Impacts of type 2 diabetes mellitus and hypertension on the incidence of cardiovascular diseases and stroke in China real-world setting: a retrospective cohort study.

OBJECTIVE: The prevalence of type 2 diabetes mellitus (T2DM) and hypertension (HTN) has notably increased in recent years. However, there is little evidence from large-scale studies assessing the joint effect of T2DM and HTN on the risk of cardiovascular events in China. This study was performed to investigate the association of T2DM and HTN with the incidence of combined vascular events (VEs) and stroke in China. DESIGN: A retrospective cohort study. SETTING: Data were collected from the SuValue database which includes the electronic medical records of >90 million patients from 161 hospitals across 18 provinces in China. PARTICIPANTS: Patients aged ≥18 with a diagnosis of T2DM and/or HTN were included. Non-T2DM and non-HTN patients were included in this study as controls. OUTCOMES: Incidence of combined VEs and stroke during the study. RESULTS: In the current study, 8012 patients with T2DM, 9653 patients with HTN, 3592 patients with both T2DM and HTN and 10 561 patients without T2DM or HTN were included. T2DM was significantly associated with combined VE and stroke risk (HR 1.332, 95% CI 1.134 to 1.565 and HR 1.584, 95% CI 1.246 to 2.014, respectively). HTN was significantly associated with combined VE and stroke risk (HR 3.244, 95% CI 2.946 to 3.572 and HR 4.543, 95% CI 3.918 to 5.268, respectively). T2DM combined with HTN was significantly associated with combined VE and stroke risk (HR 3.002, 95% CI 2.577 to 3.497 and HR 4.151, 95% CI 3.346 to 5.149, respectively). HTN was associated with a higher combined VE and stroke risk than T2DM (HR 2.435, 95% CI 2.113 to 2.805 and HR 2.868, 95% CI 2.341 to 3.513, respectively). CONCLUSION: T2DM and HTN were strongly associated with combined VE and stroke risk; however, the HTN-only group had a higher combined VE and stroke risk than the T2DM-only group.

Predictors of poor glycemic control among type 2 diabetes mellitus patients treated with antidiabetic medications: A cross-sectional study in China.

ABSTRACT: This study aimed to clarify of the predictors of poor glycemic control in type 2 diabetes mellitus (T2DM) patients treated with antidiabetic medications in China.This study was a retrospective, cross-sectional study based on SuValue database. T2DM patients aged 18 years or older performing glycosylated hemoglobin A1c (HbA1c) examinations from January 1st, 2018 to December 31st, 2018 were included and have been treated with antidiabetic medications for at least 6 months. HbA1c < 7.0% was defined as adequate glycemic control. Multivariate analysis was performed for the factors associated with poor glycemic control.A total of 13972 T2DM patients were included in this study. The adequate glycemic control rate was 44.04% (n = 6153). In the multivariate analysis, predictors of poor glycemic control include longer T2DM duration (5-10 years vs <5 years and >10 years vs <5 years, odds ratio [OR] = 1.499 and 1.581, P < .001 and P = .008), myocardial infarction (OR = 1.141, P = .041), diabetic neuropathy (OR = 1.409, P < .001), secondary hospital (OR = 1.877, P < .001), underdeveloped regions (OR = 1.786, P < .001), insulin only (OR = 3.912, P < .001), combination of oral antidiabetic agents and/or insulin use (P < .001).In conclusion, longer T2DM duration, secondary hospital, myocardial infarction, diabetic neuropathy, undeveloped regions and use of polypharmacy and insulin were associated with poor glycemic control among T2DM patients treated with antidiabetic medications. Patient education and training of health care providers may be short-term strategy to achieve adequate glycemic control.

Dyslipidemic Diet Induces Mobilization of Peripheral Neutrophils and Monocytes That Exacerbate Hemorrhagic Brain Injury and Neuroinflammation.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver condition characterized by a significant accumulation of lipids in the liver without excessive alcohol consumption. Accumulating evidence suggests a significantly increased risk of intracerebral hemorrhage (ICH) in NAFLD patients. However, it remains poorly understood whether and how NAFLD affects the outcome of hemorrhagic brain injury. Here, we examined the effects of diet-induce NAFLD on ICH injury and neuroinflammation in mice. Methods: NAFLD was induced in C57BL/6 mice by feeding with a methionine-choline deficient (MCD) diet for 4 weeks. Collagenase and autologous blood models were used to evaluate the effects of NAFLD on ICH injury and neuroinflammation. Results: MCD diet for 4 weeks induces NAFLD and hyperlipidemia in mice. Mice receiving the MCD diet have aggravated neurological deficits and brain edema after ICH. The augmentation of ICH injury was accompanied by brain infiltration of neutrophils and monocytes and increased production of pro-inflammatory factors. Before ICH, MCD diet-induced mobilization of neutrophils and monocytes in the periphery. Notably, the detrimental effects of NAFLD on ICH injury was ablated in mice receiving antibody depletion of neutrophils and monocytes. Conclusions: These results suggest that NAFLD exacerbates neuroinflammation and ICH injury.

Brain Ischemia Significantly Alters microRNA Expression in Human Peripheral Blood Natural Killer Cells.

Brain ischemia induces systemic immunosuppression and increases a host's susceptibility to infection. MicroRNAs (miRNAs) are molecular switches in immune cells, but the alterations of miRNAs in human immune cells in response to brain ischemia and their impact on immune defense remain elusive. Natural killer (NK) cells are critical for early host defenses against pathogens. In this study, we identified reduced counts, cytokine production, and cytotoxicity in human peripheral blood NK cells obtained from patients with acute ischemic stroke. The extent of NK cell loss of number and activity was associated with infarct volume. MicroRNA sequencing analysis revealed that brain ischemia significantly altered miRNA expression profiles in circulating NK cells, in which miRNA-451a and miRNA-122-5p were dramatically upregulated. Importantly, inhibition of miR-451a or miR-122-5p augmented the expression of activation-associated receptors in NK cells. These results provide the first evidence that brain ischemia alters miRNA signatures in human NK cells.

Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Azathioprine is used as a first-line treatment to prevent relapses of neuromyelitis optica spectrum disorder (NMOSD). Tocilizumab has been reported to reduce NMOSD disease activity in retrospective case reports. We aimed to compare the safety and efficacy of tocilizumab and azathioprine in patients with highly relapsing NMOSD. METHODS: We did an open-label, multicentre, randomised, phase 2 trial at six hospitals in China. We recruited adult patients (aged ≥18 years) with highly relapsing NMOSD diagnosed according to 2015 International Panel for Neuromyelitis Optica Diagnosis criteria, who had an Expanded Disability Status Scale (EDSS) score of 7·5 or lower, and had a history of at least two clinical relapses during the previous 12 months or three relapses during the previous 24 months with at least one relapse within the previous 12 months. Patients were randomly assigned (1:1) to intravenous tocilizumab (8 mg/kg every 4 weeks) or oral azathioprine (2-3 mg/kg per day) by an independent statistician using computer-generated randomisation software with permuted blocks of four. The central review committee, EDSS raters, laboratory personnel, and radiologists were masked to the treatment assignment, but investigators and patients were aware of treatment allocation. The minimum planned duration of treatment was 60 weeks following randomisation. The primary outcome was time to first relapse in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, and the per-protocol population, which included all patients who used azathioprine or tocilizumab as monotherapy. For the analyses of the primary outcome, the patients were prespecified into two subgroups according to concomitant autoimmune disease status. Safety was assessed in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03350633. FINDINGS: Between Nov 1, 2017, and Aug 3, 2018, we enrolled 118 patients, of whom 59 were randomly assigned to tocilizumab and 59 were randomly assigned to azathioprine. All 118 patients received one dose of study drug and were included in the full analysis set. 108 participants were included in the per-protocol analysis (56 in the tocilizumab group and 52 in the azathioprine group). In the full analysis set, median time to the first relapse was longer in the tocilizumab group than the azathioprine group (78·9 weeks [IQR 58·3-90·6] vs 56·7 [32·9-81·7] weeks; p=0·0026). Eight (14%) of 59 patients in the tocilizumab group and 28 (47%) of 59 patients in the azathioprine group had a relapse at the end of the study (hazard ratio [HR] 0·236 [95% CI 0·107-0·518]; p<0·0001). In the per-protocol analysis, 50 (89%) of 56 patients in the tocilizumab group were relapse-free compared with 29 (56%) of 52 patients in the azathioprine group at the end of the study (HR 0·188 [95% CI 0·076-0·463]; p<0·0001); the median time to first relapse was also longer in the tocilizumab group than the azathioprine group (67·2 weeks [IQR 47·9-77·9] vs 38·0 [23·6-64·9]; p<0·0001). In the prespecified subgroup analysis of the full analysis set stratified by concomitant autoimmune diseases, among patients without concomitant autoimmune diseases, three (9%) of 34 patients in the tocilizumab group and 13 (35%) of 37 patients in the azathioprine group had relapsed by the end of the study. Among patients with concomitant autoimmune diseases, a lower proportion of patients in the tocilizumab group had a relapse than in the azathioprine group (five [20%] of 25 patients vs 15 [68%] of 22 patients; HR 0·192 [95% CI 0·070-0·531]; p=0·0004). 57 (97%) of 59 patients in the tocilizumab group and 56 (95%) of 59 patients in the azathioprine group had adverse events. Treatment-associated adverse events occurred in 36 (61%) of 59 tocilizumab-treated patients and 49 (83%) of 59 azathioprine-treated patients. One death (2%) occurred in the tocilizumab group and one (2%) in the azathioprine group, but neither of the deaths were treatment-related. INTERPRETATION: Tocilizumab significantly reduced the risk of a subsequent NMOSD relapse compared with azathioprine. Tocilizumab might therefore be another safe and effective treatment to prevent relapses in patients with NMOSD. FUNDING: Tianjin Medical University, Advanced Innovation Center for Human Brain Protection, National Key Research and Development Program of China, National Science Foundation of China.

A pilot study on the epidemiology of hyperuricemia in Chinese adult population based on big data from Electronic Medical Records 2014 to 2018.

BACKGROUND: We performed this study based on big data from Electronic Medical Records (EMR) of outpatients and inpatients from 52 hospitals in China to investigate the prevalence of hyperuricemia in Chinese adults. METHODS: In this retrospective, descriptive study, a total of 3,363,016 subjects from 52 hospitals in 13 provinces and municipalities in China were enrolled. Eligible subjects were 18 years and older performing serum uric acid test between 2014 and 2018. Subjects were divided into the total group (including the subjects from all the clinic departments) and department-amended group (including the subjects from all the departments except endocrinology, orthopedics, and rheumatology and immunology departments). RESULTS: The prevalence of hyperuricemia in the department-amended group was lower than that in the total group (23.06% and 23.42% in 2018, respectively; P<0.0001). From 2014 to 2017, the prevalence of hyperuricemia increased year by year (18.29%, 20.02%, 20.16% and 23.06%, respectively) in the department-amended group. Besides, the prevalence of hyperuricemia was higher in men than that in women (38.00% and 11.89%, respectively; P<0.0001) and higher in southern region than in northern region (25.84% and 9.79%, respectively; P<0.0001) in department-amended group in 2018. CONCLUSIONS: Projections from our study estimate that about 271 million Chinese adults aged 18 years and older may have had hyperuricemia in 2018. These findings will be useful for the future researches and healthcare decision.

Exposure to Cigarette Smoke Augments Post-ischemic Brain Injury and Inflammation via Mobilization of Neutrophils and Monocytes.

Cigarette smoke is a major preventable risk factor of ischemic stroke. Cigarette smoke induces a significant increase in circulating leukocytes. However, it remains unclear to what extent and by what mechanisms smoke priming influences stroke severity. Here we report that exposure to cigarette smoke exacerbated ischemic brain injury in mice subjected to transient middle cerebral artery occlusion (MCAO). The augmentation of neurodeficits and brain infarction was accompanied by increased production of pro-inflammatory factors and brain infiltration of neutrophils and monocytes. Prior to brain ischemia, exposure to cigarette smoke induced mobilization of peripheral neutrophils, and monocytes. Furthermore, the detrimental effects of smoke priming on ischemic brain injury were abolished either by pharmacological inhibition of the recruitment of neutrophils and monocytes or by blockade of the NLRP3 inflammasome, an effector protein of neutrophils and monocytes. Our findings suggest that cigarette smoke-induced mobilization of peripheral neutrophils and monocytes augments ischemic brain injury.

Inhibition of activator protein 1 attenuates neuroinflammation and brain injury after experimental intracerebral hemorrhage.

AIMS: Intracerebral hemorrhage (ICH) is a devastating type of stroke without specific treatment. Activator protein 1 (AP-1), as a gene regulator, initiates cytokine expression in response to environmental stimuli. In this study, we investigated the relationship between AP-1 and neuroinflammation-associated brain injury triggered by ICH. METHODS: Intracerebral hemorrhage mice were developed by autologous blood or collagenase infusion. We measured the dynamics of AP-1 in mouse brain tissues during neuroinflammation formation after ICH. The effects of the AP-1 inhibitor SR11302 on brain injury and neuroinflammation as well as the underlying mechanisms were investigated in vivo and in vitro. RESULTS: AP-1 was significantly upregulated in mouse brain tissue as early as 6 hours after ICH, accompanied by elevations in proinflammatory factors, including interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α. Inhibition of AP-1 using SR11302 reduced neurodeficits and brain edema at day 3 after ICH. SR11302 ablated microglial IL-6 and TNF-α production and brain-infiltrating leukocytes in ICH mice. In addition, SR11302 treatment diminished thrombin-induced production of IL-6 and TNF-α in cultured microglia. CONCLUSIONS: Inhibition of AP-1 curbs neuroinflammation and reduces brain injury following ICH.

Colivelin Rescues Ischemic Neuron and Axons Involving JAK/STAT3 Signaling Pathway.

Colivelin is a neuroprotective humanin family peptide with potent long-term capacity against Aß deposition, neuronal apoptosis, and synaptic plasticity deficits in neurodegenerative disease. We seek to investigate whether this effect of Colivelin also govern ischemic brain injury, and potential mechanism underlying the Colivelin-mediated action on ischemic neurons. We adopted 60 min induction of transient focal cerebral ischemia and reperfusion in mice. We found that relative to mice receiving vehicle, Colivelin administration decreased the neurological deficits and infarct lesion induced by brain ischemia. Colivelin inhibited axonal damage and neuronal death in brain tissue, which was associated with elevated anti-apoptotic gene expression in ischemic neurons as well as increased axonal growth up until two-weeks post-stroke. Moreover, Colivelin activated STAT3 signaling, which may partially contribute to its beneficial effect against neuronal death and axon growth. In conclusion, Colivelin induce anti-apoptotic genes up-regulation, and activate JAK/STAT3 signaling after ischemic stroke, which may contribute to its effects of rescuing ischemic neuronal death and axonal remodeling. This study may justify further works to examine Colivelin as a single or adjunct therapy in ischemic stroke.

Emodin azide methyl anthraquinone derivative induced G0/ G1 arrest in HER2/neu-overexpressing MDA-MB-453 breast cancer cells.

PURPOSE: Our previous data have shown that emodin azide methyl anthraquinone derivative (AMAD) triggered mitochondrial- dependent cell apoptosis involving caspase-8-mediated Bid cleavage, and induced proteasomal degradation of HER2/neu by blocking Her2/neu binding to Hsp90. In the present study, we futher investigated the effect of this compound on the cell cycle and related molecular mechanisms in HER2/neu-overexpressing MDA-MB-453 breast cancer cells. METHODS: The cell cycle distribution was tested by flow cytometry. The expression of cell cycle-related proteins was determined by Western blot analysis; DNA agarose gel electrophoresis was used to examine the apoptosis of MDAMB- 453 cells induced by emodin AMAD. RESULTS: After MDA-MB-453 cells were treated with different concentrations of emodin AMAD for 24 hrs, cells were arrested in G0/G1 phase, and the expression of G0/G1 related proteins c/Myc, Cyclin D1, CDK4 and p-Rb changed. DNA fragmentation appeared on the agarose gel in a concentration- dependent manner. CONCLUSION: Emodin AMAD induced G0/G1 arrest in Her2/ neu-overexpressing MDA-MB-453 cancer cells. This G0/G1 arrest was associated with decreasing protein expression of c-Myc, Cyclin D1, CDK4, and p-Rb.