ABSTRACT
BACKGROUND: The COVID-19 pandemic has a heavy impact on the mental health of elderly surgical patients worldwide. In particular, the elderly patients faced considerable psychological stress due to various environmental and medical factors during the outbreak. This study aims to examine changes in mental health trends among non-cardiac surgical patients aged 65 and above in China during the COVID-19 pandemic. METHODS: This multi-center, convenient sampling, longitudinal observational study was conducted from April 1, 2020 to April 30, 2022. Primary outcome was the prevalence of postoperative depression. Secondary outcome was the prevalence of postoperative anxiety. Follow-up was conducted separately at 7 days and 30 days after surgery. Depression symptoms were assessed using the Patient Health Questionnaire 9 (PHQ-9) scale. Anxiety symptoms were assessed using Generalized Anxiety Disorder-7 (GAD-7) scale, with scores of ≥5 defining positive depression or anxiety symptoms. Multivariate logistic regression analysis was used to investigate risk factors of mental health status in more elderly patients undergoing non-cardiac surgery. RESULTS: A total of 4639 patients were included, of whom 2279 (46.0 %) were male, 752 (15.2 %) were over the age of 75, and 4346 (93.7 %) were married. The monthly prevalence trends demonstrated that compared to the outbreak period, a significant reduction in the prevalence of depression and anxiety symptoms in elderly patients who underwent surgery during the post-pandemic period. In post-pandemic period, a statistically significant decrease in the prevalence of all severity depression and anxiety patients was noted at the 7-day follow-up, but no significant decrease was observed for severe depression and anxiety in the 30-day follow-up. In COVID-19 low-risk area, a significant overall decrease in prevalence of mental health was observed during the post-pandemic period compared to the outbreak period, including 7-day depression, 7-day anxiety, 30-day depression, and 30-day anxiety (all with P < 0.001). Female and patients with ≥2 comorbidities appeared to be more susceptible to postoperative depression and anxiety during the pandemic. LIMITATION: The absence of data from the early days of the COVID-19 outbreak. CONCLUSIONS: This study analyzed the prevalence of depression and anxiety in elderly non-cardiac patients during and after the COVID-19 pandemic, focusing on dimensions such as severity, risk-areas, gender, and comorbidity. Our findings revealed a significant decrease in the prevalence of depression and anxiety in elderly surgery patients during the post-pandemic period.
ABSTRACT
Muscle diseases are closely related to autophagy disorders. Studies of autophagy inhibition indicated the importance of autophagy in muscle regeneration, while activation of autophagy can restore muscle function in some myopathies. Previous studies have revealed that mutations in the MYOT gene may lead to several kinds of hereditary myopathies. However, whether the autophagy played a crucial role in hereditary myopathy caused by MYOT mutations was still not clear. In this study, we established the MYOT knockdown human skeletal muscle cell models (HSkMCs) by small interfering RNA. Real-time PCR and Western blot studies found that the expression of p62 and LC3B-II was decreased dramatically, which suggested that silencing MYOT expression may regulate the autophagy in HSkMCs. Further immunofluorescence study on Ad-mCherry-GFP-LC3B adenovirus transfection and monodansylcadaverine (MDC) staining revealed that knocking down the expression of MYOT may inhibit the autophagy. Next, we used the autophagy inducer Earle's balanced salt solution (EBSS) and late-autophagy inhibitor bafilomycin A1 (BAF A1) to treat the HSkMCs, respectively, and found that silencing MYOT expression can inhibit the activation of autophagy by EBSS and aggravate the inhibition of autophagy by BAF A1. Finally, we also found that silencing MYOT expression can downregulate the expression of ATG7 and ATG5, two important autophagy regulatory molecules. Hence, our study may first reveal that knocking down the expression of MYOT may inhibit the autophagy. Hereditary myopathies caused by MYOT mutations may partly result from the inhibition of autophagy in HSkMCs.
Subject(s)
Autophagy , Microfilament Proteins , Muscle, Skeletal , Humans , Autophagy/genetics , RNA, Small Interfering/genetics , Transfection , Microfilament Proteins/geneticsABSTRACT
Smith-Magenis syndrome (SMS, OMIM# 182290) is a rare congenital disorder which characterized by multiple abnormalities involving in craniofacial, skeletal, otorhinolaryngolocial, neurological, behavioral and others. 17p11.2 microdeletion and RAI1 mutations have been proven to be genetic lesions of this disease. However, the relationship between RAI1 variants and different phenotypes is still unclear. The discoveries of more RAI1 mutations in patients with different phenotypes will help to elucidate the pathogenesis of the RAI1 gene. Here, we describe a young patient with schizophrenia and headache as the main clinical presentation, with SMS-like features including depression, sleep disturbance and pain-free status. Whole exome sequencing and Sanger sequencing suggested that a de novo mutation (NM_030665.3: c.4256C > T/p.S1419F) of RAI1 may be the genetic lesion of the patient. The bioinformatic program predicted that the new mutation (p.S1419F), located in an evolutionarily conserved site of RAI1, was deleterious. Further, western blot analysis suggested that the novel mutation may decrease the protein levels of RAI1 in the patient. Hence, we reported a novel mutation of RAI1 in a patient with SMS, schizophrenia and headache. Our study may expand the spectrum of RAI1 mutations which may further contribute to the mechanisms underlying SMS, schizophrenia and headache.
Subject(s)
Schizophrenia , Smith-Magenis Syndrome , Humans , Headache , Mutation , Phenotype , Schizophrenia/genetics , Smith-Magenis Syndrome/genetics , Trans-Activators/genetics , Transcription Factors/genetics , TretinoinABSTRACT
Inappropriate expansion of antibody-secreting cells (ASCs) is typical of systemic lupus erythematosus (SLE), but the regulatory signaling of pathogenic ASCs is unclear. The present study shows that brain-derived neurotrophic factor precursor (proBDNF) and its high-affinity pan-75 neurotrophin receptor (p75NTR) are highly expressed in CD19+CD27hiCD38hi ASCs in patients with SLE and in CD19+CD44hiCD138+ ASCs in lupus-like mice. The increased proBDNF+ ASCs were positively correlated with clinical symptoms and higher titers of autoantibodies in SLE. Administration of monoclonal antibodies against proBDNF or specific knockout of p75NTR in CD19+ B cells exerted a therapeutic effect on lupus mice by limiting the proportion of ASCs, reducing the production of autoantibodies and attenuating kidney injury. Blocking the biological function of proBDNF or p75NTR also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75NTR signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction.
Subject(s)
Lupus Erythematosus, Systemic , Receptors, Nerve Growth Factor , Animals , Antigens, CD19 , Autoantibodies , B-Lymphocytes , Brain-Derived Neurotrophic Factor/metabolism , Humans , Mice , Mice, Inbred C57BL , Receptors, Nerve Growth Factor/genetics , Receptors, Nerve Growth Factor/metabolism , Up-RegulationABSTRACT
Background: Many patients with type A aortic dissection (AAD) show low lymphocyte counts pre-operatively. The present study investigated the prognostic values of lymphopenia and lymphocyte subsets for the postoperative major adverse events (MAEs) in AAD patients undergoing surgery, and explore mechanisms of lymphopenia. Methods: We retrospectively analyzed pre-operative lymphocyte counts in 295 AAD patients treated at two hospitals, and evaluated their correlation with MAEs. We prospectively recruited 40 AAD patients and 20 sex- and age-matched healthy donors (HDs), and evaluated lymphocyte subsets, apoptosis, and pyroptosis by flow cytometry. Results: Multivariable regression analysis of the retrospective cohort revealed pre-operative lymphopenia as a strong predictor of MAEs (odds ratio, 4.152; 95% CI, 2.434-7.081; p < 0.001). In the prospective cohort, lymphocyte depletion in the AAD group was mainly due to loss of CD4+ and CD8+ T cells as compared with HDs (CD4+ T cells: 346.7 ± 183.6 vs. 659.0 ± 214.6 cells/µl, p < 0.0001; CD8+ T cells: 219.5 ± 178.4 vs. 354.4 ± 121.8 cells/µl, p = 0.0036). The apoptosis rates of CD4+ and CD8+ T cells were significantly higher in AAD patients relative to HDs (both p < 0.0001). Furthermore, the pre-operative CD4+ T cells count at a cut-off value of 357.96 cells/µl was an effective and reliable predictor of MAEs (area under ROC curve = 0.817; 95% CI, 0.684-0.950; sensitivity, 74%; specificity, 81%; p < 0.005). Pre-operative lymphopenia, mainly due to CD4+ T cells exhaustion by apoptosis, correlates with poor prognosis in AAD patients undergoing surgery. Conclusion: Pre-operative lymphopenia in particular CD4+ T lymphopenia via apoptosis correlates with poor prognosis in AAD patients undergoing surgery.
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OBJECTIVE: To study the epidemiological and clinical features of children with mild coronavirus disease 2019 (COVID-19). METHODS: The children who were diagnosed with mild COVID-19 in the Wuchang Shelter Hospital in Wuhan from February 5 to March 10, 2020 were enrolled as subjects. The clinical, laboratory, and lung imaging data were collected during hospitalization and isolation. This was a retrospective single-center case series analysis. RESULTS: A total of 1 124 patients with mild COVID-19 were admitted from February 5 to March 10, 2020, including 13 children (1.16%). All the 13 children (7 boys and 6 girls) were residents of Wuhan in China, with a median age of 16 years (range: 10-18 years). Of all the 13 children, 9(69%) were from family clusters of COVID-19 and 4(31%) had unknown sources of infection. The mean time from exposure to onset was 6.8 days (range: 2-13 days) in 9 children with a definite history of exposure. There were 6 symptomatic children with the main manifestations of fever, cough, weakness, and myalgia, and the mean time from onset to hospitalization was 9.2 days. Of all the 13 children, 7(54%) were asymptomatic with positive nucleic acid test of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). There were 4 children (31%) with abnormal lung CT findings, mainly patchy shadows or ground-glass opacities in the lung field, and 6 children (46%) had no symptoms with normal lung CT findings. All children had normal routine blood test results and C-reactive protein levels. Eight children underwent SARS-CoV-2 IgM and IgG tests at least once, among whom 6 had negative SARS-CoV-2 IgM but positive IgG, and 2 underwent SARS-CoV-2 IgM and IgG tests twice and had negative results. Of all the 13 children, 11(85%) had negative results of two SARS-CoV-2 nucleic acid tests during hospitalization and were discharged, and 2(15%) had positive results of four SARS-CoV-2 nucleic acid tests and were transferred to another hospital and lost to follow-up. Among the 11 children who were followed up, 1 had positive results of two SARS-CoV-2 nucleic acid tests at the isolation point, and 10 had negative results. The mean hospital stay was 10.9 days for the 13 children. Eleven children recovered during follow-up, with good living and learning conditions. CONCLUSIONS: Children with mild COVID-19 often have an uncertain history of exposure and may not have any clinical symptoms. Etiological diagnosis is more important than clinical diagnosis. The disappearance of clinical manifestations may not parallel with the result of SARS-CoV-2 nucleic acid test. SARS-CoV-2 has a long detoxification time, and there may be recurrent cases of SARS-CoV-2 positivity. Further studies are needed to investigate the production patterns of SARS-CoV-2 IgM and IgG and their effect on the body.
Subject(s)
COVID-19 , Adolescent , Child , China/epidemiology , Female , Fever , Humans , Male , Retrospective Studies , SARS-CoV-2ABSTRACT
Rationale: Brain-derived neurotrophic factor precursor (proBDNF) is expressed in the central nervous system (CNS) and the immune system. However, the role of proBDNF in the pathogenesis of multiple sclerosis (MS) is unknown. Methods: Peripheral blood and post-mortem brain and spinal cord specimens were obtained from multiple sclerosis patients to analyze proBDNF expression in peripheral lymphocytes and infiltrating immune cells in the lesion site. The proBDNF expression profile was also examined in the experimental autoimmune encephalomyelitis (EAE) mouse model, and polyclonal and monoclonal anti-proBDNF antibodies were used to explore their therapeutic effect in EAE. Finally, the role of proBDNF in the inflammatory immune activity of peripheral blood mononuclear cells (PBMCs) was verified in vitro experiments. Results: High proBDNF expression was detected in the circulating lymphocytes and infiltrated inflammatory cells at the lesion sites of the brain and spinal cord in MS patients. In the EAE mouse model, proBDNF was upregulated in CNS and in circulating and splenic lymphocytes. Systemic but not intracranial administration of anti-proBDNF blocking antibodies attenuated clinical scores, limited demyelination, and inhibited proinflammatory cytokines in EAE mice. Immuno-stimulants treatment increased the proBDNF release and upregulated the expression of p75 neurotrophic receptors (p75NTR) in lymphocytes. The monoclonal antibody against proBDNF inhibited the inflammatory response of PBMCs upon stimulations. Conclusion: The findings suggest that proBDNF from immune cells promotes the immunopathogenesis of MS. Monoclonal Ab-proB may be a promising therapeutic agent for treating MS.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Brain/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Leukocytes, Mononuclear/metabolism , Leukocytes/metabolism , Multiple Sclerosis/pathology , Protein Precursors/metabolism , Spinal Cord/metabolism , Animals , Brain/immunology , Case-Control Studies , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Humans , Leukocytes/immunology , Leukocytes, Mononuclear/immunology , Mice , Mice, Inbred C57BL , Multiple Sclerosis/immunology , Multiple Sclerosis/metabolism , Spinal Cord/immunologyABSTRACT
Since the outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, the public-facility-turned temporary hospital (PFTH) has played an important role in preventing the spread of the epidemic. Wuchang PFTH is the first one to put into clinical practice and the last one suspended in Wuhan. The National Emergency Medical Rescue Team of the Second Xiangya Hospital of Central South University, together with other 13 medical teams (841 medical staff in total), have fulfilled the task for the treatment of non-severe COVID-19 patients, without any medical staff infected. The first author of the article was the only pediatrician working in the Wuchang PFTH. The author describes and summarizes the features/functions, management/operations, and advantages/challenges of the PFTH, in order to provide reference for medical institutions and relevant departments to deal with public health emergencies.
Subject(s)
Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , COVID-19 , China , Coronavirus Infections/prevention & control , Hospitals , Humans , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , SARS-CoV-2ABSTRACT
Brain-derived neurotrophic factor precursor (proBDNF) has been reported to strengthen the dysfunction of monocytes/macrophages in animal studies. However, it is still unknown the roles of proBDNF in the dysfunction of monocytes in the inflammatory diseases in humans. In the present study, we showed that proBDNF and pan neurotrophic receptor p75 were significantly upregulated in monocytes from healthy donors (HD) after lipopolysaccharide treatment. Exogenous proBDNF treatment upregulated CD40 and proinflammatory cytokines expression in monocytes including interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. In Stanford type-A acute aortic dissection (AAD) patients, proBDNF was upregulated in CD14+ CD163+ CX3CR1+ M2- but not CD14+ CD68+ CCR2+ M1-like monocytes. In addition, sera from AAD patients activated gene expression of proinflammatory cytokines in cultured PBMCs from HD, which was attenuated by proBDNF monoclonal antibody (Ab-proB) treatment. These findings suggested that upregulation of proBDNF in M2-like monocytes may contribute to the proinflammatory response in the AAD.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Cytokines/metabolism , Macrophages/metabolism , Monocytes/metabolism , Protein Precursors/metabolism , Adult , Aortic Dissection/metabolism , Cells, Cultured , Female , Humans , Male , Middle Aged , Tumor Necrosis Factor-alpha/metabolism , Up-RegulationABSTRACT
BACKGROUND: The lncRNA NKILA has been reported to interact with NF-κB and has an important role in various human diseases. However, the role of NKILA in myocardial ischaemic injury is still unknown. METHODS: We established cell and animal models of myocardial ischaemic injury. We confirmed our findings by overexpressing NKILA, silencing myocardin and using an NF-κB pathway inhibitor in a hypoxia/reoxygenation (H/R) model of H9c2 cells. An animal model of ischaemia-reperfusion (I/R) injury was established by LAD ligation. Overexpression of NKILA was achieved by adeno-associated virus (AAV) injection through the tail vein. Annexin-V/PI staining and flow cytometric analysis were performed to test cell apoptosis. ELISAs were used to determine the secretion of inflammatory factors. TTC, HE and TUNEL staining were performed to study myocardial pathological injury. qRT-PCR or Western blotting were used to test the expression levels of NKILA, myocardin, the NF-κB pathway and apoptosis-related proteins. RESULTS: H/R and I/R treatment significantly suppressed the expression of NKILA and activated the NF-κB pathway, resulting in the loss of myocardin. Overexpressing NKILA led to the suppression of the NF-κB pathway and successfully prevented the cell apoptosis and inflammatory responses caused by H/R stimulation in H9c2 cells. Silencing myocardin reversed the protective effect of NKILA and led to severe injury in the H9c2 cells that underwent H/R. Furthermore, the NF-κB pathway inhibitor BAY11-7028 reduced the H/R injury in H9c2 cells with little effect on NKILA expression. Similar results were confirmed in an animal model of myocardial I/R injury and showed that overexpression of NKILA inhibited I/R-triggered myocardial injury in vivo. CONCLUSION: NKILA enhanced the expression of myocardin via inhibiting the NF-κB signalling pathway and preventing cell apoptosis and the inflammatory response of cardiomyocytes, thus ameliorating myocardial I/R injury.
Subject(s)
Myocardial Ischemia/genetics , Myocytes, Cardiac/physiology , NF-kappa B/genetics , Nuclear Proteins/genetics , RNA, Long Noncoding/genetics , Signal Transduction/genetics , Trans-Activators/genetics , Animals , Apoptosis/genetics , Cell Line , Cell Movement/genetics , Epithelial-Mesenchymal Transition/genetics , Hypoxia/genetics , Male , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Post-operative cognitive dysfunction (POCD) is a decline of cognitive status that commonly occurs after surgery in elderly patients. Whether DNA methylation is associated with the development of POCD remains unclear. METHODS: Subjects (N = 124) older than 65 years-of-age undergoing hip replacement surgery were enrolled. A battery of neuropsychiatric tests was used to examine the perioperative cognitive function of the patients. Early POCD was analyzed using the reliable change index (RCI), and subjects were diagnosed with POCD if RCI < -1.96. Peripheral leukocyte DNA was isolated, and DNA methylation was measured via 5-methylcytosine (mC) using Elisa. RESULTS: Twenty-four patients (19.4%) developed early POCD. There was no difference in baseline 5-mC levels by POCD status. The 5-mC levels significantly decreased on day 7 after surgery in patients who developed early POCD (P = .004), but did not change in non-POCD patients. Moreover, post-operative 5-mC levels were significantly lower in POCD patients than those in non-POCD patients (P = .003). Bivariate logistic models adjusted for age, gender, BMI, duration of anesthesia, and education level clearly demonstrated an independent association between post-operative 5-mC level and early POCD. CONCLUSIONS: Post-operative global hypomethylation of leukocyte DNA was associated with the development of early POCD. TRIAL REGISTRATION: ClinicalTrial, NCT02965235. Registered 16 November 2016, https://www.clinicaltrials.gov/ct2/results?term=NCT02965235&rank=1#rowId0.
Subject(s)
Arthroplasty, Replacement, Hip/methods , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/physiopathology , DNA Methylation/physiology , Postoperative Complications/metabolism , Postoperative Complications/physiopathology , Aged , Cognitive Dysfunction/diagnosis , Female , Geriatric Assessment/methods , Humans , Male , Neuropsychological Tests , Postoperative Complications/diagnosisABSTRACT
BACKGROUND AND OBJECTIVE: Diabetic neuropathic pain (DNP) is a common complication associated with diabetes. Currently, its underlying pathomechanism remains unknown. Studies have revealed that the recruitment of blood monocyte-derived macrophages (MDMs) to the spinal cord plays a pivotal role in different models of central nervous system injury. Therefore, the present study aimed at exploring the infiltration and function of MDMs in DNP using a mice model. METHODS: Diabetes was induced using streptozotocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Quantitative analysis of CD11b was performed and visualized by immunofluorescence. Spinal cord cells were isolated from myelin and debris by Percoll gradient. Flow cytometry was used to label CD11b and CD45 antibodies to differentiate MDMs (CD45highCD11b+) from resident microglia (CD45lowCD11b+). Mice were injected with clodronate liposomes to investigate the role of MDMs in DNP. The successful depletion of monocytes was determined by flow cytometry. RESULTS: The DNP mice model was successfully established. Compared with nondiabetic mice, diabetic mice displayed a markedly higher level of CD11b immunofluorescence in the spinal cord. The number of CD11b-positive microglia/macrophages gradually increased over the 28 days of testing after STZ injection, and a significant increase was observed on Day 14 (P < 0.01) and 28 (P < 0.01). Further analysis by flow cytometry showed that the infiltration of peripheral macrophages began to increase in 2 weeks (P < 0.001) and reached a maximum at 4 weeks (P < 0.001) post-STZ injection compared to the control. The depletion of MDMs by clodronate liposomes alleviated diabetes-induced tactile allodynia (P < 0.05) and reduced the infiltration of MDMs (P < 0.001) as well as the expression of IL-1ß and TNF-α in the spinal cord (P < 0.05). CONCLUSIONS: The infiltration of blood MDMs in the spinal cord may promote the development of painful neuropathy in diabetes.
Subject(s)
Diabetic Neuropathies/etiology , Diabetic Neuropathies/metabolism , Macrophages/immunology , Macrophages/metabolism , Animals , Biomarkers , Diabetes Mellitus, Experimental , Diabetic Neuropathies/pathology , Disease Models, Animal , Immunophenotyping , Male , Mice , Monocytes/immunology , Monocytes/metabolism , Rats , Spinal Cord/metabolismABSTRACT
Purpose: To investigate the value of US and elastography for predicting prognostic factors of papillary thyroid cancer (PTC) in the positive BRAFV600E Mutation group. Materials and Methods: A total of 116 BRAFV600E Mutation patients with PTCs were enrolled in this prospective study, who were preoperatively evaluated by US, US elasticity imaging (EI), and Virtual Touch tissue imaging (VTI) and Virtual Touch tissue quantification (VTQ) of acoustic radiation force impulse (ARFI) imaging. Multivariate logistic regression analysis was performed to assess 23 independent variables for predicting prognostic factors. Diagnostic performance was evaluated with receiver operating characteristic (ROC) curve analysis. Results: Forty-two (36.2%) of 116 PTC patients with BRAFV600E Mutation had central lymph node metastasis (LNM). Nine (7.8%) and fifty-six (48.3%) had lateral LNM and extra-thyroidal extension (ETE), respectively. In multivariate logistic regression analyses, rich internal flow [odds ratio [OR]: 6.66] was the best predictor for central LNM, followed by male sex (OR: 4.22), halo sign absence (OR: 2.78) (all P < 0.05). VTQ ratio (OR: 1.57) was the only predictor for lateral LNM (P = 0.02). Rich internal flow (OR: 6.33) was the strongest predictor for ETE, followed by male sex (OR: 3.29), halo sign absence (OR: 2.90), and VTQ ratio (OR: 1.63) (all P < 0.05). Conclusion: VTQ ratio on ARFI imaging, rich internal flow and halo sign absence on US are the predicting prognostic factors in PTC patients with BRAFV600E Mutation. The specificities were significantly increased by combining ARFI imaging and US features, which has a potential to avoid unnecessary therapeutic neck dissection in the high-risk PTC patients.
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BACKGROUND: Glucose fluctuation confers additional risks on diabetes-related vascular diseases, but the underlying mechanisms are unknown. Macrophage activation mediated by TLR4-JNK signaling plays an important role during the progress of diabetes. In the present study, we hypothesize that glucose fluctuation results in macrophage inflammation through TLR4-JNK signaling pathways. METHODS: THP-1 cells were treated with normal glucose (5 mM), constant high glucose (25 mM), and intermittent high glucose (rotation per 6 h in 5 mM or 25 mM) for 24 h. The mRNA and protein expression levels of TLR4, p-JNK, and adipocyte fatty acid-binding protein (A-FABP) were determined, and the proinflammatory cytokines TNF-α and IL-1ß were quantified. RESULTS: In constant high glucose, TLR4 expression and JNK phosphorylation levels increased, and this effect was more pronounced in intermittent high glucose. Accordingly, the expression of A-FABP and the release of the proinflammatory cytokines TNF-α and IL-1ß also increased in response to constant high glucose, an effect that also was more evident in intermittent high glucose. The inhibition of p-JNK by SP600125 did not attenuate TLR4 expression, but totally inhibited both A-FABP expression and the production of the proinflammatory cytokines TNF-α and IL-1ß in both constant and intermittent high glucose. CONCLUSIONS: Intermittent high glucose potentiates A-FABP activation and inflammatory responses via TLR4/p-JNK signaling in THP-1 cells. These findings suggest a more detrimental impact of glucose fluctuation on macrophage inflammation in diabetes-related vascular diseases than thus far generally assumed.
Subject(s)
Diabetes Complications/metabolism , Fatty Acid-Binding Proteins/metabolism , Glucose/metabolism , Inflammation/metabolism , Macrophages/metabolism , Diabetes Complications/immunology , Fatty Acid-Binding Proteins/genetics , Gene Expression Regulation , Humans , Inflammation/immunology , Inflammation Mediators/metabolism , Interleukin-1beta/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Signal Transduction , THP-1 Cells , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
A high level of circulating free fatty acids (FFAs) is known to be an important trigger for macrophage apoptosis during the development of atherosclerosis. However, the underlying mechanism by which FFAs result in macrophage apoptosis is not well understood. In cultured human macrophage Thp-1 cells, we showed that palmitate (PA), the most abundant FFA in circulation, induced excessive reactive oxidative substance production, increased malondialdehyde concentration, and decreased adenosine triphosphate levels. Furthermore, PA treatment also led to mitochondrial dysfunction, including the decrease of mitochondrial number, the impairment of respiratory complex IV and succinate dehydrogenase activity, and the reduction of mitochondrial membrane potential. Mitochondrial apoptosis was also detected after PA treatment, indicated by a decrease in cytochrome c release, downregulation of Bcl-2, upregulation of Bax, and increased caspase-3 activity. PA treatment upregulated the expression of adipocyte fatty acid-binding protein (A-FABP), a critical regulator of fatty acid trafficking and lipid metabolism. Inhibition of A-FABP with BMS309403, a small-molecule A-FABP inhibitor, almost reversed all of these indexes. Thus, this study suggested that PA-mediated macrophage apoptosis through A-FABP upregulation, which subsequently resulted in mitochondrial dysfunction and reactive oxidative stress. Inhibition of A-FABP may be a potential therapeutic target for macrophage apoptosis and to delay the progress of atherosclerosis.
Subject(s)
Adipocytes/metabolism , Apoptosis , Fatty Acid-Binding Proteins/metabolism , Macrophages/metabolism , Mitochondria/metabolism , Palmitates/metabolism , Apoptosis/drug effects , Cell Line , Fatty Acid-Binding Proteins/genetics , Humans , Macrophages/drug effects , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Palmitates/pharmacologyABSTRACT
Depression and anxiety are two affective disorders that greatly threaten the mental health of a large population worldwide. Previous studies have shown that brain-derived neurotrophic factor precursor (proBDNF) is involved in the development of depression. However, it is still elusive whether proBDNF is involved in anxiety, and if so, which brain regions of proBDNF regulate these two affective disorders. The present study aims to investigate the role of proBDNF in the hippocampus in the development of depression and anxiety. Rat models of an anxiety-like phenotype and depression-like phenotype were established by complete Freund's adjuvant intra-plantar injection and chronic restraint stress, respectively. Both rat models developed anxiety-like behaviors as determined by the open field test and elevated plus maze test. However, only rats with depression-like phenotype displayed the lower sucrose consumption in the sucrose preference test and a longer immobility time in the forced swimming test. Sholl analysis showed that the dendritic arborization of granule cells in the hippocampus was decreased in rats with depression-like phenotype but was not changed in rats with anxiety-like phenotype. In addition, synaptophysin was downregulated in the rats with depression-like phenotype but upregulated in the rats with anxiety-like phenotype. In both models, proBDNF was greatly increased in the hippocampus. Intra-hippocampal injection anti-proBDNF antibody greatly ameliorated the anxiety-like and depressive behaviors in the rats. These findings suggest that despite some behavioral and morphological differences between depression and anxiety, hippocampal proBDNF is a common mediator to regulate these two mental disorders.
ABSTRACT
OBJECTIVES: To evaluate the diagnostic performance of Virtual Touch tissue imaging quantification (VTIQ; Siemens Medical Solutions, Mountain View, CA) in combination with the Thyroid Imaging Reporting and Data System (TI-RADS) for assessing thyroid nodules referred for biopsy. METHODS: A total of 197 surgically or cytologically proven thyroid nodules in 187 patients were included. Nodules evaluated by conventional ultrasound (US) and VTIQ examinations were classified into US TI-RADS categories. The shear wave velocity (SWV) on VTIQ was assessed, and the cutoff value was obtained from a receiver operating characteristic curve analysis. Diagnostic performances of conventional US, VTIQ, and their combination were compared. RESULTS: There were 134 benign and 63 malignant nodules. The sensitivity and specificity for the US TI-RADS were 98.4% and 20.1%, respectively. The areas under the receiver operating characteristic curves for the mean, maximum, minimum, and ratio of the SWV were 0.818, 0.805, 0.799, and 0.728. With a cutoff value of 2.90 m/s, the sensitivity and specificity of the mean SWV were 71.4% and 82.8%. By applying this value or less as a standard for downgrading TI-RADS category 4a to category 3 lesions, the specificity significantly rose from 20.1% to 47.0% (P < .001) without a loss of sensitivity. CONCLUSIONS: The additional application of VTIQ can improve the specificity of the TI-RADS for evaluating thyroid nodules without a loss of sensitivity.
Subject(s)
Thyroid Nodule/diagnostic imaging , Thyroid Nodule/pathology , Ultrasonography/methods , Adolescent , Adult , Aged , Biopsy , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Radiology Information Systems , Reproducibility of Results , Retrospective Studies , Sensitivity and Specificity , Thyroid Gland/diagnostic imaging , Thyroid Gland/pathology , User-Computer Interface , Young AdultABSTRACT
The aim of the present study was to observe whether dexmedetomidine (DEX) combined with sufentanil decreased emergence agitation (EA) in children receiving sevoflurane anesthesia for cleft palate repair surgery. Children undergoing elective cleft palate repair surgery were randomly allocated into the DEX + sufentanil group (group DS; n=50) and the normal saline + fentanyl group (group SF; n=50). Patients in group DS were treated with 0.5 µg/kg DEX prior to induction of anesthesia, whereas patients in group SF received an equal volume of normal saline. Sufentanil (0.2 µg/kg) was administered to induce anesthesia, and 30 min before the end of surgery for patients in group DS. Fentanyl (2 µg/kg) was administered at the same time point for patients in group SF. Mean arterial pressure (MAP), heart rate (HR), duration of surgery and anesthesia, and the dosage of remifentanil were assessed. EA score, Pediatric Anesthesia Emergence Delirium (PAED) score and the Children and Infants Postoperative Pain Scale (CHIPPS) score were documented every 15 min in the post-anesthesia care unit (PACU). The number of cases requiring fentanyl (1 µg/kg) and the recovery profile data were analyzed. Compared with group DS (P<0.05) and the baseline (P<0.05), HR and MAP were significantly increased in group SF immediately following tracheal intubation and extubation. Mean values of maximum EA, PAED and CHIPPS scores were significantly reduced in group DS compared with group SF at 0 (P<0.01), 15 (P<0.05), and 30 min (P<0.05) after arrival at PACU. The incidence of EA in group SF was significantly increased compared with group DS (P<0.05). The dosage of remifentanil during the surgery and the number of cases requiring fentanyl (1 µg/kg) in group DS were significantly decreased compared with group SF (P<0.05). The findings of the present study suggested that DEX combined with sufentanil was able to effectively decrease the incidence of EA in children receiving sevoflurane anesthesia for cleft palate repair surgery.