Evidence that activation of Kupffer cells increases oxygen uptake after cold storage.

Fasting for long periods of time has previously been shown to increase survival following liver transplantation. The experiments reported here were designed to study the mechanism of this phenomenon. Livers stored in cold Euro-Collins solution for 16 hr were perfused subsequently for 3 hr. Oxygen uptake increased slowly, reaching maximal values after about 80 min of reperfusion. This increase in oxygen uptake was significantly greater in livers from fed rats (73 mumol/g/hr) than in livers from either 4-day fasted rats (42 mumol/g/hr) or from rats where Kupffer cells were inactivated by gadolinium chloride treatment (30 mumol/g/hr). Thus, it is likely that the increase in oxygen uptake involves activation of Kupffer cells on reperfusion. Therefore, carbon uptake, which is due predominantly to phagocytosis by Kupffer cells, was monitored in the perfused liver. Carbon uptake was increased significantly in livers from fed rats at 80 compared with 20 min of perfusion. Further, carbon uptake was diminished significantly by long-term fasting and gadolinium chloride treatment. These results indicate that oxygen uptake increases in parallel with activation of Kupffer cells in livers from fed rats and support the hypothesis that activated Kupffer cells produce factors that stimulate oxygen uptake after cold storage. In further support of this hypothesis, the observed increase in oxygen uptake was diminished when the flow rate was increased. Because mediators would be diluted as the flow rate was increased, this result is consistent with the hypothesis that oxygen uptake depends on chemical mediators released from Kupffer cells. When livers were perfused with indomethacin, a prostaglandin synthesis inhibitor, the increase in oxygen uptake observed in fed rats was reduced by 34%. Further, in livers perfused under hypoxic conditions using a low-flow model, lactate dehydrogenase release in livers from fed rats (547 U/g/hr) was significantly greater than in livers from 4-day fasted rats (397 U/g/hr), indicating that fasting increased tolerance to hypoxia. In conclusion, livers of fasted rats require less oxygen during reperfusion, most likely because activation of Kupffer cells on reperfusion is minimized. These findings could explain why survival after transplantation is improved by long-term fasting.

Accelerated idioventricular rhythm in three newborn infants with congenital heart disease.

Accelerated idioventricular rhythm was observed in three newborn infants with congenital heart disease. This ventricular arrhythmia in all of our patients did not alter the clinical features of the congenital heart disease, and it disappeared at the ages of 84 days, 40 days, and 45 days, respectively. This arrhythmia is generally considered to be benign, which also appears to be the case with the newborn infant with congenital heart disease.

[Successful treatment with idarubicin in a pediatric case of t(8;21) acute myelogenous leukemia with additional chromosomal abnormalities at relapse].

A 9-year old boy was admitted to our hospital due to a relapse of acute myelogenous leukemia (AML). A chromosomal analysis at the time of relapse revealed abnormalities in addition to 45, X,-Y, t(8;21) (q22;q22) when AML was first diagnosed. The patient was given granulocyte-colony stimulating factor (G-CSF), cytosine arabinoside (Ara-C) and aclarubicin (CAG therapy), but this treatment regimen was not effective. He was next treated with G-CSF (started 3 days prior to the administration of anticancer drugs), Ara-C, (200 mg/mm2 for 7 days), Etoposide (VP.16, 150 mg/mm2 for 5 days) and Idarubicin (8 mg/mm2 for 5 days) according to the modified Japan Cooperative Protocol ANLL 91 for children. Although his condition had been septic and he had experienced renal and respiratory failure, he achieved a complete remission after 140 days without additional therapy. The patient returned to a condition of health and received a bone marrow transplant from an unrelated donor. We concluded that this treatment regimen is effective for the relapse of AML in children.

[Malignant lymphoma of the central nervous system in a boy with immotile cilia syndrome].

Malignant lymphoma of the central nervous system in a thirteen-year-old boy with immotile cilia syndrome (ICS) is reported. He had frequent upper respiratory tract infections, chronic sinusitis and pneumonia during in childhood. Bronchiectasis was demonstrated by bronchography. The diagnosis of ICS was confirmed by the lack of dynein arms of cila in the nasal mucosa with electronmicroscopy. In 1987, he complained of headache and vomiting and a space occupied mass lesion in the left frontoparietal lobe was found by head CT scan, which was subtotally resected. Histological studies showed large cell type non-Hodgikin lymphoma of B-cell phenotype. He received radiotherapy (41Gy) to the whole brain and systemic chemotherapy consisting of adriamycin, cyclophosphamide, vincristine, prednisolone, L-asparaginase and intrathecal methotrexate, and the patient maintained complete remission for eight months. However, relapse occurred and the patient died twelve months after the initiation of treatment.

[AML(M7) associated with t(16;21)(p11;q22) showing relapse after unrelated bone marrow transplantation and disappearance of TLS/FUS-ERG mRNA].

A 3-year-old boy with poorly prognostic acute megakaryoblastic leukemia (AML M7) showing t(16;21)(p11;q22) karyotype underwent unrelated bone marrow transplantation (U-BMT) during his first hematological remission. The conditioning regimen consisted of BU, VP-16 and L-PAM. Engraftment was smooth, but the patient developed grade I acute GVHD. During hematological remission before U-BMT, the TLS/FUS-ERG chimeric transcript of t(16;21)(p11;q22) was consistently detectable as minimal residual disease (MRD) by RT-PCR. However, after U-BMT it soon became undetectable. There was no detectable MRD until 7 months after U-BMT, but bone marrow relapse occurred 10 months after U-BMT. We consider that U-BMT is a promising treatment for t(16;21)(p11;q22) AML. However, an intensified conditioning regimen or modification of GVHD prophylaxis is needed.

Glycogenolytic effect of adenosine involves ATP from hepatocytes and eicosanoids from Kupffer cells.

In the perfused liver, infusion of adenosine (50 microM) caused an increase in portal pressure and glucose output as well as a brief increase in oxygen uptake followed by a transient decrease within 1 min. Half-maximal glycogenolytic effect was observed with approximately 20 microM adenosine, and the stimulation was maximal at concentrations > 50 microM. The effect of adenosine was blocked when Kupffer cells were destroyed with gadolinium chloride treatment (10 mg/kg iv), supporting the hypothesis that eicosanoid release from Kupffer cells participates in the effect of adenosine in the liver. Although adenosine has been reported to increase eicosanoid release from perfused liver (S. vom Dahl, M. Wettstein, W. Gerok, and D. Hüssinger, Biochem. J. 270: 39-44, 1990), in this study adenosine failed to stimulate prostaglandin release from cultured Kupffer cells at concentrations ranging from 1 microM to 1 mM, casting doubt on the hypothesis that Kupffer cells are totally responsible for the effect of adenosine. In contrast, adenosine increased ATP transiently from 4 to 15 nM in effluent from perfused livers concomitant with a transient increase in carbohydrate output and portal pressure. To assess which type of hepatic cells released ATP after addition of adenosine, parenchymal, Kupffer, and endothelial cells were isolated and incubated with adenosine. Adenosine increased ATP concentrations in culture media of parenchymal cells but not from Kupffer or endothelial cells. Furthermore, ATP stimulated prostaglandin release from cultured Kupffer cells, whereas ATP (10 microM) infusion caused glucose release with kinetics similar to adenosine in perfused livers, an effect that was blocked by destroying Kupffer cells.(ABSTRACT TRUNCATED AT 250 WORDS)