Medical linear accelerator mounted mini-beam collimator: design, fabrication and dosimetric characterization.

The goal of this work was to design, build and experimentally characterize a linear accelerator mounted mini-beam collimator for use at a nominal 6 MV beam energy. Monte Carlo simulation was used in the design and dosimetric characterization of a compact mini-beam collimator assembly mounted to a medical linear accelerator. After fabrication, experimental mini-beam dose profiles and central axis relative output were measured and the results used to validate the simulation data. The simulation data was then used to establish traceability back to an established dosimetric code of practice. The Monte Carlo simulation work revealed that changes in collimator blade width have a greater influence on the valley-to-peak dose ratio than do changes in blade height. There was good agreement between the modeled and measured profile data, with the exception of small differences on either side of the central peak dose. These differences were found to be systematic across all depths and result from limitations associated with the collimator fabrication. Experimental mini-beam relative output and simulation data agreed to better than ± 2.0%, which is well within the level of uncertainty required for dosimetric traceability of non-standard field geometries. A mini-beam collimator has now been designed, built and experimentally characterized for use with a commercial linear accelerator operated at a nominal 6 MV beam energy.

Atomic carbon as a terminal ligand: studies of a carbidomolybdenum anion featuring solid-state (13)C NMR data and proton-transfer self-exchange kinetics.

Anion [CMo(N[R]Ar)(3)](-) (R = C(CD(3))(2)CH(3) or (t)Bu, Ar = 3,5-C(6)H(3)Me(2)) containing one-coordinate carbon as a terminal substituent and related molecules have been studied by single-crystal X-ray crystallography, solution and solid-state (13)C NMR spectroscopy, and density functional theory (DFT) calculations. Chemical reactivity patterns for [CMo(N[R]Ar)(3)](-) have been investigated, including the kinetics of proton-transfer self-exchange involving HCMo(N[R]Ar)(3), the carbidomolybdenum anion's conjugate acid. While the Mo triple bond C bond lengths in [K(benzo-15-crown-5)(2)][CMo(N[R]Ar)(3)] and the parent methylidyne, HCMo(N[R]Ar)(3), are statistically identical, the carbide chemical shift of delta 501 ppm is much larger than the delta 282 ppm shift for the methylidyne. Solid-state (13)C NMR studies show the carbide to have a much larger chemical shift anisotropy (CSA, 806 ppm) and smaller (95)Mo--(13)C coupling constant (60 Hz) than the methylidyne (CSA = 447 ppm, (1)J(MoC) = 130 Hz). DFT calculations on model compounds indicate also that there is an increasing MoC overlap population on going from the methylidyne to the terminal carbide. The pK(a) of methylidyne HCMo(N[R]Ar)(3) is approximately 30 in THF solution. Methylidyne HCMo(N[R]Ar)(3) and carbide [CMo(N[R]Ar)(3)](-) undergo extremely rapid proton-transfer self-exchange reactions in THF, with k = 7 x 10(6) M(-1) s(-1). Besides being a strong reducing agent, carbide [CMo(N[R]Ar)(3)](-) reacts as a nucleophile with elemental chalcogens to form carbon-chalcogen bonds and likewise reacts with PCl(3) to furnish a carbon-phosphorus bond.

The effects of nandrolone decanoate on cocaine-induced kindling in male rats.

Use and abuse of various controlled substances in recent years has reached alarming levels. Among these are cocaine and anabolic steroids. The two contrasting types of drug have common sites of action within the limbic system of the central nervous system. The ability of cocaine to provoke seizures is well documented, and sex hormones also have been shown to alter seizure types and characteristics. This project studied the consequences of co-administration of cocaine and a representative anabolic-androgenic steroid, nandrolone decanoate. Specifically, the effects of nandrolone on cocaine-induced kindling of seizures were examined. Nandrolone was shown to increase seizure rate when given in high (20mg twice weekly) intermittent doses. No statistically significant differences were observed with low (2mg) daily doses of nandrolone. The results support the hypothesis that an androgen may interact so as to modify the pattern of cocaine-related kindling. However, the potential of either pharmacodynamic and/or pharmacokinetic mechanism(s) for this interaction exists, and the nature of these interactions remains to be fully elucidated.

Relationship of dopamine to serotonin in the neonatal 6-OHDA rat model of Lesch-Nyhan syndrome.

Rats were treated as neonates with either 6-hydroxydopamine (6-OHDA) 100 micrograms or vehicle intracisternally. Upon maturation, animals receiving 6-OHDA were assigned to four groups, with two of the four groups receiving intraventricular 5,7-dihydroxytryptamine (5,7-DHT) 75 micrograms bilaterally. At 94 days of age, animals were injected with either SKF-38393 (3.0 mg/kg, intraperitoneally (i.p.)), a dopamine D1 agonist, or m-chlorophenylpiperazine (m-CPP) (3.0 mg/kg, i.p.), a 5-HT2C agonist, in an attempt to evoke behaviors such as stereotypical chewing, head-nodding, self-biting and self-mutilation. Both SKF-38393 and m-CPP induced the target behaviors in animals receiving 6-OHDA alone. Animals receiving additional 5,7-DHT treatment did not show any of the target behaviors in response to SKF-38393, but exhibited a much higher sensitivity to m-CPP. Pre-treatment with SCH-23390 in animals receiving 6-OHDA alone was effective in preventing SKF-38393-induced target behaviors, but not those induced by m-CPP. Pre-treatment with mianserin partially antagonized the effects of both SKF-38393 and m-CPP in these same animals. In groups receiving both neonatal 6-OHDA and adult 5,7-DHT, mianserin was effective in reducing m-CPP-induced behaviors, while SCH-23390 was largely ineffective. These data provide evidence of a serial relationship between the D1 and 5-HT2C receptor systems in the neostriatum of animals receiving neonatal 6-OHDA lesions.

Evaluation of risperidone in the neonatal 6-hydroxydopamine model of Lesch-Nyhan syndrome.

Rats were treated as neonates with 6-hydroxydopamine (6-OHDA) 100 mg free base in 10 microl intracisternally. Upon maturation, animals were injected with L-dopa and placed in photocell cages for monitoring of locomotion, stereotypies, and self-mutilation. Pretreatment with either risperidone or SCH-23390 significantly reduced locomotion and stereotypies. SCH-23390 eliminated L-dopa induced self-mutilation in all subjects, while risperidone eliminated self-mutilation in all but one subject.

High altitude may be synergistic with pulmonary hazards of appetite control medications fenfluramine and dexfenfluramine.

Clinical observations over the past 15 years incriminated first fenfluramine and recently dexfenfluramine in the provocation of primary pulmonary hypertension. Limited animal toxicology data tend to support this inference. The basis for respiratory pathology of high-altitude pulmonary malfunction, which reaches its maximal level in high-altitude pulmonary edema, evolves from and depends upon the occurrence of pulmonary hypertension. For this reason we hypothesize that high altitude and these two anorexic medications constitute a potentially synergistic combination, of which physicians treating patients for high-altitude illness, as well as those prescribing the drugs, should be aware.

Psychopharmacologic violence associated with cocaine abuse: kindling of a limbic dyscontrol syndrome?

1. An association of cocaine abuse with aggressive or violent behavior arising from direct pharmacologic effects of cocaine is demonstrable in the forensic and clinical literature. 2. The neurobehavioral basis for this association is considered form among known CNS actions of cocaine. A hypothesis is developed concerning the role of pharmacological kindling by cocaine that may sensitize for release of limbic-hypothalamic mechanisms of aggressive behavior, and for a drug-induced dyscontrol syndrome. 3. Parallels are drawn to kindling by electrical stimuli, and to neurophysiological research on mechanisms of aggression. 4. A role of concurrent hyperthermic effects of cocaine is suggested. 5. Potential contributions of cocaine actions on CNS serotonergic, catecholaminergic and/or adenosinergic systems are considered. 6. A likely role of concurrent ethanol ingestion to enhance the manifestation of cocaine-associated violence is recognized. 7. Pharmacological challenges, lidocaine or caffeine, are suggested as a means of detecting lowered thresholds of limbic excitability as a consequence of repeated cocaine exposures.

The effects of cocaine and nandrolone co-administration on aggression in male rats.

1. Cocaine and anabolic-androgenic steroids are among the more commonly abused substances in selected populations. These agents, when used alone or in combination, have been reported to cause aggressive tendencies in both laboratory-based animal models and in human clinical situations. This project, using a resident-intruder paradigm, examined the effects of co-administration of cocaine and a typical anabolic-androgenic steroid, nandrolone decanoate, on the development of aggression in male Sprague-Dawley rats. 2. Dose response studies demonstrated that low dose cocaine (1 mg/kg) produced more aggression in a greater percentage of animals than for either the controls or groups receiving higher doses (up to 20 mg/kg). Initially, high intermittent doses of nandrolone (20 mg twice weekly) produced more aggression; however, low daily doses of nandrolone (2 mg) produced greater levels of aggression following 4 weeks of treatment. 3. Optimal doses of cocaine and nandrolone, when administered together, resulted in aggression scores that were not significantly different from controls or either drug singly. However, a greater percentage of animals receiving both drugs exhibited aggression than did rats receiving either drug alone. 4. These results support the interpretation that the drugs interact to produce unique effects in the development of aggression. However, the complexity and extent of the interactions is great and remains to be fully elucidated.

Tunable infrared laser detection of pyrolysis products of explosives in soils.

A research program involving two applications of tunable infrared laser differential absorption spectroscopy (TILDAS) with multipass, long-path absorption cells to the detection of explosives contamination in soils is reported. In the first application, sensitive, specific real-time species concentration measurements by TILDAS have led to new understanding of the processes involved in explosives detection by the heating of contaminated soils and the quantification of the resulting pyrolysis gases. In the second, we present results of our calculations of the properties of astigmatic off-axis resonator absorption cells, which show that useful TILDAS path lengths can be achieved inside a cone penetrometer probe.

Additive hypothermic effects of cocaine and nicardipine in guinea-pigs.

1. This study investigated the thermoregulatory effects of cocaine combined with two reported antidotal treatments for acute cocaine overdosage, calcium channel blocker therapy and cold ambient temperatures. 2. Cocaine and nicardipine alone lowered the core temperature of female guinea-pigs (ambient temperature, 5 degrees C) which resulted in a drop in core temperature of approximately 2 degrees C at their highest respective doses (40 mg/kg and 50 mg/kg). 3. Nicardipine administration 30 min prior to cocaine caused an almost 2-fold drop in temperature (3.75 degrees C) relative to either drug alone. 4. The data suggest that cocaine and nicardipine produce hypothermia by different, but additive, mechanisms.

Is aluminium an etiologic contributor to alcoholic amnesia and dementia?

Neurotoxicity from excess brain exposure to aluminium (Al) is well-documented, from both clinical observations and animal experiments, to impair learning, memory and cognition. The etiology of the cognitive impairment in chronic abusers of ethanol--alcoholic amnesia or dementia--is not known, but it is likely to be multifactorial. We hypothesize that a slowly-progressive accumulation of Al in the brain, so as to reach functionally-toxic levels, may be one such factor. This could occur because of an increased permeability of intestinal mucosa to entry of Al, arising from sustained exposure of the gastrointestinal tract to alcoholic beverages, plus a trend for more frequent ingestion of antacids based on Al salts for treating gastritis or ulcers caused by such exposure. If this be true, use of Al-containing medications, as well as all avoidable exposures to Al, should be contra-indicated for chronic heavy drinkers.

Nandrolone decanoate reduces the premature mortality of cardiomyopathic hamsters.

Male hamsters of an inbred strain carrying a genetic trait for cardiomyopathy were dosed by sc injection weekly with an anabolic-androgenic steroid, nandrolone decanoate, beginning when 3 months old. Two groups (N = 17) received doses of 2 and 4 mg per animal, while a vehicle control group received an equal volume of sesame oil. Rather than a hypothesized shortening of longevity, the steroid treatment significantly prolonged survival of the hamsters, which ordinarily die of congestive heart failure. At the median time to death for controls (355 days of age, 257 days of treatment), the steroid groups had mortality of only 2/17 and 4/17 (vs. 9/17, p < 0.01).

Solitary rectal ulcer syndrome: not always ulcerated.

Our patient had a nonulcerated rectal lesion grossly resembling a villous tumor, but microscopically proving to be a solitary rectal ulcer. We have discussed the clinical and pathologic findings and the probable relationship of the lesion to straining at the stool.

Effect of methyl methacrylate on isolated atria and interaction with isoproterenol, atropine and calcium chloride.

1. Spontaneous rate and contractile force of isolated rat and rabbit atria suspended in a tissue bath were recorded before and after drugs. Methyl methacrylate monomer (MMA) alone both decreased force and increased rate dose-dependently. 2. Concentrations of calcium chloride or isoproterenol that alone increased both rate and force of rat atrial contraction were fully and only partially able, respectively, to restore force to normal after MMA. 3. Atropine prevented changes in rat atrial function from low-effective doses of MMA, but not higher ones; it also failed to prevent the reduction of contractile force by a calcium channel blocker, verapamil. 4. There are similarities but also differences between actions of MMA and verapamil on rat atria.