Molecular species of prostaglandins involved in modulating luteinising hormone pulses of female rats under infectious stress conditions.

Mammalian reproductive function is controlled by the hypothalamic-pituitary-gonadal (HPG) axis, which is suppressed under infectious stress conditions. By analysing the pulsatility of luteinising hormone (LH), we have previously demonstrated that prostaglandins (PGs) in the central nervous system mediate infectious stress to suppress the activity of the HPG axis. The present study aimed to characterise the types of PGs responsible for suppression of the HPG axis. We focused on three major types of PGs: PGE2 , PGD2 and PGF2α . We used female rats overiectomised bilaterally 1 week before the experiments. Lipopolysaccharide (100 µg kg-1 ) suppressed LH pulses at the same time as enhancing the concentration of all three PGs in the cerebrospinal fluid, which was restored by indomethacin (10 mg kg-1 ). Subsequently, we observed LH pulsatility after a single injection of each PG and after co-injection of PGE2 with PGF2α into the third cerebral ventricle. A single injection of PGE2 dose-dependently induced a transient increase in mean LH concentration and LH pulse amplitude, and PGD2 significantly increased the amplitude of LH pulses, wereas PGF2α did not affect LH pulsatility. On the other hand, co-injection of PGE2 and PGF2α induced a significant suppression of both the frequency and amplitude of LH pulses. These results suggest that PGE2 and PGF2α can represent two of the mediators that suppress the HPG axis in situations of infectious stress. Moreover, the results imply that there are two contradictory effects of PGE2 on LH pulsatility: (i) enhancive when working alone and (ii) suppressive when working together with PGF2α .

Functional organization of preoptic vasotocin and isotocin neurons in the brain of rainbow trout: central and neurohypophysial projections of single neurons.

Preoptic magnocellular neurosecretory cells (NSCs) in the brain of rainbow trout show synchronization of periodic Ca(2+) pulses, patterns of which differ between vasotocin (VT) and isotocin (IT) neurons. To provide neuroanatomical bases of the synchronized periodic Ca(2+) pulses and their biological implications, we examined the organization of preoptic VT and IT neurons in the brain of rainbow trout. The cytoarchitecture of the preoptic neurosecretory system was characterized by a confocal double-color immunofluorescence. Two to five VT neurons, and also IT neurons, aggregate to form cell-type specific clusters. VT clusters tend to localize medially, while IT clusters laterally. VT neurons are closely apposed at the proximal neuronal processes. A Golgi-like immunohistochemistry demonstrated that VT and IT fibers distribute widely in the brain, such as ventral telencephalon, diencephalon, and various mesencephalic structures, in addition to the neurohypophysial projections. Projections from single VT and IT neurons were examined by an intracellular staining with biocytin injection in a sagittally hemisected brain preparation, which contains the entire forebrain region. Single VT and IT neurons project toward the pituitary and the extrahypothalamic regions. Some IT neurons, but not VT neurons, were dye-coupled. These results support the idea that the same types of NSCs are connected to form cell-type-specific networks responsible for the synchronization of periodic Ca(2+) pulses. The organization of the preoptic neurosecretory system shown in the present study is suitable for the simultaneous control of neurohypophysial and extrahypothalamic outputs through the synchronization of electrical activity.

[Refractory acute myelogenous leukemia successfully treated with a continuous infusion chemotherapy of low dose aclarubicin and cytosine arabinoside: a case report].

A 44-year-old female with refractory acute myelogeneous leukemia had experienced an early relapse after a third complete remission (CR) with combination chemotherapy (BHAC-AMP) using daily one-shot infusion of 20 mg aclarubicin (ACR). Further treatments including intermediate dose of cytosine arabinoside (Ara-C) were not effective. After treatment with a continuous administration of low dose ACR (9 mg/day) and Ara-C (21 mg/day) for 14 days she entered a fourth CR. The mechanism of this treatment relates to both cell-killing and differentiation effects on leukemic cells.

MDR1 (multidrug resistance) gene expression in adult acute leukemia: correlations with blast phenotype.

Resistance to multiple chemotherapeutic agents is related to the production of P-glycoprotein, a transmembrane drug efflux pump that is encoded by the multidrug resistance gene (MDR1). To detect low-level or heterogenous expression of the MDR1 gene in acute leukemia, we have developed sensitive, specific and semi-quantitative protocols for measuring levels of MDR1 mRNA, based on the polymerase chain reaction. Using this assay, we screened blasts from 20 patients with untreated adult acute leukemia for evidence of MDR1 gene expression. The level of MDR1 mRNA was normalized to beta 2-microglobulin mRNA and was defined by reference to the highly resistant trimetrexate-selected leukemia cells MOLT-3/TMQ200 (1.80). MDR1 mRNA was observed in 14 out of 20 patients. Higher MDR1 mRNAs were observed in three patients with phenotypes of undifferentiated or minimally differentiated nonlymphocytic acute leukemia, as compared with other types of acute leukemia (0.98 vs. 0.25). In contrast, lower MDR1 mRNAs were found in five patients with acute promyelocytic leukemia, as compared with other types of acute leukemia (0.08 vs. 0.45). These findings suggest that MDR1 gene expression is correlated with the leucocyte differentiation stage of leukemia. MDR1 gene expression may, in part, explain the responsiveness to chemotherapy in these distinct subtypes of acute leukemia.

Acquired chronic pure red cell aplasia successfully treated with intravenous pulse methylprednisolone therapy.

A 65-year-old male patient developed acquired chronic pure red cell aplasia (PRCA) associated with hypergammaglobulinemia and positive Coombs' test during the treatment of eosinophilic pneumonia with prednisolone (PSL). His PRCA was treated with oral PSL at a dose of 60 mg/day for 3 weeks, but anemia further progressed. Immediately after high-dose intravenous pulse methylprednisolone therapy (1 g/day for 3 days) however, reticulocyte crisis occurred and his anemia rapidly improved. He has been in complete remission under a maintenance dose of PSL for more than 2 years. This patient indicates that high-dose intravenous methylprednisolone therapy is one of the useful treatments, not only for constitutional PRCA, but also for acquired chronic PRCA.

[Clinical study of miconazole on deep-seated fungal infections].

An investigation was made on the efficacy and the safety of miconazole (MCZ) in the treatment of deep seated mycosis. The drug was administered through intravenous drip infusion at dose levels of 800 to 2,000 mg/day to 21 cases of confirmed mycosis for which causative organisms was identified and to 32 cases to which other antibiotics considered to be appropriate had been administered at febrile stages but had failed to take effect, hence mycoses were strongly suspected. The overall clinical efficacy rate was 84.3% (43/51). Treatments were "remarkably effective" in 6 cases, "effective" in 37, "not effective" in 8 and "indeterminable" in 2. The efficacy rates were 100% (21/21) in the confirmed mycosis cases and 73.3% (22/30) in the suspected mycosis cases. The mycological efficacies in the cases for which causative strains were identified were: disappeared in 14 (66.7%), decreased in 4 (19%), unchanged in 2 (9.5%) and unknown in 1 (4.8%), thus the overall disappearance ratio was 70% (14/20). Chest X-ray showed the disappearance of shadow in 1 patient and improvements in 14 of 23 patients examined. Adverse reactions were observed in 5 of the 53 cases (9.4%). From these results, MCZ may be considered as a highly useful drug not only in the treatment of deep mycosis but also in cases for which mycosis is strongly suspected.

Changes of lymphocyte subsets in leukemia patients who received allogenic bone marrow transplantation.

Proportional changes of lymphocyte subsets in the peripheral blood were monitored by two-color flow-cytometry in seven leukemia patients who had received allogenic bone marrow transplantation (BMT). Lymphocyte counts, and proportions of T and B-cells returned to normal ranges between the 2nd and 12th months after BMT. Activated T-cells prominently increased after BMT, and the values gradually returned toward normal. As to lymphocyte subsets, the proportions of CD 4+ cells had remained low, while those of CD 8+ cells high for a whole observation period after BMT. The changes of CD 4+ cells were caused by the decrease of suppressor-inducer T-cells (CD 4+ Leu 8+). High proportion of CD 8+ cells was mainly associated with increased suppressor T-cells (CD 8+ CD 11+). Among natural killer (NK) cells, highly active NK cells (CD 16+ CD 57-) markedly increased shortly after BMT, and gradually returned to normal. CD 16 -CD 57+ NK cells increased beyond normal ranges after the 2nd month. The incidence or degree of acute and chronic graft-versus-host diseases (GVHD) did not correlate with the changes of any lymphocyte subsets. The present results suggest that the increase of activated T-cells shortly after BMT reflects lymphocyte reconstitution. The prolonged immune deficiency after BMT might be related to either deficient expression of homing receptor (Leu 8 antigen) on CD 4+ cells or increased suppressor T-cells (CD 8+ CD 11+). In addition, the early increase of NK cells after BMT may compensate for the immune deficiency in BMT patients.

[Clinical significance of gastrointestinal decontamination under protected environment].

Many infections are caused by the patient's own oro-intestinal microbial flora under a protected environment. Thirty-eight patients with acute leukemia and two patients with blast crisis of chronic myelocytic leukemia were treated under a protected environment with or without prophylactic antibiotics. Antibiotics used for decontamination were vancomycin (V), polymyxin B (P) and nystatin (N). The number of patients in the VPN, PN and the no antibiotic group were 13, 13 and 14, respectively. While the intestinal microbial flora was almost completely eliminated in VPN group, the number of bacteria decreased slightly in PN group. The mean number of pharyngeal and anorectal bacterial species decreased most markedly in the VPN group, but there were no significant differences among the three groups. The number of febrile days was significantly lower in the VPN and PN group than the no antibiotics group with neutrophil counts of less than 100 microliters. The average number of episodes of infection per patient was lowest in VPN group and highest in the no antibiotic group. These data indicate that VPN administration is effective for eliminating intestinal bacterial flora and resultantly protecting endogenous infections.

[Low-dose danazol therapy in idiopathic thrombocytopenic purpura].

Danazol was administered orally at a dosage of 50 mg/day to 17 patients (11 females and 6 males) with idiopathic thrombocytopenic purpura refractory to steroids and/or splenectomy. The patients had not been treated with conventional dosages of danazol. The drug was suspended in four patients because of adverse effects of danazol. In 13 patients (8 females and 5 males, mean age 44 y. o.) who received the danazol therapy for more than 6 months, there were no patients with an excellent response, and one patient had a good response to the therapy. The rest of the patients did not respond to danazol.

[Studies of intestinal microbial flora in the post-BMT (bone marrow transplantation) patients under a protected environment].

The changes of microbial burdens of six patients with leukemia (four patients with acute leukemia; two patients with chronic leukemia) were studied before and after bone marrow transplantation (BMT) under protected isolation. Oral nonabsorbable and topical antibodies were administered prophylactically to all patients. Under a protected environment, genus and species number of intestinal microbial flora were not so decreased in all patients who were treated with antibiotics, but no episodes of severe septicemia were detected due to intestinal microbial flora. From many previous reports, the same pathogen was isolated from both blood culture and stool in the patients with septicemia, however, no septicemia developed in our cases in spite of residue of many intestinal bacteria. These data have demonstrated a significant advantage of treatment with protected isolation and intensive antibiotic prophylaxis through oral, topical and intravenous administration for severe infection prevention.

[Acute renal failure following dehydration and hemolytic crisis due to pneumonia in a case of PNH].

A 41-year-old female, who had been diagnosed as having paroxysmal nocturnal hemoglobinuria (PNH) in 1985, was admitted to our hospital with cough, fever, diarrhea, vomiting and palpitation in April 1988. The chest X-ray showed pneumonia in her right lung. In the peripheral blood, red blood cell count was 1.64 x 10(6)/microliters, hemoglobin 4.7 g/dl and reticulocytes 19%. The levels of serum LDH, indirect bilirubin and creatinine were high. Pneumonia improved by the administration of antibiotics, however, anemia and renal failure deteriorated. After washed red blood cell transfusions totalling 2,000 ml and six times of hemodialysis, renal function returned to normal. This patient with PNH appeared to have developed acute renal failure by dehydration and hemolytic crisis due to pneumonia.

B-cell malignant lymphoma associated with monoclonal macroglobulinemia and cryoglobulinemia.

A 55-year-old man was admitted to our hospital with fever, ascites, generalized lymphadenopathy and hepatosplenomegaly. A cervical lymph node was biopsied and diagnosed as a diffuse mixed cell type B-cell malignant lymphoma with positive cytoplasmic IgM in plasmacytoid lymphocytes and immunoblasts. Serum protein electrophoresis disclosed a monoclonal peak and immuno-electrophoresis identified the abnormal protein as IgM kappa(k). Serum immunoquantitation revealed an IgM level of 1470 mg/dl. Bence-Jones protein of the k type was positive in the urine. Cryoglobulin with the characteristics of IgM was present in the serum. In peripheral blood, hemoglobin was 12.4 g/dl, WBC 26,500/microliters with increased abnormal cells and the platelet count 2.2 x 10(4)/microliters. Low fibrinogen and high FDP levels indicated the existence of disseminated intravascular coagulation (DIC). Gabexate mesilate (FOY) was administered at a dose of 1,000 mg/day for the DIC with very good response. After one course of combination chemotherapy (vincristine, cyclophosphamide, prednisolone, adriamycin), he achieved complete remission. However, three months later, he showed icterus and anorexia again with high levels of serum GOT and GPT and positive HBs antigen. On the 117th hospital day, he became abruptly developed right hemiplegia and coma. Cranial CT demonstrated massive thalamic bleeding in the left hemisphere with ventricular rupture, and he died on the same day.

Report of a case with chronic myelomonocytic leukemia: demonstration of leukemic monocytes lacking nonspecific esterase by flow cytometry using monoclonal antibodies.

Chronic myelomonocytic leukemia (CMML) is a rare leukemia, which is now included in myelodysplastic syndromes. In a small number of patients with CMML, problems in the diagnosis have been reported, especially when atypical morphological features in both monocytic and granulocytic cells due to dysmyelopoiesis are prominent, or when cytochemical characteristics are lost in the leukemic cells. The case history of a sixty-seven year-old male patient with CMML is described. The diagnosis of CMML in the patient was supported by the following evidence: chronic course of his disease; increased monocyte-like cells without other cause; normocytic anemia; immature granulocytic cells with hypogranular feature and giant platelets were observed in the peripheral blood. The bone marrow showed myeloid hyperplasia. Serum muramidase and vitamin B12 levels were increased, while neutrophil alkaline phosphatase score was low in the peripheral blood. Ph' chromosome was negative. The monocyte-like cells completely lacked nonspecific esterase. However the cells were confirmed as monocytic cells by flow cytometry using monoclonal antibodies to monocytes (OKM5).

Adult T-cell leukemia following long-term remission from non-Hodgkin's lymphoma.

A female patient who had been initially diagnosed with non-Hodgkin's lymphoma (NHL) and achieved complete clinical remission with combined chemotherapy, developed overt adult T-cell leukemia (ATL) after 9 yr of disease-free survival. This is the first case of the development of ATL following the complete remission of NHL. Secondary malignant neoplasms are not well-documented in patients previously diagnosed with Hodgkin's disease. Although there have been a few reports concerning the occurrence of secondary malignancy in patients with non-Hodgkin's lymphoma (NHL), there has never been a documented case of ATL following long-term survival from NHL. Here, we report a case of typical adult T-cell leukemia (ATL) which occurred after 9 yr disease-free survival from NHL.

Nodular sclerosing Hodgkin's disease with massive skin invasion.

Skin invasion is a rare manifestation in cases with Hodgkin's disease and if present mortality rate is very high. In general, almost all patients with advanced skin lesions die of the underlying disease in spite of any chemotherapy, however in case the patient recovered after intensive chemotherapy and irradiation. Moreover, the type of skin manifestation in this case is unique and quite different from the usual. This report describes a well-controlled case of Hodgkin's disease with massive and atypical skin invasion.