Analysis of the beam halo in negative ion sources by using 3D3V PIC code.

The physical mechanism of the formation of the negative ion beam halo and the heat loads of the multi-stage acceleration grids are investigated with the 3D PIC (particle in cell) simulation. The following physical mechanism of the beam halo formation is verified: The beam core and the halo consist of the negative ions extracted from the center and the periphery of the meniscus, respectively. This difference of negative ion extraction location results in a geometrical aberration. Furthermore, it is shown that the heat loads on the first acceleration grid and the second acceleration grid are quantitatively improved compared with those for the 2D PIC simulation result.

Effect of Coulomb collision on the negative ion extraction mechanism in negative ion sources.

To improve the H(-) ion beam optics, it is necessary to understand the energy relaxation process of surface produced H(-) ions in the extraction region of Cs seeded H(-) ion sources. Coulomb collisions of charged particles have been introduced to the 2D3V-PIC (two dimension in real space and three dimension in velocity space particle-in-cell) model for the H(-) extraction by using the binary collision model. Due to Coulomb collision, the lower energy part of the ion energy distribution function of H(-) ions has been greatly increased. The mean kinetic energy of the surface produced H(-) ions has been reduced to 0.65 eV from 1.5 eV. It has been suggested that the beam optics of the extracted H(-) ion beam is strongly affected by the energy relaxation process due to Coulomb collision.

Study of plasma meniscus and beam halo in negative ion sources using three dimension in real space and three dimension in velocity space particle in cell model.

Our previous study by two dimension in real space and three dimension in velocity space-particle in cell model shows that the curvature of the plasma meniscus causes the beam halo in the negative ion sources. The negative ions extracted from the periphery of the meniscus are over-focused in the extractor due to the electrostatic lens effect, and consequently become the beam halo. The purpose of this study is to verify this mechanism with the full 3D model. It is shown that the above mechanism is essentially unchanged even in the 3D model, while the fraction of the beam halo is significantly reduced to 6%. This value reasonably agrees with the experimental result.

Periventricular leucomalacia (PVL)-like lesions in two neonatal cynomolgus monkeys (Macaca fascicularis).

Periventricular leucomalacia (PVL) is a lesion of immature cerebral white matter that occurs in the perinatal period. In man, PVL is the predominant form of brain injury and a cause of cerebral palsy and cognitive deficits in premature infants. PVL affects fetuses and newborns, particularly those who have undergone oxygen deprivation as may occur in premature birth. Many clinical and pathological studies of PVL have been performed in man, but there is no clear definition of PVL in animals. A few spontaneous PVL-like cases in puppies or experimental cases in other animal species have been reported. The present study reports the histopathological and immunohistochemical features of PVL-like lesions in two neonatal cynomolgus monkeys. In both cases, there was cerebral white matter necrosis with marked infiltration of lipid-laden phagocytes and a reduction of neurons in the cerebral cortex. In case 1 there was extensive cavitation of the cerebral white matter. In case 2 there was reactive astrocytosis associated with a decrease in oligodendroglial cells and a decrease in cerebral white matter myelin. To our knowledge, this is the first report of PVL-like leucoencephalomalacia in non-human primates.

Natural course of progression of liver fibrosis in Japanese patients with chronic liver disease type C--a study of 527 patients at one establishment.

Patients with chronic hepatitis C infection show a gradual progression of fibrosis to liver cirrhosis and hepatocellular carcinoma (HCC). We studied whether the progression of liver fibrosis differed among Japanese subjects who were infected with different hepatitis C virus (HCV) genotypes. In 527 patients we examined whether there was a relationship between gender, age, history of blood transfusion, interval between date of blood transfusion and date of liver biopsy or date of diagnosis of HCC, serum alanine aminotransferase level, platelet count or HCV genotype, with the extent of liver fibrosis, classified into four stages (F1-F4). Moreover, we compared the mean rate of liver fibrosis progression per year in patients with each HCV genotype. Patients who had a higher fibrosis score tended to be older, have a lower platelet count and a longer interval since blood transfusion than those who had a lower fibrosis score. The mean rate of liver fibrosis progression was 0.12 +/- 0.15 stages per year after the blood transfusion. However, the progression rate of liver fibrosis in patients who had received a blood transfusion when they were > or = 30 years of age was 0.19 +/- 0.22, while the progression rate of liver fibrosis in the patients who had received a blood transfusion when they were < 30 years was 0.09 +/- 0.09. In conclusion, chronic hepatitis C is a progressive disease, and patients with genotype 1b, 2a and 2b have a similar rate of progression of liver fibrosis. Particular attention should be paid to patients who are infected with HCV when > or = 30 years of age, because intrahepatic fibrosis rapidly progresses in these patients.

[A case of mumps pneumonia complicated with acute respiratory failure].

A 38-year-old male with swollen parotid glands was admitted to our hospital with dyspnea on effort. Positive serum IgM antibody for mumps supported a diagnosis of mumps. Computed tomography (CT) scan showed a ground-glass appearance in both lower lungs. On the third day of hospitalization, bronchoalveolar lavage demonstrated an elevation of both the total cell (2.0 x 10(6)/cc) and the lymphocyte count (83%), as well as a decrease of the CD 4+/CD 8+ ratio (0.4). Bronchial biopsy specimens revealed infiltration of lymphocytes in both the bronchiolar walls and the alveolar septa. These data were suggestive of mumps pneumonia. The patients suffered acute respiratory failure on the seventh day of hospitalization, which improved after 3 days of high-dose methyl prednisolone therapy. This is the first report of adult mumps pneumonia in Japan. As a result of the examination of the bronchoalveolar lavage and a bronchial biopsy of viral pneumonia which had been reported in the past, mumps pneumonia was a corresponding opinion to other viral pneumonia.

[The clinical usefulness of high-dose intravenous immunoglobulin therapy for chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy].

To explore the optimum dose of intravenous immunoglobulin (i.v.Ig) for treating patients with chronic inflammatory demyelinating polyrneuropathy and multifocal motor neuropathy, we compared the usefulness of i.v.Ig among 3 treatment doses. Fifty-nine patients were randomly divided into three treatment dosage groups: 20 patients for Group I using 50 mg/kg/day x 5 days, 19 patients Group II using 200 mg/kg/day x 5 days, and 20 patients Group III using 400 mg/kg/day x 5 days. We assessed clinically and electrophysiologically the effectiveness of the treatment at 5 weeks after the initial infusion. For patients in Group I and II who had not improved (or worsened) with the first treatment, we gave a one-step larger dose in the second treatment (i.e. 200 mg/kg/day x 5 days for those who had been given 50 mg/kg/day x 5 days, 400 mg/kg/day x 5 days for those who had been given 200 mg/kg/day x 5 days) after more than 9 weeks. We found that 15% of the patients in Group I, 21% in Group II and 60% in Group III improved dose-dependently with the first intravenous immunoglobulin treatment. Seven (47%) of 16 patients in Group I and 4 (40%) of 11 patients in Group II improved after the second treatment with larger doses. Adverse reactions including chill sensation, fever, skin eruption and increase in blood GOT and GPT levels were transient and mild. One patient in Group III developed left hemiparesis showing the small infarction in the right thalamus during the course of the treatment, but the symptom was mild. In conclusion, the high-dose intravenous immunoglobulin therapy (400 mg/kg/day x 5 days) is useful for treating patients with CIDP and MMN, although care must be taken of the risk of causing cerebral infarctions.

Positron emission tomography (PET) in Machado-Joseph disease.

Positron emission tomography studies on the regional cerebral glucose metabolism (rCMRglc) and 18F-fluorodopa (18F-Dopa) uptake were performed in 3 patients with Machado-Joseph disease (MJD), a dominantly inherited degenerative disease in the cerebellum, brainstem and basal ganglia. The rCMRglc in MJD was found to be significantly decreased in the cerebellum, brainstem, striatum and whole cerebral cortex in comparison to that in normal subjects. These results of rCMRglc were different from those for dominantly inherited olivopontocerebellar atrophy (dOPCA) or cerebellar cortical degeneration (CCD), however they were similar to those for sporadic olivopontocerebellar atrophy (sOPCA) and multiple system atrophy (MSA). The 18F-Dopa uptake in MJD was found to be significantly decreased in the putamen and relatively spared in the caudate, which was different from that of MSA. In addition, these results indicate that MJD showed a dysfunction, not only in the regions with apparent pathological involvement such as cerebellum, brainstem and nigro-striatal dopaminergic system, but also in the cerebral cortex and the striatum where no pathology could be observed using conventional morphological techniques.

Nine-year follow-up study of bromocriptine monotherapy for Parkinson's disease.

A 9-year nationwide study of bromocriptine monotherapy and combination therapy with bromocriptine and levodopa in Parkinson's disease is reported. Eleven patients were on bromocriptine monotherapy, 35 patients were on combined treatment of bromocriptine and levodopa for a certain time during a 9-year period. Maintenance doses of bromocriptine at the end of the 9th year in the two groups were 11.1 mg/day in the monotherapy and 12.7 mg/day in the combination therapy group with levodopa. Changes in Hoehn and Yahr's grading between the time of trial start and the end of 108 months' treatment revealed that 5 of 11 cases in the monotherapy group remained in the same stages, the other 2 cases improved in condition from stage II to I, and another 4 deteriorated compared with pretreatment grade. On the other hand, 20 of 35 cases in the combination-therapy group reached more advanced stages, 3 patients moving to stage V. Four of them, however, improved, and 11 did not change at the end of 9 years of treatment. Although it is difficult to prove the neuroprotective effect of a dopamine receptor agonist, our long-term nation-wide collaborative studies will help us to answer the question of how bromocriptine works in pharmacokinetic aspects.

[A family of autosomal dominant facio-limb-girdle muscular dystrophy].

A family of autosomal dominant facio-limb-girdle muscular dystrophy was reported. The proband was a 28-year-old male. His father and sister suffered from a similar disease. All patients developed weakness of lower limbs and atrophy of thigh at second to fourth decades. All showed mild facial and neck flexor weakness as well as proximal dominant weakness and atrophy of four limbs. Limb muscle involvement was more severe in lower limbs than in upper limbs in all cases. Interestingly, all showed limitation of ankle dorsiflexion (tight heel cord), although distal muscles of lower limbs were not involved or only mildly involved clinically. On laboratory examination, serum CK increased slightly. Needle EMG revealed low amplitude, polyphasic MUP in limb muscles in all cases. Biopsied muscles taken from the proband showed non-specific myogenic changes. Rimmed vacuoles were not observed. Our cases were different from Bethlem myopathy, because the age of onset was late and joint contractures were mild in our cases, as compared with Bethlem myopathy. Clinical manifestations of our family showed a strong resemblance to the family reported by Girchlist et al, but similar cases were not reported in Japan.

Antibody-dependent cell-mediated cytotoxicity (ADCC) in HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP)

Defects in immune surveillance mechanisms may allow increased replication of human T-lymphotropic virus type I (HTLV-I) in peripheral blood mononuclear cells in HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). To explore this possibility, antibody-dependent cell-mediated cytotoxicity (ADCC) against HTLV-I infected cells in HAM/TSP and in asymptomatic HTLV-I-seropositive carriers (SPC), was studied. ADCC activity was significantly depressed in HAM/TSP compared to SPC subjects (p < 0.025) and was due to specific reduction in ADCC effector activity. On the other hand, there was no difference in antibody component of anti-HTLV-I ADCC (ADCC-Ab) activities between HAM/TSP and SPC, although patients with more severe forms of disease tended to have higher anti-HTLV-I ADCC-Ab activity. In HAM/TSP, depressed ADCC activity against HTLV-I due to reduced ADCC-effector activity may allow increased replication of HTLV-I which may implicate the development of inflammatory neuropathologic lesions of HAM/TSP.

[Gastrointestinal metastasis from lung cancer].

Metastasis of lung cancer to the digestive tract (excluding the esophagus) was confirmed by surgery or autopsy in 30 of the 1635 lung-cancer patients admitted to this Center during the 17-year period since 1977. The diagnosis was made before death in 7 and after death in 23. Metastasis of large cell carcinoma was the most common (3.7%), followed by adenocarcinoma (2.4%), small cell carcinoma (1.7%), and squamous cell carcinoma (0.7%). Metastasis to the stomach occurred in 0.4%, to the small intestine in 1.1% and to the colon in 0.5%. The overall percentage of metastasis to the digestive tract was 1.8%. Among the 298 cases diagnosed at autopsy, metastasis to the digestive tract occurred in 9.7%; stomach, 2.6%; small intestine, 5.7%; and colon, 3.0%. Eleven of the patients in whom the diagnosis was made at autopsy had abdominal symptoms while they were alive. In 11 cases diagnosed at autopsy, occult blood was positive in 9, but 6 of those 9 patients were asymptomatic. The occult-blood test is considered to be helpful as a supplementary diagnostic method in detecting metastasis of lung cancer to the digestive tract. Among the cases diagnosed while the patients were alive, metastasis was observed in the small intestine in 6 and in the colon in 1. The major manifestations were melena, ileus, intussusception, and perforation; 4 patients required emergency surgery. The prognosis was poor: the mean survival period from the onset of symptoms was 49 days. The direct cause of death was metastasis to the digestive tract in 5 cases. The possibility of metastasis to the digestive tract is high when progressive abdominal symptoms are observed and the stool is persistently positive on occult-blood tests.

Enhancement of sensitivity of human lung adenocarcinoma cells to growth-inhibitory activity of interferon alpha by differentiation-inducing agents.

A low concentration of differentiation inducers such as dimethylsulphoxide (DMSO), sodium butyrate, hexamethylene bisacetamide and sodium phenylacetate greatly enhanced the antiproliferative effect in vitro and in vivo of interferon alpha (IFN-alpha) to several human lung adenocarcinoma cells. The agents induced morphological changes in the adenocarcinoma cells and the agents together with IFN-alpha-induced alkaline phosphatase activity, which is a typical marker of type II pneumocyte maturation. To understand the mechanism of the DMSO-enhanced interferon sensitivity, we examined the effect of DMSO on high-affinity IFN-alpha receptor and interferon-stimulated promoter-binding factors. The lung adenocarcinoma cells were not impaired in IFN-alpha receptor and interferon-stimulated gene transactivation factor 3 (ISGF-3). Our data suggest that the enhancement of interferon sensitivity in the lung adenocarcinoma cells acts downstream of the activation of ISGF-3.

Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer.

CYP1A1 is responsible for the metabolic activation of benzo(a)pyrene in cigarette smoke, and high susceptibility to smoking-related lung cancer has been associated with the MspI polymorphism of the CYP1A1 gene. Individuals with a susceptible CYP1A1 genotype have been found to be at remarkably high risk when the genotype is combined with a deficient Mu-class glutathione S-transferase (GSTM1) genotype. In this study, we investigated the relationship between germ line polymorphisms of these genes and clinical characteristics or survival rates in 232 patients with non-small cell lung cancer (NSCLC). Statistical analysis revealed a significant association (P < 0.05) of the MspI polymorphism of the CYP1A1 gene with histological type, performance status (general conditions of patients), and the extent of the primary tumor (T-factor). On the other hand, the GSTM1 polymorphism was significantly associated with performance status, the extent of regional lymph node metastasis (N-factor), and the extent of distant metastasis (M-factor). NSCLC patients with at least one susceptible allele of the MspI polymorphism of the CYP1A1 gene [heterozygous genotype B or a rare homozygous genotype C; n = 131; median survival time (MST) = 24.2 months] were associated with a shortened survival compared with those with nonsusceptible homozygous alleles (genotype A; n = 101; MST = 65.2 months; P = 0.005 by log-rank test). Smokers with susceptible genotypes (n = 104; MST = 18.2 months) were markedly associated with a shortened survival compared with those with genotype A (n = 76; MST = 69.2 months; P = 0.024); such an association was not found among nonsmokers by genotypes. Genotype-dependent survival was also observed in patients at an advanced stage of disease (P = 0.010), but not in those at an early stage of disease (P = 0.382). Patients with the susceptible CYP1A1 genotype had remarkably shortened survivals when the genotype was combined with a deficient genotype GSTM1(-) (P = 0.017; degree of freedom = 3). Multivariate analysis by the Cox proportional hazards model also revealed that the CYP1A1 polymorphism was an independent prognostic factor in patients at a nonresectable advanced stage of NSCLC (P = 0.005; hazard ratio = 1.98; 95% confidence interval, 1.24-3.17).

Increased preproenkephalin mRNA and preprotachykinin mRNA in the striatum of Rolling mouse Nagoya.

Although Rolling mouse Nagoya (RMN) has been considered to demonstrate cerebellar dysfunction, our previous metabolic and electrophysiological studies also revealed a dysfunction of the basal ganglia, with the presumable primary site of dysfunction being the striatum. In the present study, we investigated the neurochemical functions of the striatum. In RMN, both preproenkephalin mRNA and preprotachykinin mRNA increased significantly in the striatum, with unaltered GAD mRNA, [(3)H]spiperone binding, [(3)H]QNB binding and preprosomatostatin mRNA, thus indicating the dysfunction of striatal projection neurons. These findings support the hypothesis that the site of primary dysfunction in the basal ganglia is in the striatum of RMN.

Interferon-alpha is effective in HTLV-I-associated myelopathy: a multicenter, randomized, double-blind, controlled trial.

A double-blind, multi-center study was performed on patients with HTLV-I-associated myelopathy (HAM) to evaluate the therapeutic effect of treatment with natural interferon-alpha (HLBI). Forty-eight HAM patients were enrolled and treated with either 0.3 MU (n = 15), 1.0 MU (n = 17), or 3.0 MU (n = 16) of HLBI for 28 days. Clinical evaluation included motor dysfunction, urinary disturbances, and changes of neurologic signs. The frequency of therapeutic response judged as excellent to good 4 weeks after starting therapy and 4 weeks after completion of therapy were 7.1% (1 of 14) and 8.3% (1 of 12) in the 0.3-MU group, 23.5% (4 of 17) and 26.7% (4 of 15) for the 1.0-MU group, and 66.7% (10 of 15) and 61.5% (8 of 13) for the 3.0-MU group. The therapeutic benefit in the 3.0-MU group was significantly higher than in the 0.3-MU group. There was no significant difference in the incidence of symptomatic side effects between groups. Abnormal laboratory data were obtained for some patients in the 1.0-MU and 3.0-MU groups; however, the treatment schedule could be continued in most patients. These results suggest that HAM patients may be safely treated with HLBI 3.0 MU every day for 4 weeks with favorable clinical effects.

Hemolytic anemia in wild seaducks caused by marine oil pollution.

Clinico-pathological examinations were conducted on wild white-winged scoters (Melanitta fusca) contaminated with fuel oil (Bunker C oil) from a capsized cargo ship in February 1993 in Japan. The erythrocyte count, hemoglobin concentration and hematocrit value in the oiled seaducks all were decreased and numerous immature erythrocytes were observed in blood smears. In addition, hemosiderosis was observed in the liver, kidney, and lung of some birds. We propose that the sea-ducks suffered from hemolytic anemia induced by ingestion of oil, which occurs when the birds preen their oiled plumage.

Eight-year follow-up study of bromocriptine monotherapy for Parkinson's disease.

An 8-year nationwide study of bromocriptine monotherapy and combination therapy with bromocriptine and levodopa in Parkinson's disease is reported. Fifteen patients were on bromocriptine monotherapy, and 44 patients on bromocriptine combined with levodopa for a certain time during an 8-year period. By judging from Hoehn and Yahr's grading, 4 of the 15 patients in the monotherapy group were in a better condition than before treatment, while 7 cases remained in the same grading, and only 4 showed deterioration. On the other hand, 26 of 44 patients on combination therapy showed more advanced grading at the end of 8 years compared to the stage at the onset of the trial. Maintenance doses of bromocriptine in the two groups were 12-13 mg per day, and levodopa doses were kept at a relatively low level (310-370 mg per day) during this study period. Whether dopamine receptor agonists have neuroprotective effect or not is extremely difficult to prove in human subjects, but this type of long-term follow-up study might give some clues as to these important questions.