Lower risk of progression from prediabetes to diabetes with health checkup with lifestyle education: Japan Ningen Dock study.

BACKGROUND AND AIMS: To investigate whether the progression from prediabetes to diabetes is lower among those who undertake Ningen Dock (comprehensive health checkups with lifestyle education and doctor's consultation) than those who undertake basic mandatory occupational health checkups. METHODS AND RESULTS: Subjects aged 30-69 years with complete annual data from 2008 to 2012 for either Ningen Dock or basic health checkups were enrolled. Subjects with prediabetes (fasting plasma glucose 100-125 mg/dl or HbA1c 5.7-6.4%) at baseline were selected (14,928 in the comprehensive group and 10,433 in the basic group). The incidence of diabetes (fasting plasma glucose ≥ 126 mg/dl, HbA1c ≥ 6.5% or taking glucose-lowering drugs) and the reduction of risk factors were compared. After 4 years, 3226 cases of diabetes occurred among 25,361 subjects with prediabetes. The incidence of diabetes was lower in the comprehensive group than the basic group (2.9 vs. 3.8 cases/100 person-years, hazard ratio 0.75, 95% confidence interval 0.68-0.81 after adjustment). Moreover, more overweight subjects controlled their body mass index (16.2% vs. 13.2%) and more began a daily exercise habit (11.8% vs. 8.5%) in the comprehensive group than in the basic group. The incidence of diabetes was lower in subjects who could control their weight or start daily exercise at year 1 in the comprehensive group. CONCLUSION: Progression from prediabetes to diabetes was significantly lower in subjects undertaking a comprehensive health checkup with lifestyle education. Lifestyle education at health checkup for people with prediabetes might prevent progression to diabetes by reducing modifiable risk factors.

Upper-normal waist circumference is a risk marker for metabolic syndrome in normal-weight subjects.

BACKGROUND AND AIMS: To elucidate implication of upper-normal waist circumference (WC), we examined whether the normal range of WC still represents a risk of metabolic syndrome (MetS) or non-adipose MetS components among normal-weight subjects. METHODS AND RESULTS: A total of 173,510 persons (100,386 men and 73,124 women) with normal WC (<90/80 cm in men/women) and body mass index (BMI) of 18.5-24.9 were included. Subjects were categorized as having low, moderate, and upper-normal WC for those with WC < 80, 80-84, and 85-89 cm in men and <70, 70-74, and 75-79 cm in women, respectively. The prevalence of all the non-adipose MetS components (e.g. prediabetes and borderline dyslipidemia) was significantly higher in subjects with upper-normal WC on comparison with those with low WC. Overall, the prevalence of MetS (having three or more of four non-adipose MetS components) gradually increased with increasing WC (12%, 21%, and 27% in men and 11%, 14%, and 19% in women for low, moderate, and upper-normal WC, respectively). Moreover, the risk of having a greater number of MetS components increased in subjects with upper-normal WC compared with those with low WC (odds ratios for the number of one, two, three, and four MetS components: 1.29, 1.81, 2.53, and 2.47 in men and 1.16, 1.55, 1.49, and 2.20 in women, respectively). CONCLUSION: Upper-normal WC represents a risk for acquiring a greater number of MetS components and the early stage of MetS components (prediabetes and borderline dyslipidemia), after adjusting for BMI, in a large general population with normal WC and BMI.

The number of metabolic syndrome components is a good risk indicator for both early- and late-stage kidney damage.

BACKGROUND AND AIMS: Renal hyperfiltration (early-stage kidney damage) and hypofiltration (late-stage kidney damage) are common in populations at high risk of chronic kidney disease. This study investigated the associations of renal hyperfiltration and hypofiltration with the number of metabolic syndrome (MetS) components. METHODS AND RESULTS: The study subjects included 205,382 people aged 40-74 years who underwent Specific Health Checkups in Aichi Prefecture, Japan. The prevalence of renal hyperfiltration [estimated glomerular filtration rate (eGFR) above the age-/sex-specific 95th percentile] and hypofiltration (eGFR below the 5th percentile) was compared according to the number of MetS components. We found that the prevalence of both hyperfiltration and hypofiltration increased with increasing number of MetS components (odds ratios for hyperfiltration: 1.20, 1.40, 1.42, 1.41, and 1.77; odds ratios for hypofiltration: 1.07, 1.25, 1.57, 1.89, and 2.21 for one, two, three, four, and five components, respectively, compared with no MetS components). These associations were observed in both normal weight [body mass index (BMI) < 25 kg/m(2)] and overweight (BMI ≥ 25 kg/m(2)) subjects. Renal hyperfiltration was associated with prehypertension and prediabetes, while hypofiltration was associated with dyslipidemia, abdominal obesity, overt hypertension, and overt diabetes. CONCLUSION: The number of MetS components is a good risk indicator of early- and late-stage kidney damage. Therefore, kidney function should be monitored in subjects with MetS components. MetS components should be treated as early as possible to prevent the development of kidney damage and cardiovascular diseases in people with hyperfiltration, regardless of their body weight.

Angiopoietin-like protein 2 sensitively responds to weight reduction induced by lifestyle intervention on overweight Japanese men.

OBJECTIVE: Overexpression of Angiopoietin-like protein 2 (Angptl2) in obese adipose tissues promotes adipose tissue inflammation and its-related metabolic abnormalities. In a comparative study with adiponectin, we investigated whether alterations in serum Angptl2 concentrations reflect the effect of lifestyle intervention on weight loss and improved metabolic parameters in overweight subjects. METHODS: A total of 154 Japanese men (age, 40.9±5.1 years; body mass index, 26.9±3.6 kg m(-2); abdominal circumference, 94.1±8.9 cm) underwent a 3-month lifestyle intervention and underwent follow-up for 3 months thereafter. RESULTS: Decreased serum Angptl2 levels, but not increased serum adiponectin levels, were immediately apparent at the end of 3-month lifestyle intervention. Angptl2 levels continued to decrease for 3 months in parallel with body weight loss and improvement in metabolic indicators. In subjects showing 6% weight reduction, markedly reduced Angptl2 levels were detected at the end of 3-month intervention, whereas increased adiponectin levels were detected 3 months after the end of intervention. Multivariate analysis revealed changes in serum Angptl2 levels associated with changes in triglycerides (TGs), aspartate aminotransferase and alanine aminotransferase. In contrast, changes in serum adiponectin levels were associated with altered high-density lipoprotein cholesterol (HDL-C) and fasting plasma glucose levels. CONCLUSION: A 3-month lifestyle intervention promoted weight reduction and improved glucose and lipid metabolism, an effect maintained 3 months later. Notably, our findings indicate that decreased Angptl2 levels are a good indicator of reduced visceral fat and metabolic improvement at early stages of lifestyle intervention. Thus, Angptl2 reflects adiposity and might be a key protein to regulate inflammation and TG metabolism, whereas adiponectin levels could reflect improved glucose and HDL-C metabolism.

Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma.

BACKGROUND: To evaluate the efficacy and feasibility of rituximab monotherapy in Japanese patients with relapsed or refractory aggressive B-cell lymphoma. PATIENTS AND METHODS: Sixty-eight patients were treated with rituximab at 375 mg/m(2) by eight consecutive weekly infusions. Pretreatment variables affecting overall response rate (ORR) and progression-free survival (PFS) and the relationship between pharmacokinetic parameters and efficacy were analyzed. RESULTS: The ORRs of 68 enrolled patients and 57 eligible patients were 35% [95% confidence interval (CI) 24% to 48%] and 37% (95% CI 25% to 51%), respectively. Median PFS of 53 evaluable patients was 52 days, whereas time to progression of 21 eligible responders was 245 days. Mild to moderate infusion-related toxicities were observed frequently at the first infusion, but all of them were reversible. Elevated lactate dehydrogenase (LDH) and refractoriness to prior chemotherapy were unfavorable factors affecting ORR and PFS (P <0.01). Serum trough levels of rituximab and area under the concentration-time curve for responders were higher than for non-responders (P <0.05). CONCLUSIONS: Eight consecutive weekly infusions of rituximab have significant anti-lymphoma activity for relapsed or refractory aggressive B-cell lymphoma. Several pretreatment variables and serum rituximab levels are useful for predicting its efficacy.

Clinical significance of major and minor bcr/abl chimeric transcripts in essential thrombocythemia.

BACKGROUND: Contradictory results have been reported in terms of detecting bcr/abl transcripts in patients with essential thrombocythemia. The aim of this study was to investigate whether the bcr/abl transcript could be found in patients with essential thrombocythemia (ET). METHODS: The bcr/abl transcript was amplified by the RT-nested PCR method using RNA extract from leukocytes taken from 14 essential thrombocythemia patients. The amplified DNAs were electrophoresed in 1% agarose and visualized with ethidium bromide. The DNA bands associated with the bcr/abl transcript were then extracted and followed by DNA sequence analysis. RESULTS: Major bcr/abl transcripts of the b3a2 type and minor ones of the e1a2 type were found in one and two ET patients, respectively. The incidence of bcr/abl transcripts was 21.4% (three of 14 patients). CONCLUSION: Our experiments confirmed that bcr/abl transcripts are present in some patients with essential thrombocythemia.

[The management of Hodgkin's disease with chemotherapy or combined modality treatment].

Systemic polychemotherapy and local radiation are two well-established treatments for Hodgkin's disease. With the use of modern techniques, the great majority of patients with pathologic stage I-II Hodgkin's disease can be cured with irradiation alone. Since the invention of the MOPP and ABVD schemes, polychemotherapy has become indispensable for the treatment of advanced-stage Hodgkin's disease. The role of radiotherapy in combination with chemotherapy is limited to specific indications. ABVD therapy is as effective as MOPP alternating with ABVD, and both are superior to MOPP alone in the treatment of advanced Hodgkin's disease. MOPP/ABVD hybrid chemotherapy was significantly more effective than sequential MOPP-ABVD in 8-year failure-free survival and overall survival. The patients with advanced-stage Hodgkin's disease who did not achieve a complete remission from their initial treatment with combination chemotherapy have a dismal prognosis. Those whose initial remissions had lasted longer than 12 months had a very high probability of obtaining a second complete remission when re-treated with MOPP or ABVD, but those whose remission lasted less than 12 months fared less well with any conventional-dose chemotherapy. High-dose chemotherapy and radiotherapy with autologous hemopoietic stem cell transfusion are superior in the treatment of those whose disease is refractory or resistant to the initial therapy.

Newly developed diabetic retinopathy and its preceding changes in biological markers.

To disclose the chronological changes prior to the manifestation of diabetic retinopathy (DR), we analyzed the time course of biological markers among apparently healthy diabetic subjects in a case-control study of 21,579 adults who had undergone comprehensive health examinations for > or = 10 years. We identified 54 cases who had newly developed DR, and selected 108 adults without fundus abnormalities, matching them for sex, age, and fasting plasma glucose (FPG) at the onset of the patient group's retinopathy as a referent group from the same population. In a multivariate analysis, a high average FPG (> 175 mg/dl) and a final-year FPG reduction (< -3%) were significantly associated with a 5.4 (95% CI, 1.8-15.7)- and 5.0 (95% CI, 1.0-24.7)-fold increased risk of DR, respectively. Thus, we surmised that sustained hyperglycemia and a subsequent drop in FPG might promote retinopathy in non-insulin dependent diabetes mellitus.

Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.

BACKGROUND: Mutations of the p53 gene are associated with a poor prognosis in several types of cancer. We investigated the prognostic importance of p53 mutations in patients with aggressive B-cell lymphoma. METHODS: We examined the relation between the presence or absence of a detectable p53 mutation in lymphoma cells and the response to chemotherapy and overall survival in 102 previously untreated patients with aggressive B-cell lymphoma. Mutations of the p53 gene were identified by polymerase-chain-reaction-mediated analysis of single-strand conformation polymorphisms and by direct sequencing. RESULTS: Of 102 cases of aggressive B-cell lymphoma, 22 (22 percent) involved p53 mutations. The rate of complete remission was significantly lower in patients with a tumor carrying a p53 mutation (6 of 22 patients, 27 percent) than in those with the wild-type p53 gene (61 of 80 patients, 76 percent) (P<0.001). Overall survival was significantly lower among patients with p53 mutations than among those with the wild-type p53 gene; the Kaplan-Meier estimates of survival at five years were 16 percent and 64 percent, respectively (P<0.001). Multivariate analysis incorporating prognostic factors from the international prognostic index demonstrated that p53 mutations had independent effects on the rates of complete remission and survival. When we categorized patients according to the international prognostic index, we found no effect of p53 mutations in patients in the groups at high-intermediate and high risk. However, these mutations were significantly associated (P< 0.001) with low rates of complete remission (33 percent vs. 91 percent) and survival (27 percent vs. 81 percent at five years) in the groups at low and low-intermediate risk. CONCLUSIONS: Mutations of the p53 gene are associated with a poor prognosis in patients with aggressive B-cell lymphoma.

Achievement of a complete cytogenetic response with hydroxyurea in a patient with chronic myelogenous leukemia.

Hydroxyurea rarely produces a complete cytogenetic remission in patients with chronic myelogenous leukemia (CML). In this report, we describe one case of the CML patient who achieved complete cytogenetic remission (no Ph chromosome in 20-25 metaphase cells) by treatment with hydroxyurea alone. By the fluorescent in situ hybridization (FISH) methodology using bcr/abl specific translocation probe, sequential bone marrow specimens from the patient showed the characteristic 9;22 translocation at a higher rate (9-10%) than the normal control range (2.49-4.88%) at the time of complete cytogenetic remission. Thus, it is suggested that FISH is a more sensitive method to detect the bcr/abl fusion gene than conventional cytogenetic analysis for the detection of minimal residual disease in CML.

The dual expression of minor and major bcr/abl chimeric mRNA in blast crisis of chronic myelogenous leukemia.

The hypothesis that minor bcr/abl fusion mRNA is produced in blast crisis of chronic myelogenous leukemia (CML) is examined. The RNA transcripts encoding the minor and major bcr/abl fused protein were detected by polymerase chain reaction (PCR) using RNA from peripheral blood or bone marrow cells of eight patients with blast crisis or accelerated phase of CML. The mRNA encoding for major bcr/abl was detected in all eight cases. In four patients, however, transcripts encoding for minor bcr/abl mRNA were detected, as well as major bcr/abl mRNA. The presence of minor bcr/abl mRNA was verified with the hybridization with a junction-specific probe and DNA sequencing analysis of PCR products. The appearance of minor bcr/abl fusion mRNA was associated with the lymphoblastic immunophenotype of the blast cells. In two of these four patients, samples of initial diagnosis of chronic phase of CML were available, which did not show minor bcr/abl transcript. We conclude that the appearance of minor bcr/abl mRNA transcript is associated with the terminal evolution of CML in lymphoblastic crisis.

Acquired factor VIII-specific antibody disorder accompanied by a life-threatening retroperitoneal hematoma.

A male patient, aged 58, without any discernible underlying disease developed a massive hemorrhage in the retroperitoneal cavity and in the femoral muscle. The hemorrhagic tendency of the patient was found to be due to the acquired anti-Factor VIII specific autoantibody in the blood. A concentrate of an activated prothrombin complex (FEIBA: Factor eight inhibitor bypassing activity) was administered and produced a remarkable effect in stemning the bleeding tendency of the patient. Immunosuppressive therapy was also effective for the control of the bleeding.

Detection of major and minor bcr/abl fusion gene transcripts in a patient with acute undifferentiated leukemia secondary to treatment with an alkylating agent.

In this paper we describe a patient with bcr/abl positive acute undifferentiated leukemia (AUL) derived from acquired sideroblastic anemia secondary to ifosphamide treatment given for the preceding non-Hodgkin lymphoma of the lung. Cytogenetically, Philadelphia chromosome was not detected through the whole course in this patient, and multiple chromosomal abnormalities including 5q- and monosomy 7 were found at the stage of sideroblastic anemia. The reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed no bcr/abl fusion transcript at the diagnosis of malignant lymphoma. The mRNA encoding the major bcr/abl fusion protein then appeared in the stage of sideroblastic anemia. Finally, the mRNA encoding both major and minor bcr/abl was detected in the stage of AUL transformation. MLL gene rearrangement was not found by RT-PCR analysis at any stage of the disorder. These results may be direct evidence for the induction of the bcr/abl fusion gene by treatment with an alkylating agent (ifosphamide).

Tumor necrosis factor-beta gene expression and its relationship to the clinical features and histopathogenesis of peripheral T-cell lymphomas.

We investigated the levels of tumor necrosis factor-beta (TNF-beta) mRNA in the tumorous tissues of a series of 18 patients with peripheral T-cell lymphomas (PTCL), to assess the contribution of the expression of this gene to the features of the disease. Total RNA, extracted from diagnostic tissue specimens, was subjected to semiquantitative analysis by reverse transcription-coupled polymerase chain reaction (RT-PCR). The level of TNF-beta mRNA was semiquantified against that in MT-2 cells, a line of human T cells infected with human T cell leukemia virus type I (HTLV-I). Expression of TNF-beta in neoplastic T-cells was confirmed by immunohistochemistry. The extent of TNF-beta gene expression was correlated with the histopathological features of neovascularization. There was also a relationship between the extent of TNF-beta gene expression and the presence of B-symptoms. Results suggest that TNF-beta produced by neoplastic T-cells influences clinical features and is involved in histopathogenesis of PTCL.

The close relationship between DNA replication and the selection of differentiation lineages of human erythroleukemia cell lines K562, HEL, and TF1 into either erythroid or megakaryocytic lineages.

The selection of differentiation lineages into either erythroid or megakaryocytic series was analyzed with human erythroleukemia cell lines K562, HEL, and cytokine-dependent TF1. A tumor promoter, TPA, induced a megakaryocyte marker, glycoprotein IIb/IIIa (GP IIb/IIIa) or IIIa (GP IIIa), but suppressed erythroid differentiation. On the other hand, aphidicolin, which is a potent inhibitor of DNA replication, inhibited GP IIb/IIIa or IIIa expression, but induced the expression of erythroid phenotypes. These phenomena were observed in all erythroleukemia cell lines tested. The bromodeoxyuridine labeling experiments indicated that de novo DNA synthesis was completely suppressed by aphidicolin treatment but was well preserved in TPA-treated cells. Among these three cell lines, erythropoietin (EPO) treatment induced erythroid differentiation of TF1 cells, which was dependent on GM-CSF or IL-3. In this case, EPO functioned as the survival factor and mild stimulator for cell proliferation as well as the inducer of erythroid differentiation. However, when either GM-CSF or IL-3 was depleted from the culture medium, TF1 ceased cell growth; concomitantly, hemoglobin-positive cells appeared, which is consistent with the results obtained with aphidicolin. The incubation of K562 cells for 48 h with either TPA or aphidicolin induced the irreversible commitment of cells to megakaryocytic and erythroid lineages, respectively. Our results using three different erythroleukemia cell lines suggest that a possible linkage between the DNA replication system and the selection of a differentiation lineage is the common feature of human erythroleukemia cell lines, and that these culture systems provide a suitable model for the analysis of the signal transduction system for differentiation lineage selection.

Erythroid potentiating activity of tissue inhibitor of metalloproteinases on the differentiation of erythropoietin-responsive mouse erythroleukemia cell line, ELM-I-1-3, is closely related to its cell growth potentiating activity.

The erythroid-potentiating activity (EPA) of the tissue inhibitor of metalloproteinase-1 (TIMP-1) was re-examined using ELM-I-1-3, a mouse erythroleukemia cell line, which responded well to erythropoietin. Depletion of pre-existing TIMP-1 from fetal calf serum in culture medium using monoclonal antibody suppressed erythropoietin-induced differentiation as measured by the induction of hemoglobin, commitment assay and globin mRNAs. The removal of TIMP-1 also suppressed the proliferation of ELM-I-1-3 as measured by cell number and de novo DNA synthesis. These changes were reversed by the addition of purified TIMP-1 to the culture medium. Anti-TIMP-1 antibody also blocked both hexamethylene bisacetamide (HMBA)-induced erythroid differentiation and the proliferation of both ELM-I-1-3 and Friend erythroleukemia cells. Considering previous reports analyzing the chemical induction of Friend mouse erythroleukemia cell differentiation, our results suggest that erythropoietin- or HMBA-induced erythroid differentiation might also be coupled with cell proliferation. Our 3H thymidine-uptake experiment shows that TIMP-1 removal was also effective in the inhibition of cell growth of various other cell lines in addition to erythroleukemia cell lines. These results suggest that EPA action of TIMP-1 on erythroid leukemia cell lines is closely related to its activity to promote the cell growth of various cell lines and cells including erythroleukemia cell lines.

Induction of neutrophil alkaline phosphatase gene expression by granulocyte colony-stimulating factor in chronic myelogenous leukemia.

The mechanism underlying defective neutrophil alkaline phosphatase (NAP) activity in chronic myelogenous leukemia (CML) was examined using Northern blotting analysis and NAP staining. Fourteen patients with Ph1-positive CML in the chronic phase were included in this study. Polymorphonuclear cells (PMN), containing more than 80% of stab and segmented neutrophils, were collected from peripheral blood (PB) by methylcellulose sedimentation after density gradient centrifugation. Neutrophil alkaline phosphatase mRNA (NAPmRNA) expression was very weak in all patients. When incubated with granulocyte colony-stimulating factor (G-CSF) for 24 h, the PMN of all patients expressed a detectable level of NAPmRNA. NAP score, which semiquantitatively reflects the activity of gene products, was also elevated after incubation with G-CSF in 12 patients. However, a higher dose of G-CSF was required for the maximum response than was the case for normal bone marrow PMN, which also manifested increases of NAPmRNA and its products on stimulation by G-CSF. The present study suggests that the PMN of CML express NAPmRNA and produce its products in response to G-CSF, but that they are less sensitive to G-CSF than normal bone marrow PMN.