低密度脂蛋白胆固醇：且降且争议 (综述)

低密度脂蛋白胆固醇：且降且争议 (综述) 低密度脂蛋白胆固醇:且降且争议 在哺乳动物中，脂蛋白转运系统发挥着许许多多的作用:将食物中的脂肪初始转运至肝脏;进一步将处理过的胆固醇颗粒转运至外周组织，为类固醇激素和膜合成提 供原料;加工游离脂肪酸，最终作为直接利用或储存使用的能源，这些功能对生存至关重要。胆固醇在血浆中的转运依赖于由脂蛋白颗粒，脂蛋白的中央内核为疏水 性的胆固醇酯和甘油三酯，外围由亲水性的磷脂和游离胆固醇折叠而成。 一般情况下，每个脂蛋白颗粒包括一组维持复合体结构完整性的高度保守的载脂蛋白，参与组装、分泌及受体结合的过程。传统上，根据脂蛋白的颗粒大小和 密度，可将其分为相对较大较轻的乳糜微粒、乳糜微粒残粒体和极低密度脂蛋白(VLDL)，以及颗粒较小及较重的低密度脂蛋白(LDL)和高密度脂蛋白 (HDL)。外周组织的胆固醇主要来源于 LDL 颗粒的转运，并与调节 LDL 血浆浓度的 LDL 受体结合。 LDL 受体的遗传缺陷导致其功能缺失是出现遗传性高脂血症的主要决定因素，而一种新型的单克隆抗体可延长 LDL 受体的生命周期，也为治疗这类疾病指明了一个新的主要研究方向。LDL 胆固醇颗粒更小、密度更大，内含较多的甘油三酯而胆固醇酯则较少，与之结合的载脂蛋白为载脂蛋白 B。 对临床医师而言，临床实践中很少有像 LDL 胆固醇一样如此重要的 循环分子结构。 一 直以来，流行病学证据均显示 LDL 胆固醇的升高与心肌梗死和血管疾病死亡风险的增加密切相关。经典的基因研究发现，早期出现过高的 LDL 胆固醇经常是由于 LDL 受体基因突变，从而在早期出现明显的动脉粥样硬化性血栓形成。正常人群一般在 50-60 岁出现动脉粥样硬化，而携带一个 LDL 受体相关缺陷基因的人群(杂合型家族性高胆固醇血症)通常在 30-40 岁就出现临床症状。相比之下，那些携带两个缺陷基因或复合型基因缺陷的人群有可能在青少年或 20 岁早期就出现心肌梗死和卒中。 这 些研究数据形成了一个所谓的“胆固醇暴露年”概念，它提醒我们早期降低 LDL 胆固醇或有长期的益处。孟德尔随机化研究的结果显示 LDL 胆固醇很有可能是斑块形成和进展的引发因素，而已知 LDL 可促进某些细胞过程，导致大量吞噬胆固醇的巨噬细胞出现——动脉粥样硬化斑块的标志，这与孟德尔随机化研究的数据不谋而合。 LDL 胆固醇的降低与血管事件发生率的下降密切相关，特别是在使用他汀类药物阻断胆固醇合成的限速步骤时。如果近期充满争议的公共卫生政策得以实施，那么美国和英国将有超过 1/3 的中老年人符合他汀治疗的推荐。 然而，尽管 LDL 胆固醇是心血管疾病中研究最广泛、也是最重要的危险因素，但有关其检测和降 LDL 不同药物的净风险获益比在临床 中仍然充满争议。除此之外，许多正在评估的降低 LDL 新药物在他汀治疗之外还有获益的潜质。 血脂检测的时间和 1.Friedewald 方程间接计算 VS 直接计算 一 般筛查血脂时要明确是否有高浓度的 LDL，而使用 Friedewald 方程间接计算 LDL 胆固醇是一种比较完备的方法。但由于 Friedewald 方程使用固定要素从甘油三酯中估计 VLDL，当甘油三酯过高时，计算的 LDL 浓度有可能被低估。而当未治疗的 LDL 非常低或使用强效他汀或降脂措施使 LDL 浓度极低时，这种低估将会更加严重。此外，在对胆固醇酯转移蛋白抑制剂(CETP)的某些研究中，研究者发现 HDL 浓度过高时 LDL 同样也会被低估。 因此，LDL 检测的准确性仍有待提高，可以考虑评估 LDL 的替代方法。 替 代方法之一是使用非固定的相关要素估计甘油三酯 /VLDL 比值，另一个选择则是直接检测 LDL 胆固醇浓度。在大规模人群筛查中，直接检测的 LDL 胆固醇与 Friedewald 方程估计的 LDL 胆固醇通常高度相关(r,0.9，2.7 万名健康女性)，而在糖尿病、明显肥胖或近期高脂饮食等情况下，直接检测 LDL 胆固醇在临床上略胜一筹。 与计算的 LDL 相比，直接 LDL 检测在降脂治疗后 LDL 浓度非常低 时同样也有比较准确。但当患者有肝病、肾功能不全、病变蛋白和某些遗传性高脂血症等情况下，直接检测 LDL 则有诸多限制且检测的准确性也会受到影响。 2. 空腹 VS 非空腹 与空腹血脂相比，非空腹血脂水平同样可预测心血管事件，且非空腹状态下甘油三酯的预测能力更佳。鉴于以上原因并且为减轻患者负担、提高效率，而今许多医疗中心允许在非空腹状态检测血脂。 除 了空腹检测等话题外，有关进一步血脂检测的方法也引起了激烈的争论，在常规检测总胆固醇、LDL 胆固醇和 HDL 胆固醇之外，进一步血脂检测方法可以为临床医师提供更详细的信息。理论上，由于特异性的增加，检测载脂蛋白 B 和 LDL 的颗粒大小与数量可以提高危险预测的能力。 3. 非 HDL 胆固醇 VS LDL 胆固醇 在 一项纳入 37 项前瞻性队列研究共 16.5 万参与者的 Meta 中，与使用总胆固醇和 HDL 胆固醇的预测相比，载脂蛋白 B 的附加预测信息微乎其微。相似地，在血脂筛查研究中，使用 NMR 检测的预测能力与血脂检测相当，并无多少优势。在一项对 26 项血脂检测的全面前瞻评估中，总胆固醇 /HDL 胆固醇的比值是血管风险最强的单一预测因子。 越 来越多的研究也显示，他汀治疗后患者的残余风险与 LDL 胆固醇、非 HDL 胆固醇、载脂蛋白 B 和脂蛋白(a)有关。相反的是，他汀治疗后残余风险与 HDL 的颗粒数的关系较为密切，而不是 HDL 胆固醇水平。在一项纳入 8 项他汀试验共 62154 参与者的 Meta 分析中，复发血管事件与非 HDL 胆固醇的关联强度大于 LDL 胆固醇或载脂蛋白 B。 在 某些情况下，基于 LDL 计算的风险与基于载脂蛋白、非 HDL 胆固醇或 LDL 颗粒数(LDL-P)计算的风险会出现不一致。在前瞻性女性健康研究评估血脂成分时，1/4 女性的 LDL 胆固醇与 LDL 颗粒数出现差异，1/5 女性的 LDL 胆固醇和载脂蛋白 B 不一致，1/10 女性的 LDL 胆固醇与非 HDl 胆固醇不一致。对于出现差异的参与者，当使用非 HDL 胆固醇、载脂蛋白 B 或 LDL 颗粒数计算而不是 LDL 胆固醇浓度时，这部分人群的血管风险出现大幅度的改变。 在 筛查和评估治疗效果时，使用非 HDL 胆固醇浓度可避免与 LDL 有关的许多限制。非 HDL 胆固醇并不依赖 VLDL 的估计，只需要简单地检测所有由载脂蛋白 B 携带的胆固醇，从而有助于消除某些研究出现的不一致。此外，由于非 HDL 胆固醇可直接由总胆固醇和 HDL 胆固醇计算而来，从而也可节省检测费用并避免进一步的检测。尽管抛弃 LDL 胆固醇而转向非 HDl 胆固醇仍需要大量的教育努力，但这很有可能改善所有的患者治疗。 LDL 胆固醇识别他汀获益人群的有效性 他 汀类药物可有效降低心血管事件的发生率。一项对胆固醇治疗协作组 27 项随机试验的 Meta 分析发现，他汀类药物每使 LDL 胆固醇降低 1mmol/L，主要冠脉事件的风险就降低 24%(95% CI 0?73–0?79)、卒中风险降低 15%(0?80–0?89)、冠脉血运重建降低 24%(0?73–0?79)，并且不同性别、吸烟状态和年龄人群的获益相似，在所有肥胖程度、血压水平和血糖人水平人群的获益也相似。 此 外，尚无证据显示他汀治疗会增加癌症风险(HR=1，95% CI 0.96–1.04)或癌症死亡率(0.99，0?93–1?06)。尽管有部分随机试验和 Meta 分析显示他汀治疗可轻微增加糖尿病的风险，但不论患者糖尿病的风险如何，心血管事件降低所带来的获益仍超过风险。实际上，他汀类药物正是糖尿病患者大血管 事件预防的选择。强效他汀类药物正受到美国和欧洲指南的推荐，部分患者的冠状动脉粥样硬化甚至得到逆转。 有 关他汀类药物的 Meta 分析发现，绝对风险较低患者的相对风险下降超过绝对风险较高的患者，但此类话题少有研究讨论过。这与生物学观点是一致的——在疾病早期抑制 LDL 胆固醇的合成较延迟治疗能带来更多的保护作用。实际上，在未发现心血管事件明显下降的他汀试验中，患者开始服用他汀时已出现心力衰竭和终末期肾脏病，绝对 风险已经非常高。再者，尽管压倒性的证据显示他汀治疗可有效降低 LDL 胆固醇，但基线 LDL 胆固醇水平并不能有效识别哪一类 病人会从他汀治疗中获益。 在所有的大型试验中，他汀治疗后相对风险的下降与基线 LDL 胆固醇水平无关。一方面，LDL 胆固醇是动脉粥样硬化中必不可上的生物学中介，另一方面，LDL 胆固醇只是心血管事件绝对风险相对敏感的标志物，理解这两方面的差异至关重要。 尽 管基于试验的方法给予他汀可以保证处方药物于证据明确的患者，但基于整体风险预测模型计算绝对风险仍是欧美指南他汀使用的主流方式，这种方法认为绝对风险 较高的患者通常(但并不总是)绝对风险下降更多。因此，至少在无心力衰竭或肾衰竭的患者中，绝对风险较高的患者他汀治疗后 LDL 胆固醇下降使心血管事件的减少会更多。 不幸的是，没有一 个他汀试验将整体风险评分作为一项入选标准。除此之外，当相关的试验数据缺失或绝对风险的计算几乎依据老龄(即使无心血管危险因素)时，基于流行病学模型 的治疗方法占据推荐治疗的大部分。大型一级预防试验的研究人员认为患者的他汀治疗应依据高敏 C- 反应蛋白(hsCRP)，而不是 LDL 胆固醇水平升高。 基于上述原因，部分研究人员提出了他汀 治疗的替代方法，如治疗效果的个体化预测。在许多新兴的方法中，个体化的需治疗数(iNNT)旨在平衡个体已知的治疗获益和潜在的加权风险。而另一种治疗 方法则对所有超过固定年龄阈值的所有人进行治疗，如年龄超过 55 岁 的人群。为进一步验证上述方法，相关研究不得不小心谨慎，因为不同的方法可导致推荐治疗人数的明显不同。 他汀治疗后 LDL 胆固醇达标的重要性 直 到不久以前，美国的临床医师会强烈推荐 LDL 胆固醇降到治疗的目标值，而这种方法在大部分国家仍是主流。事后分析研究数据显示，胆固醇在指定目标值 1?8 mmol/L 以下更少发生心血管事件，而指南推荐正是基于上述数据。然而，从生物学视角关注 LDL 胆固醇并没有为临床中降 LDL 胆固醇药物的使用提供一个基本的依据，因为头对头的他汀试验只比较了不同药物不同剂量之间的区别，尚未比较治疗后不同 LDL 胆固醇水平之间的区别。 LDL 胆固醇水平在整体预测风险中只占少部分，至今仍无试验显示基线或治疗中的 LDL 胆固醇会改变他汀治疗的获益效果。 因 此，近期的美国胆固醇指南不再提倡治疗达到指定的 LDL 胆固醇目标，代而推荐高风险人群使用强效他汀药物。摒弃 LDL 胆固醇目标值的政策改变应该会减少非他汀类降胆固醇药物的使用，这些药物并未显示出降低临床事件的证据。尽管指南已作出推荐，但许多临床医生仍会继续检测 治疗后的 LDL 胆固醇，但只是作为一种检验药物依从性的方法。 最新的欧洲和加拿大指南选择维持 LDL 治疗目标，而各方专家在近期也就不同地区的指南进行了激烈讨论。 降脂药物抗炎作用的重要性 炎症在所有阶段的动脉粥样硬化性血栓形成阶段均发挥着最基本的作用。他汀类药物除了降低 LDL 胆固醇之外还有抗炎作用。 他 汀类药物降低 hsCRP 的能力正是其抗炎作用的临床现。在大部分他汀试验中，经过系统地评估治疗前后 hsCRP 的水平后，研究者发现降幅最大的参与者复发血管事件的残余风险最低。在两项使用血管内超声评估粥瘤进展的他汀试验中，hsCRP 和 LDL 胆固醇下降的参与者的粥瘤进展出现延缓。 在 JUPITER 一级预防试验中，对于 hsCRPC 升高但不适于其它治疗(LDL 胆固醇已经很低)的患者，他汀类药物可降低患者的心肌梗死、卒中和全因死亡率。在二级预防试验中，JUPITER 一级预防试验中治疗后 hsCRP 较低参与者的临床结局优于 hsCRP 未下降的参与者。 影 像学研究也进一步发现强化他汀治疗可减轻动脉粥样硬化炎症，但并非所有的他汀试验均显示治疗后的 hsCRP 强烈预测参与风险，CRP 本身也只是一个全身炎症的标志物，并不是导致炎症的病因;再者，尽管残余胆固醇似乎与低度炎症和血管事件有关，但在没有明显炎症的情况下，明显升高的 LDL 胆固醇似乎仍与血管事件相关。 尽管近期的美国和加拿大指南赞同在风险评估不确定的情况下使用 hsCRP 筛查，但他汀治疗开始后炎症评估的临床实用性仍充满争议。至今为止，应对他汀治疗后 hsCRP 仍然持续升高的循证方法为增加 他汀的剂量或选用更强效的他汀类药物。 非他汀类药物用于降低 LDL 的适用性 鉴 于有强有力的证据显示他汀治疗的安全性和降低临床事件，近期的欧美指南也适当地强调了他汀治疗作为降低 LDL 胆固醇的主要治疗方法。然而，他汀类药物应作为辅助治疗，而不是饮食和生活方式干预的替代，对于依从性较高的患者，凭借自身的力量就可大幅度地降低 LDL 胆固醇。但并不是所有的患者均能耐受他汀类药物，且妊娠期间禁止服用他汀类药物。同时，临床医师在治疗家族性高脂血症期望可以加用第二种非他汀类的降脂药 进一步降低 LDL 胆固醇。 在他汀前时代，使用部分回肠旁路术等外科方法也可降低 LDL 胆固醇。而就在最近，胃旁路手术被证明可有效地降低肥胖患者的心血管事件，尽管这种获益主要与血糖改善密切相关而非血脂改变。 可降低 LDL 的非他汀类药物包括: 1. 胆汁酸结合树脂(考来替泊、考来烯胺和考来维纶)，主要优势为不经过全身吸收，因此可用于妊娠; 2. 贝特类(非诺贝特、苯扎贝特和吉非罗齐)，主要用于降低甘油三酯和升高 HDL 胆固醇; 3. 烟酸类，升高 HDL 的同时可轻微地降低 LDL 胆固醇和甘油三酯; 4. 依择麦布，为胆固醇吸收抑制剂; 5.ω- 3 脂肪酸补充剂。 尽管上述药物可改善大部分患者的血脂，但同时代的试验并无过多的证据支持这类药物对普通人群的单一治疗或他汀类药物的辅助治疗。 作为著名的例子，AIM-HIGH 试验和 HPS-2-THRIVE 试验不仅发现烟酸不能有效降低血管事件的发生，还增加了胃肠道事件和感染的危害。 相 似的是，在 FIELD 试验和 ACCORD 试验中，非诺贝特的有效性同样受到质疑，尽管亚组分析显示对甘油三酯升高和 HDL 胆固醇降低的患者有效，但这只不过是一个还需直接验证的假说。在对 VA-HIT53 试验中，吉非罗齐确实可以降低心血管事件，但这种作用与 LDL 的降低无明显相关，此外，吉非罗齐还可增加他汀治疗的副作用，通常不推荐于他汀类药物合用。 有 关ω- 3 脂肪酸补充剂的当代试验仍然众说纷纭。最终，ENHANCE 试验显示，尽管 LDL 胆固醇下降，但依择麦布并未减少颈动脉内膜中层厚度这一替代终点，至今仍缺少证据证明单独使用依择麦布可改善患者的结局，或许即将结束的 IMPROVE-IT 试验会带来这方面的重要数据。SHARP 试验对慢性肾衰竭患者进行了研究，发现他汀类药物和依择麦布联合使用可降低心血管事件，但并未研究单独使用依择麦布。因此，在临床实践中应有限制地使用上 述非他汀类药物。 新型非他汀类降胆固醇药物 尽 管他汀类药物可有效降低心血管事件，但并不是所有降 LDL 的药物都可减少心肌梗死、卒中和心血管死亡，这些药物包括绝经后激素替代治疗(HRT)和 CETP 抑制剂 torcetrapib 和达塞曲匹。不管是汀类药物的成功还是 CETP 抑制剂降低血管事件的失败，认为这是由于他汀类药物具有抗炎作用的说法只是一种假设。 同一类的不同药物有可能有不同的临床获益，另两种 CETP 抑制剂 anacetrapib 和 evacetrapib(二者均可升高 HDl 胆固醇降低 LDL 胆固醇)正在进行 III 期试验，而其它 CETP 抑制剂仍在早期研发阶段。LDL 降低的机制与心血管事件的降低密切相关，因此，任何一种新型降 LDL 胆固醇药物都应对结局进行评估。 许多降低 LDL 的新方法也在紧锣密鼓进行研究，2103 年，有两种新药物作为孤儿药得到美国食品药品监督管理局的批准，用以治疗纯合子家族性高胆固醇血症的患者，家族性高胆固醇血症是一种罕见的常染色体显性遗传病，通常由于遗传了父母 LDL 受体的突变基因所致。 这 些新药对临床进展至关重要，因为纯合子家族性高胆固醇血症患者的 LDL 胆固醇经常超过 13mmol/L，并且很早就会出现动脉粥样硬化性血栓形成的并发症。LDL 受体缺陷或阴性的患者通常对他汀治疗产生抵抗，必须依靠 LDL 去除疗法降低循环胆固醇，遗憾的是，LDL 去除疗法昂贵繁琐，不适用于大部分三级转诊中心之外的场所。 米泊美生 作为第一个批准用于家族性高胆固醇血症的新药物，米泊美生是一种较短的单链反义寡核苷酸，它可特异性地与编码载脂蛋白 B 信使 RNA 上的 20 个碱基结合，从而抑制 mRNA 的翻译，减少载脂蛋白 B 的细胞合成，从而减少 VLDL 分泌至体循环中。 目 前，3 项米泊美生的 III 期试验已在家族性高胆固醇血症患者中完成，每项试验均显示 LDL 胆固醇平均下降 25-35%，同时甘油三酯和脂蛋白(a)也出现下降。该药常见的不良反应为注射部位反应和短暂的流感样症状。由于可使部分患者出现丙氨酸氨基转移酶升高 和脂肪肝，使用时需监测肝功能，并且禁用于肝病患者。 洛美他派 洛 美他派是第二个批准用于治疗家族性高胆固醇血症的药物，它是一种微粒体甘油三酸酯转运蛋白(MTP)抑制剂，通过减少肝脏 VLDL 产生降低循环 LDL 胆固醇。微粒体甘油三酸酯转运蛋白(MTP)与肝细胞内甘油三酯转运至载脂蛋白 B、VLDL 的组装和分泌有关。 使用洛美他派抑制 MTP 的概念基础部分来源于人类中一种罕见的隐匿性遗传病——无β脂蛋白血症，该病由于 MTP 的功能缺失，VLDL 不能从肝细胞分泌，造成体循环中缺少包含脂蛋白的载脂蛋白 B。 洛美他的批准主要来自于两项开放标签试验的数据，35 名纯合子家 族性高胆固醇血症患者在他汀治疗的基础上使用洛美他派，LDL 胆固醇以剂量依赖反应的方式降低了 40-50%。正如米泊美生一样，洛美他派治疗后脂蛋白(a)也出现了下降。 该药常见的不良反应为腹泻、恶心和腹痛。由于研究中分别有 8% 和 30% 的参与者出现肝脏脂肪沉积和肝酶升高，因此，处方洛美他派的临床医生必须密切关注患者的肝功能。 PCSK9 抑制剂 前 景最广阔的降 LDL 胆固醇药物为前蛋白转化酶枯草杆菌蛋白酶可馨 -9(PCSK9)—一种由肝细胞分泌蛋白质，它可结合 LDL 受体，使其细胞内在化并随后由溶酶体降解。PSCK9 基因功能丧失性突变患者的 LDL 受体由溶酶体降解减少，使 LDL 受体在细胞表面的表达面积扩大，从而降低血浆 LDL 浓度并减少终生血管事件。相反的是，人类 PSCK9 基因的功能丧失性突变与常染色体显性遗传性高胆固醇血症有关。 在许多 II 期试验中，以 PCSK9 为靶标的单克隆抗体(单独给药或合用他汀)可大幅度降低血浆 LDL 胆固醇，这是一个很重要的观察，因为他汀治疗可间接升高血浆 PCSK9。此外，抑制 PCSK9 同样可降低脂蛋白(a)。以 PCSK9 为靶标的单克隆抗体或许不仅可以作为杂合子高胆固醇血症患者(LDL 受体活性下降)的降 LDL 药物，还适用于 LDL 受体缺陷的纯合子高胆固醇血症患者。研究也发现，对于 不耐受他汀类药物的患者，PCSK9 抗体可有效降低 LDL 胆固醇。 尽 管这类药物很有可能获准用于严重的遗传性高胆固醇血症患者，但 PCSK9 抑制剂在临床中的广泛使用还需要大规模临床试验的支持，这些试验需要仔细评估其降低心血管事件的有效性和安全性，不管是单独用于他汀不耐受患者还是作为他 汀治疗的辅助药物。全球正在进行的此类试验包括三种药物，分别是 alirocumab、bococizumab 和 evolocumab，总共有超过 6 万名的患者将使用 PCSK9 抑制剂至少达 2-4 年。 至 今为止，有关 PCSK9 抑制剂的人类研究尚未发现严重的不良反应，这与现实中的发现是一致的——少部分出生时 PCSK9 基因严重功能丧失性突变患者的寿命和生育能力正常。除此之外，几乎所有的人体细胞均保持有合成内源性胆固醇的能力，而 HDL 转运系统可将胆固醇从肝脏转运至全身器官。 但 LDL 胆固醇浓度极低时患者的认知功能影响也受到了极大的关注，此外，许多无 LDL 胆固醇的动物物种却可以维持血脂转运的完全功能过程，而 PCSK9 基因敲除小鼠模型的研究也发现肝功能异常和糖耐量异常的问题。 有 关 PCSK9 抑制剂的毒性话题使得临床医师对 LDL 胆固醇最低安全水平保持持续关注。在他汀治疗研究中，LDL 胆固醇低于 1.3mmol/L 并持续 5 年并未增加任何特殊的害处，尽管观察到糖尿 病的风险稍微增高。尽管他汀类药物降低 LDL 并未发现增加颅内出血的风险，但该终点在所有的 PCSK9 试验中仍须仔细监测。 由于 PCSK9 抑制剂脱靶外的不良反应难以评估，在该药被证明可有效减少心血管事件发生的基础上，要想在临床中接受此类药物，来自长期试验的安全性数据就显得非常重要。如果该药进入临床，单克隆抗体的费用仍将是一个实质性的话题。 抑制 PCSK9 的替代药物包括小分子抑制剂——adnectins，它通过干扰 RNA 直接抑制合成，但这种方法需要预先使用抗炎药处理减少组胺反应，从而有可能限制该药在临床中的广泛使用。 除 了抑制 PCSK9 之外，其它降低 LDL 的药物正在研究中。例如，一种以肝脏腺苷三磷酸盐 - 柠檬酸盐裂解酶和磷酸腺苷激活蛋白激酶(AMPK)为靶向的新型药物正在两项 II 期试验中进行研究，发现该药分别使高胆固醇血症患者和糖尿病患者的 LDL 胆固醇降低了 27% 和 43%。 该药同时以 LDL 胆固醇和炎症为靶标，而对胰岛素抵抗患者使用此类药物的兴趣部分来源于另一个 AMPK 激活药物—二甲双胍—可安全用于 2 型糖尿病的治疗。另一种新药为过氧化物酶体增殖物受体 -δ兴奋剂 MBX-8025，该药可改善致动脉粥样硬化血脂和降低 CRP。 LDL 胆固醇相关基因发现带来的启示 LDL 受体的基因缺陷导致循环 LDL 胆固醇极度升高，这一过程曾经指导我们理解脂代谢及其在动脉粥样硬化血栓形成早期的角色。将此类极致表型的开发作为探索和研发新型降脂药的方法同样为洛美 他派、米泊美生和 PCSK9 抑制剂的研发提供了指导。然而，显著的基因突变通常会导致血脂的明显改变，很少只出现轻微异常。 一 项对 19 万名参与者的联盟研究描述了 157 个与一项或多项血脂成分有关的基因位点。所有的位点中只有一个编码蛋白质，有 4 个位点 CETP、TRIB-1、FADS1-2-3 和 ApoA1 在统计学上与 LDL 胆固醇、甘油三酯和 HDL 胆固醇明显相关。 许多脂类相关位点还与肥胖、胰岛素抵抗和高血压等代谢特征相关。与 LDL 和甘油三酯相关的位点继而也和冠脉疾病疾病事件相关(证据支持潜在的因果效应)，而只与 HDL 胆固醇相关的位点并未明确发现这种关系(证据不太支持潜在的因果效应)。 当研究人员尝试设计需要优先考虑的新药物靶点时，这些新出现的数据描述了研究人员需要面对的大部分挑战。在转化研究过程中，路径分析、蛋白质—蛋白质之间的相互作用、基因表达的调控、精细定位和定量方法等在评估未达到全基因组意义的位点时缺一不可。 除 了上述限制外，利用基因概念的转化研究已经出现了重大的新举措，同时也可潜在地减少心血管事件的发生，而不是仅仅关注直接降低 LDL 胆固醇。例如，与他汀诱导 LDL 降低的基因位点远离他汀减 少炎症的位点。此外，可溶性胆固醇转变为胆固醇结晶通常发生在动脉粥样硬化斑块中，并且与 NLRP3 炎性体激活和白介素 -1(主要促炎因子)的局部分泌有关。 这 些信息相当重要，因为它发现了动脉内胆固醇结晶沉积和固有免疫系统激活之间的联系，这也是动脉粥样硬化血栓形成启动和进展中关键的一步。抑制白介素 1 同样会使白介素 6 信号通路的下调。有两项研究显示，白介素 6 信号通路的遗传学改变不仅可终生降低炎性标记物的浓度，还与终生心血管事件的降低有关，从而支持了动脉粥样硬化保护的概念。 基 于部分上述概念，卡那单抗和低剂量甲氨喋呤等直接降低炎症的药物正在进行的大规模试验。这两种药物最终作用于肿瘤坏死因子 -α- 白介素 -6 信号通路，这也是与 darapladib、伐瑞拉迪和 succinobucinol 等失败的抗炎药的主要不同特点。至于在抑制 PCSK9 的试验中，在关注炎症降低有效性的同时仍需注意关注安全性。 结语 总 而言之，有广泛的证据证明 LDL 胆固醇不仅是心血管风险的根本决定因素，也是动脉粥样硬化血栓形成过程病因。许多来自随机安慰剂对照试验的数据始终显示，不管是在一级预防还是二级预防 中，他汀治疗降低 LDL 胆固醇是降低心肌梗死、卒中和心血管死亡安全 高效的方法。 尽管如此，仍有许多问题充满争议:检测 LDL 的最好方法,治疗前后评估 LDL 胆固醇是否必要,LDL 胆固醇可安全地降到多少,是否所有降低 LDL 胆固醇的药物均可降低心血管风险, 对于使 LDL 胆固醇降至远低于单独使用他汀类药物所能达到的新型药物，来自应硬终点试验的安全性和有效性数据不久即将公布。从生物学观点来看，终生、早期降低 LDL 胆固醇很可能最大限度地降低绝对风险。 因此，在青年和成年早期强调饮食和生活方式改变的公共卫生项目必须积极地予以实施。 (英文版 ) Two regulations promulgated for implementation is in the party in power for a long time and the rule of law conditions, the implementation of comprehensive strictly strategic plan, implementation in accordance with the rules and discipline to manage the party, strengthen inner-party supervision of major initiatives. The two regulations supporting each other, the < code > adhere to a positive advocate, focusing on morality is of Party members and Party leading cadres can see, enough to get a high standard; < rule > around the party discipline, disciplinary ruler requirements, listed as "negative list, focusing on vertical gauge, draw the party organizations and Party members do not touch the" bottom line ". Here, the main from four square face two party rules of interpretation: the first part introduces two party Revised regulations the necessity and the revision process; the second part is the interpretation of the two fundamental principles of the revision of laws and regulations in the party; the third part introduces two party regulations modified the main changes and needs to grasp several key problems; the fourth part on how to grasp the implementation of the two regulations of the party. < code > and < Regulations > revised the necessity and revised history of the CPC Central Committee the amendment to the Chinese Communist Party members and leading cadres honest politics several guidelines > and < Chinese Communist Party discipline and Punishment Regulations > column 1 by 2015 to strengthen party laws and regulations focus. Two party regulations revision work lasted a Years, pooling the wisdom of the whole party, ideological consensus, draw historical experience, respect for the wisdom of our predecessors, which reflects the unity of inheritance and innovation; follow the correct direction, grasp the limited goals, adhere to the party's leadership, to solve the masses of the people reflect a focus on the problem. The new revision of the < code > and < rule >, reflects the party's 18 and the eighth session of the third, the spirit of the fourth plenary session, reflecting the experience of studying and implementing the General Secretary Xi Jinping series of important speech, reflects the party's eighteen years comprehensive strictly practice. (a) revised two regulations of the party need of < the ICAC guidelines > in < in 1997 Leaders as members of the Communist Party of China clean politics certain criteria (Trial) > based on revised, the promulgation and implementation of January 2010, to strengthen the construction of the contingent of leading cadres play an important role. But with the party to manage the party strictly administering the deepening, has not been able to fully meet the actual needs. Content is too complicated, "eight prohibition, 52 are not allowed to" hard to remember, and also difficult to put into practice; the second is concisely positive advocated by the lack of prohibited provisions excessive, no autonomy requirements; the third is banned terms and discipline law, both with the party discipline, disciplinary regulations repeat and Criminal law and other laws and regulations repeat; the fourth is to "clean" the theme is not prominent, not for the existing problems, and is narrow, only needle of county-level leading cadres above. < rule > is in 1997 < Chinese Communist Party disciplinary cases (Trial) > based on revision, in December 2003 the promulgation and implementation, to strengthen the construction of the party play very important role. Along with the development of the situation, which many provisions have been unable to fully meet the comprehensive strictly administering the practice needs. One is Ji law, more than half of the provisions and criminal law and other countries laws and regulations Repetition; two is the political discipline regulations is not prominent, not specific, for violation of the party constitution, damage the authority of Party Constitution of misconduct lack necessary and serious responsibility to pursue; third is the main discipline for the leading cadres, does not cover all Party members. Based on the above situation, need to < the criterion of a clean and honest administration > and < rule > the two is likely to be more relevant regulations first amendment. By revising, really put the authority of Party discipline, the seriousness in the party tree and call up the majority of Party members and cadres of the party constitution of party compasses party consciousness. (II) two party regulations revision process the Central Committee of the Communist Party of China attaches great importance to two regulations revision . Xi Jinping, general books recorded in the Fifth Plenary Session of the eighth session of the Central Commission for Discipline Inspection, on the revised regulations < > made clear instructions. According to the central deployment, the Central Commission for Discipline Inspection from 2014 under six months begin study two regulations revision. The Standing Committee of the Central Commission for Discipline Inspection 4 review revised. Comrade Wang Qishan 14 times held a special meeting to study two regulations revision, amendment clarifies the direction, major issues of principle, path and target, respectively held a forum will listen to part of the province (area) secretary of the Party committee, Secretary of the Discipline Inspection Commission, part of the central ministries and state organs Department The first party committee is mainly responsible for people, views of experts and scholars and grassroots party organizations and Party members. Approved by the Central Committee of the Communist Party of China, on 7 September 2015, the general office of the Central Committee of the Party issued a notice to solicit the provinces (autonomous regions, municipalities) Party, the central ministries and commissions, state ministries and commissions of the Party (party), the General Political Department of the military, every 3 people organization of Party of two regulations revision opinion. Central Commission for Discipline Inspection of extensive solicitation of opinions, careful study, attracting, formed a revised sent reviewers. In October 8 and October 12, Central Committee Political Bureau Standing Committee and the Political Bureau of the Central Committee After consideration of the two regulations revised draft. On October 18, the Central Committee of the Communist Party of China formally issued two regulations. Can say, two laws amendment concentrated the wisdom of the whole party, embodies the party. Second, < code > and < Regulations > revision of the basic principles of two party regulations revision work and implement the party's eighteen, ten eight plenary, the spirit of the Fourth Plenary Session of the Eleventh Central Committee and General Secretary Xi Jinping important instructions on the revised < low political criterion > and < Regulations >, highlighting the ruling party characteristics, serious discipline, the discipline quite in front of the law, based on the current, a long-term, advance as a whole, with Bu Xiuding independent < rule > and < rule >. Main principle is: first, adhere to the party constitution to follow. The constitution about discipline and self-discipline required specific, awaken the party constitution of party compasses party consciousness, maintaining the authority of the constitution. General Secretary Xi Jinping pointed out that "no rules, no side round. Party constitution is the fundamental law, the party must follow the general rules. In early 2015 held the eighth session of the Central Commission for Discipline Inspection Fifth Plenary Session of the 16th Central Committee, Xi Jinping again pointed out that constitution is the party must follow the general rules, but also the general rules." the revision of the < code > and < rule > is Method in adhere to the regulations established for the purpose of combining rule of virtue is to adhere to the party constitution as a fundamental to follow, the constitution authority set up, wake up the party constitution and party rules the sense of discipline, the party constitution about discipline and self-discipline specific requirements. 4 second is to adhere to in accordance with the regulations governing the party and the party. The Party of rule of virtue "de", mainly refers to the party's ideals and beliefs, excellent traditional style. The revised the < code > closely linked to the "self-discipline", insisting on the positive initiative, for all members, highlight the "vital few", emphasized self-discipline, focusing on the morality, and the majority of Party members and the ideological and moral standards. The revised < > Ji method separately, Ji, Ji Yan to Method, as a "negative list", emphasizing the heteronomy, focusing on vertical gauge. Is this one high and one low, a positive reaction, the strict party discipline and practice results transformation for the integration of the whole party to observe moral and discipline requirements, for the majority of Party members and cadres provides benchmarking and ruler. Third, insist on to. In view of the problems existing in the party at the present stage, the main problems of Party members and cadres in the aspect of self-discipline and abide by the discipline to make clearly defined, especially the party's eighteen years strict political discipline and political rules, organization and discipline and to implement the central eight provisions of the spirit against the four winds and other requirements into Disciplinary provisions. Not one pace reachs the designated position, focusing on in line with reality, pragmatic and effective. After the revision of major changes, major changes in the < code > and < rule > modified and needs to grasp several key problems (a) < code > < code > adhere to according to regulations governing the party and party with morals in combination, for at the present stage, the leadership of the party members and cadres and Party members in existing main problems of self-discipline, put forward principles, requirements and specifications, showing Communists noble moral pursuit, reflected at all times and in all over the world ethics from high from low 5 common requirements. One is closely linked to the "self-discipline", removal and no direct relation to the provisions of . the second is adhere to a positive advocate, "eight prohibition" 52 are not allowed to "about the content of the" negative list moved into synchronization amendment < cases >. Three is for all the party members, will apply object from the leadership of the party members and cadres to expand to all Party members, fully embodies the comprehensive strictly required. The fourth is prominent key minority, seize the leadership of the party members and cadres is the key, and put forward higher requirements than the ordinary Party members. Five is to simplify, and strive to achieve concise, easy to understand, easy to remember. The revised < code > is the ruling Party since the first insists on a positive advocate forAll Party members and the self-discipline norms, moral declaration issued to all members of the party and the National People's solemn commitment. > < criterion of a clean and honest administration consists of 4 parts, 18, more than 3600 words. After the revision of the < code >, a total of eight, 281 words, including lead, specification and Party member cadre clean fingered self-discipline norms, etc. Part 3 members low-cost clean and self-discipline, the main contents can be summarized as "four must" "eight code". Lead part, reiterated on ideal and faith, fundamental purpose, the fine traditions and work style, noble sentiments, such as "four must" the principle of requirements, strong tone of self-discipline, The higher request for 6 and supervised tenet, the foothold in permanent Bao the party's advanced nature and purity, to reflect the revised standards requirements. Members of self-discipline norms around the party members how to correctly treat and deal with the "public and private", "cheap and rot" thrifty and extravagance "bitter music", put forward the "four norms". Party leader cadre clean fingered self-discipline norms for the leadership of the party members and cadres of the "vital few", around the "clean politics", from civil servant of the color, the exercise of power, moral integrity, a good family tradition and other aspects of the leadership of the party members and cadres of the "four norms" < > < norm norm. "The Party member's self-discipline norms" and "party members and leading cadre clean fingered self-discipline norms," a total of eight, collectively referred to as the "eight". "Four must" and "eight" of the content from the party constitution and Party's several generation of leaders, especially Xi Jinping, general secretary of the important discussion, refer to the "three discipline and eight points for attention" statements, and reference some embody the Chinese nation excellent traditional culture essence of epigrams. (2) the revised regulations, the main changes in the revised Regulations > to fully adapt to the strictly requirements, reflects the according to the regulations governing the law of recognition of deepening, the realization of the discipline construction and Jin Ju. < rule > is party a ruler, members of the basic line and follow. And the majority of Party members and cadres of Party organizations at all levels should adhere to the bottom line of thinking, fear discipline, hold the bottom line, as a preventive measure, to keep the party's advanced nature and purity. 1, respect for the constitution, refinement and discipline. Revised < rule > from comprehensive comb physical constitution began, the party constitution and other regulations of the Party of Party organizations and Party discipline requirements refinement, clearly defined in violation of the party constitution will be in accordance with regulations to give the corresponding disciplinary action. The original 10 categories of misconduct, integration specification for political discipline, discipline, honesty and discipline masses Ji Law and discipline and discipline and other six categories, the content of < rule > real return to Party discipline, for the majority of Party members and listed a "negative list. 7 2, highlighting the political discipline and political rules. > < Regulations according to the stage of the discipline of outstanding performance, emphasizing political discipline and political rules, organization and discipline, in opposition to the party's leadership and the party's basic theory, basic line, basic program and basic experience, the basic requirement of behavior made prescribed punishment, increase the cliques, against the organization such as violation of the provisions, to ensure that the central government decrees and the Party of centralized and unified. 3, adhere to strict discipline in the law and discipline In front, Ji separated. Revised < Regulations > adhere to the problem oriented, do Ji separated. Any national law existing content, will not repeat the provisions, the total removal of 79 and criminal law, repeat the content of the public security management punishment law, and other laws and regulations. In the general reiterated that party organizations and Party members must conscientiously accept the party's discipline, die van comply with national laws and regulations; at the same time, to investigate violations of Party members and even criminal behavior of Party discipline and responsibility, > < Regulations distinguish five different conditions, with special provisions were made provisions, so as to realize the connection of Party discipline and state law. 4, reflect Wind building and anti-corruption struggle of the latest achievements. < rule > the party's eighteen years implement the spirit of the central provisions of the eight, against the requirements of the "four winds" and transformation for disciplinary provisions, reflecting the style construction is always on the road, not a gust of wind. In the fight against corruption out of new problems, increase the trading rights, the use of authority relatives profit and other disciplinary terms. Prominent discipline of the masses, the new against the interests of the masses and ignore the demands of the masses and other disciplinary terms and make provisions of the disposition and the destruction of the party's close ties with the masses. Discipline to protect the party's purpose. 8 of these regulations, a total of three series, Chapter 15, 178, more than 24000 words, after the revision of the regulations a total of 3 series, Chapter 11, 133, 17000 words, divided into "general" and "special provisions" and "Supplementary Provisions" Part 3. Among them, add, delete, modify the provisions of the proportion of up to nearly 90%. 1, the general general is divided into five chapters. The first chapter to the regulations of the guiding ideology, principles and scope of application of the provisions, highlight the strengthening of the party constitution consciousness, maintenance the authority of Party Constitution, increase the party organizations and Party members must abide by the party constitution, Yan Centralized centralized, would examine at all levels of the amended provisions implementing and maintaining Party discipline, and consciously accept the party discipline, exemplary compliance with national laws and regulations. The second chapter of discipline concept, disciplinary action types and effects of the regulations, will be a serious warning from the original a year for a year and a half; increase the Party Congress representative, by leaving the party above (including leave probation) punishment, the party organization should be terminated its representative qualification provisions. The third chapter of the disciplinary rules of use prescribed in the discipline rectifying process, non convergence, not close hand classified as severely or heavier punishment. "Discipline straighten "At least eighteen years of five years, these five years is to pay close attention to the provisions of the central eight implementation and anti -" four winds ". The fourth chapter on suspicion of illegal party disciplinary distinguish five different conditions, with special provisions were made provisions, to achieve effective convergence of Party and country 9 method. < rule > the provisions of Article 27, Party organizations in the disciplinary review found that party members have committed embezzlement, bribery, dereliction of duty dereliction of duty and other criminal law act is suspected of committing a crime shall give cancel party posts, probation or expelled from the party. The second is < Regulations > Article 28 the provisions of Party organizations in the disciplinary review But found that party members are stipulated in the criminal law, although not involved in a crime shall be investigated for Party discipline and responsibility should be depending on the specific circumstances shall be given a warning until expelled punishment. This situation and a difference is that the former regulation behavior has been suspected of a crime, the feeling is quite strict, and the latter for the behavior not involving crime, only the objective performance of the provisions of the criminal code of behavior, but the plot is a crime to slightly. < Regulations > the 29 provisions, Party organizations in the discipline review found that party members and other illegal behavior, affect the party's image, the damage to the party, the state and the people's interests, we should depend on the situation Seriousness given disciplinary action. The loss of Party members, seriously damaging the party's image of behavior, should be given expelled from the party. At this article is party member is in violation of the criminal law outside the other illegal acts, such as violates the public security administration punishment law, customs law, financial laws and regulations behavior. The fourth is < cases > Article 32 stipulates, minor party members and the circumstances of the crime, the people's Procuratorate shall make a decision not to initiate a prosecution, or the people's court shall make a conviction and exempted from criminal punishment shall be given within the party is removed from his post, probation or expelled from the party. Party members and crime, sheets were fined in accordance with For acts; the principal Ordinance amended the provisions of the preceding paragraph. This is the new content, in order to achieve Ji method effective convergence. Five is < > the thirty third article 10 of the provisions, the Party member due to an intentional crime is sentenced to criminal law (including probation) sheets or additional deprivation of political rights; due to negligence crime and was sentenced to three years or more (excluding three years) a penalty, shall give expelled punishment. Due to negligence crime is convicted and sentenced to three years (including three years) in prison or be sentenced to public surveillance, detention, shall in general be expelled from the party. For the individual may not be expelled from the party, should control Approval. This is followed and retained the original > < Regulations the provisions of punishment party authorization rules and report to a level party organizations. For is "party members with criminal acts, and by the criminal punishment, generally should be expelled from the party". The fifth chapter of probationary Party member of the discipline and discipline after missing members of the treatment and punishment decisions, such as the implementation of the provisions, clear the related party discipline and punishment decision made after, for duties, wages and other relevant alteration formalities for the longest time. 2, sub sub section will the original regulations of 10 categories of acts of violation of discipline integration revised into 6 categories, respectively, in violation of the punishments for acts of political discipline "in violation of discipline behavior of punishment" in violation of integrity of disciplinary action points "of violation punishments for acts of mass discipline" "the violation of work discipline, punishment" in violation of discipline of life behavior punishment "6 chapters. 3, annex" Supplementary Provisions "clear authority making supplementary provisions of, cases of interpretative organ, as well as regulations implementation time and retroactivity etc.. 11 (3) learning understanding > < regulations needs to grasp several key problems The first problem -- about the violation of political discipline behavior > < new ordinance chapter 6 the political discipline column for the six disciplines, that is the main opposition to Party leadership and the opposition of the basic theory, basic line, basic program and basic experience, basic requirements of misconduct made provisions of the disposition, especially the eighteen since the CPC Central Committee put forward the Yan Mingzheng treatment of discipline and political rules requirements and practical achievements transformation for Discipline article, increase the false debate central policies, cliques, against the organization review, make no discipline of the principle of harmony terms. These are the party's eighteen years in comprehensive strictly Process combined with the practice of rich content. (1) false debate the central policies and undermine the Party of centralized and unified the problem is made in accordance with the provisions of the party constitution. Constitution in general programme requirements adhere to democratic centralism is one of the requirements of the construction of the party must adhere to the four cardinal. Application of this principle is not only the party the basic organization principle and is also the mass line in party life, it requires that we must fully develop inner-party democracy, respect for the dominant position of Party members, safeguarding the Party member democratic rights, give full play to the enthusiasm and creativity of the party organizations at all levels and Party members, at the same time, also must implement the right concentration, ensure the party's mission < the chaos in unity and concerted action to ensure that the party's decision to get quickly and effectively implementing. The Party Central Committee formulated the major principles and policies, through different channels and ways, fully listen to the party organizations and Party members of the opinions and suggestions, but 12 is some people face to face not to say back blather "" will not say, after the meeting said, "" Taiwan does not say, and nonsense ", in fact, not only disrupt the people thought, some causing serious consequences, the damage to the Party of the centralized and unified, hinder the central policy implementation, but also a serious violation of the democratic system of principles. There is no doubt that shall, in accordance with the Regulations > 4 Specified in Article 6 to give the appropriate punishment. For did not cause serious consequences, to give criticism and education or the corresponding tissue processing. (2) about the destruction of the party's unity < New Regulations > the forty eighth to fifty second article, to damage Party's unity unified and violation of political discipline, punishment situation made explicit provisions. Article 52 of the new "in the party get round group, gangs seek private gain, cliques, cultivate private forces or through the exchange of interests, for their own to create momentum and other activities to gain political capital, given a serious warning or withdraw from their party posts disposition; if the circumstances are serious, to give Leave a party to observation or expelled from the party. (3) on against the organization review of the provisions of the constitution, party loyalty honesty is party members must comply with the obligations. Members must obey the organization decision, shall not violate the organization decided encounters by asking questions to find organization, rely on the organization, shall not deceive the organization, against the organization. For example, after the investigation does not take the initiative to explain the situation, but to engage in offensive and defensive alliance, hiding the stolen money is against survey organization, is a violation of the behavior of political discipline. Article 24 of the original > < Regulations, although the provisions of the interference, hinder group review the behavior of the fabric can be severely or 13 Aggravated punishment, but did not put this kind of behavior alone as a discipline for qualitative amount of discipline. > < new regulations increase the Article 57, "anti organization review, one of the following acts, given a warning or serious warning; if the circumstances are relatively serious, giving removed from or placed on probation within the party post; if the circumstances are serious, give expelled from the party: (a) on supply or forged, destroyed, transfer, conceal evidence; (II) to prevent others expose, providing evidence Material; (III) harboring co personnel; (4) to the organization to provide false information, to hide the fact; (5) the him against the acts of the organization review. "< rule > add this clause to the Constitution requires more specific, the previous no punishment in accordance with the definite list and put forward clear punishment in accordance with. (4) about organizing or participating in superstitious activities as < Regulations > about engage in activities of feudal superstition obstruction of social management order" violations of Article 164 the provisions, but according to the original < rule > only in disrupting production, work, social life order The case to be disciplinary treatment, in other words, alone make the feudal superstition, organize or participate in the activities of feudal superstition of, does not constitute a violation. Which is not consistent with the requirements of our party's political party. > < new regulations in this change is, superstitious activities on the political discipline, increase the Article 58, is the organization of Party members, in superstitious activities included in violation of the negative list of political discipline deserves punishment, which and Party members should adhere to the correct political principle, political standpoint and viewpoint is consistent. 14 the second question about organization and discipline violation behavior of democratic centralism is our The party's fundamental organizational system. < New Regulations > Chapter 7 "in violation of the behavior of organizational discipline punishment" mainly for violation of democratic centralism, contrary to the "four obey the discipline behavior for source classification rules. Increased not in accordance with the relevant provisions or requirements to the organization for instructions to report on major issues; do not report truthfully report about personal matters; falsify personal archives; hide before joining the party serious mistakes; leading cadres in violation of the relevant provisions of the organization, will participate in the spontaneous formation of the old Xiang, Alumni Association, comrades in arms; to obtain illegal country residence abroad or foreign nationality, illegal for private frontier Documents such as discipline terms. (1) on the report truthfully report personal matters in 2010 the Central Committee of the Communist Party of China office, office of the State Council introduced < provisions on issues related to the leading cadres to report personal >, is clear about the request, deputy division level and above leading cadres should truthfully report changes in my marriage and spouse, children, moved to the country (territory), practitioners, income, real estate, investment and other matters, for failing to report, do not report, concealed and unreported, according to the seriousness of the case, giving criticism and education, and to make a correction within a time limit, shall be ordered to make a check, the commandment Jiemian conversation, informed criticism or jobs, free Post processing, constitute violations, in accordance with the relevant provisions shall be given a disciplinary sanction. But since the original < Regulations > and there is no corresponding specific terms, the violation of the regulations, do not report, as a false report about personal matters, there is no corresponding disciplinary action terms, in practice it is difficult to operate. In this regard, in order to solve is not reported, as a false report about personal matters 15 asked censure, the new < Regulations > add the Article 67 of violation of personal matters related to reporting requirements, report truthfully report the clear punishment basis, making this kind of violation behavior is no longer free drilling for Exhibition on matters of personal checks to verify and supervision of cadres, discipline review provides a powerful discipline guarantee. (2) about the illegal organization, to fellow, alumni, friends of the war will < regulations stipulated in Article 68 of >, leading cadres of the party in violation of relevant provisions of the organization, will participate in the spontaneous formation of fellow, Alumni Association, comrade in arms to give the punishment according to the seriousness of the case. Here special needs note is three points: this provision for only the leading cadres ", reflecting the high requirements of leading cadres; second violation in 2002, the Central Commission for Discipline Inspection, the central Organization Department and the The relevant provisions of the General Political Department jointly issued the < off in leading cadres not to participate in the initiative to set up "the villagers would be" alumni "" comrades in arms organization notice >. That is to say, to the spontaneous formation of fellow, Alumni Association, comrades in arms will constitute the premise of discipline is a violation of the provisions of this. The notification specified, leading cadres are not allowed to participate in the spontaneous incorporation of fellow, alumni, between comrades association would like the organization and shall not bear the sorority Human and the organizer shall not hold the corresponding position in the sorority; shall not borrow machine woven "network" and engage in kiss sparsely, round and round the gangs, but not "align" "Jieyi Gold Orchid" behavior. The third is to emphasize here that shall be organized to participate in the initiative to set up the villager, Alumni Association, comrades in arms. The so-called 16 spontaneous was established mainly means without registration. Therefore, Party members include leading cadres in the normal range of fellow, alumni, comrades in the party is not a violation of the rules of Party discipline. The three problem about integrity violations discipline Lian Jie discipline has been eighteen years clean government and anti The focus of the work of corruption. This Ordinance to amend, honesty and discipline this biggest adjustment, the new content, most of which prescribed by the original < criterion of a clean and honest administration > 8 ban and 52 are not allowed into the basic this part. (1) the central eight provisions of the spirit and requirements into < New > in the regulations of the party's eighteen years, central resolutely implement the provisions of the eight and pay close attention to the node and intensive briefing, on public funds, private bus, public funds tourism, gifts of public funds, the big parade and lavish weddings and festive, illegal payment allowances and subsidies, illegal construction of buildings such as the original masses reflects the relatively strong, "four winds" problem of the Resolute rectification. But original < Regulations > to eat and drink, super standard reception and no clear and specific expression, new < rule > will implement eight Central provisions of the spirit of the problem increased to "clean cheap self-discipline" chapter, clear to exceed the standard, beyond the scope of the reception or borrow machine eating and drinking etc. some in violation of the provisions of the spirit of the eight central relevant persons responsible for punishment, once the violation will be according to the < rule > severely punished, binding, enhanced significantly. One is to add Article 87, about to obtain illegal, hold, and the actual use of the sports card, golf ball cards and other consumer card. Illegal access to private clubs made the punishment provisions. The second is increase the Article 97, has made provisions of the disposition of illegal self pay or 17 spamming allowances, subsidies and bonuses. The third is added to the Article 99, on violation of super standard, beyond the scope of the reception or borrow machine eat and drink to make the provisions of punishment. The fourth is to increase the Article 101, on the management of conference activities in violation of the provisions made sanctions regulations. The fifth is the increased Article 102, for violation of office space management provisions made the punishment provisions. Six is to split the original < rule > Article 78, formed article 98, Article 100 of public Models of tourism, violate the provisions on the administration of the use of discipline of the bus through the list of made a more detailed provisions, apply more operational. Seven is increased the article 96, in violation of the relevant provisions of the, to participate in public funds to pay for dinner, high consumption of entertainment, fitness activities and public funds to buy gift, send gifts to make the provisions of the disposition. On the violation of the central provisions of the spirit of the eight, in addition to > < new regulations into "violation of honesty and self-discipline" misconduct outside, is different with the original < Regulations >, revised < rule > clearly defined not only to disposition of the directly responsible persons, but also dispose of collar Guide responsibilities. (2) increased trading rights, use of authority or position influence as relatives and close to profit violation of the terms of the < New Regulations > absorption < clean politics several guidelines > the relevant provisions spirit, increase the "negative list, including trading rights, the functions and powers or duties of influence as relatives and staff around profit. Increase Article 81" mutual use of office or authority ring for each other and their spouses, children and their spouses and other relatives, around 18 personnel and other specific relationship between the people to seek benefits engage in trading rights, given a warning or serious warning Sanctions; if the circumstances are relatively serious, giving removed from or placed on probation within the party post; if the circumstances are serious, shall be expelled from the party. Increase Article 82 "connivance, acquiescence to the spouse, children and spouse etc. relatives and staff around the effect of Party members and cadres personal authority or position for personal gain, if the circumstances are relatively minor, given a warning or a serious warning; if the circumstances are relatively serious, giving removed from or placed on probation within the party post; if the circumstances are serious, the given Expelled from the party. Party members and cadres of the spouses, children and their spouses does the actual work and get salary or although the actual work but to receive significantly beyond the same rank salary standard, Party members and cadres informed fails to correct, in accordance with the provisions of the preceding paragraph. "(3) about the gifts, gifts misconduct from handling practices in recent years, engaged in official cadres received gifts, gifts problems more prominent. This has seriously affected the image of Party members and cadres, damaged the relations between the party and the masses, and is a hotbed of corruption, is really necessary for this kind of behavior to be disciplined. < rule > no on accepting gifts, gifts, Card consumption behavior to engage in simple "one size fits all", but the difference between the different separately. One is in accordance with the provisions of Article 83, accepting may affect the impartial enforcement of the official gifts, gifts, consumer cards to depending on the seriousness of the case shall be given disciplinary sanctions. That is to say, for may affect the fair execution of business gifts, gifts, consumer cards are not allowed to accept. 19 is in accordance with the provisions of Article 83, accepting was significantly higher than normal ceremony is still exchanges of gifts, gifts, consumer card to disciplinary action. This is new regulations that daily life is purely reciprocity, accepting the same thing, boys , fellow friends gifts, gifts, shopping cards, although and fair execution of business has nothing to do, also want to as the case shall be dealt with, the situation is obviously beyond normal reciprocity ". The so-called" reciprocity ", one is emphasizes the reciprocal in protocol. In other words is you to me how, I to you how, not only does not go. The second is to significantly exceeded the normal local economy level, customs and habits, economic capacity of individual gifts, gift value. Specific sanctions to according to the processing of a variety of factors to consider, as appropriate. The third is the root according to the provisions of Article 84," to Engaged in public service personnel and their spouses and children, children's spouses and other relatives and other specific relationship presented Ming Xianchao normal reciprocity of gifts, gifts, consumer card, if the circumstances are relatively serious, given a warning until probation. "In accordance with the above provisions, gift giving significantly beyond the normal reciprocity, giver constitute the discipline. (4) on illegal trading of stocks or of other regulations of securities investment < > Article 88 is engaged in punishment regulation of camp and activity in violation of the relevant provisions on. Among them, 3 will" buying and selling stocks or in other securities investment "column as one of disciplinary cases Out. First need to be clear, > < regulations did not change the provisions of the Ordinance. The ordinance of the provisions of the second paragraph of Article 77 provisions "who, in violation of the provisions of the sale of stocks" is one of the violation, and at the beginning of the first paragraph of this article "violation of 20 against the relevant provisions of the" textual representation of the repeat revision. In, just from the legislative technique removed the "personal" in violation of the provisions, content and not to change the original provisions. Need to clear is, "buy or sell a stock or of other securities investment" refers to violation of the relevant provisions refers to in April 2001, the Party Central Committee, the State Council promulgated the On the work of the party and government organs staff's personal investment in securities if dry provisions >. According to the provisions of Article 3, use of work time, office facilities, the sale of stocks and securities investment fund belongs to illegal behavior. The fourth question, about the violation of the masses of the disciplinary actions < new regulations > would violate public discipline behavior of a single set of a class of restored "three rules of discipline and eight note" in the discipline of the masses of excellent traditional. < New Regulations > Chapter 9 "to violate the masses of disciplinary action", mainly the destruction of the party's close ties with the masses of misconduct made provisions on disciplinary; enrich and perfect the super standard, beyond the scope of Xiang Qun < All to raise fund and labor, in for involving the public affairs deliberately, chinakayao, in social security, policy support, disaster relief funds and materials and other matters assigned any kind and affectionate friends, obviously unfair acts against the interests of the masses of the disciplinary terms; increase the terms not in accordance with the provisions of the public party provided, government, factory and village (neighborhood) provided etc. violation of the people's right to know the behavior of the discipline. The fifth issue, on the violation of work discipline violation of work discipline added "negative list, including Party organizations carry out strictly Main responsibility for poor discipline terms. (1) the new party organization comprehensive strictly the main responsibility of the party does not fulfill the 21 or perform poor disciplinary terms < New Regulations > has a lead people to pay attention to the new terms, that is, in chapter ten "on the violation of work discipline behavior punishment" increase in the one hundred and fourteenth "party fail to perform comprehensive strictly the main responsibility of the party or to perform comprehensive strictly the main responsibility for administering the ineffective, resulting in serious damage or serious adverse effects, to the person directly responsible and the responsibility of leadership and give a warning or serious warning. The situation is serious, giving removed from their party posts or on probation Punishment. "Here the changes. For the first time, the main responsibility write < rule >. (2) new shall report does not report or false reporting discipline shall increase the 117 bar" in the higher level units to check to inspect the work or report to the parent unit, work report of shall report the matters do not report or do not report, cause serious damage or serious adverse effects of, to the person directly responsible and the responsibility of leadership, to give warning or a serious warning; if the circumstances are serious, giving removed from their party posts or placed on probation. "For example, during the tour visits to the region, the unit Members the obligation to the inspection teams to reflect the true situation, to conceal not reported or intentionally to the inspection teams to provide false information, causing serious damage or serious adverse effects of, the person directly responsible and the responsibility of leadership should be in accordance with the provisions of < rule > Article 117 to give the appropriate punishment. (3) the new not granted in accordance with the provisions of punishment, not according to the provisions of the implementation of disciplinary measures 22 violation of the provisions of Article 115 "Party organizations have one of the following circumstances, the direct leadership responsibility. Probation: members were sentenced punished, in accordance with the provisions give disciplinary action or in violation of state law Rules of behavior should be given disciplinary punishment and dispose of; disciplinary punishment by decision or complaint review the decision made, not in accordance with the provisions of the implementation decisions on punishment of the party, position, rank, and the treatment of the matters; Party members subject to disciplinary action, not in accordance with the cadre management authority and organizational relationships of by dispose of Party members to carry out education and supervision of daily management. "What needs to be pointed out is," cliff "demoted with cars, housing, secretary problem, implementation is not a discipline and party posts and ranks treatment by the organization department is responsible for the implementation, with cars, housing by the logistics department is responsible for the implementation of, Ji Commission responsible oversight responsibilities. The six questions, about the acts violating the discipline of life "in violation of discipline of life behavior punishment", mainly to "four winds" problems and a serious violation of social morality, family virtue acts of misconduct made provisions on disciplinary, an increase of extravagant life, contrary to the social public order and good customs disciplinary terms. Worth mentioning is, > < Regulations in Article 150 about "adultery" "mistress (Cardiff) formulation in the new < rule > is removed, to expand the scope of Article 127 provisions" and others hair improper sexual relations, let face disciplinary action Wider more strict. Four, and earnestly do a good job in the < code > and < rule > implement system of life lies in execution. < code > and < Regulations > is 23 Party organizations at all levels of a strong constraint and all Party members follow. Learning and implementing the < code > and < rule > is party committees (party), commission for discipline, discipline inspection group), the majority of Party members and cadres of the common responsibility, must party caught together, the party one execution. () Party committees (party) and play and implement comprehensive strictly the main responsibility, pays special attention to the two party regulations learning cross penetration. One is to Adhere to the party constitution is fundamental to follow, and resolutely safeguard the authority of the Party Chapter. The second is to adhere to the problem oriented, to strictly political discipline and political rule moments in the first place. The third is to adhere to the discipline and rules quite in front must not allow the bottom line to break the discipline. The fourth is to seriously organize the study of propaganda and education, in the city party members to create a disciplined, about the rules of the strong atmosphere. (II) Commission for Discipline Inspection at all levels (Discipline Inspection Group) to an important basis for the revised two party regulations as, adhere to easily blame, strengthen supervision and enforcement And early method in combining Ji, increase accountability efforts. One is to two regulations within the party important basis, adhere to the party constitution duties, with strict discipline to maintain the constitution authority. The second is to adhere to high standards and keep the bottom line, adhere to Ji Yan in law and discipline, the discipline and rules quite in front, grasping grasping small, easily blame, comprehensive use of supervision and discipline of "four kinds of form" in the discipline embodies the strict requirements and care for the discipline, tighten up, Yan. According to discipline in accordance with regulations to carry out disciplinary review. Increase the violations punishment, clues can initiate an investigation on the trial of cases According to the discipline on the provisions of the proportion of processing and control manager maintains discipline. To focus on investigating non convergence, don't accept hand serious disciplinary violations at the same time, pay more attention to the general review of discipline 24 behavior, and gradually increase the lighter punishment. Four is to illuminate two party regulations, combined with the local district of the Department of party conduct Lianzheng to relevant laws and regulations system clean, timely research proposes to establish, change, waste release opinion, avoid conflict, and the fasten system of cage, and gradually formed not rot, not rot, not want to rot system and working mechanism. (3) the leadership of the party members and cadres should play an exemplary role. The rate of higher consciousness of the front of the Ordinance to lead practice self-discipline norms, leading to maintain discipline of seriousness and authority. One is the above rate, demonstration and guidance, take the lead in learning and mastering the < code > and < > the requirements and regulations, do the deep understanding, learning to use. The second is to play an exemplary role in abiding by discipline rate, take the lead in practicing self-discipline norms, firmly establish before the discipline are equal, the system has no privilege, discipline is no exception, and consciously do standards, require more strict measures more practical. Third is to consciously accept supervision, conscientiously participate in the democratic life and debriefing honesty responsibility, such as Real to the party organization to report personal matters, and to accept the supervision of the work and life of the normal, habits under the supervision of the exercise of power, to carry out the work. The fourth is to set an example for the strict enforcement of discipline. Leading cadres should take the lead in the maintenance of discipline of seriousness and authority, to dare to seriously, dare to struggle, dare to offend people, for misconduct not laissez faire, but do not indulge, not tolerate to ensure the party constitution of party compasses party put in place. (4) the majority of Party members and cadres to set high standards and hold the bottom line, consciously abide by the < code > and < rule >. One is to control the < standard > and < 25 cases >, tight Close connection with their own thoughts, practical work and life, efforts to solve the problems, to enhance the study and implement of the effectiveness and pertinence. The second is to establish a high standard and hold the bottom line, consciously in the self-discipline pursuit of high standards, strictly in the party away from the red line discipline, discipline, about the rules and know fear, distrust, the formation of the honor system, comply with the system, safeguard system of good habits. Regulations and discipline regulations of < < New Revision of the Communist Party of China clean fingered self-discipline criterion > and < Chinese Communist Party Disciplinary Regulations > is the Party Central Committee in the new situation to promote the comprehensive strictly root of the lift, the regulations of the party construction of keeping pace with the times. We should study and implement the Standards > and < > as the primary political task, adhere to the party constitution duties, adhere to the discipline of, Ji Yan in law, the full implementation of supervision and discipline accountability responsibilities for coordination and promotion "four overall" strategic layout in XX District vivid practice to provide a strong guarantee. - Si Jian Wu, and effectively enhance the implementation of the implementation of the < code > < > The consciousness of General Secretary Xi pointed out that the party is in charge of the party, to manage the party; strictly, it can cure good party. Criterion > and < rule > keep pace with the times is our party to form a new potential strictly rules, to deepen understanding of the ruling law, is a comprehensive strictly, and strengthen the supervision within the party important grasper. Criterion > closely linked to the theme of self-discipline, self-discipline intensity-modulated, focusing on morality, for the majority of Party members and cadres set to see, feel the high standard, show the Communists noble moral sentiment; District Ordinance < < rule > the constitution of discipline integration into a political discipline, organization and discipline, honesty and discipline, discipline of the masses, work discipline, discipline, emphasize discipline, focusing on established rules, to draw the party organizations and Party members do not touch the bottom line. Party committees (party) to effectively strengthen the study and publicize the implementation of the < code > and < rule > the organization and leadership of criterion > and < > a full range, multi angle, deep publicity, the formation of study and publicize and implement the boom, in order to consolidate the development of good political environment to create a positive environment and atmosphere. The majority of Party members and cadres to strict requirements, the < rule > and < Ordinance cases > as a guide to action and behavior criterion, adhere to the moral standards and discipline of the bottom line, to maintain the discipline of worship and awe, learning, compliance, and maintain party discipline and rules of the model. The discipline inspection and supervision organs and cadres to the < code > and < > as the deepening of the "three", and strengthen supervision and discipline of accountability is important to follow correctly grasp the use of supervision and discipline of "four types", promote the comprehensive strictly in new roots. Strict discipline, adhere to the discipline and rules quite in front of the enterprise in the implementation of expensive to implement to execute. The discipline inspection and supervision organs to implement the < code > and < Efforts to investigate cases > as an opportunity, adhere to the party should manage the party strictly, serious performance of their duties to promote two regulations implementation. Change discipline concept. From the simple "investigation of illegal" to a comprehensive "stare at violate discipline"; from the business case to prosecute the big cases and timely solve the signs of tilt to. From the orientation to the normal supervision; from the tube "minority" to resist the "most". Guide Party members and cadres to seriously implement the < code > and < rule >, consciously abide by the political, organizational, honest people, work, life six discipline. Urge the leadership cadres sent to play an exemplary role, take the lead in strictly enforced. Relaxation and rest Strong wind is Su Ji, closely linked to the "four winds" prone to multiple, the masses reflect the strong important nodes and, glued to the four winds "new form, new trends, seriously investigate and deal with violations of the central eight provisions of the spirit, to increase the bulletin exposure intensity, the formation of Chajiu" four winds "loudly, continue to release and discipline must be strict signal. At the same time, extended supervision tentacles, through the development of the rural and fishery party conduct Lianzheng construction inspection, issued in a timely manner, Chajiu occurred in grassroots side of corruption and unhealthy, and earnestly safeguard the interests of the masses and social stability. The creativity and discipline. Grasp and make good use of the supervision and discipline of" four types ", to ensure the Promoting clues to lots of discipline and the law of the vacuum tube, strict together. Not only to the "less" and "very few" thorough investigation severely punished, but also the "most" to maintain zero tolerance trend through layers of conductive pressure, let the discipline about the rules for each party members and cadres consciously follow. At present, it is necessary to implement the "list" management, strictly follow the clues to the disposal of five standards, make the classification of disposal, dynamic cleanup. Zadok Party committees at all levels to implement the main responsibility, comprehensive use of disciplinary action and tissue processing and other means to effectively curb the commonplace, used to see do not blame the "small problem", not because of "practice" and "exception". Prominent Discipline characteristics, the problems of violation of discipline and rules into the focus of supervision and discipline and disciplinary review. At the same time, increase case double check the intensity, the serious problems of discipline violations or "four winds" ban but not absolutely, not only to be held directly responsible, but also held leadership responsibility; not only to pursue studies the main responsibility of the Party committee, and to pursue Commission for Discipline Inspection and supervision responsibilities and promote accountability to become the new norm. The implementation of supervisory responsibility. Maintain < code > and < rule > the seriousness and authority of the discipline and rules and truly become the party's ruler. Discipline as supervision within the party the specialized agency, we must strengthen the responsibility to act, adhere to the Impartial discipline accountability, earnestly will be strict discipline, discipline must be punished, and severely punish the acts in violation of rules and regulations.