同期胰肾联合移植12例报告--德国埃森大学的经验

目的总结同期胰肾联合移植(SPK)术的治疗效果和经验。方法自2002年1月至2003年9月,以SPK术治疗胰岛素依赖型糖尿病(IDDM)合并终末期肾病(ESRD)患者12例。每例受者接受来自同一供者的胰腺和肾脏,移植肾以经典方法植入左侧盆腔,胰腺植于右下腹。1例移植胰腺静脉与受者门静脉系统吻合,11例与体静脉系统吻合。胰腺外分泌引流方法为:3例移植物十二指肠段与受者十二指肠吻合,9例与空肠上段吻合。术前应用甲泼尼龙及抗胸腺细胞球蛋白作为免疫诱导,术后以他克莫司、霉酚酸酯和泼尼松三联抗排斥药物维持。结果术后平均随访时间23个月,受者、移植胰腺和移植肾的存活率分别为100%、91.7%和91.7%。1例再次行SPK术的受者,术后出现了超急性排斥反应,且未能逆转,于术后13d切除移植物;其余11例首次行SPK术的受者中,3例(28.3%)出现急性排斥,均获成功纠治。2例受者术后移植肾功能延迟恢复,行过渡性透析。11例首次行SPK术的移植胰腺术后立即发挥了功能,分别于术后1~5d内停用胰岛素。结论同期胰肾联合移植是胰岛素依赖型糖尿病合并终末期肾病患者的一种安全而有效的治疗方法。     

Ultrastructural analysis of human natural killer cell activation

In this study we describe characteristic ultrastructural changes of CD3- large granular lymphocytes (LGL), ie, natural killer (NK) cells, following stimulation with recombinant (r) interleukin 2 (IL 2) or r- gamma interferon (r-gamma IFN) and after interaction with K562 target cells (TC) or Sepharose-bound anti-Fc gamma receptor (FcR) monoclonal antibody (MoAb). When compared to resting cells the cytolytic activity of r-IL 2- and r-gamma IFN-stimulated cells against K562 TC was enhanced. The r-IL 2-stimulated LGL were larger and consistently displayed the shape and cytoskeletal rearrangement characteristic of activated cells. The Golgi apparatus was expanded, and the number of electron-dense granules and vesicles was increased. The ultrastructural changes in r-gamma IFN-stimulated LGL were markedly different from those observed following r-IL 2 activation. Cells did not exhibit changes in size, shape, cytoskeletal organization, or in the structure of the Golgi apparatus. However, r-gamma IFN-stimulated cells exhibited distinctive changes in the structure and content of electron-dense granules with deaggregation of the matrix and parallel tubular arrays (PTAs). Within organelles apparently derived from the electron-dense granules, vesicular and tubular structures were noted that may be the morphological equivalent of cytotoxic factors produced by cytolytic effector cells. These ultrastructural observations indicate that r-IL 2 and r-gamma IFN enhance the lytic ability of NK cells by acting on distinct cell machineries. The cytolytic ability was decreased when LGL were pretreated with K562 TC or immobilized anti-FcR antibody. In both experimental conditions cells displayed ultrastructural features indicating activation as well as loss of cytoplasmic granules and other Golgi-derived organelles. Stimulation of r-gamma IFN- or r-IL 2- activated LGL with K562 TC or Sepharose-bound anti-FcR antibody decreased their cytolytic ability, with cells depleted of granules at the ultrastructural level. Intracytoplasmic fusion of granules and a massive release of the granule content were found in r-IL 2-stimulated cells, reminiscent of the mechanism of basophil degranulation. These observations suggest that multiple activation signals involving distinct surface membrane molecules induce release of cytolytic factors by both resting and activated NK cells.     

Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia

The pharmacokinetics of busulfan, given as a single daily dose (either 4 mg/kg or 150 mg/m2), was determined in 22 children undergoing bone marrow transplantation for acute leukemia. The single daily dose regimen showed similar pharmacokinetics to previously reported regimens of 4 x 1 mg/kg, except for fourfold higher mean peak plasma levels and negligible trough levels. Daily systemic exposure for single dose regimens based on weight (4 mg/kg) or surface area (150 mg/m2), respectively were very similar to regimens of (4 x 1 mg/kg) or (4 x 37.5 mg/m2). Dose (milligrams per kilogram), peak plasma level, and area under the curve (AUC) were all higher in 12 children treated with 150 mg/m2 busulfan than in 9 children treated with 4 mg/kg. AUC was age dependent for the 4 mg/kg dose but not for the 150 mg/m2 dose. The use of a 150 mg/m2 dose allows escalation of the dose above 4 mg/kg, eliminating the tendency for younger children to receive lower systemic exposure. Little toxicity was observed in this study. Clearance and distribution volume correlated negatively with age, and AUC correlated positively with dose (milligram per kilogram). Administration of busulfan as crushed rather than whole tablets reduced the delay time for appearance of busulfan in plasma but had no effect on absorption or other pharmacokinetic parameters.     

Long-term iloprost infusion therapy for severe pulmonary hypertension in patients with connective tissue diseases

Objective. To determine the effects of short-term, maximum-tolerated-dose and long-term, optimum-dose iloprost treatment of severe pulmonary hypertension associated with systemic sclerosis (SSc) and the primary antiphospholipid syndrome (APS). Methods. Three patients with SSc and 2 with APS who had failed to respond to oral vasodilator therapy for pulmonary hypertension were enrolled in a 32-week, open, prospective trial. Short-term infusion of maximum-tolerated doses and continuous infusion of optimum doses of iloprost were carried out following baseline cardiac catheterization. Catheterization was repeated at 2 and 32 weeks. All 5 patients completed the study and continued therapy for an average of 82 weeks (range 58–103). Results. Acute infusion of maximum tolerated doses significantly ameliorated the cardiac index (0.92 liters/minute/m²; P < 0.01), pulmonary artery O₂ saturation (10.6%; P < 0.05), and pulmonary resistance (−6.7 units; P < 0.05). After 2 weeks of continuous infusion of optimum doses, there was improvement in pulmonary resistance (⩾16%) and pulmonary artery O₂ saturation ( > 30%) in the 2 patients with primary APS. After 2 and 32 weeks, the 3 SSc patients showed variable hemodynamic responses. New York Heart Association functional class and exercise tolerance improved in all patients. There was 1 episode of bacteremia, and 1 patient died after 72 weeks of study. Conclusion. Continuous iloprost infusion may improve exercise tolerance and quality of life in patients with severe pulmonary hypertension associated with SSc and primary APS.