Field size effect of radiation quality in carbon therapy using passive method.

The authors have investigated the dependency of radiation quality and absorbed dose on radiation field size in therapeutic carbon beams. The field size of the broad beam, formed using the passive technique, was controlled from 20 to 100 mm per side with a multileaf collimator. The absorbed dose and radiation quality on the beam center were evaluated at several depths in a water phantom using microdosimetric technique in experiments and Monte Carlo simulations. With an increase in the field size, the radiation quality was reduced, although the absorbed dose grew at the center of the field. This indicates that the dose and radiation quality at the center of the broad beam are influenced by particles from the off-center region via large-angle scattering and that such particles have relatively low radiation quality and mainly consist of fragment particles. Because such a tendency appeared to be more remarkable in the deeper region of the water phantom, it is likely that fragment particles that are born in a water phantom have a marked role in determining the field size effect.

Impairment of gastric accommodation induced by water-avoidance stress is mediated by 5-HT2B receptors.

BACKGROUND: Psychological stress has been shown to impair gastric accommodation (GA), but its mechanism has not been elucidated. This study was conducted to clarify the role of 5-HT2B receptors in a guinea pig model of stress-induced impairment of GA. METHODS: Gastric accommodation was evaluated by measuring the intrabag pressure in the proximal stomach after administration of a liquid meal. The guinea pigs were subjected to water-avoidance stress. The role of 5-HT2B receptors in impairment of GA was investigated by administering a 5-HT2B receptor agonist (BW723C86) or antagonist (SB215505), the traditional Japanese medicine rikkunshito (RKT), a muscarinic M3 receptor antagonist (1,1-dimethyl-4-diphenylacetoxypiperidium iodide [4-DAMP]), or a nitric oxide synthase inhibitor (Nω -nitro-L-arginine [L-NNA]). KEY RESULTS: In normal animals, liquid meal-induced GA was inhibited by BW723C86, but was not affected by SB215505. The inhibition of GA by BW723C86 was reversed by co-administration of 4-DAMP. Compared to normal animals, GA in stressed animals was significantly inhibited. SB215505 and RKT significantly suppressed stress-induced impairment of GA. After meal administration, the level of cyclic guanosine monophosphate in gastric fundus tissue increased by approximately twofold in normal animals, but did not change in stressed animals. The inhibition of GA by L-NNA was suppressed by SB215505 or RKT. At a dose that did not affect GA in normal animals, BW723C86 exacerbated the impairment of GA in stressed animals. CONCLUSIONS AND INFERENCES: Stress-induced impairment of GA may be mediated by an increased responsiveness of 5-HT2B receptors, and activation of the 5-HT2B receptor signaling pathway may have an inhibitory effect on nitric oxide function.

Change in radiosensitivity with fractionated-dose irradiation of carbon-ion beams in five different human cell lines.

PURPOSE: To investigate the change in the surviving fractions by fractionated-dose irradiations with carbon ions, based on the recovery of potentially lethal damage (PLDR) and the change of radiosensitivity by every fractionated-dose irradiation. METHODS AND MATERIALS: One normal human and four human-tumor cell lines were used. Cells were irradiated with carbon ions accelerated by the Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences in Japan. The LET values were estimated to be 13.18 keV/microm for low-LET beams and 76.92 +/- 0.20 keV/microm for high-LET beams. Fractionated-dose irradiations were carried out with 5 fractions within a 24-h interval. RESULTS: The surviving fractions for the fractionated-dose irradiation with X-rays and carbon ions decreased exponentially with increasing the number of fractions in the tumor cell lines. In contrast, the surviving fractions for the carbon ions in normal human cells decreased exponentially as well as the tumor cell lines, while it tended to level off from the 3rd to the 5th fraction in the case of using X-rays. CONCLUSION: The change in both the recovery ratio of the PLDR and radiosensitivity by every fractionated-dose irradiation depends on individual cell lines and the quality of radiations.

Relative biological effectiveness for cell-killing effect on various human cell lines irradiated with heavy-ion medical accelerator in Chiba (HIMAC) carbon-ion beams.

PURPOSE: To clarify the relative biological effectiveness (RBE) values of various human cell lines for carbon-ion beams with 2 different linear energy transfer (LET) beams and to investigate the relationship between the cell-killing effect and the biophysical characters, such as the chromosome number and the area of the cell nucleus, using qualitatively different kinds of radiations. METHODS AND MATERIALS: Sixteen different human cell lines were irradiated with carbon-ion beams, having 2 different LET values (LET(infinity) = 13.3 and approximately 77 keV/microm), accelerated by the Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences in Japan. Cell-killing effect was detected as reproductive cell death using a colony-formation assay. The number of chromosomes was observed in a metaphase spread using the conventional method. The area of the cell nucleus was calculated as an ellipse on photographs using a micrometer. RESULTS: The RBE values calculated by the D(10), which is determined as the dose (Gy) required to reduce the surviving fraction to 10%, relative to X-rays, range from 1.06 to 1.33 for 13-keV/microm-beam and from 2.00 to 3. 01 for approximate 77-keV/microm-beam irradiation on each cell line. There was a good correlation in the D(10) values of each cell line between X-rays and carbon-ion beams. However, the D(10) values did not clearly depend on either the chromosome number or the area of the cell nuclei. CONCLUSION: The RBE values for HIMAC carbon-ion beams are consistent with previous reports using carbon-ion beams with the similar LET values, and the cellular radiosensitivity of different cell lines well correlate among different types of radiation.

Piperidine: a microelectrophoretic study in the mammalian brain.

Using unit recording and electrophoretic techniques, the action of piperidine on unit activity of the brain of the rat was studied. Piperidine excited 31%, and inhibited 4% of cortical cells tested. In the hippocampus and caudate nucleus, piperidine excited larger proportions of the cells tested. The actions of piperidine were blocked by tetraethylammonium but not by scopolamine.

Pipecolic acid enhancement of GABA response in single neurons of rat brain.

Using unit recording and microelectrophoresis, influence of pipecolic acid (PA), a major metabolite of lysine in the brain, on GABA and glycine responses was studied in the cerebral cortical and hippocampal pyramidal neurons of rats. With small currents, PA had no effect on the single neuron activities but enhanced GABA response without affecting glycine response. The finding provides a new evidence that PA may have a connection with central GABA system.

Effects of the Japanese herbal medicine Keishi-bukuryo-gan and 17beta-estradiol on calcitonin gene-related peptide-induced elevation of skin temperature in ovariectomized rats.

The effects of a Japanese herbal medicine, Keishi-bukuryo-gan, and 17beta-estradiol on calcitonin gene-related peptide (CGRP)-induced elevation of skin temperature were investigated in ovariectomized (OVX) rats. Ovariectomy not only potentiated CGRP-induced elevation of skin temperature and arterial vasorelaxation but also induced a lower concentration of endogenous CGRP in plasma and up-regulation of arterial CGRP receptors, suggesting that lowered CGRP in plasma due to ovarian hormone deficiency increases the number of CGRP receptors and consequently amplifies the stimulatory effects of CGRP to elevate skin temperature. Oral Keishi-bukuryo-gan (100-1000 mg/kg, once a day for 7 days) restored a series of CGRP-related responses observed in OVX rats by normalizing plasma CGRP levels in a dose-dependent manner as effectively as s.c. injection. 17Beta-estradiol (0.010 mg/kg, once a day for 7 days). However, Keishi-bukuryo-gan did not affect the lower concentration of plasma estradiol and the decreased uterine weight due to ovariectomy, although the hormone replacement of 17beta-estradiol restored them. These results suggest that Keishi-bukuryo-gan, which does not confer estrogen activity on plasma, may be useful for the treatment of hot flashes in patients for whom estrogen replacement therapy is contraindicated, as well as menopausal women.

Influence of cerebral cortex stimulation upon cough-like spasmodic expiratory response (SER) and cough in the cat.

In 27 pentobarbitalized cats, the influence of electrical stimulation of the cerebral cortex upon the spasmodic expiratory response (SER) was studied and compared with cortical influences on coughing induced by stimulation of the superior laryngeal nerve (sup. laryngeal N.). This cortical influence was evoked by electrical stimulation of the cortical nucleus of amygdala (Aco), and was very similar to coughing accompanying changes in emotional behavior and was depressed more effectively by psychotropics than by centrally acting antitussives like codeine. When anterior cingulate gyrus (ant. cingulate G.) or orbital gyrus (orbital G.) were stimulated simultaneously with Aco or sup. laryngeal N., weak stimulation was sufficient to inhibit SER, while stronger stimuli were needed for the suppression of cough. If the same cortical regions were stimulated after initiation of SER or cough, SER was markedly suppressed but cough little affected. Production of SER was facilitated by simultaneous stimulation of the piriform lobe (piriform L.) or olfactory tract (olfactory T.), whereas cough production was facilitated by simultaneous stimulation of the suprasylvian gyrus. These results suggest that SER and coughing are differently controlled by the cerebral cortex, and that SER is modulated by the limbic cortex, in particular, by ant. cingulate G., orbital G. and piriform L. The mechanism of modulation for SER is discussed.

Seasonal and activity-dependent variations of piperidine levels in the amphibian brain.

Piperidine is one of biogenic amines possessing nicotine-like synaptotropic actions on the nervous systems. Since piperidine produces multiplex physiological actions, a role for the amine as a modulator in neuroendocrine as well as neuronal functions has been supposed. In the present study, piperidine levels in the amphobian brains during activity and hibernation were examined by use of a mass fragmentographic technique and it was found that the brain piperidine concentrations significantly increased in the cold season especially during hibernation. The significance of the findings is discussed with respect to the hypnogenic effect of piperidine.

Colchicine lesions in the rat hippocampus mimic the alterations of several markers in Alzheimer's disease.

An infusion of colchicine into the hippocampi of rats resulted in destruction of hippocampal cells. Twelve days after infusion, preoperative trained colchicine-treated rats showed a significant decrease in choice accuracy in a T-maze learning task. There was also local reduction in choline acetyltransferase (ChAT) activity and significant losses of 55-kDa protein in the soluble fraction and of 50-kDa protein in myelin and synaptosomal fractions in the hippocampi of colchicine-lesioned rats. There was a marked increase in [3H]glutamate binding in the hippocampus and cortex. In contrast, [3H]quinuclidinyl benzilate binding in the hippocampus was slightly reduced, whereas [3H]dihydroalprenolol binding was not affected by the colchicine treatment. Scatchard analysis revealed that the increase in glutamate binding is due to an increase in the number of glutamate receptors without significant change in their affinity. Some of the changes caused by hippocampal infusion of colchicine resemble those seen in Alzheimer's disease suggesting the use of such rats as one model for the disease.

Pipecolic acid: a new type of alpha-amino acid possessing bicuculline-sensitive action in the mammalian brain.

Using unit recording and electrophoretic techniques, pharmacological properties of pipecolic acid (PA) were studied in the brain neurons of rats. PA response was blocked by bicuculline more effectively than GABA response but not blocked by strychnine. Stereochemical findings obtained using the HGS-model demonstrated that PA structure is almost the same as a part of bicuculline structure. The present results suggest that PA might be a new type of substance possessing bicuculline-sensitive action. The site of the action of PA was also discussed.

Electrophoretic study of pipecolic acid, a biogenic imino acid, in the mammalian brain.

Pipecolic acid (PA), one of the imino acids, is a normal constituent in the mammalian brain. It is said that PA is a major intermediate of lysine metabolism in the rat brain. Biochemical studies have suggested that PA may be involved in the regulation of synaptic mechanism in the CNS. Moreover, the pathophysiological significance of PA has been also suggested by some investigators. However, there has so far been no good evidence based on the comprehensive electrophysiological experiments. Using unit recording and microelectrophoretic technique, the action of PA on single neuron activities in the rat brain was examined. PA depressed the firing of 88 out of 115 cortical neurons tested. Only 2 were excited and 25 remained unaffected. All the identified hippocampal pyramidal neurons examined were uniformly inhibited. It has been reported that PA inhibits the uptake of GABA into the brain slices and enhances the release of GABA from the slices. Thus, it is likely that the inhibitory response due to PA may have some connections with GABAergic transmission. On the other hand, it remains to be clarified whether the specific PA sensitive receptors exist in the brain. Our findings provide a clue to the elucidation of the presumed synaptic involvement of PA in the CNS.

Actions of piperidine and dimethylphenylpiperazinium (DMPP) on afferent discharges of the cat's carotid body.

Chemoreceptor discharges were recorded in vivo from fine filaments of carotid sinus nerve; their frequency was used as index of receptor activity. Effects of piperidine on chemoreceptors were studied and compared with those of dimethylphenylpiperazinium (DMPP) on chemoreceptors in adult cats. Intracarotid-arterial injections of piperidine produced a transient increase in chemoreceptor discharges, the threshold dose ranging from 10 to 50 microgram i.a. The excitatory effect of piperidine was not affected by atropine, hexamethonium or GABA. DMPP (0.2-0.5 microgram i.a.) induced a marked increase in chemoreceptor discharges, which was abolished by hexamethonium, but not by atropine. DMPP ((2--5 microgram i.a.) induced sinus baroreceptor excitation, but piperidine did not. The results indicate that piperidine exerted excitatory effects on carotid body chemoreceptors, possibly acting on nerve endings of chemoreceptor afferent fibers.

Effects of anesthetics on piperidine levels in mouse brain.

Piperidine is one of the biogenic amines possessing potent pharmacological activity. Recent interest has focused on its possible role as an endogenous hypnogenic substance. Using a mass fragmentographic technique with deuterium-labelled piperidine as an internal standard, piperidine concentrations in brains of waking and deeply anesthetized mice were analyzed to compare piperidine levels in the brain under distinctly different states of consciousness. A rapid and significant increase in piperidine concentrations was found in the brain but not in blood of mice anesthetized with any one of pentobarbital, urethane, ether and halothane. The results, showing that CNS depression is accompanied by accumulation of piperidine in the brain, are consistent with the idea that piperidine may have a close connection with the mechanisms controlling the level of consciousness.

Changes in brain piperidine levels under anesthesia: mass fragmentographic analysis.

Piperidine is a biogenic alicyclic amine possessing potent pharmacological activity. Interest has recently been focussed on its possible role as an endogenous hypnogenic substance. Using a mass fragmentographic technique with deuterium-labelled piperidine as an internal standard, the time relations of the change in brain levels of piperidine and the anesthetic activity of urethane were determined in mice. The brain piperidine level increased prior to the loss of the righting reflex and the elevated level declined prior to the reappearance of the reflex. The change in brain piperidine level correlated with neither that in spontaneous motility nor that in body temperature. The findings favor the idea that piperidine might at least partly regulate the level of consciousness.

Potentiation of phenobarbital-induced anticonvulsant activity by pipecolic acid.

Pipecolic acid (PA) is an intermediate of lysine metabolism in the mammalian brain. Recent findings suggest a functional connection of PA as neuromodulator in GABAergic transmission. Since many drugs are postulated to produce their effects by interaction with the central GABA system, the influence of PA on the anticonvulsant activity of phenobarbital was examined. Pretreatment of mice with 50 mg . kg-1 of PA potentiated the suppressing effects of the barbiturate on electrically and chemically induced convulsions. However, there was no potentiation of the behavioral effects and hypothermia induced by phenobarbital. PA itself had no or only little effect on the convulsions, motor function and rectal temperature when given in i.p. doses up to 500 mg . kg-1. Intraventricular administration of 500 microgram of PA also did not suppress either type of convulsion, although it produced ptosis, hypotonia, sedation and hypothermia. The results are discussed in relation to GABA system.

Analysis of endogenous pyrrolidine levels by mass fragmentography.

Pyrrolidine, one of biogenic volatile amines, possesses nicotine-like synaptotropic actions on the nervous systems. In the present study, pyrrolidine levels in the tissues were examined by using mass fragmentographic technique. High concentrations of pyrrolidine were found in the seminal vesicle and lung of rabbits. Only trace amounts of pyrrolidine existed in the brain of mice and rats, although higher concentrations were detected in the brain of rabbits. In the rat brain, however, high levels of pyrrolidine were found in the pineal gland, pituitary gland and corpus striatum.

Pharmacological studies of the effect of Dai-kenchu-to on spontaneous contraction of isolated rabbit jejunum.

We studied the effects of Dai-kenchu to on the spontaneous contraction in isolated rabbit jejunum. Dai-kenchu-to (10(-3) g/ml) increased jejunal contraction, such as phasic like contraction and contractile amplitude. Zanthoxyli Fructus (2x10(-4) g/ml) exhibited an action identical to that of Dai-kenchu-to. While Zingiberis Siccatum Rhizoma (5x10(-4) g/ml) continuously decreased the amplitude of contraction. Ginseng Radix (3x10(-4) g/ml) and Saccharum Granorum (8x10(-3) g/ml) had no effect on spontaneous contraction. Dai kenchu-to and Zanthoxyli Fructus reversed the decrease of contraction produced by atropine. However, phasic like contraction induced in the absence of atropine was antagonized by atropine. Dai-kenchu-to and Zingiberis Siccatum Rhizoma further decreased spontaneous contraction in the presence of tetrodotoxin. It was clarified that Dai-kenchu-to possesses gastroprokinetic effect, and Zanthoxyli Fructus mainly contributed to this effect. It was suggested that the cholinergic and non cholinergic nervous systems were involved in increasing intestinal motility. It was also suggested that Dai-kenchu-to acted on multiple points of the intestine, and actions at these points might intensify to improve ileus.

Effects of Dai-kenchu-to on intestinal obstruction following laparotomy.

To confirm the usefulness of Dai-kenchu-to for intestinal obstruction, investigation of the effects of Dai-kenchu-to on postoperative intestinal adhesion was conducted. Repeated administrations of Dai-kenchu-to (100 or 300 mg/kg) significantly inhibited the formation of intestinal obstruction. Motor disturbance and inflammation are thought to be involved in the etiology of intestinal adhesion. A single treatment of Dai-kenchu-to (300 mg/kg) significantly reduce intestinal transit time in postoperative ileus and chemically induced ileus. Dai-kenchu-to (10(-4) g/ml) significantly inhibited COX-2 activity. These results suggest that Dai-kenchu-to prevents postoperative intestinal adhesion by gastroprokinetic and anti inflammatic effects. Dai-kenchu-to thus demonstrates positive effect on postoperative ileus.