Possible association between nonsynonymous polymorphisms of the anaplastic lymphoma kinase (ALK) gene and schizophrenia in a Japanese population.

We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys-1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3-4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.

Oxatomide for stable asthma in adults and children.

BACKGROUND: Oxatomide is a histamine H1-receptor antagonist. As an oral agent, oxatomide may be useful in managing asthma. Some guidelines recommend oxatomide for long-term prophylaxis of asthma in children. There is no clear evidence whether children or adults with asthma benefit from oxatomide. OBJECTIVES: To determine whether oxatomide alone, or in combination with other interventions, results in better disease control in people with asthma. SEARCH STRATEGY: The Collaborative Airway Group register and Collaborations trial register CENTRAL were searched using terms: oxatomide* OR Celtect OR Pinset OR KW-4354 OR Tincet. Reference lists of all relevant trials or review articles were checked. Enquiries were made of authors of included studies and relevant pharmaceutical companies. A search of 'Igaku Chuo Zasshi' and 'J-Medicine' were made using the following terms: oxatomide (also in Japanese) or Celtect (also in Japanese) or KW-4354. SELECTION CRITERIA: Studies were randomised, placebo-controlled trials and the interventions were oxatomide or matched placebo given alone or in combination with other asthma-medication for at least 4 weeks. DATA COLLECTION AND ANALYSIS: Four independent reviewers performed assessments of methodological quality and extracted relevant data. MAIN RESULTS: Six studies are included in this review. Three studies were mainly conducted in adults, two were conducted in older children (5-16 years) and one in infants (18-25 months). Trial duration was 4 to 52 weeks. Doses of oxatomide varied between studies, ranging from 1 mg/kg/day for infants to 180 mg/day for adults. Only data on adverse events was suitable for meta-analysis. Although PEF did not change significantly in any of the studies, the FVC and FEV1 improved significantly in two. There was no uniform change in symptom scores. There was no significant difference between oxatomide and placebo treatment in use of inhaled corticosteroid or bronchodilator. Two studies showed significant improvement with oxatomide as judged subjectively by physicians. Adverse events, analysed using data from 4 parallel and one cross over study, showed oxatomide to be associated with a significantly higher risk of any adverse event (OR: 2.97, 95%CI: 1.69 to 5.22) and drowsiness (OR: 5.22,95%CI: 2.53 to 10.74). REVIEWER'S CONCLUSIONS: There is no evidence to show that oxatomide has a significant effect on the control of stable asthma. Some studies reported significant benefits in subjective parameters. There was improvement in some lung function outcomes reported, but this were not consistent across measures or studies and may represent reporting bias. Adverse events, including drowsiness, were significantly greater with oxatomide than placebo.

Treatment of childhood acute myelogenous leukemia with allogeneic and autologous stem cell transplantation during the first remission: a report from the Kyushu-Yamaguchi Children's Cancer Study group in Japan.

A total of 64 newly diagnosed acute myelogenous leukemia patients (except FAB M3 and/or Down syndrome) under 18 years of age were consecutively enrolled into the study. Patients having an HLA-identical sibling (allo group) were assigned to undergo allogeneic bone marrow transplantation (allo BMT) in the first complete remission (CR). Others (non-allo group) were assigned to undergo autologous peripheral blood stem cell transplantation (PBSCT) or autologous BMT (auto BMT). Conditioning regimen was busulfan + melphalan for all transplantation. Of 64 patients (allo group 24; non-allo group 40), 59 (92.2%) achieved a CR. Eighteen relapses occurred (allo group 4; non-allo group 14) and 6 died during the first CR. The 5-year event-free survival (EFS) rate was 53.3 +/- 6.4% at a median follow-up period of 45 months. The 5-year EFS rates of allo and non-allo groups were 70.8 +/- 9.3% and 43.0 +/- 8.1%, respectively (p = .08). The EFS rates at 5 years post-transplant for allo BMT from an HLA-identical sibling (n = 18), PBSCT (11), and auto BMT (6) were 88.1 +/- 7.9%, 41.6 +/- 19.7%, and 83.3 +/- 15.2%, respectively. The outcome of allo BMT was superior to that of autograft. Auto BMT rather than PBSCT might contribute to a long-term survival in case of no available HLA-identical siblings.

[Treatment and prognosis of children with relapsed non-Hodgkin's lymphoma--a report from CCLSG-NHL 890 Study. Children's Cancer and Leukemia Study Group (CCLSG)].

To address the issue of salvageability in relapsed children with NHL who had all received the same frontline therapy, we retrospectively studied the treatment response and the outcome of 27 children who relapsed following the CCLSG-NHL890 protocol. The reinduction rates and 3-year survival rates (mean +/- SD) were as follows: lymphoblastic lymphoma (LB, n = 9), 44% & 17 +/- 14%; leukemia lymphoma syndrome (LLS, n = 8), 25% & 0%; large cell lymphoma (LC, n = 3) 100% & 67 +/- 27%; Burkitt's lymphoma (B, n = 7) 0% & 0%. Thus, the salvageability of LC lymphoma was good, but the outcome of Burkitt's lymphoma was very poor. CCLSG-NHL960 protocol for LB lymphomas and intensive multiagent regimens for LC lymphomas produced favorable response rates, but the effect of the high-dose Ara-C regimen for Burkitt's lymphoma was not determined. The initial stages of the disease seemed to be associated with the patient outcome: the outcome of the patients in stage IV was inferior to that of patients in stages II or III. Other clinical variables, such as relapse sites, relapse time and BM rescue did not affect the patients' outcome.

EEG-Linked functional magnetic resonance imaging in epilepsy and cognitive neurophysiology.

The ability to trigger functional magnetic resonance imaging (fMRI) acquisitions related to the occurrence of EEG-based physiologic transients has changed the field of fMRI into a more dynamically based technique. By knowing the temporal relationship between focal increases in neuronal firing rates and the provoked focal increase in blood flow, investigators are able to maximize the fMR-linked images that show where the activity originates. Our mastery of recording EEG inside the bore of a MR scanner has also allowed us to develop cognitive paradigms that record not only the fMR BOLD images, but also the evoked potentials (EPs). The EPs can subsequently be subjected to localization paradigms that can be compared to the localization seen on the BOLD images. These two techniques will most probably be complimentary. BOLD responses are dependent on a focal increase in metabolic demand while the EPs may or may not be related to energy demand increases. Additionally, recording EPs require that the source or sources of that potential come from an area that is able to generate far-field potentials. These potentials are related to the laminar organization of the neuronal population generating that potential. As best we know the BOLD response does not depend on any inherent laminar neuronal organization. Therefore, by merging these two recording methods, it is likely that we will gain a more detailed understanding of not only the areas involved in certain physiologic events, e.g. focal epilepsy or cognitive processing, but also on the sequencing of the activation of the various participating regions.

Visual evoked potential (VEP) measured by simultaneous 64-channel EEG and 3T fMRI.

We present the first simultaneous measurements of evoked potentials (EPs) and fMRI hemodynamic responses to visual stimulation. Visual evoked potentials (VEPs) were recorded both inside and outside the static 3T magnetic field, and during fMRI examination. We designed, constructed, and tested a non-magnetic 64-channel EEG recording cap. By using a large number of EEG channels it is possible to design a spatial filter capable of removing the artifact noise present when recording EEG/EPs within a strong magnetic field. We show that the designed spatial filter is capable of recovering the ballistocardiogram-contaminated original EEG signal. Isopotential plots of the electrode array recordings at the peak of the VEP response (approximately 100ms) correspond well with simultaneous fMRI observed activated areas of primary and secondary visual cortices.

Improvement in CNS protective treatment in non-high-risk childhood acute lymphoblastic leukemia: report from the Japanese Children's Cancer and Leukemia Study Group.

BACKGROUND: Prevention of central nervous system (CNS) leukemia by early introduction of therapy to this sanctuary site is an essential component of modern treatment strategy for acute lymphoblastic leukemia (ALL). However, the optimal form of preventive CNS therapy remains debatable. PROCEDURE: To address this issue, we evaluated the efficacy of CNS preventive therapy for 572 children with ALL who achieved complete remission in the Children's Cancer and Leukemia Study Group (CCLSG) ALL874 (1987-1990) and ALL911 (1991-1993) studies. They received risk-directed therapy based on age and leukocyte count. In the ALL 874 study, the non-high-risk (low-risk [LR] + intermediate risk [IR]) patients were randomly assigned to the conventional cranial irradiation (CRT) regimen (L874A and I874A) and the high-dose methotrexate (HDMTX) regimen without CRT (L874B and I874B). The former patients received 18-Gy CRT plus 3 doses of intrathecal (i.t.) MTX and the latter patients received 3 courses of HDMTX at 2 g/m2 plus 13 doses of ITMTX (L874B) or 4 courses of HDMTX at 4.5 g/m2 plus 1 dose of ITMTX (I874B). RESULTS: The 7-year probabilities (+/- SE) of CNS relapse-free survival were 97.3% +/- 2.6% (L874A, n = 41) vs. 90.3% +/- 5.3% (L874B, n = 39) (P = 0.25) in the LR patients, and 100% (I874A, n = 55) vs. 78.5% +/- 6.5% (I874B, n = 54) (P = 0.002) in the IR patients. The corresponding disease-free survival (DFS) rates were 79.4% +/- 6.5% vs. 74.4% +/- 7.3% (P = 0.62) in the LR group and 63.3% +/- 6.8% vs. 58.3% +/- 7.2% (P = 0.66) in the IR group. Thus, the HDMTX regimen could not provide better protection of CNS relapse as compared with the CRT regimen, although their overall efficacy was not significantly different. In the ALL 911 study, intensive systemic chemotherapy with extended i,t, injections of MTX plus cytarabine achieved a high CNS relapse-free survival (98% +/- 1.9% at 7 years) and a favorable DFS (85.5% +/- 5% at 7 years) in the IR patients. The patients in the high-risk (HR) group in both ALL874 and ALL911 studies received the 18-Gy or 24-Gy CRT with intensive systemic chemotherapy. Their 7-year probabilities of CNS relapse-free survival ranged from 88% to 95%, among which the T-ALL patients had a risk of CNS leukemia, which was 3-4 times higher compared with B-precursor ALL patients. CONCLUSIONS: These results indicate that long-term intrathecal CNS prophylaxis as well as appropriate systemic therapy for the non-high-risk patients can provide protection against CNS relapse equivalent to that provided by cranial irradiation.

[Studies of childhood non-Hodgkin's lymphoma--treatment results with the CCLSG NHL 960 protocol. Children's Cancer and Leukemia Study Group (CCLSG)].

We report here on the preliminary treatment findings of a CCLSG NHL 960 study that was initiated in March 1996. In this study, 37 patients with non-Hodgkin's lymphoma were assigned to 4 different treatment groups according to disease stage and histology: (1) localized disease; (2) advanced disease, lymphoblastic type; (3) advanced disease, large cell type; and (4) advanced disease, Burkitt type. The first three groups received the modified protocols of the NHL 890 study. Groups 1 and 3 received COPADM induction therapy (CPM, VCR, PRD, ADR, and MTX). After achieving remission, Group 1 received only maintenance therapy consisting of alternate administration of 7 drugs, while Group 3 received additional intensification therapy with combination chemotherapy consisting of MTX and Ara-C, followed by a maintenance phase involving the administration of 9 drugs. Group 2 received COPADL induction therapy (CPM, VCR, PRD, ADR, and LASP) and consolidation/intensification therapies followed by a maintenance phase. Group 4 received short-term intensive COPADM polychemotherapy. Twelve patients with localized with localized disease (stage I-II) and 25 patients with advanced disease (stage III-IV) were enrolled in this study. Except for 2 patients in the advanced disease stages who died earlier in the course of the study, all patients remained in remission.

[Bone marrow relapse in high-risk pediatric patients with acute lymphoblastic leukemia: a comparison of relapse times and initial clinical features of patients on different protocols. Children's Cancer and Leukemia Study group (CCLSG)].

To clarify the efficacy of modern intensive chemotherapy for ALL patients with unfavorable features, we compared the time to failure and initial clinical features of children who relapsed in the bone marrow or combined sites, as documented by early CCLSG studies (H811 and H851; 1981-1987) and later studies (H874 and H/HH911; 1987-1993) concerning high-risk ALL patients. In the later studies patients outcomes with new intensive regimens employing early intensification and reinduction therapy were apparently better than those of patients in the early studies with conventional regimens. When we compared the number of relapsed patients based on duration of first remission, we found that the improved outcomes for patients in the later studies were due to a decrease in the number who relapsed 7-36 months after the start of treatment (intermediate relapse), and that the percentage of those who relapsed within the first 6 months of therapy (early relapse) was higher. Patients with high initial WBC counts tended to relapse much earlier than those with low initial WBC counts. However, in the later studies, patients with high WBC counts often relapsed after the termination of therapy (late relapse). These results suggest that the intensive chemotherapy regimens used in the later studies can prevent the development of drug resistant leukemic clones, except in extremely high-risk patients likely to relapse within the first 6 months of therapy.

[Partial status epilepticus developed 41 years after psychosurgery--an electroencephalographic and neuropathological study].

The authors report an 85-year-old man with schizophrenia, who had undergone bilateral frontal gyrectomy at the age of 44 and had a single series of convulsions 6 months after the psychosurgery. Forty-one years later, he had developed partial seizures with secondary generalized seizures, and died of partial status epilepticus. Ictal EEG showed generalized high-amplitude spikes or sharp waves spreading from the left frontal region. Interictal EEG showed slowing of background activity and high-amplitude paroxysmal discharges on the left frontal and central regions. Postmortem examination of the brain revealed tissue defects in the superior and middle frontal gyri caused by resection at the time of gyrectory and old cysts in the deep frontal white matter as late sequelae of the psychosurgery. There was fibrillary gliosis in the surrounding cerebral convolutions and the deep white matter. We considered that the glial scar in the frontal lobes, on the left side in particular, had developed the epileptogenic focus. The pathophysiological mechanism by which the intractable epileptic seizures appeared 41 years after psychosurgery is discussed.

Occurrence of acute megakaryoblastic leukemia in a patient with idiopathic growth hormone deficiency.

We describe a case of a 15 year old boy who developed acute megakaryoblastic leukemia (AMKL) while receiving treatment with human growth hormone (hGH) for idiopathic growth hormone deficiency (GHD). He was diagnosed as having idiopathic GHD and given hGH from December 1991. The examination of his peripheral blood showed mild pancytopenia 2 months before the start of the hGH therapy. Since January 1992, paleness of the skin, general fatigue and fervescence progressed gradually. In February 1992, because of the occurrence of acute leukemia, administration of hGH was discontinued. Judging from the results of surface marker analysis of the blast cells, the patient was diagnosed as having AMKL. He was treated with chemotherapy for acute non-lymphoblastic leukemia from March 1992. A complete remission was obtained after 4 weeks of treatment. The chemotherapy was completed in July 1993. He remains in complete remission 26 months after diagnosis. This case suggests the importance of hematological examination and, when there is any abnormality which is not caused by GHD, such as pancytopenia, more detailed medical examinations (for example bone marrow examination) are necessary.

Asymmetrical blood flow in the temporal lobe in the Charles Bonnet syndrome: serial neuroimaging study.

Clinical features and results of neuroimagings of an 86 year old woman with the Charles Bonnet syndrome are reported. She had become completely blind bilaterally due to cataracts and glaucoma. Shortly after an operation for cataracts, she developed visual hallucinations which lasted for 22 years. She had no deterioration of intelligence. Computed tomography (CT) and magnetic resonance imaging (MRI) showed moderate generalized atrophy, particularly of the temporal lobes. A serial single photon emission computed tomography (SPECT) study during visual hallucinations demonstrated hyperperfusion in the left temporal region and the basal ganglia and hypoperfusion in the right temporal region. These findings suggest that asymmetrical blood flow, particularly in the temporal regions, may be correlated with visual hallucination in the Charles Bonnet syndrome.

Effects of acetyl-L-carnitine on the brain lipofuscin content and emotional behavior in aged rats.

The effects of long-term dosing with acetyl-L-carnitine (ALC) were examined in aged rats, and they were compared with those in young rats. ALC significantly reduced the lipofuscin deposition in the brain of aged rats. Emotional parameters such as locomotor activity and rearing behavior are lower in aged rats than in young rats, and these behaviors decreased in both age groups during the experiments. ALC diminished the decrease of these emotional behaviors, especially in rearing behavior in the aged rats. Furthermore, ALC had no effect on body weight gain. These results might reflect one of the main beneficial pharmacological mechanisms of ALC in clinical use.

[Pharmacological studies on Y-8894. (VIII). Effects on learning and memory in the radial maze task in mice].

Effects of Y-8894 on learning and memory were studied using a radial maze task in intact and scopolamine-induced amnesic mice. The following results were obtained: 1) Repeated administration of Y-8894 (1, 2.5 and 5 mg/kg, i.p.) significantly increased the number of initial correct responses (ICR) in the training session in intact mice, facilitating the learning of the maze task. Dihydroergotoxine (5 mg/kg, i.p.) significantly facilitated the learning of this task in the initial stage of the training session, but non-specifically inhibited the performance in the late stage of training. Ca-hopantenate did not modify the learning of this task. 2) A single administration of Y-8894 (2.5 or 5 mg/kg, i.p.) showed an antagonistic effect on scopolamine (1 mg/kg, s.c.)-induced amnesic mice. Dihydroergotoxine (5 mg/kg, i.p.) and Ca-hopantenate (500 mg/kg, i.p.) also significantly antagonized the ICR-decreasing effect of scopolamine. These results suggest that Y-8894 has an ameliorative and/or facilitative effect on learning and memory in the radial maze task, and Y-8894 is more potent than dihydroergotoxine and Ca-hopantenate.

[Pharmacological studies on Y-8894. (VII). Effects on transient cerebral ischemia-induced amnesia in rats].

The effects of Y-8894 on experimental amnesia in rats induced by transient cerebral ischemia (600 sec) according to the method of Pulsinelli and Brierley were studied using the one trial passive avoidance response and the pole climbing discrete avoidance response. All drugs were administered to the rats immediately after recirculation. The following results were obtained: 1) In the one trial passive avoidance response test, Y-8894 (2.5, 5 and 10 mg/kg, i.p.) improved significantly the decreased latency induced by the ischemia, and it was most effective at 5 mg/kg. Calcium-hopantenate (100, 250 and 500 mg/kg, i.p.) and dihydroergotoxine (5 and 10 mg/kg, i.p.) tended to increase the latency. On the other hand, physostigmine (0.025, 0.05 and 0.1 mg/kg, i.p.), a cholinesterase inhibitor, increased the latency significantly, and it was most effective at 0.05 mg/kg. 2) The pole climbing discrete avoidance response was significantly decreased by the ischemia compared with the sham operated group, and Y-8894 (5 mg/kg, i.p.) tended to improve this decreased avoidance response. 3) Y-8894 (5 mg/kg, i.p.) facilitated recovery from the changes in glycolytic metabolism, and inhibited the accumulation of choline due to the dysfunction of the neuronal membranes induced by the ischemia. These results show that Y-8894 has beneficial effects on experimental amnesia induced by transient cerebral ischemia.

[Pharmacological studies on Y-8894 (VI). The effect on monoamine uptake and turnover in mouse brain].

The effect of Y-8894 (+/-) 2-[[o-(2-thenyl)phenoxy]methyl] morpholine maleate, which has been shown to improve experimentally induced learning and memory deficits, on cerebral monoamine uptake and turnover was studied in the mouse. The following results were obtained: 1) It inhibited in vitro norepinephrine (NE) uptake to the mouse cerebral synaptosomal fractions about 800 and 1250 times more potently than it did those of dopamine (DA) and serotonin (5-HT), respectively. 2) It dose-dependently inhibited in vivo NE uptake, but not DA or 5-HT uptake. 3) It reduced the accumulation of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), increased that of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and had no effect on that of the DA metabolite, homovanillic acid (HVA). These effects were compared with those of imipramine, calcium hopantenate (Ca-hopantenate) and dihydroergotoxine. Y-8894 appeared to act by stimulating the noradrenergic receptor, and it acts to a lesser extent by blocking the serotonergic receptor in the brain.

[Pharmacological studies on Y-8894. (V) Effect on learning and memory in intact and experimentally amnesic rats].

The effects of Y-8894 on learning and memory were studied using the pole climbing avoidance (PCA) response in intact and experimentally induced amnesic rats. The following results were obtained: A single administration of Y-8894 (2.5 mg/kg, i.p.) to experimentally induced amnesic rats significantly antagonized the decrease in the mean number of PCA responses induced by an electroconvulsive shock (ECS). At a higher dose (10 mg/kg, i.p.), however, this effect was reduced. Repeated administration of Y-8894 (5 mg/kg, i.p.) significantly antagonized the facilitation of the extinction of the PCA response induced by exposure to CO2. Repeated administration of Y-8894 (2.5 mg/kg, i.p.) significantly facilitated the learning of the PCA response in intact rats. At a higher dose (5 mg/kg, i.p.), however, this effect was reduced. A single administration of Y-8894 (5 mg/kg, i.p. and 25 mg/kg, p.o.) significantly delayed the extinction of the PCA response in intact rats. These results suggest that Y-8894 has an ameliorative and facilitative effect on learning and memory in experimentally induced amnesic and intact rats.

[Pharmacological studies on Y-8894. (IV). Ameliorative effect on a cerebral energy metabolism disorder induced by KCN].

The amelioration of energy metabolic disturbance in cerebral anoxia is valuable for the treatment of various cerebral ischemic diseases and insufficiency. In this study, the effect of Y-8894 on the cerebral energy metabolism was investigated using a KCN-induced cerebral anoxia model with mice. The intravenous injection of a lethal dose of KCN (2.5 mg/kg) induced rapid and marked decreases of brain glucose, phosphocreatine and ATP contents, with a remarkable enhancement of lactate and AMP levels, indicating a severe disorder of the cerebral energy metabolism. This phenomenon was also shown by an irreversible deterioration of the energy charge potential (ECP), an index of the cerebral energy state. The treatment with Y-8894 (30 mg/kg, i.p.) remarkably ameliorated this KCN-induced energy metabolic disturbance: markedly reducing the changes in brain phosphocreatine, glucose and lactate contents, while keeping ATP, AMP and ECP at nearly their normal levels. In addition, these changes in the Y-8894 treated group recovered promptly to normal, whereas those in the control group were irreversible. In normal mice, Y-8894 induced a significant increase in the cerebral glucose content without affecting either the cerebral glycolytic metabolism or the energy state. The present findings suggest that Y-8894 has an ameliorative effect on the cerebral energy metabolic disturbance, and this effect likely plays an important role in the improvement of amnesia and other neurological deficits related to cerebral anoxia.