Human mini-chromosomes in mouse embryonal stem cells

We have introduced human mini-chromosomes of 4 Mb and approximately 15 Mb in size into mouse embryonal stem cells. Although these human mini- chromosomes are stable in hamster and chicken cells, they re-arrange or segregate aberrantly in the embryonal stem cells and are rapidly lost in the absence of selection. However, one of the mini-chromosomes re- arranged, acquired mouse centromeric sequences and was then stably maintained for at least 60 population doublings in culture. This mini- chromosome, which is 4 Mb in size, is a candidate for a mouse germ line chromosome vector.      

Time-resolved MR angiography of the upper abdomen: initial clinical experience

In this study, thirty-eight patients with a variety of upper abdominal diseases were examined with three-dimensional time-resolved MR angiography (7 sec/data set). Visualisation of arterial and venous anatomy was excellent in the majority of patients. Moreover, subtraction images could be calculated and organ perfusion could be assessed. It is concluded that this technique opens new perspectives for a comprehensive evaluation of vascular and parenchymal disease. Received: 14 April 1998; Revision received: 23 October 1998; Accepted: 9 November 1998     

Decreased striatal dopamine-receptor binding in sporadic ALS: glutamate hyperactivity?

The pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. The striatum receives massive glutamatergic input. Animal studies suggest that glutamate decreases striatal D2-receptor synthesis. In drug-naive, sporadic ALS patients we demonstrated decreased striatal D2-receptor binding in vivo that could be partially reversed by the glutamatergic transmission blocker riluzole. Our findings support the glutamatergic excitotoxicity hypothesis in sporadic ALS.     

Different behaviour of radioiodinated human recombinant interleukin-1 and its receptor antagonist in an animal model of infection

Recently, we demonstrated that radiolabelled interleukin-l (IL-1) specifically accumulates in focal infection in mice through interaction with its receptor. Unfortunately, systemic side-effects of IL-1 limit its clinical application. We investigated whether this problem could be circumvented by using the interleukin-1 receptor antagonist (IL-Ira), an equally sized protein that binds to the same receptors as IL-1 without induction of biological effects. Biodistribution of¹²⁵I-IL-1 and¹²⁵I-IL-Ira was determined in Swiss mice withStaphylococcus aureus-induced abscesses in the left calf muscle at 4, 12, 24 and 48 h after injection of either 0.4 MBq¹²⁵I-IL1 or 0.4 MBq¹²⁵I-IL-Ira. In vitro, the proteins displayed similar binding characteristics. High-performance liquid chromatographic analysis revealed a tendency for IL-Ira to associate with serum proteins. Both proteins rapidly cleared from most organs. However, the abscess uptake of¹²⁵I-IL-Ira was significantly lower than that of¹²⁵I-IL-1 at all time points (48 h p.i.: 0.06±0.01%ID/g vs 0.60±0.04%ID/g;P<0.02). The abscess-to-contralateral muscle ratios did not exceed 15.5±2.9 for¹²⁵I-IL-lra, while the ratios for¹²⁵I-IL-1 reached 46.9±5.7 at 48 h p.i. Despite similar in vitro receptor binding, the abscess uptake of IL-Ira was much lower than that of IL-1. The interaction of IL-Ira with serum proteins in vivo may reduce its availability for receptor binding in the infection. Although on theoretical grounds IL-Ira is very interesting, these characteristics will prevent its development as a clinically useful radiopharmaceutical to image infection.     

Decreased striatal dopamine D2 receptor binding in amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA): D2 receptor down-regulation versus striatal cell degeneration

Recently, decreased striatal dopamine D2-receptor binding was demonstrated in vivo in amyotrophic lateral sclerosis (ALS). To further elucidate the pathogenetic mechanism underlying this D2-receptor deficit, a multi-level comparison was made between 30 sporadic ALS subjects and 24 patients with multiple system atrophy (MSA), a disorder clinically characterized by bradykinesia, neuroradiologically by severe D2-receptor loss, and neuropathologically by degenerating striatal cells. The extent of D2-deficit in ALS and MSA were within the same range, but extrapyramidal signs and symptoms were virtually absent in our ALS patients. Striatal cell loss in general or competitive D2-receptor occupancy could be considered unlikely in ALS. The striatum receives massive glutamatergic input and the pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. As other mechanisms (cell loss, receptor occupancy) could be ruled out, and as animal studies suggest that (excess of) glutamate decreases striatal D2-receptor synthesis, the striatal D2-receptor deficit in ALS is most likely to be caused by a receptor down-regulation.     

单克隆抗体博来霉素A6偶联物对白血病细胞特异性结合与内化

抗CCT2单克隆抗体博来霉素A6偶联物可吸附胶体金颗粒(McAb-A6-Au)。电镜观察表明,在4℃,1h,表面有McAb-A6-Au颗粒的CEM细胞最高达78%;在37℃,4h,内化McAb-A6-Au颗粒的CEM细胞高达72%。而抗原性无关的U937细胞仅为14%。并且McAb-A6-Au颗粒能直接穿过细胞膜、核膜进入细胞浆和细胞核。37℃,1h已有10～18%的CEM细胞核内有McAb-A 6-Au颗粒。实验结果提示了单抗与博来霉素A6的偶联物与选择性地结合靶细胞,而且进入细胞速度快、穿透力强,有可能成为治疗白血病药物。