Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion.

BACKGROUND: The effects of the glycoprotein IIb/IIIa receptor inhibitor tirofiban in patients with acute ischemic stroke but who have no evidence of complete occlusion of large or medium-sized vessels have not been extensively studied. METHODS: In a multicenter trial in China, we enrolled patients with ischemic stroke without occlusion of large or medium-sized vessels and with a National Institutes of Health Stroke Scale score of 5 or more and at least one moderately to severely weak limb. Eligible patients had any of four clinical presentations: ineligible for thrombolysis or thrombectomy and within 24 hours after the patient was last known to be well; progression of stroke symptoms 24 to 96 hours after onset; early neurologic deterioration after thrombolysis; or thrombolysis with no improvement at 4 to 24 hours. Patients were assigned to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg per day, plus intravenous placebo) for 2 days; all patients then received oral aspirin until day 90. The primary efficacy end point was an excellent outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. Secondary end points included functional independence at 90 days and a quality-of-life score. The primary safety end points were death and symptomatic intracranial hemorrhage. RESULTS: A total of 606 patients were assigned to the tirofiban group and 571 to the aspirin group. Most patients had small infarctions that were presumed to be atherosclerotic. The percentage of patients with a score of 0 or 1 on the modified Rankin scale at 90 days was 29.1% with tirofiban and 22.2% with aspirin (adjusted risk ratio, 1.26; 95% confidence interval, 1.04 to 1.53, P = 0.02). Results for secondary end points were generally not consistent with the results of the primary analysis. Mortality was similar in the two groups. The incidence of symptomatic intracranial hemorrhage was 1.0% in the tirofiban group and 0% in the aspirin group. CONCLUSIONS: In this trial involving heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium-sized cerebral vessels, intravenous tirofiban was associated with a greater likelihood of an excellent outcome than low-dose aspirin. Incidences of intracranial hemorrhages were low but slightly higher with tirofiban. (Funded by the National Natural Science Foundation of China; RESCUE BT2 Chinese Clinical Trial Registry number, ChiCTR2000029502.).

Ticagrelor Aspirin vs Clopidogrel Aspirin in CYP2C19 Loss-of-Function Carriers With Minor Stroke or TIA Stratified by Risk Profile.

BACKGROUND AND OBJECTIVE: Genotype data of the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial showed that efficacy of clopidogrel aspirin depended on CYP2C19 genotype and risk profile. A stratification of patients who carried CYP2C19 loss-of-function (LOF) alleles according to the risk of recurrent stroke may be important for selecting optimal antiplatelet therapy. We aimed to compare the efficacy and safety of ticagrelor aspirin with clopidogrel aspirin in CYP2C19 LOF carriers with minor stroke or transient ischemic attack (TIA) stratified by risk profile. METHODS: Data were obtained from Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial. Low-risk and high-risk profiles were defined by Essen Stroke Risk Score (ESRS) (<3 [low risk] and ≥3 [high risk], respectively). RESULTS: A total of 6,412 CYP2C19 LOF carriers were enrolled; ticagrelor aspirin was associated with a reduced risk of primary outcome (new stroke within 90-day follow-up) in patients at low risk (hazard ratio [HR], 0.65; 95% CI, 0.48-0.82), but not in those at high risk (HR, 0.97; 95% CI, 0.73-1.29), compared with clopidogrel aspirin (p = 0.02 for interaction). Secondary outcomes generally went in the same direction as the primary outcome. The primary safety outcome of severe or moderate bleeding did not differ based on risk profile (p = 0.24 for interaction), although the incidence of total bleeding was greater with ticagrelor aspirin than with clopidogrel aspirin among patients at low risk (p < 0.01 for interaction). Analysis in the per-protocol population yielded similar results. DISCUSSION: This post hoc analysis of CHANCE-2 trial showed that CYP2C19 LOF carriers with minor stroke or TIA at low risk of recurrent stroke received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CYP2C19 LOF carriers with minor stroke or TIA at low risk, but not at high risk, of recurrent stroke (by the ESRS) received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin. TRIAL REGISTRATION INFORMATION: URL: www. CLINICALTRIALS: gov. Unique identifier: NCT04078737.

LSTM Attention Neural-Network-Based Signal Detection for Hybrid Modulated Faster-Than-Nyquist Optical Wireless Communications.

In order to improve the accuracy of signal recovery after transmitting over atmospheric turbulence channel, a deep-learning-based signal detection method is proposed for a faster-than-Nyquist (FTN) hybrid modulated optical wireless communication (OWC) system. It takes advantage of the long short-term memory (LSTM) network in the recurrent neural network (RNN) to alleviate the interdependence problem of adjacent symbols. Moreover, an LSTM attention decoder is constructed by employing the attention mechanism, which can alleviate the shortcomings in conventional LSTM. The simulation results show that the bit error rate (BER) performance of the proposed LSTM attention neural network is 1 dB better than that of the back propagation (BP) neural network and outperforms by 2.5 dB when compared with the maximum likelihood sequence estimation (MLSE) detection method.

Platelet-derived growth factor (PDGF) cross-signaling via non-corresponding receptors indicates bypassed signaling in colorectal cancer.

Platelet-derived growth factor (PDGF) signaling, besides other growth factor-mediated signaling pathways like vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), seems to play a crucial role in tumor development and progression. We have recently provided evidence for upregulation of PDGF expression in UICC stage I-IV primary colorectal cancer (CRC) and demonstrated PDGF-mediated induction of PI3K/Akt/mTOR signaling in CRC cell lines. The present study sought to follow up on our previous findings and explore the alternative receptor cross-binding potential of PDGF in CRC. Our analysis of primary human colon tumor samples demonstrated upregulation of the PDGFRß, VEGFR1, and VEGFR2 genes in UICC stage I-III tumors. Immunohistological analysis revealed co-expression of PDGF and its putative cross-binding partners, VEGFR2 and EGFR. We then analyzed several CRC cell lines for PDGFRα, PDGFRß, VEGFR1, and VEGFR2 protein expression and found these receptors to be variably expressed amongst the investigated cell lines. Interestingly, whereas Caco-2 and SW480 cells showed expression of all analyzed receptors, HT29 cells expressed only VEGFR1 and VEGFR2. However, stimulation of HT29 cells with PDGF resulted in upregulation of VEGFR1 and VEGFR2 expression despite the absence of PDGFR expression and mimicked the effect of VEGF stimulation. Moreover, PDGF recovered HT29 cell proliferation under simultaneous treatment with a VEGFR or EGFR inhibitor. Our results provide some of the first evidence for PDGF cross-signaling through alternative receptors in colorectal cancer and support anti-PDGF therapy as a combination strategy alongside VEGF and EGF targeting even in tumors lacking PDGFR expression.

PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner.

Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer and effective treatment regimens are yet to be established. Tyrosine kinase inhibitors (TKI) have widely been used as ccRCC therapeutics, but their efficacy is limited due to accompanying resistance mechanisms. Previous studies have provided substantial evidence for crosstalk between cAMP and the MAPK/ERK signaling pathway. Low levels of intracellular cAMP have been found in several human malignancies and some data suggest that elevation of cAMP expression can be achieved by phosphodiesterase 4 (PDE4) inhibition, resulting in cell growth arrest and/or cell death. The effects of crosstalk between cAMP and the MAPK/ERK pathway on the development progression in ccRCR, however, remain to be fully understood. In this study, we sought to explore the involvement of PDE4 in ccRCC and to assess its potential as a target for therapeutic intervention. We demonstrated that PDE4D is the predominant subtype of PDE4 expressed in healthy and cancerous renal cell lines, particularly in metastatic Caki-1 cells. We generated a CRISPR/Cas9-mediated PDE4D-KO Caki-1 cell model and showed that PDE4D depletion reduced cell proliferation and recovered cAMP expression in these cells. PDE4D-KO and/or PDE4 inhibition with the FDA approved PDE4 inhibitor, roflumilast, also attenuated MAPK/ERK signaling in a CRAF-dependent manner. Most interestingly, we showed that PDE4D-KO enhanced the effectiveness of the TKI, sorafenib, to stunt cell survival. In conclusion, we provide preliminary evidence of PDE4 involvement in ccRCC and suggest a rationale for dual tyrosine kinase/PDE4D targeting in patients with CRAF-dependent MAPK activation.

The antithrombosis effect of dehydroandrographolide succinate: in vitro and in vivo studies.

CONTEXT: Dehydroandrographolide succinate (DAS) is mainly used in the clinical treatment of various infectious diseases. Its potential effects on platelet aggregation and blood coagulation systems have not been reported systematically. OBJECTIVE: To explore whether DAS exerts an antithrombotic effect and its internal mechanism. MATERIALS AND METHODS: Human blood samples and Sprague-Dawley (SD) rats divided into control, aspirin (30 mg/kg), and DAS groups (200, 400 and 600 mg/kg) were used to measure the platelet aggregation rate, coagulation function, coagulation factor activity, and contents of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1α (6-keto-PGF1α). The histopathology of the SD rat gastric mucosa was also observed. All rats were administered intragastric or intraperitoneal injections once a day for 3 consecutive days. RESULTS: Compared to control group, DAS significantly inhibited the platelet aggregation rate (ED50 = 386.9 mg/kg) by decreasing TXB2 levels (1531.95 ± 649.90 pg/mL to 511.08 ± 411.82 pg/mL) and activating antithrombin III (AT-III) (103.22 ± 16.22% to 146.46 ± 8.96%) (p < 0.05). In addition, DAS significantly enhanced the coagulation factors FV (304.12 ± 79.65% to 443.44 ± 75.04%), FVII (324.19 ± 48.03% to 790.66 ± 225.56%), FVIII (524.79 ± 115.47% to 679.92 ± 143.34%), FX (34.90 ± 7.40% to 102.76 ± 29.41%) and FXI (38.12 ± 10.33% to 65.47 ± 34.08%), increased the content of Fg (2.18 ± 0.39 to 3.61 ± 0.37 g/L), shorten the PT (10.42 ± 0.44 to 9.22 ± 0.21 s), APTT (16.43 ± 1.4 to 14.07 ± 0.75 s) and TT time (37.04 ± 2.13 to 32.68 ± 1.29 s) (p < 0.05), while the aspirin group showed no such effect on these items but showed reduced activity of FII (89.21 ± 21.72% to 61.83 ± 8.95%) and FVIII (524.79 ± 115.47% to 306.60 ± 29.96%) (p < 0.05). Histopathological changes showed aspirin-induced gastric mucosa haemorrhage and the protective effect of DAS in the gastric mucosa. CONCLUSIONS: DAS is more suitable than aspirin in thromboprophylaxis treatment, which provides a reliable theoretical and experimental basis for its clinical application.

Macrophage balance fraction determines the degree of immunosuppression and metastatic ability of breast cancer.

Macrophages are important immune cells in the tumor microenvironment and can be divided into two polarized subtypes, M1 and M2. M1 type macrophages have anti-tumor effects, while M2 type macrophages have pro-tumor effect. Most of the current researches are limited to the effect of M1 or M2 macrophages on tumors, while ignoring the overall balance of macrophages. Our research suggests that the macrophage balance fraction (MBF) can more effectively and comprehensively reflect the balance of tumor associated macrophages. Using bioinformatics analysis and in vitro experiments, we found that MBF is also an effective indicator of the degree of immunosuppression and metastatic ability of breast cancer, and different MBF environment can impact the migration and invasion ability of breast cancer cells. Finally, we also found that the mechanism of MBF changes in breast cancer may be affected by breast cancer-derived exosomes. In summary, MBF was proposed and validated as a novel indicator of macrophage balance state. Using this indicator, we found that the balance of macrophages can affect the degree of immunosuppression and metastatic ability of breast cancer.

Drinking water and toilet sanitation of rural schools in Anhui during 2014-2018 / 中国学校卫生

Objective@#To understand current status of drinking water and toilet sanitation in rural schools of Anhui Province, and to provide basic knowledge for environmental sanitation improvement among rural schools in Anhui.@*Methods@#One primary school and one secondary school from each of the 5 villages from 24 counties in Anhui were selected during 2014-2018. Data was collected through information review, on-site inspections and interviews.@*Results@#School water supply methods were mainly based on local water supply from villages and towns, the rate was 58.16%, 58.95%, 65.07%, 62.78%, 67.69% from 2014 to 2018, respectively. Self-supplied water in some schools was initially untreated. The proportion of schools with sanitary toilets was 66.39%, 74.88%，76.26%，82.30%，94.20% during 2014 to 2018, respectively. The proportion of schools with toilets in the teaching building is lower than 30%. Proportions of schools with squatting toilets for girls was highest in 2017 (62.78%). The number of schools with no water faucets and no soap decreased by year, the lowest of 4.02% and 56.70% in 2018.@*Conclusion@#During the past five years, improvement has been observed in drinking water supply in rural schools in Anhui Province, however, the construction of toilets and surrounding environmental facilities still needs to be strengthened. The number of female toilet squats and the number of toilets in the teaching building and in the dormitory are relatively insufficient. While increasing the scale of toilet construction, it is also necessary to strengthen the quality of toilet management, and should pay attention to the relevant health education to teachers and students.

The axis of local cardiac endogenous Klotho-TGF-ß1-Wnt signaling mediates cardiac fibrosis in human.

BACKGROUND: Cardiovascular fibrosis is a major contributor to cardiovascular disease, the primary cause of death in patients with chronic kidney disease (CKD). We previously reported expression of endogenous Klotho in human arteries, and that CKD is a state of Klotho deficiency, resulting in vascular calcification, but myocardial expression of Klotho is poorly understood. This study aimed to further clarify endogenous Klotho's functional roles in cardiac fibrosis in patients with underlying CKD. METHODS AND RESULTS: Human atrial appendage specimens were collected during cardiac surgery from individuals with or without CKD. Cardiac fibrosis was quantified using trichrome staining. For endogenous Klotho functional studies, primary human cardiomyocytes (HCMs) were treated with uremic serum from CKD patients or recombinant human TGF-ß1. The effects of endogenous Klotho in HCMs were studied using Klotho-siRNA and Klotho-plasmid transfection. Both gene and protein expression of endogenous Klotho are found in human heart, but decreased Klotho expression is clearly associated with the degree of cardiac fibrosis in CKD patients. Moreover, we show that endogenous Klotho is expressed by HCMs and cardiac fibroblasts (HCFs) but that HCM expression is suppressed by uremic serum or TGF-ß1. Klotho knockdown or overexpression aggravates or mitigates TGF-ß1-induced fibrosis and canonical Wnt signaling in HCMs, respectively. Furthermore, co-culture of HCMs with HCFs increases TGF-ß1-induced fibrogenic proteins in HCFs, but overexpression of endogenous Klotho in HCMs mitigates this effect, suggesting functional crosstalk between HCMs and HCFs. CONCLUSIONS: Our data from analysis of human hearts as well as functional in vitro studies strongly suggests that the loss of cardiac endogenous Klotho in CKD patients, specifically in cardiomyocytes, facilitates intensified TGF-ß1 signaling which enables more vigorous cardiac fibrosis through upregulated Wnt signaling. Upregulation of endogenous Klotho inhibits pathogenic Wnt/ß-catenin signaling and may offer a novel strategy for prevention and treatment of cardiac fibrosis in CKD patients.

Heterogeneous macrophages: Supersensors of exogenous inducing factors.

As heterogeneous immune cells, macrophages mount effective responses to various internal and external changes during disease progression. Macrophage polarization, rather than macrophage heterogenization, is often used to describe the functional differences between macrophages. While macrophage polarization partially contributes to heterogeneity, it does not completely explain the concept of macrophage heterogeneity. At the same time, there are abundant and sophisticated endogenous and exogenous substances that can affect macrophage heterogeneity. While the research on endogenous factors has been systematically reviewed, the findings on exogenous factors have not been well summarized. Hence, we reviewed the characteristics and inducing factors of heterogeneous macrophages to reveal their functional plasticity as well as their targeting manoeuvreability. In the process of constructing and analysing a network organized by disease-related cells and molecules, paying more attention to heterogeneous macrophages as mediators of this network may help to explore a novel entry point for early prevention of and intervention in disease.

Estimation of the incidence of severe fever with thrombocytopenia syndrome in high endemic areas in China: an inpatient-based retrospective study.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a severe viral disease caused by SFTSV. It is important to estimate the rate of missed SFTS diagnosis and to further understand the actual incidence in high endemic areas in China. METHODS: This study was conducted in two high SFTS endemic provinces in 2015. Patients hospitalized in 2014 or within 1 year before investigation were selected after considering their clinical manifestations, specifically, fever, platelet, and white blood cell. During retrospective investigation, sera were collected to detect SFTSV antibodies to assess SFTSV infection. To further understand SFTSV infection, acute phase sera were detected; SFTSV infection rate among a healthy population was also investigated to determine the basic infection level. RESULTS: In total, 246 hospitalized cases were included, including 83 cases (33.7%) with fever, thrombocytopenia and leukopenia, 38 cases (15.4%) with fever and thrombocytopenia but without leukopenia, and 125 cases (50.8%) without fever but with thrombocytopenia and leukopenia. In total, 13 patients (5.3%) were SFTSV IgM antibody-positive, 48 (19.5%) were IgG-positive. Of the 13 IgM-positive cases, 11 (84.6%) were IgG-positive (9 with titres ≥1:400). Seropositive rates of antibodies were high (8.4% for IgM and 30.1% for IgG) in patients with fever, thrombocytopenia and leukopenia. Furthermore, among IgG-positive cases in this group, 76% (19/25) of patients' IgG antibody titres were ≥1:400. Additionally, 28 of 246 cases were initially diagnosed with suspected SFTS and were then excluded, and 218 patients were never diagnosed with SFTS; the seropositive rates of IgM and IgG in these two groups were 25% and 67.9% and 2.8% and 13.3%, respectively. These rates were 64.3% and 21.4% in 14 sera collected during acute phase of the 28 cases mentioned above. Seropositive rate of SFTSV IgG was only 1.3% in the patient-matched healthy group, and no IgM antibody was detected. A preliminary estimate of 8.3% of SFTS cases were missed in SFTS high endemic provinces. CONCLUSIONS: The actual SFTS incidence was underestimated. Effective measures such as adding a new SFTS case category - "SFTS clinical diagnosis cases" or using serological detection methods during acute phase should be considered to avoid missed diagnoses.

Anti-inflammatory effect of cannabinoid agonist WIN55, 212 on mouse experimental colitis is related to inhibition of p38MAPK.

AIM: To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid (CB) receptors, WIN55-212-2 (WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future. METHODS: We established the colitis model in C57BL/6 mice by replacing the animals' water supply with 4% dextran sulfate sodium (DSS) for 7 consecutive days. A colitis scoring system was used to evaluate the severity of colon local lesion. The plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the myeloperoxidase (MPO) activity in colon tissue were measured. The expressions of cannabinoid receptors, claudin-1 protein, p38 mitogen-activated protein kinase (p38MAPK) and its phosphorylated form (p-p38) in colon tissue were determined by immunohistochemistry and Western blot. In addition, the effect of SB203580 (SB), an inhibitor of p38, was investigated in parallel experiments, and the data were compared with those from intervention groups of WIN55 and SB alone or used together. RESULTS: The results demonstrated that WIN55 or SB treatment alone or together improved the pathological changes in mice with DSS colitis, decreased the plasma levels of TNF-α, and IL-6, and MPO activity in colon. The enhanced expression of claudin-1 and the inhibited expression of p-p38 in colon tissues were found in the WIN55-treated group. Besides, the expression of CB1 and CB2 receptors was enhanced in the colon after the induction of DSS colitis, but reduced when p38MAPK was inhibited. CONCLUSION: These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38MAPK. Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38MAPK signaling pathway and the endogenous CB system.

Suramin inhibits cell proliferation in ovarian and cervical cancer by downregulating heparanase expression.

BACKGROUND: Aberrant expression of heparanase (Hpa) is associated with apoor prognosis in ovarian and cervical cancer patients. Inhibitors of Hpa can prevent the growth and metastasis of malignant tumor cells, and suramin may be such a compound that has strong anti-proliferative effects on several kinds of cancer cells. We have therefore tested whether the growth inhibiting effect of suramin on ovarian and cervical cancer cells is due to downregulation of Hpa expression. RESULTS: Suramin at 300-600 µg/ml significantly inhibited HO-8910 PM and HeLa cell growth at 24 h, in both a time-dependent and dose-dependent manner, with an IC50 of 320 µg/ml and 475 µg/ml, respectively. Suramin at 300 µg/ml significantly decreased the expression of Hpa mRNA (P < 0.005) and protein (P < 0.005) in both HO-8910 PM and HeLa cells at 48 h. CONCLUSIONS: The inhibitory effect of suramin on Hpa enzyme may be due to downregulating of its expression in cancer cells. These findings confirm the importance of Hpa in tumor growth and the potential clinical application of Hpa inhibitors in the treatment of ovarian and cervical cancer.

p38 MAPK inhibition alleviates experimental acute pancreatitis in mice.

BACKGROUND: The mitogen-activated protein kinases (MAPKs) signaling pathway is involved in inflammatory process. However, the mechanism is not clear. The present study was to investigate the role of p38 MAPK in acute pancreatitis in mice. METHODS: Mice were divided into 4 groups: saline control; acute pancreatitis induced with repeated injections of cerulein; control plus p38 MAPK inhibitor SB203580; and acute pancreatitis plus SB203580. The pancreatic histology, pancreatic enzymes, cytokines, myeloperoxidase activity, p38 MAPK and heat shock protein (HSP) 60 and 70 were evaluated. RESULTS: Repeated injections of cerulein resulted in acute pancreatitis in mice, accompanying with the activation of p38 MAPK and overexpression of HSP60 and HSP70 in the pancreatic tissues. Treatment with SB203580 significantly inhibited the activation of p38 MAPK, and furthermore, inhibited the expression of HSP60 and HSP70 in the pancreas, the inflammatory cytokines in the serum, and myeloperoxidase activity in the lung. CONCLUSION: The p38 MAPK signaling pathway is involved in the regulation of inflammatory response and the expression of HSP60 and HSP70 in acute pancreatitis.

Bandpass sampling based digital coherent receiver with free-running local oscillator laser for phase-modulated radio-over-fiber links.

A bandpass sampling based digital coherent receiver is presented for phase modulated radio-over-fiber links with coherent detection. In the scheme, the bandpass sampling technique is introduced in RoF systems to overcome the high sampling rate requirement and front-end hardware dependency of conventional digtal coherent receivers. In particular, the selection rule of bandpass sampling rate was defined by taking into account the frequency offset induced by free-running optical local oscillator. Analytical assessment and simulations are used to determine the ultimate performance in terms of tolerances to ADC bit resolution and laser linewidth. Thereafter, a 40Mbps QPSK modulated data signal at 2.4GHz RF carrier frequency is experimentally demonstrated over the proposed 50.6-km radio-over-fiber link employing bandpass sampling.

Rural residents in China are at increased risk of exposure to tick-borne pathogens Anaplasma phagocytophilum and Ehrlichia chaffeensis.

As emerging tick born rickettsial diseases caused by A. phagocytophilum and E. chaffeensis, anaplasmosis and ehrlichiosis have become a serious threat to human and animal health throughout the world. In particular, in China, an unusual transmission of nosocomial cases of human granulocytic anaplasmosis occurred in Anhui Province in 2006 and more recent coinfection case of A. phagocytophilum and E. chaffeensis was documented in Shandong Province. Although the seroprevalence of human granulocytic anaplasmosis (former human granulocytic ehrlichiosis, HGE) has been documented in several studies, these data existed on local investigations, and also little data was reported on the seroprevalence of human monocytic ehrlichiosis (HME) in China. In this cross-sectional epidemiological study, indirect immunofluorescence antibody assay (IFA) proposed by WHO was used to detect A. phagocytophilum and E. chaffeensis IgG antibodies for 7,322 serum samples from agrarian residents from 9 provinces/cities and 819 urban residents from 2 provinces. Our data showed that farmers were at substantially increased risk of exposure. However, even among urban residents, risk was considerable. Seroprevalence of HGA and HME occurred in diverse regions of the country and tended to be the highest in young adults. Many species of ticks were confirmed carrying A. phagocytophilum organisms in China while several kinds of domestic animals including dog, goats, sheep, cattle, horse, wild rabbit, and some small wild rodents were proposed to be the reservoir hosts of A. phagocytophilum. The broad distribution of vector and hosts of the A. phagocytophilum and E. chaffeensis, especially the relationship between the generalized susceptibility of vectors and reservoirs and the severity of the disease's clinical manifestations and the genetic variation of Chinese HGA isolates in China, is urgently needed to be further investigated.

Association between 1019C/T polymorphism in the connexin 37 gene and essential hypertension.

OBJECTIVE: To investigate the association between the CX 37 1019C/T polymorphism and the susceptibility to essential hypertension (EH). METHODS: A total of 1126 cases of EH were diagnosed in the People's Hospital of Wuxi City, China. A control group consisted of 874 healthy people, i.e., non-EH patients. All cases were genotyped by DNA sequencing. RESULTS: Polymorphism C1019T on the Connexin37 gene was found in the whole population. The distribution of three genotype frequencies in both groups was in accordance with the Hardy-Weinberg equilibrium. The frequency of the CX37C allele was higher in EH patients (57.4% vs. 42.1%, χ(2)=92.5, P<0.01) compared to the control group. The frequency of C carriers (CC+TC) was 80.5% in EH patients compared to 66.7% in the control (χ(2)=49.0, P<0.01). EH risk was significantly increased in carriers of C the allele (CC+TC) over that in the TT homozygote (OR=2.06, 95% CI: 1.68 ∼ 2.52). Subsequent stratified analyses demonstrate that a significant difference exists in the frequency of C carriers between male EH patients and controls (79.2% vs. 69.1%, χ(2)=13.4, P<0.01) and in female EH patients and the control group (81.8% vs. 64.4%, χ(2)=38.7, P<0.01). The carriers of the C allele had higher EH risk compared with the TT homozygote without sex differences (male: OR=1.71, 95% CI: 1.28 ∼ 2.27; female: OR=2.48, 95%CI: 1.85 ∼ 3.31). CONCLUSION: The C allele in the CX37 gene might be associated with the susceptibility to EH in population of Wuxi, China.

The dual effect of cannabinoid receptor-1 deficiency on the murine postoperative ileus.

INTRODUCTION: Intestinal inflammatory responses play a critical role in the pathogenesis of postoperative ileus (POI). As cannabinoid receptor-1 (CB1) is involved in inhibiting gastrointestinal (GI) motility and anti-inflammation, we aimed to explore its contribution to POI. METHODS: Experimental POI was induced in adult female CB1-deficient (CB1-/-) mice and wild-type littermates (C57BL/6N) by standardized small bowel manipulation. Twenty-four hours after surgery, GI transit was assessed by charcoal transport. FITC avidin, F4/80, and myeloperoxidase immunohistochemistry techniques were used to evaluate the inflammatory response in the muscularis of ileum and colon. Expressions of p38MAPK and its phosphorylated form (pp38) in the intestine were determined. Plasma levels of proinflammatory cytokines and chemokines were measured by ELISA as well. RESULTS: POI was characterized by decreased GI transit (p<0.01) and accompanied by a marked intestinal and systematic inflammatory response in wild-type and CB1-/- mice. Increased numbers of inflammatory cells, including macrophages, neutrophils, and mast cells were observed in the muscularis of ileum and colon (p<0.01, or p<0.05). Plasma levels of interleukin-6 (IL-6), cytokine-induced neutrophil chemoattractant-1 (CINC-1/KC), and monocyte chemoattractant protein-1 (MCP-1) were elevated (p<0.01, or p<0.05). Expression of p38 and pp38 increased in the intestine (p<0.01, or p<0.05). CB1-/- mice showed an increased inflammatory response during POI, especially the systemic inflammatory markers, such as IL-6, KC, CINC1, and pp38 expression were increased as compared to those in WT mice (p<0.05). CONCLUSIONS: Intestinal motility was inhibited during POI. In this condition, inhibition of motility did not seem to be altered by the absence of CB1 receptors, however, an increased inflammatory response was observed in CB1-/- mice. Hence, CB1 receptor activation rather than inhibition may reduce the inflammatory response in POI, which has a remote potential to relate into reduced inhibition of intestinal motility during POI.

Inhibiting roles of berberine in gut movement of rodents are related to activation of the endogenous opioid system.

Although Berberine (BER) is popular in treating gastrointestinal (GI) disorders, its mechanisms are not clear yet. In order to investigate the effects and possible mechanism of BER on GI motility in rodents, we first explored GI motility by recording the myoelectrical activity of jejunum and colon in rats, and upper GI transit with a charcoal marker in mice. Then, the plasma levels of gastrin, motilin, somatostatin and glucagon-like-peptide-1 (Glp-1) were measured by ELISA or radioimmunoassay (RIA). Furthermore, endogenous opioid-peptides (ß-endorphin, dynorphin-A, met-enkephalin) were detected by RIA after treatment with BER. Our results showed that BER concentration-dependently inhibited myoelectrical activity and GI transit, which can be antagonized by opioid-receptor antagonists to different extents. The elevated somatostatin and Glp-1, and decreased gastrin and motilin in plasma, which were caused by BER application, also could be antagonized by the opioid-receptor antagonists. Additionally, plasma level of ß-endorphin, but not dynorphin-A and met-enkephalin, was increased by applying BER. Taken together, these studies show that BER plays inhibiting roles on GI motility and up-regulating roles on somatostatin, Glp-1 and down-regulating roles on gastrin, motilin. The pharmacological mechanisms of BER on GI motility and plasma levels of GI hormones were discovered to be closely related to endogenous opioid system.