Recent advances in the diagnostic methods and therapeutic strategies of transthyretin cardiac amyloidosis

Cardiac amyloidosis is a progressive disease characterized by the buildup of amyloid fibrils in the extracellular space of the heart.It is divided in 2 main types,immunoglobulin light chain amyloidosis and transthyretin amyloidosis(ATTR),and ATTR amyloidosis is further divided in 2 subtypes,non-hereditary wild type ATTR and hereditary mutant variant amyloidosis.Incidence and prevalence of ATTR cardiac amyloidosis is increasing over the last years due to the improvements in diagnostic methods.Survival rates are improving due to the development of novel therapeutic strategies.Tafamidis is the only disease-modifying approved therapy in ATTR amyloidosis so far.However,the most recent advances in medical therapies have added more options with the potential to become part of the therapeutic armamentarium of the disease.Agents including acoramidis,eplontersen,vutrisiran,patisiran and anti-monoclonal antibody NI006 are being investigated on cardiac function in large,multicenter controlled trials which are expected to be completed within the next 2-3 years,providing promising results in patients with ATTR cardiac amyloidosis.However,further and ongoing research is required in order to improve diagnostic methods that could provide an early diagnosis,as well as survival and quality of life of these patients.

人参皂苷Rg1通过抑制TTR延缓X射线颅脑照射后小鼠海马衰老

目的探讨人参皂苷Rg1延缓X射线颅脑照射后小鼠海马衰老的可能机制。方法将40只C57BL/6J小鼠随机均分为空白对照组(Con组)、颅脑照射组(IR组)、人参皂苷Rg1预处理组(Rg1组)、人参皂苷Rg1预处理颅脑照射组(Rg1+IR组)。观察各组小鼠体质量、进食情况、活动状态、精神状态、毛色与大小便评估健康状况;采用Morris水迷宫评估小鼠认知能力;采用SA-β-Gal染色检测海马齿状回衰老细胞数量;采用转录组测序分析确定Rg1抗辐射衰老的靶点;采用qRT-PCR和蛋白免疫印迹检测靶点的表达水平。结果与Con组相比,IR组小鼠体质量减轻、进食量减少、活动减少、精神倦怠、毛发灰暗、大便稀溏,出现明显的认知能力下降,海马齿状回衰老细胞增多(P<0.05)。与IR组相比,Rg1+IR组小鼠上述指标均有改善(P<0.05)。甲状腺素视黄质运载蛋白(TTR)为筛选出的最显著靶点。IR组小鼠海马中TTR表达较Con组升高(P<0.05),而Rg1+IR组TTR表达较IR组降低(P<0.05)。结论人参皂苷Rg1可能通过抑制TTR延缓X射线颅脑照射后小鼠的海马衰老,从而保护认知能力。

TTR汽车等效燃油消耗最小的能量管理策略研究

为改善通过路面实现动力耦合与电池充电的TTR汽车经济性,分析TTR汽车结构及工作模式,基于等效油耗最小的能量管理策略(ECMS),计算固定等效因子(CECMS);为使电池SOC保持稳定并控制发动机工作于低燃油消耗区,将行驶所需发动机等价总转矩及电池SOC模糊化,制定等效因子的模糊控制规则,而提出模糊自适应等效燃油消耗最小控制策略(FAECMS)。利用MATLAB/Simulink建立包含TTR汽车动力学的CECMS、FAECMS模型,选取FTP75、CLTC、WLTP 3种标准工况,当电池SOC初始值为60%时进行仿真计算,得出FAECMS相对CECMS在3种工况下电池SOC更稳定,并分别节约燃油5.5%、2.6%、8.3%。

基于ttr基因的mini-MPN-qLAMP法快速定量检测食品中沙门氏菌

该研究通过3管型微量MPN计数法(Mini Most Probable Number,mini-MPN)建立了一种快速定量检测食源性沙门氏菌的荧光定量环介导等温扩增(Quantitative Loop-Mediated Isothermal Amplification,qLAMP)方法。依据沙门菌属ttr基因设计了qLAMP和荧光定量PCR(Quantitative Polymerase Chain Reaction,qPCR)引物,结合5 h BPW增菌和MPN计数法建立了mini-MPN-qLAMP沙门氏菌快速定量检测方法;使用两种人工污染样品对mini-MPN-qLAMP法进行验证,使用Bland-Altman分析比较不同检测方法检测结果的一致性。结果表明,建立的qLAMP法与qPCR法反应特异性均良好,纯培养时qLAMP法检出限为500 CFU/mL。通过Bland-Altman分析表明所建立的mini-MPN-qLAMP法在速冻乌米饭中检测结果与mini-MPN-qPCR、mini-MPN计数法、平板计数法相比均具有较高的一致性,r^(2)≥0.994,检出限为-0.44 lg MPN/mL;而在速冻鸡胸肉中该法检测结果与mini-MPN-qPCR结果一致性最佳,r^(2)=0.990,检出限为-0.64 lg MPN/mL。肉制品中腐败杂菌会影响mini-MPN计数和平板计数结果,mini-MPN-qLAMP可排除肉制品中腐败杂菌对检测结果的影响。该研究所建立的mini-MPN-qLAMP法简单易行,准确度高,可用于食品中沙门氏菌的快速定量检测。

Clinical features of retinal amyloid angiopathy with transthyretin Gly83Arg variant

AIM:To report on the clinical features of patients with retinal amyloid angiopathy(RAA)who were identified to be caused by the transthyretin(TTR)Gly83Arg variant.METHODS:Case series of five patients diagnosed with RAA was collected at Affiliated Hospital of Zunyi Medical University from January 2010 to December 2021.The clinical features,therapeutic strategies,and prognoses of all patients were reviewed.RESULTS:Five patients with a mean age of 52.00±7.23y were diagnosed as RAA.These patients were previously diagnosed with hereditary transthyretin amyloidosis caused by the TTR Gly83Arg variant.Vitreous opacity was found in all 10 eyes,and 7 eyes developed RAA 2 to 20y after the onset of hereditary transthyretin amyloidosis.The clinical manifestations were recurrent vitreous hemorrhage in 2 eyes(29%),neovascular glaucoma in 2 eyes(29%),and iris neovascularization in 1 eye(14%).Microangioma lesions were found in all affected eyes that underwent fundus fluorescein angiography(FFA)in this group of cases,and the incidence of the retinal non-perfusion area was 67%.Although no cases of retinal neovascularization were found,the prognosis of visual acuity was not ideal.CONCLUSION:This is the first report of RAA in patients with the TTR Gly83Arg variant.Complications such as RAA and glaucoma will seriously affect the visual prognosis of patients.Thereafter,regular ophthalmic follow-up of patients with hereditary transthyretin amyloidosis is essential.And FFA after vitrectomy is very important,which can help ophthalmologists detect RAA earlier and treat it in time.

张量TTr1SVD的随机算法

张量序列秩-1奇异值分解(TTr1SVD)自然地将奇异值分解(SVD)推广到张量层面,将任意实张量分解为标准正交秩-1外积的有限和。基于其具有已知数量上限的正交秩-1外积项和易于截断误差量化的良好性质,本文首先给出了一种有利于张量分解和还原的表达形式,并提出了保持分解形式的截断TTr1SVD算法,在固定精度的同时大大降低了计算成本。受低秩矩阵逼近的随机算法的启发,本文还开发了针对固定精度问题的高效随机TTr1SVD算法。最后,给出的数值例子展现了所提算法在数据逼近和压缩方面的应用前景。

Screening for Transthyretin Cardiac Amyloidosis in Patients with Bilateral Carpal Tunnel Syndrome: Identifying Missed Opportunities for Early Detection and Treatment

Purpose: Transthyretin cardiac amyloidosis (ATTR-CA) has been linked to many extra-cardiac manifestations including bilateral carpal tunnel syndrome (CTS). The aim of this study is to analyze patients with bilateral CTS to identify patients with high-risk features or “red flags” for ATTR-CA, identify if systematic screening was done for ATTR-CA and define opportunities for improved detection. Methods: Out of >5000 patients with bilateral CTS evaluated in a single tertiary care center in Southeast Michigan (2010-2016), we retrospectively studied a focused population of patients: men > 50 years and women > 60 years old with bilateral CTS and atrial fibrillation (n = 295). Baseline demographic, comorbidities, and electrocardiographic and echocardiographic findings were analyzed. A high-risk group suspicious for ATTR-CA was identified as patients with bilateral CTS, atrial fibrillation, and concomitant “red flags” including heart failure and left ventricular hypertrophy. Results: Out of 295 patients, 51.2% were female, 75.6% were White, and 22.4% were African American. Upon comparing the high-risk group (n = 67) with the remaining study population (n = 228), both diagnosis of ATTR-CA and mortality were higher among the high-risk group (7.5% vs 0.4% and 43.3% vs 24.6%, respectively, P = 0.003). Conclusions: A substantial number of bilateral CTS patients had additional “red flags” warranting formal evaluation for ATTR-CA;however, systematic evaluation for cardiac amyloidosis was not performed in many patients. This emphasizes that Multidisciplinary collaboration is needed to create a systematic workflow and to raise awareness amongst cardiologists and other physicians for suspecting ATTR-CA in bilateral CTS patients who have additional “red flags”.

Rare manifestation of familial vitreous amyloidosis caused by Gly103Arg transthyretin

AIM:To identify and analyze the genotype of the patients with special ocular manifestations of familial vitreous amyloidosis(FVA)in a Chinese Han family.METHODS:Pars plana vitrectomy(PPV)surgery was performed on a 52-year-old Chinese woman presented with vitreous amyloidosis and progressive visual impairment,without evidence of cardiac,renal,gastrointestinal,central nervous system or peripheral nervous system dysfunction.During the surgery,the patient presented with a gray-white dense and thick cotton woollike change in the vitreous body,accompanied by complete retinal detachment.Additionally,hard,free and movable yellow-white deposits were observed in the posterior pole and surrounding retina,the vitreous and subretinal deposits were examined by Congo red staining and immunohistochemical pathological examination,and whole exome sequencing was performed on blood samples from the patient and her cousin.RESULTS:During the operation,it was discovered that there was a complete detachment of the retina and a significant amount of hard,free-floating yellow-white deposits were observed beneath the posterior pole and surrounding retina.This is an exceedingly rare ocular manifestation.Pathological examination of the vitreous and subretinal deposit specimens revealed positive Congo red staining,as well as elevated vascular endothelial growth factor(VEGF)expression in vascular endothelial cells within the sediment specimens upon immunohistochemical examination.The patient and her cousin both exhibited a heterozygous mutation in Glyl03Arg within the transthyretin(TTR)gene,resulting in a substitution of glycine(Gly)at position 103 with arginine(Arg).CONCLUSION:FVA may present with various ocular manifestations,but panretinal detachment is a rare occurrence.In cases where retinal detachment persists for an extended period of time,amyloid deposits may form under the retina through retinal tears,leading to subretinal deposits that can impede retinal reattachment and negatively impact visual prognosis.Elevated levels of VEGF in the eyes of FVA patients may indicate an overexpression state,necessitating careful postoperative follow-up.The heterozygous mutation Gly103Arg may represent a unique pathogenic site in Chinese individuals.

转甲状腺素蛋白心脏淀粉样变的诊断与治疗研究进展

转甲状腺素蛋白心脏淀粉样变是由于转甲状腺素蛋白沉积于心脏所引起的心脏功能障碍,既往被认为是一种罕见病,其发病隐匿、进展迅速、致死率高。近年来,随着诊断技术的进步,该病的检出率不断提高,各种小分子药物的不断问世也改变了以往无药可医的局面,使其死亡率有所下降。本文主要归纳了近年来转甲状腺素蛋白心脏淀粉样变在诊断和治疗方面的最新进展。

转甲状腺素蛋白淀粉样变性多发性神经病1例诊治体会

转甲状腺素蛋白淀粉样变性多发性神经病(transthyretin amyloid polyneuropathy,ATTR-PN)是由编码转甲状腺素蛋白的TTR基因致病变异导致的一种以周围神经损害为主,呈常染色体显性遗传的多系统疾病。本文报道1例ATTR-PN,希望提高临床医生对此病的认识,减少误诊率。

转甲状腺素蛋白淀粉样变心肌病一家系遗传学分析

目的:探讨转甲状腺素蛋白淀粉样变心肌病(ATTR-CM)的遗传学特征。方法:对1例以心肌肥厚所致心力衰竭为主要临床特征的ATTR-CM先证者的临床表型进行分析,通过高通量测序分析转甲状腺素蛋白(TTR)基因突变情况并进行Sanger测序验证。结果:先证者发病年龄较早,临床症状复杂。先证者及其妹妹、侄子、女儿4人存在TTR基因c.A163G(p.Lys55Glu)杂合突变。结论:本研究发现了TTR基因c.A163G(p.Lys55Glu)突变导致的ATTR-CM,异常TTR沉积主要累及心脏,症状复杂且不典型。

半挂汽车TTR预警及防侧翻控制

为及时提醒驾驶员半挂汽车的侧翻危险状态并对车辆的侧翻危险状态进行控制,以TruckSim中的半挂汽车作为真实车辆,考虑汽车运行过程中的过程噪声以及量测噪声,利用Kalman滤波技术实时估计半挂汽车的运行状态。以车辆的横向载荷转移率为侧翻指标,建立了基于模型预测的TTR(time-to-rollover)侧翻预警算法,并结合最优控制算法,制定了基于TTR侧翻预警的防侧翻控制策略。通过仿真分析,此控制策略可以有效提醒驾驶员半挂汽车的侧翻危险状况,并有效控制半挂汽车的侧翻危险状态,防止侧翻危险的发生。

妊娠期孕妇血清TTR水平变化及其用于诊断子痫前期的价值

目的:观察正常妊娠人群血清中转甲状腺素蛋白(TTR)浓度在孕期的变化,探讨血清TTR浓度在子痫前期诊断和监测病情中的价值。方法:(1)无并发症及合并症的正常妇女62例,分别于孕前、孕12~16周、20~24周、28~32周和37~41周留取静脉血清。(2)无产科并发症及内外科合并症正常孕妇50例作为对照组,诊断为妊娠期高血压疾病的孕妇分为重度子痫前期组(SPE组,30例)和妊娠期高血压、妊娠合并慢性高血压及轻度子痫前期组(GHD组,49例)。SPE组和GHD组分别于诊断时留取静脉血清,对照组分别在相应孕周留取外周静脉血清。ELISA法测定血清TTR浓度。结果:正常妇女TTR血清水平:孕前(245.65±5.02)mg/L,孕12~16周、20~24周、28~32周和37~41周血清TTR浓度分别为(649.86±43.40)mg/L、(856.10±52.28)mg/L、(410.04±22.82)mg/L、(413.71±24.17)mg/L。SPE组孕妇血清TTR浓度[(86.58±10.23)mg/L]显著低于对照组[(411.64±25.80)mg/L]及GHD组[(468.59±42.93)mg/L](P<0.05);GHD组与对照组比较差异无统计学意义(P>0.05)。结论:TTR血浆浓度在未孕时最低,随孕周增加逐渐升高,孕20~24周时达高峰,之后快速下降,到孕晚期与孕早期持平。TTR在监测病情变化及对治疗反应方面可能有一定的意义。

基于改进TTR算法的重型车辆侧翻预警系统

重型车辆具有重心高,装载量大,高宽比相对乘用车较大等特点,导致其侧翻稳定极限较低,极易发生侧翻事故。建立重型车辆侧翻预测模型,利用车辆实车试验数据离线辨识技术,辨识出3自由度车辆模型中的关键参数,然后利用改进后的车辆模型进行在线侧翻危险预测及控制,实现车辆动态侧翻特性精确预测。在此基础上,将卡尔曼滤波技术融入到改进侧翻预测时间(Time to rollover,TTR)侧翻预警算法中,选取车辆的横向载荷转移率作为侧翻极限判据,根据当前车辆状态预测未来3 s车辆的侧翻危险程度,并实时计算TTR值,一旦TTR值满足侧翻条件,系统自动触发预警装置。利用侧翻预警系统车载试验平台,对侧翻预警控制系统进行验证。侧翻预警场地试验结果表明:所开发的重型车辆侧翻预警系统可以准确有效地进行车辆侧翻危险程度预警,达到预期的开发设计目标。

基于改进TTR算法的车辆侧翻预警研究

侧翻时限(TTR)能有效用于车辆侧翻预警,然而传统的TTR方法所选定的侧翻阈值因行车条件的改变难以精确设定,会导致预警提前或滞后等问题。为了弥补传统TTR算法的不足,提高车辆侧翻预警的有效性,建立了三自由度车辆动力学模型;提出了以车辆的当前侧向加速度与实时侧向极限加速度的比值这一相对量作为侧翻评价指标,替代传统依靠侧倾角或侧向加速度等绝对量来进行侧翻预测;根据当前车辆运动状态计算未来发生侧翻时的TTR值,从而得到改进TTR侧翻预警算法。结果表明:改进TTR侧翻预警算法较传统基于侧倾角或侧向加速度的这两种TTR侧翻预警算法,能更准确地发现侧翻危险。

转甲状腺素蛋白相关家族性淀粉样多发性神经病的临床特征(附2例报告)

目的探讨我国内地Val30Met和Ala117Ser突变致转甲状腺素蛋白相关家族性淀粉样多发性神经病(TTR-FAP)的临床特征。方法回顾Val30Met突变和Ala117Ser突变所致TTR-FAP患者的临床资料各1例,并对中国内地这两类突变患者的临床特征进行归纳。。结果病例1为Val30Met突变,主要表现为周围神经功能障碍,病例2为Ala117Ser突变,周围神经、心脏循环和眼部症状均明显。服用氯苯唑酸8个月后随访病例1症状无加重,病例2有加重。回顾47例中国内地Val30Met和Ala117Ser突变TTR-FAP,Val30Met突变集中于我国北方,Ala117Ser突变主要位于南方。Ala117Ser突变累及心脏、呼吸系统和听力的比例明显高于Val30Met突变。结论中国内地TTR-FAP具有遗传异质性,分布有地域特点,确诊病程可能与治疗效果有关。

鸭TTR基因cDNA克隆和表达研究

为研究转甲状腺素蛋白(transthyretin,TTR)与肉鸭脂肪代谢的相关性,通过快速扩增cDNA末端技术(RACE)获得北京鸭TTR基因全长cDNA序列,并采用实时荧光定量PCR法对鸭TTR基因表达谱进行研究。结果显示:鸭全长TTRmRNA编码150个氨基酸的前体肽,该肽含20个氨基酸的信号肽和130个氨基酸的成熟肽;与哺乳动物相比,鸭TTR亚基N-末端序列多出的3个氨基酸Val-Ser-His,可能使鸭TTR结合甲状腺素T3的亲合力增加。定量检测结果表明,鸭TTRmRNA在脉络丛中的表达量最高,与鸡、爬行类和哺乳动物类似。本实验证实鸭TTR基因在脉络丛中的表达量比鸡更高,并首次发现TTRmRNA在鸭皮下脂肪组织中表达。

寿胎丸对RSA模型小鼠子宫蜕膜Annexin A_2及TTR表达影响的研究

目的:分析寿胎丸对复发性流产小鼠蜕膜蛋白质组的影响。方法:建立复发性流产模型。CBA/J×BALB/C建立正常妊娠模型,CBA/J×DBA/2建立复发性流产模型,将复发性流产模型CBA/J×DBA/2孕鼠按怀孕先后顺序随机分为4组,分别为模型组、寿胎丸高剂量组、寿胎丸中剂量组和寿胎丸低剂量组,从妊娠第1 d开始灌胃给药,至孕14 d处死小鼠,采用蛋白印迹和免疫组化方法检测差异蛋白质Annexin A2及TTR的蛋白表达。结果:小鼠模型组与正常组相比,蜕膜Annexin A2表达明显降低,TTR表达明显下降,差异有显著统计学意义(P<0.01);寿胎丸高、中、低剂量组与模型组相比,蜕膜Annexin A2表达均升高,寿胎丸高剂量组蜕膜TTR表达升高,差异有显著统计学意义(P<0.01)。结论:寿胎丸通过上调Annexin A2、TTR蛋白的表达,从而实现维持妊娠,降低胚胎丢失率,这可能是其安胎的作用机制之一。

转甲状腺素蛋白抑制β淀粉样蛋白聚集的分子机制研究

目的转甲状腺素蛋白(transthyretin,TTR)对阿尔茨海默病(Alzheimer’s disease,AD)具有神经保护作用,这种保护作用表现在TTR能抑制β淀粉样蛋白(amyloid beta protein,Aβ)的病理性聚集。本工作将从分子层面上探究TTR与Aβ的作用机制,揭示TTR对AD的神经保护作用。方法蛋白质-蛋白质对接用于探究不同结构形式的TTR与Aβ的作用模式,并运用分子动力学模拟方法来探究二者相互作用的动态过程。结果TTR四聚体及单体均能与Aβ单体作用,TTR四聚体的甲状腺素结合通道是Aβ单体的主要结合部位。此外,TTR四聚体的EF螺旋、EF loop同样能够结合Aβ单体。当TTR四聚体解离后,TTR单体的内部片层疏水部位暴露,该部位对Aβ单体具有较强的亲和力。TTR与Aβ聚集体作用,由于TTR单体与Aβ聚集体均为富含β折叠的结构,使得二者能够共聚集形成聚合度更高的聚集体,从而降低Aβ聚集体的细胞毒性。结论TTR四聚体和单体通过“扣押”Aβ单体来抑制Aβ的聚集,TTR单体与Aβ聚集体形成高聚合度复合物来降低Aβ聚集体的细胞毒性。本工作为基于TTR神经保护作用的抗AD药物设计和发现提供了重要的理论依据。

TTR Val50Leu突变导致家族性淀粉样多发性神经病的临床和电生理研究

目的分析TTR Val50Leu突变导致家族性淀粉样多发性神经病的临床和电生理特点。方法对一个由TTR Val50Leu突变导致的家族性淀粉样多发性神经病家系进行报道,先证者以足部疼痛为首发症状,2年内逐渐向小腿及上肢进展,并出现自主神经症状。通过对先证者及其家系中相关者进行临床表现、电生理检查及基因检测,分析该病的临床和电生理特点。结果先证者的外祖父、母亲、舅舅、弟弟(其外祖父、母亲、舅舅已故)与其具有相似症状。先证者电生理检查上肢正中神经感觉传导受累,运动正常,尺神经的感觉传导及运动传导均正常,但尺神经F波异常,下肢胫神经和腓总神经的感觉传导及运动传导均未见肯定波形,腓肠神经受累,交感皮肤反应未引出。其弟弟上肢正中神经及尺神经改变同先证者,下肢胫神经运动波幅下降,腓总神经运动正常,交感皮肤反应四肢波幅降低,余同先证者。其女儿上述电生理检查未见异常。基因检测发现三者均在TTR基因exon2存在c.148G>T突变,TTR蛋白存在Val50Leu突变。结论 TTR Val50Leu突变导致的家族性淀粉样多发性神经病家系属早发型,以足部疼痛为首发症状,进展迅速,自主神经症状出现较早。电生理符合多发性神经病表现,早期可伴有交感皮肤反应波幅降低。