Use of pressure-hold test for sterilizing filter membrane integrity in radiopharmaceutical manufacturing

The bubble point test is the de facto standard for postproduction filter membrane integrity test in the radiopharmaceutical community. However, the bubble point test depends on a subjective visual assessment of bubbling rate that can be obscured by significant diffusive gas flows below the manufacturer's prescribed bubble point. To provide a more objective means to assess filter membrane integrity, this study evaluates the pressure-hold test as an alternative to the bubble point test. In our application of the pressure-hold test, the nonsterile side of the sterilizing filter is pressurized to 85% of the predetermined bubble point with nitrogen, the filter system is closed off from the pressurizing gas and the pressure is monitored over a prescribed time interval. The drop in pressure, which has a known relationship with diffusive gas flow, is used as a quantitative measure of membrane integrity. Characterization of the gas flow vs. pressure relationship of each filter/solution combination provides an objective and quantitative means for defining a critical value of pressure drop over which the membrane is indicated to be nonintegral. The method is applied to sterilizing filter integrity testing associated with the commonly produced radiopharmaceuticals, [¹⁸F]FDG and [¹¹C]PIB. The method is shown to be robust, practical and amenable to automation in radiopharmaceutical manufacturing environments (e.g., hot cells).     

Effects of chrysotile asbestos on coho salmon and green sunfish: evidence of behavioral and pathological stress

The effects of chrysotile asbestos on larval coho salmon (Oncorhynchus kisutch) and juvenile green sunfish (Lepomis cyanellus) were investigated at levels approximating those reported in the Great Lakes basin (10(6) fibers/liter). Behavioral stress effects, such as loss of rheotaxic position and balance, were observed in salmon exposed at 3.0 X 10(6) fibers/liter and in sunfish exposed at 1.5 and 3.0 X 10(6) fibers/liter. Coho larvae at 1.5 X 10(6) fibers/liter were significantly more susceptible to an anesthetic stress test, becoming ataxic and losing equilibrium faster than control cohorts (P less than 0.001). Two of 106 larvae exposed at 3.0 X 10(6) fibers/liter developed tumorous swellings and three additional fish developed coelomic distentions. Cytological examination of ventral epidermal tissue revealed cellular histolysis, and evidence by transmission electron microscopy confirmed the presence of asbestos in the salmon larvae. Distortion of the lateral line region in asbestos-treated coho salmon was linked to behavioral and orientational aberrations. Differential mortality was not observed between control and treated groups of either test species.     

Ultrasensitive analysis of the intestinal absorption and compartmentalization of aluminium in uraemic rats: a 26Al tracer study employing accelerator mass spectrometry

BACKGROUND: Developments in accelerator mass spectrometry (AMS) now permit the determination of femtogram amounts of 26Al in blood and in various tissues with good precision and free of external contamination. METHODS: In the present study we used trace quantities of 26Al to investigate the intestinal absorption and compartmentalization of aluminium in rats with renal failure (Nx, 5/6 nephrectomy) and in pair- fed controls (C). Single oral doses of 20 ng 26Al were administered to six animals in each group and, subsequently, 24-h post-load 26Al was analysed in serum, urine, bone, liver, and spleen by means of AMS. RESULTS: Serum concentrations of 26Al were significantly lower in uraemic rats compared to controls, whereas urinary excretion was comparable (Nx, 7.11 +/- 5.78 pg/day vs C, 9.46 +/- 6.10 pg/day), suggesting a higher fraction of ultrafiltrable serum 26Al in uraemia. The target tissues of cellular transferrin-mediated 26Al uptake, liver and spleen, tended to show a larger degree of aluminium accumulation in controls (0.26 +/- 0.31 pg/g vs Nx, 0.14 +/- 0.10 pg/g and 0.37 +/- 0.27 pg/g vs Nx, 0.25 +/- 0.27 pg/g respectively). In contrast, in bone, a site of extracellular aluminium deposition, 26Al concentrations were more elevated in uraemia (1.22 +/- 0.59 pg/g vs C: 0.68 +/- 0.30 pg/g). Estimated total 26Al accumulation in all measured target tissues was significantly higher in uraemic rats (28.15 +/- 9.90 pg vs C: 17.03 +/- 7.03 pg) and total recovery of 26Al from tissue and urine was 26.58 +/- 6.74 pg in controls and 35.75 +/- 7.03 pg in uraemic animals, suggesting a fractional absorption of 0.133% and 0.175% respectively. CONCLUSIONS: Our data suggest that fractional absorption from a dietary level dose of 26Al is about 0.13%. Compartmentalization occurs in transferrin-dependent target tissues such as liver and spleen; however, in quantitative terms extracellular deposition in bone is more important. Uraemia has a significant effect on the intestinal absorption and compartmentalization of aluminium. It enhances fractional absorption and increases subsequent extracellular deposition of aluminium in bone. However, at the same time uraemia does not increase transferrin-dependent cellular accumulation of aluminium in liver and spleen.      

Treatment of malignant gliomas in adults with BCNU plus metronidazole

Summary Twenty-six adult patients with astrocytomas were treated with BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) 180–240 mg/m² 1.V. every 6–9 weeks, with metronidazole 1.5 g/m² p. o. 12 h and 1 h before BCNU and again 6 h and 24 h after BCNU. Of twenty-two evaluable patients, 9 (41%) responded with evidence of reduced tumor size on CT scan, 3 (14%) stabilized and 10 (45%) failed. Patients with no prior chemotherapy or radiotherapy, good performance. status, low grade tumors, and age 50 years had the highest response rates, although differences were not statistically significant. Median survival and duration of response have not been reached with a median follow-up time of ten months. Hematological toxicity was dose-limiting and was probably not augmented by the metronidazole. There was one death from infection that was possibly drug-related. Gastrointestinal toxicity was substantial, and was probably increased by the metronidazole.While the combination of BCNU and metronidazole were tolerable, the response rate seen was no higher than that noted for BCNU alone, and further studies using this dose-schedule are not recommended in astrocytomas.Presented at the 13th International Congress of Chemotherapy, Vienna Austria, August 1983.     

Implementation of Beam's Eye View into routine treatment planning and delivery

The use of oblique fields in the chest and abdomen is fraught with uncertainty, especially in the location of critical structures on simulator and port films. Targets near these structures may be underdosed because of the physician's uncertainty in shaping the treatment fields. To help alleviate this problem, we have found the Beam's Eye View option of the Theraplan Treatment Planning System to be a useful and effective tool. The Beam's Eye View program uses the external and internal contours we enter into the treatment planning system from CT scans. Once the necessary contours have been entered from the desired CT slices, the software will project the view that the beam would see as it passes through these structures. Using this "Beam's Eye View," we can determine the optimum angle and field shape to treat our target and minimize critical structure dose.     

Evaluating the hazard of dodecyl alkyl sulphate to natural ecosystems using indigenous protistan communities

The effect of the surfactant dodecyl alkyl sulphate (C12AS) on the structure and function of lotic protistan assemblages was examined using the Experimental Stream Facility (ESF) operated by the Procter and Gamble Company. Population- and community-level responses to C12AS were monitored on introduced substrates placed in the channels 28 days prior to dosing (mature communities) as well as those placed in the channels on day 0 of dosing (immature communities), to allow for a broad assessment of the effect of the chemical on processes contributing both to community development and maintenance. C12AS appeared to elicit a subsidy response from the native protistan assemblage which may have resulted from both positive and negative responses at trophic levels above and below the assemblage. Protistan responses to the surfactant tended to occur more rapidly and be more sensitive than those documented for invertebrates and fish. C12AS elicited a modest response (i.e. a 20% change) from several reliable parameters including community respiration (reduced dissolved oxygen at 289 g per L), protozoan species richness (increased at 63 g per L) and protozoan community composition (increased dissimilarity at 1254 g per L). Responses to C12AS exceeded expected exposures in the real world by a factor of six or greater thereby indicating that the hazard of exposure to C12AS to stream communities is low. The results of this study support the use of mesocosms as decisive tools for evaluating the hazard posed by consumer product chemicals to natural communities and ecosystems     

Cutaneous versus Muscular Perception of Electrically Evoked Tetanic Pain

This work was supported in part by Laval University (sabbatical leave of Dr. A.Y. Bélanger), the School of Kinesiology at Simon Fraser University, and Medtronic of Canada Inc. There is much speculation in athletic, physical therapy, and sports medicine circles about the relative cutaneous (superficial) vs. muscular (deep) perception of pain felt during maximum electrically evoked tetanic muscle contraction. To date, very few studies have addressed the basic question of whether pain perception during electrical stimulation is more superficial (cutaneous) or deep in muscular tissue. The purpose of this study was to determine, in a group of 10 healthy male subjects, the effect of a complete sensory nerve block at the thigh on the qualities (intensity, sensory, affective) of pain (elicited by electrically induced tetanic muscle contraction) as measured by the Short-Form McGill Pain Questionnaire felt during high amplitude, 50-Hz electrical stimulation (ES) of the vastus lateralis muscle. The findings from this study provide clear evidence that a healthy individual's tolerance level to pain induced during electrically evoked maximum tetanic muscle contraction depends as much on deep muscle stimulation as it does on cutaneous or superficial stimulation. Indeed, the results show a statistically significant decrease of approximately 50% in all three qualities of pain (intensity, sensory, and affective) following the elimination of cutaneous pain pathways via the nerve blocking procedure (p < 0.05). Until it is demonstrated that the same results hold for patients who often experience pain prior to ES treatments, any clinical implications would seem to be premature. For now, clinicians must be aware that muscle, as much as skin, may limit one's ability to tolerate high amplitude ES treatments. Further research is needed on the cutaneous vs. muscular perception of electrically evoked pain in healthy and diseased populations as well as on the issue of subject and patient experience vs. nonexperience with ES. J Orthop Sports Phys Ther 1992;16(4):162-168.     

A randomized placebo-controlled double-blind trial of lipid-lowering strategies in patients with renal insufficiency: diet modification with or without fenofibrate

BACKGROUND: Renal insufficiency is characterized by lipoprotein abnormalities including elevated triglyceride levels. PATIENTS AND METHODS: The safety and efficacy of micronized fenofibrate as a treatment for dyslipidemia in patients with progressive renal insufficiency was evaluated in a randomized, placebo-controlled double-blind study comparing fenofibrate and dietary modification to dietary modification alone. Patients were evaluated following a 3-month pre-randomization period of dietary counseling. Twenty-eight patients with moderate renal insufficiency and triglyceride levels 2.3 mmol/l or LDL/HDL ratio 5 were randomized to placebo (n = 12) or fenofibrate (n = 16) therapy. Treatment and dietary counseling continued for 6 months. RESULTS: Ten of 16 patients (63%) treated with fenofibrate achieved a 30% reduction in triglyceride levels or LDL/HDL ratio reduction < 5 compared to 2 of 17% in the placebo group (p = 0.015). Triglyceride levels were significantly reduced in the fenofibrate group (-31%) versus placebo (+1.3%, p = 0.003). In compliant patients (n = 25) there was also a significantly greater increase in HDL cholesterol levels in the fenofibrate group (+19.9%) compared to placebo (-4.7%, p = 0.001). Changes in measured creatinine clearance were not significantly different between the groups and there were no serious adverse effects of treatment. CONCLUSION: Fenofibrate therapy combined with dietary modification effectively reduced triglyceride levels in renal insufficiency patients without serious adverse effects.     

缺血预处理程序中心肌环磷酸腺苷含量及环磷酸腺苷依赖蛋白激酶活性的变化

目的:制备大鼠在体缺血再灌注模型,观察缺血预处理程序中心肌环磷酸腺苷含量及环磷酸腺苷依赖蛋白激酶活性的变化。方法:实验于2005-03/2006-10在解放军沈阳军区总医院医学实验动物中心和全军心血管研究所实验室完成。实验分组:选用健康雌性SD大鼠36只,根据预适应程序分为第1,2,3次缺血,第1,2,3次再灌注,每一时间点6只大鼠。实验过程:用手术套管法造成左冠状动脉主干缺血及再灌注。所有实验动物在实验程序结束后,取出心脏迅速置液氮保存备用。实验评估:用放射免疫法测环磷酸腺苷水平,生化法测环磷酸腺苷依赖蛋白激酶活性变化。结果:36只大鼠均进入结果分析。①环磷酸腺苷含量:第1次再灌注组低于第1次缺血组[(0.325±0.015),(0.395±0.024)pmol/g,t=6.06,P<0.001],第2次再灌注组低于第2次缺血组[(0.523±0.017),(0.708±0.067)pmol/g,t=6.56,P<0.001],第3次再灌注组低于第3次缺血组[(0.567±0.031),(0.712±0.038)pmol/g,t=7.24,P<0.001]。②环磷酸腺苷依赖蛋白激酶活性:第1次再灌注组低于第1次缺血组[(10.115±1.000),(16.351±0.849)pkat/g,t=11.12,P<0.001],第2次再灌注组低于第2次缺血组[(11.877±2.213),(14.869±0.619)pkat/g,t=3.31,P<0.01],第3次再灌注组低于第3次缺血组[(11.745±0.987),(14.766±0.329)pkat/g,t=7.09,P<0.001]。③缺血预处理程序中心肌环磷酸腺苷含量及环磷酸腺苷依赖蛋白激酶活性随缺血及再灌注呈周期性波动。在5min缺血预处理时表现为明显增高,而在间隔的再灌注程序中恰呈相反改变,有明显下降的趋势。结论:环磷酸腺苷及环磷酸腺苷依赖蛋白激酶的周期性波动变化可能是激发心肌缺血预处理的机制之一,环磷酸腺苷可能在预处理保护作用中起一些作用。