Calculation of energy distributions of charged particles produced by neutrons from 0.14 to 65 MeV in tissue substitutes.

Energy distributions of secondary charged particles were calculated in tissue substitutes irradiated by neutrons from 0.14 to 65 MeV, using the Particle and Heavy Ion Transport code System. The calculations were compared with experimental data measured by tissue equivalent proportional counters (TEPC). It is found that the calculated distributions of the lineal energy, y, generally agree well with the measured ones for neutrons from several 100 keV to 15 MeV. In the case of 40 and 65 MeV neutron irradiations, wall effects of TEPC should be considered and the fluence of alphas is underestimated by the calculations. Integrated dose contributions of the secondary charged particles are generally in good agreement with those of the measured ones.

Development of a quasi-monoenergetic neutron field using the 7Li(p,n)7Be reaction in the energy range from 250 to 390 MeV at RCNP.

A quasi-monoenergetic neutron field using the (7)Li(p,n)(7)Be reaction has been developed at the ring cyclotron facility at the Research Center for Nuclear Physics (RCNP), Osaka University. Neutrons were generated from a 10-mm-thick Li target injected by 250, 350 and 392 MeV protons and neutrons produced at 0 degrees were extracted into the time-of-flight (TOF) room of 100-m length through the concrete collimator of 10 x 12 cm aperture and 150 cm thickness. The neutron energy spectra were measured by a 12.7-cm diam x 12.7-cm long NE213 organic liquid scintillator using the TOF method. The peak neutron fluence was 1.94 x 10(10), 1.07 x 10(10) and 1.50 x 10(10) n sr(-1) per muC of 250, 350 and 392 MeV protons, respectively. The neutron spectra generated from various thick (stopping length) targets of carbon, aluminium, iron and lead, bombarded by 250 and 350 MeV protons, were also measured with the TOF method. Although these measurements were performed to obtain thick target neutron yields, they are also used as a continuous energy neutron field. These neutron fields are very useful for characterising neutron detectors, measuring neutron cross sections, testing irradiation effects for various materials and performing neutron shielding experiments.

Radiation safety design for the J-PARC Project.

The High-Intensity Proton Accelerator Project, named J-PARC, is in progress, with the aim of enabling studies on the latest basic science and the advancement of nuclear technology. In the project, a high-energy proton accelerator complex with the world's highest instantaneous intensity is under construction. In order to establish a reasonable shielding design, both simplified and detailed design methods were used in the shielding design of J-PARC. This paper reviews the present status of the radiation safety design study for J-PARC.

Genomic discordance between monozygotic twins discordant for schizophrenia.

OBJECTIVE: Genomic DNA of monozygotic twins discordant for schizophrenia was analyzed to determine whether their genomes were truly identical. METHOD: The subjects were monozygotic male twins, one of whom had DSM-III-R schizophrenia, undifferentiated type. Genomic DNA was extracted from leukocytes and was applied to restriction landmark genome scanning analysis, which was developed for a high-speed survey of restriction sites throughout a genome and measurement of their copy number in each locus. RESULTS: After comparisons of patterns with approximately 2,000 spots, the authors detected at least two spots with autoradiographic intensities that obviously differed in the two twins. CONCLUSIONS: The discrepancies likely were generated either by differences in the methylation status at NotI sites between the twins or by submicroscopic changes occurring at NotI-flanking sites in one twin after (or simultaneous with) twinning. In either case, the difference may influence the transcription level of one or more genes.

Age-related changes in basal dendrite and dendritic spine of hippocampal pyramidal neurons (CA1) among SAMP1TA/Ngs--quantitative analysis by the rapid Golgi method.

It has been confirmed that a substrain of the senescence-accelerated mouse SAMP1TA/Ngs develops learning disturbance-like behavior at 3 months of age, exhibits almost normal behavior at 5 months, and manifests learning disturbance at 7 months. The changes with age in basal dendrites and dendritic spines of CA1 pyramidal neurons were quantitatively evaluated by the Golgi method using male SAMP1TA/Ngs. The correlation between the change in learning ability and the morphometry was examined. The number of dendritic spines in the 3- and 7-month-old groups was significantly lower than that in the 5-month-old group. It is presumed that the disturbance in acquisition of learning ability at 3 months of age is secondary to the immaturity of neurons, while the learning disturbance at 7 months of age is due to neuronal aging. This substrain, which is characterized by the impairment of acquired learning ability due to senescence, is useful as a model for studies on human brain dysfunction associated with senescence.

Malformation in infants of mothers with epilepsy receiving antiepileptic drugs.

To assess the relative contribution of antiepileptic drugs (AEDS) to occurrence of congenital malformations, we compared two prospective studies. We analyzed data for 14 AEDs for total daily doses (drug score) and eight background factors. From the first study, the drug score and polytherapy--particularly the use of valproate plus carbamazepine--were suspected to be primary factors for increased incidence of congenital malformation. In the other study, the drug score for each case was decreased, and polytherapy--particularly valproate plus carbamazepine--was changed to monotherapy before conception. These changes significantly decreased the incidence of malformations. Among risk factors, only the doses of methylphenobarbital for mothers of infants with malformations were significantly higher than those for mothers of infants without malformations. Statistical differences were seen in drug score, number of AEDs, maternal age at delivery, seizure type, and etiology of epilepsy between the two groups. When data were corrected for seizure type, maternal age at delivery, or etiology of epilepsy, the difference in the incidence of malformations did not disappear, but it did disappear when data were corrected for drug score or number of AEDs. These results support our previous observations that AEDs are primary factors for the increased incidence of congenital malformation in infants of mothers with epilepsy.

Immunohistochemical study of the cells infiltrating human renal allografts by the ABC and the IGSS method using monoclonal antibodies.

Sixty renal allograft tissues obtained from 29 patients were stained with hematoxylin and eosin. These tissues were histologically classified into 4 patterns according to the distribution pattern of the infiltrating cells: normal, focal, focal-diffuse, and diffuse types. Clinical signs of acute rejection were observed in 88% of the patients with the diffuse type infiltration, and 83% of those with the focal-diffuse type infiltration but in only 13% of those with the focal type infiltration. Twenty-four renal allografts were analyzed by the ABC and the IGSS methods using monoclonal antibodies. The number of T cells (Leu 1) accounted for about 80% of the total number of infiltrating cells; 2-8% of the cells were B cells (Leu 12); about 10% were NK/K cells (Leu 7); and 4-6% were monocytes/macrophages (Leu M3). As to helper/inducer T cell (Leu3a) and killer/suppressor T cell (Leu2a), which are T lymphocyte subsets, there were more Leu3a- than Leu2a-positive cells in focal type tissue, but there were more Leu2a- than Leu3a-positive cells in focal-diffuse and diffuse type tissue. In most cases that developed clinical signs of acute rejection, there were more Leu2a- than Leu3a-positive cells. The Leu3a/Leu2a ratio in most of the AZA-administered cases dropped immediately after the transplantation and maintained a low value, but in the CSA-administered cases it decreased gradually post-transplant.

Direct renal action of captopril (SQ 14225): dissociation of natriuretic and vascular actions in isolated perfused rat kidney.

Direct effects of captopril on renal function were examined in isolated perfused rat kidneys. Captopril induced a significant increase in urinary volume and urinary sodium excretion (1.8- and 1.7-fold, respectively; both p less than 0.005), whereas urinary potassium excretion and renovascular resistance were not significantly changed. Because the perfusion medium lacks angiotensinogen, kininogen and aldosterone, the natriuretic action in perfused kidneys may not be related to its inhibitory action on angiotensin I converting enzyme or kininase II. Because the natriuresis was not accompanied by changes in renovascular resistance, it is suggested that captopril possesses a direct natriuretic action and that this property may partly explain the mechanism of captopril-induced natriuresis clinically observed.

Characterization of a zinc finger protein ZAN75: nuclear localization signal, transcriptional activator activity, and expression during neuronal differentiation of P19 cells.

The ZAN75 cDNA was first identified in NIH 3T3 cells and codes for a DNA-binding protein with two zinc finger motifs. In this study, we characterized the nuclear localization signal of ZAN75, tested if ZAN75 regulates transcription, and examined its expression during embryonic development and neuronal differentiation of P19 mouse embryonal carcinoma cells. By examining the cellular localization of deletion mutants of ZAN75 fused to green fluorescence protein, ZAN75 was revealed to have a bipartite nuclear localization signal sequence upstream of the zinc finger domains. The N-terminal region of ZAN75, when fused to the GAL4 DNA-binding domain, strongly activated transcription. The expression of ZAN75 mRNA was found to be developmentally regulated, showing the highest expression in E11.5 embryos. In situ hybridization experiments using E11.5 embryos showed a high expression of the transcripts in neuronal tissues such as brain and neural tube. The expression of ZAN75 was transiently increased at both the mRNA and the protein levels when P19 cells were treated with retinoic acid to induce neuronal differentiation. Taken together, these results indicate that ZAN75 is a transcriptional activator with a bipartite nuclear localization signal and may play a role in neuronal differentiation.

Lack of association between the hKCa3 gene and Japanese schizophrenia patients.

Several researchers have suggested an association between large numbers of CAG repeats in the hKCa3 gene and schizophrenia. However, these reports remain inconclusive and require further investigation. We tried to replicate these results in 112 Japanese schizophrenia patients and 102 control subjects of highly matched age and sex by applying an allele dichotomization model. No association was found. The overall distributions of allele frequencies were not significantly different between schizophrenic patients and normal control subjects. In addition, we tested the association between the size of the CAG repeats and the scores on three dimensions (positive and negative symptoms, and disorganization), but no significant results were obtained. Our results do not support the involvement of the hKCa3 gene in schizophrenia, at least in the Japanese population.

Strategy for lymphadenectomy of gastric cancer.

To determine the extent of lymphadenectomy necessary to cure early gastric cancer, the relationship between the frequency of nodal involvements and the extent of the primary invasion was examined in 274 patients with primary cancer of the stomach. We also evaluated the relationship between the number of metastatic lymph nodes, the pattern of metastases to the nodes, and the histologic type of the primary tumor. In early gastric cancer, lymph node metastasis was more frequent in protruded-type cancer with invasion into the submucosa more than 3 cm in diameter and located in the lower third of the stomach, but was limited to the group 1 lymph nodes, which were defined as being anatomically located nearest to the cancer. In cancer invading into the muscularis propria, metastasis to the group 2 or 3 lymph nodes, which were defined as being anatomically located farther from the cancer than group 1, was found. The number of lymph nodes involved and extent of cancer metastasis in these lymph nodes metastasis, differentiated early gastric cancer had more lymph node involvement and wider extent of metastases than undifferentiated cancers. The cancer cells sometimes replaced most of the node and invaded the perinodal fatty tissue, even in early gastric cancer. In addition, it is occasionally difficult to distinguish macroscopically early gastric cancer with submucosal invasion from cancer invaded into the muscle layer. In conclusion, group 1 and 2 lymph nodes, including perinodal fatty tissue, should be removed completely, even in early gastric cancer, except for carcinoma in situ, particularly when the cancer is of the differentiated type.

Site of action of galanin in the cholinergic transmission of guinea pig small intestine.

The mode and site of action of galanin were examined in the guinea pig small intestine. Galanin (3 x 10(-9)-10(-7) M) inhibited the twitch contractions of longitudinally and circularly oriented muscle strips mediated by the stimulation of cholinergic neurons, but not the contractions mediated by direct stimulation of smooth muscle cells with carbachol. Galanin (3 x 10(-9)-10(-7) M) inhibited both the electrically stimulated and the tetrodotoxin-resistant high K+ (40 mM)-induced increase of [3H]acetylcholine outflow from the ileal strips preloaded with [3H]choline, in a concentration dependent fashion. The inhibitory effect of galanin was antagonized by galantide and produced self-desensitization. The spontaneous and stimulated outflow of [3H]noradrenaline and [3H]gamma-aminobutyric acid were not affected by galanin even at 10(-7) M. Thus, galanin inhibits the motility of guinea pig ileum by inhibition of acetylcholine release from the enteric cholinergic neurons. Galanin may act on the specific receptor located on soma-dendritic regions and nerve terminals of cholinergic neurons.

C-type natriuretic peptide-22 differentiates between natriuretic peptide receptors in rat choroid plexus and subfornical organ.

Atrial natriuretic peptide (ANP) receptors in the rat choroid plexus and subfornical organ were characterized with C-type natriuretic peptide-22 (CNP-22) and 125I-Tyr0-CNP-22. The receptor autoradiographic method we used revealed that 125I-Tyr0-CNP-22 specifically bound to the choroid plexus, but only slightly to the subfornical organ, areas densely labeled with 125I-alpha-rat ANP (125I-rANP). CNP-22 significantly inhibited 125I-rANP binding to the choroid plexus; however, the peptide did not affect 125I-rANP binding to the subfornical organ. Thus, the characteristics of ANP receptors in the rat choroid plexus and subfornical organ are probably different.

Regional difference in correlation of 5-HT4 receptor distribution with cholinergic transmission in the guinea pig stomach.

Localization and function of 5-HT4 receptors in the stomach were examined in mucosa-free preparations of antrum, corpus and fundus from guinea pig stomach by determination of acetylcholine release and in vitro receptor autoradiography. Specific [125I]SB207710, (1-n-butyl-4-piperidinyl) methyl-8-amino-7-iodo-1,4-benzodioxane-5-carboxylate, binding sites were detected in 3 regions of the stomach. High densities of binding were observed in the myenteric plexus of antrum and corpus, but not fundus. In mucosa-free preparations treated with 5-HT1, 5-HT2 and 5-HT3 receptor antagonists, 5-HT (10(-8)-10(-6) M) potentiated the electrically stimulated (0.5 Hz, 1 ms) outflow of [3H]acetylcholine from antrum and corpus strips preloaded with [3H]choline, but not from fundus strips, and the potentiation was antagonized by SB204070, (1-n-butyl-4-piperidinyl) methyl-8-amino-7-chloro-1,4-benzodioxane-5-carboxylate. Thus, 5-HT4 receptors are located on myenteric cholinergic neurons in the antrum and corpus of guinea pig stomach and their activation evokes the release of acetylcholine.

Epidemiological studies of schizophrenia in Japan.

This article examines epidemiological studies of schizophrenia in Japan. It is divided into three major sections: (1) methodological problems associated with epidemiological studies; (2) an overview of the history of epidemiology in Japan; and (3) an epidemiological study on incidence rates in Nagasaki, which was conducted as part of the World Health Organization Collaborative Study on Determinants of Outcome of Severe Mental Disorders. In general, although some differences in schizophrenic subtypes have been found, prevalence and incidence rates of schizophrenia in Japan are not significantly different from those reported in other countries.

Expression of gicerin, a cell adhesion molecule, in the abnormal retina in silver plumage color mutation of Japanese quail (Coturnix japonica).

Silver plumage color mutant (B/B) quail has an abnormal retina characterizing the transdifferentiation of retinal pigment epithelium (RPE) following the retinal separation in the early developmental stage. In the present study; (i) the expression of gicerin, an immunoglobulin-superfamily cell adhesion molecule, was examined in the retina of B/B quail. In the wild-type quail, gicerin protein was enriched in the apical membrane (facing the neural retina, NR) of RPE cells on embryonic day (E) 4 and then appeared also in NR cells from E5. However, in the B/B retina, no gicerin expression was found in the transdifferentiation area of RPE prior to the retinal separation. (ii) In addition to this, microinjection of anti-gicerin polyclonal antibody into the eyeball of wild-type quail on E3 caused the retinal separation and induced the transdifferentiation of RPE into new NR. These observations suggest that the decrease of gicerin expression might participate in the retinal separation and RPE-transdifferentiation in B/B quail.

Different effects of antidepressants on dissociation of 3H-imipramine from solubilized binding sites of rat brain.

1. The effects of several antidepressants and 5-hydroxytryptamine on dissociation of 3H-imipramine from solubilized binding sites were investigated. 2. Binding sites were solubilized from rat brain membranes and gelfiltrated on a column of Sephacryl S-300. 3. Most of the agents used allowed biphasic dissociation with 1mM of displacing agent and without using dilution-induced dissociation. This biphasic dissociation without nonspecific effects of membranes may be due to the existence of low-affinity binding sites. 4. Dissociation of up to 40 min followed first-order kinetics. The dissociation half-life of 3H-imipramine with the various displacing agents was calculated at from 15.0 to 25.0 min, and the differences among the agents were not so significant as the attenuation or the acceleration of the dissociation was indicated. The lower concentration of the displacing agents may obscure the modulation of the dissociation.

Comparison of in-phantom dose distributions for coronary angiography using an x-ray machine and synchrotron radiation.

Coronary cineangiography using synchrotron radiation is anticipated, owing to the high intensity and availability of monoenergy. To investigate allowable dose levels in clinical application, absorbed dose distribution in a tissue substitute phantom for a conventional x-ray machine was measured with thermoluminescent dosimeters at the University of Tsukuba under the practical conditions used for digital angiography. The dose rate at a 0.5-cm depth was 0.145 Gy/s, and the dose per frame was 0.725 mGy for the irradiation period of 5 ms per frame. For synchrotron radiation, the dose distribution measurement was made at a 5-GeV AR (Accumulation Ring) of the High Energy Accelerator Research Organization, in which a polymethylmethacrylate (PMMA) phantom was irradiated with the strongest beam available at the facility, which was 33.32 keV, 5.2 x 6.2 cm2 beam. Using this beam, a 1-mm-diameter coronary artery has been visualized at 1% iodine concentration at the AR. Nonhomogeneous strength distribution in the beam was observed in the vertical direction. The maximum dose rate was 0.556 Gy/s, and it attenuated to 1/3000 at a 30-cm depth in the beam center. At the deep positions, the doses were influenced by the high harmonics, which was confirmed with an EGS4 Monte Carlo calculation. Outside the beam, beam contamination on both sides of the main beam affected the doses. For comparison to the x-ray machine, the measured dose was analytically converted to that needed for a 5.2 x 16 cm2 beam that is used for clinical application. The dose rate at 0.5-cm depth was found to be 0.215 Gy/s, which is 1.48 times larger than that for x-rays. Moreover, the attenuation rate in the phantom was significantly greater than that of the x-ray machine, because of the difference of the energy spectra between the x-rays and synchrotron radiation used.

Intrauterine growth in the offspring of epileptic women: a prospective multicenter study.

The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs (AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2-8.0) or Canadian children (RR 2.6; 95% CI: 1.1-6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2-6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4-9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5-13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6-10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.

Congenital malformations due to antiepileptic drugs.

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.