X(γ)刀输出吸收剂量的测量与验证

目的：目前，国内X（γ）刀的国家检定规程正在起草之中，本文的目的是为X（γ）刀剂量测量提供合理的设备与吸收剂量计算方法。材料与方法：利用德国PTW-UNIDOS剂量仅与有效体积为0．015cc的针尖电离室及自制的小体积半导体探测器相匹配，在160mm直径的有机玻璃球形模体内测量X（γ）刀的输出吸收剂量，并验证其治疗计划的实际输出剂量，得到较满意的结果。结论：为了保证剂量的准确度，X（γ）刀治疗计划系统的实际输出剂量应定期在现场测量与验证，所用探测器的直径应小于射野直径的1／2，小灵敏体积的半导体探测器适宜X（γ）刀小野(如：Ф4mm)的测量。     

Development and characterization of DNAzyme candidates demonstrating significant efficiency against human rhinoviruses

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Magnesium restores high K-induced inactivation of the fast Na channel in guinea pig ventricular muscle

The effect of extracellular magnesium concentration (Mg_o) on the upstroke of the action potential was studied in guinea pig ventricular muscle under various K⁺ concentrations (2.7–19mM). Increased Mg_o shifted the steady state inactivation curve of the fast Na channel in the depolarizing direction and this effect was concentration-dependent (0–20mM). Such an effect could explain the Mg-induced increase in maximum rate of rise of the action potential which Späh and Fleckenstein (1979) proposed to be due to a Mg channel.     

Pharmacokinetic studies of high-dose metoclopramide with and without forced diuresis

Summary The pharmacokinetics of high-dose metoclopramide (10 mg/kg body wt. in five infusions of 2 mg/kg body wt. each) was studied in 11 patients (5 females, 6 males) in two groups: group A with and group B (consisting of five patients) without forced diuresis. When the drug was infused, forced diuresis had no influence on the pharmacokinetics of metoclopramide (serum level after the 1st infusion was 851±361 ng/ml in group A versus 840±348 ng/ml in group B; after the 5th infusion it was 2,005±588 ng/ml in group A versus 2,463±1,350 ng/ml in group B). There were significant differences in the 24-h serum levels (582±308 ng/ml in group A versus 379±170 ng/ml in group B;P<0.05) and in the elimination half life (8.5±2.6 h in group A versus 6.1±1.1 h in group B;P<0.05). The results demonstrate that the dosage regimen originally suggested by Gralla for cytostatic drugs, with forced diuresis for high-dose metoclopramide therapy, may also be applied, with no dosage reduction, with to other cytostatic drugs which do not require forced diuresis.     

低剂量γ射线辐照对血清一氧化氮及一氧化氮合酶水平的影响

目的：观察低剂量γ射线照射人离体外周血对血清中一氧化氮（NO）和一氧化氮合酶（NOS）水平的影响。方法：采集10份健康献血员全血，肝素抗凝，然后采用γ射线照射，照射剂量率为17Gy／min，总吸收剂量为1Gy，分别于照射前及照射后1h，2h采用分光光度法检测血清中NO含量和NOS活性。结果：经γ射线照射1h后，血清中NO及NOS水平与照射前比较明显升高（P〈0.01）；照射后2h，血清中NOS水平与照射后1h比较无统计学差异（P〉0、05），但是还明显高于照射前的水平（P〈0．01）；在照射后2h，血清中NO含量与照射后1h比较明显降低（P〈0.01），但仍明显高于照射前水平（P〈0．01）。结论：采用剂量为1Gy的γ射线照射外周血，可引起血清中NO水平及NOS活性的显著升高．从而为低剂量辐照自体血回输对肿瘤的辅助治疗提供了理论支持。     

Effect of various doses of palm vitamin E and tocopherol on aspirin-induced gastric lesions in rats

This study examined the effects of vitamin E on the prevention of aspirin-induced gastric lesions. The study was divided into two phases. Phase 1 determined the effects of various doses of palm vitamin E on the factors affecting mucosal integrity. Thirty-two male rats of the Sprague-Dawley strain (200-250 g) were randomly divided into four groups. Group I was fed a normal diet (control), Groups II, III and IV were fed a diet supplemented with palm vitamin E in a dose of 60 mg/kg food, 100 mg/kg food and 150 mg/kg food, respectively. The rats were killed after 4 weeks of feeding for the determination of gastric malondialdehyde (MDA), acid and mucus content. There was a significant decrease in gastric MDA and gastric acid in all the palm vitamin E supplemented groups compared to control. However, these doses of palm vitamin E had no significant effect on gastric mucus. The phase 2 study determined the effect of multiple doses of palm vitamin E and tocopherol on the prevention of aspirin-induced gastric lesions. Fifty rats of the same weight and strain were randomized into seven groups. Group I was fed a normal diet; groups II to IV were fed with a palm vitamin E enriched diet in doses of 60 mg, 100 mg and 150 mg/kg food, respectively; groups V to VII were fed with a tocopherol-enriched diet in doses of 20 mg, 30 mg and 50 mg/kg food, respectively. After 4 weeks of feeding with the respective diets the rats were challenged with a single intra-gastric dose of 400 mg/kg body weight aspirin suspended in propylene glycol. The rats were killed 6 h post-aspirin exposure for the determination of gastric lesion index and gastric parameters as mentioned in the phase I study. The gastric lesions index was significantly lower in all the vitamin E groups compared to control. The lowest ulcer index was observed in the groups that received 100 mg of palm vitamin E and 30 mg tocopherol in the diet. However, there was no significant difference in ulcer indices between palm vitamin E and tocopherol-treated groups. The lower ulcer index was only accompanied by lower gastric MDA content. We conclude that both palm vitamin E in doses of 60 mg, 100 mg and 150 mg/kg food as well as tocopherol in doses of 20 mg, 30 mg and 50 mg/kg food are equally effective in preventing aspirin-induced gastric lesions. The most probable mechanism is through their ability in limiting the lipid peroxidation that is involved in aspirin-induced gastric lesions.     

Fluconazole induces genotoxicity in cultured human peripheral blood mononuclear cells via immunomodulation of TNF-α, IL-6, and IL-10: new challenges for safe therapeutic regimens

Context: Fluconazole (FNZ) is a drug used in antifungal therapy. However, the minimum FNZ dose to interfering with immune responses or inducing DNA damage is still unknown.

Objective: This study investigated the toxicological profile of FNZ on cultured human peripheral blood mononuclear cells (PBMCs) treated with different concentrations of this azole.

Materials and methods: Cultured PBMCs were exposed to FNZ (6, 12, 30, 60 and 120?μg/mL) and the toxicological profile was assessed by the following parameters: cytotoxic and nuclear division index (necrotic, apoptotic and viable cells), DNA damage (alkaline comet test), mutagenic potential (micronucleus test), cytokine modulation (IL-1, IL-6, IL-10, TNF-α, IFN-γ), and predictive toxicity (Osiris^® and LAZAR^® programs).

Results: Our results demonstrated that FNZ induced cellular DNA damage and mutagenicity at concentrations above the plasma peak (>30?μg/mL) and 6?μg/mL, respectively, which was associated with increased TNF-α, and decrease IL-6 and IL-10 concentrations. These effects may be related to increased apoptosis and cytotoxic nuclear division index in the cultured PBMCs. In silico results indicated potential mutagenic, tumorigenic, irritant, and carcinogenic effects, which were partially confirmed by the above assays.

Discussion and conclusions: Together, these findings suggest the need to rationalize the use of FNZ, especially if it is used for long periods or with concomitant pathologies requiring azole therapy that may increase FNZ's plasma concentration.     

Time course of the increase in airway responsiveness associated with late asthmatic reactions to toluene diisocyanate in sensitized subjects

To understand better the mechanism of the increase in airway responsiveness associated with late asthmatic reactions, we determined the time course of toluene diisocyanate (TDI) effect on airway responsiveness in six sensitized subjects who exhibited a late asthmatic response after TDI exposure (0.018 +/- 0.005 ppm, 30 min) in the laboratory. Airway responsiveness was assessed before TDI exposure and then at 8 hr, 1 day, 1 wk, and 1 mo after TDI exposure. To assess responsiveness we determined the provocative dose of methacholine causing a decrease in FEV1 of 20% (PD20FEV1). The methacholine PD20 decreased from 0.50 mg geometric standard error of the mean (GSEM = 1.54) to 0.06 mg (GSEM = 1.55) (p less than 0.001) at 8 hr after exposure to TDI, was still decreased to 0.15 mg (GSEM = 1.93) (p less than 0.05) at 1 day, returned to 0.26 mg (GSEM = 1.91) (p greater than 0.05) at 1 wk, and returned to 0.43 mg (GSEM = 1.71) at 1 mo, indicating that full recovery occurred within 1 to 4 wk. These results demonstrate that TDI-induced late asthmatic response is associated with a reversible increase in airway responsiveness to methacholine and suggest that the TDI effect is linked to an acute inflammatory response in the airways.     

Aspirin-Interleukin-3 Interrelationships in Patients With Anti-Phospholipid Syndrome

PROBLEM: Previously we reported on the generation of experimental anti-phospholipid syndrome (APS) in mice. These models were employed to evaluate the efficacy of various novel therapeutic modalities including interleukin-3 (IL-3) and low dose aspirin. The efficacy of the latter was found to be interrelated. Low dose aspirin is capable of inhibiting the activity of the enzyme cyclooxygenase which is responsible for the metabolism of arachidonic acid towards the production of prostaglandins. This shifts the metabolism of arachidonic acid to the other pathway and leads to an overproduction of leukotrienes. The leukotrienes act as stimulators of IL-3 production, a positive cytokine in pregnancy which enhances placental and fetal development. In the current study we evaluated the IL-3 levels in pregnant women with APS and expanded our knowledge on the interrelationships between aspirin, arachidonic acid metabolites and IL-3 in the human system. METHODS: IL-3 levels were recorded in the serum of pregnant women with APS and compared to a control pregnant group. In addition peripheral blood mononuclear cells from healthy subjects were incubated with different concentrations of aspirin or with arachidonic acid metabolites (Leukotriene B4, C4 or PGE₂), and IL-3 production in the culture fluids was evaluated. RESULTS: Serum level of IL-3 in pregnant patients with primary APS, APS secondary to SLE and SLE was lower in comparison to the control group. The in vitro studies revealed that only low dose aspirin (10 mg/μl) stimulated IL-3 production while higher doses of the drug failed to induce the cytokine generation. Leukotriene B4 and C4 were stimulatory whereas PGE₂ acted as inhibitor of IL-3 production. CONCLUSIONS: The serum level of IL-3 is decreased to pregnant women with primary or secondary APS. Low dose aspirin is capable of stimulating EL-3 production in vitro most probably through an elevation of leukotriene production, which may explain its beneficial activity in preventing the manifestations of APS.     

Radiotherapy alone in breast cancer. I. Analysis of tumor parameters, tumor dose and local control: the experience of the Gustave-Roussy Institute and the Princess Margaret Hospital

This retrospective study involved 463 breast cancer patients treated by radiotherapy alone at the Princess Margaret Hospital and at the Institut Gustave-Roussy. These patients either had operable tumors, but were unfit for general anesthesia, or had inoperable tumors due to local contraindications to surgery. Results were analyzed according to tumor response, local recurrence rate, tumor size, tumor fixation, nodal fixation and tumor dose. Conventional statistical analysis of local control showed two significant factors: tumor dose and tumor size. Multivariate analysis permitted to define an "individual risk" (IR) of local recurrence according to three independent factors: tumor size, tumor fixation, and nodal fixation. It was shown that the IR was a good prognostic factor for local control. Increase in tumor dose gave a similar effect in the local recurrence relative risk for all the IR groups. According to the slope of the dose-effect curve, it was deduced that a dose increase of 15 Gy can decrease the relative risk of local recurrence 2-fold. In fact, it was shown that tumor dose was the most significant independent factor on local control, able to produce up to a 10-fold increase compared to 2-fold decrease for tumor size. If the IR of local recurrence is known, a theoretical predictive value on local control, taking into account the tumor dose, can be determined according to the present data.