Different profiles of circulating angiogenic factors and adipocytokines between early- and late-onset pre-eclampsia.

OBJECTIVE: Circulating angiogenic factors have been shown to be important in the pathophysiology of pre-eclampsia. Blood levels of adipocytokines differ in pre-eclampsia relative to controls and may also play an important role in disease pathogenesis. Differences in the circulating levels of these molecules were compared between matched normotensive controls and women with pre-eclampsia with onset before or at/after 32 weeks, and according to whether the women were of normal weight (18.5 < body mass index < 25) or overweight. DESIGN: A cross-sectional study of 110 pregnant Japanese women who visited the Department of Obstetrics and Gynecology, Okayama University Hospital, Okayama, Japan. SETTING: Tertiary referral centre serving 2000 births. METHODS: Serum concentrations of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), soluble endoglin (sEng), adiponectin and leptin were measured in women with pre-eclampsia and in normotensive controls matched for age, gestational week, parity and body mass index. Main outcome measures Serum levels of sFlt-1, PlGF, the sFlt-1/PlGF ratio, sEng, adiponectin and leptin. RESULTS: The sFlt-1/PlGF ratio in early-onset pre-eclampsia was significantly higher than that in late-onset pre-eclampsia (112.0 +/- 30.2 versus 45.4 +/- 43.8, P = 0.037). There was a significant elevation of leptin in both subtypes relative to controls (early: 58.6 +/- 18.3 ng/ml versus 26.0 +/- 6.7 ng/ml, P = 0.001; late: 39.5 +/- 9.2 ng/ml versus 22.0 +/- 4.3 ng/ml, P = 0.005), but adiponectin was increased only in late-onset pre-eclampsia (36.5 +/- 13.4 microg/ml versus 12.0 +/- 4.3 microg/ml, P = 0.003). Significant differences in angiogenic factors and adiponectin were found between normal and overweight women only in late-onset pre-eclampsia. CONCLUSIONS: These data suggest that there are different profiles of angiogenic factors and adipocytokines between women who develop early- and late-onset pre-eclampsia.

Mutation of putative divalent cation sites in the alpha 4 subunit of the integrin VLA-4: distinct effects on adhesion to CS1/fibronectin, VCAM-1, and invasin.

To investigate the functional significance of putative integrin divalent cation binding sites, several mutated alpha 4 subunit cDNAs were constructed. Mutants contained the conservative substitution of Glu for Asp or Asn at the third position in each of three putative divalent cation sites. Transfection of wild-type or mutated alpha 4 into K562 cells yielded comparable expression levels and immunoprecipitation profiles. However, for all three alpha 4 mutants, adhesion to CS1/fibronectin was greatly diminished in either the presence or absence of the stimulatory anti-beta 1 mAb TS2/16. Constitutive adhesion to vascular cell adhesion molecule (VCAM) 1 was also diminished but, unlike CS1 adhesion, was restored upon TS2/16 stimulation. In contrast, adhesion to the bacterial protein invasin was minimally affected by any of the three mutations. For each of the mutants, the order of preference for divalent cations was unchanged compared to wild-type alpha 4, on CS1/fibronectin (Mn2+ > Mg2+ > Ca2+), on VCAM-1 (Mn2+ > Mg2+ = Ca2+) and on invasin (Mg2+ = Ca2+). However for the three mutants, the efficiency of divalent cation utilization was decreased. On VCAM-1, 68-108 microM Mn2+ was required to support half-maximal adhesion for the mutants compared with 14-18 microM for wild-type alpha 4. These results indicate (a) that three different ligands for VLA-4 show widely differing sensitivities to mutations within putative divalent cation sites, and (b) each of the three putative divalent cation sites in alpha 4 have comparable functional importance with respect to both divalent cation usage and cell adhesion.

Phase I Study Evaluating the Combination of Afatinib with Carboplatin and Pemetrexed After First-line EGFR-TKIs.

BACKGROUND/AIM: Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. PATIENTS AND METHODS: We evaluated the safety and antitumor efficacy of afatinib combined with carboplatin and pemetrexed in EGFR-mutated non-small-cell lung cancer (NSCLC) patients who progressed during first-generation EGFR-TKIs. RESULTS: Ten patients received 20 or 30 mg/day afatinib with carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2). Dose-limiting toxicities included delay of afatinib ≥14 days, grade 3 diarrhea, grade 3 hypokalemia, grade 3 serum amylase increase and grade 4 thrombocytopenia. The recommended dose of afatinib was 20 mg/day in this combination therapy. Overall response rate was 30% and median progression-free survival was 13.7 months. CONCLUSION: This is the first study to investigate the combination of afatinib, carboplatin and pemetrexed. At the recommended dose, this combination was well tolerated and had a good clinical efficacy.

Expression and potential role of peroxisome proliferator-activated receptor gamma in the placenta of diabetic pregnancy.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed predominantly in adipose tissue and is known to be involved in adipocyte differentiation and insulin sensitivity. Recent reports indicated that PPARgamma-deficient mice were embryonic lethal due to abnormal placental development, suggesting that PPARgamma plays an important role in normal development of placenta. On the other hand, expression of vascular endothelial growth factor (VEGF), the other important factor in placental development, has been demonstrated to be regulated by PPARgamma in vascular smooth muscle cells. Also, diabetic pregnancy is often associated with defective placental functions. In order to investigate physiological roles of PPARgamma and VEGF in placental development during diabetic pregnancy, we examined the expressions of PPARgamma and VEGF in placentas, which were obtained from normal and streptozotocin-induced diabetic pregnant mouse, and studied in vitro effects of hyperglycemic condition and PPARgamma ligands (rosiglitazone and 15-deoxy-delta(12,14)prostaglandin J(2)) on trophoblasts using human choriocarcinoma cell lines. In diabetic mouse placentas (n=5), expressions of PPARgamma and VEGF proteins significantly increased as compared with these in normal placenta (n=3 or 4). In vitro studies indicated that hyperglycemic condition (42 mM) significantly enhanced the PPARgamma expression and hCG production, and significantly suppressed cell proliferation, however these effects were attenuated by PPARgamma ligands that accompanied with increased VEGF production. These data suggest that the PPARgamma pathway might be involved in the impairment of placental development induced by high glucose conditions, and that VEGF might play some roles in this pathway.

Defining extracellular integrin alpha-chain sites that affect cell adhesion and adhesion strengthening without altering soluble ligand binding.

It was previously shown that mutations of integrin alpha4 chain sites, within putative EF-hand-type divalent cation-binding domains, each caused a marked reduction in alpha4beta1-dependent cell adhesion. Some reports have suggested that alpha-chain "EF-hand" sites may interact directly with ligands. However, we show here that mutations of three different alpha4 "EF-hand" sites each had no effect on binding of soluble monovalent or bivalent vascular cell adhesion molecule 1 whether measured indirectly or directly. Furthermore, these mutations had minimal effect on alpha4beta1-dependent cell tethering to vascular cell adhesion molecule 1 under shear. However, EF-hand mutants did show severe impairments in cellular resistance to detachment under shear flow. Thus, mutation of integrin alpha4 "EF-hand-like" sites may impair 1) static cell adhesion and 2) adhesion strengthening under shear flow by a mechanism that does not involve alterations of initial ligand binding.

Effects of insulin, dexamethasone and glucagon on the production of apolipoprotein A-I in cultured rat hepatocytes.

Cultured rat hepatocytes were used to study the effects of hormones on the production of apo A-I. In addition, we compared these effects with the production of albumin. Hepatocytes were isolated from normal adult rat livers and cultured in MEM, as nearly confluent monolayers. In the absence of hormones, apo A-I and albumin accumulated in the culture medium almost linearly for periods up to 24 h. The rates of accumulation of apo A-I and albumin in the medium were 22 ng/mg cell protein per h and 1.2 micrograms/mg cell protein per h, respectively. During the incubations the cellular contents of apo A-I remained constant. Insulin stimulated the production of albumin at concentrations over 10(-10) M, but inhibited the production of apo A-I at concentrations over 10(-8) M. Dexamethasone showed no significant effects on albumin production but stimulated apo A-I production at concentrations over 10(-6) M. Glucagon inhibited the production of albumin and apo A-I dose-dependently at concentrations over 10(-10) M. Thus, the production of albumin and apo A-I are presumably controlled by different regulatory mechanisms.

Effect of insulin, glucagon or dexamethasone on the production of apolipoprotein A-IV in cultured rat hepatocytes.

We studied the effects of insulin, glucagon or dexamethasone on the production of apolipoprotein A-IV (apo A-IV) by cultured rat hepatocytes, using specific radioimmunoassay for rat apo A-IV. We also compared the effect of these hormones on the production of apo A-IV with those of albumin and apo A-I, reported previously. In the absence of hormones, apo A-IV and albumin in culture medium increased almost linearly for periods up to 24 h. The rates of accumulation of apo A-IV and albumin in the medium were 15.4 ng/mg cell protein per h and 1.2 micrograms/mg cell protein per h, respectively. The concentration of intracellular apo A-IV remained constant during the incubation. Insulin stimulated the production of albumin, but inhibited the production of apo A-IV dose-dependently. Glucagon inhibited the production of both albumin, and apo A-IV dose-dependently. Dexamethasone showed no significant effects on albumin production, but stimulated apo A-IV production. Thus, apo A-IV production in hepatocytes is regulated by several hormones with different effects on albumin production. The regulatory effects of these hormones on apo A-IV production were almost identical with the effects observed in a course of apo A-I synthesis, suggesting that the production of the two apoproteins are regulated by similar mechanisms.

Clinical significance of LEA-1 expression in adult acute myeloid leukemia.

In this study, we examined expressions of several adhesion molecules (AdMs), i.e. leukocyte function antigen-1 (LFA-1: CD11a/CD18), Hermes homing receptor (CD44) and intercellular adhesion molecule-1 (ICAM-1: CD54), on leukemia cells from 51 adult patients with newly diagnosed acute myeloid leukemias (AMLs) to elucidate clinical significance of these AdM expressions. Those expressions in lymphoid malignancies have been correlated with tumor evolutions, but CD44 was detected in all the AML cases examined and CD54 expression did not associate with their clinical characteristics or outcomes. However, we found that LFA-1 expressions significantly correlated with splenomegaly, resistance to induction chemotherapies and short survival periods in AML patients.

Bcl-2 protein expression and gut neurohormonal polypeptide/amine production in colorectal carcinomas and tumor-neighboring mucosa, which closely correlate to the occurrence of tumor.

To clarify whether advanced colorectal carcinomas and tumor-neighboring mucosa simultaneously produce both Bcl-2 protein and gut neurohormonal polypeptides and/or amines, and the interrelationship of these phenomenon, we studied retrospective analysis of Bcl-2 protein production and neuroendocrine characteristics in 52 cases of advanced colorectal carcinoma and surrounding mucosa. All of the tumor-neighboring mucosa presented hyperplasia. The rates of enhanced immunoreactivity of the tumor-neighboring mucosa and of positive immunoreactivity of the carcinomas against human Bcl-2 protein and against human vasoactive intestinal polypeptide, pancreatic polypeptide and somatostatin were 78.8% and 94.2%, 82.7% and 59.6%, 78.8% and 67.3%, and 88.5% and 84.6% respectively. Double immunostaining for Bcl-2 protein and each peptide hormone revealed simultaneous expression. In contrast, that of tumor-neighboring mucosa and carcinomas to serotonin and chromogranin-A and to argyrophilia were 11.5% and 1.9%, 32.7% and 17.3%, and 26.9% and 21.2%, respectively. We concluded that tumor-neighboring crypt cells displayed not only hyperplasia but also neuroendocrine characteristics and that enhanced Bcl-2 protein immunoreactivity correlated with tumor occurrence in the wall of the colorectum. The production of Bcl-2 protein by tumor cells and tumor-neighboring crypt cells indicates that the bcl-2 protooncogene may act not only as an inhibitor of apoptosis but also as an inducer of neuroendocrine differentiation from the latent characteristics of the endodermal stem cell.

Hematologic response in patients with aplastic anemia after long-term administration of recombinant human granulocyte colony-stimulating factor and erythropoietin.

Twenty patients with aplastic anemia underwent long-term administration (10 weeks) of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in doses from 50 to 800 micrograms/m2 per day by intravenous infusion or 50 to 100 micrograms/m2 per day by subcutaneous injection and re-combinant human erythropoietin (rhEPO) in doses ranging from 2000 to 8000 IU/m2 per day by intravenous injection three times a week for at least 4 weeks. The goal was to evaluate whether therapy ameliorated pancytopenia in these patients as well as to determine its safety. All assessable patients showed a substantial increase in absolute neutrophil count, with a recovery of myeloid components (granulocyte series) in the bone marrow, after 2 to 10 weeks of treatment. An increase > 1.5 g/dL in hemoglobin (Hb) concentration was observed in 2 patients (10%). A decrease > 50% in red cell transfusion requirement was observed in 2 patients (10%). Seven patients showed recovery of neutropenia, anemia, and platelet count. In addition, there was no serious infection before or during therapy, and side effects were mild. Of the 20 patients, 3 showed a dramatic improvement in severe anemia after 10 weeks of treatment accompanying a recovery of erythroid components in the bone marrow. They no longer require red cell transfusions and have had normal Hb concentrations and normal ferrokinetics. These results indicate that long-term administration of rhG-CSF and rhEPO may benefit some patients with aplastic anemia. Further studies will be necessary to elucidate the mechanism by which rhGCSF and rhEPO stimulate hematopoiesis and improve hematologic abnormalities in these patients.

Beta1 integrins play an essential role in adhesion and invasion of pancreatic carcinoma cells.

To investigate the role of beta1 integrins in pancreatic carcinoma invasion, we analyzed the relationship between the activity of beta1 integrins and the invasive ability of human pancreatic carcinoma cell lines. AsPC1, BxPC3, PANC1, SU8686, KP1NL, KP2, and H48N cells had high expression of beta1 and alpha6 subunits, and various levels of alpha2, alpha3, and alpha5 expression as determined by flow cytometry. Cell adhesion assay revealed that alpha2beta1, alpha5beta1, and alpha6beta1 integrins were the predominant adhesion receptors for collagen, fibronectin, and laminin, respectively. Beta1 integrins on different cell types showed a wide range of constitutive activity. Anti-beta1 monoclonal antibody (MAB) TS2/16 rapidly activated beta1 integrins, and thus TS2/16 requirement in cell adhesion represented the levels of constitutive activity of beta1 integrins. Notably, as the result of in vitro chemoinvasion assay, the levels of constitutive activity of beta1 integrins correlated with the invasive ability of pancreatic carcinoma cells. The inhibitory anti-beta1 MAB 13 completely blocked the invasion of these cell lines. Alternatively, the stimulatory anti-beta1 MAB TS2/16 strongly inhibited the invasion. These results show an essential role of beta1 integrins in invasion of pancreatic carcinoma cells and also suggest subtle regulatory mechanisms of cell invasion.

Development of Sjögren's syndrome during treatment with recombinant human interferon-alpha-2b for chronic hepatitis C.

A 63-year-old woman with type C chronic active hepatitis developed Sjögren's syndrome after being treated with recombinant interferon-alpha-2b. After 3 months' interferon-alpha administration, serum levels of gamma-globulin (4.5 g/dl) and titers of antinuclear and anti-SS-A antibodies were greatly increased, anti-SS-B antibody appeared, and the erythrocyte sedimentation rate was elevated. Although no xerostomia was exhibited, the patient experienced conjunctival dryness. Schirmer's test showed reduced lacrimal gland function and a gum test showed reduced salivary gland function. Sialography revealed scattered pools of retained contrast media with a diameter of around 1-2 mm. Based on these findings, a diagnosis of Sjögren's syndrome was made. This present case may provide important information regarding the pathogenesis of Sjögren's syndrome.

Plasma nitrite/nitrate concentrations as a tumor marker for hepatocellular carcinoma.

Since plasma concentrations of nitrite/nitrate, the stable end-products of nitric oxide, increase in patients with hepatocellular carcinoma (HCC) correlatively to tumor volume, we examined the ability of plasma nitrite/nitrate to discriminate between those patients with HCC and those without and compared the diagnostic performance of the parameter with that of serum alpha-fetoprotein (AFP) concentrations. Plasma nitrite/nitrate and serum AFP concentrations were measured using a Griess reaction and a solid phase enzyme immunoassay, respectively. Eighty-nine patients with chronic liver diseases (CLD) with (n=39) or without HCC (n=50) and 50 healthy control subjects participated in the study. A receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value and accuracy. The areas under ROC curves for nitrite/nitrate and AFP were calculated to be 0.758 and 0.812, respectively, which were not significantly different. There was no correlation between the concentrations of plasma nitrite/nitrate and serum AFP. The sensitivity, the specificity, and diagnostic efficiency were 79.5, 72.0, and 75.3%, respectively, for nitrite/nitrate, and 74.4, 76.0, and 75.3%, respectively, for AFP. Based on a partial ROC curve, the clinical utility of plasma nitrite/nitrate as a tumor marker approximated that of serum AFP, but exceeded in AFP-negative patients. Indeed, nitrite/nitrate was positive in 70% of AFP-negative HCC patients. The simultaneous determinations of serum AFP and plasma nitrite/nitrate concentrations gave significant improvement in detection of HCC in CLD patients compared with that of serum AFP alone.

Three-year follow-up of the Japanese patients with microvascular angina attributable to coronary microvascular spasm.

BACKGROUND: We recently reported that coronary microvascular spasm could cause angina in patients with chest pain and normal coronary arteriograms. However, the long-term prognosis of these patients or the effect of calcium channel blockers is not known. METHODS: Of consecutive 283 patients who underwent acetylcholine testing for the evaluation of chest pain, we identified 68 patients with microvascular angina attributable to coronary microvascular spasm. All patients were discharged on calcium channel blockers and followed up for an average period of 3.3 years. RESULTS: As compared with those having epicardial spasm (n=169), there was a female predominance in the microvascular spasm group (P<0.01), and 81% of the female patients were postmenopausal. During the follow-up, no patient died and one patient (1%) developed non-Q wave myocardial infarction. The frequency of chest pain was unchanged or increased in 24 patients (36%) and decreased or disappeared in 42 patients (64%). The angina status was improved only in 16 of 33 patients treated with calcium channel blockers alone. By contrast, it was improved in 18 of 21 patients on the combination of calcium channel blockers and angiotensin converting enzyme inhibitors (P<0.05). CONCLUSIONS: Patients with microvascular angina in the present study were more women and had a different risk factor profile as compared with those having epicardial spasm. Long-term prognosis was excellent with regard to mortality, but angina persisted in many patients even on calcium channel blockers. The result warrants prospective studies to evaluate the efficacy of angiotensin converting enzyme inhibitors as adjunct to calcium channel blockers in this population.

Circadian variations and prednisolone-induced alterations of circulating lymphocyte subsets in man.

We determined the circadian variations and prednisolone (PSL)-induced alterations of circulating lymphocyte subsets in 10 healthy adults by two-color flow cytometry using monoclonal antibodies to various lymphocyte subsets in order to collect fundamental data for monitoring of the subsets in clinical practice. This study first examined the changes of CD5+ B cells, gamma delta+ or gamma delta-T cells, activated (HLA-DR+) CD4+ or CD8+ cells, CD11b+ or CD11b-CD8+ cells, and natural killer (NK) cell subsets (CD16+CD57-, CD16+CD57+, CD16-CD57+), in addition to other subsets described before. Compared with the base line values obtained at 9:00 (AM) on day 1, lymphocytes, total B cells, CD5+ B cells, total T cells, gamma delta-T cells, CD4+ cells, activated CD4+ cells, CD45RA-CD4+ cells, and activated CD8+ cells were significantly increased at 20:00 (PM). However, the numbers of CD45RA+CD4+ cells, CD11b+ or CD11b-CD8+ cells and three NK cells subsets did not show significant circadian variations. After oral PSL (30 mg), which was given at 7:00 (AM) on day 2, lymphocytes and almost all lymphocyte subsets, except for CD16+CD57- cells, were significantly decreased; these changes recovered between 13 and 26 hours after PSL administration. The circadian variations and PSL-induced alterations of lymphocyte subsets were relatively comparable, but PSL administration cause a decrease in a wider range of lymphocyte subsets including relatively corticosteroid-resistant subsets such as CD45RA+CD4+ cells, CD8+ cell and NK cell subsets.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical studies of a newly developed miconazole preparation for intravenous drip infusion (MJR-1761) in hematologic disease patients with deep-seated fungal infections].

The efficacy and safety of a newly developed miconazole preparation (MJR-1761) for intravenous drip infusion were evaluated in 22 patients with hematological diseases complicated by documented or suspected deep-seated fungal infections. They consisted of 15 patients with fungemia, 2 patients with pulmonary mycosis, and 5 patients with mycosis of the digestive tract. Of the 5 patients, 3 had a complication of fungemia and 1 a complication of urinary tract mycosis. Of the 22 patients, 21 were clinically evaluable. All the patients were included in safety evaluation. The effective rate was 86% (18/21) when moderately improved or better evaluations were included, and the usefulness rate was 81% (17/21) when moderately or more useful evaluations were taken into consideration. Side effects occurred in 4 patients, and abnormal laboratory values were obtained in 4 patients. All these changes, which were previously reported, improved after the discontinuation of the treatment. The results presented indicate that the miconazole intravenous drip infusion solution used in this study is as effective as conventional similar preparations. Since the infusion solution need not be diluted immediately before use, it is simple to use, and its safety may be highly rated. The purpose can be met with less volume of solution per use than before because the preparation contains as much as 200 mg of miconazole in 75 ml of solution. This preparation seems to lend itself better to clinical application than conventional similar infusion solutions.

Decay-accelerating factor (DAF, CD55)-negative T lymphocytes in the peripheral blood of Sjögren's syndrome patients.

OBJECTIVE: To clarify possible associations of decay-accelerating factor (DAF, CD55), expressed on circulating lymphocyte subsets and other hematologic cells, with corresponding cytopenias observed in primary Sjögren's syndrome (SS). METHODS: DAF expression on peripheral blood (PB) cells was determined in 21 patients with SS and 11 healthy controls by single or 2 color flow cytometry. RESULTS: In the PB from SS patients, anemia, monocytopenia, neutropenia, and lymphocytopenia were observed. Compared to the controls, the percentages of DAF-negative cells were higher in CD4+ and CD8+ T cell subsets from SS patients, but the expression of DAF was similar in the other PB cells, including CD19+ B cells, CD56+ NK cells, monocytes, granulocytes, and erythrocytes. The percentages of DAF-negative cells among the CD4+ and CD8+ cells were positively correlated in SS patients, but the numbers of cells in both subsets were decreased in those patients being treated with prednisolone. However, these proportional changes are thought to reflect a decrease in the numbers of DAF-positive CD4+ and CD8+ cells, because the absolute numbers of circulating DAF-positive CD4+ and CD8+ cells, but not DAF-negative cells, were significantly decreased in SS patients. In addition, DAF-negative cells were detectable in both CD45RA+ (naive) and CD45RO+ (memory) T cells from healthy individuals, and the expression of DAF was remarkably increased in both subsets after in-vitro activation with concanavalin-A. CONCLUSION: DAF-negative cells are proportionally increased among circulating CD4+ and CD8+ T cells in SS patients, although such changes are due to decreased numbers of DAF-positive cells within each subset. When considering previous observations, the DAF-negative CD4+ and CD8+ cells probably belong to activated T cell subsets in both SS patients and controls. However, the patterns of DAF expression seemed to be different between activated T cells recognized in the PB, and those induced by in vitro-stimulation.

[Hypereosinophilia after allogeneic bone marrow transplantation. A possible role of IL-5 overproduction by donor T-cells chronic GVHD].

Chronic graft-versus-host disease (GVHD) is thought to result from abnormalities of several cytokine regulations in vivo. We analyzed interleukin-5 (IL-5) production by peripheral lymphocytes in a patient showing hypereosinophilia associated with chronic GVHD after allogeneic bone marrow transplantation. IL-5 production by activated T-lymphocytes which are known to play a major role in chronic GVHD was upregulated when stimulated by PMA + ionomycin. Therefore, hypereosinophilia observed in our patient may be correlated with IL-5 production in donor T-lymphocytes.

[Pure red cell aplasia induced by erythromycin and furosemide effects on in vitro erythroid colony forming unit (CFU-E)].

A 84-year-old man was treated with antibiotics including erythromycin and a diuretic (furosemide) because of acute heart failure and pneumonia. During the treatment, he developed moderate anemia (Hb 8.7g/dl). His anemia improved after the treatment. He again developed marked anemia (Hb 6.3g/dl) during the second treatment with erythromycin and furosemide and received blood transfusions. Bone marrow aspiration study revealed severe erythroid hypoplasia (0.2%). He was referred to our hospital, but he was not treated because his hemoglobin levels and reticulocyte count increased (80%) and his bone marrow showed increased erythroblasts (41.5%). His anemia gradually improved without any treatment. We diagnosed the case as drug-induced pure red cell aplasia (PRCA). We cultured bone marrow cells obtained from the present case and four normal healthy volunteers by a plasma clot method to determine the effects of two drugs on the number of erythroid colony forming unit (CFU-E). Furosemide strongly inhibited the CFU-E colony formation in the patient, but the inhibition effect of erythromycin was moderate. Furthermore, CFU-E was markedly suppressed by a combination of erythromycin and furosemide in both patient and control materials. These results indicate that both furosemide and erythromycin were related to the occurrence of PRCA in this patient.

[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.