Direct evidence of electronic ferroelectricity in YbFe2O4 using neutron diffraction and nonlinear spectroscopy.

We report the first observation of room temperature spontaneous electric polarization in an electronic ferroelectric material, a YbFe2O4 single crystal. The observation was based on second harmonic generation (SHG), a nonlinear optical process. Tensor analysis of the SHG signal revealed that this material has a polar charge superstructure with Cm symmetry. This result settles the long-term discussion on the uncertainty about electronic ferroelectric properties, including the charge order structure. We present a complete picture of the polar charge ordering of this material via consistent results from two different characterization methods. The SHG signal shows the same temperature dependence as the superlattice signal observed in neutron diffraction experiments. These results prove ferroelectric coupling to electron ordering in YbFe2O4, which results in electronic ferroelectricity which is enabled by the real space ordering of iron cations with different valences. The existence of electronic ferroelectricity holds promise for future electronics technologies where devices run a thousand times faster than frequency of the present CPU (a few gigahertz) embedded in smartphones, etc.

Six months of maintenance chemotherapy after intensified treatment for acute lymphoblastic leukemia of childhood.

PURPOSE: We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy. PATIENTS AND METHODS: Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92-13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis. RESULTS: The mean (+/- SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% +/- 3.4% and 81.5% +/- 2.2%, respectively, at 5. 5 years after diagnosis. EFS rates by risk category were similar (60. 2% +/- 6.0% for standard risk, 57.7% +/- 5.6% for high risk, and 62. 5% +/- 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% +/- 2.7%, 80.0% +/- 4.1%, and 72.1% +/- 4.5%, respectively, P <.0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% +/- 7. 9% (standard risk), 42.6% +/- 8.1% (high risk), and 9.6% +/- 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important. CONCLUSION: Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.

Delay of the diagnostic lumbar puncture and intrathecal chemotherapy in children with acute lymphoblastic leukemia who undergo routine corticosteroid testing: Tokyo Children's Cancer Study Group study L89-12.

PURPOSE: To determine the effects of eliminating initial lumbar punctures in 418 consecutively treated children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients were enrolled onto a trial conducted in central Japan between 1989 and 1992. Treatment consisted of standard four-drug induction therapy followed by a risk-based intensification phase, reinduction therapy, late intensification, and remission maintenance therapy (total of 104 weeks). The initial lumbar puncture, with an intrathecal injection of chemotherapy, was performed after 1 week of prednisolone sensitivity testing (day 8). End points included response to prednisolone, CNS status at the time of the day 8 lumbar puncture, subsequent adverse events in CNS and bone marrow, and event-free survival (EFS). RESULTS: The remission induction rate was 93.1% with a 6-year EFS rate (+/- SE) of 68.7% +/- 2.4%, which is similar to historical results for patients who received their diagnostic lumbar puncture and first instillation of intrathecal chemotherapy on day 0. Overall, 84.5% of the patients had good responses to prednisolone, whereas 15.5% had poor responses. Clinical outcome was strikingly better for the good responders (6-year EFS, 74.1% +/- 2.5% compared with 40.1% +/- 6.4% for patients with poor responses), suggesting that omission of intrathecal chemotherapy did not alter the predictive value of drug sensitivity testing. Eighteen patients experienced CNS relapse as their first adverse event (cumulative risk, 5.1%; 95% confidence interval, 2.7% to 7.4%), coincident with reports from groups using conventional strategies of CNS clinical management. Bleeding into the CSF at the time of the day 8 lumbar puncture was apparent in 29 cases (8.1%), but leukemic blasts were identified in only two. CONCLUSION: Delay of the initial lumbar puncture and intrathecal injection of chemotherapy seems to be feasible in children with ALL. Further controlled evaluations are needed to establish the validity of this conclusion.

An effective chemotherapeutic regimen for acute myeloid leukemia and myelodysplastic syndrome in children with Down's syndrome.

In recent pediatric collaborative studies of acute myeloid leukemia (AML), patients with Down's syndrome (DS) have better outcome than other patients when they were treated according to their intensive AML protocols. This may be attributed to enhanced sensitivity of DS AML cells to selected chemotherapeutic agents. We evaluated a less intensive chemotherapeutic regimen which was specifically designed for children with AML-DS. Remission induction chemotherapy consisted of daunorubicin (25 mg/m2/day for 2 days), cytosine arabinoside (100 mg/m2/day for 7 days), and etoposide (150 mg/m2/day for 3 days). Patients received one to seven courses of consolidation therapy of the same regimen. Thirty-three patients were enrolled on the study and their clinical, hematologic and immunophenotypic features were analyzed. Of the 33 patients, all were younger than 4 years and diagnosed as having acute megakaryoblastic leukemia or myelodysplastic syndrome. All patients achieved a complete remission and estimated 8 year event-free survival rate was 80+/-7%. Three patients relapsed and two died due to cardiac toxicity and one due to septic shock. The results of our study showed that patients with AML-DS constitute a unique biologic subgroup and should be treated according to a less intensive protocol designed for AML-DS.

Long-term follow-up of childhood acute lymphoblastic leukemia in Tokyo Children's Cancer Study Group 1981-1995.

The objectives were as follows: Firstly, to estimate the overall probability of event-free survival (EFS) and isolated CNS relapse in the studies for children with acute lymphoblastic leukemia (ALL) during the 1980s and 1990s. Secondly, to report the EFS according to presenting features and lineage. Thirdly, to evaluate the treatment results re-classified by the risks of NCI criteria. Four consecutive protocol studies were performed in the Tokyo Children's Cancer Study Group: L81-10 protocol (1981-1984, 189 patients), L84-11 (1984-1989, 484 patents), L89-12 (1989-1992, 418 patients) and L92-13 (1992-1995, 347 patients). Overall EFS at 5 years in each protocol was 56.5 +/- 3.8(1 s.e.)%, 71.0 +/- 2.1%, 67.8 +/- 2.3%, and 63.4 +/- 2.7%, respectively. The cumulative isolated CNS relapse rate at 5 years was 8.1 +/- 2.1%, 3.5 +/- 0.9%, 3.6 +/- 1.0%, 1.0 +/- 0.6. The EFS in SR/HR (standard risk/high risk) according to the NCI criteria in B-precursor ALL at 5 years was 61.9 +/- 4.3%/41.4 +/- 7.4% (lineage was not confirmed.), 72.5 +/- 2.6%/63.4 +/- 5.0%, 77.4 +/- 2.7%/56.3 +/- 4.7%, and 67.8 +/- 3.4%/56.7 +/- 5.4% in each protocol. Also EFSs according to NCI SR/HR at 5 years of T-ALL in protocols L84-11, L89-12 and L92-13 were 55.6 +/- 16.6%/60.9 +/- 10.1%, 72.7 +/- 13.4%/51.6 +/- 9.1%, and 77.1 +/- 14.4%/53.6/10.1%, respectively. The truncation of maintenance therapy to 6 months resulted in a decreased EFS in L92-13, particularly due to an increase of bone marrow relapse after cessation of therapy in SR and HR. The NCI risk criteria work properly even in the patients treated by different intensities, so that it makes the comparison possible among the patients in various groups. The overall EFSs in childhood ALL improved in 1980s, but it seemed stable or decreased in 1990s. The short maintenance therapy resulted in poor outcome in SR on the L92-13 protocol. Many of these late relapsers were effectively rescued and overall survival remained at a high level. The proportion of patients who received cranial irradiation reduced without any increase of the CNS events.

Ultrafast electronic state conversion at room temperature utilizing hidden state in cuprate ladder system.

Photo-control of material properties on femto- (10(-15)) and pico- (10(-12)) second timescales at room temperature has been a long-sought goal of materials science. Here we demonstrate a unique ultrafast conversion between the metallic and insulating state and the emergence of a hidden insulating state by tuning the carrier coherence in a wide temperature range in the two-leg ladder superconductor Sr(14-x)Ca(x)Cu24O41 through femtosecond time-resolved reflection spectroscopy. We also propose a theoretical scenario that can explain the experimental results. The calculations indicate that the holes injected by the ultrashort light reduce the coherence among the inherent hole pairs and result in suppression of conductivity, which is opposite to the conventional photocarrier-doping mechanism. By using trains of ultrashort laser pulses, we successively tune the carrier coherence to within 1 picosecond. Control of hole-pair coherence is shown to be a realistic strategy for tuning the electronic state on ultrafast timescales at room temperature.

Neutral-ionic phase separation and one-dimensional ferroelectricity in organic relaxors

Microscopic phase segregation by chemical doping and resultant anomalous dielectric response have been investigated for tetrathiafulvalene-p-chloranil complex doped with trichloro-p-benzoquinone ( QCl3). Beyond a critical QCl3 content, the system shows a behavior of relaxor ferroelectrics, as characterized by strong frequency dispersion and a rounded peak shape of gigantic dielectric susceptibility. The relaxor phase arises from one-dimensional ferroelectricity, as evidenced by a diffuse x-ray scattering, in which interchain ferroelectric coupling associated with neutral-ionic transition is interrupted by impurity-generated neutral microclusters.

Cord blood transplantation from sibling donors in Japan. Report of the national survey.

A joint national survey on cord blood transplantation (CBT) was conducted in Japan and 18 sibling CBTs were reported. Diseases of the patients were leukemia (ten), neuroblastoma (one), bone marrow failure (four) and inborn errors of metabolism (three). A volume of 50-141 ml of cord blood containing 27-197 x 10(7) nucleated cells was collected from sibling infants soon after delivery. HLA antigens were identical in 14 and one to three antigens mismatched in four. Engraftment of donor cord blood was achieved in 17 cases. Autologous hematopoiesis was recovered in one case. Days of engraftment were 13-29 days (median 19 days) for neutrophils (500/microliter), 18-67 days (median 30 days) for reticulocytes (2%) and 21-96 days (median 46 days) for platelets (50 x 10(3)/microliter). Acute GVHD was grade 0 in seven cases, grade I in five cases and grade II in one case in HLA-identical pairs, but became grade II in two cases and grade III in two cases in HLA-mismatched pairs. Chronic GVHD of limited type developed in two out of 17 evaluable cases, however both responded to immunosuppressive therapy. Altogether, 14 out of 18 patients are currently surviving 4-27 months following transplantation. Probabilities of overall survival and disease free survival were estimated to be 77.0 and 71.8% using Kaplan-Meier tests. These findings suggest the feasibility of cord blood transplantation from sibling donors and the possibility of unrelated cord blood transplantation. A cord blood banking system is necessary for the universal use of cord blood stem cells from unrelated donors.

Expression of MDR-1/P-glycoprotein in childhood acute megakaryoblastic leukemia cells.

Multidrug resistance is a major clinical problem in chemotherapy of malignant disease. Acute megakaryoblastic leukemia (AMKL) is a rare form of childhood leukemia, and is often more resistant to many anticancer chemotherapeutic drugs compared to other types of childhood leukemia. There have been reports of the increased expression in hematologic malignancy of multidrug resistant (mdr-1) gene, which encodes for a transmembrane glycoprotein P-glycoprotein that acts as an efflux pump for structurally unrelated chemotherapeutic drugs. We investigated the malignant cells of 15 newly diagnosed childhood AMKL patients by immunocytochemical analysis and found P-glycoprotein expression in all samples from these patients. RNA prepared from five patients at the time of presentation confirmed the expression of mdr-1 specific message in all cases by Northern blot analysis. These results imply that malignant cells from all childhood AMKL might express the mdr-1/P-glycoprotein.

Establishment of a new human megakaryoblastic cell line, CMY, with chromosome 17p abnormalities.

A new megakaryoblastic cell line CMY was established from a Down's syndrome patient suffering from acute megakaryoblastic leukemia. The karyotypes of CMY showed deletion of chromosome 17 or the translocation of 17p, whereas the blasts of the patient did not reveal these abnormalities of chromosome 17 by conventional karyotype analysis. Blasts of the patient failed to respond to chemotherapy and complete remission could not be attained. The abnormalities of 17p became progressively predominant in the patient. These results suggest that the blasts of a minor clone which had the abnormalities of chromosome 17p might have existed in the patient from the beginning and CMY was established from the minor clone. Investigation of p53 gene by PCR-SSCP analysis revealed that blasts of the patient showed normal patterns, while CMY showed an abnormally migrating band in exon 5 alone. This result suggests that another novel oncogenic factor(s) besides p53 might be present on chromosome 17p and other tumor suppresser genes need to be studied.

[The penetration of cefpiramide into the skin].

To investigate the skin penetration of cefpiramide (CPM, SM-1652), a broad-spectrum and long acting cephem antibiotic, 1 g of CPM was administered by single bolus intravenous injection to patients under general anesthesia during operations for full-thickness skin grafting. The CPM levels in both the serum and the skin were determined by bioassay at specified time intervals, and the following results were obtained. 1. Peak CPM concentrations in the serum (mean: 292.78 micrograms/ml) were observed 10 minutes after administration, and declined very slowly thereafter. 2. Peak CPM concentrations in the skin (mean: 23.05 micrograms/g) were observed 2 hours after administration, and then also declined very slowly. 3. The ratio of skin to serum concentrations was 16% when the peak CPM concentrations in the skin were obtained (2 hours after the administration). These results show that effective CPM concentrations were maintained in the skin for a long period, indicating a good therapeutic action against skin infections.

[Clinical studies on cefadroxil in pediatrics (author's transl)].

The present paper reports the results which were obtained in a clinical trial of cefadroxil (CDX), a new oral cephalosporin, in the pediatric field. (1) A total of 20 patients with infectious diseases including 9 urinary tract infection, 7 acute tonsillitis, 2 scarlet fever, 1 pyodermia and 1 recurrent bronchitis were treated with CDX. Of the 20 cases, the clinical response was excellent in 15 cases (75%), good in 4 cases (20%), and fair in 1 case (5%). (2) Efficacy classified by causative organisms was as follows; E. coli, 100%; S. pyogenes, 87.5%. (3) Neither adverse reactions nor abnormal laboratory results were observed.

[Clinical evaluation of cefpiramide in 6 cases of infection in children].

Cefpiramide (CPM) was given to 4 patients with respiratory tract infection (H. influenzae 3 cases, P. aeruginosa 1 case), 1 patient with enteritis (enteropathogenic E. coli) and 1 patient with sepsis (E. cloacae). Bacteriological eradication was observed in 5 cases (83.3%), and clinical effectiveness was 66.7%. Serum concentration of CPM at a dose of 15 mg/kg after intravenous drip-infusion for 30 minutes was 105 micrograms/ml at the end of infusion and 67 micrograms/ml at 1 hour. Bacteriological eradication by the administration of CPM was rapidly occurred in 3 strains of H. influenzae including 1 strain of beta-lactamase producing ABPC-resistant one, and 1 strain of P. aeruginosa in the sputum. One patient aged 2 years and 5 months with pneumonia was cured by the treatment of CPM as an outpatient. No side effects were observed except 1 case of vascular pain. It was concluded that CPM is a useful drug for the treatment of bacterial infections in children.

[Fundamental and clinical studies of ceftazidime in the field of pediatrics].

We have studied ceftazidime (CAZ), a cephem antibiotic of the new generation, for its antibacterial activity against H. influenzae and clinical effects. Antibacterial activity: MICs of CAZ for 142 strains of H. influenzae including 11 ABPC-resistant strains which were clinically isolated, were determined, and the results were good for all the strains. Clinical effects: CAZ was administered to 9 children with infections. Suspected causative organisms were H. influenzae, E. coli, P. aeruginosa, group B Streptococcus and S. pneumoniae. Eradication of these organisms was confirmed in all the strains except for one in which the antibacterial effect of CAZ was unknown. Clinical efficacy was excellent or good in all the cases. No side effect was observed except for eosinophilia noted in 1 case.

[Clinical studies of 9, 3"-diacetylmidecamycin (author's transl)].

1. We had a chance to administer the "MOM dry syrup' (MOM fine granules) to 22 patients: 6 patients with streptococcal infections and 16 patients with other respiratory tract infections. The clinical efficacy was good in 16 cases and its rate was 80%. 2. The causative organisms were isolated from 9 cases: 6 cases with S. pyogenes, 2 with S. pneumoniae and 1 case with B. pertussis. All of the clinical isolates were eradicated except for the S. pyogenes strains. 3. Any remarked side effects were not observed but only eosinophilia in 2 cases. 4. Because of no bitterness of the MOM dry syrup, all the children take it easily. 5. MOM was effective in all the cases of pertussis and Mycoplasma pneumoniae pneumonia. As for streptococcal and pneumococcal infections, it is necessary to administer MOM under the control of bacterial sensitivity.

[Hyperkalemia in a cyclosporine A-treated allogeneic bone marrow transplant recipient].

A 9-year-old boy was admitted with the diagnosis of myelodysplastic syndrome (FAB RAEB in T). The patient was treated with busulfan and cyclophosphamide and transplanted with bone marrow cells from an HLA identical sister. Cyclosporin A (CyA) and short term methotrexate (MTX) was given for prophylaxis against graft versus host disease (GvHD). The serum potassium value was observed to increase to 6.3 mEq/l during the period of CyA therapy. The serum potassium value returned to 4 mEq/l when CyA treatment was decreased to a serum concentration of less than 50 ng/ml (FPIA). On day 90 post transplantation the patient was diagnosed as relapsed. The patient was preconditioned with cyclophosphamide and total body irradiation and a second bone marrow transplantation was performed using cells from the same donor. He was treated again with CyA and short term MTX for the prevention of GvHD. Once again the patient became hyperkalemic with 6.8 mEq/l. The serum creatinine level was 0.9 mg/dl, the GFR was 52.1 ml/min, FEK was 7.1%. Pseudohypoaldosteronism or hyporeninemic hypoaldosteronism was suspected. To investigate this possibility a renin/aldosterone stimulation test was performed. We speculate that an idiosyncratic response to CyA resulted in pseudohypoaldosteronism and produced a defect in potassium secretion.

[Treatment of acute lymphoblastic leukemia of young adults (15-22 years of age): results of co-operative study with internal medicine and pediatrics].

Ten young adults (15-22 years of age) with acute lymphoblastic leukemia were treated with the protocol of internal medicine and pediatrics co-operative study group since 1989. All patients had complete remission within 5 weeks. Four of 6 patients of low risk group (less than 30,000/microliter of WBC count at diagnosis) and 1 of 4 patients of high risk group have continued the complete remission. Three patients relapsed in bone marrow (BM), and 2 patients in both BM and central nervous system (CNS). All patients could be treated without serious complications except for infection. We obtained the good results of treatment for the low risk group, but did not for the high risk group in this study. Little is known about acute lymphoblastic leukemia in young adults because these individuals are at the borderline age between internal medicine and pediatrics. Taken together with the psychologically distinct age of these patients, it is necessary to establish a closer relationship between internal medicine and pediatrics.

Probing the metal-insulator phase transition in the (DMEDO-EBDT)2PF6 single crystal by optical measurements.

The temperature and polarization dependence of the optical reflectivity  spectra of a quasi-one-dimensional 1/4-filled band system, (DMEDO-EBDT)(2)PF(6), have been investigated. We observed clear anisotropy in the electronic structures corresponding to the anisotropic transport properties. The appearance of a charge gap (E(g) > 0.1 eV) and transfer of the spectral weight accompanied by the metal-insulator phase transition were clearly observed. In addition, a split of the intramolecular vibrational modes was observed, which strongly suggested the existence of charge disproportionation in the low temperature phase. We also observed a photoinduced reflectivity change, which implied the occurrence of a photoinduced phase transition from the low temperature insulating phase to the high temperature metallic phase.

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bbeta and TSLC1 in neuroblastoma.

Recent advances in neuroblastoma (NB) research addressed that epigenetic alterations such as hypermethylation of promoter sequences, with consequent silencing of tumor-suppressor genes, can have significant roles in the tumorigenesis of NB. However, the exact role of epigenetic alterations, except for DNA hypermethylation, remains to be elucidated in NB research. In this paper, we clarified the direct binding of MYCN to Bmi1 promoter and upregulation of Bmi1 transcription by MYCN. Mutation introduction into an MYCN binding site in the Bmi1 promoter suggests that MYCN has more important roles in the transcription of Bmi1 than E2F-related Bmi1 regulation. A correlation between MYCN and polycomb protein Bmi1 expression was observed in primary NB tumors. Expression of Bmi1 resulted in the acceleration of proliferation and colony formation in NB cells. Bmi1-related inhibition of NB cell differentiation was confirmed by neurite extension assay and analysis of differentiation marker molecules. Intriguingly, the above-mentioned Bmi1-related regulation of the NB cell phenotype seems not to be mediated only by p14ARF/p16INK4a in NB cells. Expression profiling analysis using a tumor-specific cDNA microarray addressed the Bmi1-dependent repression of KIF1Bbeta and TSLC1, which have important roles in predicting the prognosis of NB. Chromatin immunoprecipitation assay showed that KIF1Bbeta and TSLC1 are direct targets of Bmi1 in NB cells. These findings suggest that MYCN induces Bmi1 expression, resulting in the repression of tumor suppressors through Polycomb group gene-mediated epigenetic chromosome modification. NB cell proliferation and differentiation seem to be partially dependent on the MYCN/Bmi1/tumor-suppressor pathways.

Long-term results of Tokyo Children's Cancer Study Group trials for childhood acute lymphoblastic leukemia, 1984-1999.

We report the long-term results of Tokyo Children's Cancer Study Group's studies L84-11, L89-12, L92-13, and L95-14 for 1846 children with acute lymphoblastic leukemia, which were conducted between 1984 and 1999. The value of event-free survival (EFS)+/-s.e. was 67.2+/-2.2% at 10 years in L84-11, which was not improved in the following two studies, and eventually improved to 75.0+/-1.8% at 10 years in L95-14 study. The lower EFS of the L89-12 reflected a high rate of induction failure because of infection and delayed remission in very high-risk patients. The L92-13 study was characterized by short maintenance therapy; it resulted in poor EFS, particularly in the standard-risk (SR) group and boys. Females did significantly better than males in EFS in the early three studies. The gender difference was not significant in overall survival, partly because >60% of the males survived after the testicular relapse. Randomized studies in the former three protocols revealed that intermediate- or high-dose methotrexate therapy significantly reduced the testicular relapse rate. In the L95-14 study, gender difference disappeared in EFS. Contrary to the results of larger-scale studies, the randomized control study in the L95-14 reconfirmed with updated data that dexamethasone 8 mg/m(2) had no advantage over prednisolone 60 mg/m(2) in the SR and intermediate-risk groups. Prophylactic cranial irradiation was assigned to 100, 80, 44, and 44% of the patients in the studies, respectively. Isolated central nervous system relapse rates decreased to <2% in the last two trials. Secondary brain tumors developed in 12 patients at 8-22 years after cranial irradiation. Improvement of the remission induction rates and the complete omission of irradiation are currently main objectives in our studies.