Intramuscular and intravenous atropine: comparison of effects in the heat-stressed rat

In our rat model of human heat injury we have administered atropine intravenously (iv); for clinical use in man, administration is by either the intramuscular (im) or iv route. In order to determine potential differences due to route of administration, we compared the dose-response effects of im and iv administration in rats. Adult male rats (500 g) were heat-stressed (41.5 degrees C) while unrestrained which enabled them to thermoregulate by saliva spreading activity. We quantitated the effects of im or iv atropine (10-4000 micrograms.kg-1) on the following variables: heating rate (rate of rise of core temperature), % weight loss (saliva production), and fecal loss (intestinal motility). Further, we examined the effects of atropine on pupil dilation in restrained rats at 26 degrees C. Heating rate was identical for both routes of atropine administration at 200 micrograms.kg-1 (equivalent to the standard 2-mg dosage in man), but the range of doses over which there was a dose-response effect on heating rate with iv administration (10-1000 micrograms.kg-1) was markedly truncated with the im route (10-50 micrograms.kg-1). Both im and iv atropine had similar effects on weight loss rate and mydriasis. The iv route is preferred because that route produced the most consistent results and the most sensitive physiological response (heating rate) is affected over a wider dose range.     

A heat-stressed rat model to determine relative anticholinergic and anticholinesterase drug potency

We have reported that atropine, the prototype of muscarinic anticholinergic drugs, elicits a dose-dependent increase in core temperature of heat-stressed rats. In the present study, we have quantified the effects of other anticholinergic drugs on increments in core temperature and have derived the following potencies relative to atropine: imipramine 0.004, amitriptyline 0.02, chlorpromazine 0.1, atropine 1, L-hyoscyamine 2, atropine methyl nitrate 4, and scopolamine 16. Additionally, we quantified the efficacy of carbamates to reduce the elevated heating rate of atropinized rats as a measure of anticholinesterase efficiency. The results indicated the following relative potencies: neostigmine 8, physostigmine 2, and pyridostigmine 1. We have concluded that alterations in core temperature responses to exposure to hot environments may be a useful and sensitive bioassay for anticholinergic and anticholinesterase efficacy.     

An empirical model for calculating electron dose distributions

Dose-distributions in radiation fields are calculated for purpose of irradiation planning from measured depth dose and cross-distributions predominantly. Especially in electron fields the measuring effort is high to this, because these distributions have to be measured for all occurring irradiation parameters and in many different tissue depths. At the very least it can be shown for the 6...10 MeV electron radiation of the linear accelerator Neptun 10p that all required distributions can be calculated from each separately measured depth dose and cross-distribution. For this depth dose distribution and the measured border decrease of cross-distribution are tabulated and the abscissas are submitted to a linear transformation x' = k.x. In case of depth dose distribution the transformation factor k is dependent on electron energy only and in cross-distribution on tissue depth and source-surface-distance additionally.     

Low dose of uranium induces multigenerational epigenetic effects in rat kidney

Purpose: A protocol of chronic exposure to low dose of uranium was established in order to distinguish the sexual differences and the developmental process that are critical windows for epigenetic effects over generations.

Methods: Both male and female rats were contaminated through their drinking water with a non-toxic solution of uranyl nitrate for 9 months. The exposed generation (F0) and the following two generations (F1 and F2) were examined. Clinical monitoring, global DNA methylation profile and DNA methyltransferases (DNMTs) gene expression were analyzed in kidneys.

Results: While the body weight of F1 males increased, a small decrease in kidney and body weight was observed in F2 males. In addition, global DNA hypermethylation profile in kidney cells was observed in F1 and F2 males. qPCR results reveal a significant increase of methyltransferase genes expression (DNMT1 and DNMT3a) for F2 females.

Conclusions: In the field of public health policy and to raise attention to generational effects for the risk assessment of the environmental exposures, low doses of uranium do not imply clinical effects on adult exposed rats. However, our results confirm the importance of the developmental windows’ sensitivity in addition to the sexual dimorphisms of the offspring.     

Ocular melanoma: total dose and dose rate effects with Co-60 plaque therapy

From 1968 to 1987, 123 consecutive patients with nonmetastatic choroidal melanoma were treated with cobalt-60 plaques. One hundred sixteen patients were followed up for a mean of 3.8 years. Twenty patients had local failure, and 14 patients had distant failure. Complications included 32 cataracts, and seven enucleations were required. Local recurrence did not correlate with tumor height, tumor volume, dose, or dose rate. Increased volume (P = .004) and height (P = .01) correlated with increased rates of distant metastases. Dose adjusted for volume did not correlate with the rate of metastases.     

PET显像监测中药复智散治疗阿尔茨海默病大鼠疗效的可行性研究

目的 研究PET技术评价中药复智散（FZS）治疗自然老化阿尔茨海默病（AD）大鼠疗效的可行性。方法采用中药FZS治疗10只AD大鼠模型30d后,通过Morris水迷宫测试大鼠行为学改变;另10只AD大鼠以蒸馏水连续30d灌胃,作为对照组,10只正常成年大鼠作为空白对照组。所有大鼠分别行18F-脱氧葡萄糖（FDG）、2-（4＇-N-11C-甲胺基苯）-6-羟基苯并噻唑（PIB）PET脑显像,并取脑组织样本行HE染色、β淀粉样蛋白（AB）免疫荧光、5-溴-2-脱氧尿嘧啶核苷（BrdU）免疫荧光和神经元核心抗原（NeuN）免疫荧光染色。采用SPSS13．0软件对行为学测试结果行配对t检验。结果FZS治疗后AD大鼠行为学较AD对照组有明显改善,药物治疗组AD大鼠潜伏期[（32．5±10．8）s]明显短于AD对照组[（102．6±8．8）s]（t=15．7987,P=0．000t）,PET显像显示治疗后AD大鼠脑内葡萄糖代谢有所改善,而淀粉样物质的显像未见明显好转,该结果与病理结果一致。结论PET显像可作为在体评价AD疗效的一种手段;中药FZS可以通过增加神经细胞的增殖和存活而改善老年大鼠的记忆能力。     

Test of the antiorthostatic suspension model on mice: effects on the inflammatory cell response

We tested the antiorthostatic suspension model for use as a 1G model to study the effects of factors that will be encountered during space travel on inflammation. We found no differences in inflammatory cells induced in antiorthostatically suspended mice. However, the superoxide response (used for oxidative killing of bacteria such as S. aureus) was impaired in antiorthostatically oriented mice compared to control mice. Elevated corticosterone levels were found in antiorthostatically suspended mice and indicate that stress may be a factor in the model. If the stress factor of the model correlates with the physiological stress of space flight, antiorthostatic suspension may be an acceptable model for studying inflammatory responses in mice.     

Acute chondrocyte response to controlling joint instability in an osteoarthritis rat model

Objective

Osteoarthritis is a common consequence of anterior cruciate ligament (ACL) injury. Joint instability induced by ACL transection is involved in the chondrocyte response in the articular cartilage degeneration process. The aim of this study was to confirm the effect of controlling joint instability after ACL injury by investigating the chondrocyte reaction in the early osteoarthritic disease process.

Methods

For inducing different joint conditions (stability and instability), 15 Wistar rats were randomized into three groups: ACL transection with joint instability (ACL-T, n = 5), controlled abnormal joint movement with ACL transection (CAJM, n = 5), and control (n = 5). One week after surgery, all rats were euthanized and their knees removed. Histological analysis was performed on the knee cartilages, which involved evaluation of cell numbers and density.

Results

There were no significant differences in chondrocyte numbers among the three groups within each articular cartilage zone (surface, middle, and deep zones) nor between zones (P > 0.05). In contrast, the chondrocyte cell density area was significantly suppressed in the CAJM compared to the ACL-T group in each zone (surface zone, P = 0.019).

Conclusions

Early control of joint instability induced by ACL injury inhibited chondrocyte hypertrophy in articular cartilage. This result indicates that knee joint instability increases mechanical stress, and the controlling of these joint movements might provide a new treatment approach for the long-term prevention of osteoarthritis.

     

Experimental study of the pharmacokinetics and dose response of ferrite particles used as a contrast agent in MRI of the normal liver of the rabbit

Superparamagnetic ferrite is a specific magnetic resonance imaging (MRI) contrast agent for the liver and the spleen. The large electronic magnetic moments of the ferrite particles create local field inhomogeneities that shorten the transversal relaxation time and reduce the spin-echo amplitude and the intensity of the liver and spleen signals in MR images. MRI was performed at 1.5 T using a SE sequence with TR/TE = 300/15 milliseconds. Pharmacokinetics were studied on five rabbits during five hours and up to 11 days after ferrite injection with doses ranging from 0.2 to 1 mg Fe/kg. Dose responses (0.2 mg to 8 mg Fe/kg) were studied on 11 additional rabbits, at three hours and three days after injection. Results show that the effect of ferrite on the liver images is stable between 30 minutes and 6 hours, and that the liver images recover their intensities before injection after about two days. The liver intensity drops to half its value for a dose of 1.25 mg Fe/kg (for TR/TE = 300/15 milliseconds). Our results support the conclusions from studies on other animal species that ferrite should be considered a useful MRI contrast agent for clinical investigations of the liver.     

The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model

Purpose: To provide a comprehensive understanding of how the selection of radiation dose affects the temporal and spatial progression of radiation-induced necrosis in the rat model.

Materials and methods: Necrosis was induced with a single fraction of radiation exposure, at doses ranging between 20 and 60?Gy, to the right hemisphere of 8-week-old Fischer rats from a linear accelerator. The development and progression of necrosis in the rats was monitored and quantified every other week with T1- and T2-weighted gadolinium contrast-enhanced MRI studies.

Results: The time to onset of necrosis was found to be dose-dependent, but after the initial onset, the necrosis progression rate and total volume generated was constant across different doses ranging between 30 and 60?Gy. Radiation doses less than 30?Gy did not develop necrosis within 33 weeks after treatment, indicating a dose threshold existing between 20 and 30?Gy.

Conclusion: The highest dose used in this study led to the shortest time to onset of radiation-induced necrosis, while producing comparable disease progression dynamics after the onset. Therefore, for the radiation-induced necrosis rat model using a linear accelerator, the most optimum results were generated from a dose of 60?Gy.     

低剂量电离辐射对大鼠海马新生神经元树突生长发育的抑制作用

目的 观察电离辐射对幼年大鼠海马齿状回新生神经元树突生长发育的影响。方法 SD大鼠按随机数字表法分为照射组(20只)和健康对照组(20只),照射组给予单次2 Gy全脑照射。所有大鼠均予海马区立体定向注射反转录病毒标记新生神经元,免疫荧光染色观察照射后不同时间新生神经元树突形态的变化。结果 与健康对照组相比,照射组在照射后2周和4周新生神经元树突总长度、最长树突的长度均显著减少(t=3.10、2.07、2.94、4.02,P<0.05),神经元分支数在照射后2周显著减少(t=2.23,P<0.05)。照射后4周,海马区新生神经元数量显著降低(t=8.43,P<0.05)。结论 低剂量电离辐射可抑制幼年大鼠海马齿状回新生神经元的生长发育,这可能是射线致海马依赖的认知功能障碍发生的机制之一。     

High-dose 166Ho-DOTMP in myeloablative treatment of multiple myeloma: pharmacokinetics, biodistribution, and absorbed dose estimation.

Thirty-two patients with multiple myeloma were treated with high doses of 166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid (DOTMP) and were a subset of patients enrolled in a multicenter phase I/II dose escalation myeloablative trial. 166Ho with beta-emission (half-life, 26.8 h; beta-particle energies, 1.85 MeV [51%] and 1.77 MeV [48%]; gamma-photons, 80.6 keV [6.6%] and 1.38 MeV [0.9%]) was complexed to DOTMP, a macrocyclic tetraphosphonate. Pharmacokinetics, dosimetry, and biodistribution were studied. METHODS: Patients were treated at escalating dose levels of 20, 30, and 40 Gy to the bone marrow in combination with high-dose melphalan, with or without total-body irradiation, to evaluate toxicity and efficacy. After infusion with 1,110 MBq (30 mCi) of 166Ho-DOTMP for evaluation of biodistribution and dosimetry calculation, patients received the calculated amount of radioactivity for therapy in a single administration based on estimated dose calculations. RESULTS: Thirty-two patients participated in the study and were then treated. The average amount of administered radioactivity was 74.3 GBq (2,007 mCi) (range, 21.5-147.5 GBq [581-3,987 mCi]) of 166Ho-DOTMP. CONCLUSION: 166Ho-DOTMP has physical and pharmacokinetic characteristics compatible with high-dose myeloablative treatment of multiple myeloma.     

In vivo 31P nuclear magnetic resonance spectroscopy of rat 9L gliosarcoma treated with BCNU: dose response of spectral changes

The 9L gliosarcoma, grown subcutaneously in juvenile Fischer 344 rats, was studied by in vivo 31P NMR spectroscopy following treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea. Dose-dependent increases in the proportion of high-energy phosphates were observed for doses between 10 and 36 mg/kg (from 80% of the LD10 to greater than the LD50). These doses reduced clonogenic cell survival in a dose-dependent fashion by as much as 3 log orders and resulted in up to 16 days of growth delay (to pretreatment tumor volume). Increases in high-energy phosphates (relative to Pi) in the tumor were greater at higher doses despite the higher levels of clonogenic cell killing and the substantial host systemic toxicity.     

Otolith-organ mechanics: lumped parameter model and dynamic response

The otolith organs comprise a second-order system whose response is overdamped and whose dynamics can be expressed by two time constants. The long time constant has been experimentally measured at 10 s. The short time constant is approximately 0.0002 s using a maximum mechanical displacement criterion for the otoconial layer. With these two values determined, the system dynamic response indicates that, between the two system corner frequencies, the peripheral sensory cells (primary Type II cells) report skull velocity information to the central nervous system, and striolar cells (primary Type I cells) report skull acceleration information to the central nervous system. Below the lower corner frequency, peripheral sensory cells report skull acceleration information to the central nervous system, and striolar sensory cells report rate of change of acceleration information to the central nervous system.     

Microplasmin and tissue plasminogen activator: comparison of therapeutic effects in rat stroke model at multiparametric MR imaging

PURPOSE: To prospectively compare therapeutic and hemorrhagic effects of microplasmin and tissue plasminogen activator (tPA) in stroke therapy by using multiparametric magnetic resonance (MR) imaging in a photothrombotic rat stroke model. MATERIALS AND METHODS: The animal experiment complied with institutional regulations for laboratory animals. Stroke was induced in rats with photothrombotic occlusion of middle cerebral artery (MCA). T2-weighted, perfusion-weighted (PW), and diffusion-weighted (DW) MR imaging was performed 1 hour and 24 hours after occlusion. On the basis of PW and DW images at 1 hour, 49 rats with cortex and subcortex involvement and with perfusion-diffusion mismatch were randomly assigned into one of four groups: control group, group treated with 7.5 mg microplasmin, group treated with 10 mg/kg microplasmin, or group treated with 10 mg/kg tPA. Agents were intravenously injected 1.5 hours after occlusion. Infarct size and hemorrhagic transformation were assessed with MR imaging and histomorphologic findings. Neurologic deficit was scored. Measurements were statistically analyzed. RESULTS: There were 13 rats in the control group, 13 in the 7.5 mg/kg microplasmin group, nine in the 10 mg/kg microplasmin group, and 14 in the 10 mg/kg tPA group. Despite similar baseline perfusion-diffusion mismatch, histochemically defined total infarct volume was reduced from 25% +/- 5 (standard deviation) in control group to 21% +/- 2, 20% +/- 4, and 20% +/- 5 in 7.5 mg/kg microplasmin, 10 mg/kg microplasmin, and tPA groups, respectively, as similarly shown on T2-weighted, DW, and PW images at 24 hours (P < .05). Cerebral hemorrhage rate at 24 hours was higher in tPA group than in the other three groups. Bederson score of neurologic deficits was significantly reduced in treated groups compared with that in control group. CONCLUSION: Perfusion-diffusion mismatch appeared useful in selecting candidates for thrombolytic therapy. Multiparametric MR imaging allowed noninvasive assessment of effects of microplasmin and tPA in rats; microplasmin had a significantly lower hemorrhagic rate.     

Adaptive response: Part II. Further modeling for dose rate and time influences

PURPOSE: For adaptive response (AR) behavior, to model and analyze the dose rate dependence of AR. To examine and to model the influence of time interval between primer and challenge dose on the magnitude of radioprotection. METHOD AND MATERIALS: Microdosimetry is used to examine effects of rate of critical volume specific energy depositions on activation of AR and induction of deleterious damage. The dose rate dependent adaptive response data, Shadley and Wiencke and Shadley et al. on AR fading, are analyzed. RESULTS: We obtain good agreement with observed AR behavior. The 4-6 hour activation time for AR is from time necessary for the accumulation of enzymatic resources from the increased radioprotective capability for the recognition and repair of deleterious DNA damage and perhaps resources for reduction of RSO. The Shadley and Wiencke data, for the low 1.0 cGy primer dose, is as a result of a minimum rate of specific energy depositions (hits) for adaptive response to become operative and become fully activated. Increased deleterious damage with increased dose rate for a high 50 cGy primer dose is from a reduction in dose rate sparing as the rate approaches acute exposure. CONCLUSIONS: The microdosimetric model substantiates the prior observations in Part I that only several radiation-induced charged particle cell nucleus traversals are sufficient to activate adaptive response. Further however we find here that a minimum dose rate threshold is necessary. The model shows promise to provide insight into adaptive response time and dose rate behavior.     

Adaptive response: Part II. Further modeling for dose rate and time influences

Purpose: For adaptive response (AR) behavior, to model and analyze the dose rate dependence of AR. To examine and to model the influence of time interval between primer and challenge dose on the magnitude of radioprotection.

Method and materials: Microdosimetry is used to examine effects of rate of critical volume specific energy depositions on activation of AR and induction of deleterious damage. The dose rate dependent adaptive response data, Shadley and Wiencke and Shadley et al. on AR fading, are analyzed.

Results: We obtain good agreement with observed AR behavior. The 4 – 6 hour activation time for AR is from time necessary for the accumulation of enzymatic resources from the increased radioprotective capability for the recognition and repair of deleterious DNA damage and perhaps resources for reduction of RSO. The Shadley and Wiencke data, for the low 1.0 cGy primer dose, is as a result of a minimum rate of specific energy depositions (hits) for adaptive response to become operative and become fully activated. Increased deleterious damage with increased dose rate for a high 50 cGy primer dose is from a reduction in dose rate sparing as the rate approaches acute exposure.

Conclusions: The microdosimetric model substantiates the prior observations in Part I that only several radiation-induced charged particle cell nucleus traversals are sufficient to activate adaptive response. Further however we find here that a minimum dose rate threshold is necessary. The model shows promise to provide insight into adaptive response time and dose rate behavior.