In vivo endoscopic ultrasound imaging with a rotational-scanning, all-optical ultrasound probe.

All-optical ultrasound manipulates ultrasound waves based on laser and photonics technologies, providing an alternative approach for pulse-echo ultrasound imaging. However, its endoscopic imaging capability is limited ex vivo by the multifiber connection between the endoscopic probe and the console. Here, we report on all-optical ultrasound for in vivo endoscopic imaging using a rotational-scanning probe that relies on a small laser sensor to detect echo ultrasound waves. The acoustically induced lasing frequency change is measured via heterodyne detection by beating the two orthogonally polarized laser modes, enabling a stable output of ultrasonic responses and immunity to low-frequency thermal and mechanical disturbances. We miniaturize its optical driving and signal interrogation unit and synchronously rotate it with the imaging probe. This specialized design leaves a single-fiber connection to the proximal end and allows fast rotational scanning of the probe. As a result, we used a flexible, miniature all-optical ultrasound probe for in vivo rectal imaging with a B-scan rate of 1 Hz and a pullback range of ∼7 cm. This can visualize the gastrointestinal and extraluminal structures of a small animal. This imaging modality offers an imaging depth of 2 cm at a central frequency of ∼20 MHz, showing promise for high-frequency ultrasound imaging applications in gastroenterology and cardiology.

Proposal for complete characterization of attosecond pulses from relativistic plasmas.

In this study, we propose two full-optical-setup and single-shot measurable approaches for complete characterization of attosecond pulses from surface high harmonic generation (SHHG): SHHG-SPIDER (spectral phase interferometry for direct electric field reconstruction) and SHHG-SEA-SPIDER (spatially encoded arrangement for SPIDER). 1D- and 2D-EPOCH PIC (particle-in-cell) simulations were performed to generate the attosecond pulses from relativistic plasmas under different conditions. Pulse trains dominated by single isolated peak as well as complex pulse train structures are extensively discussed for both methods, which showed excellent accuracy in the complete reconstruction of the attosecond field with respect to the direct Fourier transformed result. Kirchhoff integral theorem has been used for the near-to-far-field transformation. This far-field propagation method allows us to relate these results to potential experimental implementations of the scheme. The impact of comprehensive experimental parameters for both apparatus, such as spectral shear, spatial shear, cross-angle, time delay, and intensity ratio between the two replicas has been investigated thoroughly. These methods are applicable to complete characterization for SHHG attosecond pulses driven by a few to hundreds of terawatts femtosecond laser systems.

Genetic Associations With Stable Warfarin Dose Requirements in Han Chinese Patients.

ABSTRACT: Warfarin is a commonly prescribed anticoagulant for valvular heart disease that plays an important role in clinical management to prevent thrombotic events. In this study, we aim to perform a comprehensive study to investigate the genetic biomarkers of stable warfarin dose in the Han Chinese population. We performed an integrative study on 211 Han Chinese patients with valvular heart disease. A total of 40 single nucleotide polymorphisms (SNPs) in 10 important genes (CYP2C9, VKORC1, ABCB1, CYP4F2, APOE, PROC, GGCX, EPHX1, CALU, and SETD1A) which are involved in the warfarin metabolic pathway and equilibrium of coagulation and anticoagulation were selected. We applied MassARRAY technology to genotype the 40 SNPs identified in these Han Chinese patients. Our results showed that 13 SNPs on 6 genes (CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A) were associated with the individual stable warfarin dose. Two VKORC1 SNPs (rs9934438 and rs2359612) were the strongest genetic factors determining warfarin dose requirements (P = 8 × 10-6 and 9 × 10-6, respectively). Rs4889599 in SETD1A was first reported to be associated with warfarin dose at a significant level of 0.001 in our study (Padjust = 0.040 after Bonferroni correction). We discovered that genetic variants in CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A may affect the stable warfarin dose requirement in Han Chinese patients with valvular disease. The discovery of these potential genetic markers will facilitate the development of advanced personalized anticoagulation therapy in Han Chinese patients.

Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction.

CD4(+) T cell activation plays a key role in facilitating wound healing after myocardial infarction (MI). Exosomes (EXs) secreted from dendritic cells (DCs) can activate T cells in tumor models; however, whether DEXs (DC-EXs) can mediate CD4(+) T cell activation and improve wound healing post-MI remains unknown. This study sought to determine whether DEXs mediate CD4(+) T cell activation and improve cardiac function post-MI in mice. We used supernatants of hypoxic primary or necrotic HL-1 cardiomyocytes to simulate the post-MI cardiomyocyte microenvironment in vitro. Cultured bone marrow-derived DCs (BMDCs) from mice were stimulated with the supernatants of normal (Control group), hypoxic primary or necrotic HL-1 cardiomyocytes (MI group); a subset of BMDCs remained unstimulated (Negative group). DEXs were then isolated from the BMDC supernatants and either incubated with CD4(+) T cells or injected into mice via the tail vein. In this study, we found that the supernatants of both hypoxic primary and necrotic HL-1 cardiomyocytes upregulate DC maturation markers. After the injection of DEXs, a greater number of MI-DEXs are recruited by the mouse spleen and with greater rapidity than control- or negative-DEXs. Confocal imaging and flow cytometry revealed that MI-DEXs exhibited higher uptake by splenic CD4(+) T cells than the control- and negative-DEXs, and this increase was correlated with significantly greater increases in the expression of chemokines and the inflammatory cytokines IFN-γ and TNF by the CD4(+) T cells in vitro and in vivo. In addition, the injection of MI-DEXs improved cardiac function in mice post-MI. These results suggest that DEXs could mediate the activation of CD4(+) T cells through an endocrine mechanism and improve cardiac function post-MI. Our findings provide the basis for a novel strategy for the treatment of MI through the systemic delivery of DEXs.

Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway.

Whether dendritic cell (DC) derived exosomes play a role in the progression of endothelial inflammation and atherosclerosis remains unclear. Using a transwell system and exosome release inhibitor GW4869, we demonstrated that mature DCs contributed to endothelial inflammation and exosomes were involved in the process. To further confirm this finding, we isolated exosomes from bone marrow dendritic cell (BMDC) culture medium (named DC-exos) and stimulated human umbilical vein endothelial cell (HUVEC) with these DC-exos. We observed that mature DC-exos increased HUVEC inflammation through NF-κB pathway in a manner similar to that of lipopolysaccharide. After a protein array analysis of exosomes, we identified and confirmed tumour necrosis factor (TNF)-α on exosome membrane being the trigger of NF-κB pathway in HUVECs. We then performed an in vivo study and found that the aorta endothelial of mice could uptake intravenously injected exosomes and was activated by these exosomes. After a period of 12 weeks of mature DC-exos injection into ApoE-/- mice, the atherosclerotic lesions significantly increased. Our study demonstrates that mature DCs derived exosomes increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway. This finding extends our knowledge on how DCs affect inflammation and provides a potential method to prevent endothelial inflammation and atherosclerosis.

microRNA-181a represses ox-LDL-stimulated inflammatory response in dendritic cell by targeting c-Fos.

Oxidized LDL (ox-LDL) activates dendritic cells (DCs), thereby initiating inflammation responses in atherosclerosis, yet the modulatory mechanisms remain unclear. MicroRNAs (miRNAs) are important regulators for DC functions. This study evaluated the regulation by miRNAs of the ox-LDL-induced DC immune response. In CD11c(+) DCs from ApoE-deficient mice with hyperlipidemia, microRNA miR-181a was significantly up-regulated. In cultured bone marrow-derived DCs (BMDCs), ox-LDL promoted DC maturation and up-regulated miR-181a expression. Abundance of miR-181a attenuated ox-LDL-induced CD83 and CD40 expression, inhibited the secretion of interleukin (IL)-6 and TNF-α, and up-regulated IL-10, an important anti-inflammatory cytokine that was inhibited by ox-LDL. Inhibition of the endogenous miR-181a reversed the effects on CD83 and CD40 as well as the effects on IL-6 and TNF-α. The putative target genes of miR-181a were evaluated by gene ontology assessment, and the c-Fos-mediated inflammation pathway was identified. miR-181a targeted the 3' untranslated region of c-Fos mRNA by luciferase experiments. Thus, abundance of miR-181a reduced c-Fos protein, whereas inhibition of miR-181a increased c-Fos protein in BMDCs. We therefore suggest that miR-181a attenuates ox-LDL-stimulated immune inflammation responses by targeting c-Fos in DCs.

Rosuvastatin-attenuated heart failure in aged spontaneously hypertensive rats via PKCα/ß2 signal pathway.

There are controversies concerning the capacity of Rosuvastatin to attenuate heart failure in end-stage hypertension. The aim of the study was to show whether the Rosuvastatin might be effective or not for the heart failure treatment. Twenty-one spontaneously hypertensive rats (SHRs) aged 52 weeks with heart failure were randomly divided into three groups: two receiving Rosuvastatin at 20 and 40 mg/kg/day, respectively, and the third, placebo for comparison with seven Wistar-Kyoto rats (WKYs) as controls. After an 8-week treatment, the systolic blood pressure (SBP) and echocardiographic features were evaluated; mRNA level of B-type natriuretic peptide (BNP) and plasma NT-proBNP concentration were measured; the heart tissues were observed under electron microscope (EM); myocardial sarcoplasmic reticulum Ca(2+) pump (SERCA-2) activity and mitochondria cytochrome C oxidase (CCO) activity were measured; the expressions of SERCA-2a, phospholamban (PLB), ryanodine receptor2 (RyR2), sodium-calcium exchanger 1 (NCX1), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase inhibitor-1 (PPI-1) were detected by Western blot and RT-qPCR; and the total and phosphorylation of protein kinase Cα/ß (PKCα/ß) were measured. Aged SHRs with heart failure was characterized by significantly decreased left ventricular ejection fraction and left ventricular fraction shortening, enhanced left ventricular end-diastolic diameter and LV Volume, accompanied by increased plasma NT-proBNP and elevated BNP gene expression. Damaged myofibrils, vacuolated mitochondria and swollen sarcoplasmic reticulum were observed by EM. Myocardium mitochondria CCO and SERCA-2 activity decreased. The expressions of PLB and NCX1 increased significantly with up-regulation of PPI-1 and down-regulation of CaMKII, whereas that of RyR2 decreased. Rosuvastatin was found to ameliorate the heart failure in aged SHRs and to improve changes in SERCA-2a, PLB, RyR2, NCX1, CaMKII and PPI-1; PKCα/ß2 signal pathway to be suppressed; the protective effect of Rosuvastatin to be dose dependent. In conclusion, the heart failure of aged SHRs that was developed during the end stage of hypertension could be ameliorated by Rosuvastatin.

Identification of shared genetic susceptibility locus for coronary artery disease, type 2 diabetes and obesity: a meta-analysis of genome-wide studies.

Type 2 diabetes (2DM), obesity, and coronary artery disease (CAD) are frequently coexisted being as key components of metabolic syndrome. Whether there is shared genetic background underlying these diseases remained unclear. We performed a meta-analysis of 35 genome screens for 2DM, 36 for obesity or body mass index (BMI)-defined obesity, and 21 for CAD using genome search meta-analysis (GSMA), which combines linkage results to identify regions with only weak evidence and provide genetic interactions among different diseases. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to the best linkage evidence within each bin. For each disease, bin 6.2 achieved genomic significanct evidence, and bin 9.3, 10.5, 16.3 reached suggestive level for 2DM. Bin 11.2 and 16.3, and bin 10.5 and 9.3, reached suggestive evidence for obesity and CAD respectively. In pooled all three diseases, bin 9.3 and 6.5 reached genomic significant and suggestive evidence respectively, being relatively much weaker for 2DM/CAD or 2DM/obesity or CAD/obesity. Further, genomewide significant evidence was observed of bin 16.3 and 4.5 for 2DM/obesity, which is decreased when CAD was added. These findings indicated that bin 9.3 and 6.5 are most likely to be shared by 2DM, obesity and CAD. And bin 16.3 and 4.5 are potentially common regions to 2DM and obesity only. The observed shared susceptibility regions imply a partly overlapping genetic aspects of disease development. Fine scanning of these regions will definitely identify more susceptibility genes and causal variants.

"Pro-resolution" and anti-inflammation, a role of RvE1 in anti-atherosclerosis and plaque stabilization.

Inflammation governs atherosclerosis and is firmly regulated. Endogenous mechanisms to keep inflammation self-limiting are unclear. In the present article, we propose that RvE1 (resolution E1), an endogenous lipid mediator, inhibits inflammation through "pro-resolution" and counter-modulating immunity in atherosclerosis. The background comes from studies on the potent programming of resolution and immuno-inflammation of RvE1 and its precursor, eicosapentaenoic acid, in treating chronic inflammatory disease with unknown mechanisms. In light of the interaction between RvE1 and leukotrieneB4 (LTB4) and their potential impaired immunity regulation hematostasis, we hypothesize that RvE1 play an anti-atherosclerosis and plaque stabilization role through "pro-resolution" and anti-inflammation which may be realized by blocking LTB4/BLT1 (receptor of LTB4) pathway. Our hypothesis generates potentially clinical viewpoint to systematically look for pro- and anti-inflammation and "pro-resolution" process in atherosclerosis. Furthermore, we suggest that RvE1 might be particularly indicated for the treatment of atherosclerotic diseases and plaque stabilization which might ensure an effective management for patients with coronary artery disease.

Mitochondrial aldehyde dehydrogenase 2 deficiency aggravates energy metabolism disturbance and diastolic dysfunction in diabetic mice.

Diabetes causes energy metabolism disturbance and may lead to cardiac dysfunction. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects cardiac function from myocardial damage. Therefore, understanding of its roles in diabetic heart is critical for developing new therapeutics targeting ALDH2 and mitochondrial function for diabetic hearts. This study investigated the impact of ALDH2 deficiency on diastolic function and energy metabolism in diabetic mice. Diabetes was induced in ALDH2 knockout and wild-type mice by streptozotocin. Cardiac function was determined by echocardiography. Glucose uptake, energy status, and metabolic profiles were used to evaluate cardiac energy metabolism. The association between ALDH2 polymorphism and diabetes was also analyzed in patients. Echocardiography revealed preserved systolic function and impaired diastolic function in diabetic ALDH2-deficient mice. Energy reserves (phosphocreatine/adenosine triphosphate ratio) were reduced in the diabetic mutants and were associated with diastolic dysfunction. Western blot analysis showed that diabetes induces accumulated lipid peroxidation products and escalated AMP-activated protein kinase-LKB1 pathway. Further, ALDH2 deficiency exacerbated the diabetes-induced deficient myocardial glucose uptake and other perturbations of metabolic profiles. Finally, ALDH2 mutations were associated with worse diastolic dysfunction in diabetic patients. Together, our results demonstrate that ALDH2 deficiency and resulting energy metabolism disturbance is a part of pathology of diastolic dysfunction of diabetic hearts, and suggest that patients with ALDH2 mutations are vulnerable to diabetic damage. KEY MESSAGE: ALDH2 deficiency exacerbates diastolic dysfunction in early diabetic hearts. ALDH2 deficiency triggers decompensation of metabolic reserves and energy metabolism disturbances in early diabetic hearts. ALDH2 deficiency potentiates oxidative stress and AMPK phosphorylation induced by diabetes via post-translational regulation of LKB1. Diabetic patients with ALDH2 mutations are predisposed to worse diastolic dysfunction.

Streptococcus acidominimus causing invasive disease in humans: a case series.

INTRODUCTION: Streptococcus acidominimus is a member of the viridans group streptococci and is rarely pathogenic in humans, making it difficult to assess its epidemiologic and clinical significance. CASE PRESENTATION: We report the cases of five Han Chinese patients with invasive diseases caused by S. acidominimus over a one-year time frame. Three of the patients developed continuous fever after surgery, consisting of a successful elective laparoscopic cholecystectomy (case 1), a laparoscopic esophageal resection and gastroesophageal anastomosis (case 2), and a liver transplant in a patient with liver cancer (case 3). For these three patients, cultures of the purulent drainage material grew S. acidominimus. Case 4 concerns a 52-year-old man who developed sepsis 48 hours after hospitalization for hepatitis, liver cirrhosis and hepatitis-related glomerulonephritis. Case 5 concerns a 55-year-old woman receiving regular hemodialysis who had low-grade fever for one month. For these two patients, blood cultures grew S. acidominimus. An antimicrobial susceptibility test revealed that S. acidominimus was resistant to clindamycin and, to some degree, beta-lactam or macrolides. The S. acidominimus from the patient on hemodialysis was resistant to multiple antibiotics. CONCLUSION: S. acidominimus is an ever-increasing cause of disease, especially in patients who are critically ill. It is showing increased resistance to antimicrobial agents, so in patients with viridans group streptococci infections, it is necessary to identify the species to improve the clinical management of S. acidominimus.

Transmesosigmoid hernia: case report and review of literature.

Transmesosigmoid hernia has previously been considered as a rare condition. The clinical symptoms can be nonspecific. Here, we report a case of acute intestinal obstruction because of transmesosigmoid hernia. In addition, after a comprehensive review of PubMed and China National Knowledge Infrastructure, we present a review of 22 cases of transmesosigmoid hernia. We summarize several valuable clinical features that help early recognition of transmesosigmoid hernia. As a result of easy strangulation, in patients without a history of surgery or abdominal inflammation who present with symptoms of progressive or persistent small bowel obstruction (SBO), surgeons should consider the possibility of transmesosigmoid hernia. In addition, based on our data, in patients with SBO because of transmesosigmoid hernia, the defect is usually 2-5 cm in diameter. Furthermore, because of the high risk of strangulation with transmesosigmoid hernia, it is mandatory to reassess the condition timely and periodically when patients receive conservative treatment.

Two cases of bacterial suppurative thyroiditis caused by Streptococcus anginosus.

Acute suppurative thyroiditis (AST) is a rare clinical condition. Streptococcus anginosus has a propensity of producing empyema in the head and neck. Here, we reported two cases of AST caused by S. anginosus. A 44-year-old man presented with anterior neck tender swelling and odynophagia for 12 days. He had thyrotoxicosis. He was initially diagnosed as thyroid cancer due to the misleading computed tomography report. Fine needle aspiration (FNA) yielded pus and neutrophils. S. anginosus was isolated from pus. After aspiration of abscess and treatment with sensitive antibiotics, he recovered uneventfully with 3 weeks treatment. He was euthyroid 3 months later. The other case is a 40-year-old women complained of fever and left neck swelling for 20 days. Magnetic resonance imaging showed left neck inflammatory changes. FNA revealed pus and inflammatory cells infiltration. She had moderately decreased level of thyroid-stimulating hormone (TSH). Blood cultures were positive for S. anginosus. After penicillin treatment, TSH level returned to normal range, and the nodule gradually resolved. She recovered uneventfully after 5 weeks treatment. S. anginosus has a previously unappreciated clinical niche in AST. Once AST is clinically concerned, FNA procedure should be performed as early as possible.

CXCR6 deficiency ameliorated myocardial ischemia/reperfusion injury by inhibiting infiltration of monocytes and IFN-γ-dependent autophagy.

BACKGROUND: Emerging evidence shows that the chemokine CXCL16 plays an important role in the pathogenesis of myocardial remodeling and development of heart failure following ischemia/reperfusion (I/R) injury. CXCR6, the receptor for CXCL16, is also critically involved. However, the underlying mechanism remained uncertain, and the aim of this research was to investigate this mechanism in CXCR6 knockout (KO) mice. METHODS AND RESULTS: CXCR6 KO mice and wild type (WT) mice had no overt phenotype at baseline in the absence of injury, but difference was shown in response to I/R induction. Compared with WT mice, CXCR6 KO mice exhibited a lower infarction size (31.86 ± 1.808% vs. 43.09 ± 1.519%), and better cardiac function (measured by LVEF, LVFS, +dp/dt, LVEDP, and LVSP) following I/R. Moreover, cardiac levels of IFN-γ and IFN-γ-dependent autophagy were found to be significantly attenuated in CXCR6 KO mice. Further data showed that cardiac-enhanced IFN-γ secretion was not induced by cardiomyocytes, but by infiltrated monocytes in the myocardium in response to I/R injury. In vivo injection of IFN-γ and in vitro co-cultured cardiomyocytes with CD11b+ monocytes confirmed IFN-γ activated autophagic response, and induced cardiac dysfunction in a paracrine manner. CONCLUSIONS: The study suggested that since disruption of the CXCL16/CXCR6 signaling cascade had a cardio-protective effect against I/R injury, the underlying mechanism might be that I/R triggered the infiltration of monocytes into the myocardium, and induced cardiac autophagy through CXCL16/CXCR6-dependent paracrine secretion of IFN-γ.

Aspirin for primary prevention of cardiovascular events in patients with diabetes: A meta-analysis.

BACKGROUND: To systematically review trials concerning the benefit and risk of aspirin therapy for primary prevention of cardiovascular events in patients with diabetes mellitus. METHODS: We searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. Eligible studies were prospective, randomized controlled trials of aspirin therapy for primary cardiovascular prevention in patients with diabetes with follow-up duration at least 12 months. RESULTS: 7 trials included 11,618 individuals with diabetes. Aspirin therapy was not associated with a statistically significant reduction in major cardiovascular events (relative risk [RR] 0.92, 95% confidence interval [CI] 0.83-1.02, p=0.11). Aspirin use also did not significantly reduce all-cause mortality (0.95, 95% CI 0.85-1.06; p=0.33), cardiovascular mortality (0.95, 95% CI 0.71-1.27; p=0.71), stroke (0.83, 95% CI 0.63-1.10; p=0.20), or myocardial infarction (MI) (0.85, 95% CI 0.65-1.11; p=0.24). There was no significant increased risk of major bleeding in aspirin group (2.46, 95% CI 0.70-8.61; p=0.16). Meta-regression suggested that aspirin agent could reduce the risk of stroke in women and MI in men. CONCLUSIONS: In patients with diabetes, aspirin therapy did not significantly reduce the risk of cardiovascular events without an increased risk of major bleeding, and showed sex-specific effects on MI and stroke.

Efficacy and safety of intracoronary autologous bone marrow-derived cell transplantation in patients with acute myocardial infarction: insights from randomized controlled trials with 12 or more months follow-up.

BACKGROUND: Until now there was no systematic review concerning the chronic effects of intracoronary bone marrow-derived cell (BMC) transplantation in patients with acute myocardial infarction (MI). HYPOTHESIS: Improvement of cardiac function in patients with acute MI post BMC transplantation might last longer than 12 months. METHODS: We searched MEDLINE, EMBASE, and the Cochrane database through June 2009. Eligible studies were randomized controlled trials of intracoronary BMC transfer in acute MI patients with follow-up duration equal to or longer than 12 months. RESULTS: A total of 8 trials involving 725 participants were identified. Compared with controls, BMC transplantation significantly improved left ventricular ejection fraction (LVEF) by 4.37% (95% confidence interval [CI]: 2.66%-6.08%; P < 0.00001), reduced left ventricular end-diastolic volume (LVEDV) by 5.71 mL (95% CI: 2.03-9.40 mL; P = 0.002), left ventricular end-systolic volume (LVESV) by 8.94 mL (95% CI: 4.22-13.66 mL; P = 0.0002), and infarct size by 2.42% (95% CI: 1.33%-3.51%, P < 0.00001). Bone marrow-derived cell treatment also significantly reduced the risk of death (relative risk [RR]: 0.33, 95% CI: 0.13-0.89; P = 0.03), while the risk of reinfarction was similar between the 2 groups (RR: 0.62, 95% CI: 0.09-4.12; P = 0.62). Subgroup analysis showed that the BMC transplantation-induced LVEF increase was more significant in patients age < 55 and with cells transferred 6 or 7 days after MI. CONCLUSION: Beneficial effects of intracoronary BMC transplantation could last more than 12 months in acute MI patients.

Effects of intensive glucose control on incidence of cardiovascular events in patients with type 2 diabetes: a meta-analysis.

BACKGROUND: The effects of intensive glucose control over conventional glucose control on cardiovascular outcomes of patients with type 2 diabetes remain uncertain. METHODS: We searched MEDLINE, EMBASE, and the Cochrane database to identify randomized controlled trials that compared the effects of intensive glucose control and conventional glucose control, on cardiovascular events in patients with type 2 diabetes. RESULTS: Seven trials involving 34,144 participants with type 2 diabetes were included. Intensive glucose control significantly reduced major cardiovascular events by 10% (relative risk (RR) 0.90, 95% CI 0.85-0.96; P = 0.0006), and non-fatal myocardial infarction by 16% (0.84, 95% CI 0.76-0.93; P = 0.0006) at the expense of increased incidence of severe hypoglycemia (2.30, 95% CI 1.74-3.03; P < 0.00001), while all-cause mortality, cardiovascular death, non-fatal stroke, and heart failure were similar between the two groups. Subgroup analyses showed that patients with longer follow-up duration, shorter diabetic duration, less glycosylated hemoglobin (HbA1c) reduction, higher HbA1c concentration at follow-up, and lower base-line HbA1c benefited more from intensive glucose control. CONCLUSION: An intensive glucose control strategy can effectively reduce the risk of major cardiovascular events but at the expense of a significantly increased risk of severe hypoglycemia in patients with type 2 diabetes.