Plasma CD147 reflects histological features in patients with lupus nephritis.

OBJECTIVE: A glycosylated transmembrane protein, CD147, has been implicated in regulating lymphocyte responsiveness and leukocyte recruitment. As lupus nephritis (LN) often follows a relapsing-remitting disease course, accurate understanding of the disease activity would be extremely helpful in improving prognosis. Unfortunately, neither clinical nor serological data can accurately reflect the histological features of LN. The present study investigated whether CD147 can accurately predict pathological features of LN. METHODS: Plasma and spot urine samples were collected from 64 patients who underwent renal biopsy between 2008 and 2011. Disease activity for LN tissues was evaluated using the biopsy activity index, and compared to levels of biomarkers including CD147. RESULTS: In LN tissues, CD147 induction was striking in injured glomeruli and infiltrating inflammatory cells, but not in damaged tubules representing atrophy. Plasma CD147 levels accurately reflected the histological disease activity. However, prediction using a single molecule would be quite difficult because of the complex pathogenesis of LN. The diagnostic accuracy of multiplex parameters indicated that the combination including plasma CD147 might yield excellent diagnostic abilities for guiding ideal LN therapy. CONCLUSION: Plasma CD147 levels might offer useful insights into disease activity as a crucial biomarker in patients with LN.

Analysis of a questionnaire on adverse reactions to blood donation in Japan.

In 2007, the Japanese Red Cross Blood Center performed a large-scale questionnaire study of post-donation adverse reactions. The questionnaire was distributed to 98,389 donors, and the answers were returned by 55,231 (56.1%). In total, 2,877 (5.2%) complained of an adverse reaction. Assuming that there were no adverse reactions for the 46,150 donors who did not reply, the rate of adverse reaction can be speculated to be 2.8%. Our study strongly suggests that blood centers have long underestimated the risks of vaso-vagal reactions. Taking at least 6h of careful rest after donation would be a helpful counter measure.

Consecutive national surveys of ABO-incompatible blood transfusion in Japan.

BACKGROUND AND OBJECTIVES: Morbidity and mortality from ABO-incompatible transfusion persist as consequences of human error. Even so, insufficient attention has been given to improving transfusion safety within the hospital. MATERIALS AND METHODS: National surveys of ABO-incompatible blood transfusions were conducted by the Japanese Society of Blood Transfusion, with support from the Ministry of Health, Labor and Welfare. Surveys concluded in 2000 and 2005 analysed ABO-incompatible transfusion data from the previous 5 years (January 1995 to December 1999 and January 2000 to December 2004, respectively). The first survey targeted 777 hospitals and the second, 1355 hospitals. Data were collected through anonymous questionnaires. RESULTS: The first survey achieved a 77.4% response rate (578 of 777 hospitals). The second survey collected data from 251 more hospitals, but with a lower response rate (61.2%, or 829 of 1355 hospitals). The first survey analysed 166 incidents from 578 hospitals, vs. 60 incidents from 829 hospitals in the second survey. The main cause of ABO-incompatible transfusion was identification error between patient and blood product: 55% (91 of 166) in the first survey and 45% (27 of 60) in the second. Patient outcomes included nine preventable deaths from 1995 to 1999, and eight preventable deaths from 2000 to 2004. CONCLUSION: Misidentification at the bedside persists as the main cause of ABO-incompatible transfusion.

Specific binding of amyloid-beta-protein to IMR-32 neuroblastoma cell membrane.

In flow cytometry using two detecting methods, we have found that amyloid-beta-protein(1-40) [Abeta(1-40)] has high affinity to IMR-32 neuroblastoma cell membrane when it is aggregated to form beta-sheet conformation, whereas random coil small Abeta-species has low affinity. The difference in the binding ability to the cell membranes well accounts for the cytotoxicity of Abeta(1-40); namely, aggregated beta-sheet Abeta(1-40) gives cytotoxicity higher than random coil Abeta(1-40). Specific binding between Abeta(1-40) and ganglioside GM1 of the raft-like domain in lipid membrane is suggested from a surface plasmon resonance (SPR) experiment.

Association of MBL gene polymorphisms with major bacterial infection in patients treated with high-dose chemotherapy and autologous PBSCT.

A growing body of evidence indicates that genetic factors are involved in an increased risk of infection. We investigated whether mannose-binding lectin (MBL) gene polymorphisms that cause low levels of MBL are associated with the occurrence of major infections in patients, mainly bearing hematological malignancies, after high-dose chemotherapy (HDT) rescued by autologous peripheral blood stem cell transplantation (auto-PBSCT). A retrospective evaluation of 113 patients treated with HDT and auto-PBSCT revealed that the low-producing genotypes, B/B and B/LXA, were associated with major bacterial infection (P=0.0016, OR 7.9). We next performed a nation-wide large-scale study to assess the allele frequency of the MBL coding mutation in a total of 2623 healthy individuals in Japan. The frequency of allele B was estimated to be approximately 0.2, almost the same in seven different areas of Japan. This common occurrence suggests that MBL deficiency may play an important role in the clinical settings of immunosuppression.

Influence of transplanted dose of CD56+ cells on development of graft-versus-host disease in patients receiving G-CSF-mobilized peripheral blood progenitor cells from HLA-identical sibling donors.

We investigated effects of variations in the cellular composition of G-CSF-mobilized peripheral blood progenitor cell (G-PBPC) allografts on clinical outcomes of allogeneic PBPC transplantation. We retrospectively analyzed transplanted doses of various immunocompetent cells from 27 HLA-identical sibling donors in relation to engraftment, incidence of graft-versus-host disease (GVHD), and survival. Significant variability was documented in both absolute numbers and relative proportions of CD34+, CD2+, CD3+, CD4(high)+, CD4+25+, CD8(high)+, CD19+, CD56+, and CD56+16+ cells contained in these allografts. Stepwise Cox regression analysis revealed that the CD56+ cell dose was significantly inversely correlated with the incidence of GVHD. Thus, there was a significantly higher incidence of grade II acute GVHD in patients receiving a lower CD56+16+ cell dose (hazard ratio (HR) 0.0090; 95% confidence interval (CI), <0.00001-3.38; P=0.031), a higher incidence of chronic GVHD in those receiving allografts with a lower CD56+16+ to CD34+ ratio (HR <0.00001; 95% CI <0.00001-0.0007; P=0.0035), and a higher incidence of extensive chronic GVHD in those receiving allografts with a lower CD56+ to CD34+ ratio (HR <0.00001; 95% CI <0.00001-0.053; P=0.0083). These results suggest that CD56+ cells in G-PBPC allografts from HLA-identical sibling donors may play an important role in preventing the development of GVHD.

Hemophagocytic syndrome: a rare complication of allogeneic nonmyeloablative hematopoietic stem cell transplantation.

We report two cases of patients with malignant lymphoma who presented with early onset of hemophagocytic syndrome after nonmyeloablative allogeneic peripheral blood stem cell transplantation. Fever and skin eruption developed early after transplantation, and neurological symptoms preceded cytopenia and worsened progressively. Activated macrophages with hemophagocytosis were found in bone marrow of the two patients at day 15 and 56, respectively. The fact that no obvious infectious agents associated with hemophagocytic syndrome were detected, and that serum soluble interleukin-2 receptor concentrations were elevated in the early phase after transplantation, reflecting the activation of donor-derived T cells, suggests that this complication resulted from an alloimmune response.

Intracellular cytokine profile of CD14 positive cells in patients with hematologic malignancies and solid tumors during hematologic recovery phase after intensive chemotherapy designed to mobilize peripheral blood stem cells.

We studied intracellular cytokines in monocytes by flow cytometry from 28 patients with hematologic malignancies and solid tumors to analyze the role of monokines in the hematologic recovery phase for peripheral blood stem cell harvest. The patients were divided into three groups: the first group, A, had a documented infection; the second group, B, had fever of unknown origin; and the third group, C, was afebrile. We found an increase in intracellular IL-1alpha, IL-6, IL-8 and TNF-alpha positive monocytes as CD14 positive gated cells cultured with lipopolysaccharide in all groups, but no increase was found with medium only when cultured for 4 h. We also found an increase in intracellular IL-1a, IL-6, IL-8 and TNF-alpha positive monocytes cultured with autologous serum for 4 h, but only in group A. The rate of intracellular cytokine positive cells was higher in monocytes cultured with only autologous serum from group A patients compared to those cells from the other groups; the data concerning IL-1a, IL-6 and TNF-alpha reached statistical significance (P < 0.05). However, increasing intracellular cytokine levels in the control group of patients exhibiting only infectious disease were observed. Thus, it appear that pro-inflammatory intracellular cytokine levels in monocytes are only related to microbial infections.

The property of a novel v2 receptor mutant in a patient with nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus (NDI) is characterized by resistance of the kidneys to the action of arginine vasopressin (AVP); X-linked recessive NDI is caused by an inactivating mutation of the vasopressin type-2 (V2) receptor. Several missense mutations in the first or second extracellular loop of the V2 receptor have been reported, and some of these mutant receptors were confirmed to have reduced affinities for ligand binding. We detected a novel V2 receptor gene mutation, a substitution of cysteine for arginine-104 (R104C) located in the first extracellular loop of the V2 receptor, in a patient with congenital NDI. Functional analysis by transient expression studies with COS-7 cells showed binding capacity of R104C mutant diminished as 10% of wild type, but binding affinity was strong rather than wild type. In the result of AVP stimulation studies, maximum cAMP accumulation of R104C decreased as 50% of wild type. On the other hand, a designed mutant receptor, substituted serine for arginine-104 as a model of modified R104C mutant receptor removed the influence of the sulfhydryl group in cysteine-104, recovered binding capacity up to 50% of wild type and maximum cAMP accumulation as 82% of wild type. Our study demonstrated that the R104C mutation of the V2 receptor was a cause of NDI. The mechanism of renal resistance to AVP was the reduction of ligand binding, and adenylyl cyclase activation depended on the V2 receptor. In addition, we confirmed that the sulfhydryl group of the cysteine-104 caused most part of R104C mutant receptor dysfunction.

Prevalence of hepatitis B or C virus infections in patients with non-Hodgkin's lymphoma.

BACKGROUND: Hepatitis C virus (HCV) and hepatitis B virus (HBV) are not only hepatotropic, but also lymphotropic viruses. Recently, some reports suggested that these viruses may participate in the development of malignant lymphoproliferative disorders. METHODS: We investigated the prevalence of HCV or HBV infection in 348 patients with non-Hodgkin's lymphoma (NHL). We also compared these prevalences with those in blood donors as a control group representing the general population in our area (n= 1,513,358). Next, we evaluated the clinical and pathologic characteristics of HCV- or HBV-infected NHL cases. Non-Hodgkin's lymphoma was classified according to the Working Formulation classification. RESULTS: Thirty-seven cases (14.9%) were found to be infected with HCV or HBV; of these, 20 (8.1%) were infected with HCV, and 17 (6.9%) with HBV. In male NHL patients, the rate of HCV infection was significantly higher than in an age- and sex-matched population in the same area (P < 0.001, Mantel-Haenszel test). The rate of HBV infection also tended to be higher in the population (P = 0.0551). In contrast, in female NHL patients, the rate of HCV or HBV infection was not higher than in the general population. In HCV-infected cases, 15 cases (75%) had B-cell NHL and 16 cases (80%) were classified as being in the intermediate grade; B-cell NHL comprised 83% of all NHL cases. In HBV-infected NHL cases, 11 (65%) were of B-cell type and 10 (58%) were classified as being in the intermediate grade. CONCLUSIONS: The high prevalence of HCV or HBV infections in our study population provides epidemiologic evidence suggesting that HCV and HBV infections may be involved in the development of a subgroup of NHL in males. Our investigation also revealed that both HCV- and HBV-infected NHL patients showed certain similarities in clinical and pathologic manifestations.

Guidelines for irradiation of blood and blood components to prevent post-transfusion graft-vs.-host disease in Japan.

The Japanese Red Cross analysed the results of questionnaires sent in 1993 regarding post-transfusion graft-vs.-host disease (PT-GVHD) from hospitals; the majority of patients with PT-GVHD in 1993 were transfused for cardiovascular or cancer surgery, and about 10 patients had died yearly from PT-GVHD in the following few years. The Japan Society of Blood Transfusion (JSBT) organized a subcommittee for the prevention of PT-GVHD, and issued a fourth version of guidelines for the irradiation of blood to prevent PT-GVHD. These guidelines recommended transfusion of irradiated blood for cardiosurgery, cancer surgery, elderly recipients and severe trauma, as well as congenital immunodeficient recipients, newborn infants and other immunocompromised patients. Also recommended was irradiation not only of blood within 72 h after collection but also of blood stored for 14 days. Reported PT-GVHD has diminished to a few cases in recent years.

Induction of MTG8-specific cytotoxic T-cell lines: MTG8 is probably a tumour antigen that is recognized by cytotoxic T cells in AML1-MTG8-fused gene-positive acute myelogenous leukaemia.

Several reports have demonstrated the persistent detection of AML1-MTG8 fusion products, representing minimal residual disease (MRD), in patients with t(8;21) acute myelogenous leukaemia (AML) who are in long-term remission. It is probable that immune-mediated mechanisms that are able to suppress the expansion of MRD may result in the continuance of remission. It was previously shown that some t(8;21) AML patients had high anti-MTG8 antibody titres. MTG8 expression in normal adult tissues is limited to the brain or heart in which human leucocyte antigen (HLA) class I cell-surface antigens are either not or are only faintly detectable. We hypothesized that the overexpression of the MTG8 gene in t(8;21) AML cells could act as a possible tumour antigen, which might be able to induce the immune-mediated suppression of the expansion of MRD. We were able to induce HLA-A0201-restricted cytotoxic T-lymphocyte (CTL) lines against an MTG8 peptide (MTG8b amino acids 182-191) using monocyte-derived dendritic cells from a healthy donor. T-cell receptor (TCR)Valpha17, TCRVbeta14 and 15, and TCRJbeta2.1 and 2.3 are predominantly used in these CTL lines. Our data, which suggest that the MTG8 protein could be one of the tumour antigens recognized by CTLs, may be helpful in further investigations of TCR analysis in t(8;21) AML patients with HLA-A0201 who are in long-term remission.

Combination of preoperative embolization of the right portal vein and hepatic artery prior to major hepatectomy in high-risk patients: a preliminary report.

BACKGROUND/AIMS: Preoperative transhepatic portal vein embolization may not always be sufficient to achieve the desired changes in contralateral hepatic volume and function. The beneficial role of additional transcatheter arterial embolization performed after inadequate response to preoperative transhepatic portal vein embolization is described. METHODOLOGY: Four patients underwent both preoperative transhepatic portal vein embolization and transcatheter arterial embolization, and 6 control patients underwent preoperative transhepatic portal vein embolization only. Changes in right liver lobe volume fraction, residual left lobe volume fraction, and prediction score (low-risk, < 45; borderline, 45-55; high-risk > 55); were evaluated. RESULTS: 1) The change in right liver lobe volume after both preoperative transhepatic portal vein embolization and transcatheter arterial embolization (volume after/before) was 0.75 times that of the original level whereas after preoperative transhepatic portal vein embolization, they were only 0.81 times that of the original level. 2) The change in residual left liver volume after both preoperative transhepatic portal vein embolization and transcatheter arterial embolization (volume after/before) was 1.40 times that of the original level whereas after preoperative transhepatic portal vein embolization they were only 1.30 times than the original level. The changes in left liver volume after preoperative transhepatic portal vein embolization/transcatheter arterial embolization was more favorable than those after preoperative transhepatic portal vein embolization only. 3) The change in prediction score after both preoperative transhepatic portal vein embolization and transcatheter arterial embolization (after/before) was 0.81 times that of the original level. All prediction score in high-risk patients recovered to the borderline or safety zone. Change after preoperative transhepatic portal vein embolization only (before/after) was 0.87 times that of the original level. 4) All 4 patients who underwent both preoperative transhepatic portal vein embolization and transcatheter arterial embolization received right hepatic lobectomy successfully and returned to their normal life style. CONCLUSIONS: Preoperative occlusion of right hepatic inflow vessels increased the volume and function of the contralateral lobe where high-risk patients recovered to the borderline zone for major hepatic resection.

The efficacy of predeposited autologous blood transfusions in general pediatric surgery.

Allogeneic blood transfusions are associated with a risk of infection, immunological reactions, immunosuppression, and the induction of antibodies in blood cells. We report our results of giving predeposited autologous blood transfusions (PABT) to children when it was anticipated that transfusions would be required for an elective operation. Autologous blood was collected for deposit from 16 patients ranging in age from 1 to 11 years old (mean 5.6 years old, mode 4 years old), and weighing from 9.7 to 42 kg (mean 20.8kg). They included 12 patients with pectus excavatum (funnel chest) and 4 patients with choledochal cyst (CBD). Blood was collected once from 2 patients and twice from the other 14 patients, then centrifuged and stored in a freezer at -80 degrees C. Between 7 and 14 ml/kg was collected at one time, the total mean volume of predeposited blood being 21.0 +/- 3.3 ml/kg for the children operated on for funnel chest, and 16.2 +/- 4.5 ml/ kg for those operated on for CBD. None of the patients required allogeneic transfusions and no complications occurred. PABT was found to be a safe and effective means for elective general pediatric surgical procedures for avoidance of allogeneic blood transfusion.

Effects of chronic neutral endopeptidase inhibition in rats with cyclosporine-induced hypertension.

OBJECTIVE: Cyclosporine (CysA), a potent immunosuppressant, is associated with hypertension and nephrotoxicity. Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides and endothelin-1 (ET-1). We conducted the present study to determine whether or not the NEP inhibitor, ecadotril, prevents cyclosporine-induced hypertension and to clarify the mechanisms responsible for the hypotensive effects of ecadotril. DESIGN AND METHODS: We studied the chronic effects of ecadotril (30 mg/kg per day) on blood pressure; the production of ET-1 and C-type natriuretic peptide (CNP); endothelial nitric oxide synthase (eNOS) activity; and the expression of messenger RNA (mRNA), for each substance in blood vessels of CysA-induced hypertensive rats. RESULTS: CysA (25 mg/kg per day) given for 4 weeks increased the blood pressure from 116 +/- 14 mmHg to 159 +/- 15 mmHg, in rats. This increase was blunted by the co-administration of ecadotril (blood pressure: 134 +/- 14 mmHg). CysA increased plasma NEP activity. CysA increased the production of ET-1 and the expression of ET-1 mRNA without affecting CNP synthesis and endothelin converting enzyme (ECE)-1 mRNA expression. CysA decreased the eNOS activity and eNOS mRNA levels. Addition of the NEP inhibitor decreased the synthesis of ET-1 and ET-1 mRNA levels and increased the eNOS activity and the eNOS mRNA levels. Vascular CNP synthesis and ECE-1 mRNA expression in rats treated with ecadotril did not differ from those in rats treated with CysA and ecadotril. CONCLUSION: These results indicate that chronic NEP inhibition may prevent the CysA-induced hypertension by decreasing local ET-1 synthesis and partly increasing vascular nitric oxide production.

Idiopathic hyperaldosteronism: analysis of aldosterone synthase gene.

We analyzed the CYP11B2, the gene encoding aldosterone synthase, in mononuclear leukocytes in eight patients with primary aldosteronism due to zona glomerulosa hyperplasia (idiopathic hyperaldosteronism) and compared the results with aldosterone-producing adenomas. In idiopathic hyperaldosteronism, aldosterone synthase activity was significantly increased in accordance with gene expression (P < 0.05), compared with aldosterone-producing adenomas. No genetic mutations were found in coding regions of DNA. The T (-344) C allele polymorphism was present in a similar frequency in the general population. In one patient with idiopathic hyperaldosteronism. de novo homozygous mutation in upstream of the 5' flanking region C (-463) T was detected, which cannot be explained by polymorphism. The pathophysiological significance of this mutation for aldosterone hypersecretion is not known. There were no mutations in the known promoter sequences for angiotensin II related cis-segments. Possible contribution of co-regulators for angiotensin 11-induced signalling pathway is discussed.

Inverse association of soy product intake with serum androgen and estrogen concentrations in Japanese men.

The cross-sectional relationships of soy product intake and serum testosterone, estrone, estradiol, sex hormone-binding globulin, and dihydrotestosterone were examined in 69 Japanese men. Soy product intake was estimated from a semiquantitative food frequency questionnaire. Serum estradiol concentration was significantly inversely correlated with soy product intake (r = -0.32, p = 0.009), and serum estrone concentration was nonsignificantly inversely correlated with soy product intake (r = -0.24, p = 0.05) after controlling for age, body mass index, smoking status, and ethanol intake. Total and free testosterone concentrations were inversely correlated with soy product intake after controlling for the covariates, but these correlations were of border line significance (r = -0.25, p = 0.05 and r = -0.25, p = 0.06, respectively). Similar correlations were observed for these hormones with isoflavone intake from soy products. The data suggest that soy product intake may be associated with the endogenous hormone levels in Japanese men.

Rationality/antiemotionality personality and selected chronic diseases in a community population in Japan.

OBJECTIVE: To clarify the relationships of the rationality/antiemotionality (R/A) personality with past histories of seven chronic diseases and current smoking habits in a community population in Japan. METHODS: A questionnaire survey was conducted of all residents aged 35 years old or over (n = 37,287) in Takayama city, Gifu prefecture, Japan; the response rate was 90.3%. Data from 13,091 males and 14,061 females who completed all relevant questions were analyzed. The subjects were asked to complete an 11-item R/A personality scale developed by Grossarth-Maticek et al. (1985). Past histories of seven major chronic diseases and current smoking habit were also asked in the questionnaire. RESULTS: Among males, the R/A scale score was significantly lower in those who had stroke, diabetes or allergy than in those who did not. Among females, the R/A scale score was significantly lower in those who had stroke, allergy or stomach cancer than in those who did not. Among females, current smokers had significantly lower R/A scores than non-smokers. After controlling for age, smoking and drinking, the R/A score was significantly and negatively associated with stroke among males and females; it was significantly and negatively associated with diabetes and allergy among males. CONCLUSION: Our findings are contrary to those observed in Yugoslavia and West Germany, and suggest a cultural difference in the relationship between the R/A personality and disease occurrence.

[Nonmyeloablative stem cell transplantation with low-dose total body irradiation (200 cGy) for a 55-year-old woman with acute lymphoblastic leukemia].

We describe a 55-year-old woman with acute lymphoblastic leukemia (ALL) in the first remission who underwent nonmyeloablative stem cell transplantation with conditioning consisting of low-dose total body irradiation and postgrafting cyclosporine and mycophenolate mofetil. Myelosuppression was mild, but on day 28 her bone marrow showed 8.8% lymphoblasts. We withdrew the cyclosporine, but the patient developed grade 2 acute GVHD and eosinophilia. The proportion of bone marrow lymphoblasts decreased transiently to 1.0% on day 40, but later increased again and the patient died on day 85. Application of this approach to patients with ALL needs to be examined on a large scale.