Investigation of the anti-complement agents, FUT-175 and K76COOH, in discordant xenotransplantation

Abstract: We examined whether hyperacute rejection (HAR) of a discordant xenograft in a nonhuman primate model could be inhibited by the anticomplement agents, FUT-175 (FUT) and K76COOH (K76). The inhibitory effect of FUT and K76 on baboon sera was studied in vitro by i) complement-mediated hemolysis of sheep erythrocytes (by measuring serum CH50) and ii) cytotoxicity to cultured pig kidney (PK15) cells. The in vivo administration of FUT (at 0.2–25 mg/kg/h i.v. continuously) and K76 (50 mg/kg i.v. bolus) allowed evaluation of the serum levels of these drugs. Both FUT and K76 inhibited serum CH50 in a concentration-dependent manner. An enhanced effect was obtained by combining K76 with FUT therapy. High concentrations of FUT (>10^-4 M) and K76 (>10³ μxg/ml) were necessary to suppress serum CH50 to <5% of the normal level. However, PK15 cytotoxicity remained at >50% in the presence of i) 10^-4 M of FUT, ii) 10³ μg/ml of K76, and iii) 10^-6 M of FUT + 10³ μg/ml of K76. Pig heart transplantation (HTX) was performed in two baboons receiving FUT (1 mg/kg/h i.v. continuously) and K76 (at 200 mg/kg ×1 or 400 mg/kg + 200 mg/kg × 2 i.v, respectively). Cytotoxicity of the serum to PK15 cells at the time of HTX showed 39% and 1% cell death, respectively, in these two baboons, and the CH50 level was 1% (of control level) and 0%, respectively. Graft survival was 4.5 hours and 10 hours (with death of the baboon), respectively (compared with a mean of 29 minutes in control experiments). Both excised grafts showed typical features of hyperacute rejection. Immunopathological studies revealed deposition of C1q, C3d, C6, properdin, and Factor B, demonstrating that complement activation was not fully inhibited by FUT and K76. We conclude that i) FUT and K76 are indeed potent complement inhibitors, ii) the dosages of FUT and K76 necessary to suppress complement-mediated injury cannot be extrapolated from previously reported data obtained from serum CH50 levels, and iii) higher (possibly toxic) dosages will be required to inhibit complement activation completely. It seems unlikely that HAR will be prevented by these drugs alone, although they may be beneficial when combined with other forms of therapy.     

Comparative analysis of NK/T-cell lymphoma and peripheral T-cell lymphoma in Korea: Clinicopathological correlations and analysis of EBV strain type and 30-bp deletion variant LMP1

Natural killer/T-cell lymphoma (NKTL) and peripheral T-cell lymphomas (PTCL) are prevalent in the Asian population and exhibit a high association with the Epstein-Barr virus (EBV). Moreover, differentiation of these two groups is often difficult and problematic. We investigated 35 cases of NKTL (22 nasal cases and 13 extranasal cases) and 30 cases of PTCL in terms of their clinical features, immunohistology, EBV positivity, EBV strain-type polymorphism and latent membrane protein 1 (LMP1) deletion variant distribution. Eighteen cases (82%) of nasal NKTL and seven (54%) of extranasal NKTL showed EBV positivity by EBV in situ hybridization. Fifteen cases (50%) of PTCL revealed EBV positivity. EBV strain type A was predominant in NKTL (18:5), and EBV strain types A and B were distributed evenly in PTCL (6:6). EBV-positive patients had significantly shorter survival than EBV-negative patients (P < 0.05), and EBV positivity correlated with advanced clinical stage (P < 0.05). Patients harboring type A EBV showed slightly poorer prognoses than those having type B, though it was not obviously statistically different (P = 0.07). The LMP1 deletion variant was prevalent in both NKTL (three wild-type LMP1, 15 deletion variants) and PTCL (three wild-type LMP1, eight deletion variants, two coexistent forms) patients, but did not have prognostic impact. Our results indicate that EBV acts as a negative prognostic factor in NKTL and PTCL, and that the intrinsic properties of a specific viral strain might influence the clinical behavior of these diseases.     

47例骨髓穿刺干抽的临床和病理分析

分析４７例骨髓穿刺干抽的临床和病理改变，干抽占同期１３１９例骨穿的３．６％。根据骨髓细胞的密度和间质纤维增殖的程度，把干抽的原因分为４类：高细胞伴间质细胞增多者１９例（４２．２％）；间质细胞增多者１４例（３１．１％）；高细胞者８例（１７．８％）及低细胞者４例（８．９％）。主要疾病为：急性淋巴细胞白血病（２５．５％），急性非淋巴细胞白血病（１７．０％），慢性白血病（１４．９％），骨髓转移瘤（１０．６     

白三烯C_4对大鼠胃粘膜微循环的影响及其在急性胃粘膜损伤中的作用

探讨了静注白三烯C_4(0.1ng·100g~(-1))对胃粘膜微循环的影响及其在急性胃粘膜损伤中的作用。实验由Wistar系雄性大鼠,实验前禁食24hr,饮水不限。发现:1.胃粘膜表层毛细血管口径迅速变细,部分消失,集合细静脉口径亦变细;10分钟时集合细静脉明显淤血和出血。2.氢气清除法证明,胃粘膜血流量明显减少,注后第15分钟时由注前1.230±0.093(M±SE)降至0.521±0.079ml·min~(-1)·100g~(-1)(P<0.01)。3.反射光谱法证明,胃粘膜局部表层微循环血液量(△Er)和Hb氧饱和度(F),均有不同程度下降。4.静注白三烯C_4(0.1ng·100g~(-1))及盐酸灌胃(0.2N1ml)均未见明显胃粘膜损伤,两者并用则损伤明显加重。结果表明,外源性白三烯C_4可引起严重胃粘膜微循环障碍,是诱发溃疡形成的重要因素之一。     

Negative conversion of antimitochondrial antibody in primary biliary cirrhosis: a case of autoimmune cholangitis

Autoimmune cholangitis is a clinical constellation of chronic cholestasis, histological changes of chronic nonsuppurative cholangitis and the presence of autoantibodies other than antimitochondrial antibody (AMA). It is uncertain whether this entity is definitely different from AMA positive primary biliary cirrhosis (PBC), though it shows some differences. We report a case of autoimmune cholangitis in a 59-year-old woman, who had been previously diagnosed as AMA-positive PBC associated with rheumatoid arthritis, has been converted to an AMA-negative and anticentromere antibody-positive PBC during follow-up. The response to ursodeoxycholic acid treatment is poor except within the first few months, but prednisolone was dropping the biochemical laboratory data.     

Nonspecific induction of immunoglobulin M antibodies to periodontal disease-associated microorganisms after polyclonal human B-lymphocyte activation by Fusobacterium nucleatum.

The production of antibodies to oral bacteria was determined in lymphocyte cultures stimulated with sonicated Fusobacterium nucleatum, a potent inducer of polyclonal B-cell activation. After 9 days the cultures were examined by a microenzyme-linked immunosorbent assay for immunoglobulin M (IgM) antibodies to F. nucleatum, Bacteroides gingivalis, Actinomyces viscosus, and Streptococcus sanguis. Antibodies to these four bacteria were detected in cultures stimulated with polyclonal B-cell activation-inducing concentrations of F. nucleatum. However, significant concentrations of antibodies to F. nucleatum, but not to the other three microorganisms, were produced in cultures that received suboptimal polyclonal B-cell activation-inducing doses of F. nucleatum. Absorption studies indicated the specificity of the antibodies to each of the bacteria tested. IgM antibody production induced by F. nucleatum was enhanced by the addition of T cells. The production of IgM antibodies to the bacteria was reproducible in cultures from a single person tested on 3 consecutive days. The concentration of antibodies in replicate cultures, however, fluctuated greatly. To obtain consistent responses on successive days, multiple replicate cultures were required. These results suggest that F. nucleatum, which is frequently present in subgingival plaque, could induce the production of antibodies not only to F. nucleatum, but also to other microorganisms associated with periodontal diseases.     

心室晚电位的时间－频率表示法的进一步改进

在心室晚电位的研究中，我们引入了信号的时间一频率表示法，并根据晚电位的具体特性用Ｗｉｇｎｅｒ分布法（维格纳分布）把信号表示为在时间及频率空间中的能量分布。由于Ｗｉｇｎｅｒ分布的优异性质使我们有可能更准确表示出心室晚电位的存在。但当输入信号是两个信号的线性叠加时，Ｗｉｇｎｅｒ分布的结果会出现一个交叉项，相当于引入干扰。针对此不足，作者介绍改进方案，消除部分交叉项，收到较好的效果，并给出一些仿真及应用实例。     

Spontaneous disruption of mycotic aneurysm involving innominate artery

We report a case of ruptured mycotic aneurysm involving innominate artery requiring an urgent surgical treatment. A 62-yr-old woman presented with fever and dyspnea. Previously, she was diagnosed with colon cancer and received right hemicolectomy and one cycle of adjuvant chemotherapy. On echocardiogram, pericardial effusion was noted and emergency pericardiocentesis was performed. CT scan revealed aortic aneurysm involving ascending aorta and innominate artery, and thrombi surrounding those structures. Patch repair of the defect in the ascending aorta and ringed Goretex graft to bypass the innominate and ascending aorta were performed. We believe that this is the first case of ruptured mycotic aneurysm involving innominate artery.