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Dexmedetomidine is an alpha 2 agonist and has been reported to have proconvulsant actions. To investigate the interaction of dexmedetomidine with convulsant anaesthetics, we studied effects on seizure threshold in cats during enflurane anaesthesia. Cats were prepared with chronic implantation of electrodes for recording of the cortical electroencephalogram (EEG) and midbrain reticular formation multi-unit activity (R-MUA). Seizure threshold, the reciprocal of the number of electrical stimuli required to induce generalized EEG seizure activity x 1000 (seizure induction index (SII)), was assessed. The effects of dexmedetomidine 1, 10 and 100 micrograms kg-1 i.v. and yohimbine 500 micrograms kg-1, an alpha 2 antagonist, on SII during 3.5% enflurane anaesthesia were investigated. Dexmedetomidine significantly increased SII at 10 and 100 micrograms kg-1, and this effect was reversed by yohimbine. We found that high-dose dexmedetomidine reduced seizure threshold during enflurane anaesthesia.

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UNLABELLED: Xenon (Xe) suppresses wide dynamic range neurons in cat spinal cord to a similar extent as nitrous oxide (N2O). The antinociceptive action of N2O involves the descending inhibitory system. To clarify whether the descending inhibitory system is also involved in the antinociceptive action of Xe, we compared the effects of Xe on the spinal cord dorsal horn neurons with those of N2O in spinal cord-transected cats anesthetized with alpha-chloralose and urethane. We investigated the change of wide dynamic range neuron responses to touch and pinch by both anesthetics. Seventy percent Xe significantly suppressed both touch- and pinch-evoked responses in all 12 neurons. In contrast, 70% N2O did not show significant suppression in touch- and pinch-evoked responses. These results suggest that the antinociceptive action of Xe might not be mediated by the descending inhibitory system, but instead may be produced by the direct effect on spinal dorsal horn neurons. IMPLICATIONS: Xenon (Xe) is an inert gas with anesthetic properties. We examined the antinociceptive effects of Xe and nitrous oxide (N2O) in spinal cord-transected cats. Our studies indicate that Xe has a direct antinociceptive action on the spinal cord that is greater than that of N2O.

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We have compared the effects of xenon and nitrous oxide on central nervous system (CNS) electrical activity during sevoflurane anaesthesia in cats by recording the electroencephalogram (EEG), multi-unit activity of the midbrain reticular formation (R-MUA) and somatosensory evoked potentials (SEP). Basal anaesthesia with 2% and 5% sevoflurane was used. With 2% sevoflurane, 70% xenon initially produced rhythmic slow waves which were followed by bursts of high-amplitude sharp waves interrupted by low amplitude slow waves on the EEG. Xenon induced an initial increase, followed by a decrease in R-MUA. Nitrous oxide 70% decreased the amplitude of the EEG activity which was associated with an increase in R-MUA. Xenon suppressed the amplitude of both the initial positive and negative deflections of the SEP to a greater extent than nitrous oxide. With 5% sevoflurane anaesthesia, both anaesthetics increased the frequency of spikes on the EEG and facilitated R-MUA. These findings indicate that xenon has a stimulatory action on CNS background activity and a suppressive action on CNS reactive capability which is more potent than that of nitrous oxide.

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Primary familial and congenital polycythaemia (PFCP) is a rare disease characterized by congenital erythrocytosis inherited in an autosomal dominant fashion. Recently, mutations in the erythropoietin receptor (EpoR) have been identified in PFCP families. We describe a Japanese family with an autosomal dominant inheritance of PFCP. An in vitro colony assay demonstrated hypersensitivity of erythroid progenitors to erythropoietin (Epo) in affected family members. Sequence analysis of RT-PCR products amplified from the C-terminal region of EpoR transcripts in affected family members revealed that they were all heterozygous for C and T bases at position 5986, which suggested a genetic mutation (C to T) on one allele of EpoR. This mutation gave rise to a translation termination codon TAG at amino acid 435. Thus, the resulting EpoR is a truncated protein product lacking all 74 amino acids downstream of the mutation. To date, all genetic mutations affecting a family with PFCP, including this one, have been located in the cytoplasmic negative regulatory region of the EpoR. All mutations gave rise to truncated Epo receptors between Tyrosine 427 and Tyrosine 455. The phosphotyrosines in this region of EpoR have been demonstrated to be binding sites for SHP-1 phosphatase. Therefore PFCP is presumably brought about as a result of genetic mutations which cause the loss of the SHP-1 binding site in the cytoplasmic region of EpoR.

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We compared the effects of xenon (Xe) on the spinal cord dorsal horn neurons with those of nitrous oxide (N2O) in cats anesthetized with chrolarose and urethane. We assessed the potency of both anesthetics by the inhibition of wide dynamic range neuron responses evoked by cutaneous noxious (pinch) stimulation to a hindpaw. During 70% Xe inhalation, the responses of 7 of 11 neurons to pinch stimulation were suppressed. N2O, 70%, suppressed it in 8 of 11 neurons. The potency of Xe and N2O was compared in six neurons that were suppressed by both anesthetics. After 20 min of Xe inhalation, the response to pinch was suppressed to 49.5% +/- 8.2% (mean +/- SE), while N2O, 70% in oxygen, suppressed it to 45.9% +/- 7.9%. The difference between N2O and Xe was not significant. We conclude that Xe and N2O suppress the spinal cord dorsal horn neurons to a similar degree.

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Treatment results were evaluated in 45 children with acute myeloblastic leukemia (AML) treated on the ANLL-9205 protocol of the Children's Cancer Leukemia Study Group (CCLSG, Japan). In this protocol, terarubicin (THP-ADR), vincristine and continuous infusion of cytosine arabinoside (Ara C) were applied for remission induction therapy (AVC), and VP16+ high dose Ara C were used sequentially for 32 or 48 weeks. Eleven patients received stem cell transplantation. Thirty-eight out of the 43 eligible patients (88.4%) achieved complete remission, and the overall 3-year event-free survival (EFS) was 55.6% (S.E.,10%). This favorable response was attributed mainly to the high induction rate of patients with the M5, M7 FAB subtypes and higher WBC counts (> or = 10 x 10(9)/L). There was no difference in the 3-year EFS of these patients who discontinued treatment between 32 weeks and 48 weeks. Serious toxicities were not observed in this study. These findings suggest that the ANLL-9205 protocol is an effective and safe treatment regimen for childhood AML. When comparing the treatment period of 32 or 48 weeks, the difference was not statistically significant.

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In January 1985, a single protocol consisting of cyclophosphamide, vincristine, tetrahydropyranyl adriamycin, and cis-platinum for the treatment of advanced neuroblastoma was begun nationwide in Japan and was found to improve clinical results significantly in terms of 2- or 3-year survival rate. Between January 1985 and December 1988, 113 eligible patients (7 infants younger than 12 months of age with stage IVA disease and 106 patients aged 12 months or older with stage III or IV disease) were enrolled and followed up for 5 years or more after initiation of treatment, as of March 1994. In this study, the usefulness of the protocol for the treatment of advanced neuroblastoma was evaluated with survival rates in relation to age, tumor site, stage, and N-myc amplification for patients surviving more than 5 years after initiation of the protocol. Fifty of the 113 patients were alive 5 years or more after initiation of the treatment, 39 without any episodes of disease recurrence. Fourteen (70%) of 20 patients with stage III, 6 (50%) of 12 with stage IVB, and 24 (30%) of 81 with stage IVA disease were alive and disease-free 5 years after initiation of the protocol. Twenty (56%) of 36 patients without N-myc amplification were alive at 5 years after initiation of the protocol. Only one patient who was alive without evidence of the disease at 5 years had recurrence afterward.

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Effect of nitrous oxide (N2O) on the somatosympathetic A- and C-reflexes was investigated using artificially ventilated rats anesthetized with alpha-chloralose and urethane. Somatocardiac sympathetic A- and C-reflexes were elicited in the inferior cardiac nerve by electrical stimulation of A and C afferent fibers of the tibial nerve, respectively. Both reflexes were depressed by inhalation of N2O for 20 min. The depression was greater in the C-reflex than in the A-reflex. The depressive effects of N2O on both reflexes were unchanged after pretreatment with intravenous naloxone (0.2 or 2.0 mg/kg) or by prolongation of the inhalation of N2O for 2 h. These results suggest that the opioid receptor is not involved and that acute tolerance is not developed in the depressive action of N2O on the somatosympathetic A- and C-reflexes.

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Superinduction of human interferon-beta (HuIFN-beta) from human glioma cells has greater cytotoxicity than purified HuIFN-beta derived from fibroblasts. However, superinduction requires several reagents like polyI:polyC, cycloheximide, and actinomycin D, which may contaminate the conditioned medium and obscure the effect of superinduced HuIFN-beta. The present study used minimum doses of polyI:polyC and cycloheximide without actinomycin D to superinduce HuIFN-beta. The superinduced HuIFN-beta was purified by passing the medium through molecular sieve column chromatography. Fractionation of the eluate provided semipurified superinduced HuIFN-beta which demonstrated a growth inhibitory effect against both the U251-MG autologous human glioma cell line and the SK-MG-1 homologous glioma cell line. This effect was neutralized by addition of anti-HuIFN-beta monoclonal antibody (YSB-1). In a separate experiment, combinations of superinduction reagents were found not to have growth inhibitory effects because all inhibition in superinduced medium was completely neutralized by YSB-1. Superinduced HuIFN-beta has a pure growth inhibitory effect on both autologous and homologous glioma cells, so may affect autocrine secretion of cytokines.

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A 5 year old female developed femoral pain, fever, and hemorrhagic tendency. She was diagnosed as having acute promyelocytic leukemia (APL). Approximately 2 weeks after the administration of all-trans retinoic acid (ATRA), she developed a high fever, edema, and respiratory distress which met the criteria for retinoic acid syndrome. At first, we tried to treat the patient with oral corticosteroid, however, this approach was unsuccessful. Considering the worsening of her condition, we then chose to administer a large dose of intravenous dexamethasone therapy for 3 days. Immediately after this therapy, she became afebrile, respiratory distress and edema disappeared, and there was a general improvement of the symptoms. All-trans retinoic acid at the reduced dose of 25 mg/m2, was continued for an additional 6 weeks and then discontinued. Since the cessation of dexamethasone and ATRA, there has been no relapse of APL in this patient. Although based on only one case, we recommend the intravenous high-dose dexamethasone pulse therapy (13 mg/m2 per day, for 3 days) for treating retinoic acid syndrome which develops in pediatric APL patients treated with ATRA.

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Glycoproteins are metabolized through an asialoglycoprotein metabolic pathway in vivo. They are desialylated and taken up by the liver via an asialoglycoprotein receptor. Fibroblast-derived natural human interferon-beta is a glycoprotein having a single asparagine-linked sugar chain. Although natural human interferon-beta may also be metabolized through this pathway, there is very little information about the biologic features of human asialointerferon-beta. We evaluated the pharmacokinetics and biologic activities of human native and asialointerferon-beta s. After intravenous administration to rabbits, human asialointerferon-beta was cleared from the blood circulation faster than the human native interferon-beta. More asialoprotein was distributed to the liver than the native type, but it induced less 2'5'-oligoadenylate synthetase. The human asialointerferon-beta had less activity than the human native interferon-beta on cell growth inhibition and 2'5'-oligoadenylate synthetase induction in Hep-G2 and HuH6 human hepatoblastoma cells. Southern blotting using a hepatitis B virus-transfected HuH6 cell line, HB611, revealed that the inhibition of hepatitis B virus DNA replication by the asialoprotein was weaker than that by the native protein. The results showed that the different effects exerted by the human native and asialointerferon-beta s may be a result of recognition of the sugar chains by rabbit hepatocytes or by human hepatoblastoma cells. The results also suggested that the terminal sialic acid of the sugar chains in natural human interferon-beta significantly affects its pharmacokinetics and biologic activities.

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Mouse Ehrlich ascites tumor cells secrete a 100 kD protein when they are stimulated by murine interferon-beta (2000 IU/ml). This 100 kD protein was purified from conditioned medium by chromatography on phenyl-Sepharose CL-4B, phosphocellulose, DEAE-Sephacel, and Vydac C4 columns and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A single species of 100 kD protein was isolated, and its N-terminal sequence analysis suggested that mouse Ehrlich ascites tumor cell-derived interferon-induced 100 kD protein is a novel protein.

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From 1985 to 1989, 69 patients with non-Hodgkin's lymphoma (NHL) were treated by members of the Children's Cancer and Leukemia Study Group of Japan with a protocol consisting of vincristine, prednisolone, cyclophosphamide, doxorubicin, high-dose methotrexate (HD-MTX), mercaptopurine and cytarabine; central nervous system (CNS) prophylaxis with intrathecal MTX and hydrocortisone (NHL855). The 4-year event-free survival (EFS) was 78% (S.E., 10%) for patients with localized disease (n = 18) and 38% (S.E., 7%) for those with advanced disease (n = 51). Among the patients with advanced disease, those with non-lymphoblastic lymphoma tended to have a better 4-year EFS than those with lymphoblastic lymphoma (52% vs. 25%). Based on these findings, we initiated a new protocol NHL890 in which patients were assigned to two different chemotherapies according to the histology. Non-lymphoblastic subtype was treated almost identically to NHL855 while asparaginase and VP-16 were newly added in the consolidation-maintenance phase in advanced-stage lymphoblastic lymphoma. Sixty-seven patients with advanced disease were assessable. The overall 4-year EFS for advanced disease improved to 69% (S.E., 6%). A significant improvement was gained in the lymphoblastic lymphoma with a 4-year EFS of 56% (S.E., 11%) as compared with 25% (S.E., 9%) in the preceding study (P < 0.05). These findings suggest the importance of histology in the treatment of advanced-stage non-Hodgkin's lymphoma in childhood.

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To evaluate the relationship between the sugar chain structure and biological activity, fibroblast-derived glycosylated human interferon-beta, Chinese hamster ovary cell-derived glycosylated recombinant human interferon-beta and Escherichia coli-derived unglycosylated recombinant human interferon-beta were evaluated using human hepatoblastoma cells in vitro. Native fibroblast interferon-beta expressed more cell-growth inhibitory action, 2'5'-oligoadenylate synthetase induction, and the inhibition of hepatitis B virus DNA replication than its asialoform and two recombinant interferon-betas. These results showed that the sugar chain structure of human interferon-beta affects its biological activity on human hepatoblastoma cells.

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Among 484 male patients with acute lymphoblastic leukemia (ALL) registered into the protocols CCLSG 811, 841 and 874, from 1981 through 1990, 246 patients completed their protocols and were in continuous complete remission (CCR) for more than 3 years. One hundred and seven patients received bilateral testicular biopsies at the time of cessation of maintenance chemotherapy. Eight patients (7.5%) were found to have occult testicular leukemia (TL). Three of them did not receive any additional therapy and all suffered subsequent relapses; one bone marrow relapse and two testicular relapses. The other 3 patients received testicular radiation combined with an additional 2 years of chemotherapy, resulting in CCR for more than 6 years 10 months, 7 years 6 months, and 8 years 6 months. One with chemotherapy alone and another with radiation alone showed subsequent relapse. Overt TL after negative initial biopsy was developed in 3 (3.0%) of the 99 patients. All of them received testicular radiation with chemotherapy, resulting again in CCR for more than 1 year 0 months and 5 years 3 months; one patient showed relapse in testes and bone marrow after 3 years 8 months of CCR. These studies suggested that occult TL has an adverse prognostic significance unless retrieval chemotherapy is given and that performance of testicular biopsy at completion of maintenance chemotherapy is not contributory to prolongation of disease-free survival for males with ALL because the treatment employing testicular radiation plus retrieval chemotherapy for both occult TL and isolated overt TL after off-therapy is similarly very effective.

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In 1985, a nationwide single protocol (cyclophosphamide, vincristine, tetrahydropyranyl Adriamycin, and cisplatin) for the treatment of advanced neuroblastoma was begun in Japan and was found to significantly increase the 3-year survival rate--to 70% for stage III, and to 45% for stage IV. In this study, the authors investigated the efficacy of this protocol for advanced neuroblastoma with or without N-myc amplification. In 159 of the 233 patients with advanced neuroblastoma treated with this protocol (between January 1985 and March 1993), genomic amplification of N-myc was determined. These 159 patients were divided into two groups according to the number of N-myc copies, ie, those with fewer than 10 copies (105 patients) and those with 10 or more copies (54 patients). The survival curves for the two groups were significantly different. The 5-year survival rate for patients with 10 or more copies was 43.9%; this is surprisingly high in comparison to results of previous studies in which no survivors were expected in cases of advanced neuroblastoma with highly amplified N-myc. Persistent bone marrow suppression was common, but there were no deaths attributable to drug side effects. Five patients with fewer than copies of N-myc amplification died more than 3 years after initial treatment. Three of the five had tumors with an unfavorable Shimada classification, and two had diploid nuclear DNA content. The authors conclude that the protocol resulted in dramatic improvement in the patients with advanced neuroblastoma, even with high N-myc amplification.(ABSTRACT TRUNCATED AT 250 WORDS)

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The clinical characteristics and treatment outcome in 40 children with acute promyelocytic leukemia (APL) treated at institutions participating in the Children's Cancer and Leukemia Study Group (CCLSG) were studied retrospectively. The median age at diagnosis was 8 years old. Bleeding diathesis was the predominant presenting symptom (90%), associated with laboratory findings of disseminated intravascular coagulation. Hepatomegaly, splenomegaly and lymphadenopathy were observed in 35%, 10%, and 15% of the cases, respectively. The median WBC count was 4.25 x 10(9)/l. Anemia (hemoglobin < 8 g/dl) and thrombocytopenia (< 30 x 10(9)/l) were present in more than half of the patients. Cytogenetic studies demonstrated the characteristic 15; 17 translocation in about 90% of the patients analyzed. Induction therapy consisted of cytosine arabinoside and an anthracycline, with or without other agents. Twenty-nine patients (73%) achieved complete remission (CR) while early fatal hemorrhage was the predominant cause of induction failure. The survival rates continued to decrease (28% at 3 years, 24% at 5 years, and 7.9% at 10 years) due to late marrow relapses. Anthracycline cardiotoxicity was fatal in three patients in remission. These clinical features of childhood APL should be taken into account in the development of new protocols.

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The expression of cytoplasmic antigens in 77 cases of acute leukemia were analyzed by flow cytometry using the following monoclonal antibodies: CD3, CD22, anti-myeloperoxidase (MPO-7) and anti-mu-heavy chain. CD22 antigen was detected in the cytoplasm of all non-T-ALL patients excluding one not-tested patient. In two patients with unclassified ALL, surface CD22 antigen was not expressed but cytoplasmic CD22 antigen was strongly expressed. Three out of 9 patients with common ALL were cytoplasmic mu-heavy chain-positive, so these patients were diagnosed as Pre-B ALL. In four out of 8 patients with T-ALL, CD3 antigen was not expressed on the cell surface membrane. However all of T-ALL patients excluding one non-tested patient were cytoplasmic CD3-positive. The cytoplasmic expression of myeloperoxidase antigen was detected in twenty out of 21 patients with acute non-lymphoblastic leukemia (ANLL). One megakaryocytic leukemia patient was MPO-negative. In two ANLL patients, the percentage of MPO for conventional cytochemical staining was undetectable or low, but MPO antigens were positive (77% and 70%) for flow cytometric analysis. All of 46 non-T ALL patients were cytoplasmic MPO-negative, however 4 out of 10 T-ALL patients were cytoplasmic MPO-positive. The study proved that the analysis of cytoplasmic CD3, CD22, mu-chain and MPO antigens were very useful to define the cell lineage of leukemia and to classify ALL and ANLL. It is necessary to study further whether the expression of MPO in the cytoplasm of T-ALL was non-specific reaction or whether MPO precursors are expressed in the cytoplasm of T-ALL.

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The crystal structure of recombinant murine interferon-beta as elucidated by Senda et al. (Proc. Jap. Acad. 66B: 77-80 (1990); EMBO J. 11: 3193-3201 (1992)) appears to represent the basic structural framework of all Type I interferons including interferons-beta and all subtypes of interferons-alpha of various mammalian origin. Now the huge accumulated data on the structure-activity relationship of Type I interferons using various chemical and genetic techniques can be systematically evaluated in terms of the three-dimensional structure. Structural comparison with other cytokines, for which three-dimensional structures have been established, including interferon-gamma and considerations on the evolution of cytokines and cytokine receptors are also given.

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