Experiments with rectangular supersonic jets with potential noise reduction technology.

This paper describes the aeroacoustics experiments conducted with supersonic jets, exhausting from rectangular nozzles with an aspect ratio of 2, to examine the jet noise reduction by two different methods. The first method involves the use of fluid inserts, which are produced by distributed air blowing into the diverging section of a convergent-divergent exhaust nozzle. The second method involves the integration of fluid shields in dual flow rectangular jets. In the dual flow nozzle, a single shield below the exit is augmented with fluid shields extending on both sides of the rectangular jet. The purpose of the extended bypass flow is to reduce the noise radiated to the sides of a jet aircraft. In addition to the nozzles with the two noise reduction configurations, acoustic measurements are performed with a single flow rectangular jet, referred to as the baseline. In all cases, the jets are operated as overexpanded, shock-containing jets. In some cases, the jets are operated with the core flow mixtures of helium and air to simulate high temperature jets. The far-field noise measurements are performed on an arc with the microphones approximately 70 equivalent nozzle diameters from the nozzle exit. For the purposes of assessing the noise reduction capability of the dual stream jet, comparisons are made with a baseline rectangular jet on an equal thrust per unit exit area basis. The nondimensional acoustic spectra and overall sound pressure level directivities are shown and compared.

Estimation of glycaemic control in the past month using ratio of glycated albumin to HbA1c.

AIMS: To evaluate comprehensively the use of the glycated albumin to HbA1c ratio for estimation of glycaemic control in the previous month. METHODS: A total of 306 children with Type 1 diabetes mellitus underwent ≥10 simultaneous measurements of glycated albumin and HbA1c . Correlation and concordance rates were examined between HbA1c measurements taken 1 month apart (ΔHbA1c ) and glycated albumin/HbA1c ratio fluctuations were calculated as Z-scores from the cohort value at enrolment of this study cohort (method A) or the percent difference from the individual mean over time (method B). RESULTS: Fluctuations in glycated albumin/HbA1c ratio (using both methods) were weakly but significantly correlated with ΔHbA1c , whereas concordance rates were significant for glycaemic deterioration but not for glycaemic improvement. Concordance rates were higher using method B than method A. CONCLUSIONS: The glycated albumin/HbA1c ratio was able to estimate glycaemic deterioration in the previous month, while estimation of glycaemic improvement in the preceding month was limited. Because method B provided a better estimate of recent glycaemic control than method A, the individual mean of several measurements of the glycated albumin/HbA1c ratio over time may also identify individuals with high or low haemoglobin glycation phenotypes in a given population, such as Japanese children with Type 1 diabetes, thereby allowing more effective diabetes management.

A prospective, randomized trial of conventional, dose-accelerated corticosteroids and intravenous immunoglobulin in children with newly diagnosed idiopathic thrombocytopenic purpura.

To determine the minimal essential treatment for childhood acute idiopathic thrombocytopenic purpura (ITP), a prospective, randomized trial was conducted focusing on hemorrhagic manifestation as well as platelet count. Subjects with a platelet count of <10 x 10(3)/microL or 10 to 29 x 10(3)/microL and mucosal bleeding (group 1) were randomly assigned to receive intravenous immunoglobulin (IVIg) at 1 to 2 g/kg, conventional oral prednisolone (o-PSL) (2 mg/kg for 2 weeks). parenteral methylprednisolone (mPSL) (5 mg/kg for 5 days), or pulsed parenteral methylprednisolone (PmPSL) (30 mg/kg for 3 days). Subjects with a platelet count of 10 to 29 x 10(3)/microL without mucosal bleeding (group 2) were randomized to receive either o-PSL or no treatment. In subjects with a platelet count of 30 x 10(3)/microL or higher (group 3), patients undergoing no specific treatment were monitored. In group 1, IVIg offered faster platelet enhancement compared with o-PSL and mPSL, although neither mPSL no PmPSL showed any advantage, even over o-PSL. Platelet response was uniformly excellent when pretreatment platelet coun was > or = 10 x 10(3)/microL. Furthermore, the presence or absence of mucosal bleeding in subjects with a platelet count <10 x 10(3)/microL had no effect on the response to treatment. In group 2, platelet increase was indifferently attained with or without o-PSL. These data suggest that childhood acute ITP with a platelet count > or = 10 x 10(3)/microL may be left untreated or may be treated with o-PSL when mucosal bleeding is evident, whereas for those with a platelet count <10 x 10(3)/microL, IVIg is the most predictable platelet enhancer. Thus, a platelet count of 10 x 10(3)/microL seems to be informative enough to decide whether to treat childhood acute ITP.

Intracranial hemorrhage in children with immune thrombocytopenic purpura

We sent questionnaires to hospitals in Japan in order to study the incidence and conditions of intracranial hemorrhage (ICH) in children with immune thrombocytopenic purpura (ITP). From 1980 to 1995, 11 cases of ICH were reported in eight patients with ITP at 35 institutions. One patient had ICH four times, but only one patient died of the condition. From 1990 through 1995, ICH occurred in four (0.52%) of 772 patients with ITP. None of the patients died. The platelet count when ICH occurred was 5.2 +/- 3.7 x 10(9)/l (mean +/- SD) (n = 11). Four of the eight patients (1980-1995) had received active treatment [e.g. intravenous immunoglobulin G (i.v. IgG)] immediately before ICH occurred. In seven cases (1980-1995), possible causes of ICH, including menstruation (n = 2) and viral infections (n = 3), were identified. Systemic lupus erythematosus (SLE) later developed in three patients. Although the incidence of ICH in children with ITP has not decreased compared with the rates in earlier studies, the mortality rate has decreased markedly. Our results suggest that menstruation, infection, and risk factors for progression to SLE may help to predict ICH in children with ITP. Large-scale prospective trials are needed to identify risk factors for ICH.

Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia.

The improved outcome of acquired aplastic anemia (AA) has revealed later complications, such as myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). We retrospectively analyzed 167 children with severe acquired AA. Eleven of 50 children treated with cyclosporin (CSA) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) developed MDS/AML; 8 of these were within 36 months of the diagnosis of AA, much earlier than previous reports. Six of the 11 children received rhG-CSF exceeding 10 microg/kg/d, and 9 received rhG-CSF therapy for over 1 year. Ten children showed monosomy 7 at diagnosis of MDS. All of the 11 children were administered both CSA and rhG-CSF. There was no development of MDS/AML among 41 children treated with either CSA or rhG-CSF or among 48 children who underwent bone marrow transplantation. A well-controlled clinical trial is warranted to determine whether therapeutic modalities affect the development of MDS/AML in children with severe acquired AA.

Thrombocytopenia in neonates born to women with autoimmune thrombocytopenic purpura.

We conducted a survey by questionnaire to clarify the actual conditions of neonates born to mothers with autoimmune thrombocytopenic purpura (ATP) in Japan. We investigated 93 pregnancies (1 resulting in twins) in 31 hospitals between 1985 and 1994. Forty-nine of the neonates (52%) had thrombocytopenia (below 150 x 10(9)/L). Nineteen neonates (20%) showed a bleeding tendency, but this was generally mild. In only one neonate (1%) (a case of asymptomatic intracranial hemorrhage, ICH), deep bleeding occurred due to thrombocytopenia. The lowest platelet count of neonates after birth occurred on day 4, not on day 0. There was no correlation between maternal and neonatal platelet counts. However, there was an apparent correlation between the neonatal platelet count on day 0 and the lowest platelet count after birth. Treatment of the mothers with intravenous high-dose gamma-globulin and prednisolone did not prevent risk of neonatal thrombocytopenia significantly.

Testicular morphological changes in children with acute lymphoblastic leukemia following chemotherapy.

Morphological changes in the testis induced by chemotherapy given according to the Tokyo Children's Cancer Study Group (TCCSG) regimens were studied in children with acute lymphoblastic leukemia (ALL). After informed consent, testicular biopsies were performed 14 times in 12 patients at the end of treatment. The testicular morphology in all cases had sustained a degree of damage. The tubular fertility index (TFI), calculated as the percentage of seminiferous tubules containing identifiable spermatogonia, was from 0 to 42.8% (mean 33.4%) below the normal value. Infiltration of leukemic cells was the most significant factor contributing to the decrease in TFI. There were no differences in the TFI among the TCCSG protocols. Formation of sperm was recognized in six cases, whose ages were 7, 8, 9, 10, 15 and 19 years. In two children, testicular biopsy was performed twice. In the second biopsy, TFI was elevated and sperm formation with the maturation of Leydig cells was observed. A number of other pathological changes were observed: modification of spermatogonia, Sertoli cells and inclusion bodies in spermatogonia, abnormal maturation of Leydig cells, evidence of interstitial fibrosis and thickening of the basement membrane. These results suggest that recent strong chemotherapy for the treatment of ALL might cause severe but not fatal damage to children's testicular tissue. As chemotherapy escalates, more investigation of testicular function will be necessary.

[Hereditary elliptocytosis].

Recently a number of different red cell membrane skeletal abnormalities have been identified in patients with hereditary elliptocytosis (HE). In Japanese patients with HE, most of skeletal abnormality was protein 4.1 abnormalities. alpha-spectrin abnormality was found only one lineage in Japan, in spite of these abnormalities were most common abnormalities in western countries. On the contrary beta-spectrin abnormalities were found in two lineages, in spite of these abnormalities were rare abnormalities in western countries. The other abnormalities, such as band 3 abnormalities and glycophrin abnormalities, were found in HE. We described here about clinical features and above mentioned abnormalities of red cell membrane skeleton in HE.

[Glutathione synthetase deficiency].

CASE REPORT: The patient was a boy born in June, 1990. The proband's father had a history of nonspherocytic hemolytic anemia. The patient was anemic at birth (Hb 11.9 g/dl) and had a hemolytic attack on postnatal day 2. His hemolysis became well compensated, and his second hemolytic episode occurred at three years of age. CLINICAL AND LABORATORY FINDINGS: The patient's mental development had so far been normal and he has no neurological symptoms. His only clinical manifestation has been compensated hemolytic anemia with a hemoglobin concentration of about 11.0 g/dl and a reticulocyte count of 3-6%. He was positive on the Heinz body formation test, and target cells were seen on his peripheral blood smear. The osmotic fragility test yielded slightly increased value. Decreased reduced glutathione (GSH) was observed (4.4 mg/dlRBC) (normal range: 63.9 +/- 9.6), and he also had decreased glutathione synthetase (GS) activity of 0.03 U/gHb (0.38 +/- 0.08 U/gHb). A diagnosis of GS deficiency was made. Decreased glutathione S-transferase (GST) activity was also found (0.57 U/gHb) (normal range: 6.65 +/- 1.20). DISCUSSION: GS deficiency has been reported in about 30 families all over the world. This patient was the first Japanese patient with red cell GS deficiency.

Recombinant human interferon alpha-2b (rh IFN alpha-2b) therapy for steroid resistant idiopathic thrombocytopenic purpura (ITP).

The efficacy of recombinant human interferon alpha-2b (rh IFN alpha-2b) in the treatment of steroid resistant idiopathic thrombocytopenic purpura (ITP) was studied in 50 cases. Forty-one patients treated with rh IFN alpha-2b three times a week, six of 18 (33.3%) in the low dose group (150 x 10(4)IU: 3 MIU) and four of 20 (20.0%) in the high dose group (300 x 10(4)IU: 3 MIU) responded with platelet counts increasing to above 50 x 10(9)/L. Because of the exacerbation of thrombocytopenia and nasal bleeding, treatment was discontinued within 2 weeks in three patients out of 41 cases. On the other hand, six of nine patients (66.7%) treated with 3 MIU of IFN alpha-2b once a week for 8 weeks showed satisfactory response. Treatment with either administration schedule did not result in sustaining platelet counts above 50 x 10(9)/L for a long time after treatment. The results indicate that once a week administration schedule of rh IFN alpha-2b is more efficacious for platelet counts increasing for short period in patients who failed to respond to steroid and other medications than other schedules. The maintenance of this treatment schedule will allow sustained increased platelet levels, resulting in relief of bleeding tendency, while also being cost effective in comparison with other IFN treatment schedules and achieving better patient compliance without flu-like symptoms.

Autoantibodies and CD5+ B cells in childhood onset immune thrombocytopenic purpura.

We evaluated platelet associated immunoglobulin (PIag) G, PaIgM, platelet associated autoantibodies to platelet glycoprotein IIb/IIIa (Pa-GPIIb/IIIa), the percentage of CD5+ B cells and the amount of platelet-bound anti-GPIIb/IIIa monoclonal antibody (mAb) in the peripheral blood of 29 patients with childhood onset chronic immune thrombocytopenic purpura (c-ITP). The percentage of CD5+ B cells ranged from 2 to 8% (4.7 +/- 2.0) in control patients and 1 to 18% (6.2 +/- 4.2) in the ITP patients. There was no overall significant difference between the two groups, but the percentage of CD5+B cells in six of the ITP patients was higher than the mean + 2 s.d. of the controls. There was a significant correlation between the percentage of CD5+ B cells and PaIgM (y = 1.73x + 13.4, r=0.40, P < 0.05). This finding is the basis for the speculation that CD5+ B cells may play an important role in the production of PaIgM in vivo. There was no correlation between the amounts of PaIgG and Pa-GPIIb/IIIa). This suggests that the amount of PaIgG does not accurately reflect of the amount of Pa-GPIIb/IIIa. Furthermore, we have demonstrated that autoantibodies to GPIIb/IIIa are directed to more that one epitope.

Ex vivo expansion of umbilical cord blood hematopoietic progenitor cells by combinations of cytokines.

Ex vivo expansion of hematopoietic progenitor cells in the umbilical cord blood mononuclear cells (CB-MNC) was investigated in liquid culture system with various combinations of cytokines (stem cell factor [SCF], interleukin [IL]-3, IL-6, granulocyte-colony stimulating factor [G-CSF], erythropoietin [EPO], and interferon [INF]-gamma). Non-lineage-committed hematopoietic progenitor cells and lineage committed hematopoietic progenitor cells were represented as CD34+CD38- and CD34+CD38+ subpopulations, respectively. Although absolute CD34+CD38- cell numbers decreased even in the presence of multicytokines, the combinations of SCF plus IL-6 and SCF plus IL-3 plus IL-6 plus IFN-gamma were significantly effective in maintaining CD34+CD38- cells than the other combinations (P < 0.05). After 4 weeks of culture. CD34+CD38- cells disappeared in all combinations of cytokines. Absolute CD34+CD38+ cell numbers increased in the presence of cytokines. Maximal expansion of CD34+CD38+ cells were observed in the combinations of SCF plus IL-3 plus IL-6 plus EPO (19.8 +/- 3.3-fold) and SCF plus IL-3 plus IL-6 plus G-CSF (18.3 +/- 2.6). The combination of SCF plus IL-3 plus IL-6 was also effective to expand CD34+CD38- cells (15.8 +/- 3.9). However, the expansion was transient and they decreased to zero within 3 weeks. In the combinations of SCF plus IL-6 and SCF plus IL-3 plus IL-6 plus INF-gamma, maximal expansion was inferior to the others but CD34+CD38+ cells were maintained more than 4 weeks. These results suggested that the indication of CBT can be expanded into older children by ex vivo augmentation of CB hematopoietic progenitor cells using multi-cytokines.

Effects of cytokines on hematopoietic progenitor cells in cord blood, in bone marrow, and in peripheral blood mobilized by chemotherapy and G-CSF.

We compared the effects of various combinations of cytokines (stem cell factor [SCF], interleukin [IL]-3, IL-6, granulocyte-colony stimulating factor [G-CSF], erythropoietin [EPO]) among the growth of human hematopoietic progenitor cells from cord blood (CB), bone marrow (BM), and peripheral blood mononuclear cells (MNC) mobilized by chemotherapy and G-CSF (PB) in a semi-solid medium. Macroscopic colonies, that were visible to the naked eye, were formed from PB-MNC within 1 week even without cytokines. They consisted of blasts containing macrophage-like cells with immature nuclei on Wright stain, and were strongly accelerated by IL-3. Macroscopic colonies were also formed from CB-MNC. However, they appeared after 1-3 weeks and synergistic effects of SCF with other cytokines, especially EPO, were prominent. Macroscopic colonies were not formed from BM-MNC. Granulocyte-colony stimulating factor was effective in increasing colony forming units of granulocyte macrophage from BM-MNC and they appeared between 1 and 2 weeks. These results suggested that the quality of hematopoietic progenitor cells was different among blood sources. This might lead to different bone marrow recovery patterns after transplantation of each blood source. The appropriate cytokines should be added to evaluate their exact potential.

The effects of antifungal chemoprophylaxis and empiric therapy on invasive fungal infection in neutropenic children with malignant neoplasms.

Since January 1987, chemoprophylaxis and empiric therapy with antifungal drugs have been used routinely in neutropenic children with neoplasms. The incidence of terminal invasive fungal infection (IFI) diagnosed by autopsy findings is compared in two groups: group A, consisting of 25 patients autopsied between January 1982 and December 1986, and group B, consisting of 14 patients autopsied between January 1987 and December 1991. There was no difference in the incidence of IFI between the two groups, but the characteristics of IFI appeared to differ. With the recent intensification of chemotherapy, the patients in group B had more risk factors for IFI. It might therefore have been anticipated that group B patients may have shown an increase in IFI. No such increase was observed, suggesting that the prophylaxis was effective. Autopsy findings also showed that the target organs of IFI were localized and that systemic candidiasis was decreased in group B. It is thus concluded that the present antifungal countermeasures are effective, although some problems still remain.

Immunthrombocytopenic purpura as a model for pathogenesis and treatment of autoimmunity.

In honour of Professor Rossi's 80th birthday we review the development of our understanding of the immune and auto-immune nature of the pathogenesis of immune thrombocytopenic purpura (ITP). The immune aspects have been documented by postviral alterations of the cellular and humoral immune system, by new methods of specific auto-antibody detection against platelet glycoproteins and by the therapeutic effect of administering immunoglobulin concentrate from healthy blood donors. The various possible mechanisms of action of immunoglobulin treatment have led to use of this treatment as an alternative for other immune-related disorders. The treatment of severe chronic ITP in children, however, remains unsatisfactory. With a new international clinical and laboratory study of children and adolescents with early chronic ITP we are continuing the investigation of the pathogenesis and treatment of ITP.

Umbilical cord blood as a rich source of immature hematopoietic stem cells.

To investigate immaturity of hematopoietic progenitor cells in umbilical cord blood mononuclear cells (CB-MNC), the formation of macroscopic colonies and mixed-cell colonies was assayed by methylcellulose culture with various combinations of cytokines (stem cell factor [SCF], interleukin [IL]-3, IL-6, granulocyte-colony stimulating factor [G-CSF], erythropoietin [EPO]) and compared with bone marrow (BM)-MNC. Moreover, distribution of the subpopulations divided by CD34, CD38, HLA-DR and CD33 was compared by flow-cytometry. Colonies derived from CB-MNC were so large that they could be observed with the naked eye and consisted of a variety of types of hematopoietic cells. Mixed-cell colonies were formed to a much greater extent in CB-MNC than in BM-MNC. Addition of EPO, IL-3, and SCF had rapid effects on the growth of mixed-cell colonies. The subpopulations of immature hematopoietic progenitor cells (CD34+, CD38-, HLA-DR-), which are supposed to be able to differentiate into hematopoietic precursors and stromal cells, were significantly higher in CB-MNC (8.7 +/- 6.6%) than in BM-MNC (0.0 +/- 0.1%; P < 0.001). These results suggest that CB is a rich source of immature hematopoietic progenitor cells compared to BM.

Lymphoma syndrome leukemia revealed interesting finding on brain CT and ultrasound scan of abdomen at the initial presentation.

This paper reports on a patient with lymphoma syndrome leukemia (LSL) who showed interesting findings on brain computed tomography (CT) and ultrasound scans of the abdomen at the initial presentation. The patient was a 5 year old girl. When she was admitted to our hospital, there were many lymph nodes palpable. The abdomen was distended and the liver and spleen were palpable below the umbilicus. Hematologic examinations revealed a leukocyte count of 275,800/microL with 98% lymphoblasts. Chest X-ray film revealed a mediastinal mass. The diagnosis of LSL was made. Her brain CT scan showed a low density area in the right thalamic region without contrast enhancement; infarction was suspected. Furthermore, her abdominal ultrasound scan showed hepatosplenomegaly, kidney swelling with increasing echogenicity and hydronephrosis and stones in the renal pelvis and bladder. These findings are unprecedentedly rare in cases of childhood acute lymphoblastic leukemia (ALL), much less in LSL.

[Effective combination therapy by recombinant erythropoietin and cepharanthin in a girl with refractory anemia].

A 3-year-old girl was admitted with a one-month history of a tendency to bleed to Jikei Kashiwa hospital in May, 1992. She developed pancytopenia as follows; hemoglobin: 8.6 g/dl, red blood cell: 316 x 10(4)/microliters, reticulocyte: 9,480/microliters, white blood cell: 2,500/microliters (neutrophil: 400/microliters) and platelet count: 2.7 x 10(4)/microliters. Her bone marrow was hypoplastic, but was so dysplastic in 3 cell-lines as to be diagnosed as hypoplastic refractory anemia. After two courses of methylprednisolone pulse therapy followed by oral prednisolone therapy which were not effective and were supplemented by blood transfusions, the treatment of 20mg/day oral Cepharanthin, a biscoclaurine alkaloid, and intravenous recombinant human erythropoietin (rhEPO) twice a week at dose of 6,000 U/week was initiated in January, 1993. About 3 months later she showed a steady rise in hemoglobin concentration (from 4.1 to 11.9 g/dl) and platelet count (from 4,000 to 39,000/microliters). Although the rhEPO was tapered and ceased in September, 1993, her hemoglobin concentration has ranged from 11.0 to 11.9 g/dl and her platelet count from 30,000 to 40,000/microliters by giving her Cepharanthin and low dose prednisolone.