Foscarnet against human herpesvirus (HHV)-6 reactivation after allo-SCT: breakthrough HHV-6 encephalitis following antiviral prophylaxis.

High incidences of human herpesvirus (HHV)-6 encephalitis have recently been reported from several Japanese SCT centers. To evaluate the effect of low-dose foscarnet (PFA) in preventing HHV-6 infection among recipients of unrelated BM or cord blood (CB), we examined consecutive cohorts without prophylaxis against HHV-6 (cohort 1, n=51) and with PFA prophylaxis (cohort 2, PFA 50 mg/kg/day for 10 days after engraftment, n=67). Plasma real-time PCR assay was performed weekly. High-level reactivation defined as HHV-6 DNA > or =10(4) copies/mL by day 70 was the primary endpoint. No significant reduction of high-level reactivation was seen in cohort 2 (19.4%) compared with cohort 1 (33.8%, P=0.095). A trend was identified toward fewer high-level HHV-6 reactivations in cohort 2 among recipients of unrelated BM (P=0.067), but no difference in incidence was observed among CB recipients (P=0.75). Breakthrough HHV-6 encephalitis occurred following PFA prophylaxis in three patients, and incidence of HHV-6 encephalitis did not differ between cohort 1 (9.9%) and cohort 2 (4.5%, P=0.24). In conclusion, 50 mg/kg/day of PFA does not effectively suppress HHV-6 reactivation and cannot prevent all cases of HHV-6 encephalitis. To effectively prevent HHV-6 encephalitis, alternative approaches based on the pathogenesis of HHV-6 encephalitis will probably be required.

Correlations of HHV-6 viral load and plasma IL-6 concentration with HHV-6 encephalitis in allogeneic stem cell transplant recipients.

This study investigated factors associated with the development of human herpesvirus (HHV)-6 encephalitis. Among 111 enrolled subjects, 12 patients developed central nervous system (CNS) dysfunction. CNS dysfunction in four patients was found to have no association with HHV-6. The remaining eight patients displayed HHV-6 encephalitis (n=3), limbic encephalitis (HHV-6 DNA in cerebrospinal fluid was not examined; n=3) or CNS dysfunction because of an unidentified cause (n=2). Real-time PCR showed CNS dysfunction in the latter eight patients, which developed concomitant with the appearance of high plasma levels of HHV-6 DNA (> or =10(4) copies/ml). Overall, eight of the 24 patients with high-level HHV-6 DNA developed CNS dysfunction, whereas no patients developed CNS dysfunction potentially associated with HHV-6 infection if peak HHV-6 DNA was <10(4) copies/ml. We next analyzed plasma concentrations of IL-6, IL-10 and tumor necrosis factor-alpha among patients who displayed high-level plasma HHV-6 DNA and found elevated IL-6 concentrations preceding HHV-6 infection in patients who developed CNS dysfunction. (Mean+/-s.d.: 865.7+/-1036.3 pg/ml in patients with CNS dysfunction; 56.5+/-192.9 pg/ml in others; P=0.01). These results suggest that high-level HHV-6 load is necessary for the development of HHV-6 encephalitis, and systemic inflammatory conditions before HHV-6 infection form the preparatory conditions for progression to encephalopathy.

Plasma HHV-6 viral load-guided preemptive therapy against HHV-6 encephalopathy after allogeneic stem cell transplantation: a prospective evaluation.

Human herpesvirus 6 (HHV-6) causes life-threatening encephalopathy in recipients of allogeneic SCT, but no consensus has been reached regarding appropriate preventive methods. This study evaluated a plasma HHV-6 viral load-guided preemptive approach against HHV-6-associated encephalopathy. Plasma real-time PCR assay was performed once a week. Among 29 patients, 19 developed positive plasma HHV-6 DNA. Median maximum plasma HHV-6 DNA was 4593.5 copies/ml plasma (range, 150.0-127 891.0 copies/ml plasma). In one of eight events with low-level HHV-6 DNA (defined as <1000 copies/ml plasma) and four of seven events with mid-level HHV-6 DNA (1000-9999.5 copies/ml plasma), HHV-6 loads in plasma subsequently continued increasing. Ganciclovir was administered against six of nine patients with high-level HHV-6 DNA (> or =10,000 copies/ml plasma). High-level HHV-6 DNA resolved similarly in both groups with or without ganciclovir therapy. Among the nine patients with high-level HHV-6 DNA two developed encephalopathy. As encephalopathy developed before the detection of high-level HHV-6 DNA in plasma, these two patients had not received preemptive ganciclovir therapy. In conclusion, our preemptive approach against HHV-6-associated encephalopathy cannot prevent all cases of HHV-6 encephalopathy in SCT recipients due to the dynamic kinetics of plasma HHV-6 viral load.

Cefepime or carbapenem treatment for febrile neutropenia as a single agent is as effective as a combination of 4th-generation cephalosporin + aminoglycosides: comparative study.

1998, a consensus meeting was held in Miyazaki, Japan, to develop an approach to management of febrile neutropenia (FN). The K-HOT study group decided to examine whether this proposal was applicable to clinical practice in a multicenter study. Patients who developed fever with neutrophil counts <1,000/microL were randomized to receive either a single antibiotic, cefepime or one of the carbapenems, or a combination of cefepime and an aminoglycoside. Patients who became afebrile within the first 3 days were continued on the same treatment. Patients who remained febrile were switched to a combination regimen if they were randomized to receive a single agent, and patients on combination medication were changed from cefepime to another cephalosporin. A total of 165 patients were entered into the trial. One hundred fifty-three patients were evaluable for response. The average age was 52 years, and 70% of the patients had acute leukemia. Severe neutropenia, defined as <100/microL at the time of FN, was seen in 62% of the patients on entry and during the course of treatment 71% of patients experienced neutrophil counts of <100/microL. Microbiologically documented infection was seen in 6.5% for monotherapy, and 10.5% for a combination treatment, and fever of unknown origin occurred in 75.3% and 59.2% of the patients in each regimen, respectively. Excellent to good response was seen in two-thirds of the patients in all treatment groups. Adverse events were minimal, and three early deaths were observed at days 9, 16, and 16 among patients treated with a single antibiotic and three in the combination regimen group at days 14, 15, and 20. These results indicate that cefepime or a carbapenem alone is as effective as a combination of cefepime and an aminoglycoside for treating FN.

Antioxidant changes in the hypertrophied heart due to energy metabolic disorder.

Oxidative stress has been implicated in the pathogenesis of both heart hypertrophy and heart failure. Hypertrophied heart, in response to pressure overload, is associated with an increase in antioxidant capacity and a decrease in oxidative stress. However, in the hypertrophied heart due to energy metabolic disorder, antioxidant capacity has not been investigated. Antioxidant changes in juvenile visceral steatosis (JVS) mice, a model of heart hypertrophy due to disorder of fatty-acid oxidation, were examined at 4 weeks (developing hypertrophy stage) and 8 weeks of age (established hypertrophy stage). Superoxide dismutase activity in the JVS mice was higher than that in control mice at 4 weeks of age and was not different from that in the control mice at 8 weeks of age. Glutathione peroxidase activity in the JVS mice at 8 weeks of age was lower than that in the control mice. Catalase activity showed no significant differences between the control and the JVS mice. Lipid peroxidation in the JVS mice was significantly reduced at 4 weeks of age and increased toward control levels at 8 weeks of age. The levels of vitamin E in the heart were increased in the JVS mice at 8 weeks of age. To determine whether antioxidants affect the pathogenesis of hypertrophy in this model, long-term treatments of vitamin E and 2-mercaptopropionyl glycine were performed. Vitamin E treatment partially reduced the heart hypertrophy in these mice. The present study shows that heart hypertrophy in the JVS mice is accompanied with increased antioxidant capacity as indicated in other animal models of heart hypertrophy. The precise mechanism of heart hypertrophy in JVS mice is still unknown, but oxidative stress may play a role in the pathogenesis of heart hypertrophy.

Fetal aortic blood flow assessment from the relationship between fetal aortic diameter pulse and flow velocity waveforms during fetal development.

BACKGROUND: Blood flow is calculated from mean velocity across the vessel and its cross-sectional area and is related to the fetal growth. AIM: To investigate the relationship between diameter pulse waveform (DPW) and flow velocity waveform (FVW) in the fetal descending aorta during fetal development. STUDY DESIGN: Doppler ultrasound and a phase-locked loop echo tracking system were used to measure the FVW and DPW in the fetal descending aorta, respectively. SUBJECTS: We studied 137 normal-growth fetuses (normal group, 20-40 weeks) and 51 fetuses with high umbilical artery pulsatility index (umbilical placental insufficiency, UPI group, 26-40 weeks). OUTCOME MEASURES: We measured the systolic (Sd), diastolic (Dd) diameters, time diameter integral (TDI) and time velocity integral (TVI) and then calculated the TVI x TDI and TVI to TDI ratio. RESULTS: Normal fetal growth was associated with an increase in Sd, Dd, pulse amplitude, TVI, TDI and TVI x TDI. The FVW began to resemble the DPW with decreasing downstream resistance produced by growth of the placenta. The TVI was increased relative to the TDI. The differences in Sd, Dd, TDI and TVI x TDI between the normal and UPI groups were not significant. The TVI was decreased relative to the TDI. There was a decrease in the TVI as a ratio of the TDI. The Dd per unit fetal weight was high in the compromised fetuses. Fetal outcome was examined in relation to the TVI to TDI ratio. Those with a low ratio (below 10th centile) exhibited significantly more adverse indices of fetal outcome. CONCLUSIONS: In fetal compromise there is an increase in diastolic pressure in association with high placental resistance, which causes a major increase in afterload. The efficient circulation associated with fetal growth might be represented by an increase in the ratio of the TVI to the TDI (an index of efficient circulation) when these waveform shapes resemble each other.

Involvement of 1,2-diacylglycerol in improvement of heart function by etomoxir in diabetic rats.

Abnormal lipid metabolism has been proposed to be involved in the pathogenesis of diabetic cardiomyopathy. In this study, we measured myocardial lipid levels, including 1,2-diacylglycerol (1,2-DAG) and ceramide (CM), and myocardial function in diabetic rats. We also evaluated the effects of etomoxir (ETM), a carnitine palmitoyl transferase I inhibitor, on diabetic rat hearts from the viewpoints of alterations in lipid second messengers and myocardial function. Rats were injected with streptozotocin (60 mg/kg) to induce diabetes and were treated 5 weeks later with ETM (18 mg/kg) for 8 days. In diabetic rats, heart rate, systolic blood pressure, and fractional shortening were significantly reduced compared with those in controls. Treatment of diabetic rats with ETM ameliorated myocardial dysfunction other than heart rate. Myocardial 1,2-DAG levels in diabetic rats were significantly elevated compared with those in controls, while myocardial CM levels were not. ETM treatment caused an additional increase in myocardial 1,2-DAG levels in diabetic rats, but the CM levels did not change. There was a marked difference in fatty acid pattern of 1,2-DAG between diabetic and ETM-treated diabetic rat hearts. The fatty acids 18:1 and 18:2 were significantly increased and the fatty acids 16:0, 18:0, 20:4, and 22:6 were significantly reduced in ETM-treated diabetic rat hearts. These data suggest 1,2-DAG is involved in ameliorating myocardial dysfunction in diabetic rats and that its source is different between diabetic and ETM-treated diabetic rats. CM is unlikely to be involved in the pathogenesis of diabetic cardiomyopathy or the improvement of cardiac contractility in diabetic rats by ETM.

Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation.

Adult T cell leukemia/lymphoma (ATL) is a poor prognosis T cell malignancy. In order to improve the outcome, we employed allogeneic stem cell transplantation (allo-SCT) for ATL in 10 patients, nine of whom were from HLA-identical siblings and one from an unrelated donor. Conditioning regimens varied among the patients except that all received total body irradiation. The patients tolerated the regimens well with mild, if any toxicity, and engraftment occurred in all cases. Median leukemia-free survival after allo-SCT was 17.5+ months (range 3.7-34.4+). Six of the 10 patients developed acute GVHD (one case each with grade I, III or IV, and three cases with grade II) and three patients developed extensive chronic GVHD. Four patients died after allo-SCT during the study period from either acute GVHD (grade IV), pneumonitis, gastrointestinal bleeding or renal insufficiency. Two of the 10 cases with no symptoms of GVHD relapsed with clinical ATL. These results strongly suggest that allo-SCT may improve the survival in ATL if a controlled degree of GVHD develops.

Calcineurin inhibitor attenuates cardiac hypertrophy due to energy metabolic disorder.

BACKGROUND: Several studies have shown that calcineurin may play a critical role in the signalling of cardiac hypertrophy in various experimental models. OBJECTIVE: To elucidate whether calcineurin is involved in cardiac hypertrophy due to energy metabolic disorder by using the juvenile visceral steatosis (JVS) mouse, which is a murine model of systemic carnitine deficiency. METHODS AND RESULTS: Cardiac hypertrophy in JVS mice (C3H strain) progresses gradually after birth and is present until eight weeks of age. In this study, calcineurin activity in JVS mice increased significantly at four weeks of age (the developing stage of cardiac hypertrophy) compared with age-matched control mice. Treatment with calcineurin inhibitor FK506 (0.5 or 1.0 mg/kg/day) from the age of four to eight weeks attenuated cardiac hypertrophy without beneficially affecting cardiac function. Gene expression, accompanied by cardiac hypertrophy, was also suppressed by the FK506 treatment. CONCLUSIONS: The activation of calcineurin is involved in the development of cardiac hypertrophy in the JVS mouse, and calcineurin inhibition may be useful for reducing cardiac hypertrophy.

Cardiogenic shock triggered by verapamil and atenolol: a case report of therapeutic experience with intravenous calcium.

Cardiogenic shock developed in a 72-year-old Japanese woman during combination therapy with verapamil and atenolol for recurrent supraventricular arrhythmia. She had coronary atherosclerosis, liver cirrhosis and bradycardia-tachycardia syndrome. Despite of the high-dose catecholamines and counterpulsation, she progressively deteriorated. Bolus administration of intravenous calcium chloride (CaCl2) immediately resolved her hemodynamic collapse.

[A randomized trial of conventional dose vs reduced dose in BHAC-DM therapy for acute myelogenous leukemia in elderly patients].

Twenty-nine patients aged 60-75 years with newly diagnosed acute myelogenous leukemia (AML) were randomized to receive BHAC-DM either at a reduced dose (S-1 group, n = 13; BHAC 150 mg/m2 1-7 day, DNR 30 mg/m2 1-3 day, 6MP 70 mg/m2 1-7 day) or the conventional dose (S-2 group, n = 16; BHAC 200 mg/m2 1-7 day, DNR 40 mg/m2 1-3 day, 6MP 70 mg/m2 1-7 day). On day 7, patients were given therapy for 2 more days if the ratio of blasts in their bone marrow was more than 15%. Granulocyte-colony stimulating factor was injected when the leukocyte count decreased below 1,000/microliter. The rates of complete remission were 46.2% in the S-1 group and 43.8% in the S-2 group. No significant differences in response distinguished the 2 groups. The mortality rate during myelosuppression was 1/13 in the S-1 group and 1/16 in the S-2 group. The rate of treatment-related death was 10.1% for all patients. Grade-4 adverse effects were not seen in any of the patients. We concluded that the conventional dose of BHAC-DM was as acceptable as the reduced dose in elderly patients with AML.

Allogeneic bone marrow transplantation-related transmission of human T lymphotropic virus type I (HTLV-I).

We report here the first case report of bone marrow transplantation (BMT)-related transmission of human T lymphotropic virus type-I (HTLV-I). Antibodies against HTLV-I-associated antigens (anti-HTLV-I) were detected in the serum from the BMT recipient 12 days post BMT. IgG against gag core proteins (anti-p19 and anti-p24) appeared earlier than IgM against gag and env proteins (anti-p19, anti-p24 and anti-gp46) during seroconversion. The data presented here differs from blood transfusion-related seroconversion. This phenomenon may be due to the engraftment of anti-HTLV-I producing cells from the donor.

Reactive oxygen species production of neutrophils in patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid.

We measured N-formyl-methionyl-leucyl-phenylalanine-induced reactive oxygen species production by neutrophils from three patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid using a luminol-enhanced chemiluminescence assay. The maximum level of reactive oxygen species production during all-trans retinoic acid treatment was 58.8 +/- 2.3 x 10(4) (mean +/- SEM) counted photons per seconds (cps), which was significantly higher (p<0.0001) than that of neutrophils from health volunteers (13.3 +/- 2.3 x 10(4) cps).

Clonal identities and multiple isotype transcripts in hematological diseases revealed by a single-strand conformation polymorphism analysis of the immunoglobulin heavy chain messenger signals.

A single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction (PCR)-amplified products of immunoglobulin (Ig) heavy chain rearrangements can be used to analyze B cell clonalities and clonal identities of B cells from different samples. However, the usefulness of the PCR-SSCP analysis is not fully assessed in B cell malignancies. For example, we did not know whether the PCR-SSCP method can be used to detect tumor-related clones in peripheral blood of patients with multiple myeloma and Waldenström's macroglobulinemia. In addition, because genomic DNA is used in the PCR-SSCP method, we could obtain no information about the isotype of the expanded B cell clone. In this study, we combined the reverse transcriptase (RT)-PCR of immunoglobulin heavy chain transcripts with an SSCP analysis and thus analyzed eight healthy individuals, five patients with B chronic lymphocytic leukemia, four patients with multiple myeloma and three patients with Waldenström's macroglobulinemia. Clonal B cell populations were detected as discrete bands in the RT-PCR-SSCP analysis that can be readily detected over the background of polyclonal rearrangements. Circulating tumor-related clones were detected in all but one peripheral blood sample from multiple myeloma and Waldenström's macroglobulinemia patients and B cell clones in peripheral blood and bone marrow from these patients showed a similar mobility on SSCP gel. Because the transcripts of different isotypes were separately analyzed, we could thus determine the isotype of B cell clones as well. When monoclonal Igs of different isotypes were detected in the individual samples, we analyzed the relationship of each monoclonal band by excising the band and then further analyzing it by a PCR-SSCP analysis. RT-PCR amplification in conjunction with the SSCP analysis is thus considered to be a useful method to detect and characterize the B cell clones in hematological diseases.

A rapid method for determination of the relative copy number of HTLV-I proviral genome in HTLV-I carriers and adult T-cell leukemia patients by polymerase chain reaction.

Ten adult T-cell leukemia (ATL) patients and 11 asymptomatic human T-cell leukemia virus type I (HTLV-I) carriers were examined by polymerase chain reaction (PCR) assay with a reduced sensitivity to evaluate its utility in detecting the relative copy number of the HTLV-I genome in clinical samples. Differences in the intensities of the PCR products were observed between the acute type ATL patients and ATL patients in remission or carriers. Intense bands were found in all acute type ATL patients (6/6, 100%), while specific bands were seen in only 2 carriers (2/11, 18.2%). The bands found in one of the two patients in remission were weak. One patient, who had acute type ATL, had achieved a remission but later relapsed. Using this technique, we examined the differences in the intensities of the bands of the PCR products in a patient with acute type ATL who had achieved remission but later relapsed. Thus, this technique may be of clinical importance in diagnosing acute ATL and assessing the effect of therapy.

[Efficacy of combination with granisetron and methylprednisolone for nausea, vomiting and appetite loss in remission induction chemotherapy of acute myeloid leukemia--a randomized comparative trial between granisetron alone and granisetron plus methylprednisolone].

The prevention of nausea, vomiting and appetite loss induced by remission induction chemotherapy for acute myeloid leukemia was compared by randomization between granisetron alone and combination with granisetron plus methylprednisolone. Granisetron was administered at 40 micrograms/kg during chemotherapy, and methylprednisolone was administered concomitantly at 125 mg/body for 3 days or more in the combination group. The single and combination groups comprised 14 and 13 patients, respectively, and there was no significant difference between the background of both groups. To evaluate the effect they were scored according to 4 grades, and evaluated every 24 hours from the start of chemotherapy to 5 days after its completion. The complete inhibition rate of vomiting was as high as 71.4% and 92.3% in the single and combination groups, respectively, showing no significant difference. The grade of vomiting was mild in both groups. Nausea was noted in 71.4% and 46.2%, respectively, and the inhibitory effect tended to be higher in the combination group. Appetite loss developed in 92.9% and 41.7%, respectively, and the prevention effect was clearly higher in the combination group. The prevention effects on nausea 7, 8 and 10 days after the start of chemotherapy, on appetite loss 2-10 days after it, and 2-5 days after its completion, were higher in the combination group. Granisetron revealed an excellent inhibitory effect on vomiting induced by remission induction chemotherapy for acute myeloid leukemia, but combination with granisetron and methylprednisolone was considered useful for nausea in the latter half of the treatment period and for appetite loss during the whole period.

[Epstein-Barr virus associated Richter's syndrome accompanied by interstitial pneumonia].

A 65-year-old man who had an 8-year history of chronic lymphocytic leukemia was admitted to our hospital on February 19, 1998 because of high fever, dry cough, and weight loss. Laboratory data on admission included serum lactate dehydrogenase at 980 IU/l, CRP at 21.8 mg/dl, and soluble interleukin-2 receptor at 7,280 U/ml. The results of serological tests for Epstein-Barr virus (EBV) antibodies were as follows: EBV capsid antigen IgG 1:2560, EBV early antigen IgG 1:640, and EBV nuclear antigens 1:20. Computed tomography revealed diffuse interstitial pneumonia in both lungs, hepatosplenomegaly with multiple nodules, and enlarged intra-abdominal lymph nodes. In addition, Gallium-67 scintigraphy demonstrated abnormal accumulations. Although the patient initially responded well to combination chemotherapy, he eventually deteriorated and died on November 2, 1988, despite salvage chemotherapy. Postmortem needle biopsy specimens from the liver and spleen revealed diffuse proliferation of polymorphic large lymphoma cells. The lymphoma cells were positive for L-26, latent membrane protein 1, and EBV nuclear antigen, but negative for UCHL-1 and CD3, 5, 10, and 30. In situ hybridization procedures disclosed the presence of EBV-encoded small RNA in lymphoma cells. These findings suggested the possibility of association with EBV infection in some cases of Richter's syndrome.

Eosinophilia associated with adult T-cell leukemia: role of interleukin 5 and granulocyte-macrophage colony-stimulating factor.

To clarify the mechanism of eosinophilia in adult T-cell leukemia (ATL), we studied three ATL patients having marked eosinophilia. Eosinophil-predominant colony-stimulating activity was detected in the serum of one patient and in the conditioned media (CM) from cultured ATL cells from two patients. Soluble interleukin 5 (IL-5), but no interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), was detected in sera from all patients. On the other hand, GM-CSF was produced in vitro by ATL cells from all cases, whereas detectable IL-3 and IL-5 was produced by cells from only one, suggesting that in the other two cases, the serum IL-5 was produced by the normal reacting lymphocytes. The fact that no patient showed marked neutrophilia supports the possibility that IL-5 may have a leading role in the development of eosinophilia, with GM-CSF produced by ATL cells playing a complementary role.