarily driven by the Intrapsychic Foundations subscale. Finally, for those randomized to CR, there were significant, medium-sized correlations between training task improvement, neuropsychological improvement and functioning measures. CONCLUSIONS: This suggests a complex, multifactorial relationship between CR, and cognitive and functional change.
Subject(s)
Cognitive Remediation/methods , Psychotic Disorders/rehabilitation , Schizophrenia/rehabilitation , Activities of Daily Living , Adult , Attention , Female , Humans , Male , Memory , Middle Aged , Neuropsychological Tests , Psychotic Disorders/physiopathology , Psychotic Disorders/psychology , Schizophrenia/physiopathology , Schizophrenic Psychology , Spatial Memory , Task Performance and Analysis , Verbal LearningABSTRACT
Neocortical pyramidal cells can integrate two classes of input separately and use one to modulate response to the other. Their tuft dendrites are electrotonically separated from basal dendrites and soma by the apical dendrite, and apical hyperpolarization-activated currents (Ih) further isolate subthreshold integration of tuft inputs. When apical depolarization exceeds a threshold, however, it can enhance response to the basal inputs that specify the cell's selective sensitivity. This process is referred to as apical amplification (AA). We review evidence suggesting that, by regulating Ih in the apical compartments, adrenergic arousal controls the coupling between apical and somatic integration zones thus modifying cognitive capabilities closely associated with consciousness. Evidence relating AA to schizophrenia, sleep, and anesthesia is reviewed, and we assess theories that emphasize the relevance of AA to consciousness. Implications for theories of neocortical computation that emphasize context-sensitive modulation are summarized. We conclude that the findings concerning AA and its regulation by arousal offer a new perspective on states of consciousness, the function and evolution of neocortex, and psychopathology. Many issues worthy of closer examination arise.
ABSTRACT
A broad neuron-centric conception of contextual modulation is reviewed and re-assessed in the light of recent neurobiological studies of amplification, suppression, and synchronization. Behavioural and computational studies of perceptual and higher cognitive functions that depend on these processes are outlined, and evidence that those functions and their neuronal mechanisms are impaired in schizophrenia is summarized. Finally, we compare and assess the long-term biological functions of contextual modulation at the level of computational theory as formalized by the theories of coherent infomax and free energy reduction. We conclude that those theories, together with the many empirical findings reviewed, show how contextual modulation at the neuronal level enables the cortex to flexibly adapt the use of its knowledge to current circumstances by amplifying and grouping relevant activities and by suppressing irrelevant activities.
Subject(s)
Cerebral Cortex/cytology , Cerebral Cortex/physiology , Models, Neurological , Nerve Net/physiology , Neurons/physiology , Computer Simulation , HumansABSTRACT
BACKGROUND: Cognition is increasingly being recognized as an important aspect of psychotic disorders and a key contributor to functional outcome. In the past, comparative studies have been performed in schizophrenia and schizo-affective disorder with regard to cognitive performance, but the results have been mixed and the cognitive measures used have not always assessed the cognitive deficits found to be specific to psychosis. A set of optimized cognitive paradigms designed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) Consortium to assess deficits specific to schizophrenia was used to measure cognition in a large group of individuals with schizophrenia and schizo-affective disorder. METHOD: A total of 519 participants (188 with schizophrenia, 63 with schizo-affective disorder and 268 controls) were administered three cognitive paradigms assessing the domains of goal maintenance in working memory, relational encoding and retrieval in episodic memory and visual integration. RESULTS: Across the three domains, the results showed no major quantitative differences between patient groups, with both groups uniformly performing worse than healthy subjects. CONCLUSIONS: The findings of this study suggests that, with regard to deficits in cognition, considered a major aspect of psychotic disorder, schizophrenia and schizo-affective disorder do not demonstrate major significant distinctions. These results have important implications for our understanding of the nosological structure of major psychopathology, providing evidence consistent with the hypothesis that there is no natural distinction between cognitive functioning in schizophrenia and schizo-affective disorder.
Subject(s)
Cognition Disorders/physiopathology , Psychotic Disorders/physiopathology , Schizophrenia/physiopathology , Adult , Cognition Disorders/etiology , Female , Humans , Male , Memory, Episodic , Memory, Short-Term/physiology , Mental Recall/physiology , Middle Aged , Neuropsychological Tests , Psychotic Disorders/complications , Schizophrenia/complications , Visual Perception/physiologyABSTRACT
BACKGROUND: People with schizophrenia demonstrate perceptual organization impairments, and these are thought to contribute to their face processing difficulties. METHOD: We examined the neural substrates of emotionally neutral face processing in schizophrenia by investigating neural activity under three stimulus conditions: faces characterized by the full spectrum of spatial frequencies, faces with low spatial frequency information removed [high spatial frequency (HSF) condition], and faces with high spatial frequency information removed [low spatial frequency (LSF) condition]. Face perception in the HSF condition is more reliant on local feature processing whereas perception in the LSF condition requires greater reliance on global form processing. Past studies of perceptual organization in schizophrenia indicate that patients perform relatively more poorly with degraded stimuli but also that, when global information is absent, patients may perform better than controls because of their relatively increased ability to initially process individual features. Therefore, we hypothesized that people with schizophrenia (n=14) would demonstrate greater face processing difficulties than controls (n=13) in the LSF condition, whereas they would demonstrate a smaller difference or superior performance in the HSF condition. RESULTS: In a gender-discrimination task, behavioral data indicated high levels of accuracy for both groups, with a trend toward an interaction involving higher patient performance in the HSF condition and poorer patient performance in the LSF condition. Patients demonstrated greater activity in the fusiform gyrus compared to controls in both degraded conditions. CONCLUSIONS: These data suggest that impairments in basic integration abilities may be compensated for by relatively increased activity in this region.
Subject(s)
Cerebral Cortex/physiopathology , Discrimination, Psychological , Face , Facial Expression , Magnetic Resonance Imaging , Schizophrenia/physiopathology , Space Perception , Adult , Antipsychotic Agents/therapeutic use , Expressed Emotion , Female , Humans , Male , Schizophrenia/drug therapy , Sex FactorsSubject(s)
Chromosomes, Human, Pair 6 , Diabetes Mellitus/congenital , Fathers , Mesoderm/pathology , Placenta Diseases/pathology , Uniparental Disomy , Adult , Diabetes Mellitus/blood , Diabetes Mellitus/genetics , Female , Humans , Infant, Newborn , Infant, Newborn, Diseases/blood , Infant, Newborn, Diseases/genetics , Male , Pedigree , Placenta Diseases/genetics , Pregnancy , Time Factors , Uniparental Disomy/genetics , Uniparental Disomy/pathologyABSTRACT
BACKGROUND: Charcot-Marie-Tooth type 1A (CMT1A) is an autosomal dominant polyneuropathy due to a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene. This mutation is not modified during inheritance. OBJECTIVES: We set forth to test the hypothesis that in a subgroup of CMT1A patients there is clinical anticipation, namely an increase in disease severity over generations. METHODS: Thirty-nine CMT1A mutation-positive patients in 16 families and 23 parent-offspring pairs were evaluated. This included 14 families with 2 generations and 2 families with 3 generations. Age of presentation was assessed by interviewing the patients and clinical severity was measured using the CMT neuropathy score (CMTNS). RESULTS: In 21/23 parent-child pairs and 14/16 families, there was an earlier age of presentation in children of genetically affected parents. The mean age of onset in the progeny was 12.61 years compared to 41.22 years in the parent generation, (p < 0.001). Mean severity in the younger generation was slightly higher than that of the parent generation. When corrected for the age difference, the trend for a worse phenotype in the younger generation became statistically significant (p < 0.02,Wilcoxon signed rank test). CONCLUSIONS: Our findings suggest that in a subgroup of CMT1A patients there is an increase in clinical severity over generations. The mechanism responsible for this observation remains unknown. Our findings should be validated on a larger cohort of CMT1A families.
Subject(s)
Anticipation, Genetic , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/physiopathology , Genetic Predisposition to Disease/genetics , Mutation/genetics , Myelin Proteins/genetics , Adolescent , Adult , Age Factors , Age of Onset , Aged , Aged, 80 and over , Charcot-Marie-Tooth Disease/ethnology , Child , Chromosomes, Human, Pair 17/genetics , Cohort Studies , DNA Mutational Analysis , Disability Evaluation , Ethnicity/genetics , Family , Female , Genetic Markers/genetics , Genetic Predisposition to Disease/ethnology , Genetic Testing , Genotype , Humans , Male , Middle Aged , Peripheral Nerves/metabolism , Peripheral Nerves/physiopathology , Phenotype , Severity of Illness IndexABSTRACT
OBJECTIVES: An inflammatory response to altered lipoproteins that accumulate in the arterial wall is a major component of the pathogenesis of atherosclerosis. Statins reduce plasma levels of low-density lipoprotein (LDL) and are effective treatments for atherosclerosis. It is hypothesized that they also modulate inflammation. The aim of this study was to examine whether lovastatin inhibits macrophage inflammatory processes and clarify its mechanism of action. METHODS AND RESULTS: We examined the effects of statins on phagocytosis of antibody-coated red blood cells by cultured human monocytes and mouse peritoneal macrophages. Lovastatin, simvastatin, and zaragozic acid, a squalene synthase inhibitor, blocked Fc receptor-mediated phagocytosis by cultured human monocytes and mouse peritoneal macrophages. The inhibitory effect of lovastatin on Fc receptor-mediated phagocytosis was prevented completely by addition of mevalonate, farnesyl pyrophosphate, LDL, or cholesterol to the culture medium. The inhibitory effect of zaragozic acid was reversed by addition of LDL, but not by the addition of geranylgeranyl pyrophosphate, to the medium. In addition, the effect of lovastatin on phagocytosis is a function of cell activation because treatment of cells with tumor necrosis factor-alpha or lipopolysaccharide prevented inhibition of phagocytosis by lovastatin. CONCLUSIONS: The inhibition of Fc receptor-mediated phagocytosis of lovastatin is related to its effect on cholesterol biosynthesis rather than its effect on the formation of isoprenoids.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Macrophage Activation/physiology , Macrophages/metabolism , Macrophages/physiology , Phagocytosis/physiology , Receptors, Fc/antagonists & inhibitors , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cells, Cultured , Cholesterol/analogs & derivatives , Cholesterol/chemical synthesis , Cholesterol/pharmacology , Extracellular Matrix/immunology , Extracellular Matrix/metabolism , Humans , Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Immunoglobulin G/metabolism , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/physiology , Lipopolysaccharides/pharmacology , Lipoproteins/chemistry , Lipoproteins/pharmacology , Lovastatin/pharmacology , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Phagocytosis/drug effects , Pinocytosis/drug effects , Receptors, Fc/physiology , Simvastatin/pharmacology , Tricarboxylic Acids/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Vacuoles/metabolismABSTRACT
Zyxin, a focal adhesion molecule, interacts specifically with the E6 protein from human papillomavirus (HPV) type 6 in a yeast two-hybrid screen of a cDNA library prepared from human keratinocytes. Zyxin does not interact significantly with E6 proteins from HPV types 11, 16, or 18. The interaction was confirmed by in vitro and in vivo analyses and it requires the LIM domains (Lin-11, Isl-1, and Mec-3 [G. Freyd, S. K. Kim, and H. R. Horvitz, Nature 344:876-879, 1990]) found at the carboxyl terminus of zyxin. Cotransfection of E6 from HPV ((6)E6) and zyxin results in the accumulation of zyxin in the nucleus where it can function as a transcriptional activator. (6)E6 can also mobilize endogenous zyxin to the nucleus.
Subject(s)
Cell Nucleus/metabolism , Metalloproteins/metabolism , Oncogene Proteins, Viral/metabolism , Papillomaviridae/metabolism , Animals , Binding Sites , Cell Line , Cytoskeletal Proteins , DNA Primers , Fluorescent Antibody Technique , Glycoproteins , Humans , Metalloproteins/chemistry , Precipitin Tests , Protein Binding , Protein Transport , Recombinant Fusion Proteins/metabolism , Trans-Activators/metabolism , Two-Hybrid System Techniques , ZyxinABSTRACT
A microscopic scattering model is developed to expedite simulation studies of ultrasound imaging in soft tissue using multichannel transducer probes. The model fully accounts for the physics of broadband signals, propagating wave packets, and time delay focusing. Analytical results are presented for 2-D transducer arrays; 1-D results can be trivially extracted by setting the number of rows equal to unity. The 2-D cross-correlation and the 2-D form of the Mallart-Fink (MF) focusing factor are calculated. It is demonstrated that the scattering model reduces to the 2-D form of the monochromatic van Cittert Zernike (VCZ) analysis. Simulation results for the focusing factor are presented, and comparisons are given between the values obtained from simulation, analytical theory, and actual water tank experiments. The comparative results are all in close accord with each other.
Subject(s)
Ultrasonography/statistics & numerical data , Biomedical Engineering , Humans , Models, Theoretical , Scattering, Radiation , TransducersABSTRACT
Production of reactive oxygen species (ROS) and other proinflammatory substances by macrophages adherent to matrix proteins that contain or have been modified by oxidized LDL (oxLDL) may play an important role in atherogenesis. In vitro, human macrophages adhere to matrixes containing oxLDL via scavenger receptors and are signaled to produce ROS partly by interactions of the class B scavenger receptor (SR-B) CD36 with ligands on the matrix. In this report, we show that macrophages from mice genetically deficient in SR-A or CD36 adhered equally as well and produced equal amounts of ROS on interaction with matrix-associated oxLDL. In contrast, macrophages from mice genetically deficient in the CD18 chain of beta(2)-integrins produced insignificant amounts of ROS on interaction with oxLDL-containing matrixes, even though they adhered to these matrixes as efficiently as did macrophages from wild-type mice. Antibodies against CD18, CD11b, or EDTA, the last of which chelates divalent cations required for integrin function, had no effect on adhesion of normal mouse or human macrophages to matrixes containing oxLDL but almost completely inhibited ROS production by macrophages adherent to this matrix. Thus, CD11b/CD18 plays an important role in regulating production of ROS by mouse and human macrophages adherent to matrixes containing oxLDL. It may play a hitherto-unsuspected role in regulating macrophage signaling pathways involved in inflammation and atherogenesis.
Subject(s)
CD11 Antigens/physiology , CD18 Antigens/physiology , Lipoproteins, LDL/metabolism , Macrophages/metabolism , Reactive Oxygen Species/metabolism , Animals , Arteriosclerosis , Cell Adhesion , Extracellular Matrix Proteins/metabolism , Humans , Mice , Oxidation-Reduction , Signal TransductionABSTRACT
Tenascin is an extracellular matrix protein found in adults in T cell-dependent areas of lymphoid tissues, sites of inflammation, and tumors. We report here that it inhibited chemotaxis of chemoattractant-stimulated human monocytes and chemoattractant-stimulated polymorphonuclear leukocytes (PMN) through three-dimensional gels composed of collagen I or Matrigel, and chemotaxis of leukotriene B4-stimulated PMN through fibrin gels. The inhibitory effect of tenascin on monocyte or PMN chemotaxis through these matrices was reversed by Abs directed against alpha5beta1 integrins or by a peptide (GRGDSP) that binds to beta1 integrins. Tenascin did not affect leukotriene B4- or fMLP-stimulated expression of beta1 or beta2 integrins, but did exert a small inhibitory effect on PMN adhesion and closeness of apposition to fibrin(ogen)-containing surfaces. Thus, alpha5beta1 integrins mediate the inhibitory effect of tenascin on monocyte and PMN chemotaxis, without promoting close apposition between these leukocytes and surfaces coated with tenascin alone or with tenascin bound to other matrix proteins. This contrasts with the role played by alpha5beta1 integrins in promoting close apposition between fMLP-stimulated PMN and fibrin containing surfaces, thereby inhibiting chemotaxis of fMLP-stimulated PMN through fibrin gels. Thus, chemoattractants and matrix proteins regulate chemotaxis of phagocytic leukocytes by at least two different mechanisms: one in which specific chemoattractants promote very tight adhesion of leukocytes to specific matrix proteins and another in which specific matrix proteins signal cessation of migration without markedly affecting strength of leukocyte adhesion.
Subject(s)
Cell Migration Inhibition , Chemotaxis, Leukocyte/physiology , Collagen/physiology , Extracellular Matrix/physiology , Laminin/physiology , Monocytes/physiology , Neutrophils/physiology , Proteoglycans/physiology , Receptors, Fibronectin/antagonists & inhibitors , Tenascin/antagonists & inhibitors , Animals , Antibodies, Monoclonal/physiology , CD18 Antigens/biosynthesis , Cell Adhesion/physiology , Chemotaxis, Leukocyte/immunology , Chick Embryo , Drug Combinations , Epitopes/biosynthesis , Humans , Immune Sera/physiology , Immunoglobulin Fab Fragments/physiology , Immunoglobulin G/physiology , Integrin beta1/biosynthesis , Interleukin-8/physiology , Leukotriene B4/physiology , Lymphocyte Activation , Monocytes/immunology , Monocytes/metabolism , N-Formylmethionine Leucyl-Phenylalanine/pharmacology , Neutrophils/immunology , Neutrophils/metabolism , Oligopeptides/physiology , Receptors, Fibronectin/immunology , Receptors, Fibronectin/physiology , Tenascin/immunology , Tenascin/physiology , Tumor Necrosis Factor-alpha/physiologyABSTRACT
The high prevalence of neurocognitive deficits in schizophrenia, and their association with poorer outcomes, has created interest in treatments that can improve neurocognitive functioning in this illness. While a variety of rehabilitation interventions have been developed, many are not appropriate for the most severely ill patients, whose attention spans are so short that they cannot attend to the material being presented. For this population, the only neurocognitive rehabilitation methods with demonstrated effectiveness are those that involve the operant conditioning technique known as shaping. In this article, we review the rationale for the use of shaping-based methods as neurocognitive retraining techniques for treatment-refractory schizophrenia patients, review published reports using this intervention, and offer suggestions for the future development of this method from both clinical and research perspectives.
Subject(s)
Attention , Cognition Disorders/rehabilitation , Conditioning, Operant , Schizophrenia/rehabilitation , Schizophrenic Psychology , Cognition Disorders/psychology , Humans , Treatment OutcomeABSTRACT
The CTC series of cobalt chelates display in vitro and in vivo activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). The experiments described here identify the stage in the virus life cycle where CTC-96 acts and demonstrate that the drug inhibits infection of susceptible cells. CTC-96 at 50 microg/ml has no effect on adsorption of virions to Vero cell monolayers. Penetration assays reveal that CTC-96 inhibits entry of the virus independent of gC and cellular entry receptors. This observation was supported by the failure to detect the accumulation of virus-specified proteins and alpha mRNA transcripts when CTC-96 is present at the onset of infection. Moreover, virion-associated alphaTIF does not accumulate in the nucleus of cells infected in the presence of CTC-96. CTC-96 targets the initial fusion event between the virus and the cell and also inhibits cell-to-cell spread and syncytium formation. Furthermore, CTC-96 inhibits plaque formation by varicella-zoster virus and vesicular stomatitis virus as efficiently as by HSV-1. Collectively, these experiments suggest that CTC-96 is a broad-spectrum inhibitor of infection by enveloped viruses and that it inhibits HSV-1 infection at the point of membrane fusion independent of the type of virus and cellular receptors present.
Subject(s)
Antiviral Agents/pharmacology , Cobalt/pharmacology , Herpesvirus 1, Human/drug effects , Organometallic Compounds/pharmacology , Animals , Antiviral Agents/chemistry , CHO Cells , Cell Nucleus/metabolism , Chlorocebus aethiops , Cricetinae , Herpes Simplex Virus Protein Vmw65/metabolism , Herpesvirus 1, Human/metabolism , Herpesvirus 1, Human/physiology , Herpesvirus 3, Human/drug effects , Humans , Molecular Structure , Organometallic Compounds/chemistry , RNA, Messenger , Receptors, Virus/metabolism , Vero Cells , Viral Envelope Proteins/metabolism , Viral Proteins/metabolism , Virus Replication/drug effectsABSTRACT
The multifunctional herpes simplex virus type 1 (HSV-1) protein IE63 (ICP27) interacts with the essential pre-mRNA splicing factor, spliceosome-associated protein 145 (SAP145), and in infected cells IE63 and SAP145 colocalize. This interaction was reduced or abrogated completely using extracts from cells infected with IE63 viral mutants, with mutations in IE63 KH and Sm homology domains, which do not exhibit host shutoff or inhibit splicing. In the presence of IE63, splicing in vitro was inhibited prior to the first catalytic step and the B/C complex formed during splicing was shifted up in mobility and reduced in intensity. With the use of splicing extracts, IE63 and SAP145 both comigrated with the B/C complex, suggesting that they interact within this complex to inhibit B/C complex formation or conversion. The inhibition of splicing may facilitate the export of viral or cellular transcripts, possibly via other protein partners of IE63. These data provide important new insights into how IE63 influences pre-mRNA processing during HSV-1 infection.
Subject(s)
Herpesvirus 1, Human/metabolism , Immediate-Early Proteins/metabolism , RNA Splicing , RNA-Binding Proteins/metabolism , Spliceosomes/metabolism , Binding Sites , Catalysis , HeLa Cells , Herpesvirus 1, Human/genetics , Heterogeneous-Nuclear Ribonucleoproteins , Humans , Ribonucleoproteins/metabolismABSTRACT
The most pervasive and least well-addressed problem in cognitive studies of schizophrenia is the propensity of schizophrenia patients to show inferior performance on a variety of cognitive tasks. Consequently, apparent specific cognitive abnormalities may actually reflect the interaction of task discriminating power with generalized deficit. L. J. Chapman and J. P. Chapman (1973a) suggested psychometric approaches for eliminating such artifactual group differences. Unfortunately, their solution neglects important issues of process specification and does not provide a viable strategy for process-oriented investigators. Psychometric remediation of artifactual Group x Task interactions inevitably confounds the processes being measured, resulting in theoretically ambiguous findings. Moreover, evidence that changes in measurement reliability can both increase and decrease group discrimination challenges a basic underlying assumption of the Chapmans' matching solution. This article presents a process-oriented approach to solving this problem in schizophrenia research.
Subject(s)
Cognition , Psychometrics/methods , Psychomotor Performance , Schizophrenia/diagnosis , Schizophrenic Psychology , Case-Control Studies , Confounding Factors, Epidemiologic , Humans , Neuropsychological Tests/standards , Research Design/standards , Schizophrenia/complicationsABSTRACT
Class A scavenger receptors (SR-A) mediate microglial interaction with fibrillar beta-amyloid (fAbeta). We report here that neonatal microglia from SR-A knockout mice (SR-A-/-) adhere to surface-bound fAbeta, and produce reactive oxygen species (ROS) as efficiently as wildtype microglia; that both wildtype and SR-A-/- microglia express SR-BI; that antibodies against SR-BI do not affect adhesion or ROS production by wildtype microglia, but inhibit adhesion and ROS production of SR-A-/- microglia to immobilized fAbeta by approximately 40%. Adhesion to fAbeta-coated surfaces, and uptake of fAbeta by both wildtype and SR-A-/- microglia was almost completely inhibited by incubation with fucoidan. Thus SR-BI and SR-A mediate similar effector functions in neonatal microglia, which suggests that SR-BI plays as important a role as SR-A, and can maintain the wildtype phenotype in SR-A-/- microglia.
Subject(s)
Amyloid beta-Peptides/metabolism , CD36 Antigens/genetics , CD36 Antigens/immunology , Membrane Proteins , Microglia/immunology , Peptide Fragments/metabolism , Receptors, Immunologic , Receptors, Lipoprotein , Alzheimer Disease/immunology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/immunology , Animals , Animals, Newborn , Antineoplastic Agents/pharmacology , Brain/cytology , CD36 Antigens/metabolism , Carbocyanines/metabolism , Carbocyanines/pharmacology , Cell Adhesion/drug effects , Cell Adhesion/immunology , Cells, Cultured , Fluorescent Dyes/metabolism , Fluorescent Dyes/pharmacology , Gene Expression/immunology , Liver/metabolism , Mice , Mice, Inbred BALB C , Mice, Knockout , Microglia/cytology , Microglia/metabolism , Peptide Fragments/immunology , Polysaccharides/pharmacology , Reactive Oxygen Species/metabolism , Receptors, Scavenger , Scavenger Receptors, Class A , Scavenger Receptors, Class BABSTRACT
In Alzheimer's disease (AD), fibrillar beta-amyloid protein (fAbeta) accumulates in the walls of cerebral vessels associated with vascular smooth muscle cells (SMCs), endothelium, and pericytes, and with microglia and astrocytes in plaques in the brain parenchyma. Scavenger receptor class A (SR-A) and class B, type I (SR-BI) mediate binding and ingestion of fAbeta by cultured human fetal microglia, microglia from newborn mice, and by cultured SMCs. Our findings that SR-BI participates in the adhesion of cultured microglia from newborn SR-A knock-out mice to fAbeta-coated surfaces, and that microglia secrete reactive oxygen species when they adhere to these surfaces prompted us to explore expression of SR-BI in vivo. We report here that astrocytes and SMCs in normal adult mouse and human brains and in AD brains express SR-BI. In contrast, microglia in normal adult mouse and human brains and in AD brains do not express SR-BI. These findings indicate that SR-BI may mediate interactions between astrocytes or SMCs and fAbeta, but not of microglia and fAbeta, in AD, and that expression of SR-BI by rodent microglia is developmentally regulated. They suggest that SR-BI expression also is developmentally regulated in human microglia.