A 63-Year-Old Male with D-Transposition of the Great Arteries Who Had an Early Form of the Arterial Switch Operation

We describe a 63-year-old male who appears to have undergone an early form of the arterial switch operation for D-transposition of the great arteries performed in the mid-1960s.We review the clinical and imaging data that support our conclusion.He had a diagnostic cardiac catheterization which demonstrated severe pulmonary hypertension responsive to epoprostenol and oxygen.Our case may represent one example of the experimental surgical work done prior to Dr.Adibe Jatene’s description of thefirst successful arterial switch performed in 1975.

Modulation of p75 neurotrophin receptor mitigates brain damage following ischemic stroke in mice

Stroke is a significant leading cause of death and disability in the United States(Tsao et al.,2022).Approximately 87% of strokes fall into the ischemic category,mainly caused by arterial blockage(Jayaraj et al.,2019).Although the only FDA-approved effective medication is tissue plasminogen activator(tPA),it should be administrated within 4.5 hours of ischemic stroke.Furthermore,tPA has been an integral part of managing acute ischemic stro ke.

Anti-tumor efficacy of Calculus bovis: Suppressing liver cancer by targeting tumor-associated macrophages

Despite significant advances in our understanding of the molecular pathogenesis of liver cancer and the availability of novel pharmacotherapies,liver cancer remains the fourth leading cause of cancer-related mortality worldwide.Tumor relapse,resistance to current anti-cancer drugs,metastasis,and organ toxicity are the major challenges that prevent considerable improvements in patient survival and quality of life.Calculus bovis(CB),an ancient Chinese medicinal drug,has been used to treat various pathologies,including stroke,convulsion,epilepsy,pain,and cancer.In this editorial,we discuss the research findings recently published by Huang et al on the therapeutic effects of CB in inhibiting the development of liver cancer.Utilizing the comprehensive transcriptomic analyses,in vitro experiments,and in vivo studies,the authors demonstrated that CB treatment inhibits the tumor-promoting M2 phenotype of tumor-associated macrophages via downregulating Wnt pathway.While multiple studies have been performed to explore the molecular mechanisms regulated by CB,this study uniquely shows its role in modulating the M2 phenotype of macrophages present within the tumor microenvironment.This study opens new avenues of future investigations aimed at investigating this drug’s efficacy in various mouse models including the effects of combination therapy,and against drug-resistant tumors.

Same day discharge after structural heart disease interventions in the era of the coronavirus-19 pandemic and beyond

With recent advancements in imaging modalities and techniques and increased recognition of the long-term impact of several structural heart disease interventions,the number of procedures has significantly increased.With the increase in procedures,also comes an increase in cost.In view of this,efficient and cost-effective methods to facilitate and manage structural heart disease interventions are a necessity.Same-day discharge(SDD)after invasive cardiac procedures improves resource utilization and patient satisfaction.SDD in appropriately selected patients has become the standard of care for some invasive cardiac procedures such as percutaneous coronary interventions.This is not the case for the majority of structural heart procedures.With the coronavirus disease 2019 pandemic,safely reducing the duration of time spent within the hospital to prevent unnecessary exposure to pathogens has become a priority.In light of this,it is prudent to assess the feasibility of SDD in several structural heart procedures.In this review we highlight the feasibility of SDD in a carefully selected population,by reviewing and summarizing studies on SDD among patients undergoing left atrial appendage occlusion,patent foramen ovale/atrial septal defect closure,Mitra-clip,and trans-catheter aortic valve replacement procedures.

Assessing adaptability and response of vegetation to glacier recession in the afro-alpine moorland terrestrial ecosystem of Rwenzori Mountains

The objective of this study was to explore vegetation adaptability in a changing afro-alpine moorland terrestrial ecosystem on Mt. Rwenzori and to determine whether there were any links with response of vegetation to glacier recession. We analyzed the composition and distribution of plant species in relation to soils, geomorphic processes, and landscape positions in the Alpine zone. To accomplish this objective, archival data sources and published reports for this ecosystem were reviewed. A field trip was conducted in 2010 to study in detail seven vegetation sampling plots that were systematically selected using GIS maps and a nested-quadrat sampling design framework along an altitudinal gradient in the lower and upper alpine zones. Using these sampling plots, 105 vegetation and 13 soil samples were assessed in the alpine zone. Soil samples were taken for laboratory testing and analysis. The results show statistically significant differences in pH, OM, N, P, Ca, Mg, and K pools between soils samples drawn from the lower and upper alpine sites （p 〈 0.0033）. Furthermore, we observed a significant vegetation formation with numerous structural forms, but there was a limited diversity of speeies. The most significant forms included Alchemilla carpets, Bogs, Dendrosenecio woodland, and Scree slopes. The lower alpine area （3500-3900 masl） had a more diverse plant species than other areas, especially Alchemilla argyrophylla and Dendrosenecio adnivalis species that were evident due to well-drained deeper soils. The Alchemilla subnivalis were evident at a higher altitude of above 4000 mask Shifts in the Astareeeae （e.g. Senecio species） were particularly prominent even on recently deglaciated areas. The spatial variations of species distribution, structure, and composition suggest there are serious implications in terms of ecosystem adaptability, resilience, and stability that require further evaluation.

Striatum-specific mechanisms regulate neuronal cell cycle re-entry:the choice between life and death

Mitochondria dysfunction occurs in the aging brain as well as in several neurodegenerative disorders and predisposes neuronal cells to enhanced sensitivity to neurotoxins.In particular,defects in any of the mitochondria respiratory chain complexes lead to impaired adenosine triphosphate production resulting in diseases that often affect the central nervous system.For instance,innate deficits in succinate dehydrogenase(SDH)mitochondria respiratory chain complex II activity caused by genetic mutations in SDH subunits lead to early-onset neurodegeneration(Jain-Ghai et al.,2013),while several adult-onset genetic neurodegenerative disorders are associated with variable levels of complex II deficiency in the central nervous system(Túnez et al.,2010).Also,chemically induced complex II deficiency leads to neurodegeneration.

卒中：回眸2019

2019年初,嫦娥四号探测器在月球背面成功着陆,通过巧妙设计的中继星,首次实现了月球背面与地球的信息传递。延续了中国航天人一贯的体现浪漫中国文化的命名风格,中继星被命名为“鹊桥”(图1)。如果说医学研究是探索医学领域难题的“嫦娥”,那专业杂志就是通过论文的发表,将科研成果不断展现到公共视野的“鹊桥”。在新桃旧符即将更换的年底,让我们一起回眸2019年,梳理一年来在各大专业医学期刊上发表的卒中领域最具影响力的临床研究,这些将深刻改变我们未来的临床实践。

药动学和药效学评价生物制品:挑战与局限性(英文)

近年来,重组蛋白多肽和蛋白质已发展成为主流药物。多肽和蛋白类药物在临床前和临床研究以及治疗用药中均占有相当大的比重。理解药物动力学和药效动力学,包括剂量-浓度-效应之间的关系,对于包括多肽和蛋白类在内的任何药物都是至关重要的,因为它奠定了优化给药方案和临床合理用药的基础。比起传统的基于小分子的疗法,多肽和蛋白类药物的药物暴露/效应评价往往由于下列因素而变得复杂:(1)与内源性多肽、蛋白及营养物质的相似性;(2)能在分子水平直接参与体内生理过程;(3)具有高分子特性及免疫原性;(4)由于存在着很多相似的分子,目标物的分析和量化具有一定的挑战性。不像传统的小分子药物,多肽和蛋白质口服后往往没有治疗活性。为选择最适当的给药途径,需要全面了解多肽和蛋白质理化性质以外的吸收特性,包括化学和代谢稳定性、吸收部位、免疫反应性、跨膜过程以及主动摄取和外排过程。肽和蛋白质的各种分布特性决定了其在靶器官能否达到适宜浓度从而发挥预期疗效,而结合现象和受体介导的细胞摄取有可能使这个问题更加复杂化。消除过程作为药物全身暴露的一个关键因素,可以是众多通路的综合,包括肾脏及肝脏代谢通路以及广义的蛋白水解作用与受体介导的内吞作用。多肽和蛋白质为基础药物的药代动力学/药效学结合研究常因其与内源性物质密切的相互作用以及生理调节反馈机制而错综复杂。本文重点阐述了与大多数生物制品相关的一些主要动力学特性及过程,为具有药效特性的多肽和蛋白质疗法提供范例。理解了生物疗法和传统小分子药物之间药动学与药效学的差异,将有助于从事药物研发的科学家以及医疗保健人员在药物开发和应用药物治疗过程中用最适宜的方法去处理、评价和用药。

HIF-1α pathway: role, regulation and intervention for cancer therapy

Hypoxia-inducible factor-1 (HIF-1) has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels) is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1α pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1α pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1α in cancer, and recent therapeutic approaches targeting this important pathway.

Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia

With the cure rate of childhood acute lymphoblastic leukemia （ALL） approaching 90%, further improvement in the treatment outcome and quality of life of patients will require better understanding of the mechanisms of drug resistance, identifying new leukemic cell genetic lesions that are amendable to available target therapy, and optimizing treatment based on host pharmacodynamics and pharmacogenomics. Deeper characterization of leukemic cell genetic abnormalities has discovered new subtypes of leukemia such as early T-cell precursor ALL and Philadelphia chromosome-like ALL, and identified many genomic alterations that have diagnostic, prognostic, or therapeutic implications. In this regard, several novel fusion transcripts are responsive to ABL tyrosine kinase inhibitors and potentially to JAK inhibitors. Genome-wide analyses have also unraveled the role of inherited cancer predisposing genes and small nucleotide polymorphisms of several genes in the development of childhood ALL. These advances promise to lead to more sophisticated personalized treatment strategies in the near future.

Taxane resistance in castration-resistant prostate cancer: mechanisms and therapeutic strategies

Despite its good initial response and significant survival benefit in patients with castrationresistant prostate cancer(CRPC), taxane therapy inevitably encounters drug resistance in all patients.Deep understandings of taxane resistant mechanisms can significantly facilitate the development of new therapeutic strategies to overcome taxane resistance and improve CRPC patient survival. Multiple pathways of resistance have been identified as potentially crucial areas of intervention. First, taxane resistant tumor cells typically have mutated microtubule binding sites, varying tubulin isotype expression,and upregulation of efflux transporters. These mechanisms contribute to reducing binding affinity and availability of taxanes. Second, taxane resistant tumors have increased stem cell like characteristics,indicating higher potential for further mutation in response to therapy. Third, the androgen receptor pathway is instrumental in the proliferation of CRPC and multiple hypotheses leading to this pathway reactivation have been reported. The connection of this pathway to the AKT pathway has received significant attention due to the upregulation of phosphorylated AKT in CRPC. This review highlights recent advances in elucidating taxane resistant mechanisms and summarizes potential therapeutic strategies for improved treatment of CRPC.

Transcriptome and Proteome Expressions Involved in Insulin Resistance in Muscle and Activated T-Lymphocytes of Patients with Type 2 Diabetes

We analyzed the genes expressed （transcriptomes） and the proteins translated （pro- teomes） in muscle tissues and activated CD4^＋ and CD8^＋ T-lymphocytes （T-cells） of five Type 2 diabetes （T2DM） subjects using Affymetrix microarrays and mass spectrometry, and compared them with matched non-diabetic controls. Gene expressions of insulin receptor （INSR）, vitamin D receptor, insulin degrading enzyme, Akt, insulin receptor substrate-1 （IRS-1）, IRS-2, glucose transporter 4 （GLUT4）, and enzymes of the glycolytic pathway were decreased at least 50% in T2DM than in controls. However, there was greater than two-fold gene upregulation of plasma cell glycoprotein-1, tumor necrosis factor a （TNFα）, and gluconeogenic enzymes in T2DM than in controls. The gene silencing for INSR or TNFα resulted in the inhibition or stimulation of GLUT4, respectively. Proteome profiles corresponding to molecular weights of the above translated transcriptomes showed different patterns of changes between T2DM and controls. Meanwhile, changes in transcriptomes and proteomes between muscle and activated T-cells of T2DM were comparable. Activated T-cells, analogous to muscle cells, expressed insulin signaling and glucose metabolism genes and gene products. In conclusion, T-cells and muscle in T2DM exhibited differences in expression of certain genes and gene products relative to non-diabetic controls. These alterations in transcriptomes and proteomes in T2DM may be involved in insulin resistance.

Transcatheter arterial chemoembolization in recurrent unresectable hepatocellular carcinoma after orthotopic liver transplantation

Aim: To investigate the survivals and efficacy of the doxorubicin drug eluting beads transcatheter arterial chemoembolization (TACE) in patients with recurrent hepatocellular carcinoma (HCC) status post orthotopic liver transplantation. Methods: Consecutive patients with HCC who underwent orthotopic liver transplantation from 2005 to 2012 were reviewed. Patients who developed recurrent HCC after orthotopic liver transplantation and received doxorubicin drug eluting beads TACE therapy were identified and included in the study. Survivals were calculated from the time of 1st doxorubicin drug eluting beads TACE of recurrent HCC. Kaplan Meier estimator with log rank test was used for survival analysis. Results: Eight patients had recurrent HCC after orthotopic liver transplantation and received doxorubicin drug eluting beads TACE. The overall median survival of these patients was 15.6 months. Two patients had significantly poorer overall median survival from doxorubicin drug eluting beads TACE (3.4 months) and both showed elevated serum alpha-fetoprotein levels (> 400 ng/mL) and extra-hepatic metastases (P = 0.03). Patients with poorly differentiated HCC in explant liver had the poor median overall survival (3.6 months) compared to the patients with well-to-moderately differentiated HCC (21.7 months, P = 0.004). Conclusion:Doxorubicin drug eluting beads TACE appears to be an effective treatment option for patients with recurrent HCC after orthotopic liver transplantation.

颅内出血患者抗栓药逆转指南美国神经重症监护学会和美国重症医学会对医疗卫生专业人员的声明

背景抗栓药的使用，包括抗凝药、抗血小板药和溶栓药，在过去10年中日益增多并且预计将继续上升。虽然抗栓药相关性颅内出血可能是灾难性的，但快速逆转凝血功能障碍可能有助于限制血肿增大和改善转归。方法美国神经重症监护学会联合美国重症医学会组建了一个国际性多机构委员会，涉及的专业领域包括神经重症监护、神经内科、神经外科、卒中、血液学、血液病理学、急诊医学、药学、护理和指南制定，目的是进行文献评价并制定一份循证实践指南。该委员会进行了正式的文献检索，并对符合标准的研究进行了评价。结果利用GRADE方法学，委员会提出了在颅内出血情况下逆转维生素K拮抗药、直接Xa因子拮抗药、直接凝血酶抑制药、普通肝素、低分子肝素、类肝素、戊多糖、溶栓药和抗血小板药的推荐意见。结论该指南提供了及时和循证的抗栓药逆转策略以协助临床医生治疗抗栓药相关性颅内出血。