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Biomedical subjects

T Inukai

Publications and source records attributed to T Inukai.

At least 19 recordsLinked to original sources
PubMed2006

Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19.

Hypercalcemia is relatively rare but clinically important complication in childhood leukemic patients. To clarify the clinical characteristics, mechanisms of hypercalcemia, response to management for hypercalcemia, incidence of t(17;19) and final outcome of childhood acute lymphoblastic leukemia (ALL) accompanied by hypercalcemia, clinical data of 22 cases of childhood ALL accompanied by hypercalcemia (>12 mg/dl) reported in Japan from 1990 to 2005 were retrospectively analyzed. Eleven patients were 10 years and older. Twenty patients had low white blood cell count (<20 x 10(9)/l), 15 showed hemoglobin> or =8 g/dl and 14 showed platelet count > or =100 x 10(9)/l. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcemia was confirmed in 11 of the 16 patients in whom elevated-serum level or positive immunohistochemistry of PTHrP was observed. Hypercalcemia and accompanying renal insufficiency resolved quickly, particularly in patients treated with bisphosphonate. t(17;19) or add(19)(p13) was detected in five patients among 17 patients in whom karyotypic data were available, and the presence of E2A-HLF was confirmed in these five patients. All five patients with t(17;19)-ALL relapsed very early. Excluding the t(17;19)-ALL patients, the final outcome of ALL accompanied by hypercalcemia was similar to that of all childhood ALL patients, indicating that the development of hypercalcemia itself is not a poor prognostic factor.

Adolescent↗
PubMed2006

Resistance of infant leukemia with MLL rearrangement to tumor necrosis factor-related apoptosis-inducing ligand: a possible mechanism for poor sensitivity to antitumor immunity.

Malignant cells generally acquire some immune escape mechanisms for clonal expansion. Immune escape mechanisms also contribute to the failure of graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (allo-SCT). Infant leukemias with mixed-lineage leukemia (MLL) rearrangement have a remarkably short latency, and GVL effect after allo-SCT has not been clearly evidenced in these leukemias. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- and FasL-mediated cytotoxic pathways play important roles in cytotoxic T-lymphocyte- and natural killer cell-mediated antitumor immunity and optimal GVL activity. We investigated the in vitro sensitivity of MLL-rearranged acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) cells to TRAIL- and FasL-mediated cytotoxicity. Most of cell lines and primary leukemia cells were highly resistant to TRAIL primarily owing to low cell-surface expression of death receptors in ALL and simultaneous expression of decoy receptors in AML. Nearly half of cell lines and majority of primary leukemia cells showed low sensitivity to FasL. These results suggest that resistance to death-inducing ligands, particularly to TRAIL, could be one of the mechanisms for a rapid clonal expansion and a poor sensitivity to the GVL effect in infant leukemias with MLL rearrangement.

Drug Resistance, Neoplasm↗
PubMed2005

Cervical angina: a seemingly still neglected symptom of cervical spine disorder?

STUDY DESIGN: Retrospective, case series. DESIGN: A review of 10 surgical cases with symptoms of cervical angina. OBJECTIVE: To stress the importance of symptoms of cervical angina in patients with cervical spine disorders. SETTING: Fukui University Hospital, Japan. RESULTS: A total of 10 patients complaining of symptoms of cervical angina were admitted with a tentative diagnosis of coronary artery disease. Pain relief was achieved by anterior surgical decompression in all patients. CONCLUSION: We stress that physicians should be aware of the symptoms of cervical angina and that surgical intervention often leads to complete relief of symptoms.

Adult↗
PubMed2004

Role of transposable elements in the propagation of minisatellites in the rice genome.

A survey of minisatellites (MSs) in 5.3 Mb of randomly selected rice DNA sequences from public databases was carried out to clarify the role of transposable elements (TEs) in the dispersal of MSs in the rice genome. The estimated frequency of MSs in this sample was one per 23.4 kb, and this frequency is approximately equivalent to that of Class I microsatellites in the rice genome. Of the MSs in the 5.3-Mb sequence sample, 82% were found to be present in multiple copies in the rice genome, and all of these were a part of TE sequences. In this study at least 61 TE groups were identified as MS carriers. It was also shown that the GC-rich MS pOs6.2H, which was previously reported to be one of the interspersed MSs in the rice genome, is a component of an En/Spm-like element. These results indicate that the majority of MSs in the rice genome are maintained in TEs, and amplified and dispersed as components of the TEs. The G+C content of the multi-locus MS sequences reflected that of the TE sequences containing those MSs, but no obvious bias towards the high G+C content of DNA was observed. Single locus MSs also did not show any obvious bias towards the high G+C content of DNA in the rice genome. In this respect, the MSs in the rice genome are quite different from those in the human genome: in the latter, the majority of MSs show an obvious bias towards the high G+C content of DNA.

Base Composition↗
PubMed2004

Enhancement of fibrinolysis in poorly controlled, hospitalized type 2 diabetic patients by short-term metabolic control: association with a decrease in plasminogen activator inhibitor 1.

Impaired fibrinolysis in type 2 diabetes may be caused by an increased plasma concentration of plasminogen activator inhibitor 1 (PAI-1), although the effects of short-term hypoglycemic therapy on fibrinolytic activity are poorly understood. This study investigated the effects of metabolic improvement on fibrinolysis activity and plasma concentrations of PAI-1 in poorly controlled, hospitalized type 2 diabetic patients. Forty-eight poorly controlled type 2 diabetic patients were studied; 26 were subsequently treated with sulfonylurea (SU) and 22 with insulin. The plasma concentrations of plasmin-alpha2-antiplasmin (PAP), a measure of fibrinolytic activity, plasma PAI-1, and fasting triglycerides and glucoses were measured at the beginning and the end of hospitalization. The body mass index and fasting triglyceride decreased significantly after treatment (p < 0.0001). The plasma concentration of PAP increased significantly (p < 0.01), and the plasma PAI-1 decreased by 50% after treatment. There was an inverse correlation between the changes in the plasma concentrations of PAP and PAI-1 (r= - 0.36, p = 0.023). Treatment with SU or insulin showed an increase in plasma PAP with a concomitant decrease in the plasma PAI-1 with equivalent glycemic control. In poorly controlled type 2 diabetic patients, the plasma PAP concentration can be significantly increased and the plasma PAI-1 antigen significantly reduced, even with short-term metabolic improvements including weight reduction, a better lipid profile, and tighter glycemic control with either SU or insulin therapy, and that enhanced fibrinolysis may be mediated partly through a decrease in the plasma PAI-1 after metabolic control.

Adult↗
PubMed2003

Plasma interleukin-6 is associated with coagulation in poorly controlled patients with Type 2 diabetes.

AIMS: We investigated the relationship between interleukin (IL)-6 and coagulation, i.e. whether changes in the plasma IL-6 are associated with those in coagulation markers (D dimer and fibrinogen) after glycaemic control with sulphonylurea or insulin in poorly controlled patients with Type 2 diabetes. METHODS: We studied 42 patients with Type 2 diabetes, including 19 subsequently treated with sulphonylurea, 23 treated with insulin and 48 control subjects. All patients were in poor glycaemic control and were hospitalized for 3 weeks. At the beginning and end of treatment, we measured plasma concentrations of IL-6, fibrinogen, and D dimer. RESULTS: Plasma concentrations of IL-6 and D dimer were significantly higher in diabetic patients than in controls (P<0.0001 for both). In all patients with diabetes, the plasma concentration of IL-6 decreased significantly (P<0.001) after treatment. Changes in the plasma IL-6 during hospitalization were positively correlated with those in plasma D dimer and fibrinogen (r=0.664, P<0.0001; r=0.472, P=0.0042, respectively). Treatment with sulphonylurea or insulin caused a similar fall in the plasma IL-6 concentration with a concomitant decrease in the BMI and an equal improvement in glycaemia. CONCLUSIONS: In poorly controlled patients with Type 2 diabetes, plasma IL-6 concentrations were reduced significantly even by short-term metabolic control. As changes in the plasma concentrations of D dimer are related to plasma IL-6, plasma IL-6 may reflect a pro-coagulant as well as an inflammatory state in patients with Type 2 diabetes.

Blood Coagulation↗
PubMed2003

The connection between QT dispersion and autonomic neuropathy in patients with type 2 diabetes.

It is controversial whether an increase in the QT dispersion (QTd) on the electrocardiogram (ECG) reflects cardiac autonomic neuropathy in diabetic patients. In the current study, the QTd was compared in 60 type 2 diabetic patients and in 30 healthy subjects, and its association with autonomic neuropathy in diabetic patients was investigated. An increased QTd was found in diabetic patients, compared to healthy subjects. The QTd had significant negative associations with the log of the low and high frequency power (log LF and HF, respectively) of the power spectral analyses (PSA) of heart rate variations and the systolic blood response during standing (Delta BP). There was no significant difference in the QTd between patients with and without sympathetic skin response (SSR), reflecting peripheral sympathetic function. A significant positive correlation was also found between QTd and the systolic blood pressure (SBP). On the other hand, there was no correlation between QTd and serum total cholesterol (TC), triglycerides (TG), fasting plasma glucose (FPG), hemoglobin (Hb) A (1C) concentrations or body mass index (BMI). By multiple regression analysis, the log HF, which reflects cardiac parasympathetic function, and the SBP alone were significantly associated with QTd as the dependent variable. The Delta BP and log LF, which partially reflect sympathetic nerve function, had no significant associations with QTd. These findings suggest that QTd reflects cardiac autonomic neuropathy (relative parasympathetic neuropathy) and that the QTd is also influenced by SBP, independent of autonomic neuro-function.

Adult↗
PubMed2003

Primary antiphospholipid syndrome associated with acute adrenal failure.

We describe a 48-year-old woman with primary antiphospholipid syndrome who developed acute adrenal failure after an operation for a uterine myoma. After surgery, she developed a preshock state with hypotension, hypoglycemia, and hyponatremia. A diagnosis of primary antiphospholipid syndrome was made based not only on her past history of skin ulceration and recurrent spontaneous abortions but also on the presence of anticardiolipin antibodies. An abdominal computed tomography showed a bilateral enlargement of the adrenal glands but no high-density region in either gland. The patient recovered from the shock-like syndromes after the administration of glucocorticoids. Because it is possible that patients with antiphospholipid syndrome have acute or chronic adrenal failure caused by repeated hemorrhage or thrombosis, it may be important to monitor adrenal function in patients when the presence of this antibody is detected.

Acute Disease↗
PubMed2002

Ligand activation of peroxisome proliferator-activated receptor gamma induces apoptosis of leukemia cells by down-regulating the c-myc gene expression via blockade of the Tcf-4 activity.

The peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily, is expressed at highest levels in adipose tissue and functions as a central regulator in the process of adipocyte differentiation. In the present study, we showed that human leukemic cell lines, not only myeloid but also lymphoid, express PPAR gamma and its activation by natural ligand (15-deoxy-Delta(12,14) - prostaglandin J(2)) and synthetic ligand (troglitazone) profoundly inhibited their proliferation by induction of apoptosis preferentially in the serum-free culture. We pursued its mechanism using the representative cell lines, and found that induction of apoptosis was accompanied by caspase-3 activation and specifically blocked by its inhibitor. While status of several apoptosis-related molecules remained unchanged, the c-Myc expression was markedly down-regulated within 24 h after troglitazone treatment. The c-myc mRNA levels were dramatically reduced at 1 h and became undetectable at 12 h after troglitazone treatment, which proved to be accompanied by complete blockade of the Tcf-4 activity in the electrophoretic mobility shift assay. We succeeded in establishing HL-60 cell lines growing well in the presence of troglitazone in the long-term serum-free culture. They showed neither induction of apoptosis nor down-regulation of the c-Myc expression via blockade of the Tcf-4 activity after troglitazone treatment. This is the first identification of the linkage between PPAR gamma-mediated apoptosis and down-regulation of the c-myc gene expression.

Antineoplastic Agents↗
PubMed2002

Elevation of von Willebrand factor in plasma in diabetic patients with neuropathic foot ulceration.

AIMS: The present study examines the relationship between markers of endothelial dysfunction and diabetic neuropathy or consequent neuropathic foot ulceration in patients with Type 2 diabetes mellitus. METHODS: We studied 65 Type 2 diabetic patients including 25 diabetic patients without neuropathy, 27 with neuropathy but no history of foot ulceration, and 13 with neuropathic ulceration. Plasma concentrations of von Willebrand factor (vWF) and soluble thrombomodulin (TM), measures of endothelial dysfunction, were determined by enzyme immunoassays. We performed various tests quantifying aspects of diabetic neuropathy including vibration perception threshold (VPT; for sensory neuropathy), coefficient of variation of R-R intervals (CVR-R; for cardiac autonomic neuropathy), and cold-induced vasodilation in the great toe for peripheral sympathetic neuropathy. RESULTS: CVR-R and cold-induced vasodilation were significantly diminished in patients with neuropathic foot ulceration compared with patients with neuropathy but no history of foot ulceration. Plasma vWF concentrations were positively correlated with VPT and cold-induced vasodilation test, and were inversely correlated with CVR-R. Multivariate analysis disclosed that VPT and percentage vasodilation were independent factors for plasma vWF. Plasma vWF was significantly elevated in patients with foot ulceration compared with patients without neuropathy or those with neuropathy but not foot ulceration. However, plasma TM concentrations did not differ between the three groups. CONCLUSIONS: Diabetic patients with neuropathic foot ulceration had severe impairment of cardiac autonomic and peripheral sympathetic nerves. Elevation of vWF in plasma was associated with neuropathic foot ulceration, linking endothelial dysfunction to foot ulceration.

Autonomic Nervous System↗
PubMed2002

Clinical usefulness of corrected QT intervals in diabetic autonomic neuropathy in patients with type 2 diabetes.

BACKGROUND: It is recognized that QTc intervals reflect autonomic nerve function. To investigate the clinical usefulness of corrected QT intervals (QTc) in assessing autonomic nerve function in type 2 diabetes, we measured QTc intervals using Bazett's formula in 58 type 2 diabetic patients and 20 age-matched healthy subjects. METHODS: We examined relationships between QTc intervals and the coefficient of variation of RR intervals (CV(RR)), systolic blood pressure response to standing, and sympathetic skin response (SSR) whose tests reflect autonomic nerve function. We also studied the correlation between QTc and blood pressure or serum lipid concentrations. RESULTS: QTc intervals in diabetic patients were significantly longer than those in healthy subjects and showed a significant but weak negative correlation with CV(RR), as well as systolic blood pressure response to standing. No significant difference in QTc intervals was observed between patients with and without a detectable SSR. QTc intervals showed a significant positive correlation with systolic and diastolic blood pressure although it did not correlate with serum lipid concentrations. QTc also tended to be long in obese diabetic subjects (body mass index > 25). CONCLUSION: QTc intervals might also be affected by other factors such as arteriosclerotic macroangiopathy and obesity, and not only autonomic nerve function. Therefore it might be considered as an overall index for complications, and not for pure autonomic impairment.

Aged↗
PubMed2001

The JAK2 inhibitor AG490 predominantly abrogates the growth of human B-precursor leukemic cells with 11q23 translocation or Philadelphia chromosome.

The Janus kinase (JAK) family is one of intracellular protein tyrosine kinases (PTKs) present in hematopoietic and lymphoid cells and has been shown to play a crucial role in a variety of biological responses. It was reported that a human B-precursor leukemic cell line was potently inhibited in its proliferation by one of synthetic PTK inhibitors (tyrphostins), AG490, via anti-JAK2 activity. However, no extensive studies about it have been performed. In the present study, we tested 16 human lymphoid leukemic cell lines (B-precursor, 12; T cell, four) for their sensitivity to AG490 using 3H-thymidine incorporation and colony formation assays, and found that B-precursor cell lines with 11q23 translocation or Philadelphia chromosome (Ph1) whose JAK2 proved to be constitutively phosphorylated were predominantly sensitive to AG490 at a concentration that has few inhibitory effect on normal hematopoiesis. We first revealed the association of JAK2 with BCR-ABL in Ph1-positive cell lines and with Bruton's tyrosine kinase (BTK) in cell lines with 11q23 translocation by coimmunoprecipitation experiments. Of interest, AG490 markedly down-regulated phosphorylation of JAK2, but rather transiently up-regulated phosphorylation of BCR-ABL and BTK, suggesting direct implication of AG490 in the process of the JAK2 dephosphorylation. These results indicate that AG490 exerts a potent inhibitory activity to B-precursor leukemia with specific chromosomal abnormalities, and a therapeutic approach using AG490 is expected.

Antineoplastic Agents↗
PubMed2001

Changes in skin blood flow in type 2 diabetes induced by prostacyclin: association with ankle brachial index and plasma thrombomodulin levels.

In a previous study, we reported that beraprost sodium (BPS), a stable prostaglandin I(2) (PGI(2)) analog, increases skin blood flow in the feet of both control subjects and patients with type 2 diabetes, and that the flow increase induced by BPS is lower in diabetic patients than in controls. The present study was undertaken to clarify factors associated with smaller increases in skin blood flow in the feet of patients with type 2 diabetes after the administration of BPS, and to investigate the relationship between microalbuminuria and the changes in skin blood flow induced by the PGI(2) analog. We studied 61 patients with type 2 diabetes: 10 received placebo (control) and 51 (31 with normoalbuminuria and 20 with microalbuminuria) received BPS. Using laser Doppler flowmetry, we measured the skin blood flow at the pulp of the right big toe before and 90 minutes after administration of 40 microg BPS, and calculated the change in blood flow, i.e., delta flux (peak flux at 90 minutes - basal flux at 0 minutes). Plasma concentrations of soluble thrombomodulin (TM) were determined using an enzyme immunoassay (EIA) sandwich method. BPS significantly increased skin blood flow in the treatment group compared with the placebo group (P <.01). The delta flux was positively correlated with the value of the ankle brachial index (ABI) (r =.41, P <.0038) and was negatively correlated with plasma TM levels (r = -.53, P <.0001). By multiple regression analysis both the ABI value and the plasma TM level retained a significant influence on delta flux. Furthermore, both the delta flux and the ABI value in patients with microalbuminuria were lower than in patients with normoalbuminuria (P <.05). The results suggest that BPS increases the skin blood flow of the toe of patients with type 2 diabetes and that the increased flow is independently influenced by the value of the ABI and the plasma TM levels; in addition, microalbuminuria is associated with the impairment of vasodilation in the feet in response to BPS.

Adult↗
PubMed2001

Relationship between plasma soluble thrombomodulin levels and insulin resistance syndrome in type 2 diabetes: a comparison with von Willebrand factor.

Endothelial dysfunction plays a pivotal role in the initial stage of atherosclerosis. Insulin resistance is associated with accelerated atherosclerosis, especially coronary heart disease. To elucidate the relationship between endothelial dysfunction and insulin resistance or insulin resistance syndrome in patients with type 2 diabetes, we investigated the correlation between plasma soluble thrombomodulin (TM) and von Willebrand factor (vWF), measures of endothelial dysfunction, and the degree of insulin resistance evaluated by homeostasis assessment models of insulin resistance (HOMA-IR), or variables of insulin resistance syndrome. We studied 53 patients with type 2 diabetes, 23 treated with diet alone and 30 treated with sulfonylureas, who had normal renal function. The plasma soluble TM concentrations were highly correlated with HOMA-IR (r=0.64, p<0.0001), the plasma insulin (r=0.72, p<0.0001), the systolic blood pressure (r=0.45, p=0.0005), and the plasma fibrinogen (r=0.43, p=0.0018), while they were inversely correlated with the serum HDL cholesterol concentrations (r=-0.27, p=0.0344). The plasma vWF concentrations were positively correlated with HOMA-IR (r=0.35, p=0.0151) and the plasma fibrinogen (r=0.32, p=0.0203), but not with the plasma insulin, the systolic blood pressure or the HDL cholesterol concentrations. Furthermore, plasma TM, but not vWF, was positively correlated with total number of variables of insulin resistance syndrome (r=0.45, p=0.0005). These results indicate that endothelial dysfunction may be associated with the pathogenesis of insulin resistance syndrome as well as insulin resistance, and that the plasma TM might reflect endothelial damage better than the plasma vWF in the state of insulin resistance in patients with type 2 diabetes.

Adult↗