In vivo nitric oxide transfer of a physiological NO carrier, dinitrosyl dithiolato iron complex, to target complex

Dinitrosyl dithiolato iron complex (DNIC) has been identified as an endogenous NO carrier, yet in vivo mechanisms of NO donation remain undefined. Transnitrosylation, in which a coordinated NO group is transferred to another metal complex, has been observed in transition-metal-nitrosyl chemistry. In this study, we used three kinds of iron dithiocarbamate complexes (Fe-DTCs) as NO acceptors to elucidate in vivo transnitrosylation of diglutathionyl dinitrosyl iron complex [DNIC-(GS)(2)]. Fe-DTCs were administered to mice after the injection of DNIC-(GS)(2) and electron paramagnetic resonance (EPR) spectra were measured both in the resected organs and in the upper abdomen of living mice. The spectral feature gradually changed from an initial DNIC-(GS)(2) signal to mononitrosyl iron dithiocarbamate one, suggesting that NO-Fe-DTC was formed through in vivo reaction of DNIC-(GS)(2) with Fe-DTC. The spectral results in in vitro and in vivo systems indicate that NO-Fe-DTCs can be formed not only by the transfer of coordinated NO-group(s) in DNIC-(GS)(2) but also by the abstraction of Fe-NO group in DNIC-(GS)(2) by free DTC ligands. Transnitrosylation proceeded more rapidly in blood than in liver and kidney; and more efficiently in kidney than in liver. Further, the ability to accept NO from DNIC was dependent on water-solubility of Fe-DTCs. Thus, in vivo transnitrosylation from DNIC to exogenous iron complex could be observed and this reaction was influenced by biological constituents and properties of iron complex. These results demonstrate that the transnitrosylation from DNIC to intrinsic NO acceptors like metalloproteins has a probable significance in in vivo NO transfer process.     

Liposome clearance in mice: the effect of a separate and combined presence of surface charge and polymer coating

The purpose of our work was to compare the biodistribution of liposomes with different surface properties. Phosphatidylcholine (PC)/cholesterol (Chol) liposomes were prepared containing 6% mol of a charged lipid (stearylamine, SA; phosphatidic acid, PA; or phosphatidyl serine, PS) and/or polyethylene glycol (PEG)-PE of different MW (750 and 5000). ζ-Potentials and liposome clearance in mice were investigated. In vitro, the attachment of PEG in a similar fashion neutralizes the effect of any charged component. In vivo, the chemical nature of a charged lipid becomes important. Both short PEG750 and longer PEG5000 inhibit the clearance of positively charged SA-liposomes, while only longer PEG5000 inhibits the clearance of negatively charged PA-liposomes and none of the PEGs inhibit the clearance of negatively charged PS-liposomes. The opsonins with different molecular size may be involved in the clearance of liposomes containing different charged lipids.     

Percutaneous tumor ablation: increased necrosis with combined radio-frequency ablation and intravenous liposomal doxorubicin in a rat breast tumor model

PURPOSE: To determine whether a combination of intravenous liposomal doxorubicin and radio-frequency (RF) ablation increases tumor destruction compared with RF alone in an animal tumor model. MATERIALS AND METHODS: R3230 mammary adenocarcinoma 1.4-1.8-cm- diameter nodules were implanted subcutaneously in 132 female Fischer rats. Initially, tumors were treated with (a) conventional, monopolar RF (mean, 250 mA +/- 25 [SD] at 70 degrees C +/- 1 for 5 minutes) ablation alone, (b) RF ablation followed by intravenous administration of 1 mg of liposomal doxorubicin, (c) RF ablation followed by intravenous administration of 1 mg of empty liposomes, (d) RF ablation and direct intratumoral administration of liposomal doxorubicin, or (e) no treatment. Subsequently, the dose (0.06-2.00 mg) of liposomal doxorubicin, the timing of administration (3 days before to 3 days after RF ablation), and the time of pathologic examination (0-72 hours after treatment) were varied. RESULTS: Mean coagulation diameter for treated tumors follows: 6.7 mm +/- 0.6, RF ablation alone; 11.1 mm +/- 1.5, RF ablation and intravenous administration of empty liposomes (P <.05, compared with RF ablation alone); and 8.4 mm +/- 1.1, RF ablation with intratumoral administration of liposomal doxorubicin (P <.05, compared with RF ablation alone). Maximal increased mean coagulation diameter (13.1 mm +/- 1.5) was observed with a combination of liposomal doxorubicin and RF ablation (P <.001, for all comparisons). The increased coagulation for combination therapy developed over 48 hours after therapy. Coagulation diameter did not vary with the doxorubicin concentration range and was not dependent on the timing of administration of liposomal doxorubicin from 3 days before to 24 hours after RF ablation. CONCLUSION: Intravenous administration of liposomal doxorubicin can improve RF ablation, since it increases coagulation diameter in solid tumors compared with RF ablation alone or a combination of RF ablation with administration of empty liposomes.     

Telemedicine and spaceflight

Medical assessment and treatment of crews during spaceflight is primarily perfomed by the Earth-based medical staff analyzing information received by telemetry and onboard preventive and medical treatment facilities. In the coming decades, the building of the International Space Station (ISS) will be the most important near-Earth space exploration project. Remote monitoring and distance support of the crewmembers by the Earth-based clinical medicine specialists will become increasely important. The international nature of the ISS will require integrating medical support systems of the participating countries. Consideration must also be given to biomedical ethics and the confidentiality of the medical information exchanged. In Russia, the construction of the telemedicine network for the Russian node of the ISS has been completed. It is evident that during interplanetary flight biomedical problems will be much more difficult than during orbital flights of the same duration. Such a long-duration flight will require development of a special telemedical support system, as well as onboard facilities, which will present many new challenges. This new system will involve the integration of information technologies with biology, as well as physics and chemistry, representing a new interdisciplinary technological breakthrough.     

新型金属氧化物半导体场效应晶体管探测器在放疗剂量监控中的应用

目的探索和评估自行开发研制的新型金属氧化物半导体场效应晶体管(MOSFET)探测器在体实时剂量测量中的应用特性。方法分别使用医科达加速器8、15MV光子线,以及6、8、12、18 MeV电子束刻度MOSFET探测器。根据探测器灵敏度随能量变化情况评估MOSFET探测器能量依赖性。使用8MV光子线在0～50 Gy范围内观察MOSFET探测器读数随累积剂量变化的线性情况,确定MOSFET探测器剂量测量的线性区间。将MOSFET探测器固定在圆柱形PMMA体模中央,顺时针每15°检测探测器信号响应,判断MOSFET探测器方向性。对1例乳腺癌放疗患者应用MOSFET探测器进行了全程剂量监测。在使用NE-2571指形电离室对该患者放疗计划剂量计算进行物理验证后,分别于首次治疗、每周1次治疗及最后1次治疗中应用MOSFET探测器测量患者体表吸收剂量,并将测量结果与该处计划剂量进行比较,确定乳腺癌三维放疗的总体剂量偏差。结果对8、15 MV光子线和6～18MeV电子束测量结果显示,MOSFET探测器灵敏度随能量变化的幅度＜2．5%。这表明MOSFET探测器对中高能射线具有较好的能量响应。在6 V门控电压状态下,MOSFET探测器在0～50 Gy的剂量范围内保持了较好的剂量线性,最大偏差＜3．0%。在每次测量前和测量后分别刻度MOSFET探测器并取其平均值可使其剂量线性误差控制在1%以内。该MOSFET探测器信号响应在270～90°之间呈现出各向同性,读数偏差＜1．5%。但在探测器背面(135～225°之间)的信号响应明显变小,背面与正面的读数偏差最大可达10．0%。应用于患者实时剂量监测的结果显示,实际测量剂量与计划剂量相比平均偏差2．8%,最大偏差＜5．0%,符合AAPM 13号报告对体外放疗剂量总不确定度的质量控制标准。结论该MOSFEYT探测器体积小,操作简单,对中高能辐射具有较好的能量响应和剂量线性,为治疗计划剂量验证和人体吸收剂量测量提供了一种较好的剂量工具。     

Pharmacokinetics, toxicity, and efficacy of ends-modified raf antisense oligodeoxyribonucleotide encapsulated in a novel cationic liposome.

Raf-1 protein serine threonine kinase plays an important role in cell survival and proliferation. Antisense inhibition of Raf-1 expression has been shown to enhance the cytotoxic effects of radiation and anticancer drugs. Here we have evaluated the toxicity, pharmacokinetics, and antitumor efficacy of a novel formulation of liposome-entrapped raf antisense oligodeoxyribonucleotide (LErafAON). The LErafAON preparation showed high liposome entrapment efficiency of rafAON (>85%) and stability at room temperature. In CD2F1 mice, administration of LErafAON produced no morbidity/mortality (5-35 mg/kg/dose, i.v., x12). Dose-related elevations in liver enzymes (alanine aminotransferase and aspartate aminotransferase) and histopathological changes in liver were noted in LErafAON and blank liposome groups. No morbidity/mortality and changes in clinical chemistry or histopathology were observed in New Zealand white rabbits (3.75 mg/kg/dose, i.v., x8; 6.5 mg/kg/dose, i.v., x6) or in cynomolgous monkeys (3.75 or 6.25 mg/kg/dose, i.v., x9). Transient decrease in total hemolytic complement activity (approximately 62-74%) and increases in C3a (approximately 3-fold) and Bb levels (approximately 5-12-fold) were observed in LErafAON and blank liposome groups of monkeys. A 30 mg/kg i.v. dose of LErafAON in human prostate tumor (PC-3)-bearing BALB/c athymic mice gave a terminal plasma half-life of 27 h, and intact rafAON could be detected in plasma and in normal and tumor tissues for up to at least 48 h. In monkeys, the terminal plasma half-life of 30.36 +/- 23.87 h was observed at an i.v. dose of 6.25 mg/kg. LErafAON (25 mg/kg/dose, i.v., x10) or ionizing radiation (3.8 Gy/day, x5) treatment of PC-3 tumor-bearing athymic mice led to tumor growth arrest, whereas a combination of LErafAON and ionizing radiation treatments resulted in tumor regression. LErafAON treatment caused inhibition of Raf-1 protein expression in normal and tumor tissues in these mice (>50%, versus controls). These data have formed a basis of the clinical Phase I studies of LErafAON for cancer treatment.     

Cancer in rodents: does it tell us about cancer in humans?

Information obtained from animal models (mostly mice and rats) has contributed substantially to the development of treatments for human cancers. However, important interspecies differences have to be taken into account when considering the mechanisms of cancer development and extrapolating the results from mice to humans. Comparative studies of cancer in humans and animal models mostly focus on genetic factors. This review discusses the bio-epidemiological aspects of cancer manifestation in humans and rodents that have been underrepresented in the literature.     

Memory impairments and oxidative stress in the hippocampus of in-utero cocaine-exposed rats

We examined whether significant oxidative stress is induced in the brain of juvenile rats exposed in utero to cocaine, and contributes to their mnesic difficulties. We measured nitric oxide generation, using electron paramagnetic resonance, and the thiobarbituric acid reactive species as specific indexes of lipid peroxidation. Both nitric oxide and lipid peroxidation were elevated in the hippocampus of in-utero cocaine-exposed rats as compared with control animals. In-utero cocaine-exposed rats developed significant learning impairments in the water-maze, shown by probe test retrieval deficits. In parallel, behavioural sessions resulted in increases of thiobarbituric acid reactive species levels only in control animals. Therefore, in-utero cocaine exposure resulted in a significant oxidative stress in basal conditions, which may be related to impaired learning ability.     

Longitudinal assessment of coping abilities at exacerbation and stabilization in schizophrenia

BACKGROUND: Coping strategies play an important role in one's ability to adapt to stressful life conditions such as schizophrenia. To better understand the nature of various coping mechanisms at various stages in schizophrenia, this study examined task-, emotion-, and avoidance-oriented coping strategies and explored associated clinical factors at exacerbation and stabilization phases of the illness. METHOD: Patients with schizophrenia were examined twice (at exacerbation phase, N = 237 and at stabilization phase, N = 148) with the Coping Inventory for Stressful Situations, and standardized measures of psychopathology and emotional distress severity, side effects, insight, self-constructs, social support, and quality of life. Multiple regression analysis was performed with coping strategies as dependent variables at exacerbation and stabilization including analysis of any change during the 16-month follow-up period. RESULTS: Analysis indicated that emotion coping strategies were used more at exacerbation than at stabilization phase. Regression analysis demonstrated emotional distress to be a strong predictor of emotion-oriented coping, with self-efficacy and social support being the best predictors of task and avoidance coping strategies, respectively. Individual changes in these variables also appear to be important predictors for fluctuations of these coping strategies over time. Severity of symptoms accounted for 3.5% and 5.5% to 9% of the total variance of emotion- and task-oriented coping strategies, respectively. CONCLUSIONS: Emotion, task, and avoidance coping strategies and their predictors are influenced and may vary over the course of schizophrenia illness. Experienced emotional distress, self-efficacy, and social support are the best predictors of coping strategies both at exacerbation and stabilization phases of illness.