促进糖尿病患者足溃疡愈合的干预措施指南(2023年更新版)——《国际糖尿病足工作组:糖尿病相关的足病预防与管理指南(2023)》的一部分

创面处理的原则,包括清创、创面准备和使用涉及改变创面生理以促进愈合的新技术,在试图治愈慢性糖尿病相关的足溃疡时是至关重要的。此外,糖尿病相关的足溃疡的发病率和治疗成本不断上升,这就需要结合作为金标准的多学科治疗已有共识,运用高质量的疗效和成本效益证据来支持和加强慢性糖尿病相关的足溃疡创面愈合的干预措施。本指南是2023年国际糖尿病足工作组(IWGDF)针对促进糖尿病患者足溃疡愈合的干预措施的循证指南。它是对2019年IWGDF指南的更新。我们遵循推荐、评估、发展、评价分级(GRADE)方法,以患者-干预-对照-结果(PICO)形式设计临床问题从而得出重要结果,进行系统综述,制定评判表汇总,并为每个问题撰写推荐和理由。每条推荐的形式都是基于系统综述中发现的证据,并使用GRADE评判汇总项目,包括理想和不理想的效果、证据的可信度、对患者的价值、所需的资源、成本效益、公平性、可行性和可接受性;我们制定的推荐由作者同意并由独立专家和利益相关者审查。根据系统综述和从证据到决策过程的结果,我们提出29条推荐。我们对使用干预措施改善糖尿病患者足溃疡的愈合提出了一些有条件的支持性推荐。这些推荐包括蔗糖八硫酸盐敷料的使用,对手术后的创面使用负压疗法,使用胎盘衍生产品,使用自体白细胞、血小板、纤维蛋白贴剂,使用局部氧疗,以及使用高压氧,但我们强调在任何情况下这些推荐应在单独应用最佳标准治疗无法治愈伤口且有资源可用于干预的情况下使用。这些关于创面愈合的推荐应该有助于提高糖尿病伴足溃疡患者的疗效,我们希望这些推荐能得到广泛的实施。然而,尽管作为推荐基础的许多证据的准确性正在提高,但总体上仍然很差,我们鼓励在这一领域进行更多、质量更好的试验,包括那些有关卫生经济学分析的试验。

Do tensile and shear forces exerted on cells influence mechanotransduction through stored energy considerations?

All tissues in the body are subjected externally to gravity and internally by collagenfibril and cellular retractive forces that create stress and energy equilibrium required for homeostasis.Mechanotransduction involves mechanical work(force through a distance)and energy storage as kinetic and potential energy.This leads to changes in cell mitosis or apoptosis and the synthesis or loss of tissue components.It involves the application of energy directly to cells through integrin-mediated processes,cell-cell connections,stretching of the cell cytoplasm,and activation of the cell nucleus via yes-associated protein(YAP)and transcriptional coactivator with PDZ-motif(TAZ).These processes involve numerous complexes,intermediate molecules,and multiple pathways.Several pathways have been identified from research studies on vertebrate cell culture and from studies in invertebrates.These pathways involve mechanosensors and other molecules that activate the pathways.This review discusses the mitogen-activated protein kinase(MAPK)family,Hippo,Hedgehog,and Wingless-related integration site(WNT)/βcatenin signaling pathways.The mediators covered includeβcatenin,ion channels,growth factors,hormone receptors,members of the Ras superfamily,and components of the linker of nucleoskeleton and cytoskeleton(LINC)complex.However,the interrelationship among the different pathways remains to be clarified.Integrin-mediated mechanotransduction involves direct tensile loading and energy applied to the cell membrane via collagenfibril stretching.This energy is transferred between cells by stretching the cell-cell connections involving cadherins and the WNT/βcatenin pathway.These alterations induce changes in intracellular events in the cytoskeleton and nuclear skeleton caused by the release of YAP and TAZ.These coactivators then penetrate through the nuclear pores and influence nuclear cell function.Alteration in the balance of forces and energy applied to cells and tissues is hypothesized to shift the cell-extracellular matrix mechanical equilibrium by modifying mechanotransduction.The shift in equilibrium can lead to either tissue synthesis,genetic modifications,or promotefibrotic diseases,including epithelial cell-derived cancers,depending on the local metabolic conditions.

Improvement of hepatic fibrosis after tenofovir disoproxil fumarate switching to tenofovir alafenamide for three years

BACKGROUND Both tenofovir alafenamide(TAF)and tenofovir disoproxil fumarate(TDF)are the first-line treatments for chronic hepatitis B(CHB).We have showed switching from TDF to TAF for 96 weeks resulted in further alanine aminotransferase(ALT)improvement,but data remain lacking on the long-term benefits of TDF switching to TAF on hepatic fibrosis.AIM To assess the benefits of TDF switching to TAF for 3 years on ALT,aspartate aminotransferase(AST),and hepatic fibrosis improvement in patients with CHB.METHODS A single center retrospective study on 53 patients with CHB who were initially treated with TDF,then switched to TAF to determine dynamic patterns of ALT,AST,AST to platelet ratio index(APRI),fibrosis-4(FIB-4)scores,and shear wave elastography(SWE)reading improvement at switching week 144,and the associated factors.RESULTS The mean age was 55(28-80);45.3%,males;15.1%,clinical cirrhosis;mean baseline ALT,24.8;AST,25.7 U/L;APRI,0.37;and FIB-4,1.66.After 144 weeks TDF switching to TAF,mean ALT and AST were reduced to 19.7 and 21,respectively.From baseline to switching week 144,the rates of ALT and AST<35(male)/25(female)and<30(male)/19(female)were persistently increased;hepatic fibrosis was also improved by APRI<0.5,from 79.2%to 96.2%;FIB-4<1.45,from 52.8%to 58.5%,respectively;mean APRI was reduced to 0.27;FIB-4,to 1.38;and mean SWE reading,from 7.05 to 6.30 kPa after a mean of 109 weeks switching.The renal function was stable and the frequency of patients with glomerular filtration rate>60 mL/min was increased from 86.5%at baseline to 88.2%at switching week 144.CONCLUSION Our data confirmed that switching from TDF to TAF for 3 years results in not only persistent ALT/AST improvement,but also hepatic fibrosis improvement by APRI,FIB-4 scores,as well as SWE reading,the important clinical benefits of long-term hepatitis B virus antiviral treatment with TAF.

糖尿病患者足溃疡减压指南(2023年更新版)——《国际糖尿病足工作组:糖尿病相关的足病预防与管理指南(2023)》的一部分

减轻组织的机械性压力在治愈糖尿病相关的足溃疡所需的多种干预措施中最为重要。本文是2023年国际糖尿病足工作组(IWGDF)发布的减压治疗促进糖尿病相关的足溃疡愈合的循证指南,也是对2019年IWGDF指南的更新。我们遵循推荐、评估、发展和评价分级(GRADE)方法学,以患者-干预-比较-结局(patient-intervention-control-outcome,PICO)模式设计临床问题和重要结果,进行系统评价和Meta分析,制定评判表汇总,为每个问题编写推荐和理由。每项推荐都是基于系统综述中发现的证据,在无证据情况下则采用专家意见,以及对判断项目的GRADE等级总结进行仔细权衡,包括可预期和不可预期的影响、证据的确定性、患者价值、所需资源、成本效益、公平性、可行性和可接受性。为了治愈糖尿病患者神经性前足底或中足底溃疡,要使用不可拆卸的齐膝高减压装置作为首选减压干预措施。如果患者存在对不可拆卸减压装置的禁忌证或不能耐受,考虑使用可拆卸齐膝(或踝)高减压装置作为减压干预措施的第二选择。如果无可用的减压装置,考虑使用合适的鞋具结合毡制泡沫作为减压干预措施的第三选择。如果这种非手术减压治疗不能治愈前足底溃疡,可以考虑跟腱延长术、跖骨头切除术、关节置换术或跖骨截骨术。为了治疗继发于屈趾畸形的神经性足底或小趾远端溃疡,可行趾屈肌腱切开术。为了促进后足、非足底或并发感染或缺血的溃疡的愈合,提出了进一步的推荐。所有推荐都已在减压临床路径中进行了总结,以帮助促进本指南在临床实践中的实施。这些减压推荐将帮助医务人员为糖尿病相关的足溃疡患者提供最佳的治疗和预后,降低患者感染、住院和截肢的风险。

Recurrent stroke admissions with vs without COVID-19 and associated in-hospital mortality: A United States nationwide analysis, 2020

BACKGROUND Coronavirus disease 2019(COVID-19)has been shown to increase the risk of stroke.However,the prevalence and risk of recurrent stroke in COVID-19 patients with prior stroke/transient ischemic attack(TIA),as well as its impact on mor-tality,are not established.AIM To evaluate the impact of COVID-19 on in-hospital mortality,length of stay,and healthcare costs in patients with recurrent strokes.METHODS We identified admissions of recurrent stroke(current acute ischemic stroke admissions with at least one prior TIA or stroke)in patients with and without COVID-19 using ICD-10-CM codes using the National Inpatient Sample(2020).We analyzed the impact of COVID-19 on mortality following recurrent stroke admissions by subgroups.RESULTS Of 97455 admissions with recurrent stroke,2140(2.2%)belonged to the COVID-19-positive group.The COVID-19-positive group had a higher prevalence of diabetes and chronic kidney disease vs the COVID-19 negative group(P<0.001).Among the subgroups,patients aged>65 years,patients aged 45–64 years,Asians,Hispanics,whites,and blacks in the COVID-19 positive group had higher rates of all-cause mortality than the COVID-19 negative group(P<0.01).Higher odds of in-hospital mortality were seen in the group aged 45-64(OR:8.40,95%CI:4.18-16.91)vs the group aged>65(OR:7.04,95%CI:5.24-9.44),males(OR:7.82,95%CI:5.38-11.35)compared to females(OR:6.15,95%CI:4.12-9.18),and in Hispanics(OR:15.47,95%CI:7.61-31.44)and Asians/Pacific Islanders(OR:14.93,95%CI:7.22-30.87)compared to blacks(OR:5.73,95%CI:3.08-10.68),and whites(OR:5.54,95%CI:3.79-8.09).CONCLUSION The study highlights the increased risk of all-cause in-hospital mortality in recurrent stroke patients with COVID-19,with a more pronounced increase in middle-aged patients,males,Hispanics,or Asians.

Comparison of success rate and intraocular pressure spikes between selective laser trabeculoplasty and micropulse laser trabeculoplasty in African American and Hispanic patients

AIM:To examine the efficacy and safety of micropulse laser trabeculoplasty(MLT)versus selective laser trabeculoplasty(SLT)in a large cohort of primarily African American and Hispanic patients.METHODS:A single center retrospective comparative cohort review conducted at Cook County Health facilities that included patients with a diagnosis of open angle glaucoma or ocular hypertension who received an SLT or MLT procedure between January 2017 and May 2021.RESULTS:Totally 131 eyes of 99 patients were analyzed.The 77 eyes received SLT and 54 received MLT.Seven out of 77 eyes in the SLT group(9.1%)and 1 out of 54 eyes in the MLT group(1.9%)had an IOP spike(defined as>5 mm Hg)at either 1h or 1wk after procedure(P=0.05,Chisquared test with Haldane-Anscombe correction).The procedure failure rate at one year was 50%for SLT and 48%for MLT(P=0.31).CONCLUSION:MLT has a significantly lower incidence of pressure spikes and a similar treatment failure rate at 1-year post-procedure,demonstrating that it is a reasonable alternative compared to SLT.

Chemical exposures and suspected impacton Gulf War Veterans

Gulf War Illness(GWI) encompass a spectrum of maladies specific to troops deployed during the Persian Gulf War(1990–1991). There are several hypothesized factors believed to contribute to GWI, including(but not limited to)exposures to chemical agents and a foreign environment(e.g., dust, pollens, insects, and microbes). Moreover, the inherent stress associated with deployment and combat has been associated with GWI. While the etiology of GWI remains uncertain, several studies have provided strong evidence that chemical exposures, especially neurotoxicants,may be underlying factors for the development of GWI. This mini style perspective article will focus on some of the major evidence linking chemical exposures to GWI development and persistence decades after exposure.

The Impact of Digital Payment on Consumer Behavior in China

To continue China’s economic growth,plenty of research has been conducted to find the relationship between advancing payment methods and thriving consumption.Currently,digital payment is the latest and most mature way in China.Instead of being a single application for online transactions,digital payment represents a complete online shopping environment.To generally review the impact of digital payment on consumer behavior in China,literature containing research on consumers from different age groups and gender will be collected and concluded.This research takes women and undergraduate students as the critical research object because people ubiquitously consider these two groups of people as the primary consumers in the e-commerce market.After arranging information from the research about three stages that cover the shopping intention by digital payment,consumer psychology,and consumer behavior,this review concludes that economic growth is potentially attained by digital payment in a secure online environment,with the business target at profit maximization at the same time keeping consumers rationale in a normal range,especially for woman and undergraduate students.

A new method for preparing a rat intracerebral hemorrhage model by combining focused ultrasound and microbubbles

Background:We aimed to prepare a non-invasive,reproducible,and controllable rat model of intracerebral hemorrhage with focused ultrasound(FUS).Methods:A rat intracerebral hemorrhage(ICH)model was established by combining FUS and microbubbles(μBs),and edaravone was used to verify whether the free radical scavenger had a protective effect on the model.The brain tissue of each group was sectioned to observe the gross histology,blood-brain barrier(BBB)permeability,cerebral infarction volume,and histopathological changes.Results:Compared with the FUS group,the BBB permeability was significantly increased in the FUS+μBs(F&B)group(p=0.0021).The second coronal slice in the F&B group had an obvious hemorrhage lesion,and the FUS+μBs+edaravone(F&B&E)group had smaller hemorrhage areas;however,ICH did not occur in the FUS group.The cerebral infarction volume in the F&B group was significantly larger than that in the FUS group(p=0.0030)and F&B&E group(p=0.0208).HE staining results showed that nerve fibrinolysis,neuronal necrosis,microglia production,and erythrocytes were found in both the F&B group and the F&B&E group,but the areas of the nerve fibrinolysis and neuronal necrosis in the F&B group were larger than the F&B&E group.Conclusions:A rat ICH model was successfully prepared using theμBs assisted FUS treatment,and edaravone had a therapeutic effect on this model.This model can be used to study the pathophysiological mechanism of ICH-related diseases and in preclinical research on related new drugs.

Diabetes among Muslims during Ramadan:A narrative review

Fasting during the month of Ramadan is one of the five fundamental principles of Islam,and it is obligatory for healthy Muslim adults and adolescents.During the fasting month,Muslims usually have two meals a day,suhur(before dawn)and iftar(after dusk).However,diabetic patients may face difficulties when fasting,so it is important for medical staff to educate them on safe fasting practices.Prolonged strict fasting can increase the risk of hypoglycemia and diabetic ketoacidosis,but with proper knowledge,careful planning,and medication adjustment,diabetic Muslim patients can fast during Ramadan.For this review,a literature search was conducted using PubMed and Google Scholar until May 2023.Articles other than the English language were excluded.Current strategies for managing blood sugar levels during Ramadan include a combination of patient education on nutrition,regular monitoring of blood glucose,medications,and insulin therapy.Insulin therapy can be continued during fasting if properly titrated to the patients’needs,and finger prick blood sugar levels should be assessed regularly.If certain symptoms such as hypoglycemia,hyperglycemia,dehydration,or acute illness occur,or blood glucose levels become too high(>300 mg/dL)or too low(<70 mg/dL),the fast should be broken.New insulin formulations such as pegylated insulin and medications like tirzepatide,a dual agonist of gastric-inhibitory peptideand glucagonlike-peptide 1 receptors,have shown promise in managing blood sugar levels during Ramadan.Non-insulin dependent medications like sodium-glucose-cotransporter-2 inhibitors,including the Food and Drug Administration-approved ertugliflozin,are also being used to provide additional cardiovascular benefits in patients with type 2 diabetes.

自身抗体阳性复发性自然流产患者的子宫动脉血流阻力变化

目的:研究自身抗体阳性的复发性自然流产(RPL)患者的子宫动脉血流阻力(U-RI)指数的变化。方法:回顾分析189例RPL患者(≥3)的临床资料,比较孕前自身抗体阳性和阴性患者的U-RI指数。结果:抗磷脂抗体(APA)阳性患者的U-RI明显高于APA阴性组(P=0.018),APA-Ig G阳性组和APA-Ig A阳性组的U-RI明显高于APA阴性组(P=0.015,P=0.030),APA-Ig G、APA-Ig A阳性组的U-RI分别与APA-Ig G、APA-Ig A阴性组比较,差异有统计学意义(P=0.025,P=0.049),抗磷脂酸抗体(APAA)阳性组和抗磷脂酰肌醇抗体(APIA)阳性组的U-RI明显高于APA阴性组(P=0.045,P=0.048)。抗核抗体(ANA)阳性组和阴性组的U-RI比较,差异无统计学意义(P=0.235)。ANA阳性不同滴度和不同荧光核型组的U-RI比较,差异无统计学意义(P=0.384,P=0.181);其他抗体:anti-thyroid antibody(ATA)、ds DNA、ss DNA、Histone及Scl70阳性组和阴性组的URI比较,差异均无统计学意义(P>0.05)。结论:APA阳性的RPL患者子宫动脉血流容易出现高阻,可能会引起子宫动脉血流灌注不足现象发生。

复发性流产患者NK细胞毒性和子宫动脉血流灌注对妊娠结局的影响

目的：探讨复发性流产（RPL）患者NK细胞毒性和子宫动脉血流灌注对妊娠结局的影响。方法：回顾分析162例RPL患者的临床资料,根据妊娠结局分为流产组（n=30）和分娩组（n=132）,比较两组的NK细胞毒性和子宫动脉血流阻力指数（U-RI）变化。结果：流产组的孕前NK细胞毒性高于分娩组,差异有统计学意义（P=0.02）,两组的孕前U-RI比较差异无统计学意义（P=0.12）;早孕期流产组各孕周的NK细胞毒性均高于分娩组,但差异无统计学意义（P〉0.05）。U-RI在早孕期较孕前明显降低（P〈0.001）,且分娩组U-RI随孕周增加逐渐降低;与分娩组相比,孕7、8、9周时流产组的URI明显升高,差异有统计学意义（P=0.008,P=0.001,P=0.043）。结论：孕前NK细胞毒性增高,孕7~9周子宫动脉血流灌注量下降的患者再次自然流产风险增高,两者为独立危险因素。

一例并殖吸虫病患者的虫卵DNA序列分析鉴定(英文)

[目的 ]运用分子生物学技术分析虫卵基因序列鉴定并殖吸虫病类型。 [方法 ]先从并殖吸虫病患者痰中分离出虫卵 ,然后PCR扩增出虫卵中完整的核糖体DNA第二间隔区基因 (ITS2 ) ,并直接用于测序从而获得该基因的核苷酸序列。同时 ,亦用同法分别从动物宿主粪便中分离出的卫氏并殖吸虫和斯氏狸殖吸虫虫卵中获得ITS2基因序列作为DNA参照分析。此外 ,本文也对从患者痰中分离出的虫卵进行详细的形态学特征描述分析。 [结果 ]来自患者的虫卵ITS2基因序列与参照的卫氏并殖吸虫虫卵的基因序列 10 0 %一致 ,而与来自斯氏狸殖吸虫虫卵的基因序列只有 92 %核苷酸相同。此外 ,从形态学上讲 ,来自患者的虫卵形态特征更与卫氏并殖吸虫虫卵相似。 [结论 ]通过基因序列分析 ,可确诊患者所患的是卫氏并殖吸虫病。

新生儿成熟度和产后日龄对血清钾水平的影响

目的 探讨新生儿成熟度和产后日龄对血清钾浓度的影响。方法 回顾性分析了胎龄为 2 4～ 2 8周 (A组 ) ,2 9～ 3 2周 (B组 ) ,3 3～ 3 6周 (C组 )和 3 7～ 4 2周 (D组 )新生儿生后 1～ 72h内的血清钾水平及其变化。结果 ①新生儿的胎龄、体重和尿量与血清钾水平存在着线性关系。②生后 1～ 2 4h ,A组新生儿的血清钾水平最高 ,B组次之 ,C和D组相当 ,为最低。生后 4 8h内 ,A和B组的血清钾水平开始下降 ,并于 72h内下降至C和D组新生儿水平。C和D组新生儿生后 72h内的血清钾水平无明显变化。③A ,B和C组早产儿生后 2 4h内高钾血症 (≥7.0mmol/L)发生率分别为 2 0 .0 % ,12 .5%和 4 .0 % ;2 4例高钾血症患儿经常规治疗后 ,14例 (58.3 % )于 72h内血钾降至 7.0mmol/L以下并存活 ;10例 (4 1.7% )高钾血症状态持续存在 ,其中 7例死亡。D组足月儿于生后 72h内未出现高钾血症。结论 新生儿的成熟度和产后胎龄影响血清钾水平 ;极不成熟新生儿 (2 4～ 3 2周 )在生后 2 4h内具有较高的血清钾水平 ,继之随生后日龄的增加而降低 ;早产儿可有致命性高钾血症存在 ,常规治疗仅部分有效。

rK39免疫层析试条在新疆黑热病诊断和流行病学调查中的应用

目的观察rK39免疫层析试条对新疆不同类型黑热病的诊断及流行病学调查中的应用价值。方法用rK39试条检查不同地区确诊的黑热病患者;用rK39-ELISA和rK39免疫层析试条检查不同流行地区居民血清标本与利什曼素皮内反应结果进行比较分析。结果对来自新疆不同地区的黑热病患者共1204例,用rK39试条检测抗体阳性者1169例,阳性率97.09%。其中人源型黑热病患者1052例中1031例阳性,阳性率98.0%;荒漠型黑热病患者158例中阳性143例,阳性率90.5%。二者之间差异显著(P<0.001),荒漠型患者阳性率较低。人源型黑热病流行区居民中rK39抗体阳性率在既往有黑热病史者中为42.7%～59.3%,在无既往史的居民中仅为2.2%～5.8%。在随访的rK39阳性,皮内反应阴性的18人中有4人在4和6个月后出现症状,确诊为黑热病。在黑热病治愈后2年内94.6%的患者rK39抗体仍为阳性。9年后仍有82.5%保持阳性。结论rK39层析试条对新疆黑热病患者有很高的诊断价值。其保存、携带方便,操作简单适于在基层现场使用。由于其可在潜伏期中发现黑热病患者。故可用于在流行地区皮内反应阴性的居民中进行免疫学检测,早期发现病人。由于黑热病患者治愈后血清中rK39抗体长期存在,故不适用于预后判定和疗效评价。

中国区域蒸发潜力不均性发展趋势及其气候成因分析

气象台站20 cm蒸发皿观测资料自然正交分解显示,1980～2000年中国区域气温显著增加期间,长江中游至河套、东北等区域地表年蒸发潜力呈增加趋势;相反在长江以南、东部和西南等地区年蒸发潜力呈下降趋势.辐射观测资料分析结果表明,自20世纪70年代中国区域太阳入射能整体呈下降趋势,因此对于蒸发潜力增加的地区,太阳辐射产生的热力作用并不是决定蒸发潜力发展趋势的唯一原因.通过对大气风动力和干燥力等因子的分析证实,大气动力作用是造成中国区域地表蒸发潜力空间不均性分布的主要原因.同时1980～2000年NOAAAVHRR遥感数据分析结果也表明,地表覆盖类型的变换以及植被覆盖率的下降,引发的地表热力作用和地表物理性质变化,是造成蒸发潜力空间分布不均性加大的另一项重要原因.

苏芸金杆菌微胶囊剂型与标准菌粉灭蚊幼效果比较

本文报道按美国哈佛大学专利技术制备的苏芸金杆菌微胶囊剂型(EBTI)与标准菌粉剂(SBTI)灭蚊幼效果比较。结果表明:1 在BTI为0.007～0.002ppm低浓度时,EBTI灭蚊幼持效显著高于SBTI(P<0.01),在施用后第4wk仍保持100％的蚊幼死亡率;而相同浓度的SBTI组在施用第2wk后,蚊幼死亡率逐周下降,显著低于EBTI组(P<0.01),至第4wk灭蚊幼效力消失。表明EBTI比相同浓度SBTI持效长、毒效高。2 趋势性假设检验结果示SBTI在BTI浓度≤0.025ppm时,蚊幼死亡率随用药时间延长而呈下降趋势(X^2=8.17～24.08,P<0.01);而EBTI组在BTI浓度为0.025～0.007ppm时,蚊幼死亡率保持100％,表明EBTI最适长效高效低剂量BTI血浓度为0.007ppm。

Hepatitis C virus NS5A promotes insulin resistance through IRS-1 serine phosphorylation and increased gluconeogenesis

AIM: To investigate the mechanisms of insulin resistance in human hepatoma cells expressing hepatitis C virus(HCV) nonstructural protein 5A(NS5A).METHODS: The human hepatoma cell lines,Huh7 and Huh7.5,were infected with HCV or transientlytransfected with a vector expressing HCV NS5 A. The effect of HCV NS5 A on the status of the critical players involved in insulin signaling was analyzed using realtime quantitative polymerase chain reaction and Western blot assays. Data were analyzed using Graph Pad Prism version 5.0.RESULTS: To investigate the effect of insulin treatment on the players involved in insulin signaling pathway,we analyzed the status of insulin receptor substrate-1(IRS-1) phosphorylation in HCV infected cells or Huh7.5 cells transfected with an HCV NS5 A expression vector. Our results indicated that there was an increased phosphorylation of IRS-1(Ser307) in HCV infected or NS5 A transfected Huh7.5 cells compared to their respective controls. Furthermore,an increased phosphorylation of Akt(Ser473) was observed in HCV infected and NS5 A transfected cells compared to their mock infected cells. In contrast,we observed decreased phosphorylation of Akt Thr308 phosphorylation in HCV NS5 A transfected cells. These results suggest that Huh7.5 cells either infected with HCV or ectopically expressing HCV NS5 A alone have the potential to induce insulin resistance by the phosphorylation of IRS-1 at serine residue(Ser307) followed by decreased phosphorylation of Akt Thr308,Fox01 Ser256 and GSK3β Ser9,the downstream players of the insulin signalingpathway. Furthermore,increased expression of PECK and glucose-6-phosphatase,the molecules involved in gluconeogenesis,in HCV NS5 A transfected cells was observed.CONCLUSION: Taken together,our results suggest the role of HCV NS5 A in the induction of insulin resistance by modulating various cellular targets involved in the insulin signaling pathway.

Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer

Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer （HCC）. Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors （＂small molecule inhibitors＂） and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin （mTOR） upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation, roTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.

Testicular expression of survivin and human telomerase reverse transcriptase(hTERT)associated with spermatogenic function in infertile patients

Aim： To characterize the coexpression of survivin, an inhibitor of apoptosis （IAF）, and human telomerase reverse transcriptase （hTERT） in human testes with varying spermatogenic function. Methods： Transcript levels of survivin mRNA and hTERT mRNA were determined in normal testes （n = 11） and testes with defective spermatogenesis （n = 28） using real-time reverse-transcription polymerase chain reaction （RT-PCR）. The histological work-up was performed according to a modified Johnsen score. Results： Expressions of both survivin and hTERT were highest at median levels of 96.8 and 709 in normal spermatogenesis and dropped to 53.3 and 534 in testes with postmeiotic spermatogenic arrest （n = 10）. In severe spermatogenic failure （n = 18）, survivin expression was lacking in most specimens （n = 16）, whereas at least low levels of testicular hTERT expression were largely detectable with a normalized expression of 73 in premeiotic spermatogenic arrest （n = 7） and 45 in patients with Sertoli cell-only syndrome （SCOS） （n = 3）. Both survivin and hTERT expressions increased with a progressing Johnsen score （P for trend = 0.001）. Conclusion： Although both survivin and hTERT are correlated with spermatogenic function, they show different expression patterns in testes of infertile patients. These findings substantiate results from studies in the rodent testis suggesting a predominant expression of survivin in meiotically dividing germ cells. （Asian J Andro12006 Jan; 8： 95-100）