Janus kinase-3 (JAK3) inhibition: a novel immunosuppressive option for allogeneic transplantation

Current immunosuppressive therapy in clinical organ transplantation is based on drugs that suppress various functions of immunocompetent cells but still affect cells and organ compartments other than the immune system. Hence, these drugs have considerable side effects which lead to increased morbidity and reduced life-quality of transplant recipients. A major step forward in the rationale design of clinical immunosuppression resides in the elucidation of molecular targets that play a critical role specifically within the immune system. Recently, Janus kinase 3 (JAK3) has been identified as such a molecule. Genetic absence or ablation of this tyrosine kinase is associated with defective T-cell immunity that results in severe combined immunodeficiency (SCID) without apparent changes in other organ systems. Furthermore, pharmacological inhibition has significantly prolonged allograft survival in several experimental models of organ transplantation. The present review provides an overview of the emerging role of JAK3 in the immune system and the development of JAK3-inhibiting drugs. The potential clinical application of JAK3 inhibitors in organ transplantations is discussed in the light of a recent series of successful kidney transplantations in non-human primates immunosuppressed solely with a novel JAK3 inhibitor.     

Treatment of a Humeral Metastasis with a Composite Allograft-Prosthetic Reconstruction

Abstract Background: The treatment of impending pathological fractures and symptomatic metastases involving the upper extremity articulations remains a challenge for the trauma surgeon. While the goals of treatment of bony metastases are clearly defined (early restoration of function, excellent pain control and minimal surgical trauma), these are not always easy to realize in upper extremity periarticular metastases. Case Study: A patient with a metastasis of a mediastinal nerve sheet tumor, involving the proximal 12 cm of the right humerus, including the whole head and both the tubercles, is described. A complete resection up to the level of the deltoid insertion was performed. In order to restore maximal function, the shoulder joint was reconstructed using a reversed total shoulder prosthesis. A fresh frozen cadaver proximal humerus was used as an allograft to obtain a secure stabilization of the prosthesis. Short-term results were very promising with restoration of ADL (activities of daily living) functionality within 3 months. Abduction and elevation > 100°, exorotation up to 20° and gluteal endorotation could be performed at that time. Conclusion: To the authors knowledge, this report is the first to describe reconstruction of the shoulder joint using a reversed shoulder prosthesis-allograft construction in case of a resection for malignancy.     

Anti-CD40 ligand monoclonal antibody induces a permissive state, but not tolerance, for murine peripheral nerve allografts

Anti-CD40 ligand monoclonal antibody prevents the interaction between CD40 and its T-cell-based ligand, thereby resulting in selective inhibition of T cell costimulation without pan-T-cell suppression. This antibody has found application in several animal models of solid organ transplantation. This study investigated use of anti-CD40 ligand antibody to promote acceptance of nerve allografts. In Experiment 1, 40 BALB/cj mice with tibial nerve transplants were administered anti-CD40 ligand antibody, a control antibody, or no treatment. In Experiment 2, 40 BALB/cj mice underwent the same regimen as in Experiment 1, but were later challenged with a second nerve allograft 3 weeks after discontinuation of treatment. Animals treated with anti-CD40 ligand antibody in Experiment 1 exhibited improved functional recovery and greater mean fiber count, fiber density, and percent nerve fiber than animals treated with control antibody or no antibody (P < 0.05). These permissive effects on nerve regeneration were associated with immune unresponsiveness on Elispot assay. The benefit of anti-CD40 ligand therapy did not persist after withdrawal of treatment (Experiment 2). Active blockade of the CD40 costimulatory pathway with murine anti-CD40 ligand antibody therefore induces a permissive state conducive to nerve regeneration across allografts but does not establish long-term tolerance.     

Diagnostic significance of semiquantitative and quantitative parameters of Tc99m-Ethylenedicystine renal allograft scintigraphy

OBJECTIVES: No objective parameters for renal allograft evaluation have yet been described for Tc99m-Ethylenedicystine. This study evaluates the diagnostic significance of different quantitative and semi-quantitative parameters of renal allograft scintigraphy using Tc99m-Ethylenedicystine. METHODS: A total of 72 renal dynamic scintigraphic studies were performed within 2-weeks of renal transplantation in 42 patients. The graft perfusion, kidney/aorta ratio, washout index and retention index were derived from all studies. All these parameters were evaluated for their ability to distinguish between a normal graft, a graft with acute rejection (AR), and a graft with acute tubular necrosis (ATN). Histopathological verification of diagnosis was obtained in all cases. RESULTS: Studies were subdivided into 3 groups according to histopathological findings: acute rejection (n = 42), normal (n = 18) and acute tubular necrosis (n = 12). Normal allografts were visualized with in 2.66 +/- 0.59 seconds of visualization of abdominal aorta. The K/A ratio, wash out index and retention index was 15.22 +/- 6.86, 1.67 +/- 0.45, and 5.48 +/- 0.98 respectively. Allografts with ATN were visualized with in 3.36 +/- 0.80 seconds of visualization of abdominal aorta. The K/A ratio, wash out index and retention index was 12.73 +/- 6.74, 0.60 +/- 0.14, and 9.18 +/- 1.48 respectively. In AR, allografts were visualized 15.18 +/- 9.48 seconds after visualization of abdominal aorta. The K/A ratio, wash out index and retention index was 7.07 +/- 2.15, 0.63 +/- 0.11, and 2.26 +/- 1.28 respectively. CONCLUSIONS: Retention index can separate all the three condition of normal, acute rejection and acute tubular necrosis from each other. Retention index of < 4 suggests acute rejection, a value between 4 and 7 suggests normal allograft and a value of > or = 7 is suggestive of acute tubular necrosis. However, perfusion, K/A ratio and washout index can not segregate all the three groups.     

Recurrent Sepsis from an Oral Focus and a Duodenal Fistula Following Allograft Repair of a Perforated Mycotic Aortic Aneurysm

Summary BACKGROUND: Perforated mycotic aortic aneurysms remain a major problem in vascular surgery. These patients continue to present a challenge to both the vascular surgeon and the medical microbiologist, although improvements in graft materials, transplant surgery and perioperative management have led to decreased mortality. METHODS: The case report summarizes the medical history of a 44-year-old male treated at our hospital for perforated Salmonella mycotic aneurysm and recurrent septic episodes. RESULTS: The patient suffered from recurrent septic episodes originating in the oral cavity and a duodenal fistula for more than five years following an alloplastic aortobiiliacal bypass. The pathogenesis, diagnostic approach and management of this case are discussed. CONCLUSIONS: Duodenal fistulae following aortic graft implantation are a rare, but serious complication, which will cause septic episodes and graft infection. This case demonstrates that a careful identification of the involved pathogens may aid the identification of the infectious focus.     

Allograft dermal implant (AlloDerm) in a previously irradiated field

OBJECTIVE: To evaluate the integration of AlloDerm (LifeCell Corp., The Woodlands, TX) in a field exposed to external-beam radiation (EBR) by analyzing graft thickness, fibroblast recellularization, and neovascularization. STUDY DESIGN: Randomized control. METHODS: Thirty-six male Sprague-Dawley rats (n = 36) were randomly assigned to four groups. One hind leg of each rat was exposed to 20 Gy of EBR; the other limb served as the nonirradiated control. Two weeks after irradiation, AlloDerm was implanted into both hind legs. Grafts were harvested at 3, 4, 6, and 14 weeks after implantation and underwent histological analyses. RESULTS: There was no statistically significant difference in graft thickness, fibroblast count, or neovascularization between the grafts placed in the irradiated bed and the controls (n = 33, P = .332, P = .336, and P = .057, respectively). However, at week 3, fibroblast counts in the graft placed in the field exposed to EBR were significantly lower than those of controls (P = .019), although at week 14 the counts in the experimental limb were higher than those of the controls (P = .002). Graft thickness (P = .001) and fibroblast count (P < .004) were lower at week 14 than at earlier time periods for both the experimental and control grafts. CONCLUSIONS: In the rat model, graft thickness and neovascularization of the AlloDerm dermal implant do not appear to be adversely affected by a field that has received EBR. Fibroblast ingrowth may be hindered in the early postimplantation period but appears to normalize in the long term. Furthermore, overall graft thickness and fibroblast counts decrease over time, regardless of irradiation status.     

小鼠未成熟睾丸同种异体移植的动物模型建立和改进

目的:初步探索采用同品系ICR小鼠作为受体小鼠,建立小鼠未成熟睾丸同种异体移植的动物模型。方法:采用6天龄ICR乳鼠未成熟睾丸作为供体,移植于已去势的同品系ICR受体小鼠颈背部皮下。移植后3、4、5周处死小鼠,观察移植物成活状况和移植物体积,HE染色评估移植物组织病理学的情况。荧光定量PCR检测异位成活的移植物组织内TESK1mRNA表达水平,供体睾丸和相应周龄小鼠睾丸组织作为对照。结果:移植后小鼠睾丸体积增长明显,于移植4周后进入平台期,移植前体积(17.3±2.6)mm3,移植3周组体积(203.1±14.3)mm3,移植4周组体积(236.4±27.5)mm3,移植5周组体积(220.9±17.4)mm3。组织病理学显示,移植物组织内曲细精管发育良好,生精功能正常,移植组曲细精管完整性和中空率3组间差异无统计学意义(P0.05)。TESK1mRNA表达水平随着移植时间延长逐渐增高,移植前TESK1mRNA水平为对照组的(1.19±0.1)倍,移植3周组mRNA水平为移植前小鼠的(6.74±0.8)倍,移植5周组为移植3周组的(11.23±1.2)倍,差异有统计学意义(P0.05)。结论:采用封闭系ICR小鼠作为受体的ICR小鼠未成熟睾丸移植是可行的。     

自体肌腱与同种异体肌腱重建前交叉韧带早期对比研究

目的：比较自体肌腱与同种异体肌腱重建前交叉韧带术后早期疗效差异。方法自2011年10月~2012年10月行前交叉韧带重建患者163例。根据采用移植物的不同将患者分为自体组85例,异体组78例。术后随访1个月,比较两组患者的手术时间、引流量、发热天数、术后第7天患肢肿胀程度、患肢肌力恢复程度、术后第3天及第7天CRP值。结果异体组的手术时间（39.2±1.3）min显著低于自体组（52.6±1.7）min,术后异体组引流量（106.7±2.6）ml与自体组（102.6±4.3）ml无明显差异,异体组发热天数（4.6±0.5）d显著长于自体组（1.3±0.2）d,异体组术后患肢早期肌力恢复程度显著高于自体组,异体组的患肢肿胀程度显著低于异体组,异体组术后第3天CRP值（32.9±1.2）mg/L与自体组（31.5±0.8） mg/L无显著差异,异体组术后第7天CRP值（91.7±9.6）mg/L显著高于自体组（12.8±6.1）mg/L。结论异体组术后早期临床疗效优于自体组。     

三种前路手术方法治疗颈椎不稳的临床比较研究

目的分析比较三种颈前路手术对颈椎不稳的治疗效果。方法选择84例患者手术前后情况进行回顾。第Ⅰ组38例为椎间盘切除减压自体髂骨植骨融合并钛板内固定术患者,第Ⅱ组17例为椎间异体骨笼植入融合术患者,第Ⅲ组29例为钛板内固定＋椎间异体骨笼植入融合术患者。比较三组改善率、植入物融合率、椎间隙高度及颈椎生理曲度的恢复程度,并结合手术时间、并发症及治疗总费用,评估三种治疗方案的优缺点。结果三组患者术后JOA评分均得到改善,有效率达90%,术后椎间隙高度恢复,颈椎生理曲度维持良好。无钢板、螺钉折断、滑脱等并发症,三组改善率、植入物的融合率、椎间隙高度及颈椎生理曲度的恢复程度无统计学差异（P〉0.05）,加用内固定手术时间及费用随之增加,应用自体髂骨移植费用相对便宜。结论充分的前路减压及牢固的植骨融合是手术关键,合理的选择病例,根据不同的病例特点科学地制订手术方法可取得满意的疗效。     

外固定器加同种异体骨移植治疗儿童干骺端良性骨肿瘤

目的 通过单臂多功能外固定器超关节固定加同种异体骨植入填塞骨肿瘤刮除后所留空腔，以解决儿童干骺端骨质广泛破坏的良性骨肿瘤(或类肿瘤病变)手术中遇到的固定困难和骨质缺损问题。方法 经治疗12例干骺端良性骨肿瘤患儿，术中均先用外固定器进行超关节固定，后行肿瘤刮除，同种异体骨材料和／或辅以自体骨植入填塞肿瘤刮除后所留空腔。结果 经随访12～60个月，平均26个月。大部分病例固定牢固，植入骨愈合良好，肢体长度差小于2cm。较好地解决了儿童干骺端良性骨肿瘤的保肢问题。仅少部分病例遗留关节僵硬。结论 多功能外固定器加同种异体骨植入是治疗儿童干骺端骨质破坏广泛的良性骨肿瘤的一种较好方法。