Extravasation of albumin in tissues of normal and septic baboons and sheep.

Extravasation of albumin was measured in the tissues of normal and septic baboons and sheep. A group of normal animals (4 baboons, 4 sheep) was anesthetized for 6 hr and then given radioactively labeled albumin and red blood cells intravenously. The labeled albumin and red blood cells were allowed to equilibrate for exactly 15 min, at which time the animals were deliberately killed. Volumes of distribution of labeled albumin and red blood cells were then determined in the lungs, heart, liver, spleen, brain, and skeletal muscle of the baboons and in the lungs, heart, liver, and spleen of the sheep. Another group of animals (6 baboons, 14 sheep) were made septic by infusing live Escherichia coli organisms. The animals were resuscitated and volumes of distribution of albumin and red blood cells determined as in the normal animals. The volume of distribution of albumin was greater than the volume of distribution of red blood cells in all tissues in both species, both in control animals and in septic animals, with the exception of the spleen and skeletal muscle of the baboons and the spleen of the sheep. That is, albumin extravasated readily in most of the tissues of the animals, even within only 15 min of equilibration. There was moderate but significant extravasation in the lungs, heart, and brain. There was marked extravasation in the liver. Extravasation tended to be more pronounced in the septic animals. With this extensive degree of albumin extravasation, administration of albumin to patients, especially septic patients, is unlikely to prevent edema except in the spleen and skeletal muscle.     

Antibody-dependent lymphocyte-mediated cytotoxicity (Ab-LMC), definition of the "K cell" in the rat.

The nature and membrane characteristics of the "K cell" of antibody-dependent lymphocyte-mediated cytotoxicity (Ab-LMC) were investigated in a widely used rat model of transplantation. Treatment of sensitized effector cell populations with anti-immunoglobulin and complement eliminated K cell cytotoxicity without diminishing the component of T cell-mediated injury. EA and EAC depletion experiments, although demonstrating no loss of K cell cytotoxicity after removal of complement receptor-bearing lymphocytes, produced a marked abrogation of cytotoxicity following the removal of the Fc receptor-bearing lymphocyte pool. Studies on phagocytic properties showed K cell activity to be shared by an adherent as well as a nonadherent cell population. Thus, the Fc receptor emerged as the only constant surface marker of the rat K cell in Ab-LMC.     

小牛血去蛋白提取物对胃溃疡患者的疗效评价

目的：探讨小牛血去蛋白提取物(DCBE)对胃溃疡的治疗作用。方法：选择年龄20～70岁之间，经胃镜检查确诊为活动期胃溃疡的住院患60例。治疗组32例采用静脉滴注DCBE(800mg，qd)和法莫替丁(100mg,bid)治疗；对照组28例采用静脉滴注法莫替丁(100mg，bid)单独治疗。用药2、4wk行胃镜检查，观察自觉缓解症状、时间、愈合率和总有效率。结果：治疗组自觉症状缓解时间明显缩短；给药后2、4wk治疗组及对照组胃镜检查溃疡愈合率分别为78.1％，46.4％及84.4％，71.4％。结论：DCBE能显促进胃溃疡的愈合。     

Ortho-substituted PCBs kill thymocytes.

The effects of exposure of acutely dissociated rat thymocytes to various polychlorinated biphenyl (PCB) congeners were examined using flow cytometry. Non-planar, ortho-substituted congeners caused a rapid cell death at low micromolar concentrations, while coplanar, dioxin-like congeners at the same concentration were without significant effect. The most potent of the congeners studied was PCB 52 (2,2',5,5'-tetrachlorobiphenyl), which had an IC50 of 3.96 microM at 20 min. Prior to loss of viability there was a decrease in mitochondrial membrane potential Delta Psi m, an accumulation of intracellular calcium, and a progressive leakiness of the plasma membrane. Application of PCB 52 in calcium-free medium reduced the calcium accumulation, but did not reduce cell death. Agents that depolarized mitochondria also did not induce the same degree of cell death caused by PCB 52. Cyclosporin A, which prevents opening of the mitochondria permeability transition channel, protected against cell death but did not protect against mitochondrial depolarization or calcium accumulation. Rapamycin and FK 506 at high concentration provided partial protection against cell death. These observations indicate that the ortho-substituted PCB 52 disrupts plasma, mitochondrial and endoplasmic reticulum membranes. We hypothesize that PCB 52 incorporates into lipid bilayers and with its bulky, three-dimensional ortho-substituted congener structure disrupts membrane function to a greater degree than coplanar congeners.     

Nuclear morphometry and molecular biomarkers of actinic keratosis, sun-damaged, and nonexposed skin.

Computer-assisted image analysis is useful for quantifying the histologic and molecular changes of sun-induced squamous cell carcinoma progression. We used the CAS 200 image analysis system to measure nuclear morphometric parameters, p53 expression, and proliferation markers in actinic keratosis (AK), sun-exposed, and normal skin in 51 patients. Nuclear morphometry revealed significant increases in nuclear absorbance, irregularity of nuclear shape, and nuclear size in AK compared with normal and sun-damaged skin. These parameters showed significantly greater variability in AK nuclei. Argyrophyllic nucleolar organizer area and number were also significantly greater in AK compared with sun-damaged skin and normal skin. Ki67 and p53 expressions were both increased in sun-damaged skin relative to normal and greater still in AK. These data are evidence that sun damage induces proliferation and p53 abnormalities before the appearance of nuclear abnormalities and their associated DNA instability. Following these changes during a skin cancer chemopreventative trial can then help assess the efficacy of the agent and help determine where in the progression of neoplastic changes it exerts its biological effects.     

Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel

OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.     

Intraperitoneal pretarget radioimmunotherapy with CC49 fusion protein.

PURPOSE: This study examined a pretarget radioimmunotherapy strategy for treatment of an i.p. tumor model (LS174T). EXPERIMENTAL DESIGN: The strategy used regional administration (i.p.) of a novel targeting molecule composed of four CC49 anti-tumor-associated glycoprotein 72 (TAG-72) single-chain antibodies linked to streptavidin as a fusion protein (CC49 fusion protein); 24 hours later, a synthetic clearing agent was administered i.v. to produce hepatic clearance of unbound CC49 fusion protein/synthetic clearing agent complexes. Four hours later, a low molecular weight radiolabeled reagent composed of biotin conjugated to the chelating agent 7,10-tetra-azacyclododecane-N,N',N',N'-tetraacetic acid (DOTA) complexed with (111)In-, (90)Y-, or (177)Lu-DOTA-biotin was injected. RESULTS: Radiolocalization to tumor sites was superior with i.p. administration of radiolabeled DOTA-biotin as compared with i.v. administration. Imaging and biodistribution studies showed excellent tumor localization of radioactivity with (111)In- or (177)Lu-DOTA-biotin. Tumor localization of (111)In-DOTA-biotin was 43% ID/g and 44% ID/g at 4 and 24 hours with the highest normal tissue localization in the kidney with 6% ID/g at 48 and 72 hours. Therapy studies with (90)Y-DOTA-biotin at doses of 400 to 600 microCi or (177)Lu-DOTA-biotin at doses of 600 to 800 microCi produced significant prolongation of survival compared with controls (P = 0.03 and P < 0.01). CONCLUSIONS: Pretarget radioimmunotherapy using regional administration of CC49 fusion protein and i.p. (90)Y- or (177)Lu-DOTA-biotin represents a successful therapeutic strategy in the LS174T i.p. tumor model and this strategy may be applicable to human trials in patients with i.p. ovarian cancer.     

Phase I study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: expression analysis of genes related to outcome.

PURPOSE: To establish the feasibility of capecitabine with concurrent radiotherapy (XRT) in patients with locally advanced (LA) pancreatic cancer and evaluate the effect of XRT on thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and tumor necrosis factor-alpha (TNF-alpha). PATIENTS AND METHODS: Fifteen patients with LA pancreatic cancer received three-dimensional conformal XRT to a dose of 50.4 Gy with capecitabine at escalating doses from 600 to 1,250 mg/m2 bid (Monday through Friday). Following chemo-XRT, stable and responding patients were treated with capecitabine 2,000 mg/m2 orally bid for 14 days every 21 days. Tumor specimens were procured with endoscopic ultrasound-guided fine-needle aspiration 1 week before and 2 weeks after chemo-XRT to evaluate TP, DPD, and TNF-alpha mRNA levels. RESULTS: Dose-limiting grade 3 diarrhea was observed in two of six patients treated at a capecitabine dose of 1,000 mg/m2 with XRT. Three patients (20%) achieved partial response. Mean percent difference in TP pre- and post-XRT was 119.2% (P = .1934). There was no significant differences in mean TNF-alpha, or DPD levels pre- and post-XRT (P = .1934 and .4922, respectively). TP and TNF-alpha levels were not significantly correlated both at pre- and post-XRT (P = .670 and P < .154, respectively). Median value of TP:DPD ratios at baseline was 2.65 (range, 0.36 to 11.08). No association between TP:DPD ratio and efficacy of capecitabine or severity of toxicities was identified. CONCLUSION: The recommended dose for phase II evaluation is capecitabine 800 mg/m2 bid (Monday through Friday) with concurrent XRT. This approach offers an easy alternative to intravenous fluorouracil as a radiosensitizer in these patients. Role of TP and TP:DPD ratio warrants further investigation in a larger clinical trial.     

TCDD and PCBs inhibit breast cancer cell proliferation in vitro

The effects on cell proliferation of arylhydrocarbon receptor (AhR) agonists in estrogen-responsive T47D and ZR-75-1 cells were investigated. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the non-ortho-substituted polychlorinated biphenyl (PCB) congeners, PCB 77, PCB 81, PCB 126, and PCB 169 each inhibited 17β-estradiol (E₂)-stimulated cell proliferation in a dose–responsive manner. In the absence of added E₂, TCDD, PCB 77, PCB 81, and PCB 169 had no significant effect on cell proliferation, while PCB 126 at high concentrations caused slight elevations. The order of effective inhibition of E₂-stimulated cell proliferation by the PCB congeners was: PCB 81>PCB 126PCB 169>PCB 77. In the comparative literature, mammalian TEFs for these congeners toxic potency are in the order: PCB 126>PCB 169>PCB 81PCB 77 [Organohalogen Compd. 34 (1997) 237]. Our results thus show an unexpected different pattern for the inhibitory effects of PCBs congeners on E₂-mediated cell proliferation.