Global disease burden of COPD from 1990 to 2019 and prediction of future disease burden trend in China.

OBJECTIVES: This study aimed to assess and predict the disease burden attributable to chronic obstructive pulmonary disease (COPD) in a timely, comprehensive, and reliable manner, thereby mitigating the health hazards of COPD. STUDY DESIGN AND METHODS: Data on the disease burden owing to COPD from 1990 to 2019 were extracted from the Global Burden of Disease (GBD) Study 2019. Linear regression analysis was used to calculate the estimated annual percentage change (EAPC) in the age-standardized rates. Non-parametric tests were used for subgroup analysis. The Bayesian age-period-cohot (BAPC) model integrated nested Laplace approximations to predict the disease burden over the next 25 years. Sensitivity analysis was performed using the Norpred APC model. RESULTS: Globally, the COPD-related age-standardized incidence rate decreased from 216.48/100,000 in 1990 to 200.49/100,000 in 2019, with an EAPC of -0.33. But the number of new cases increased from 8,722,966 in 1990 to 16, 214, 828 in 2019. Trends in prevalence, deaths, and disability-adjusted life years (DALYs) were the same as incidence. There were significant differences in disease burden between the genders and all age groups (P < 0.05) in China. The projections suggested that the COPD-related number of new cases and deaths in China would increase by approximately 1.5 times over the next 25 years. CONCLUSIONS: The number of incidence, prevalence, deaths, and DALYs had all increased in China in the past and would continue to grow over the next 25 years. Therefore, measures should be taken to target risk factors and high-risk groups.

Overexpression of dishevelled 2 is involved in tumor metastasis and is associated with poor prognosis in hepatocellular carcinoma

Purpose. Although hepatocellular carcinoma (HCC) is one of the most common malignant tumors, its molecular mechanism is still unknown. Dishevelled 2 (Dvl2) is one of the downstream targets of non-canonical Wnt signaling, which has been demonstrated to be of great importance in the progression of cancers. Nevertheless, the expression mechanisms and physiological significance of Dvl2 in HCC remain unclear. Methods. Western blotting and immunohistochemistry were used to measure Dvl2 protein expression in HCC and adjacent normal tissues of 101 patients. Wound healing and transwell assays were used to determine cell migration and invasion. Results. Dvl2 expression was upregulated in HCC tissues compared to the adjacent normal tissues. Moreover, its expression level was significantly correlated with histological grade (P = 0.042), metastasis (P = 0.005) and vein invasion (P = 0.009) in patients with HCC. Wound healing and transwell assays showed that knockdown of Dvl2 reduced cell migration and invasion in HepG2 cells. Finally, we confirmed that Dvl2 could regulate the migration and invasion of HCC cells by interacting with P62 in non-canonical Wnt signaling. Conclusions. Our data showed that Dvl2 was overexpressed in HCC tissues and was also correlated with poor prognosis, suggesting that Dvl2 is a novel therapeutic target for HCC (AU)

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Overexpression of dishevelled 2 is involved in tumor metastasis and is associated with poor prognosis in hepatocellular carcinoma.

PURPOSE: Although hepatocellular carcinoma (HCC) is one of the most common malignant tumors, its molecular mechanism is still unknown. Dishevelled 2 (Dvl2) is one of the downstream targets of non-canonical Wnt signaling, which has been demonstrated to be of great importance in the progression of cancers. Nevertheless, the expression mechanisms and physiological significance of Dvl2 in HCC remain unclear. METHODS: Western blotting and immunohistochemistry were used to measure Dvl2 protein expression in HCC and adjacent normal tissues of 101 patients. Wound healing and transwell assays were used to determine cell migration and invasion. RESULTS: Dvl2 expression was upregulated in HCC tissues compared to the adjacent normal tissues. Moreover, its expression level was significantly correlated with histological grade (P = 0.042), metastasis (P = 0.005) and vein invasion (P = 0.009) in patients with HCC. Wound healing and transwell assays showed that knockdown of Dvl2 reduced cell migration and invasion in HepG2 cells. Finally, we confirmed that Dvl2 could regulate the migration and invasion of HCC cells by interacting with P62 in non-canonical Wnt signaling. CONCLUSIONS: Our data showed that Dvl2 was overexpressed in HCC tissues and was also correlated with poor prognosis, suggesting that Dvl2 is a novel therapeutic target for HCC.

[Role of probiotics in treatment of nonalcoholic fatty liver disease].

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in China and manifests as simple fatty liver, non-alcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Studies have shown that intestinal flora can affect the development and progression of NAFLD via the "gut-liver axis" . Probiotics are active microorganisms with beneficial effects on the host, and more and more studies have found that probiotics play a positive role in improving NAFLD. They are cheaper, less harmful, and safer compared with antibiotics and surgery, and therefore, it may become a new method for the prevention and treatment of NAFLD. This article reviews the research advances in probiotics in the treatment of NAFLD, in order to provide a basis for the treatment of NAFLD using probiotics.

Candidate genes for the development of hair follicles in Hu sheep.

The aim of this study was to detect candidate genes for the development of hair follicles in the Hu sheep breed. Seven genes have been detected in large, medium, and small wave follicles of Hu sheep using gene chip technology. The histological features of the follicles of newborn Hu-lambs were combined with fluorescence quantitative PCR technology to detect the correlation between the expression of the seven genes and hair follicle development. Among the genes studied, matrix metalloproteinase 2 (MMP2), bone morphogenetic protein-7 (BMP7), and sideroflexin 1 (SFXN1) showed a significantly different pattern of expression in large, medium, and small wave follicles (P < 0.05). The expression of MMP2 had a significant positive correlation with secondary follicles in large waves (P < 0.05), while the expression of BMP7 had a significant correlation with primary follicle diameter in small wave follicles, and a highly significant positive correlation with the number of secondary follicles in the small waves (P < 0.01). The expression of SFXN1 was significantly and positively correlated with the diameters of small wave primary follicles; it also showed a highly significant positive correlation with secondary follicle diameters. Although other genes are associated with hair follicles, their expression in large, medium, and small wave follicles was not significant. We propose that BMP7, MMP2, and SFXN1 genes could be important candidate genes for use in breeding Hu lambs with early coat development.

Comparison of the effect of dabigatran and dalteparin on thrombus stability in a murine model of venous thromboembolism.

UNLABELLED: ESSENTIALS: Does thrombus stability alter the presentation of venous thromboembolism and do anticoagulants alter this? In a murine model, we imaged a femoral vein thrombus and quantified emboli in the pulmonary arteries. Dabigatran decreases thrombus stability via factor XIII increasing embolization and pulmonary emboli. This cautions against the unapproved use of dabigatran for acute initial treatment of deep vein thrombosis. BACKGROUND: Venous thromboembolism (VTE) is a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE). Thrombus instability possibly contributes to progression of DVT to PE, and direct thrombin inhibitors (DTIs) may alter this. AIM: To develop a model to assess thrombus stability and its link to PE burden, and identify whether DTIs, in contrast to low-molecular-weight heparin (LMWH), alter this correlation. METHODS: Twelve minutes after ferric chloride-induced thrombus formation in the femoral vein of female mice, saline, dalteparin (LMWH) or dabigatran (DTI) was administered. Thrombus size and embolic events breaking off from the thrombus were quantified before treatment and at 10-min intervals after treatment for 2 h using intravital videomicroscopy. Lungs were stained for the presence of PE. RESULTS: Thrombus size was similar over time and between treatment groups. Total and large embolic events and pulmonary emboli were highest after treatment with dabigatran. Variations in amounts of pulmonary embolic events were not attributed to variations in thrombus size. Large embolic events correlated with the number of emboli per lung slice independent of treatment. Embolization in factor XIII deficient (FXIII(-/-) ) saline-treated mice was greater than that in wild-type (WT) saline-treated mice, but was similar to WT dabigatran-treated mice. CONCLUSION: We have developed a mouse model of VTE that can quantify emboli and correlate this with PE burden. Consistent with clinical data, dabigatran, a DTI, acutely decreases thrombus stability and increases PE burden compared with LMWH or saline, which is a FXIII-dependent effect.

MIF4G domain containing protein regulates cell cycle and hepatic carcinogenesis by antagonizing CDK2-dependent p27 stability.

The CDK inhibitor p27(kip1) plays crucial roles in cell cycle regulation and cancer progression. Through yeast two-hybrid screening, we identified MIF4G domain containing protein (MIF4GD) as a novel binding partner for p27. The association of MIF4GD and p27 was verified using immunoprecipitation and glutathione S-transferase (GST) pull-down assays. Interaction with MIF4GD led to the stabilization of p27 both in the nucleus and in the cytoplasm in hepatocellular carcinoma (HCC) cells as a result of suppressed phosphorylation of p27 by CDK2 at threonine187. Serum stimulation decreased the levels of MIF4GD and p27 simultaneously. In addition, MIF4GD overexpression resulted in increased p27 levels and reduced cell proliferation, while knockdown of MIF4GD promoted cell cycle progression with decreased p27 levels in cells. Furthermore, overexpression of MIF4GD reduced colony formation and inhibited xenograft tumor growth in nude mice. Finally, we found that both MIF4GD and p27 were expressed at low levels in HCC tissues compared to non-cancerous tissues, and that low expression levels of MIF4GD and p27 were associated with significantly worse prognosis in HCC patients. Our results suggest that MIF4GD is a potential regulator of p27-dependent cell proliferation in HCC. These findings provide a rational framework for the development of potential HCC therapy by targeting the MIF4GD-p27 interaction.

Artificial pneumothorax in CT-guided radioactive iodine-125 seed implantation in the treatment of mediastinal tumors.

OBJECTIVE: To explore the efficacy and safety of CT-guided radioactive Iodine-125 seed implantation in treating mediastinal tumors in the thorax with artificial pneumothorax. PATIENTS AND METHODS: Artificial pneumothorax was created using the 22 G thoracic puncture needle in 36 patients with mediastinal tumors, followed by CT-guided radioactive Iodine-125 seed implantation. An equal volume of gas was extracted after the treatment. RESULTS: The treatment was completed in 35 patients. The tumor target volumes for the radiation treatment were not significantly different before and after the artificial pneumothorax (p = 0.265). No severe complications such as refractory pneumothorax, hemoptysis, or diffuse hemorrhage in the implantation area was observed. CONCLUSIONS: Artificial pneumothorax can reduce the CT image interference caused by the needle tract bleeding during the radioactive Iodine-125 implantation.

Texting while driving: is speech-based text entry less risky than handheld text entry?

Research indicates that using a cell phone to talk or text while maneuvering a vehicle impairs driving performance. However, few published studies directly compare the distracting effects of texting using a hands-free (i.e., speech-based interface) versus handheld cell phone, which is an important issue for legislation, automotive interface design and driving safety training. This study compared the effect of speech-based versus handheld text entries on simulated driving performance by asking participants to perform a car following task while controlling the duration of a secondary text-entry task. Results showed that both speech-based and handheld text entries impaired driving performance relative to the drive-only condition by causing more variation in speed and lane position. Handheld text entry also increased the brake response time and increased variation in headway distance. Text entry using a speech-based cell phone was less detrimental to driving performance than handheld text entry. Nevertheless, the speech-based text entry task still significantly impaired driving compared to the drive-only condition. These results suggest that speech-based text entry disrupts driving, but reduces the level of performance interference compared to text entry with a handheld device. In addition, the difference in the distraction effect caused by speech-based and handheld text entry is not simply due to the difference in task duration.

Comparison of the effect of coagulation and platelet function impairments on various mouse bleeding models.

Haemostatic impairments are studied in vivo using one of several murine bleeding models. However it is not known whether these models are equally appropriate for assessing coagulation or platelet function defects. It was our study objective to assess the performance of arterial, venous and combined arterial and venous murine bleeding models towards impaired coagulation or platelet function. Unfractionated heparin (UFH) or αIIbß3inhibitory antibody (Leo.H4) were administered to mice, and their effects on bleeding in saphenous vein, artery, and tail tip transection models were quantified and correlated with their effects on plasma clotting and ADP-induced platelet aggregation, respectively. All models exhibited similar sensitivity with UFH (EC50 dose = 0.19, 0.13 and 0.07 U/g, respectively) (95% CI = 0.14 - 0.27, 0.08 - 0.20, and 0.03 - 0.16 U/g, respectively). Maximal inhibition of ex vivo plasma clotting could be achieved with UFH doses as low as 0.03 U/g. In contrast, the saphenous vein bleeding model was less sensitive to αIIbß3 inhibition (EC50 = 6.9 µg/ml) than tail transection or saphenous artery bleeding models (EC50 = 0.12 and 0.37 µg/ml, respectively) (95% CI = 2.4 - 20, 0.05 - 0.33, and 0.06 - 2.2 µg/ml, respectively). The EC50 of Leo.H4 for ADP-induced platelet aggregation in vitro (8.0 µg/ml) was at least 20-fold higher than that of the tail and arterial, but not the venous bleeding model. In conclusion, venous, arterial and tail bleeding models are similarly affected by impaired coagulation, while platelet function defects have a greater influence in models incorporating arterial injury.

Distribution of vasopressin, oxytocin and vasoactive intestinal polypeptide in the hypothalamus and extrahypothalamic regions of tree shrews.

Vasopressin (VP), oxytocin (OXT) and vasoactive intestinal polypeptide (VIP) in the brain modulate physiological and behavioral processes in many vertebrates. Day-active tree shrews, the closest relatives of primates, live singly or in pairs in territories that they defend vigorously against intruding conspecifics. However, anatomy concerning peptidergic neuron distribution in the tree shrew brain is less clear. Here, we examined the distribution of VP, OXT and VIP immunoreactivity in the hypothalamus and extrahypothalamic regions of tree shrews (Tupaia belangeri chinensis) using the immunohistochemical techniques. Most of VP and OXT immunoreactive (-ir) neurons were found in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. In addition, VP-ir or OXT-ir neurons were scattered in the preoptic area, anterior hypothalamic areas, dorsomedial hypothalamic nucleus, stria terminalis, bed nucleus of the stria terminalis and medial amygdala. Interestingly, a high density of VP-ir fibers within the ventral lateral septum was observed in males but not in females. Both VP-ir and VIP-ir neurons were found in different subdivisions of the suprachiasmatic nucleus (SCN) with partial overlap. VIP-ir cells and fibers were also scattered in the cerebral cortex, anterior olfactory nucleus, amygdala and dentate gyrus of the hippocampus. These findings provide a comprehensive description of VIP and a detailed mapping of VP and OXT in the hypothalamus and extrahypothalamic regions of tree shrews, which is an anatomical basis for the participation of these neuropeptides in the regulation of circadian behavior and social behavior.

Anesthesia management for open fetal intrauterine surgery.

OBJECTIVE: Open fetal surgery is usually performed during the second trimester in a fetus suffering from severe congenital diseases, thus enabling the pregnancy to continue until delivery. MATERIALS AND METHODS: The key of this treatment is to promote uterine relaxation enough to maintain both maternal and fetal circulation stable and once surgery is completed, to offer a perfect analgesic to avoid the contractions due to pain, and finally to reduce preterm delivery. RESULTS: Successful anesthesia is fundamental to this surgery. CONCLUSION: The authors have performed three cases under inhalation anesthesia combined with successful epidural anesthesia.

Exacerbation of glycoprotein VI-dependent platelet responses in a rhesus monkey model of Type 1 diabetes.

Thrombosis is a life-threatening complication of diabetes. Platelet reactivity is crucial to thrombus formation, particularly in arterial vessels and in thrombotic complications causing myocardial infarction or ischaemic stroke, but diabetic patients often respond poorly to current antiplatelet medication. In this study, we used a nonhuman primate model of Type 1 diabetes to measure early downstream signalling events following engagement of the major platelet collagen receptor, glycoprotein (GP)VI. Diabetic monkeys were given enough insulin to maintain their blood glucose levels either at ~8 mM (well-controlled diabetes) or ~15 mM (poorly controlled diabetes). Flow cytometric analysis was used to measure platelet reactive oxygen species (ROS) generation, calcium mobilisation, receptor surface expression, and immature platelet fraction. We observed exacerbated intracellular ROS and calcium flux associated with engagement of GPVI in monkeys with poorly controlled diabetes. GPVI surface levels did not differ between healthy monkeys or the two diabetic groups. Treatment of platelets with the specific Syk inhibitor BAY61-3606 inhibited GPVI-dependent ROS and, importantly, reduced ROS generation in the poorly controlled diabetes group to that observed in healthy monkeys. These data indicate that glycaemic control is important in reducing GPVI-dependent platelet hyperreactivity and point to a potential antithrombotic therapeutic benefit of Syk inhibition in hyperglycaemic diabetes.

Diannexin, an annexin A5 homodimer, binds phosphatidylserine with high affinity and is a potent inhibitor of platelet-mediated events during thrombus formation.

BACKGROUND: Shielding of procoagulant phosphatidylserine (PS) with annexin A5 attenuates thrombosis, but annexin A5 (35.7 kDa) is rapidly cleared from the circulation. In contrast, Diannexin, a 73.1 kDa homodimer of annexin A5, has an extended half-life. OBJECTIVES: To quantify the affinity of Diannexin for PS, examine its interaction with activated platelets and determine its effects on platelet-mediated events during thrombus formation. METHODS: The affinities of Diannexin and annexin A5 for PS-containing lipid bilayers were compared using surface plasmon resonance, and binding to activated platelets was assessed by flow cytometry. Calibrated automated thrombography and thromboelastography were employed to study the effects of Diannexin on thrombin generation and platelet-fibrin clot formation, respectively, whereas intravital videomicroscopy was used to examine its effect on platelet accumulation and activation after laser-induced injury to murine cremaster arterioles, and a tail tip bleeding model was used to explore its effects on hemostasis. RESULTS: Diannexin and annexin A5 bind PS with K(D) values of 0.6 and 5 nm, respectively, and both bind to the same subpopulation of PS-exposing platelets. Diannexin inhibited thrombin generation and platelet-fibrin clot formation in vitro at 10 nm (P<0.05-0.001 compared with control), and reduced platelet accumulation at 1 µg g(-1) (P<0.05) and activation at 0.25 µg g(-1) (P<0.001) in experimentally induced arterial thrombi in mice while increasing blood loss at 1 µg g(-1) (P<0.01). CONCLUSIONS: Diannexin binds to PS with high affinity and is a potent inhibitor of platelet-mediated events during thrombus formation.

Self-assembly of a colloidal interstitial solid with tunable sublattice doping.

We determine the phase diagram of a binary mixture of small and large hard spheres with a size ratio of 0.3 using free-energy calculations in Monte Carlo simulations. We find a stable binary fluid phase, a pure face-centered-cubic (fcc) crystal phase of the small spheres, and binary crystal structures with LS and LS(6) stoichiometries. Surprisingly, we demonstrate theoretically and experimentally the stability of a novel interstitial solid solution in binary hard-sphere mixtures, which is constructed by filling the octahedral holes of an fcc crystal of large spheres with small spheres. We find that the fraction of octahedral holes filled with a small sphere can be completely tuned from 0 to 1. Additionally, we study the hopping of the small spheres between neighboring octahedral holes, and interestingly, we find that the diffusion increases upon increasing the density of small spheres.

Expression of aquaporin-4 in human supratentorial meningiomas with peritumoral brain edema and correlation of VEGF with edema formation.

Peritumoral brain edema is a common complication of meningiomas. It is believed that vascular endothelial growth factor (VEGF), as an angiogenic factor, plays a vital role in edema formation. Aquaporin-4 (AQP4) is a small integral membrane protein that regulates water in the normal brain. However, the expression of AQP4 and its relationship to VEGF in edematous meningiomas are not well known. We studied tumor specimens of 59 human supratentorial meningiomas. Western blot analysis was used to detect the expression of AQP4, and double-labeling immunofluorescence histochemical staining was performed to determine the relationship between AQP4 and VEGF. The AQP4 expression was significantly higher in the edema group, in which the protein level was correlated with the extent of edema. Greater VEGF expression was also observed in the edema group, and a relationship between AQP4 and VEGF was found. We conclude that AQP4 is involved in peritumoral brain edema formation in meningiomas and is also closely related to the expression of VEGF.

Simulation of nucleation in almost hard-sphere colloids: the discrepancy between experiment and simulation persists.

In this paper we examine the phase behavior of the Weeks-Chandler-Andersen (WCA) potential with ßε = 40. Crystal nucleation in this model system was recently studied by Kawasaki and Tanaka [Proc. Natl. Acad. Sci. U.S.A. 107, 14036 (2010)], who argued that the computed nucleation rates agree well with experiment, a finding that contradicted earlier simulation results. Here we report an extensive numerical study of crystallization in the WCA model, using three totally different techniques (Brownian dynamics, umbrella sampling, and forward flux sampling). We find that all simulations yield essentially the same nucleation rates. However, these rates differ significantly from the values reported by Kawasaki and Tanaka and hence we argue that the huge discrepancy in nucleation rates between simulation and experiment persists. When we map the WCA model onto a hard-sphere system, we find good agreement between the present simulation results and those that had been obtained for hard spheres [L. Filion, M. Hermes, R. Ni, and M. Dijkstra, J. Chem. Phys. 133, 244115 (2010); S. Auer and D. Frenkel, Nature 409, 1020 (2001)].

Crystal nucleation of hard spheres using molecular dynamics, umbrella sampling, and forward flux sampling: a comparison of simulation techniques.

Over the last number of years several simulation methods have been introduced to study rare events such as nucleation. In this paper we examine the crystal nucleation rate of hard spheres using three such numerical techniques: molecular dynamics, forward flux sampling, and a Bennett-Chandler-type theory where the nucleation barrier is determined using umbrella sampling simulations. The resulting nucleation rates are compared with the experimental rates of Harland and van Megen [Phys. Rev. E 55, 3054 (1997)], Sinn et al. [Prog. Colloid Polym. Sci. 118, 266 (2001)], Schätzel and Ackerson [Phys. Rev. E 48, 3766 (1993)], and the predicted rates for monodisperse and 5% polydisperse hard spheres of Auer and Frenkel [Nature 409, 1020 (2001)]. When the rates are examined in units of the long-time diffusion coefficient, we find agreement between all the theoretically predicted nucleation rates, however, the experimental results display a markedly different behavior for low supersaturation. Additionally, we examined the precritical nuclei arising in the molecular dynamics, forward flux sampling, and umbrella sampling simulations. The structure of the nuclei appears independent of the simulation method, and in all cases, the nuclei contains on average significantly more face-centered-cubic ordered particles than hexagonal-close-packed ordered particles.

Fibrinogen controls human platelet fibronectin internalization and cell-surface retention.

BACKGROUND: We recently demonstrated that platelet aggregation occurred in fibrinogen-deficient mice. In these animals, platelet fibronectin (Fn) content was increased 3-5 fold, suggesting that Fn may also be involved in platelet aggregation. METHODS AND RESULTS: We compared platelet Fn content from a severe hypofibrinogenemic patient (with approximately 0.5% of normal fibrinogen levels) with his parents (heterozygous) and healthy donors. A significant increase in the patient's platelet Fn content was detected by immunoblot, flow cytometry, and immunoelectron microscopy (IEM). To examine the possible contribution of platelet Fn to platelet aggregation, we examined cell-surface Fn expression after thrombin treatment. Unexpectedly, IEM detected only trace amounts of Fn retained on the patient's platelet surface, and flow cytometry indicated that surface Fn was approximately 6-fold lower than that of his parents and tenfold lower than that of healthy donors. An ELISA further confirmed that the patient's platelet Fn was primarily released into the extracellular medium. To test whether retention of surface Fn was due to fibrin formation on the platelet surface, an antifibrin antibody (T2 G1) was employed. Fibrin was detected on platelets from healthy donors and from the father, but was negligible on the patient's platelets. Consistent with these data, when gel-filtered platelets of healthy donors were treated with thrombin receptor activation peptide (SFLLRN-NH(2); no conversion of fibrinogen to fibrin), little surface Fn was detected. CONCLUSION: Fibrinogen not only competitively inhibits human platelet Fn internalization but also controls platelet-surface Fn retention via fibrin formation. The Fn-fibrin interaction is one possible mechanism to promote Fn interaction with platelets.