doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH)

Subcortical laminar heterotopia (SCLH), or 'double cortex', is a cortical dysgenesis disorder associated with a defect in neuronal migration. Clinical manifestations are epilepsy and mental retardation. This disorder, which mainly affects females, can be inherited in a single pedigree with lissencephaly, a more severe disease which affects the male individuals. This clinical entity has been described as X- SCLH/LIS syndrome. Recently we have demonstrated that the doublecortin gene, which is localized on the X chromosome, is implicated in this disorder. We have now performed a systematic mutation analysis of doublecortin in 11 unrelated females with SCLH (one familial and 10 sporadic cases) and have identified mutations in 10/11 cases. The sequence differences include nonsense, splice site and missense mutations and these were found throughout the gene. These results provide strong evidence that loss of function of doublecortin is the major cause of SCLH. The absence of phenotype-genotype correlations suggests that X-inactivation patterns of neuronal precursor cells are likely to contribute to the variable clinical severity of this disorder in females.      

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.      

Phase II study of continuous-infusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas

Background: Ifosfamide has important activity in pretreated soft tissue sarcomas (STS), and recent data support a clinically significant dose-response relationship for this agent. Administration by continuous infusion and hematopoietic support have rendered dose intensification regimens possible by reducing both hematologic and non-hematologic toxicities. The optimal dose and schedule of ifosfamide when given at high doses remain to be defined. In a previous phase I study, we demonstrated the feasibility of a continuous infusion (c.i.) high-dose ifosfamide (HDI) regimen in the ambulatory setting for patients with advanced solid tumors. The objective of the present phase II study was to assess the antitumor activity and toxicity of such a schedule in patients with advanced pretreated STS.Patients and methods: Thirty-eight patients with advanced and/or metastatic STS, all pretreated with an anthracycline with or without standard-dose ifosfamide, were treated. Ifosfamide was given by c.i. at a dose of 3.5 g/m²/day over four consecutive days, with equidose mesna uroprotection over five days. G-CSF was added at a dose of 200 µg/m²/day subcutaneously from day 6 to day 12. Cycles were repeated every three weeks in the outpatient setting.Results: A total of 159 cycles of therapy were given (median 4 per patient, range 3–6). Treatment compliance was generally satisfactory. The major toxicity was hematologic, with six febrile neutropenic episodes requiring hospitalisation and parenteral antibiotics. Acute renal failure occurred in one patient after three cycles of therapy; central nervous system toxicity was mild. An overall response rate of 39% was observed (95% confidence interval, 26% to 55%), with one complete and 14 partial remissions. All but one of the responder patients had previously received standard-dose ifosfamide. The median response duration was nine months (range 5–21+ months), and the overall median survival ranged from 6–30+ months (median 13 months).Conclusions: High-dose ifosfamide is an active regimen in anthracycline- pretreated STS. Future clinical trials should be aimed at evaluating the impact of different administration schedules on clinical response and outcome. The potential role of HDI as front-line chemotherapy as well as in the adjuvant treatment of STS needs to be investigated in randomized trials.     

Endoscopy in non-neoplastic cholestasis

The role of endoscopic treatment of cholestasis is well codified as an alternative or adjuvant therapy to surgery, particularly in those cases where non malignant cause has been identified. Non-neoplastic cholestasis therefore benefits very substantially from endoscopic treatment in a context where the traditional surgical approach presents limitations in terms of morbidity and mortality. It should be borne in mind, however, that the two approaches are strictly complementary for the correct management of these patients.     

平贝碱乙的分离和鉴定

本文报道了自东北平贝母(Fritillaria ussuriensis Maxim)中分得一种新的甾体生物碱,经光谱(IR,MS,¹HNMR及¹³CNMR)解析和衍生物制备,推定其结构为5α,17β,22α-cevanine-3 β,6α,12α,14α,16β,20β-hexol,定名为平贝碱乙。     

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。