The global epidemiology of upper and lower gastrointestinal bleeding in general population:A systematic review

BACKGROUND Gastrointestinal bleeding(GIB)is a common and potentially life-threatening clinical event.To date,the literature on the long-term global epidemiology of GIB has not been systematically reviewed.AIM To systematically review the published literature on the worldwide epidemiology of upper and lower GIB.METHODS EMBASE®and MEDLINE were queried from 01 January 1965 to September 17,2019 to identify population-based studies reporting incidence,mortality,or casefatality rates of upper GIB(UGIB)or lower GIB(LGIB)in the general adult population,worldwide.Relevant outcome data were extracted and summarized(including data on rebleeding following initial occurrence of GIB when available).All included studies were assessed for risk of bias based upon reporting guidelines.RESULTS Of 4203 retrieved database hits,41 studies were included,comprising a total of around 4.1 million patients with GIB worldwide from 1980–2012.Thirty-three studies reported rates for UGIB,four for LGIB,and four presented data on both.Incidence rates ranged from 15.0 to 172.0/100000 person-years for UGIB,and from 20.5 to 87.0/100000 person-years for LGIB.Thirteen studies reported on temporal trends,generally showing an overall decline in UGIB incidence over time,although a slight increase between 2003 and 2005 followed by a decline was shown in 5/13 studies.GIB-related mortality data were available from six studies for UGIB,with rates ranging from 0.9 to 9.8/100000 person-years,and from three studies for LGIB,with rates ranging from 0.8 to 3.5/100000 person-years.Casefatality rate ranged from 0.7%to 4.8%for UGIB and 0.5%to 8.0%for LGIB.Rates of rebleeding ranged from 7.3%to 32.5%for UGIB and from 6.7%to 13.5%for LGIB.Two main areas of potential bias were the differences in the operational GIB definition used and inadequate information on how missing data were handled.CONCLUSION Wide variation was seen in estimates of GIB epidemiology,likely due to high heterogeneity between studies however,UGIB showed a decreasing trend over the years.Epidemiological data were more widely available for UGIB than for LGIB.

The new kid on the block in insect pest management:sprayable RNAi goes commercial

Insect pest damage to crops is a threat to global food security(Tilman et al.,2011).Climate change,the evolution of insecticide resistance,and the phasing out of insecticides due to environmental and safety concerns exacerbate this problem.Farmers urgently need safe and effective crop protection tools to sustainably generate yields that meet ever-increasing global demand.

从天然提取物或分离部位中以碳酸酐酶II为靶点的抗骨质疏松活性筛选(英文)

目的是以碳酸酐酶II (CAII)为靶点筛选其抑制剂 ,以期寻找抗骨质疏松活性样品。实验是在 96孔酶标板上对来源于 1 78个科、 60 8个属、 1 0 2 0种动植物 2 91 9个提取物或分离部位样品在CA II模型上进行了批量筛选。结果表明在 1 0 μg ml浓度下发现了来源于 40个科、61个属、72个种的 1 0 0个样品有活性 ,其中 5个样品的IC50 小于 2 50 μg ml,2 2个样品的IC50 在 2 51～ 5 0 0 μg ml范围 ,73个样品的IC50 在 5 0 1～1 0 0 0 μg ml范围。通过以上工作我们认为以碳酸酐酶II为分子靶点的体外筛选方法稳定、方便、快速、微量、有效 ,特别适用于天然产物的抗骨质疏松活性筛选。

基于极值概率分布函数的中国早稻高温热害时空分布统计特征

揭示水稻高温热害风险特征对农业适应气候变化具有重要意义。本研究以中国早稻种植区为研究区域,基于早稻种植区214个气象站1971—2015年的数据,利用Mann-Kendall非参数趋势检验方法和极值概率分布理论,探究中国早稻高温热害的时空变化趋势和极值概率分布规律。研究发现:1)反映早稻高温热害的两个指标即高温热害累计天数(ADHS,accumulateddaysofheatstress)和热害有害积温(HDD,heatstressdegree days)的均值在湖南中南部、江西中部、浙江和福建中部较大,表明这些区域的早稻遭受高温热害的风险较大;从Mann-Kenall趋势检验看,两个指标在超过1/3的站点都呈显著增加的趋势,说明高温热害风险在这些站点显著增加,尤其20世纪90年代以后超过1/2的站点两个指标都呈显著增加的趋势。2)超过1/2以上的站点的高温热害累计天数和高温有害积温都满足极值概率函数分布。对于高温热害累计天数,56个站点满足耿贝尔分布(Gumbel),82个站点满足广义极值分布(GEV);对于热害有害积温,61个站点满足耿贝尔分布,58个站点满足广义极值分布。3)两个高温热害指标的10年、50年、100年重现期的空间分布规律和2个指标的均值空间分布类似,即均值较大的区域,其10年、50年、100年重现期对应的重现期水平(return level)也较大;重现期水平与经度、纬度和海拔无明显相关关系。研究结果有助提升对早稻高温热害时空趋势和概率分布规律的认识,可为农业适应气候变化和农业天气指数保险设计等方面提供理论参考。

从天然提取物或分离部位中以烯醇式丙酮酸转移酶为靶点的抗细菌活性筛选(英文)

目的是以烯醇式丙酮酸转移酶 (EPT)为靶点筛选其抑制剂 ,以期寻找抗细菌活性样品。实验是在 96孔酶标板上对来源于 16 9个科、 5 6 0个属、 916种动植物 2 4 90个提取物或分离部位样品在EPT模型上进行了批量筛选。结果表明在 96 15 μg/ml浓度下发现了来源于 80个科、 16 9个属、 2 18个种的 30 9个样品有活性 ,其中 14个样品的IC50 小于 10 0 0 μg/ml,4 0个样品的IC50 在 10 0 1～ 30 0 0 μg/ml范围 ,83个样品的IC50 在 30 0 1～ 5 0 0 0 μg/ml范围 ,172个样品的IC50 在 5 0 0 1～ 96 15 μg/ml范围。通过以上工作我们认为以烯醇式丙酮酸转移酶为分子靶点的体外筛选方法稳定、方便、快速、微量、有效 。

Biomarkers for hepatocellular carcinoma: What's new on the horizon?

Treatment of advanced hepatocellular carcinoma remains unsatisfying and so far only prognostic biomarkers like α-fetoprotein have been established. No clear predictive biomarker is currently available for standard of care therapies, including targeted therapies like sorafenib. Novel therapeutic options like immune checkpoint inhibitors may pose new challenges to identification and validation of such markers. Currently, PD-L1 expression via immunohistochemistry and tumor mutational burden via next-generation sequencing are explored as predictive biomarkers for these novel treatments. Limited tissue availability due to lack of biopsies still restricts the use of tissue based approaches. Novel methods exploring circulating or cell free nucleic acids(DNA, RNA or miRNAcontaining exosomes) could provide a new opportunity to establish predictive biomarkers. Epigenetic profiling and next-generation sequencing approaches from liquid biopsies are under development. Sample size, etiologic and geographical background need to be carefully addressed in such studies to achieve meaningful results that could be translated into clinical practice. Proteomics, metabolomics and molecular imaging are further emerging technologies.

Hepatocellular carcinoma: Therapeutic advances in signaling,epigenetic and immune targets

Hepatocellular carcinoma(HCC)remains a global medical burden with rising incidence due to chronic viral hepatitis and non-alcoholic fatty liver diseases.Treatment of advanced disease stages is still unsatisfying.Besides first and second generation tyrosine kinase inhibitors,immune checkpoint inhibitors have become central for the treatment of HCC.New modalities like epigenetic therapy using histone deacetylase inhibitors(HDACi)and cell therapy approaches with chimeric antigen receptor T cells(CAR-T cells)are currently under investigation in clinical trials.Development of such novel drugs is closely linked to the availability and improvement of novel preclinical and animal models and the identification of predictive biomarkers.The current status of treatment options for advanced HCC,emerging novel therapeutic approaches and different preclinical models for HCC drug discovery and development are reviewed here.

Influence of solvent mixtures on HPMCAS-celecoxib microparticles prepared by electrospraying

Hypromellose acetate succinate(HPMCAS) microparticles containing the poorly-water soluble drug celecoxib(CEL) were prepared by electrospraying intended for oral drug delivery. Various solvent mixtures with different solubility for CEL and HPMCAS were used to induce changes in the polymer structural conformation of the microparticles. The performance of the prepared microparticles was evaluated by studying the solid state from, particle size and morphology, radial drug distribution and drug release. CEL was amorphous in all electrosprayed HPMCAS microparticles. The particle size and morphology was dependent on the solubility of HPMCAS in the solvent mixture used with poorer solvents resulting in smaller microparticles with rougher appearance. The CEL distribution on the particles surface was relatively homogeneous and similar for all microparticles. Drug release from the microparticles was observed at a higher rate depending on the solubility of HPMCAS in the solvent used for electrospraying, and in all cases an at least 4-fold higher rate was observed compared with the crystalline drug. Drug precipitation from the supersaturated solution was inhibited by HPMCAS for all microparticles based on its parachute effect while crystalline CEL did not reach supersaturation. This study demonstrated that electrospraying can be used to produce microparticles with tailored properties for pharmaceutical application by adjusting solvent selection.

高血压急症的治疗——钙离子拮抗剂尼群地平的一种新剂型与心痛定胶囊的比较

现已开发迅速发挥作用的尼群地平新型口服制剂,其包装为塑料小瓶,内含1ml乙醇溶液和5mg尼群地平。 本研究的目的在于观察尼群地平新剂型在高血压急症中的降压作用。用心痛定(10mg的胶囊)作对照,其对高血压急症的降压作用和剂量业已得到充分肯定。 由德国23个研究中心进行随机、双盲、平行分组比较。

Epigenetics and pancreatic cancer:Pathophysiology and novel treatment aspects

An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16ink4a, are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.

Aspirin plus Pseudoephedrine (Aspirin Complex) for the Treatment of Symptoms of Upper Respiratory Tract Infection

Upper respiratory tract infections or common colds are a multi-symptom disease which is usually symptomatically treated with fixed dose multi-active ingredient medicinal products which are commonly used as non-prescription and over the counter. However, the active ingredients combined require a particular and clinically sound justification. Analgesics and decongestant can be combined to treat simultaneously the prominent symptoms cold-related pain (e.g. headache, muscle aches and pains), fever, inflammationand nasal/sinus congestion. This overview provides a summary of the evidence supporting the combination of acetylsalicylic acid (aspirin) and pseudoephedrine available in the common cold product Aspirin? Complex.

具有芳香气味的皮革

皮革制造商在未来不仅应有能力提供手感好、外表美观的产品,而且还应有能力提供一些具有适量的长效香味的产品。最新的技术已经可以将香水微滴(1～10um)封装在聚氨酯微胶囊中,并且应用到皮革上,当皮革受到机械应变,就可释放出芳香气味。与直接喷涂香水技术只能在有限时间内发挥作用相比,利用聚氨酯微胶囊封装香水技术,就可获得长效持久的芳香效果。

全球化学品管理战略:机遇和风险

由以往和化学品安全相关的国际活动发展而来的国际化学品管理战略(SAICM)得到了联合国环境署(UNEP)理事会的支持.全球化学品行业认为SAICM应该被作为实现世界可持续发展首脑会议议定目标的路线图.全球在化学品安全使用问题上的不断进步将要求生产者、销售者、使用者、政府和其他利益相关方在生产链各有关环节责任分担的基础上采取共同协调的行动.从这个意义上说,制定一个全球战略提供了通过建立新的伙伴关系来实现化学品安全的机会.但是,如果SAICM成为国家、地区和国际层面附加的更严格的调控手段的基础,则其可能达不到期望的影响.

Risk factors for major gastrointestinal bleeding in the general population in Finland

BACKGROUND Data on non-drug related risk-factors for gastrointestinal bleeding(GIB)in the general population are limited,especially for life-style factors,clinical measurements and laboratory parameters.AIM To identify and investigate non-drug risk factors for major GIB in the general population of Finland.METHODS We performed a retrospective cohort study using data from the FINRISK health examination surveys,which have been conducted every 5 years across Finland from 1987 to 2007.Participants were adults aged 25 years to 74 years,excluding those with a previous hospitalization for GIB.Follow-up from enrollment was performed through linkage to national electronic health registers and ended at an event of GIB that led to hospitalization/death,death due to any other cause,or after 10 years.Covariates included demographics,socioeconomic and lifestyle factors,clinical measurements,laboratory parameters and comorbidities.Variable selection was undertaken using Least Absolute Shrinkage and Selection Operator(LASSO)and factors associated with GIB were identified using Cox regression.RESULTS Among 33,508 participants,403(1.2%)experienced GIB[256 men(63.5%);mean age,56.0 years(standard deviation(SD)±12.1)]and 33105 who did not experience GIB[15768 men(47.6%);mean age,46.8(SD±13)years],within 10 years of follow-up.Factors associated with a significantly increased risk of GIB were baseline age[per 10-year increase;hazard ratio(HR)1.62,95%confidence interval(CI):1.42-1.86],unemployment(HR:1.70,95%CI:1.11-2.59),body mass index(BMI)(HR:1.15,95%CI:1.01-1.32),gamma-glutamyl transferase(GGT)(HR:1.05,95%CI:1.02-1.09),precursors of GIB(HR:1.90,95%CI:1.37-2.63),cancer(HR:1.47,95%CI:1.10-1.97),psychiatric disorders(HR:1.32,95%CI:1.01-1.71),heart failure(HR:1.46,95%CI:1.04-2.05),and liver disorders(HR:3.20,95%CI:2.06-4.97).Factors associated with a significantly decreased risk of GIB were systolic blood pressure(SBP)(HR:0.78,95%CI:0.64-0.96),6-10 cups of coffee a day(HR:0.67,95%CI:0.46-0.99),or>10 cups(HR:0.43,95%CI:0.23-0.81).CONCLUSION Our study confirms established risk-factors for GIB and identifies potential risk-factors not previously reported such as unemployment,BMI,GGT,SBP and coffee consumption.

A drospirenone-containing oral contraceptive improved bleeding pattern and personal satisfaction in 914 women from Jordan, Lebanon and Syria

Aim: We assessed bleeding pattern, tolerance and patient satisfaction of an oral contraceptive containing 3 mg drospirenone and 30 mcg ethinyl estradiol (DRSP/EE) under real-life conditions. Study Design: We performed a multicenter, prospective, 6-cycle, observational study in Canada, Europe and the Middle East. Detailed analyses of the three Middle East countries, Jordan, Lebanon andSyriawere presented here. The efficacy variables included an assessment of bleeding patterns, premenstrual symptoms of water retention and patient satisfaction, as determined by a visual analogue scale. Results: A total of 914 women were enrolled. The percentage of women with intermenstrual bleeding decreased from 37.4%, 48.7% and 32.2% at baseline to 9.7%, 6.1% and 10.9% at the end of cycle6 inJordan, Lebanon and Syria, respectively (creased sharply in all three countries (p Amenorrhea decreased significantly in Lebanon and Syria (p < 0.005). In addition, signs of water retention like abdominal bloating, breast tenderness and swelling of extremities decreased significantly over the course of 6 treatment cycles (p < 0.001). Patient satisfaction increased for all investigated items. Upon completion of the study, 82.7% of women answered “Yes” to continue treatment with this oral contraceptive. Conclusion: The oral contraceptive containing 3 mg drospirenone and 30 mcg ethinyl estradiol has beneficial effects on bleeding pattern, symptoms of water retention and patient satisfaction.

全球化学品管理战略:机遇和风险

由以往和化学品安全相关的国际活动发展而来的国际化学品管理战略(SAICM)得到了联合国环境署(UNEP)理事会的支持.全球化学品行业认为SAICM应该被作为实现世界可持续发展首脑会议议定目标的路线图.全球在化学品安全使用问题上的不断进步将要求生产者、销售者、使用者、政府和其他利益相关方在生产链各有关环节责任分担的基础上采取共同协调的行动.从这个意义上说,制定一个全球战略提供了通过建立新的伙伴关系来实现化学品安全的机会.但是,如果SAICM成为国家、地区和国际层面附加的更严格的调控手段的基础,则其可能达不到期望的影响.

Evidence of active oviposition avoidance to systemically applied imidacloprid in the Colorado potato beetle

Agricultural pests can develop behavioral resistance to insecticides by choosing to feed or oviposit on insecticide-free hosts.As young larvae have relatively low mobility,oviposition preferences from female adults may play a critical role in shaping the evolu-tionary trajectory of pest populations.While oviposition avoidance of insecticide-treated hosts was found in different agriculture pests,it remains unclear whether female adults actively choose to occupy insecticide-free hosts.To address this question,we investigated feeding and oviposition preferences between imidacloprid-treated and imidacloprid-free plants in the Colorado potato beetle,Leptinotarsa decemlineata Say,a major potato pest.We performed behavioral choice assays on two strains that differed in both fecundity and insecticide resistance.We found that one strain preferred to feed on the insecticide-free plants and that this preference is not innate.Meanwhile,the other strain chose plants for feeding and oviposition randomly.Further analyses of the moving patterns of the beetles suggested that the oviposition preference in the first strain is likely due to active learning.

Chimeric protein probes for C5a receptors through fusion of the anaphylatoxin C5a core region with a small-molecule antagonist

Blockade of the interaction of anaphylatoxin C5a with its receptor C5aR1 has been actively studied as a potential treatment for many inflammatory diseases;but current C5a antagonists exhibit inadequate potency and poor species cross-reactivity, and novel biochemical tools are needed to investigate whether the core region of C5a contains important interaction epitopes that can explain these limitations. Herein, we report the development of chimeric protein C5a probes containing both the complete core region of rat or human C5a, and the small-molecule antagonist PMX53-1. These probes were chemically synthesized through hydrazide-based native chemical ligation of a linear peptide hydrazide with the requisite cyclopeptidic antagonist, both of which were made by solid-phase synthesis. Quasi-racemic X-ray crystallography established that attachment of PMX53-1 did not affect the structure of the core region of C5a. Subsequent C5aR1 activity assays demonstrated the probes can provide valuable insights into the development of C5a antagonists;for example, they exhibited significantly better binding affinity and much improved species cross-reactivity than PMX53-1, supporting the notion that the effect of some epitopes outside the C-terminus of C5a should be taken into consideration when designing better C5a antagonists. Surprisingly, the core region of C5a was found to partially agonize C5aR1, suggesting the presence of more than one agonistic interaction in the binding of C5a to C5aR1. This study exemplifies the value of chemical protein synthesis in developing novel receptor probes for drug discovery research.

Resistance to anti-tubulin agents:From vinca alkaloids to epothilones

This review describes the mechanism of action-inhibition of microtubules-and the most important mechanisms of resistance for vinca alkaloids,taxanes and epothilones.Resistance is a major problem in vinca and taxane chemotherapy and arises in most cases from overexpression of efflux pumps that transport the drugs out of the cancer cells and from modifications of the target,the microtubules,by overexpression of tubulin isotypes or by attachment of proteins to the ends of the microtubules so that the target is no longer recognized by the drugs.In some cases,however,this process can have the opposite effect,leading to sensitization,e.g.,for vinca alkaloids in cases where taxanes are not or no longer effective.The link between resistance due to efflux pumps and the pharmacokinetics and metabolism of the drugs is also covered.Other types of resistance that are addressed include detoxification of drugs within the cancer cell and blockade of apoptosis,post-translational modifications of microtubules and other protein pathways,micro-RNAs,induction of oncogenes,and cancer stem cells,which,taken together,offer particularly multifold possibilities for preventing drug activity.The use of biomarkers for the prediction of clinical outcome and for the direction of future therapy is also addressed.

Ultrasmall,elementary and highly translational nanoparticle X-ray contrast media from amphiphilic iodinated statistical copolymers

To expand the single-dose duration over which noninvasive clinical and preclinical cancer imaging can be conducted with high sensitivity,and well-defined spatial and temporal resolutions,a facile strategy to prepare ultrasmall nanoparticulate X-ray contrast media(nano-XRCM)as dual-modality imaging agents for positron emission tomography(PET)and computed tomography(CT)has been established.Synthesized from controlled copolymerization of triiodobenzoyl ethyl acrylate and oligo(ethylene oxide)acrylate monomers,the amphiphilic statistical iodocopolymers(ICPs)could directly dissolve in water to afford thermodynamically stable solutions with high aqueous iodine concentrations(>140 mg iodine/mL water)and comparable viscosities to conventional small molecule XRCM.The formation of ultrasmall iodinated nanoparticles with hydrodynamic diameters of ca.10 nm in water was confirmed by dynamic and static light scattering techniques.In a breast cancer mouse model,in vivo biodistribution studies revealed that the64Cu-chelator-functionalized iodinated nano-XRCM exhibited extended blood residency and higher tumor accumulation compared to typical small molecule imaging agents.PET/CT imaging of tumor over 3 days showed good correlation between PET and CT signals,while CT imaging allowed continuous observation of tumor retention even after 10 days post-injection,enabling longitudinal monitoring of tumor retention for imaging or potentially therapeutic effect after a single administration of nano-XRCM.