The Bach1/HO-1 pathway regulates oxidative stress and contributes to ferroptosis in doxorubicin-induced cardiomyopathy in H9c2 cells and mice.

Doxorubicin (DOX) is one of the most frequently used chemotherapeutic drugs belonging to the class of anthracyclines. However, the cardiotoxic effects of anthracyclines limit their clinical use. Recent studies have suggested that ferroptosis is the main underlying pathogenetic mechanism of DOX-induced cardiomyopathy (DIC). BTB-and-CNC homology 1 (Bach1) acts as a key role in the regulation of ferroptosis. However, the mechanistic role of Bach1 in DIC remains unclear. Therefore, this study aimed to investigate the underlying mechanistic role of Bach1 in DOX-induced cardiotoxicity using the DIC mice in vivo (DOX at cumulative dose of 20 mg/kg) and the DOX-treated H9c2 cardiomyocytes in vitro (1 µM). Our results show a marked upregulation in the expression of Bach1 in the cardiac tissues of the DOX-treated mice and the DOX-treated cardiomyocytes. However, Bach1-/- mice exhibited reduced lipid peroxidation and less severe cardiomyopathy after DOX treatment. Bach1 knockdown protected against DOX-induced ferroptosis in both in vivo and in vitro models. Ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis, significantly alleviated DOX-induced cardiac damage. However, the cardioprotective effects of Bach1 knockdown were reversed by pre-treatment with Zinc Protoporphyrin (ZnPP), a selective inhibitor of heme oxygenase-1(HO-1). Taken together, these findings demonstrated that Bach1 promoted oxidative stress and ferroptosis through suppressing the expression of HO-1. Therefore, Bach1 may present as a promising new therapeutic target for the prevention and early intervention of DOX-induced cardiotoxicity.

Anti-N-methyl-D-aspartate Receptor Encephalitis in People Living with HIV: Case Report and Literature Review.

With the increase in the number of cases of autoimmune encephalitis (AE), the cerebrospinal fluid (CSF) of people living with HIV (PLWH) showing abnormal behavior, cognitive impairment or abnormal movements should be actively screened for the antibody panel of AE. Early recognition and treatment can prevent severe seizures or coma and markedly improve the prognosis of patients. The first-line immunotherapy for AE includes intravenous methylprednisolone and immunoglobulin. However, whether long-time immunosuppressive maintenance therapy is needed is debated. For PLWH, immunosuppressive therapy and even steroids could be more challenging. Here, we review and summarize the clinical characteristics often reported cases and report one case from our center to improve the diagnosis and treatment of anti-N-methyl-D-aspartate receptor encephalitis in PLWH.

The STING inhibitor C-176 attenuates MPTP-induced neuroinflammation and neurodegeneration in mouse parkinsonian models.

Recent emerging evidence reveals that cGAS-STING-mediated Type I interferon (IFN) signaling axis takes part in the microglial-associated neuroinflammation. However, the potential role of pharmacological inhibition of STING on neuroinflammation and dopaminergic neurodegeneration remains unknown. In the present study, we investigated whether pharmacological inhibition of STING attenuates neuroinflammation and neurodegeneration in experimental models of Parkinson's disease. We report that therapeutic inhibition of STING with C-176 significantly inhibited the activation of downstream signaling pathway, suppressed neuroinflammation, and ameliorated MPTP-induced dopaminergic neurotoxicity and motor deficit. Furthermore, pharmacological inhibition of STING with C-176 attenuated proinflammatory response in BV2 microglial cells exposed to LPS/MPP+. More importantly, C-176 also reduced NLRP3 inflammasome activation both in vitro and in vivo. The results of our study suggest that pharmacologic inhibition of STING protects against dopaminergic neurodegeneration and neuroinflammation that may act at least in part through suppressing NLRP3 inflammasome activation. STING signaling may hold great promise for the development of new treatment strategy for PD.

The clinical and virological features of two children's coinfections with human adenovirus type 7 and human coronavirus-229E virus.

Objective: Human adenovirus (HAdV) coinfection with other respiratory viruses is common, but adenovirus infection combined with human coronavirus-229E (HCoV-229E) is very rare. Study design and setting: Clinical manifestations, laboratory examinations, and disease severity were compared between three groups: one coinfected with HAdV-Ad7 and HCoV-229E, one infected only with adenovirus (mono-adenovirus), and one infected only with HCoV-229E (mono-HCoV-229E). Results: From July to August 2019, there were 24 hospitalized children: two were coinfected with HAdV-Ad7 and HCoV-229E, and 21 were infected with a single adenovirus infection. Finally, one 14-year-old boy presented with a high fever, but tested negative for HAdV-Ad7 and HCoV-229E. Additionally, three adult asymptotic cases with HCoV-229E were screened. No significant difference in age was found in the coinfection and mono-adenovirus groups (11 vs. 8 years, p = 0.332). Both groups had the same incubation period (2.5 vs. 3 days, p = 0.8302), fever duration (2.5 vs. 2.9 days, p = 0.5062), and length of hospital stay (7 vs. 6.76 days, p = 0.640). No obvious differences were found in viral loads between the coinfection and mono-adenovirus groups (25.4 vs. 23.7, p = 0.570), or in the coinfection and mono-HCoV-229E groups (32.9 vs. 30.06, p = 0.067). All cases recovered and were discharged from the hospital. Conclusion: HAdV-Ad7 and HCoV-229E coinfection in healthy children may not increase the clinical severity or prolong the clinical course. The specific interaction mechanism between the viruses requires further study.

Nomogram-Based Risk Model of Small (≤5 mm) Intracranial Aneurysm Rupture in an Eastern Asian Study.

Background and Purpose: Risk stratification of small unruptured intracranial aneurysms (IAs) (< =5 mm) is important for clinical decision-making and management. The aim of this study was to develop an individualized rupture risk model for small IAs in an eastern Asian population. Methods: This study retrospectively enrolled 343 patients with ruptured (n = 96) and unruptured (n = 285) small IAs. Clinical data and aneurysmal morphology were taken into consideration, regression analysis was performed to identify significant variables, and these variables were then incorporated into a predictive nomogram. The diagnostic performance of the nomogram was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC) and calibration plot. Clinical effectiveness was validated by decision curve analysis (DCA). The PHASES score calculated for each case was used for comparison. Results: The nomogram achieved an AUC of 0.849 (95% CI: 0.805-0.893), with a sensitivity of 86.5%, a specificity of 70.9%, and accuracy of 74.7%, which was superior to PHASES score system (AUC = 0.693, sensitivity = 83.6%, specificity = 48.8%, and accuracy = 57.5%). A good agreement between predicted rupture risk and actual rupture status in the small aneurysms was observed, and DCA illustrated the benefit of using the nomogram when decisions needed to be made clinically. Conclusions: The nomogram based on clinical and morphological risk factors can be useful in assisting clinicians with individualized assessments and benefit-risk balancing in patients with small IAs (< =5 mm).

Fully Automatic Classification of Brain Atrophy on NCCT Images in Cerebral Small Vessel Disease: A Pilot Study Using Deep Learning Models.

Objective: Brain atrophy is an important imaging characteristic of cerebral small vascular disease (CSVD). Our study explores the linear measurement application on CT images of CSVD patients and develops a fully automatic brain atrophy classification model. The second aim was to compare it with the end-to-end Convolutional Neural Networks (CNNs) model. Methods: A total of 385 subjects such as 107 no-atrophy brain, 185 mild atrophy, and 93 severe atrophy were collected and randomly separated into training set (n = 308) and test set (n = 77). Key slices for linear measurement were manually identified and used to annotate nine linear measurements and a binary classification of cerebral sulci widening. A linear-measurement-based pipeline (2D model) was constructed for two-types (existence/non-existence brain atrophy) or three-types classification (no/mild atrophy/severe atrophy). For comparison, an end-to-end CNN model (3D-deep learning model) for brain atrophy classification was also developed. Furthermore, age and gender were integrated to the 2D and 3D models. The sensitivity, specificity, accuracy, average F1 score, receiver operating characteristics (ROC) curves for two-type classification and weighed kappa for three-type classification of the two models were compared. Results: Automated measurement of linear measurements and cerebral sulci widening achieved moderate to almost perfect agreement with manual annotation. In two-type atrophy classification, area under the curves (AUCs) of the 2D model and 3D model were 0.953 and 0.941 with no significant difference (p = 0.250). The Weighted kappa of the 2D model and 3D model were 0.727 and 0.607 according to standard classification they displayed, mild atrophy and severe atrophy, respectively. Applying patient age and gender information improved classification performances of both 2D and 3D models in two-type and three-type classification of brain atrophy. Conclusion: We provide a model composed of different modules that can classify CSVD-related brain atrophy on CT images automatically, using linear measurement. It has similar performance and better interpretability than the end-to-end CNNs model and may prove advantageous in the clinical setting.

Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson's disease model.

Microglia-mediated neuroinflammation and mitochondrial dysfunction play critical role in the pathogenic process of Parkinson's disease (PD). Mitophagy plays central role in mitochondrial quality control. Hence, regulation of microglial activation through mitophagy could be a valuable strategy in controlling microglia-mediated neurodegeneration and neuroinflammation. Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA). Several preclinical studies have reported the beneficial effects of UA on age-related conditions by increasing mitophagy and blunting excessive inflammatory responses. However, the specific role of UA in pathology of PD remains unknown. In this study, we showed that treatment with UA reduced the loss of dopaminergic neurons, ameliorated behavioral deficits and neuroinflammation in MPTP mouse model of PD. Further study revealed that UA promotes mitophagy, restores mitochondrial function and attenuate proinflammatory response in BV2 microglial cells exposed to LPS. Moreover, UA also reduced NLRP3 inflammasome activation both in vitro and in vivo. Importantly, disruption of microglial mitophagy with pharmacological or genetic approach partly blunted the neuroprotective effects of UA in MPTP mouse model of PD. Collectively, these results provide strong evidence that UA protects against dopaminergic neurodegeneration and neuroinflammation. The mechanism may be related with its inhibition of NLRP3 inflammasome activation via promoting mitophagy in microglia.

Paraneoplastic myelitis associated with durvalumab treatment for extensive-stage small cell lung cancer.

Paraneoplastic neurologic syndromes(PNSs) caused by immune checkpoint inhibitors(ICIs) is rare and requires clinicians to differentiate between disease progression and immune-related adverse effects(irAEs). We hereby report the case of immune-related myelitis accompanied by positive paraneoplastic autoantibodies following durvalumab treatment for extensive-stage small cell lung cancer (ES-SCLC). A 70-year-old Chinese woman with ES-SCLC was administered durvalumab with etoposid-platinum(EP) as first-line treatment. Four cycles after treatment with EP plus ICI, she developed immune-related myelitis with positive paraneoplastic autoantibodies (CV2, SOX1, ZIC4). Spinal MRI showed diffuse abnormal signal shadow in the cervicothoracic spinal cord. She was discontinued for chemotherapy, and treated with high-dose steroids, intravenous immunoglobulin and plasmapheresis, maintenance therapy with steroids resulted in a favorable neurologic outcome. This is the first report of durvalumab-related PNSs. We supposed that the development of paraneoplastic myelitis was causally related to immune activation by durvalumab. Prompt diagnosis and therapeutic intervention are essential for the effective treatment of paraneoplastic myelitis.

Urolithin A protects dopaminergic neurons in experimental models of Parkinson's disease by promoting mitochondrial biogenesis through the SIRT1/PGC-1α signaling pathway.

Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of PD. Recent reports have highlighted the protective role of urolithin A (UA), a gut metabolite produced from ellagic acid-containing foods such as pomegranates, berries and walnuts, in several neurological disorders including Alzheimer's disease and ischemic stroke. However, the potential role of UA in PD has not been characterized. In this study, we investigated the underlying mechanisms for role of UA in 6-OHDA-induced neurotoxicity in cell cultures and mice model of PD. Our results revealed that UA protected against 6-OHDA cytotoxicity and apoptosis in PC12 cells. Meanwhile, administration of UA to 6-OHDA lesioned mice ameliorated both motor deficits and nigral-striatal dopaminergic neurotoxicity. More important, UA treatment significantly attenuated 6-OHDA-induced mitochondrial dysfunction in PC12 cells accompanied by enhanced mitochondrial biogenesis. Mechanistically, we demonstrated that UA exerts neuroprotective effects by promoting mitochondrial biogenesis via SIRT1-PGC-1α signaling pathway. Taken together, these data provide new insights into the novel role of UA in regulating mitochondrial dysfunction and suggest that UA may have potential therapeutic applications for PD.

Single and Repeated Episodes of Candida Species Isolated From Cerebrospinal Fluid for Diagnosing Probable Candida meningitis.

Background: The clinical relevance of single or repeated episodes of Candida spp. in cerebrospinal fluid (CSF) in adult patients is debatable. Methods: Forty-two patients with positive Candida episodes in CSF were enrolled in this retrospective study. Results: A total of 42.9% (18/42) were determined to have probable Candida meningitis (PCM). Neurosurgery [odds ratio (OR) (95% confidence interval), OR: 14.4 (1.6-126.1), P = 0.004], lumbar drainage [OR: 5.8 (1.5-23.3), P = 0.009], VP shunt [(OR: 5.6 (1.2-25.8), P = 0.020)], external ventricular drainage [OR: 4.7 (1.3-17.7), P = 0.018], CRP ≥ 10.0 mg/L [OR: 4.9 (1.3-18.1), P = 0.034], and postsurgical broad-spectrum antibiotics [OR: 9.5 (1.8-50.5), P = 0.004] were risk factors associated with PCM. A single CSF Candida episode for the diagnosis of PCM had 7.7% (0.4-37.9%) sensitivity and 20.7% (8.7-40.3%) specificity, whereas repeated episodes of Candida had 66.7% (41.2-85.6%) sensitivity and 95.8% (76.9-99.8%) specificity. No significant difference was found in radiological imaging or CSF profiles between PCM and non-PCM patients. A total of 37.5% (9/24) of patients without PCM received empirical antifungal treatment, and 88.9% (16/18) of patients with PCM received preemptive antifungal treatment. PCM patients had hospitalized mortality rates of 50.0% (9/18). The odds ratio of mortality was 23.0 (2.5-208.6) for PCM patients compared with non-PCM patients (P = 0.001). Conclusion: Both single and repeated positive CSF samples have low validity for the diagnosis of PCM, suggesting that novel strategies for diagnosis algorithms of PCM are urgently needed. Empirical antifungal treatment should be started immediately for suspicious patients with risk factors.

Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins.

The PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although most APL cases are cured by PML/RARα-targeting therapy, relapse and resistance can occur due to drug-resistant mutations. Here we report that thermal stress destabilizes the PML/RARα protein, including clinically identified drug-resistant mutants. AML1/ETO and TEL/AML1 oncofusions show similar heat shock susceptibility. Mechanistically, mild hyperthermia stimulates aggregation of PML/RARα in complex with nuclear receptor corepressors leading to ubiquitin-mediated degradation via the SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize PML/RARα via distinct mechanisms and are synergistic in primary patient samples and in vivo, including three refractory APL cases. Collectively, our results suggest that by taking advantage of a biophysical vulnerability of PML/RARα, thermal therapy may improve prognosis in drug-resistant or otherwise refractory APL. These findings serve as a paradigm for therapeutic targeting of fusion oncoprotein-associated cancers by hyperthermia. SIGNIFICANCE: Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers.See related commentary by Wu et al., p. 300.

Integrin α4ß1/VCAM-1 Interaction Evokes Dynamic Cell Aggregation Between Immune Cells and Human Lung Microvascular Endothelial Cells at Infectious Hemolysis.

Bacterial and viral infection is a common cause of pneumonia, respiratory failure, and even acute respiratory distress syndrome. Increasing evidence indicates that red blood cells (RBCs) may contribute to immune response and inflammation. However, the precise molecular mechanisms that link RBC and hemolysis to the development and progression of inflammatory pathologies are not entirely understood. In this study, we used bacterial endotoxin, lipopolysaccharide (LPS), to mimic an infectious hemolysis and found that RBCs dynamically regulated cell aggregation between immune cells and human lung microvascular endothelial cells (HLMVEC). When RBCs were treated with LPS, integrin α4ß1 was increased and was accompanied by cytokines and chemokines release (TNF-α, IL-1ß, IL-6, IL-8, IFN-γ, CXCL12, CCL5, CCL7 and CCL4). Upon α4ß1 elevation, RBCs not only facilitated mature monocyte derived dendritic cell (mo-DCs) adhesion but also promoted HLMVEC aggregation. Furthermore, co-culture of the supernatant of LPS pre-treated RBCs with mo-DCs could promote naïve CD4 T cell proliferation. Notably, the filtered culture from LPS-lysed RBCs further promoted mo-DCs migration in a concentration dependent manner. From a therapeutic perspective, cyclic peptide inhibitor of integrin α4ß1 combined with methylprednisolone (α4ß1/Methrol) remarkably blocked RBCs aggregation to mo-DCs, HLMVEC, or mo-DCs and HLMVEC mixture. Moreover, α4ß1/Methrol dramatically reduced mo-DCs migration up-regulated glucocorticoid-induced leucine zipper in mo-DCs, and ultimately reversed immune cell dysfunction induced by hemolysis. Taken together, these results indicate that integrin α4ß1 on RBCs could mediate cell-cell interaction for adaptive immunity through influencing cell adhesion, migration, and T cell proliferation.

Admission Homocysteine as a Potential Predictor for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is a primary cause of poor prognosis after aneurysmal subarachnoid hemorrhage (aSAH) and needs close medical attention in clinical practice. Homocysteine (Hcy) has been implicated in cerebrovascular diseases. This study aimed to investigate whether serum Hcy could help to predict the occurrence of DCI in aSAH patients, and compare its diagnostic value with traditional methods. METHODS: We enrolled 241 aSAH patients in this study. Serum Hcy levels were collected from each patient. The baseline information was reviewed and analyzed. The binary logistic regression was used to explore the relation of serum Hcy levels with occurrence of DCI, and diagnostic performance of serum Hcy for predicting DCI was evaluated using a receiver operating characteristic (ROC) curve. RESULTS: The admission serum Hcy levels were found significantly higher in aSAH patients with DCI than those without (P < 0.001). The serum Hcy levels were positively correlated with the World Federation of Neurosurgical Societies (WFNS) scores, modified Fisher scores as well as Hunt and Hess scores at admission. Multivariate analysis revealed that occurrence of DCI was associated with serum Hcy levels (Odds Ratio [OR] = 1.257; 95% Confidence Interval [CI], 1.133-1.396, P < 0.001), modified Fisher scores (OR = 1.871; 95%CI, 1.111-3.150, P = 0.018) and Hunt and Hess scores (OR = 2.581; 95%CI, 1.222-5.452, P = 0.013) after adjusting for the significant variables in univariate analysis. Meanwhile, serum Hcy levels achieved good performance for DCI prediction (area under the curve [AUC], 0.781; 95%CI, 0.723-0.831, P < 0.001). CONCLUSION: Serum homocysteine might have the potential to be a useful and cost-effective biomarker for predicting the occurrence of DCI in aSAH patients.

Impaired autophagy in microglia aggravates dopaminergic neurodegeneration by regulating NLRP3 inflammasome activation in experimental models of Parkinson's disease.

Microglia-mediated inflammation plays an important role in the pathogenesis of several neurodegenerative diseases including Parkinson's disease (PD). Recently, autophagy has been linked to the regulation of the inflammatory response. However, the potential role of microglial autophagy in the context of PD pathology has not been characterized. In the present study, we investigated whether impaired microglial autophagy would affect dopaminergic neurodegeneration and neuroinflammation both in vivo and in vitro. In vitro, BV2 microglial cells were exposed to LPS in the presence or absence of autophagy-related gene 5 (Atg5) small interference RNA (Atg5-siRNA). For in vivo study, microglial Atg5 conditional knockout (Atg5flox/flox; CX3CR1-Cre) mice and their wild-type littermates (Atg5flox/flox) were intraperitoneally injected with MPTP to induce experimental PD model. Our results revealed that disruption of autophagy by Atg5-siRNA aggravated LPS-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2 conditioned medium. In mice, impaired autophagy in microglia exacerbated dopaminergic neuron loss in response to MPTP. The mechanism by which the deficiency of microglial autophagy promoted neuroinflammation and dopaminergic neurodegeneration was related to the regulation of NLRP3 inflammasome activation. These findings demonstrate that impairing microglial autophagy aggravates pro-inflammatory responses to LPS and exacerbates MPTP-induced neurodegeneration by modulating NLRP3 inflammasome responses. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for PD.

Imaging characteristics of Intrasellar cavernous hemangioma: A case report.

RATIONALE: Intrasellar cavernous hemangiomas (ICHs) are rare vascular lesions that arise in the sellar region. ICHs are usually misdiagnosed and treated as pituitary adenomas. Therefore, a preoperative diagnosis is particularly important, especially when the goal is complete resection. PATIENT CONCERNS: A 55-year-old woman presented with a 1-month history of intermittent dizziness. Magnetic resonance imaging (MRI) revealed a well-demarcated abnormal ellipsoid signal in the sellar region (size: 2.7 cm × 1.7 cm), with a mulberry-like enhancement after gadolinium injection. Computed tomography revealed an intrasellar mass without calcification that extended into the left cavernous sinus and was faintly contrast-enhanced. Angiography revealed a tumor with mildly delayed staining fed by the C5 segment of the right internal carotid artery. DIAGNOSIS: An intrasellar cavernous hemangioma based on neuroradiological examinations. INTERVENTIONS: The patient underwent surgery with an endoscopic endonasal transsphenoidal approach to debulk the lesion and obtain tissue for the pathological diagnosis. OUTCOMES: Blood spurting was observed after puncture, and the capsule was stained blue. Lesion removal was stopped, and the patient underwent gamma knife surgery 1 week later. She remained in good condition during the follow-up. LESSONS: Sponge-like or mulberry-like lesions can be identified on MRI after gadolinium injection and can facilitate a preoperative diagnosis of ICH. Currently, surgical debulking with cranial nerve decompression during the acute stage and subsequent gamma knife radiosurgery are considered to be a safe and effective treatment.

The Clinical and Radiological Manifestations in Coronavirus Disease 2019 With Negative Nucleic Acid Results.

BACKGROUND: Coronavirus disease 2019 (COVID-19) was a new emerging disease with high infectiousness. Its diagnosis primarily depended on real-time polymerase chain reaction (RT-PCR) results. This study investigated epidemiological, clinical, and radiological characteristics of COVID-19 with negative RT-PCR results before confirmation. METHODS: Patients with COVID-19 were enrolled and divided into 2 groups: a negative group with negative RT-PCR results before confirmation and a positive group with positive results at the first detection. Epidemiological and clinical features were compared. Dynamic chest computerized tomography (CT) images of the negative group were evaluated. RESULTS: Ninety-nine laboratory-confirmed patients with COVID-19 including 8 patients (8%) with negative RT-PCR results were included. Patients from the negative group had similar epidemiological features: the average age (50.25 ±â€…13.27 years in the negative group and 53.70 ±â€…16.64 years in the positive group) and gender distribution (males made up 50% of the negative group and 62.6% of the positive group) were comparable. No significant differences were observed in clinical symptoms between the 2 groups. We found that fever was the most common symptom for both groups, followed by cough, expectoration, chest distress, fatigue, and gastroenterological symptoms. Moreover, ground-glass opacities and consolidations were the main manifestation in chest CT of patients with COVID-19 with or without confirmed RT-PCR results. CONCLUSIONS: Regardless of initial RT-PCR results, patients with COVID-19 had similar epidemiological, clinical, and chest CT features. Our study suggests value from early chest CT scans in COVID-19 screening and dynamic significance of radiology in disease monitoring should guide clinical decisions.

Coronavirus disease 2019 (COVID-19): chest CT characteristics benefit to early disease recognition and patient classification-a single center experience.

BACKGROUND: The current outbreak of coronavirus disease 2019 (COVID-19), epi-centered in Wuhan, Hubei Province of the China, has become a global health emergency. Several studies from China have recently provided the evidence of epidemiological, clinical, laboratory, and outcomes of COVID-19 patients. Investigation on the role of chest CT in patient screening and management course in a large cohort remains paucity. METHODS: This was a retrospective observational study based on the data collected between January 19 and 2020 to February 15, 2020. A clinic workflow using chest CT and RT-PCR assay to screen suspected patient was reviewed. Clinical data were evaluated and patients were classified to mild, common, severe and critical group. Chest CT characteristics of each patient were evaluated and a CT scoring system was applied to grade the lung involvement. RESULTS: Of 98 enrolled patients, 1, 29, 51 and 17 were clinically classified into mild, common, severe and critical group, respectively. Eighty-three patients (84.7%) demonstrated ground-glass opacity (GGO), 76 patients (77.5%) demonstrated consolidation and 18 patients (18.4%) demonstrated crazy-paving pattern on chest CT. Based on the CT scoring, 2, 35, 55 and 6 patients were categorized to grade 0, grade 1, grade 2 and grade 3, respectively, which significantly consistent with clinical classification (kappa =0.638, P﹤0.05). Twenty-nine patients admitted from fever clinic, with an average interval of 1.2 days (range, 0-4 days) between CT examination and onset of symptom. Three of these patients had negative initial RT-PCR result while abnormalities displayed on the initial chest CT. CONCLUSIONS: Peripheral lung distributed GGO and consolidation, without subpleural sparing, are the most common manifestations on chest CT of COVID-19. Abnormalities on chest CT can occur in an early stage of COVID-19, even when RT-PCR assay negative, which may help to early recognition and rapid diagnosis of this disease.

Pharmacological Inhibition of HDAC6 Attenuates NLRP3 Inflammatory Response and Protects Dopaminergic Neurons in Experimental Models of Parkinson's Disease.

AIM: To investigate the role of histone deacetylase 6 (HDAC6) deacetylation activity in nucleotide-binding oligomerization domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammatory response and explore the effects of pharmacological inhibition of HDAC6 with tubastatin A (TBA) on dopaminergic injury. METHODS: Using 6-OHDA-induced Parkinson's disease (PD) models, we examined the effects of TBA on NLRP3 activation and cell injury in SH-SY5Y cells. We also investigated the effects of TBA on NLRP3 inflammatory responses and dopaminergic injury in the nigrostriatal system in mice and analyzed the acetylation levels of peroxiredoxin2 (Prx2) and oxidative stress. RESULTS: TBA inhibited 6-OHDA-induced NLRP3 activation, as demonstrated by decreased expressions of NLRP3 and matured caspase-1 and IL-1ß, and also alleviated glial proliferation and dopaminergic neuronal degeneration. Notably, TBA recovered acetylation levels of Prx2 and reduced oxidative stress. CONCLUSION: Our findings indicate that pharmacological inhibition of HDAC6 with TBA attenuates NLRP3 inflammation and protects dopaminergic neurons, probably through Prx2 acetylation. This study suggests that the deacetylase catalytic domain of HDAC6 is a potential target for PD treatment.

TREM2 deficiency aggravates α-synuclein-induced neurodegeneration and neuroinflammation in Parkinson's disease models.

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are known to increase the risk of developing Alzheimer disease and Parkinson's disease (PD). However, the potential role of TREM2 effect on synucleinopathy has not been characterized. In this study, we investigated whether loss of TREM2 function affects α-synucleinopathy both in vitro and in vivo. In vitro, BV2 microglial cells were exposed to α-synuclein (α-syn) in the presence or absence of TREM2 small interference RNA. For in vivo studies, wild-type controls and TREM2 gene knockout mice were intracranially injected in the substantia nigra with adeno-associated viral vectors expressing human α-syn (AAV-SYN) to induce PD. Our results revealed that knockdown of TREM2 aggravated α-syn-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2-conditioned medium. In mice, TREM2 knockout exacerbated dopaminergic neuron loss in response to AAV-SYN. Moreover, both in vitro and in vivo TREM2 deficiency induced a shift from an anti-inflammatory toward a proinflammatory activation status of microglia. These data suggest that impairing microglial TREM2 signaling aggravates proinflammatory responses to α-syn and exacerbates α-syn-induced neurodegeneration by modulating microglial activation state.-Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., Lou, H. TREM2 deficiency aggravates α-synuclein-induced neurodegeneration and neuroinflammation in Parkinson's disease models.