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BACKGROUND: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking. METHODS: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain. RESULTS: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain. CONCLUSION: These results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.
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Núcleos Ventrais do Tálamo , Animais , Camundongos , Masculino , Neuralgia do Trigêmeo/fisiopatologia , Neuralgia/fisiopatologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Optogenética , Limiar da Dor/fisiologiaRESUMO
Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia, however no effective treatments are available. Here, based on magnetic resonance imaging studies of patients with white matter damage, we found that this damage is associated with disorganized cortical structure. In a mouse model, optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell (OPC) proliferation, remyelination in the corpus callosum, and recovery of cognitive ability after cerebral hypoperfusion. The therapeutic effect of such stimulation was restricted to the upper layers of the cortex, but also spanned a wide time window after ischemia. Mechanistically, enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons. Additionally, skin stroking, an easier method to translate into clinical practice, activated the somatosensory cortex, thereby promoting OPC proliferation, remyelination and cognitive recovery following cerebral hypoperfusion. In summary, we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion. It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.
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Microglia regulate synaptic function in various ways, including the microglial displacement of the surrounding GABAergic synapses, which provides important neuroprotection from certain diseases. However, the physiological role and underlying mechanisms of microglial synaptic displacement remain unclear. In this study, we observed that microglia exhibited heterogeneity during the displacement of GABAergic synapses surrounding neuronal soma in different cortical regions under physiological conditions. Through three-dimensional reconstruction, in vitro co-culture, two-photon calcium imaging, and local field potentials recording, we found that IL-1ß negatively modulated microglial synaptic displacement to coordinate regional heterogeneity in the motor cortex, which impacted the homeostasis of the neural network and improved motor learning ability. We used the Cre-Loxp system and found that IL-1R1 on glutamatergic neurons, rather than that on microglia or GABAergic neurons, mediated the negative effect of IL-1ß on synaptic displacement. This study demonstrates that IL-1ß is critical for the regional heterogeneity of synaptic displacement by coordinating different actions of neurons and microglia via IL-1R1, which impacts both neural network homeostasis and motor learning ability. It provides a theoretical basis for elucidating the physiological role and mechanism of microglial displacement of GABAergic synapses.
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Aprendizagem , Microglia , Cálcio , Neurônios GABAérgicos , Interleucina-1beta , SinapsesRESUMO
Microglia play a crucial role in interacting with neuronal synapses and modulating synaptic plasticity. This function is particularly significant during postnatal development, as microglia are responsible for removing excessive synapses to prevent neurodevelopmental deficits. Dysregulation of microglial synaptic function has been well-documented in various pathological conditions, notably Alzheimer's disease and multiple sclerosis. The recent application of RNA sequencing has provided a powerful and unbiased means to decipher spatial and temporal microglial heterogeneity. By identifying microglia with varying gene expression profiles, researchers have defined multiple subgroups of microglia associated with specific pathological states, including disease-associated microglia, interferon-responsive microglia, proliferating microglia, and inflamed microglia in multiple sclerosis, among others. However, the functional roles of these distinct subgroups remain inadequately characterized. This review aims to refine our current understanding of the potential roles of heterogeneous microglia in regulating synaptic plasticity and their implications for various brain disorders, drawing from recent sequencing research and functional studies. This knowledge may aid in the identification of pathogenetic biomarkers and potential factors contributing to pathogenesis, shedding new light on the discovery of novel drug targets. The field of sequencing-based data mining is evolving toward a multi-omics approach. With advances in viral tools for precise microglial regulation and the development of brain organoid models, we are poised to elucidate the functional roles of microglial subgroups detected through sequencing analysis, ultimately identifying valuable therapeutic targets.
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Doença de Alzheimer , Esclerose Múltipla , Humanos , Microglia/fisiologia , Plasticidade Neuronal/fisiologia , Doença de Alzheimer/metabolismo , Neurônios/metabolismo , Esclerose Múltipla/patologiaRESUMO
NK cells play a role in various cancers, but their role in head and neck squamous cell carcinoma (HNSCC) still needs to be explored. All public data are obtained from the Cancer Genome Atlas Program (TCGA) database. All analysis was performed using specific packages in R software. In our study, we quantified the immune microenvironment of HNSCC through multiple algorithms. Next, we identified NK cell-associated genes by quantifying NK cells, including SSNA1, TRIR, PAXX, DPP7, WDR34, EZR, PHLDA1 and ELOVL1. Then, we explored the single-cell expression pattern of these genes in the HNSCC microenvironment. Univariate Cox regression analysis indicated that the EZR, PHLDA1 and ELOVL1 were related to the prognosis of HNSCC patients. Following this, we selected EZR for further analysis. Our results showed that the patients with high EZR expression might have a poor prognosis and worse clinical features. Biological enrichment analysis showed that EZR is associated with many oncogenic pathways and a higher tumour stemness index. Meanwhile, we found that EZR can remodel the immune microenvironment of HNSCC. Moreover, we noticed that EZR could affect the immunotherapy and specific drug sensitivity, making it an underlying clinical target. In summary, our results can improve the understanding of NK cell in HNSCC. Meanwhile, we identified EZR as the underlying clinical target of HNSCC.
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Carcinoma , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Células Matadoras Naturais , Neoplasias de Cabeça e Pescoço/genética , Imunidade , Microambiente Tumoral/genética , Proteínas de TransporteRESUMO
The study was conducted to assess medical staffs' fear of receiving the fourth dose of the Coronavirus disease 2019 (COVID-19) vaccine. From December 17, 2022, to January 31, 2023, an online survey was conducted to assess the fear among medical staffs regarding the administration of the fourth dose of the COVID-19 vaccine. The participants were exclusively drawn from a tertiary grade hospital in Taizhou. Out of the 1, 832 medical staffs invited to participate in the questionnaire, a total of 613 (33.5%) provided valid responses for subsequent analysis. Among them, 81 (13.8%) expressed fear of receiving the fourth dose of COVID-19. The fear was significantly influenced by these factors: the presence of serious food/drug allergic reactions (OR = 3.84, 95% CI: 1.40-10.52), received booster COVID-19 vaccine (OR = 0.20, 95% CI: 0.11-0.35), opinion on vaccination requirement (OR = 0.20, 95% CI: 0.11-0.35), viewpoint (OR = 0.23, 95% CI: 0.12-0.44) with scores ≥10, and positive attitude toward vaccination (OR = 0.21, 95% CI: 0.13-0.35). Our study revealed that a subset of medical staffs still harbor apprehension toward receiving the fourth dose of the new COVID-19 vaccine. Factors influencing this fear encompass allergic reactions, booster COVID-19 vaccine, as well as opinion, viewpoint, and attitude toward vaccination. Educating medical staffs on these factors may help mitigate their fear.
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Vacinas contra COVID-19 , COVID-19 , Medo , Vacinação , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Estudos Transversais , População do Leste Asiático , Hipersensibilidade , Corpo Clínico , Vacinação/psicologiaRESUMO
Zoledronic acid (ZOL) is a potent antiresorptive agent that increases bone mineral density (BMD) and reduces fracture risk in postmenopausal osteoporosis (PMOP). The anti-osteoporotic effect of ZOL is determined by annual BMD measurement. In most cases, bone turnover markers function as early indicators of therapeutic response, but they fail to reflect long-term effects. We used untargeted metabolomics to characterize time-dependent metabolic shifts in response to ZOL and to screen potential therapeutic markers. In addition, bone marrow RNA-seq was performed to support plasma metabolic profiling. Sixty rats were assigned to sham-operated group (SHAM, n = 21) and ovariectomy group (OVX, n = 39) and received sham operation or bilateral ovariectomy, respectively. After modeling and verification, rats in the OVX group were further divided into normal saline group (NS, n = 15) and ZOL group (ZA, n = 18). Three doses of 100 µg/kg ZOL were administrated to the ZA group every 2 weeks to simulate 3-year ZOL therapy in PMOP. An equal volume of saline was administered to the SHAM and NS groups. Plasma samples were collected at five time points for metabolic profiling. At the end of the study, selected rats were euthanatized for bone marrow RNA-seq. A total number of 163 compound were identified as differential metabolites between the ZA and NS groups, including mevalonate, a critical molecule in target pathway of ZOL. In addition, prolyl hydroxyproline (PHP), leucyl hydroxyproline (LHP), 4-vinylphenol sulfate (4-VPS) were identified as differential metabolites throughout the study. Moreover, 4-VPS negatively correlated with increased vertebral BMD after ZOL administration as time-series analysis revealed. Bone marrow RNA-seq showed that the PI3K-AKT signaling pathway was significantly associated with ZOL-mediated changes in expression (adjusted-p = 0.018). In conclusion, mevalonate, PHP, LHP, and 4-VPS are candidate therapeutic markers of ZOL. The pharmacological effect of ZOL likely occurs through inhibition of the PI3K-AKT signaling pathway.
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Purpose: This study aimed to establish the multienzyme isothermal rapid amplification with a lateral flow dipstick (MIRA-LFD) assay and evaluate its performance in detection of A. baumannii in spiked blood specimens. Methods: The study was divided into two stages: a pilot study to establish the methodology and a clinical validation study to evaluate its performance. In the first step, we designed primers specific to detect A. baumannii, optimized the MIRA-LFD assay and analyzed its performance regarding limits of detection, reproducibility, specificity, and efficiency of detection using real-time PCR method. In the second step, we obtained 50 spiked blood isolates and detected these pathogens by MIRA-LFD assay. The MIRA-LFD time was 15 min from DNA sample amplification to complete pathogen detection. Results: The developed MIRA-LFD assay displayed a detection limit of 6 CFU/mL for detecting A. baumannii, which was significantly better than that of real-time PCR method, and no cross-reactivity was observed in other non-A. baumannii studied. The results obtained with 50 spiked blood isolates suggested that the developed MIRA-LFD assay had high specificity and sensitivity for identifying A. baumannii. Conclusions: This study demonstrates that the established MIRA-LFD assay is time-saving, more effective and sensitive, which may become a powerful tool for rapid and reliable diagnosis of bloodstream infection caused by A. baumannii in primary hospitals.
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Acinetobacter baumannii , Acinetobacter baumannii/genética , Projetos Piloto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Técnicas de Amplificação de Ácido Nucleico/métodosRESUMO
The study aimed to determine the willingness of medical staff to have their children vaccinated with a COVID-19 booster in Taizhou, China. From March 21 to April 19, 2022, an online questionnaire survey was conducted to assess the willingness of medical staff to vaccinate their children with a booster dose of the COVID-19 vaccine. Of the 1,252 medical staff in a tertiary grade hospital in Taizhou who were invited to answer the structured questionnaire, 514 (41.1%) samples had valid information for further data analysis. Four hundred thirty-seven medical staff (85.0%) were willing to have their children receive vaccine boosters. After adjustments for confounding factors, the opinion ('Do you think your child needs a booster vaccination against COVID-19?') (yes vs. no, OR = 6.91, 95% CI: 3.29-14.54), the viewpoint ('What are your thoughts the effectiveness of COVID-19 vaccine boosters for children?' (≥12 vs. <12, OR = 13.81, 95% CI: 4.03-), and the attitude ('Your attitude to whether your child is boosting the Covid-19 vaccine?') (yes vs. no, OR = 4.66, 95% CI: 2.30-9.44) were significantly associated with their willingness to have their children receive a COVID-19 vaccine booster. A moderate percentage of the respondents expressed willingness to have their children receive booster vaccines. The findings implied that factors affecting medical staffs' willingness to vaccinate their children with a COVID-19 vaccine booster included viewpoint, opinion, and attitudes.
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Vacinas contra COVID-19 , COVID-19 , Criança , Humanos , COVID-19/prevenção & controle , Corpo Clínico , China , VacinaçãoRESUMO
BACKGROUND: Whether neuroinflammation causes comorbid mood disorders in neuropathic pain remains elusive. Here we investigated the role of high mobility group box 1 protein (HMGB1), a proinflammatory cytokine, in the medial prefrontal cortex (mPFC) in anxiety comorbidity of neuropathic pain. METHODS: Neuropathic pain was induced by partial transection of the infraorbital nerve (p-IONX) or partial sciatic nerve ligation (PSL) in mice and evaluated by measuring nociceptive thresholds to mechanical and heat stimulation. Anxiety-like behaviors were assessed by elevated plus maze, light dark box and open field tests. Aversive or anti-aversive effect was detected by conditioned place preference test. Neuronal activity was evaluated by single-unit and patch clamp recordings. The contribution of mPFC pyramidal neurons to anxiety was further examined by selectively inhibiting them by optogenetics. HMGB1 expression was measured by immunohistochemistry and western blotting. Antagonism of HMGB1 was achieved by injecting anti-HMGB1 monoclonal antibody (mAb) intracerebrally or intraperitoneally. RESULTS: Anxiety-like behaviors were presented earlier after p-IONX than after PSL. HMGB1 expression was upregulated in the mPFC temporally in parallel to anxiety onset, rather than in other regions associated with anxiety. The upregulation of HMGB1 expression and its translocation from the nucleus to cytoplasm in the mPFC occurred predominantly in neurons and were accompanied with activation of microglia and astrocytes. Infusion of anti-HMGB1 mAb into the mPFC during the early and late phases after either p-IONX or PSL alleviated anxiety-like behaviors and aversion without changing pain sensitization, while local infusion of exogenous ds-HMGB1, the proinflammatory form of HMGB1, into the mPFC induced anxiety and aversion but not pain sensitization in naïve mice. In addition to reversing established pain sensitization and anxiety simultaneously, intraperitoneal injection of anti-HMGB1 mAb reduced HMGB1 upregulation and suppressed the hyperexcitability of layer 2/3 pyramidal neurons in the mPFC after p-IONX. Moreover, optogenetic inhibition of mPFC pyramidal neurons alleviated anxiety in p-IONX mice. CONCLUSION: These results demonstrate that HMGB1 in the mPFC drives and maintains anxiety comorbidity in neuropathic pain by increasing the excitability of layer 2/3 pyramidal neurons, and justify antagonism of HMGB1, e.g., neutralization by mAb, as a promising therapeutic strategy for neuropathic pain with anxiety comorbidity.
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Neuralgia , Animais , Ansiedade/complicações , Comorbidade , Citoplasma , Camundongos , Neuralgia/metabolismo , Córtex Pré-Frontal/metabolismoRESUMO
INTRODUCTION: Parental vaccine-hesitancy can lead to delays or refusal to vaccinate children despite the availability of vaccines. This is a population-based, cross-sectional study investigating whether parents in China are hesitant to vaccinate their children with a COVID-19 vaccine booster. METHODS: Parents in Taizhou, China, responded to a self-reported online questionnaire on their hesitancy to vaccinate their children with a COVID-19 vaccine booster. Of the 1252 parents who were invited to answer the structured questionnaire, 514 (41.1%) samples had valid data for data analysis. RESULTS: A total of 41.8% of participants were hesitant to give their children a COVID-19 vaccine booster. After adjusting for confounders, parental gender (female vs. male parent, OR=0.56 95% CI: 0.32-0.87), parental opinion (yes vs. no, OR=0.17, 95% CI: 0.09-0.30), parental attitudes (yes vs. no, OR=0.28, 95% CI: 0.16-0.50), the presence of people around them who are generally hesitant to receive COVID-19 booster vaccines for children (yes vs. no, OR=0.14, 95%CI: 0.08-0.23), the individual hesitancy of people around them to administer booster COVID-19 vaccines to children (yes vs. no, OR=0.02, 95%CI: 0.02-0.22), and parents' hesitancy to receive a booster vaccine for their children showed significant correlation. The disparity of factors related to booster vaccine-hesitancy for children between fathers and mothers was also found. CONCLUSIONS: We found that a moderate proportion of parents reported that they were hesitant to give their children a COVID-19 vaccine booster. The results suggest that an in-depth, dynamic assessment and further health education planning are necessary to reduce Chinese parents' hesitancy to vaccinate their children.
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COVID-19 , Vacinas , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Criança , China/epidemiologia , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Imunização Secundária , Masculino , Pais , VacinaçãoRESUMO
Our previous study showed that H3 receptor antagonists reduced neuronal apoptosis and cerebral infarction in the acute stage after cerebral ischemia, but through an action independent of activation of histaminergic neurons. Because enhanced angiogenesis facilitates neurogenesis and neurological recovery after ischemic stroke, we herein investigated whether antagonism of H3R promoted angiogenesis after brain ischemia. Photothrombotic stroke was induced in mice. We showed that administration of H3R antagonist thioperamide (THIO, 10 mg·kg-1·d-1, i.p., from D1 after cerebral ischemia) significantly improved angiogenesis assessed on D14, and attenuated neurological defects on D28 after cerebral ischemia. Compared with wild-type mice, Hrh3-/- mice displayed more blood vessels in the ischemic boundary zone on D14, and THIO administration did not promote angiogenesis in these knockout mice. THIO-promoted angiogenesis in mice was reversed by i.c.v. injection of H3R agonist immepip, but not by H1 and H2 receptor antagonists, histidine decarboxylase inhibitor α-fluoromethylhistidine, or histidine decarboxylase gene knockout (HDC-/-), suggesting that THIO-promoted angiogenesis was independent of activation of histaminergic neurons. In vascular endothelial cells (bEnd.3), THIO (10-9-10-7 M) dose-dependently facilitated cell migration and tube formation after oxygen glucose deprivation (OGD), and H3R knockdown caused similar effects. We further revealed that H3R antagonism reduced the interaction between H3R and Annexin A2, while knockdown of Annexin A2 abrogated THIO-promoted angiogenesis in bEnd.3 cells after OGD. Annexin A2-overexpressing mice displayed more blood vessels in the ischemic boundary zone, which was reversed by i.c.v. injection of immepip. In conclusion, this study demonstrates that H3R antagonism promotes angiogenesis after cerebral ischemia, which is independent of activation of histaminergic neurons, but related to the H3R on vascular endothelial cells and its interaction with Annexin A2. Thus, H3R antagonists might be promising drug candidates to improve angiogenesis and neurological recovery after ischemic stroke.
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Anexina A2 , Isquemia Encefálica , AVC Isquêmico , Receptores Histamínicos H3 , Animais , Camundongos , Histidina Descarboxilase/genética , Histidina Descarboxilase/metabolismo , Receptores Histamínicos H3/metabolismo , Histamina , Células Endoteliais/metabolismo , Isquemia Encefálica/tratamento farmacológico , Camundongos Knockout , Infarto CerebralRESUMO
Progressive ischemic stroke (PIS) is featured by progressive neurological dysfunction after ischemia. Ischemia-evoked neuroinflammation is implicated in the progressive brain injury after cerebral ischemia, while Caspase-1, an active component of inflammasome, exaggerates ischemic brain injury. Current Caspase-1 inhibitors are inadequate in safety and druggability. Here, we investigated the efficacy of CZL80, a novel Caspase-1 inhibitor, in mice with PIS. Mice and Caspase-1-/- mice were subjected to photothrombotic (PT)-induced cerebral ischemia. CZL80 (10, 30 mg·kg-1·d-1, i.p.) was administered for one week after PT onset. The transient and the progressive neurological dysfunction (as foot faults in the grid-walking task and forelimb symmetry in the cylinder task) was assessed on Day1 and Day4-7, respectively, after PT onset. Treatment with CZL80 (30 mg/kg) during Day1-7 significantly reduced the progressive, but not the transient neurological dysfunction. Furthermore, we showed that CZL80 administered on Day4-7, when the progressive neurological dysfunction occurred, produced significant beneficial effects against PIS, suggesting an extended therapeutic time-window. CZL80 administration could improve the neurological function even as late as Day43 after PT. In Caspase-1-/- mice with PIS, the beneficial effects of CZL80 were abolished. We found that Caspase-1 was upregulated during Day4-7 after PT and predominantly located in activated microglia, which was coincided with the progressive neurological deficits, and attenuated by CZL80. We showed that CZL80 administration did not reduce the infarct volume, but significantly suppressed microglia activation in the peri-infarct cortex, suggesting the involvement of microglial inflammasome in the pathology of PIS. Taken together, this study demonstrates that Caspase-1 is required for the progressive neurological dysfunction in PIS. CZL80 is a promising drug to promote the neurological recovery in PIS by inhibiting Caspase-1 within a long therapeutic time-window.
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Lesões Encefálicas , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Inflamassomos , Modelos Animais de Doenças , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Microglia , Infarto Cerebral , Caspase 1 , Lesões Encefálicas/patologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Camundongos Endogâmicos C57BLRESUMO
PURPOSES: In order to investigate the association between serum periostin levels and the variation of its encoding gene POSTN and the prevalence of vertebral fractures and bone mineral density (BMD) in Chinese postmenopausal women, an association study was performed. MATERIALS AND METHODS: 385 postmenopausal women were recruited. For participants without a history of vertebral fracture, lateral X-rays of the spine covering the fourth thoracic spine to the fifth lumbar spine were performed to detect any asymptomatic vertebral fractures. Ten tag-single nucleotide polymorphisms (SNP) of POSTN were genotyped. Serum periostin levels, biochemical parameters, and BMD were measured individually. RESULTS: rs9603226 was significantly associated with vertebral fractures. Compared to allele G, the minor allele A carriers of rs9603226 had a 1.722-fold higher prevalence of vertebral fracture (p = 0.037). rs3923854 was significantly associated with the serum periostin level. G/G genotype of rs3923854 had a higher serum periostin level than C/C and C/G (67.26 ± 19.90 ng/mL vs. 54.57 ± 21.44 ng/mL and 54.34 ± 18.23 ng/mL). Furthermore, there was a negative correlation between the serum level of periostin and BMD at trochanter and total hip. CONCLUSION: Our study suggested that genetic variation of POSTN could be a predicting factor for the risk of vertebral fractures. The serum level of periostin could be a potential biochemical parameter for osteoporosis in Chinese postmenopausal women.
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Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Densidade Óssea/genética , China , Feminino , Humanos , Fraturas por Osteoporose/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/genética , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/genéticaRESUMO
Isoprene is the most abundant precursor of global secondary organic aerosol (SOA). The epoxide pathway plays a critical role in isoprene SOA (iSOA) formation, in which isoprene epoxydiols (IEPOX) and/or hydroxymethyl-methyl-α-lactone (HMML) can react with nucleophilic sulfate and water producing isoprene-derived organosulfates (iOSs) and oxygen-containing tracers (iOTs), respectively. This process is complicated and highly influenced by anthropogenic emissions, especially in the polluted urban atmospheres. In this study, we took a 1-year measurement of the paired iOSs and iOTs formed through the IEPOX and HMML pathways at the three urban sites from northern to southern China. The annual average concentrations of iSOA products at the three sites ranged from 14.6 to 36.5 ng m-3. We found that the nucleophilic-addition reaction of isoprene epoxides with water dominated over that with sulfate in the polluted urban air. A simple set of reaction rate constant could not fully describe iOS and iOT formation everywhere. We also found that the IEPOX pathway was dominant over the HMML pathway over urban regions. Using the kinetic data of IEPOX to estimate the reaction parameters of HMML will cause significant underestimation in the importance of HMML pathway. All these findings provide insights into iSOA formation over polluted areas.
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Poluentes Atmosféricos , Compostos de Epóxi , Aerossóis/análise , Butadienos , Hemiterpenos , Pentanos , Sulfatos , ÁguaRESUMO
BACKGROUND: The duration of beta-blocker therapy in patients without heart failure (HF) or left ventricular systolic dysfunction after acute myocardial infarction (AMI) is unclear. HYPOTHESIS: Continuous beta-blocker therapy is associated with an improved prognosis. METHODS: This is a prospective, multicenter, cohort study. One thousand four hundred and eighty-three patients eventually met the inclusion criteria. The study groups included the continuous beta-blocker therapy group (lasted ≥6 months) and the discontinuous beta-blocker therapy group (consisting of the no-beta-blocker therapy group and the beta-blocker therapy <6 months group). The inverse probability treatment weighting was used to control confounding factors. The study tried to learn the role of continuous beta-blocker therapy on outcomes. The median duration of follow-up was 13.0 months. The primary outcomes were cardiac death and major adverse cardiovascular events (MACE). The secondary outcomes were all-cause death, stroke, unstable angina, rehospitalization for HF, and recurrent myocardial infarction (MI). RESULTS: Compared with discontinuous beta-blocker therapy, continuous beta-blocker therapy was associated with a reduced risk of unstable angina, recurrent MI, and MACE (hazard ratio [HR]: 0.51; 95% CI: 0.32-0.82; p = 0.006); but this association was not available for cardiac death (HR: 0.57; 95% CI: 0.24-1.36; p = 0.206). When compared to the subgroups of no-beta-blocker therapy and beta-blocker therapy <6 months, respectively, continuous beta-blocker therapy was still observed to be associated with a reduced risk of unstable angina, recurrent MI, and MACE. CONCLUSIONS: Continuous beta-blocker therapy was associated with a reduced risk of unstable angina or recurrent MI or MACE in patients without HF or left ventricular systolic dysfunction after AMI.
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Insuficiência Cardíaca , Infarto do Miocárdio , Disfunção Ventricular Esquerda , Antagonistas Adrenérgicos beta/efeitos adversos , Angina Instável , Estudos de Coortes , Morte , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Estudos Prospectivos , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/etiologiaRESUMO
White matter injury is the major pathological alteration of subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion. It is characterized by progressive demyelination, apoptosis of oligodendrocytes and microglial activation, which leads to impairment of cognitive function. Triptolide exhibits a variety of pharmacological activities including anti-inflammation, immunosuppression and antitumor, etc. In this study, we investigated the effects of triptolide on white matter injury and cognitive impairments in mice with chronic cerebral hypoperfusion induced by the right unilateral common carotid artery occlusion (rUCCAO). We showed that triptolide administration alleviated the demyelination, axonal injury, and oligodendrocyte loss in the mice. Triptolide also improved cognitive function in novel object recognition test and Morris water maze test. In primary oligodendrocytes following oxygen-glucose deprivation (OGD), application of triptolide (0.001-0.1 nM) exerted concentration-dependent protection. We revealed that the protective effect of triptolide resulted from its inhibition of oligodendrocyte apoptosis via increasing the phosphorylation of the Src/Akt/GSK3ß pathway. Moreover, triptolide suppressed microglial activation and proinflammatory cytokines expression after chronic cerebral hypoperfusion in mice and in BV2 microglial cells following OGD, which also contributing to its alleviation of white matter injury. Importantly, mice received triptolide at the dose of 20 µg·kg-1·d-1 did not show hepatotoxicity and nephrotoxicity even after chronic treatment. Thus, our results highlight that triptolide alleviates whiter matter injury induced by chronic cerebral hypoperfusion through direct protection against oligodendrocyte apoptosis and indirect protection by inhibition of microglial inflammation. Triptolide may have novel indication in clinic such as the treatment of chronic cerebral hypoperfusion-induced SIVD.