Exercise Intolerance in Patients With Heart Failure: JACC State-of-the-Art Review

Exercise intolerance is the cardinal symptom of heart failure (HF) and is of crucial relevance, because it is associated with a poor quality of life and increased mortality. While impaired cardiac reserve is considered to be central in HF, reduced exercise and functional capacity are the result of key patient characteristics and multisystem dysfunction, including aging, impaired pulmonary reserve, as well as peripheral and respiratory skeletal muscle dysfunction. We herein review the different modalities to quantify exercise intolerance, the pathophysiology of HF, and comorbid conditions as they lead to reductions in exercise and functional capacity, highlighting the fact that distinct causes may coexist and variably contribute to exercise intolerance in patients with HF.     

Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies

In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals.The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2 S,6 S;2 R,6 R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis.We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT_1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine.     

重复经颅磁刺激联合盐酸帕罗西汀对卒中后抑郁症患者治疗效果观察

目的 探讨重复经颅磁刺激(rTMS)联合盐酸帕罗西汀对卒中后抑郁症(PSD)患者HAMD评分及血清神经肽Y(NPY)、促肾上腺皮质激素释放因子(CRF)、脑源性神经营养因子(BDNF)水平变化的影响。 方法 选取郑州大学第二附属医院2014年11月至2017年2月PSD患者68例,随机数字表法分组,各34例。对照组采用盐酸帕罗西汀,观察组采用盐酸帕罗西汀+rTMS,两组均持续治疗2个月。入院时及治疗结束后统计对比两组抑郁评分(HAMD、MARDS、SDS)、血清NPY、BDNF、CRF水平、临床疗效及不良反应发生率。 结果 ①两组治疗后MARDS、HAMD及SDS分值低于治疗前,且观察组较对照组低(P＜0.05);②两组治疗有效率比较,观察组94.12%(32/34)较对照组64.71%(22/34)高(P＜0.05);③两组治疗后血清CRF水平低于治疗前,BDNF及NPY水平高于治疗前,且观察组各指标优于对照组(P＜0.05);④两组不良反应发生率比较,观察组14.71%(5/34)与对照组8.82%(3/34)间差异无统计学意义(P＞0.05)。 结论 联合采用盐酸帕罗西汀及rTMS治疗卒中后抑郁症效果显著,可有效改善血清NPY、BDNF、CRF水平,降低HAMD评分,减轻患者抑郁程度,提高治疗效果,且不会增加不良反应发生风险,具有安全性。     

V4 region of the HIV-1 envelope gene mediates immune escape and may not promote the development of broadly neutralizing antibodies

To date, inducing the production of broadly neutralizing antibodies (bnAbs) against HIV-1 in humans has been unsuccessful. Several studies have explored the coevolution of HIV-1 and neutralizing antibodies (nAbs), but little is known about what affects the lack of bnAbs after long-term infection. A better understanding of the coevolution of the virus and nAbs in cases involving no bnAb production will help in the design of an effective HIV-1 vaccine. An individual with acute CRF01_AE HIV-1 infection who lacked bnAbs at just over 2 years post-infection (p.i.) was identified from a cohort of HIV negative men who have sex with men. The coevolution of the viral envelope gene and nAbs was studied over 741 days p.i. Strain-specific antibodies (ss-Abs) to the transmitted/founder (T/F) virus developed within 54 days p.i., but plasma collected at subsequent time points could not neutralize synchronous viruses until 557 days p.i., when the plasma acquired low-level synchronous but not heterologous neutralizing activity. The V4 region of envelope gene mutated firstly and continually evolve up to 2 years p.i. Multiple variations in the V4 region, including substitutions, deletions and glycosylation mutations, were driven by ss-Abs and mediated immune escape partially by impacting the binding of nAbs to the virus. The remarkable variations in the V4 region mediated immune escape from ss-Abs and contributed to the affinity maturation of ss-Abs against the T/F virus but may not promote the development of bnAbs. Thus, the V4 region might not be a good target for an HIV-1 vaccine.     

丹参多酚酸盐对慢性肾功能衰竭胱抑素C的影响

目的:观察丹参多酚酸盐对慢性肾功能衰竭患者胱抑素C(cystation C,CysC)的影响。方法:选取慢性肾功能衰竭患者60例,随机分为对照组和治疗组,每组各30例。对照组予以降低血压、纠正酸中毒、纠正贫血、纠正肾性骨病等常规治疗,治疗组在对照组的基础上加用丹参多酚酸盐治疗。观察两组患者治疗前后血CysC水平的变化。结果:治疗后治疗组血CysC水平较治疗前明显下降,差异有统计学意义(P0.05),而对照组治疗前后变化不明显,治疗组与对照组治疗后血CysC水平比较有明显下降,差异有统计学意义(P0.05)。结论:丹参多酚酸盐可以降低慢性肾功能衰竭患者CysC的水平,改善肾功能。     

益气利水方隔药灸治疗慢性肾功能衰竭

目的:观察益气利水方隔药灸联合西医综合治疗脾肾阳虚型慢性肾功能衰竭的临床疗效,并观察其对患者生活质量的改善程度。方法:80例脾肾阳虚型慢性肾功能衰竭患者随机平均分为观察组和治疗组。对照组给予西医综合治疗,治疗组在对照组治疗基础上采用益气利水方隔药灸疗法,两组疗程均为2个月。比较两组患者治疗前后症状体征积分、生活质量评分,血肌酐(serum creatinine,Scr)、血尿素氮(blood urea nitrogen,BUN)、24小时尿β2微球蛋白(β2-microglobulin,β2-MG)、内生肌酐清除率(creatinine clearance,Ccr)、红细胞计数(red blood cell,RBC)、血红蛋白(hemoglobin,Hb)水平。结果:治疗组有效率(70.0%)明显优于对照组(42.5%),差异有统计学意义(P<0.01)。治疗后,治疗组各种症状均有显著改善,改善率均高于70%,与对照组比较,差异均有统计学意义(P<0.05)。治疗组治疗后的Scr、BUN以及24小时尿β2-MG明显下降(P<0.05),Ccr明显升高(P<0.05),RBC明显升高(P<0.05);以上指标与对照组治疗后比较,差异均有统计学意义(P<0.05)。治疗组治疗后的生活质量评分显著高于治疗前(P<0.05),且显著高于对照组治疗后(P<0.05)。结论:益气利水方隔药灸联合西医治疗脾肾阳虚型慢性肾功能衰竭疗效显著,可有效改善患者肾功能,提高患者生活质量。     

云南省HIV-1 CRF01_AE毒株基因型耐药研究

目的 了解云南省HIV-1 CRF01_AE毒株的流行分布及基因型耐药情况。 方法 收集2018—2021年云南省抗病毒治疗失败的HIV/AIDS患者的人口学资料,采集患者血浆,逆转录聚合酶链反应扩增HIV-1 pol基因蛋白酶和逆转录酶区并进行序列测定,对基因型为CRF01_AE的序列进行耐药情况分析。结果 通过基因型耐药检测共获得967例亚型为CRF01_AE序列,其中男性682例（占70.5%）,耐药509例,耐药率为52.6%,异性性传播813例（占84.1%）,同性性传播95例（占9.8%）。同性性传播的耐药率最高,为65.3%;治疗时长<12个月的耐药率最低,为35.9%,36~<48个月耐药率最高,为58.1%。核苷类反转录酶抑制剂（NRTIs）耐药率为33.9%,非核苷类反转录酶抑制剂（NNRTIs）的耐药率为48.5%,蛋白酶抑制剂（PIs）的耐药率较低为1.3%。NRTIs类药物中阿巴卡韦（ABC）、恩曲他滨（FTC）和拉米夫定（3TC）耐药率较高,分别为为32.9%、32.4%和32.4%;NNRTIs类药物中奈韦拉平（NVP）和依非韦仑（EFV）耐药率较高,分别为47.6%和47.5%,均以高度耐药为主。一线治疗方案耐药率56.2%高于二线治疗方案耐药率29.5%,差异有统计学意义（P<0.001）。NRTIs耐药突变位点中,以M184V/I突变位点为主,突变率为30.0%;NNRTIs耐药突变位点中,以K103N/Q/S突变位点为主,突变率为28.1%;PIs耐药位点突变率相对较低,主要的耐药突变位点是L33F,突变率为3.7%。结论 云南省抗病毒治疗失败亚型CRF01_AE的患者耐药率有所降低,但部分地区及人群的耐药率仍较高,应加强对重点地区和人群的管理,加强耐药监测,对治疗失败的患者及时掌握耐药情况,合理调整治疗方案。