Takashi Tomoda

Prevention of influenza by the intranasal administration of cold-recombinant, live-attenuated influenza virus vaccine : importance of interferon-γ production and local IgA response

To clarify which immunological factors were more effective in preventing influenza virus infection, we measured immunological parameters induced by vaccination and infection in vivo and in vitro. Healthy adult subjects (n = 128) were divided into vaccinated (n = 85) and untreated (n = 43) groups. Eighty-five were vaccinated intranasally with a trivalent cold-adapted recombinant influenza virus vaccine containing type A (H1N1 and H3N2) and B viruses. Subjects were mostly seropositive before vaccination. In 29 (80.6%) of the 36 examinees showing a prevaccination HI antibody titre of less than 1:128, the titre increased more than four times after vaccination. On the other hand, an increase of more than four times was found in four (8.2%) of the 49 individuals who had shown a prevaccination titre of more than 1:128. The IgA antibody was negligibly detected in the nasal wash specimens before vaccination, and was induced by vaccination in some cases. Lymphocyte proliferation and interleukin 2 (IL-2) production in cultured lymphocytes of the same subjects stimulated by H1N1 virus in vitro were correlated with the HI antibody titre. However, the interferon gamma (IFN-gamma) production was low before vaccination, regardless of the HI antibody titre, and showed a significant increase after vaccination. It was suggested that local IgA response and IFN-gamma production play important roles in the prevention of influenza. Since there was the outbreak of influenza A (H1N1) in Kochi Prefecture after completion of blood samples 6-8 weeks after the second vaccination, we examined the above hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Persistently High Epstein-Barr Virus (EBV) Loads in Peripheral Blood Lymphocytes from Patients with Chronic Active EBV Infection

Chronic active Epstein-Barr virus infection (CAEBV) is a severe illness with unusual EBV activation that persists for years, and its pathogenesis is largely unknown. After the creation of an accurate and reproducible polymerase chain reaction system to quantify EBV DNA, virus loads in peripheral blood lymphocytes (PBL) were determined in 54 children: 15 with CAEBV, 16 with infectious mononucleosis (IM), and 23 healthy children. Children with CAEBV and those with IM had high virus loads. Lower loads were detected in 47% of seropositive healthy donors. There were two distinct differences between children with CAEBV and those with IM: The former had greater viral replication (10(3)-10(7) copies/2.5x10(5) PBL) than those with IM, and viral replication declined in children with IM whereas active replication persisted for years in subjects with CAEBV. Persisting high virus loads are a possible diagnostic criterion for CAEBV. EBV loads may enable classification and prognosis of EBV infections.

Focal pachypolymicrogyria in three siblings.

The malformation of focal pachypolymicrogyria might be the manifestation of an X-linked recessive disorder according to the results of this study. Three siblings revealed focal pachypolymicrogyria on magnetic resonance imaging (MRI) and had a strong family history of epilepsy and mental retardation. All three siblings had the same mother; the father of Patient 1 was not related to the mother, but the father of Patients 2 and 3 was related to her. The MRI of the father of Patients 2 and 3 demonstrated focal pachypolymicrogyria. The mothers MRI was normal. In this family, epilepsy or mental retardation was found mainly in the males (Patient 3 was an exception), and they were all born to female members of this family, not male. Patient 3 was probably a homozygote with an X-linked recessive inheritance, and therefore, she demonstrated the most severe clinical findings.

Primary changes in liver damage by aspirin in rats

Background: It has been known that acetylsalicylic acid (ASA) causes liver cell damage, however, its mechanisms remain obscure.

Inhibition of interferon-γ- and phorbol ester-induced HLA-DR and interleukin-1 production by the expression of a transfected poly(ADP-ribose) synthetase gene in human leukemia THP-1 cells

Abstract We have examined a correlation between an expression level of poly(ADP-ribose) synthetase gene and the stage of monocytic differentiation. We ?????? three human leukemia cell lines, U937, THP-1, and J111, whose differentiation stage was characterized by nitroblue tetrazolium reduction activity, non-specific esterase activity, phagocytic activity and a cell surface differentiation. When THP-1 cells were treated with either interferon-γ or phorbol ester, mRNA level of the synthetase decreased and HLA-DR or interleukin-1 was induced, respectively. We transfected expression plasmid of the exogenous synthetase gene to examine whether the down-regulation of the synthetase is a necessary step to induce these proteins. An expression of the exogenous synthetase gene inhibited the interferon-γ- and phorbol ester-dependent induction of HLD-DR and interleukin-1. The results suggest that down-regulation of the synthetase may be a signal mediator of immunological response such as HLA-DR or interleukin-1 production in monocytes.

Two primary doses of diphtheria-tetanus-acellular pertussis vaccine induce immunological responses to Bordetella pertussis as strong as those induced by three primary doses

Pertussis vaccinations are administered worldwide under various conditions and schedules with diphtheria-tetanus-pertussis (DTP). In Japan, a general vaccination with three primary doses of diphtheria-tetanus-acellular pertussis (DTaP) at 4-week intervals and one booster dose 12 months after the primary series have been used since 1981. Decreasing the number of doses of the vaccination would lessen the physical and economic costs. To compare the immunological response to two versus three primary doses, we assessed antibody and cellular immune responses in health children. The anti-filamentous hemagglutinin (anti-FHA) and anti-pertussis toxin (anti-PT) antibody responses to two primary doses of DTaP before a booster were significantly lower than the responses to three primary doses. Although these antibody levels were low in children who received two primary doses, the FHA-induced DNA synthesis was equal to that of the children who received three doses. The anti-FHA and anti-PT antibody levels 4 weeks after the booster following two doses were similar to the levels following three doses, and high antibody titers were maintained over a long period. In areas where contact with bacteria is expected, two primary doses of DTaP may be adequate to induce the necessary level of immunological responses.

Marked increase of peripheral blood myeloblasts following G‐CSF therapy in a patient with acute lymphoblastic leukemia

A 9 year old boy with acute lymphoblastic leukemia (ALL) received recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) and showed a marked increment of myeloblasts in the peripheral blood. He was administered repeated courses of intermediate‐dose cytosine arabinoside (Ara‐C) therapy (1500 mg/m2, days 1–5) for frequent central nervous system (CNS) relapse of ALL. The peripheral white blood cell nadir was less than 1000/μL, so he was treated with rhG‐CSF. A marked increment of peripheral blood blasts was noted 3–5 days after rhG‐CSF treatment. These cells decreased with the appearance of mature myeloid cells and disappeared about 2 weeks after the start of treatment. These findings suggested that the blasts might have the ability to differentiate into mature myeloid cells. A control patient with repeated CNS relapse of ALL showed no increment of peripheral blood blasts after similar repeated courses of Ara‐C without rhG‐CSF treatment. Cultured peripheral blood blasts obtained from the present patient showed differentiation into mature myeloid cells by morphological studies and surface marker analysis. These findings indicate that the peripheral blood blasts drawn by G‐CSF were not leukemic blasts but normal myeloblasts.

Experimental study on Reye's syndrome: Inhibitory effect of interferon alfa on acetylsalicylate-induced injury to rat liver mitochondria

Viral infection and acetylsalicylate (ASA)-induced mitochondrial aberration have been reported to play important roles in the pathogenesis of Reyes syndrome. We report that increasing amounts of ASA (0 to 250 mumol/L) resulted in increases in state 4 respiration and decreases in state 3 respiration in rat liver mitochondria in vitro when using alpha-ketoglutarate and/or beta-hydroxybutyrate as respiratory substrates, but not when using succinate as substrate. Interferon alfa (IFN-alpha) (1.5 to 5 x 10(4)IU/mL, approximately 1/100 the therapeutic dosage for humans) and interleukin-1 (IL-1) (1.5 to 2 x 10(4)IU/mL, nearly equivalent to the therapeutic dosage) decreased the severity of the above effects via interaction with mitochondrial membranes. Interferon gamma (IFN-gamma) and interleukin-2 (IL-2) had no such protective effect. Electron microscopic observation indicated that IFN-alpha prevented the induction of mitochondrial swelling by ASA. These results suggest that IFN-alpha may prove to be effective for the treatment of Reyes syndrome.

Fluctuation of gene expression for poly(ADP-ribose) syntetase during hemin-induced erythroid differentiation of human leukemia K562 cells and its reversion process

We have studied the regulation of gene expression for poly(ADP-ribose) synthetase during erythroid differentiation and its reversion process. When human leukemia K562 cells were incubated in the presence of 80 microM hemin, benzidine-positive cells appeared at day 2 and 90% of the cells became positive at day 6. However, RNA blot analysis reveals that mRNA for gamma-globin was already abundant in untreated K562 cells and the level of the message was slightly increased by hemin-treatment. Spectroscopic analysis and polyacrylamide gel electrophoresis of the induced cell extracts indicate that hemoglobin molecules were not detected in untreated cells, and increased successively up to day 6. The hemin-induced cells were thoroughly washed, and then recultured in the absence of hemin. The benzidine-positive cells mostly disappeared 3 days after the elimination of the inducer. During the hemin-induced erythroid differentiation, the activity and mRNA for poly(ADP-ribose) synthetase decreased to 50% and 20% of the initial level at day 3 and a low level of the gene expression was maintained afterwards, whereas the activity and mRNA returned to the initial value 1 day after hemin elimination. The results indicate that the hemin-induced erythroid differentiation of K562 cells is a reversible process and depression of the synthetase may be involved in the progress of differentiation.

Fetal valproate syndrome with reduction deformity of limb

A case is reported of a female infant having multiple anomalies, including epicanthic folds, hypertelorism, bifid nasal bridge, shallow philtrum, low‐set ears, brain atrophy, cleft palate, hemangioma on the chest, and reduction deformity of the left upper limb. This is the first case where an infant who was exposed to sodium valproate intra‐uterine has a reduction deformity of the upper limb.