RESUMO
BACKGROUND: Patients with bipolar disorder (BD) show reduced fractional anisotropy (FA) compared to patients with major depressive disorder (MDD). Little is known about whether these differences are mood state-independent or influenced by acute symptom severity. Therefore, the aim of this study was (1) to replicate abnormalities in white matter microstructure in BD v. MDD and (2) to investigate whether these vary across depressed, euthymic, and manic mood. METHODS: In this cross-sectional diffusion tensor imaging study, n = 136 patients with BD were compared to age- and sex-matched MDD patients and healthy controls (HC) (n = 136 each). Differences in FA were investigated using tract-based spatial statistics. Using interaction models, the influence of acute symptom severity and mood state on the differences between patient groups were tested. RESULTS: Analyses revealed a main effect of diagnosis on FA across all three groups (ptfce-FWE = 0.003). BD patients showed reduced FA compared to both MDD (ptfce-FWE = 0.005) and HC (ptfce-FWE < 0.001) in large bilateral clusters. These consisted of several white matter tracts previously described in the literature, including commissural, association, and projection tracts. There were no significant interaction effects between diagnosis and symptom severity or mood state (all ptfce-FWE > 0.704). CONCLUSIONS: Results indicated that the difference between BD and MDD was independent of depressive and manic symptom severity and mood state. Disruptions in white matter microstructure in BD might be a trait effect of the disorder. The potential of FA values to be used as a biomarker to differentiate BD from MDD should be further addressed in future studies using longitudinal designs.
Assuntos
Transtorno Bipolar , Transtorno Depressivo Maior , Substância Branca , Humanos , Transtorno Bipolar/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Anisotropia , Estudos Transversais , Substância Branca/diagnóstico por imagem , ManiaRESUMO
Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.
Assuntos
Transtorno Bipolar , Transtornos Psicóticos , Esquizofrenia , Transtorno da Personalidade Esquizotípica , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Transtornos Psicóticos/diagnóstico por imagem , Transtorno da Personalidade Esquizotípica/diagnóstico por imagemRESUMO
Adverse outcome pathways (AOPs) are organized sequences of key events (KEs) that are triggered by a xenobiotic-induced molecular initiating event (MIE) and summit in an adverse outcome (AO) relevant to human or ecological health. The AOP framework causally connects toxicological mechanistic information with apical endpoints for application in regulatory sciences. AOPs are very useful to link endophenotypic, cellular endpoints in vitro to adverse health effects in vivo. In the field of in vitro developmental neurotoxicity (DNT), such cellular endpoints can be assessed using the human "Neurosphere Assay," which depicts different endophenotypes for a broad variety of neurodevelopmental KEs. Combining this model with large-scale transcriptomics, we evaluated DNT hazards of two selected Chinese herbal medicines (CHMs) Lei Gong Teng (LGT) and Tian Ma (TM), and provided further insight into their modes-of-action (MoA). LGT disrupted hNPC migration eliciting an exceptional migration endophenotype. Time-lapse microscopy and intervention studies indicated that LGT disturbs laminin-dependent cell adhesion. TM impaired oligodendrocyte differentiation in human but not rat NPCs and activated a gene expression network related to oxidative stress. The LGT results supported a previously published AOP on radial glia cell adhesion due to interference with integrin-laminin binding, while the results of TM exposure were incorporated into a novel putative, stressor-based AOP. This study demonstrates that the combination of phenotypic and transcriptomic analyses is a powerful tool to elucidate compounds' MoA and incorporate the results into novel or existing AOPs for a better perception of the DNT hazard in a regulatory context.
Assuntos
Rotas de Resultados Adversos , Células-Tronco Neurais , Síndromes Neurotóxicas , Humanos , Ratos , Animais , Laminina/farmacologia , Síndromes Neurotóxicas/etiologia , Estresse Oxidativo , Medição de Risco/métodosRESUMO
In everyday life, we have to make decisions under varying degrees of risk. Even though previous research has shown that the manipulation of sleep affects risky decision-making, it remains unknown whether individual, temporally stable neural sleep characteristics relate to individual differences in risk preferences. Here, we collected sleep data under normal conditions in fifty-four healthy adults using a portable high-density EEG at participants' home. Whole-brain corrected for multiple testing, we found that lower slow-wave activity (SWA, an indicator of sleep depth) in a cluster of electrodes over the right prefrontal cortex (PFC) is associated with higher individual risk propensity. Importantly, the association between local sleep depth and risk preferences remained significant when controlling for total sleep time and for time spent in deep sleep, i.e., sleep stages N2 and N3. Moreover, the association between risk preferences and SWA over the right PFC was very similar in all sleep cycles. Because the right PFC plays a central role in cognitive control functions, we speculate that local sleep depth in this area, as reflected by SWA, might serve as a dispositional indicator of self-regulatory ability, which in turn reflects risk preferences.
Assuntos
Córtex Cerebral , Eletroencefalografia , Adulto , Humanos , Córtex Pré-Frontal , Sono , Fases do SonoRESUMO
Due to their neurodevelopmental toxicity, flame retardants (FRs) like polybrominated diphenyl ethers are banned from the market and replaced by alternative FRs, like organophosphorus FRs, that have mostly unknown toxicological profiles. To study their neurodevelopmental toxicity, we evaluated the hazard of several FRs including phased-out polybrominated FRs and organophosphorus FRs: 2,2',4,4'-tetrabromodiphenylether (BDE-47), 2,2',4,4',5-pentabromodiphenylether (BDE-99), tetrabromobisphenol A, triphenyl phosphate, tris(2-butoxyethyl) phosphate and its metabolite bis-(2-butoxyethyl) phosphate, isodecyl diphenyl phosphate, triphenyl isopropylated phosphate, tricresyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tert-butylphenyl diphenyl phosphate, 2-ethylhexyl diphenyl phosphate, tris(1-chloroisopropyl) phosphate, and tris(2-chloroethyl) phosphate. Therefore, we used a human cell-based developmental neurotoxicity (DNT) in vitro battery covering a large variety of neurodevelopmental endpoints. Potency according to the respective most sensitive benchmark concentration (BMC) across the battery ranked from <1 µM (5 FRs), 1<10 µM (7 FRs) to the >10 µM range (3 FRs). Evaluation of the data with the ToxPi tool revealed a distinct ranking (a) than with the BMC and (b) compared to the ToxCast data, suggesting that DNT hazard of these FRs is not well predicted by ToxCast assays. Extrapolating the DNT in vitro battery BMCs to human FR exposure via breast milk suggests low risk for individual compounds. However, it raises a potential concern for real-life mixture exposure, especially when different compounds converge through diverse modes-of-action on common endpoints, like oligodendrocyte differentiation in this study. This case study using FRs suggests that human cell-based DNT in vitro battery is a promising approach for neurodevelopmental hazard assessment and compound prioritization in risk assessment.
Assuntos
Retardadores de Chama , Tritolil Fosfatos , Feminino , Humanos , Compostos de Bifenilo , Exposição Ambiental/análise , Retardadores de Chama/análise , Retardadores de Chama/toxicidade , Éteres Difenil Halogenados/análise , Técnicas In Vitro , Organofosfatos , Fosfatos/análiseRESUMO
There are many situations where resources are distributed between two parties and where the deciding party has information about the initial distribution and can change its outcome, for example, the allocation of budget for funds or bonuses, where the deciding party might have self-interested motives. Although the neural underpinnings of distributional preferences of resources have been extensively studied, it remains unclear if there are different types of distributional preferences and if these types underlie different disposing neural signatures. We used source-localized resting EEG in combination with a data-driven clustering approach to participants' behavior in a distribution game in order to disentangle the neural sources of the different types of distributional preferences. Our findings revealed four behavioral types: Maximizing types always changed initial distributions to maximize their personal outcomes, and compliant types always left initial distributions unchanged. Disadvantage-averse types only changed initial distributions if they received less than the other party did, and equalizing types primarily changed initial distributions to fair distributions. These behavioral types differed regarding neural baseline activation in the right inferior frontal gyrus. Maximizing and compliant types showed the highest baseline activation, followed by disadvantage-averse types and equalizing types. Furthermore, maximizing types showed significantly higher baseline activation in the left orbitofrontal cortex compared to compliant types. Taken together, our findings show that different types of distributional preferences are characterized by distinct neural signatures, which further imply differences in underlying psychological processes in decision-making.
Assuntos
Lobo Frontal , Córtex Pré-Frontal , Tomada de Decisões , Humanos , MotivaçãoRESUMO
The call for a paradigm change in toxicology from the United States National Research Council in 2007 initiates awareness for the invention and use of human-relevant alternative methods for toxicological hazard assessment. Simple 2D in vitro systems may serve as first screening tools, however, recent developments infer the need for more complex, multicellular organotypic models, which are superior in mimicking the complexity of human organs. In this review article most critical organs for toxicity assessment, i.e., skin, brain, thyroid system, lung, heart, liver, kidney, and intestine are discussed with regards to their functions in health and disease. Embracing the manifold modes-of-action how xenobiotic compounds can interfere with physiological organ functions and cause toxicity, the need for translation of such multifaceted organ features into the dish seems obvious. Currently used in vitro methods for toxicological applications and ongoing developments not yet arrived in toxicity testing are discussed, especially highlighting the potential of models based on embryonic stem cells and induced pluripotent stem cells of human origin. Finally, the application of innovative technologies like organs-on-a-chip and genome editing point toward a toxicological paradigm change moves into action.
Assuntos
Células-Tronco Pluripotentes Induzidas , Testes de Toxicidade , Humanos , Técnicas In Vitro , Estados UnidosRESUMO
Laughter is a multifaceted signal, which can convey social acceptance facilitating social bonding as well as social rejection inflicting social pain. In the current study, we addressed the neural correlates of social intent attribution to auditory or visual laughter within an fMRI study to identify brain areas showing linear increases of activation with social intent ratings. Negative social intent attributions were associated with activation increases within the medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC). Interestingly, negative social intent attributions of auditory laughter were represented more rostral than visual laughter within this area. Our findings corroborate the role of the mPFC/ACC as key node for processing "social pain" with distinct modality-specific subregions. Other brain areas that showed an increase of activation included bilateral inferior frontal gyrus and right superior/middle temporal gyrus (STG/MTG) for visually presented laughter and bilateral STG for auditory presented laughter with no overlap across modalities. Similarly, positive social intent attributions were linked to hemodynamic responses within the right inferior parietal lobe and right middle frontal gyrus, but there was no overlap of activity for visual and auditory laughter. Our findings demonstrate that social intent attribution to auditory and visual laughter is located in neighboring, but spatially distinct neural structures.
Assuntos
Percepção Auditiva/fisiologia , Mapeamento Encefálico , Giro do Cíngulo/fisiologia , Riso , Córtex Pré-Frontal/fisiopatologia , Percepção Social , Lobo Temporal/fisiologia , Teoria da Mente/fisiologia , Percepção Visual/fisiologia , Adulto , Feminino , Giro do Cíngulo/diagnóstico por imagem , Humanos , Intenção , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/diagnóstico por imagem , Lobo Temporal/diagnóstico por imagem , Adulto JovemRESUMO
The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8(+) T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.
Assuntos
Antígeno CTLA-4/genética , Lectinas Tipo C/genética , Antígenos Comuns de Leucócito/genética , Ativação Linfocitária/genética , Lectinas de Ligação a Manose/genética , Receptores de Superfície Celular/genética , Animais , Apresentação de Antígeno/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/imunologia , Regulação da Expressão Gênica/genética , Humanos , Tolerância Imunológica/genética , Lectinas Tipo C/imunologia , Antígenos Comuns de Leucócito/imunologia , Ativação Linfocitária/imunologia , Receptor de Manose , Lectinas de Ligação a Manose/imunologia , Camundongos , Proteínas Proto-Oncogênicas c-bcl-6/genética , Receptores de Superfície Celular/imunologia , Linfócitos T Citotóxicos/imunologia , Ativação Transcricional/genéticaRESUMO
Major depressive disorder (MDD) is characterized by a biased emotion perception. In the auditory domain, MDD patients have been shown to exhibit attenuated processing of positive emotions expressed by speech melody (prosody). So far, no neuroimaging studies examining the neural basis of altered processing of emotional prosody in MDD are available. In this study, we addressed this issue by examining the emotion bias in MDD during evaluation of happy, neutral, and angry prosodic stimuli on a five-point Likert scale during functional magnetic resonance imaging (fMRI). As expected, MDD patients rated happy prosody less intense than healthy controls (HC). At neural level, stronger activation in the middle superior temporal gyrus (STG) and the amygdala was found in all participants when processing emotional as compared to neutral prosody. MDD patients exhibited an increased activation of the amygdala during processing prosody irrespective of valence while no significant differences between groups were found for the STG, indicating that altered processing of prosodic emotions in MDD occurs rather within the amygdala than in auditory areas. Concurring with the valence-specific behavioral effect of attenuated evaluation of positive prosodic stimuli, activation within the left amygdala of MDD patients correlated with ratings of happy, but not neutral or angry prosody. Our study provides first insights in the neural basis of reduced experience of positive information and an abnormally increased amygdala activity during prosody processing.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/fisiopatologia , Emoções/fisiologia , Percepção da Fala/fisiologia , Adulto , Mapeamento Encefálico , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Humanos , Julgamento/fisiologia , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologiaRESUMO
BACKGROUND: The obstructive sleep apnea syndrome (OSAS) is characterized by temporary cerebral hypoxia which can cause cognitive dysfunction. On the other hand, hypoxia induced neurocognitive deficits are detectable after general anesthesia. The objective of this study was to evaluate the impact of a high risk of OSAS on the postoperative cognitive dysfunction after intravenous anesthesia. METHODS: In this single center trial between June 2012 and June 2013 43 patients aged 55 to 80 years with an estimated hospital stay of at least 3 days undergoing surgery were enrolled. Patients were screened for a high risk of OSAS using the STOP-BANG test. The cognitive function was assessed using a neuropsychological test battery, including the DemTect test for cognitive impairment and the RMBT test for memory, the day before surgery and within 36 h after extubation. RESULTS: Twenty-two of the 43 analyzed patients were identified as patients with a high risk of OSAS. Preoperatively, OSAS patients showed a significant worse performance only for the DemTect (p = 0.0043). However, when comparing pre- and postoperative test results, the OSAS patients did not show a significant loss in any test but significantly improved in RMBT test, whereas the control group showed a significant worse performance in three of eight tests. In five tests, we found a significant difference between the two groups with respect to the change from pre- to postoperative cognitive function. CONCLUSION: Patients with a high risk of OSAS showed a less impairment of memory function and work memory performance after intravenous anesthesia. This might be explained by a beneficial effect of intrinsic hypoxic preconditioning in these patients.
Assuntos
Anestesia Intravenosa/tendências , Disfunção Cognitiva/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Síndromes da Apneia do Sono/epidemiologia , Idoso , Anestesia Intravenosa/efeitos adversos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Projetos Piloto , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/psicologia , Estudos Prospectivos , Fatores de Risco , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/psicologiaRESUMO
Notch signaling can promote tumorigenesis in the nervous system and plays important roles in stem-like cancer cells. However, little is known about how Notch inhibition might alter tumor metabolism, particularly in lesions arising in the brain. The gamma-secretase inhibitor MRK003 was used to treat glioblastoma neurospheres, and they were subdivided into sensitive and insensitive groups in terms of canonical Notch target response. Global metabolomes were then examined using proton magnetic resonance spectroscopy, and changes in intracellular concentration of various metabolites identified which correlate with Notch inhibition. Reductions in glutamate were verified by oxidation-based colorimetric assays. Interestingly, the alkylating chemotherapeutic agent temozolomide, the mTOR-inhibitor MLN0128, and the WNT inhibitor LGK974 did not reduce glutamate levels, suggesting that changes to this metabolite might reflect specific downstream effects of Notch blockade in gliomas rather than general sequelae of tumor growth inhibition. Global and targeted expression analyses revealed that multiple genes important in glutamate homeostasis, including glutaminase, are dysregulated after Notch inhibition. Treatment with an allosteric inhibitor of glutaminase, compound 968, could slow glioblastoma growth, and Notch inhibition may act at least in part by regulating glutaminase and glutamate.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Metaboloma , Receptores Notch/antagonistas & inibidores , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Óxidos S-Cíclicos/farmacologia , Glioblastoma/metabolismo , Ácido Glutâmico/metabolismo , Glutaminase/antagonistas & inibidores , Homeostase , Humanos , Tiadiazóis/farmacologiaRESUMO
Social psychology studies show that awareness of one's eventual death profoundly influences human cognition and behaviour by inducing defensive reactions against end-of-life-related anxiety. Much less is known about the impact of reminders of mortality on brain activity. Here we tested whether reminders of mortality can induce a modulation of the slow electroencephalographic activity triggered by somatosensory nociceptive or auditory threatening stimulation and if this modulation is related to mood and anxiety as well as personality traits. We found a specific slow wave (SW) modulation only for nociceptive stimulation and only following mortality salience induction (compared to reminders of an important failed exam). The enhancement of SW negativity at the scalp vertex was associated with increased state anxiety and negative mood, whereas higher self-esteem was associated with reduced SW amplitude. In addition, mortality salience was linked to an increased amplitude of frontal delta band, which was correlated also with increased positive mood and higher self-esteem. The results indicate that SW and delta spectral activity may represent both proximal and distal defences associated with reminders of death and that neurophysiological correlates of somatosensory representation of painful and threatening stimuli may be useful for existential neuroscience studies.
Assuntos
Atitude Frente a Morte , Ondas Encefálicas/fisiologia , Córtex Cerebral/fisiologia , Eletroencefalografia/métodos , Nociceptividade/fisiologia , Adulto , Afeto/fisiologia , Ansiedade/psicologia , Ritmo Delta/fisiologia , Feminino , Humanos , Masculino , Autoimagem , Adulto JovemRESUMO
BACKGROUND: To eliminate chronic hepatitis C virus (HCV) infection by 2030, 90% of those infected must be diagnosed and 80% treated. In Switzerland, >40% of the estimated 32,000 infected people are still undiagnosed. In the canton of St Gallen, HCV prevalence and cascade of care have only been studied in the centralised opioid agonist therapy (OAT) setting (institutions), although about 80% of OAT patients are treated decentrally (general practitioner [GP] or pharmacy). AIM: To describe HCV prevalence and cascade of care among patients in the decentralised OAT programme of the canton of St Gallen, Switzerland, and compare it to contemporaneous data from the centralised setting. METHODS: For each patient receiving his/her OAT from a GP or pharmacy on 1 April 2021, the cantonal medical office sent a questionnaire to the prescribing GP. Patient characteristics, HCV antibody (Ab)/RNA screening uptake, HCV Ab/RNA prevalence and HCV treatment uptake were obtained and compared to those of patients of the Medizinisch-soziale Hilfsstelle 1 in St Gallen (centralised setting). RESULTS: Of the 563 OAT patients under the care of 127 GPs, 107 patients from 41 GPs could be analysed (median age: 48 years [IQR: 40-56]; ongoing intravenous drug use: 25%; OAT provider: 66% GP, 34% pharmacy). HCV Ab screening uptake was 68% (73/107) with an HCV Ab prevalence of 68% (50/73) among those tested. Of the HCV Ab-positive patients, 84% (42/50) were HCV RNA-tested, among whom 57% (24/42) were viraemic. HCV treatment uptake was 83% (20/24), with 95% (19/20) achieving a sustained virological response. Non-uptake of HCV screening and treatment tended to be higher among patients receiving OAT at the pharmacy vs at the GP's office: 37% vs 26% (p = 0.245) for screening and 30% vs 7% (p = 0.139) for treatment. The proportion never HCV Ab-tested and the proportion of HCV Ab-positives never HCV RNA-tested was significantly higher in the decentralised compared to the centralised setting: 32% vs 3% (p <0.001) never Ab-tested and 16% vs 0% (p = 0.002) never RNA-tested. In contrast, HCV treatment uptake (83% vs 78%), sustained virological response rate (95% vs 100%) and residual HCV RNA prevalence among the HCV Ab-positive (12% vs 14%) were comparable for both settings. CONCLUSION: In the decentralised OAT setting of the canton of St Gallen, HCV Ab prevalence is high. Since HCV Ab and RNA screening uptake are markedly lower than in the centralised setting, potentially >40% of patients with chronic HCV are not diagnosed yet. HCV screening in the decentralised setting needs improvement, e.g. by increasing awareness and simplifying testing. High HCV treatment uptake and cure rates are possible in centralised and decentralised settings.
Assuntos
Hepatite C Crônica , Hepatite C , Abuso de Substâncias por Via Intravenosa , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Analgésicos Opioides/uso terapêutico , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Estudos Transversais , Suíça/epidemiologia , Prevalência , Antivirais/uso terapêutico , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepacivirus/genética , Abuso de Substâncias por Via Intravenosa/epidemiologia , RNARESUMO
Bone fracture healing is regulated by mechanobiological cues. Both, extracellular matrix (ECM) deposition and microvascular assembly determine the dynamics of the regenerative processes. Mechanical instability as by inter-fragmentary shear or compression is known to influence early ECM formation and wound healing. However, it remains unclear how these external cues shape subsequent ECM and microvascular network assembly. As transcriptional coactivators, the mechanotransducers yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) translate physical cues into downstream signaling events, yet their role in sprouting angiogenesis into the hematoma after injury is unknown. Using bone healing as model system for scar-free regeneration, the role of endothelial YAP/TAZ in combination with tuning the extrinsic mechanical stability via fracture fixation is investigated. Extrinsically imposed shear across the gap delayed hematoma remodeling and shaped the morphology of early collagen fiber orientations and microvascular networks, suggesting that enhanced shear increased the nutrient exchange in the hematoma. In contrast, endothelial YAP/TAZ deletion has little impact on the overall vascularization of the fracture gap, yet slightly increases the collagen fiber deposition under semi-rigid fixation. Together, these data provide novel insights into the respective roles of endothelial YAP/TAZ and extrinsic mechanical cues in orchestrating the process of bone regeneration.
Assuntos
Hematoma , Mecanotransdução Celular , Colágeno/metabolismo , Mecanotransdução Celular/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Consolidação da Fratura/fisiologia , Humanos , Hematoma/metabolismo , Hematoma/patologia , Osso e Ossos/metabolismo , Osso e Ossos/patologiaRESUMO
BACKGROUND: The aim of this work was to demonstrate the bony bond strength and resilience of a three-dimensional titanium mesh coating of an artificial acetabulum produced using the diffusion bonding technique. Under the extreme conditions ranging from abrasion-related osteolysis to acetabular perforation, the degree of residual bone and the integrity of the coating were determined. The remaining zones of the (still) stable bone connection are inevitably exposed to a greater load of the layer adhesion between the titanium mesh and the core shell. The investigation was intended to provide information about the stages of damage according to Paprosky in which it was still justifiable to leave the implant in place and simply change the inlay from the purely material-technical point of view of a stable coating. The bond between bone and implant was examined with regard to a possible retention of the implant for its adaptive remodeling up to 27 years. MATERIALS AND METHODS: In a retrospective study, 31 explanted human acetabular cups of the Harris-Galante II type, with an average lifetime of 19.7 years (11-27 years), were examined by means of digital area measurement to determine both the bone areas remaining on the coating and the damaged areas of the titanium mesh. Periacetabular bone loss was recorded in a modified Paprosky (PAP) damage classification. Full hemispherical sections of 4 acetabular cups with a life time of 16, 20, 22 and 27 years were examined histopathologically using the diamond cut technique. RESULTS: The periacetabular bone loss resulted in damage class PAP I in 8 cases, PAP IIa in 7 cases, PAP IIb in 2 cases, PAP IIc in 9 cases, PAP IIIa in 3 cases and PAP IIIa in 2 cases PAP IIIb. The average amount of bone that was still firmly attached to the coating after explantation was 17% (0-70%) of the total cup surface. Paprosky I accounted for 44.1%, and PAP IIa and IIb stadiums together a total of 17.1%. The average bone fraction of the implants no longer anchored in the host bed at stages IIc, IIIa and IIIb was 2%. The average coating damage was 11% (0-100%) and was exclusively attributable to the unstable implants of stages IIc, IIIa and IIIb. The histopathological findings showed adaptive bone remodeling, that was detectable for up to 27 years through the titanium mesh down to the interface with the solid acetabular core. The titanium wire mesh was mostly surrounded by lamellar, mature bone. CONCLUSION: The results show that the connection between the Tivanium cup and the previously oldest and unchanged sintered coating - in the form of a three-dimensional titanium mesh applied in point and line contact - is very load-resistant even under the extreme loads of periacetabular osteolysis and cup perforations. Since there was no damage to the coating in periacetabular damage stages Paprosky I, IIa and IIb, it is justifiable in these damage stages to leave the implant in situ and to continue to use it with sole replacement of the inlay, but leaving the socket shell. The third-generation acetabular cup (Trilogy) with unchanged three-dimensional titanium mesh coating has been implanted in over 1.2 million cases for 26 years. After a long service life, an increasing number of wear and tear conditions can be expected in today's mostly elderly and vulnerable patient clientele. In view of the results presented here, the early detection of damage would make it possible to avoid costly and stressful explantation of the entire acetabular cup in favor of replacing the sole inlay in Paprosky stages I, IIa and IIb.
RESUMO
The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differentiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction protocols yielded nearly 100% NESTIN-positive hiPSC-derived neural progenitor cells (hiNPCs), though with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed to apply such MEA-based spike sorting. These models are promising tools not only in toxicology but also for drug development and disease modeling.
Assuntos
Células-Tronco Neurais , Neurônios , Animais , Humanos , Células Cultivadas , Microeletrodos , Neurônios/metabolismo , Células-Tronco Neurais/metabolismo , Diferenciação CelularRESUMO
Feeling pain and seeing it in others activates largely overlapping neural substrates. A recent study (Corradi-Dell'Acqua C, Hofstetter C, Vuilleumier P. J Neurosci 31: 17996-18006, 2011) for the first time raises the question of whether shared neural activations specifically code pain-related contents or merely their negative-aversive implication. The authors conclude that mid-insula and mid-cingulate share information specific to the presence of pain, whereas anterior insula shares information about its aversive content. We suggest that, together with valence and arousal, the control of saliency and threat may have an important heuristic potential in the study of empathy for pain.
Assuntos
Mapeamento Encefálico , Emoções/fisiologia , Giro do Cíngulo/fisiologia , Dor/fisiopatologia , Dor/psicologia , Feminino , HumanosRESUMO
BACKGROUND: Digital equity denotes that all individuals and communities have equitable access to the information technology required to participate in digital life and can fully capitalize on this technology for their individual and community gain and benefits. Recent research highlighted that COVID-19 heightened the existing structural inequities and further exacerbated the technology-related social divide, especially for racialized communities, including new immigrants, refugees, and ethnic minorities. The intersection of challenges associated with racial identity (eg, racial discrimination and cultural differences), socioeconomic marginalization, and age- and gender-related barriers affects their access to health and social services, education, economic activity, and social life owing to digital inequity. OBJECTIVE: Our aim is to understand the current state of knowledge on digital equity and the digital divide (which is often considered a complex social-political challenge) among racialized communities in urban cities of high-income countries and how they impact the social interactions, economic activities, and mental well-being of racialized city dwellers. METHODS: We will conduct an integrative review adapting the Whittemore and Knafl methodology to summarize past empirical or theoretical literature describing digital equity issues pertaining to urban racialized communities. The context will be limited to studies on multicultural cities in high-income countries (eg, Calgary, Alberta) in the last 10 years. We will use a comprehensive search of 8 major databases across multiple disciplines and gray literature (eg, Google Scholar), using appropriate search terms related to digital "in/equity" and "divide." A 2-stage screening will be conducted, including single citation tracking and a hand search of reference lists. Results will be synthesized using thematic analysis guidelines. RESULTS: As of August 25, 2022, we have completed a systematic search of 8 major academic databases from multiple disciplines, gray literature, and citation or hand searching. After duplicate removal, we identified 8647 articles from all sources. Two independent reviewers are expected to complete the 2-step screening (title, abstract, and full-text screening) using Covidence followed by data extraction and analysis in 4 months (by December 2022). Data will be extracted regarding digital equity-related initiatives, programs, activities, research findings, issues, barriers, policies, recommendations, etc. Thematic analysis will reveal how barriers and facilitators of digital equity affect or benefit racialized population groups and what social, material, and systemic issues need to be addressed to establish digital equity for racialized communities in the context of a multicultural city. CONCLUSIONS: This project will inform public policy about digital inequity alongside conventional systemic inequities (eg, education and income levels); promote digital equity by exploring and examining the pattern, extent, and determinants and barriers of digital inequity across sociodemographic variables and groups; and analyze its interconnectedness with spatial dimensions and variations of the urban sphere (geographic differences). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40068.
RESUMO
There is a call for a paradigm shift in developmental neurotoxicity (DNT) evaluation, which demands the implementation of faster, more cost-efficient, and human-relevant test systems than current in vivo guideline studies. Under the umbrella of the Organisation for Economic Co-operation and Development (OECD), a guidance document is currently being prepared that instructs on the regulatory use of a DNT in vitro battery (DNT IVB) for fit-for-purpose applications. One crucial issue for OECD application of methods is validation, which for new approach methods (NAMs) requires novel approaches. Here, mechanistic information previously identified in vivo, as well as reported neurodevelopmental adversities in response to disturbances on the cellular and tissue level, are of central importance. In this study, we scientifically validate the Neurosphere Assay, which is based on human primary neural progenitor cells (hNPCs) and an integral part of the DNT IVB. It assesses neurodevelopmental key events (KEs) like NPC proliferation (NPC1ab), radial glia cell migration (NPC2a), neuronal differentiation (NPC3), neurite outgrowth (NPC4), oligodendrocyte differentiation (NPC5), and thyroid hormone-dependent oligodendrocyte maturation (NPC6). In addition, we extend our work from the hNPCs to human induced pluripotent stem cell-derived NPCs (hiNPCs) for the NPC proliferation (iNPC1ab) and radial glia assays (iNPC2a). The validation process we report for the endpoints studied with the Neurosphere Assays is based on 1) describing the relevance of the respective endpoints for brain development, 2) the confirmation of the cell type-specific morphologies observed in vitro, 3) expressions of cell type-specific markers consistent with those morphologies, 4) appropriate anticipated responses to physiological pertinent signaling stimuli and 5) alterations in specific in vitro endpoints upon challenges with confirmed DNT compounds. With these strong mechanistic underpinnings, we posit that the Neurosphere Assay as an integral part of the DNT in vitro screening battery is well poised for DNT evaluation for regulatory purposes.