Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas

Four patients with refractory malignant B cell lymphomas were treated with continuous intravenous (IV) infusions of murine monoclonal antibody (MoAb) 1F5 (anti-CD20) over five to ten days. Dose-dependent levels of free serum 1F5 were detected in all patients. Two patients had circulating tumor cells and in both cases 90% of malignant cells were eliminated from the blood stream within four hours of initiation of serotherapy. Antigenic modulation did not occur, and sustained reduction of circulating tumor cells was observed throughout the duration of the infusions. Serial bone marrow aspirations and lymph node biopsies were examined by immunoperoxidase and immunofluorescence techniques to ascertain MoAb penetration into extravascular sites. High doses (100 to 800 mg/m2/d and high serum 1F5 levels (13 to 190 micrograms/mL) were required to coat tumor cells in these compartments in contrast to the low doses that were adequate for depletion of circulating cells. Clinical response appeared to correlate with dose of MoAb administered with progressive disease (52 mg), stable disease (104 mg), minor response (1,032 mg), and partial response (2,380 mg) observed in consecutive patients. The patient treated with the highest 1F5 dose achieved a 90% reduction in evaluable lymph node disease, but the duration of this remission was brief (six weeks). This study demonstrates that high doses of 1F5 can be administered to patients with negligible toxicity by continuous infusion and that clinical responses can be obtained in patients given greater than 1 g of unmodified antibody over a ten-day period.     

Collection of pluripotential hematopoietic stem cells by cytapheresis

Successful complete hematopoietic reconstitution (CHR) using nonleukemic peripheral stem cells (PSC) after marrow ablation has been reported in animals but not man. Previous studies of cytapheresis products from humans, as a prelude to use for CHR, have documented the presence of committed myeloid (CFU-GM) and erythroid (BFU-E) precursors. We have examined mononuclear cell (MNC) products collected on the Fenwal CS3000 Blood Cell Separator for these plus the more primitive mixed (granulo-, erythro-, mono-, and megakaryocytic) cell colony-forming units (CFU-GEMM) and for various lymphocytic subpopulations (LSP). One to two-hour products contained 36 +/- 7 CFU- GEMM/10(6) MNC (mean +/- SE, n = 8) or 490 +/- 131/ml product. This compared favorably with blood (23 +/- .4/10(6) MNC or 46 +/- 8/ml, n = 14) and bone marrow (146 +/- 58/10(6) MNC, n = 12). Collection efficiency for E-rosette-positive cells approximated that for total lymphocytes and was variable for other LSP. Recovery of CFU-GEMM after freezing in 10% dimethylsulfoxide at a controlled rate and storage in liquid N2 was 54% +/- 8% (n = 8). Cytapheresis collection of large numbers of pluripotent hematopoietic precursors and demonstration of adequate recovery of these after cryopreservation, both previously unreported, are significant steps toward eventual CHR using nonleukemic PSC.     

Pharmacological preconditioning by diazoxide downregulates cardiac L-type Ca2+ channels

BACKGROUND AND PURPOSE

Pharmacological preconditioning (PPC) with mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channel openers such as diazoxide, leads to cardioprotection against ischaemia. However, effects on Ca²⁺ homeostasis during PPC, particularly changes in Ca²⁺ channel activity, are poorly understood. We investigated the effects of PPC on cardiac L-type Ca²⁺ channels.

EXPERIMENTAL APPROACH

PPC was induced in isolated hearts and enzymatically dissociated cardiomyocytes from adult rats by preincubation with diazoxide. We measured reactive oxygen species (ROS) production and Ca²⁺ signals associated with action potentials using fluorescent probes, and L-type currents using a whole-cell patch-clamp technique. Levels of the α_1c subunit of L-type channels in the cellular membrane were measured by Western blot.

KEY RESULTS

PPC was accompanied by a 50% reduction in α_1c subunit levels, and by a reversible fall in L-type current amplitude and Ca²⁺ transients. These effects were prevented by the ROS scavenger N-acetyl-L-cysteine (NAC), or by the mitoK_ATP channel blocker 5-hydroxydecanoate (5-HD). PPC signficantly reduced infarct size, an effect blocked by NAC and 5-HD. Nifedipine also conferred protection against infarction when applied during the reperfusion period. Downregulation of the α_1c subunit and Ca²⁺ channel function were prevented in part by the protease inhibitor leupeptin.

CONCLUSIONS AND IMPLICATIONS

PPC downregulated the α_1c subunit, possibly through ROS. Downregulation involved increased degradation of the Ca²⁺ channel, which in turn reduced Ca²⁺ influx, which may attenuate Ca²⁺ overload during reperfusion.     

A supervised land cover classification of a western Kenya lowland endemic for human malaria: associations of land cover with larval Anopheles habitats

Background  

A supervised land cover classification was developed from very high resolution IKONOS satellite data and extensive ground truth sampling of a ca. 10 sq km malaria-endemic lowland in western Kenya. The classification was then applied to an investigation of distribution of larval Anopheles habitats. The hypothesis was that the distribution and abundance of aquatic habitats of larvae of various species of mosquitoes in the genus Anopheles is associated with identifiable landscape features.     

垂体催乳素瘤的诊断和治疗指南

首次测定确立高催乳血症必需避免过度的静脉穿刺压力,理想的情况是醒后或饭后致少1h来测试.     

Family physician views about primary care reform in Ontario: a postal questionnaire

Background  

Primary care reform initiatives in Ontario are proceeding with little information about the views of practicing family physicians.     

茶碱对有呼吸窘迫综合征的极早产儿患血管运动性肾病的预防作用研究：一项随机双盲安慰剂对照试验

背景:血管运动性肾病是早产儿常见的肾功能障碍性疾患。目的:确定茶碱是否可以预防有呼吸窘迫综合征的极早产儿罹患血管运动性肾病。方法:随机双盲安慰剂对照试验,50例胎龄≤32周须辅助通气的早产儿。婴儿接受3d茶碱(1m g/kg)或安慰剂静脉注射。每天测定其24h尿量。在第2、第5及第11天,收集血样及12h尿并进行电解质、肌酐、尿素分析。结果:茶碱组患儿的第1天排尿量的组别x(s)为2.4(0.9)m l/(kg·h),显著高于安慰剂组[1.6(1.0)m l/(kg·h);P=0.023]。茶碱组少尿或无尿的发生率(5%)显著低于安慰剂组(33%)。在第一次给予茶碱/安慰剂后24h,茶碱…