De Novo Donor‐Specific Human Leukocyte Antigen Antibody Screening in Kidney Transplant Recipients After the First Year Posttransplantation: A Medical Decision Analysis

Screening for de novo donor‐specific antibodies (dnDSA) in stable kidney transplant recipients is routine practice in some centers. Patients with DSA are at increased risk of graft loss and early intervention may improve outcomes. However, the costs and benefits of dnDSA surveillance are unknown. A medical decision analysis to examine a screening strategy was developed for kidney transplant recipients who had stable graft function and were DSA negative 1 year posttransplant. In the base case, a modest 25% reduction in graft loss in dnDSA–positive patients treated with increased immunosuppression resulted in 0.04618 quality‐adjusted years (QALYs) gained. However, benefits from reduced graft loss were eliminated if there was a small increased risk of death from added therapy. The incremental cost effectiveness was marginal at approximately $120 000–250 000 per QALY, but could be more or less favorable depending on several key variables such as efficacy of treatment, screening costs, incidence rate of subclinical dnDSA, and patient survival. Screening performed the best in patients with lower mortality rates and higher baseline incidence rates of dnDSA. Further study is warranted to gather the necessary high‐quality evidence to justify screening.     

FRD上皮组织特殊染色液在宫颈病变筛查中的应用

目的：探讨叶酸受体介导的宫颈特殊染色法(FRD)上皮组织特殊染色液在宫颈病变检查中的临床价值。方法选取2014年5月至2015年11月就诊于松岗人民医院妇产科门诊行宫颈病变筛查的受检者100例,均同时给予FRD宫颈特殊染色检测和液基细胞学(TCT)检测,两种检测中任何一项提示阳性则进一步行阴道镜宫颈活检,并将检测结果与病理结果进行比较。结果与病理诊断结果比较,FRD检测的敏感性、特异性、阳性预测率、阴性预测率、误诊率、漏诊率分别为80.72%、84.21%、75.00%、90.14%、26.88%、20.00%,TCT检测的结果则分别为83.12%、83.12%、73.47%、87.67%、25.79%、19.28%,两种检测方法所得数据比较差异均无统计学意义(P>0.05)。结论 FRD上皮组织特殊染色液检测和TCT检测在宫颈病筛查中的临床价值相当,但采用FRD上皮组织特殊染色液检测具有操作简单、诊断全面、成本低廉以及结果快速等优点,值得临床推广。     

Activation of voltage‐gated sodium current and inhibition of erg‐mediated potassium current caused by telmisartan,an antagonist of angiotensin II type‐1 receptor,in HL‐1 atrial cardiomyocytes

Telmisartan (TEL) is a non‐peptide blocker of angiotensin II type‐1 (AT₁) receptor. However, the mechanisms through which this drug interacts directly with ion currents in hearts remain largely unclear. Herein, we aim to investigate the effects of TEL the on ionic currents and membrane potential of murine HL‐1 cardiomyocytes. In whole‐cell recordings, addition of TEL stimulated the peak and late components of voltage‐gated Na⁺ currents (I_Na) with different potencies. The EC₅₀ values required to achieve the stimulatory effect of this drug on peak and late I_Na were 0.2 and 1.2 μmol/L, respectively, and the current‐voltage relationship of peak I_Na shifted toward less‐depolarized potentials during exposure to TEL. Telmisartan not only increased peak I_Na but also prolonged the inactivation time course of late I_Na. Amiodarone (Amio) or ranolazine (Ran), but not angiotensin II, could reverse TEL‐mediated effects. The drug enhanced the recovery rate of I_Na inactivation and exerted an inhibitory effect on erg‐mediated K⁺ and L‐type Ca²⁺ currents. In whole‐cell current‐clamp recordings, addition of the drug resulted in prolongation of the duration of action potentials (APs) in a dose‐dependent manner in HL‐1 cells; Amio or Ran could reverse this increase in AP durations. Telmisartan‐mediated prolongation of AP was attenuated in KCNH2 siRNA‐transfected HL‐1 cells. In cultured smooth muscle cells of the human coronary artery, TEL enhanced I_Na amplitudes and slowed current inactivation. Stimulation by TEL of I_Na in HL‐1 cells did not simply increase current magnitude but altered current kinetics, thereby suggesting state‐dependent activation. Telmisartan may have greater affinity to the open/inactivated state than to the resting state residing in Na_V channels. Collectively, TEL‐mediated stimulation of I_Na and inhibition of I_K(erg) could be an important ionic mechanism underlying the increased cell excitability of HL‐1 cells; these actions, however, cannot be entirely explained by its blockade of AT₁ receptor.     

Carbonic anhydrase enzymes for regulating mast cell hematopoiesis and type-2 inflammation: a patent evaluation (WO2017/058370)

Introduction: Activity modulators of carbonic anhydrases hold great potential for several therapeutic applications against ophthalmologic and neurological disease, cancer, and infectious diseases. The involvement of carbonic anhydrase in the regulation of mast cell response opens new ways for the treatment of mastocytosis, allergic inflammation, and parasite infection.

Areas covered: The application claims the use of carbonic anhydrase activity modulators (inhibitors or activators) for treating allergic disease, bacterial infection, fungal infection, viral infection, mastocytosis, or mast cell–mediated inflammation.

Expert opinion: Although there is a lack of essential biological data, this patent proposes a new type of applications for carbonic anhydrase inhibitors and deserves further studies. This may lead to new advances in the field of carbonic anhydrase with potential therapeutic implications in the management of type-2 inflammation.     

LAMP微流控芯片快速检测三种食源性致病菌

建立一种结合环介导等温扩增(Loop-mediated isothermal amplification,LAMP)和微流控芯片技术检测沙门氏菌、大肠杆菌O157、金黄色葡萄球菌三种食源性致病菌的方法,实现对3种致病菌的快速检测。通过比对选取3种致病菌特异性基因、沙门氏菌侵袭蛋白A(hlyA)基因、大肠杆菌O157脂多糖编码(rfbE)基因、金黄色葡萄球菌耐药基因FemA基因作为目的基因,设计LAMP引物,通过实时LAMP筛选合格引物。设计微流控芯片,将引物冻干后固化到芯片上,制成LAMP微流控芯片。选择合适的LAMP反应体系,添加显色剂,加入芯片中,反应结果通过肉眼或仪器判读。使用标准菌株检验芯片的特异性与敏感性,并使用人工污染样品进一步检验其在实际样品检测时的敏感性。结果表明:制成的LAMP微流控芯片具有较好的特异性,3种致病菌的检测敏感性均可达到100 cfu/ml,可用于食源性致病菌的现场快速检测。     

基础试验不同时长对直立倾斜试验结果的影响

目的　探讨延长基础试验时间对神经介导性晕厥（neurally mediated syncope,NMS)患者直立倾斜试验（head-up tilt test, HUTT)阳性率的影响。方法　连续选取2019年4—10月在大连医科大学附属第一医院门诊及住院考虑神经介导性晕厥患者82例,交替顺序分为30 min基础试验组和45 min基础试验组。比较两组患者的试验结果阳性率、阳性反应分型、晕厥或晕厥前兆发作时间等。结果　30 min基础试验组阳性反应23例（56.1%）,45 min基础试验组阳性反应24例（58.5%）,两组阳性率无明显差异。基础试验阶段呈阳性反应9例,均为45 min基础试验组患者。其余73例（89%）需药物激发进行阳性结果诊断。总阳性反应类型在两组间无明显差异,以血管抑制型多见。药物激发后发生阳性反应时间在两组间差异有统计学意义［（4.96±3.2）min vs (7.93±3.1）min,P＜0.01］,30 min基础试验组多发生在含药5 min之内,45 min基础试验组阳性反应时间多发生在5 min之后。45 min基础试验组较30 min基础试验组阳性病例检查总时间明显延长［（52.93±3.1）min vs (34.67±1.3)min,P<0.05］。结论　45 min基础时程HUTT较30 min基础时程HUTT可增加10%的无药物激发阳性反应者,但诊断NMS整体阳性率并未提高。45 min基础试验组患者行药物激发阳性反应时间推迟,总检查时间明显延长。大多数NMS患者可以通过30 min基础时程HUTT获得确定诊断。     

腺病毒载体介导肝细胞生长因子基因对血管内皮细胞的作用

目的：研究腺病毒载体介导肝细胞生长因子（HGF）基因感染血管内皮细胞后在正常供氧、缺氧及缺氧后复氧的情况下细胞的凋亡情况。方法：将分离、培养的内皮细胞分为3组，分别给予M199（对照组）、HGF（HGF组）和HGF基因腺病毒载体（Ad-HGF组），分别在正常供氧、缺氧及缺氧后复氧3种情况下观察细胞的凋亡情况。结果：Ad-HGF组及HGF组细胞凋亡数均低于对照组（P〈0．01），Ad-HGF组与HGF组细胞凋亡数差异无显著性意义。结论：腺病毒载体介导HGF基因感染内皮细胞后能在缺氧情况下有效地阻止细胞凋亡。     

Intravenous immunoglobulin significantly reduces exposure of concomitantly administered anti‐C5 monoclonal antibody tesidolumab

Awareness of drug‐drug interactions is critical in organ transplant recipient management. However, biologic agents interfering with monoclonal antibodies is not widely considered. We report the effect of high‐dose intravenous immunoglobulin (IVIg) on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the human anti‐C5 monoclonal antibody tesidolumab (LFG316) in end‐stage renal disease patients awaiting kidney transplant. In this single‐center, phase 1, open‐label, parallel‐group study, 8 patients were assigned to receive either single‐dose tesidolumab + IVIg or tesidolumab alone, with 56‐day follow‐up. Within‐group PK parameters were consistent. Mean tesidolumab exposure decreased 34%, clearance increased 63%, and half‐life decreased 41% comparing tesidolumab + IVIg to tesidolumab alone. IVIg influence on tesidolumab elimination was most evident in the first 3 weeks. Complete suppression of both total and alternative complement activities was maintained for 4 weeks in the tesidolumab alone group and for 2 weeks in the tesidolumab + IVIg group. Tesidolumab was well tolerated. IVIg infused before tesidolumab affected tesidolumab PK and PD, resulting in a shortened period of full complement activity inhibition. These findings suggest a clinically relevant impact of IVIg on monoclonal antibody clearance and indirectly hint at an IVIg mechanism of action in treating autoimmune diseases and allosensitization by accelerating pathogenic IgG antibody degradation. Trial registration number: NCT02878616.     

Contrasting effects of B cell depletion on CD4+ and CD8+ memory T cell responses generated after transplantation

Alloreactive memory T cells play a key role in transplantation by accelerating allograft rejection and preventing tolerance induction. Some studies using µMT mice, which are constitutionally devoid of B cells, showed that B cells were required for the generation of memory T cells after allotransplantation. However, whether B cell depletion in normal adult mice has the same effect on memory responses by CD4⁺ and CD8⁺ T cells activated after transplantation has not been thoroughly investigated. In this study, we tested the effect of anti‐CD20 antibody‐mediated B cell depletion on CD4⁺ and CD8⁺ memory T cell alloresponses after skin transplantation in wild‐type mice. We found that B cell depletion prevented the development of memory alloresponses by CD4⁺ T cells but enhanced that of CD8⁺ memory T cells. Next, we tested the influence of B cell depletion on hematopoietic chimerism. In OT‐II CD4⁺ anti‐OVA TCR transgenic mice sensitized to ovalbumin antigen, B cell depletion also impaired allospecific memory T cell responses and thereby enhanced donor hematopoietic chimerism and T cell deletion after bone marrow transplantation. This study underscores the complexity of the relationships between B and T cells in the generation and reactivation of different memory T cell subsets after transplantation.