追求持久免疫控制:写在聚乙二醇干扰素α上市10周年

国内外对于慢性乙型肝炎(CHB)抗病毒治疗的目标是清晰一致的,即最大限度地长期抑制病毒复制,从而延缓肝脏疾病的进展,减少肝硬化、肝细胞癌或肝衰竭的发生.但对于治疗过程中的治疗终点仍存在争议.2012年版EASL指南在2009年版的基础上提出的治疗终点仍然包括理想治疗终点、满意治疗终点、基本治疗终点:理想治疗终点是停止治疗后持续HBsAg消失,伴有或不伴抗-HBs血清学转换;满意治疗终点是停止治疗后持续病毒学应答和生物化学应答;基本治疗终点是在长期治疗中维持病毒学应答[1].     

HBsAg的血清清除能进一步降低使用核苷类似物后病毒获得完全抑制患者的肝癌风险

<正>【据《J Hepatol》2019年3月报道】题:HBsAg血清学清除能够进一步降低核苷类似物治疗后实现病毒完全抑制患者进展为肝癌的风险(作者Yip TC等)在已通过临床治疗获得病毒完全抑制的慢性乙型肝炎(CHB)患者中,实现HBs Ag血清学清除达到功能性治愈是否具有额外的临床获益,这一问题目前尚不清楚。     

慢性乙型肝炎免疫致病机制和免疫治疗现状

核苷类似物和干扰素等抗病毒药物已被广泛应用于慢性乙型肝炎(CHB)的临床治疗,并取得了一定疗效.然而现有的抗病毒药物虽可显著抑制HBV复制,但却不能完全清除体内的共价闭合环状DNA(cccDNA),难以持久恢复患者的抗病毒免疫功能,导致HBsAg长期存在.因此,要实现HBsAg血清学转化,清除慢性HBV感染患者体内cccDNA,必须依靠患者特异性抗病毒免疫能力的恢复.     

拉米夫定长期维持应答患者血清乙型肝炎表面抗原水平的变化特点

目的 了解拉米夫定长期治疗下血清HBsAg的动态变化特点.方法 研究对象为HBeAg阳性、拉米夫定为初始抗病毒治疗且取得快速和持久(从治疗24周至观察期末HBV DNA持续检测不到)病毒学应答的慢性乙型肝炎患者.血清HBsAg定量检测采用雅培Architect方法,HBV基因型用直接测序法确定.结果 3年观察期间有26例(57.8%)患者发生HBeAg转阴(其中1例HBsAg转阴).治疗12周时血清HBsAg水平中位数降至基线的39.5%(P<0.01),但之后下降不明显.血清HBsAg的变化特征在HBcAg转阴或持续阳性的患者间相似.基因B型患者在治疗头12周血清HBsAg水平下降幅度较基因C型更大(75.5%比26.0%,P<0.05).在个体患者中,血清HBsAg的动态变化类型主要有双相型(治疗12和24周HBsAg低于基线的60%)和稳定型(治疗12和24周HBsAg高于基线的80%).基线血清HBsAg水平低(比数比值为0.020,95%可信区间为0.002~0.743,P<0.05)和基因C型感染(比数比值为8.206,95%可信区间为1.070~62.948,P<0.05)是血清HBsAg在拉米夫定长期治疗下下降不明显的主要因素.结论 血清HBsAg在拉米夫定快速和持久抑制HBV复制时主要表现为两种变化类型,并和HBV基因型关系密切.     

慢性乙型肝炎抗病毒治疗的进展

由于乙肝病毒(HBV)是肝炎发生和发展的基础,因此清除病毒是慢性乙型肝炎治疗的关键。清除病毒的策略有2种:清除感染了 HBV 的肝细胞和抑制(或杀灭)病毒本身(表1)。     

加用干扰素治疗核苷(酸)类似物经治的HBsAg低水平的慢性乙型肝炎患者获得临床治愈的效果观察

目的探讨核苷(酸)类似物(NAs)经治的慢性乙型肝炎患者获得临床治愈的优势人群,为临床医生追求乙型肝炎临床治愈提供更多的方法。方法选取2017年10月—2019年10月在鹤壁市第三人民医院接受NAs治疗且HBsAg低水平的慢性乙型肝炎患者42例作为研究对象,分为联合治疗组(A组,n=22)和NAs单药治疗组(B组,n=20)。A组采用NAs联合聚乙二醇干扰素(PEG-IFN)抗病毒治疗48周,部分患者24周停用PEG-IFN继续NAs单药治疗。B组仅采用NAs抗病毒治疗,两组均观察至48周,通过乙型肝炎五项定量检测评估疗效。计量资料两组间比较采用t检验;计数资料两组间比较采用Fisher精确检验。影响因素相关分析采用logistic回归法。结果 48周治疗终点A组的HBsAg清除率(45.5%)和HBsAg血清学转换率(31.8%)远高于B组(均为0)(P值均001);HBsAg 1000 IU/ml、500 IU/ml、100 IU/ml、10 IU/ml人群的HBsAg清除率分别为52.6%、615%、66.7%和100%;HBsAg在500～1000 IU/ml、100～500 IU/ml、10～100 IU/ml、10 IU/ml区间人群的HBsAg清除率分别为33.3%、50%、40%和100%。4例基线HBsAg 10 IU/ml者(占联合治疗组18.2%),联合治疗12周取得临床治愈,观察至48周时2例抗-HBs100 IU/ml,2例抗-HBs1000 IU/ml。HBsAg清除的多因素logsitic回归分析结果显示:开始联合治疗时的年龄对HBsAg清除存在影响(OR=0.877,95%CI:0.781～0.985,P=0.026),HBsAg阴转患者的年龄集中在36～49(44.20±4.49)岁;基线HBsAg水平也对HBsAg清除存在影响(OR=0.996,95%CI:0.992～1.000,P=0.050)。结论加用IFN治疗核苷(酸)类似物经治的HBsAg低水平的慢性乙型肝炎患者能够显著提高临床治愈率,年龄越小、HBsAg水平越低,联合治疗时间越短,相较于NAs用药时间、种类,年龄和基线HBsAg水平更关键。     

慢性乙型肝炎病毒感染的抗病毒治疗

当今世界约有200万乙型肝炎病毒携带者,这些人均有发展成慢性肝炎、肝硬化及肝细胞癌的危险.而且可能为疾病的传染源.所以需要有效的治疗.抗病毒治疗治疗慢性HBV感染的目的是清除复制及非复制型病毒,从而防止HBV感染的进一步传播及出现进行性肝损和肝细胞癌(HCC).HBeAg阳性患者体内有进行复制的病毒,并有活动性肝病,所以使用抗病毒治疗得益最大.若在慢性HBV感染的早期开始治疗,在整合有HBV基因组的肝细胞克隆尚未稳定建立前进行,则HBV可完全清除,HBsAg转阴而抗-     

恩替卡韦长疗程后联合或序贯IFNα治疗慢性乙型肝炎的效果与安全性分析

目的探讨经恩替卡韦(ETV)长期治疗,有效抑制HBV DNA后,采取序贯或联合IFNα治疗与单用ETV治疗的疗效与安全性比较。方法收集2013年1月-2015年12月南通大学附属吴江医院门诊和住院的慢性乙型肝炎患者27例,所有患者已经ETV抗病毒治疗3年或以上,HBV DNA阴性,无IFN治疗禁忌证,将纳入患者随机分为3组,每组9例。对照组:继续ETV治疗;序贯组:更换为IFNα序贯治疗;联合组:联合IFNα治疗。检测治疗0、12、24、36、48周时血清HBV DNA、HBV血清标志物、血常规、肝功能,观察治疗情况,记录结果并进行统计分析。计量资料多组间比较采用单因素方差分析,进一步两两比较采用Scheffe检验。结果无退出研究病例,无严重不良事件发生;序贯组有1例24周后出现了病毒反弹,但无临床症状,肝功能各项生化指标正常。治疗结束时,序贯组和联合组HBsAg下降的绝对值均显著高于对照组(P值均<0.001);序贯组和联合组各有2例出现了HBsAg的阴转,阴转率22%;对照组未出现HBsAg的阴转病例。结论 ETV有效抑制病毒复制后的IFNα序贯或联合治疗可能是安全的,HBsAg下降水平优于ETV单药治疗,少数患者出现临床治愈。     

HBeAg血清学清除后患者发生肝癌和HBsAg转阴的长期随访结果和预后评分

正【据《J Hepatol》2018年3月报道】题:HBeAg血清学清除后患者发生肝癌和HBsAg转阴的长期随访结果和预后评分(作者JamesF等)目前,HBeAg血清学清除(ESC)后的长期意义尚不明确。香港大学通过获得长期HBeAg清除(ESC)患者的大型队列研究,观察其发生肝细胞癌(HCC)以及HBsAg血清学清除情况,旨在构建该人群临床结局、影响因     

慢性乙型肝炎抗病毒治疗的进展

由于乙肝病毒(HBV)是肝炎发生和发展的基础．因此清除病毒是慢性乙型肝炎治疗的关键。消除病毒的策略有2种：清除感染了HBV的肝细胞和抑制(或杀灭)病毒本身。     

Recovery of Palladium(II) and Platinum(IV) in Novel Extraction Systems

Recovery of platinum group metals (PGM) from complex aqueous solutions generated as a result of leaching of various spent materials (e.g., spent automotive converters) is a vital issue in the context of the circular economy. In this study pyridinium derivatives containing an imidoamide or imine moiety (i.e., 3-[1-(2-ethylhexyloxyimine)methane]-1-propylpyridinium chloride, 3-[1-(decyloxyimine)methane]-1-propylpyridinium chloride, 3-[1-(decyloxyimine)ethane]-1-propylpyridinium chloride and 4-[1-amine(2-ethylhexyloxyimine)]-1-propylpyridinium chloride) are proposed as novel extractants for recovery of palladium(II) and platinum(IV) from model chloride aqueous solutions. The results of liquid-liquid extraction from one-component solutions of palladium(II) or platinum(IV) showed that quaternary pyridinium salts can be used as effective extractants for platinum metal ions. Moreover, PGM extraction from a two-component mixture proved no evident selectivity in the transfer of one of the metal ions to the organic phase. As the best extractant among the investigated ones, D3EI-PrCl (with straight alkyl chain at substituent) can be pointed out, however, problems with effective stripping or phase disengagement after stripping should be indicated as a drawback of the organic phases used. Further investigation should focus on the improvement of the organic phase properties (e.g., increase in hydrophobicity of the extractants and addition of an organic phase modifier) towards stripping efficiency.     

Molecular code for protein insertion in the endoplasmic reticulum membrane is similar for N(in)-C(out) and N(out)-C(in) transmembrane helices

Transmembrane α-helices in integral membrane proteins can have two orientations in the membrane: N_in–C_out or N_out–C_in. Previous studies of model N_out–C_in transmembrane segment have led to a detailed, quantitative picture of the “molecular code” that relates amino acid sequence to membrane insertion efficiency in vivo [Hessa T, et al. (2007) Molecular code for transmembrane helix recognition by the Sec61 translocon. Nature 450:1026–1030], but whether the same code applies also to N_in–C_out transmembrane helices is unknown. Here, we show that the contributions of individual amino acids to the overall efficiency of membrane insertion are similar for the two kinds of helices and that the threshold hydrophobicity for membrane insertion can be up to ≈1 kcal/mol lower for N_in–C_out compared with N_out–C_in transmembrane helices, depending on the neighboring helices.     

Cellulose (delta)18O is an index of leaf-to-air vapor pressure difference (VPD) in tropical plants

Cellulose in plants contains oxygen that derives in most cases from precipitation. Because the stable oxygen isotope composition, δ(18)O, of precipitation is associated with environmental conditions, cellulose δ(18)O should be as well. However, plant physiological models using δ(18)O suggest that cellulose δ(18)O is influenced by a complex mix of both climatic and physiological drivers. This influence complicates the interpretation of cellulose δ(18)O values in a paleo-context. Here, we combined empirical data analyses with mechanistic model simulations to i) quantify the impacts that the primary climatic drivers humidity (e(a)) and air temperature (T(air)) have on cellulose δ(18)O values in different tropical ecosystems and ii) determine which environmental signal is dominating cellulose δ(18)O values. Our results revealed that e(a) and T(air) equally influence cellulose δ(18)O values and that distinguishing which of these factors dominates the δ(18)O values of cellulose cannot be accomplished in the absence of additional environmental information. However, the individual impacts of e(a) and T(air) on the δ(18)O values of cellulose can be integrated into a single index of plant-experienced atmospheric vapor demand: the leaf-to-air vapor pressure difference (VPD). We found a robust relationship between VPD and cellulose δ(18)O values in both empirical and modeled data in all ecosystems that we investigated. Our analysis revealed therefore that δ(18)O values in plant cellulose can be used as a proxy for VPD in tropical ecosystems. As VPD is an essential variable that determines the biogeochemical dynamics of ecosystems, our study has applications in ecological-, climate-, or forensic-sciences.     

Synthesis of Isothianaphthene (ITN) and 3,4-Ethylenedioxy-Thiophene (EDOT)-Based Low-Bandgap Liquid Crystalline Conjugated Polymers

Copolymers, consisting of isothianaphthene and phenylene derivatives with liquid crystal groups, were synthesized via Migita-Kosugi-Stille polycondensation reaction. IR absorption, UV-vis optical absorption, and PL spectroscopy measurements were carried out. Thermotropic liquid crystallinity of the polymers with bandgap of ~2.5 eV was confirmed.     

Effects of enhanced afterload (methoxamine) and contractile state (dobutamine) on the left ventricular late-systolic wall stress-dimension relation

Although the left ventricular (LV) end-systolic pressure-dimension relation is a load-independent, sensitive index of contractile state, its accurate determination requires afterload manipulation. The slope value of the late-systolic stress-dimension relation determined under resting conditions has been suggested as an alternative index of contractility that can be assessed without pharmacologie intervention. To evaluate this relation, 14 normal subjects were studied by M-mode echocardiography, phonocardlography and indirect carotid pulse tracings during infusion of methoxamine to increase afterload. Seven of these subjects were also studied after infusion of dobutamine to increase contractility. Continuous systolic stress-dimension trajectories were computer generated from digitized tracings. The late-systolic portions of these curves were found to be linear and the slope and intercept were determined. The slope value was sensitive to both afterload and contractility, and the magnitude of change in slope value was relatively greater during afterload enhancement than during inotropic stimulation. A strong correlation of slope value with peak systolic stress was found. Thus, the late-systolic stress-dimension relation is linear with a slope value which is dependent on both LV contractility and afterload. Like other ejection phase indexes, the usefulness of this index is limited by its inability to distinguish changes in contractile state from alterations in loading conditions.     

pH (low) insertion peptide (pHLIP) inserts across a lipid bilayer as a helix and exits by a different path

What are the molecular events that occur when a peptide inserts across a membrane or exits from it? Using the pH-triggered insertion of the pH low insertion peptide to enable kinetic analysis, we show that insertion occurs in several steps, with rapid (0.1 sec) interfacial helix formation, followed by a much slower (100 sec) insertion pathway to give a transmembrane helix. The reverse process of unfolding and peptide exit from the bilayer core, which can be induced by a rapid rise of the pH from acidic to basic, proceeds approximately 400 times faster than folding/insertion and through different intermediate states. In the exit pathway, the helix–coil transition is initiated while the polypeptide is still inside the membrane. The peptide starts to exit when about 30% of the helix is unfolded, and continues a rapid exit as it unfolds inside the membrane. These insights may guide understanding of membrane protein folding/unfolding and the design of medically useful peptides for imaging and drug delivery.     

Flexible endoscopic clip-assisted Zenker's diverticulotomy (with videos)

BACKGROUND: In treating Zenker's diverticulum (ZD), there are potential risks associated with flexible endoscopic diverticulotomy without suturing or stapling. Rigid endoscopic stapler-assisted diverticulotomy has limitations. The septum is usually not completely dissected with either technique. OBJECTIVE: Our purpose was to evaluate the feasibility of flexible endoscopic clip-assisted diverticulotomy (ECD) for complete septum dissection. DESIGN: Case report. SETTING: Academic center. PATIENT: An elderly male with symptomatic residual ZD. INTERVENTIONS: After 1 endoclip (InScope multiclip applier, Ethicon Endo-Surgery) was placed on each side of the cricopharyngeal bar, the septum was easily and completely dissected between these 2 clips down to the bottom of the diverticulum into the esophageal mucosa with a needle-knife. MAIN OUTCOME MEASUREMENT: Symptom resolution and complications. RESULTS: Complete esophageal symptom resolution without complications. LIMITATION: Case report. CONCLUSIONS: ECD is feasible, easy, safe, and effective for complete septum dissection. This is the first reported case of ECD. ECD provides another option in managing ZD with flexible endoscopy.