Left Atrial Appendage Occlusion,A Misnomer?: Where Do We Go From Here?

The importance of the left atrial appendage (LAA) as the source of thromboembolism including stroke in patients with nonvalvular atrial fibrillation is well documented, with more than 90% of ischemic strokes related to a LAA thrombus. Although oral anticoagulation has been the standard of care, approximately 50% to 60% of patients either have contraindications to oral anticoagulation or do not continue the medication beyond the first year. This led to the development of local site-specific therapy to occlude the LAA by either surgical or transcatheter means. Despite marked advancements, incomplete LAA closure with surgical and transcatheter approaches remains frequent. The etiology of incomplete LAA closure and its clinical implications remain unclear. Multiple strategies are in development including changes in deployment techniques, a new device design, and alternative approaches to leak closure.     

Viral hepatitis: Past,present, and future

Each hepatitis virus—Hepatitis A, B, C, D, E, and G—poses a distinct scenario to the patient and clinician alike. Since the discovery of each virus, extensive knowledge regarding epidemiology, virologic properties, and the natural clinical and immunologic history of acute and chronic infections has been generated. Basic discoveries about host immunologic responses to acute and chronic viral infections, combined with virologic data, has led to vaccines to prevent Hepatitis A, B, and E and highly efficacious antivirals for Hepatitis B and C. These therapeutic breakthroughs are transforming the fields of hepatology, transplant medicine in general, and public and global health. Most notably, there is even an ambitious global effort to eliminate chronic viral hepatitis within the next decade. While attainable, there are many barriers to this goal that are being actively investigated in basic and clinical labs on the local, national, and international scales. Herein, we discuss pertinent clinical information and recent organizational guidelines for each of the individual hepatitis viruses while also synthesizing this information with the latest research to focus on exciting future directions for each virus.     

Utilization of and Outcomes Associated with Intravascular Ultrasound during Deep Venous Stent Placement among Medicare Beneficiaries

PurposeTo evaluate temporal trends, practice variation, and associated outcomes with the use of intravascular ultrasound (US) during deep venous stent placement among Medicare beneficiaries.Materials and MethodsAll lower extremity deep venous stent placement procedures performed between January 1, 2017, and December 31, 2019 among Medicare beneficiaries were included. Temporal trends in intravascular US use were stratified by procedural setting and physician specialty. The primary outcome was a composite of 12-month all-cause mortality, all-cause hospitalization, or repeat target vessel intervention. The secondary outcome was a composite of 12-month stent thrombosis, embolization, or restenosis.ResultsAmong the 20,984 deep venous interventions performed during the study period, 15,184 (72.4%) utilized intravascular US. Moderate growth in intravascular US use was observed during the study period in all clinical settings. There was a variation in the use of intravascular US among all operators (median, 77.3% of cases; interquartile range, 20.0%–99.2%). In weighted analyses, intravascular US use during deep venous stent placement was associated with a lower risk of both the primary (adjusted hazard ratio, 0.72; 95% confidence interval [CI], 0.69–0.76; P < .001) and secondary (adjusted hazard ratio, 0.32; 95% CI, 0.27–0.39; P < .001) composite end points.ConclusionsIntravascular US is frequently used during deep venous stent placement among Medicare beneficiaries, with further increase in use from 2017 to 2019. The utilization of intravascular US as part of a procedural strategy was associated with a lower cumulative incidence of adverse outcomes after the procedure, including venous stent thrombosis and embolization.     

温阳解郁颗粒调节BDNF/TrkB/ERK信号通路保护皮质酮诱导损伤型海马神经细胞的作用机制研究＊

目的 观察温阳解郁颗粒（Wenyang Jieyu granule，WYJY）对皮质酮（Corticosterone，CORT）诱导损伤型小鼠海马神经细胞（TH22 cell）的保护作用，基于脑源性神经营养因子（Brain derived neurotrophic factor， BDNF）/酪氨酸激酶B（Tyrosine kinase B， TrkB）/细胞外信号调节蛋白激酶（Extra cellular regulated protein kinases， ERK）信号通路探讨WYJY保护海马神经细胞的作用机制。方法 体外构建小鼠海马神经细胞皮质酮诱导损伤模型，以不同浓度的WYJY和氟西汀（Fluoxetine，FXT）含药血清作用于模型细胞，细胞增殖-毒性检测（Cell Counting Kit-8， CCK-8）法分析细胞活性，倒置显微镜下观察给药前后细胞形态结构的改变，采用蛋白免疫印迹法（Western Blot）、实时荧光定量PCR（Quantitative real-time PCR， qPCR）法检测神经细胞内凋亡因子（BCL2-Associated X， Bax）、抗凋亡因子（B-cell lymphoma-2， Bcl-2）、BDNF、Trkb、ERK以及丝氨酸/苏氨酸激酶（Phospho-p90RSK， RSK）、环磷腺苷效应元件结合蛋白（cAMP-response element binding protein， CREB）蛋白表达水平以及相关基因的表达水平。结果 在浓度为459.5 μmol·L^-1的CORT作用24 h后，HT22细胞的活性抑制率达到50%，在此条件作用下细胞形态结构损伤明显，凋亡程度严重，细胞上清中BDNF的含量显著减少（P<0.05），细胞内凋亡相关因子Bax/Bcl-2的比值明显升高（P<0.01），BDNF、Trkb、ERK、RSK、CREB磷酸化蛋白表达水平和mRNA表达水平明显降低（P<0.01）；以5%的浓度为2.85 g·kg^-1的WYJY和10%的FXT含药血清作用于受损的HT22细胞后，HT22细胞存活率明显提升（P<0.01），细胞结构的损伤明显改善，细胞凋亡程度减轻，细胞外BDNF的含量显著升高（P<0.05），细胞内Bax/Bcl-2比值显著下调（P<0.01），BDNF、Trkb、ERK、RSK、CREB磷酸化蛋白表达水平和mRNA表达水平显著提升（P<0.05，P<0.01）。结论 温阳解郁颗粒可有效保护高浓度CORT造成的小鼠海马神经细胞损伤。调控BDNF/Trkb/ERK通路，放大CREB信号传导，影响Bcl-2、BDNF水平，可能是其保护海马神经元，发挥抗抑郁疗效的重要机制。     

ArgD of Mycobacterium tuberculosis is a functional N-acetylornithine aminotransferase with moonlighting function as an effective immune modulator

Mycobacterium tuberculosis (M. tuberculosis) encodes an essential enzyme acetyl ornithine aminotransferase ArgD (Rv1655) of arginine biosynthetic pathway which plays crucial role in M. tuberculosis growth and survival. ArgD catalyzes the reversible conversion of N-acetylornithine and 2 oxoglutarate into glutamate-5-semialdehyde and L-glutamate. It also possesses succinyl diaminopimelate aminotransferase activity and can thus carry out the corresponding step in lysine biosynthesis. These essential roles played by ArgD in amino acid biosynthetic pathways highlight it as an important metabolic chokepoint thus an important drug target. We showed that M. tuberculosis ArgD rescues the growth of ΔargD E. coli grown in minimal media validating its functional importance. Phylogenetic analysis of M. tuberculosis ArgD showed homology with proteins in gram positive bacteria, pathogenic and non-pathogenic mycobacteria suggesting the essentiality of this protein. ArgD is a secretory protein that could be utilized by M. tuberculosis to modulate host innate immunity as its moonlighting function. In-silico analysis predicted it to be a highly antigenic protein. The recombinant ArgD protein when exposed to macrophage cells induced enhanced production of pro-inflammatory cytokines TNF, IL6 and IL12 in a dose dependent manner. ArgD also induced the increased production of innate immune effector molecule NOS2 and NO in macrophages. We also demonstrated ArgD mediated activation of the canonical NFkB pathway. Notably, we also show that ArgD is a specific TLR4 agonist involved in the activation of pro-inflammatory signaling for sustained production of effector cytokines. Intriguingly, ArgD protein treatment activated macrophages to acquire the M1 phenotype through the increased surface expression of MHCII and costimulatory molecules CD80 and CD86. ArgD induced robust B-cell response in immunized mice, validating its antigenicity potential as predicted by the in-silico analysis. These properties of M. tuberculosis ArgD signify its functional plasticity that could be exploited as a possible drug target to combat tuberculosis.