Transcriptomic studies in tolerance: Lessons learned and the path forward

Immunosuppression after solid organ transplantation is a delicate balance of the immune response and is a complex phenomenon with many factors involved. Despite advances in the care of patients receiving organ transplants the adverse effects associated with immunosuppressive agents and the risks of long-term immunosuppression present a series of challenges and the need to weigh the risks and benefits of either over or under-immunosuppression. Ideally, if all transplant recipients could develop donor-specific immunological tolerance, it could drastically improve long-term graft survival without the need for immunosuppressive agents. In the absence of this ideal situation, the next best approach would be to develop tools to determine the adequacy of immunosuppression in each patient, in a manner that would individualize or personalize therapy. Despite current genomics-based studies of tolerance biomarkers in transplantation there are currently, no clinically validated tools to safely increase or decrease the level of IS that is beneficial to the patient. However, the successful identification of biomarkers and/or mechanisms of tolerance that have implications on long-term graft survival and outcomes depend on proper integration of study design, experimental protocols, and data-driven hypotheses. The objective of this article is to first, discuss the progress made on genomic biomarkers of immunological tolerance and the future avenues for the development of such biomarkers specifically in kidney transplantation. Secondly, we provide a set of guiding principles and identify the pitfalls, advantages, and drawbacks of studies that generate genomic data aimed at understanding transplant tolerance that is applicable to all solid transplants.     

新冠肺炎患者和细菌性肺炎患者血清差异表达的细胞因子特征分析

目的 了解新型冠状病毒肺炎（新冠肺炎）患者与细菌性肺炎患者细胞因子的差异,探讨新冠肺炎免疫病理机制,为新冠肺炎提供新的治疗靶点。方法 收集轻型新冠肺炎患者（新冠肺炎组）、细菌性肺炎患者（细菌性肺炎组）和健康志愿者（健康对照组）3组各15份血清标本,进行48种细胞因子的检测,比较3组间细胞因子表达谱的差异。检测10例新冠肺炎患者在治疗不同时间点的血清标本中48种细胞因子表达,分析其与新冠肺炎患者的临床特征及疾病进展的相关性。结果 新冠肺炎组与细菌性肺炎组比较中,巨噬细胞迁移抑制因子（MIF）、生长调节致癌基因α（GROα）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和TNF-β在新冠肺炎组中上调（P均< 0.05）。而 IL-10、IL-18、IL-2受体α和IFN-γ诱导的单核细胞因子（MIG）在细菌性肺炎组中上调（P均< 0.05）。巨噬细胞集落刺激因子（M-CSF）在新冠肺炎患者住院治疗的第2周有明显的下调;单核趋化蛋白-1（MCP-1）的变化与新冠肺炎患者的核酸检测结果变化一致。结论 新冠肺炎患者和细菌性肺炎患者体内存在不同的细胞因子表达谱。M-CSF和MCP-1在新冠肺炎疾病进展中起着重要作用。     

A pilot study of a chiropractic intervention for management of chronic myofascial temporomandibular disorder

BackgroundTemporomandibular pain has multiple etiologies and a range of therapeutic options. In this pilot study, the authors assessed the feasibility of conducting a larger trial to evaluate chiropractic treatment of temporomandibular disorders (TMDs).MethodsThe authors assigned 80 participants randomly into one of the following four groups, all of which included a comprehensive self-care program: reversible interocclusal splint therapy (RIST), Activator Method Chiropractic Technique (AMCT) (Activator Methods International, Phoenix), sham AMCT and self-care only. They made assessments at baseline and at month 2 and month 6, including use of the Research Diagnostic Criteria for Temporomandibular Disorders.ResultsThe authors screened 721 potential participants and enrolled 80 people; 52 participants completed the six-month assessment. The adjusted mean change in current pain over six months, as assessed on the 11-point numerical rating scale, was 2.0 (95 percent confidence interval, 1.1–3.0) for RIST, 1.7 (0.9–2.5) for self-care only, 1.5 (0.7–2.4) for AMCT and 1.6 (0.7–2.5) for sham AMCT. The authors also assessed bothersomeness and functionality.ConclusionsThe authors found the study design and methodology to be manageable. They gained substantial knowledge to aid in conducting a larger study. AMCT, RIST and self-care should be evaluated in a future comparative effectiveness study.Practical ImplicationsThis pilot study was a necessary step to prepare for a larger study that will provide clinicians with information that should be helpful when discussing treatment options for patients with TMD.     

New priorities: Analysis of the New Kidney Allocation System on UCLA patients transplanted from the deceased donor waitlist

UNOS implemented a new Kidney Allocation System (New KAS) on December 4, 2014 with a primary goal of increasing equity to organ transplant for patients that were immunologically or socially disadvantaged by the previous allocation system (Previous KAS) that prioritized long wait times. We examined the effects of the New KAS on patients transplanted from the UCLA deceased donor waitlist during the first year and compared to the last year of the Previous KAS. The total number of deceased donor kidney transplants was increased in the New KAS as compared to the Previous KAS (178 vs 148). Transplant of regraft patients and of highly sensitized patients with cPRA ? 99% was significantly increased in the New KAS (New KAS vs Previous KAS, 29.8% vs 11.5%, p ? 0.0001, and 26.4% vs 2.7%, p ? 0.0001, respectively). In the New KAS, the percentage of patient’s receiving allografts imported from outside our local area was also significantly increased (34.8% vs 15.5%, p < 0.0001). In the New KAS, 59.7% and 48.3% of imported organs were allocated to very highly sensitized (?99% cPRA) or re-graft patients, respectively, as compared to 8.7% and 8.7% during the Previous KAS (p < 0.001). Recipients and donors with age differences exceeding 15 years were decreased in the New KAS as compared to the Previous KAS (36.5 vs 48.7%, p?0.032). There was a 40.1% reduction in transplant to patients in the 65+ age group in the New KAS (p ? 0.025). The percentage of patients transplanted with preformed donor specific antibody (DSA) was similar in the New as compared to the Previous KAS (19.7% vs 15.5%) and, patients were transplanted with a range of 1–3 preformed DSA of weak to moderate strength. Cold ischemic time was significantly increased over all organs, and in patients transplanted with preformed DSA during the New as compared to the Previous KAS (17.5 vs 19.1 h and 17.2 vs 22.2, p < 0.04 and p < 0.03, respectively). Episodes of delayed graft function and the number of biopsies for cause were similar between the New and the Previous KAS. However, there were more events of biopsy proven antibody mediated rejection in patients transplanted since the start of the New KAS. The data show that the New KAS is working at the center level as designed to better age match recipients and donors and to increase transplantation of very highly sensitized patients through broader sharing.     

颏唇角改变对中国汉族人群软组织侧貌影响的审美评价

目的 研究颏唇角对软组织侧貌审美的影响.方法 选择软硬组织测量值均符合中国人正常标准的年轻男性、女性各一名,拍摄自然头位时的侧貌照片后,应用Photoshop软件通过改变其颏唇沟深度进而定量改变颏唇角,获得男女两组各17张图像.邀请专业组23人和非专业组59人分别对两组图像以VAS量表施行审美评分.结果 男性组最佳颏唇角为137°～142°,专业组可接受范围为122°～157°,非专业组可接受范围为122°～162°.女性组最佳颏唇角为121°,专业组及非专业组可接受的范围均为111°～146°.结论 在中国汉族人群中,理想的颏唇角大小具有明显性别差异,中国人对男性颏唇沟深度的容忍度更高.提示治疗方案制定时,需要考虑男性女性不同的颏唇角审美标准.     

Evaluation of cyclic flexural fatigue resistance of 25/0.04 and 25/0.06 twisted file rotary nickel‐titanium endodontic instruments

Twisted files (TFs) are rotary nickel‐titanium (NiTi) instruments that are produced with a newly developed manufacturing process that is supposed to improve their properties, especially flexibility and resistance to cyclic flexural fatigue failure. The aim of this study was to study the cyclic flexural fatigue failure resistance of tip size International Standards Organization 25 TFs with two tapers 0.04 and 0.06 and to compare them with the Profile (PF) rotary NiTi files of similar tip size and taper. Four groups of fifteen files were used in this study. TF (25/0.04), TF (25/0.06), PF (25/0.04) and PF (25/0.06) were tested using the cyclic flexural fatigue testing device. The time to failure during cyclic flexural fatigue testing was recorded. The mean time required for the instrument to fail under cyclic flexural fatigue testing was 235.5 ± 68 s for 25/0.04 TF, 188.5 ± 75 s for 25/0.06 TF, 180.3 ± 102 s for 25/0.04 PF and 156.3 ± 17 s for 25/0.06 PF. The difference between the time to failure of 25/0.04 TF and 25/0.06 TF was not statistically significant. The difference between the time to failure of TF and PF of similar tip size and taper was not statistically significant. The findings of this study indicate that size 25/0.04 and 25/0.06 TFs had similar resistance to cyclic flexural fatigue failure. In addition, TFs were not superior, in terms of resistance to cyclic flexural fatigue failure, to PF of similar tip size and taper.     

应用基因表达谱芯片研究高果糖大鼠胰岛素抵抗相关基因

目的 比较正常大鼠和高果糖大鼠骨骼肌组织基因表达差异,探讨胰岛素抵抗的发病分子机制.方法 实验大鼠分为正常对照组和高果糖组;从大鼠骨骼肌组织抽提mRNA,经逆转录分别用Cy3、Cy5荧光标记,获得两组动物来源cDNA探针;cDNA探针与4096条大鼠cDNA基因表达谱芯片杂交,扫描,重复2次实验,通过计算机数据处理.结果 筛选出胰岛素抵抗差异表达的基因共140条,基因上调有62条,基因下调有78条.结论 从骨骼肌组织中筛选出大量的差异表达基因,这些基因可能参加了胰岛素的发生发展过程.