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Akira Hasegawa

Publications and source records attributed to Akira Hasegawa.

At least 19 recordsLinked to original sources
PubMed2025

Kinome analysis of Madurella mycetomatis identified kinases in the cell wall integrity pathway as novel potential therapeutic drug targets in eumycetoma caused by Madurella mycetomatis.

Eumycetoma is a neglected tropical subcutaneous disease most commonly caused by the fungus Madurella mycetomatis. Currently, eumycetoma is treated by a combination of antifungal therapy and surgery, with limited success rates. To identify novel drug targets we used an in silico approach to determine the kinases present in M. mycetomatis genome and rank them as potential drug targets. In total 132 predicted kinases were identified in M. mycetomatis, of which 21 were predicted to be essential for fungal viability and 4 of these had no human orthologues. Two were linked to the Cell Wall Integrity (CWI) signalling pathway and were expressed in a Galleria mellonella infection model. Several kinase inhibitors were identified after in silico modelling, however only 8 were able to inhibit growth. Five had predicted binding affinity with components of the CWI. Altogether, the CWI shows potential as a drug target for further evaluation.

Madurella↗
PubMed2006

HSF1 and constitutively active HSF1 improve vascular endothelial function (heat shock proteins improve vascular endothelial function).

We have been examining the role of heat shock factor 1 (HSF1) in the pleiotropic effects of statins. In parallel studies, we found that statin induces the nuclear translocation of HSF1 and that a decoy oligonucleotide encoding the heat shock element inhibits the statin-induced expression of heat shock protein 70, endothelial nitric oxide synthase (eNOS) and thrombomodulin. Also, in vascular endothelial cells, increases in the expression of human HSF1 corresponded with elevated steady-state levels of eNOS and thrombomodulin and reduced levels of endothelin-1 and plasminogen activator inhibitor-1. We also found that heat shock proteins induced eNOS and thrombomodulin expression and reduced PAI-1 and ET-1 expression. In particular, a combination of HSP70 and HSP90 strongly induced eNOS expression and reduced PAI-1 expression. In the current studies, we generated a constitutively active form of HSF1 and found that it is more effective than the wild-type HSF at inducing thrombomodulin and eNOS expression and decreasing endothelin-1 and plasminogen activator inhibitor-1 expression. These results show that the wild-type and constitutively active forms of HSF1 induce anticoagulation and relaxation factors in vascular endothelial cells and could therefore be used to treat cardiovascular disease.

Aorta↗
PubMed2006

Increase in serum troponin-I following rotational atherectomy reliably predicts the occurrence of reversible wall motion abnormalities.

BACKGROUND: There is growing evidence that microdebris pulverized by rotational atherectomy (RA) may have a deleterious effect on coronary microcirculation and ventricular contraction. However, the incidence and the predictors of worsening of left ventricular wall motion following RA are unknown. METHODS: Thirty patients without a known previous anterior wall myocardial infarction who underwent RA-facilitated angioplasty for de novo lesions of left anterior descending coronary artery were evaluated. Global and anterior wall regional left ventricular ejection fraction (LVEF and AREF) were analyzed before and after RA. Serum troponin-I, CK, and CK-MB concentrations were assayed. RESULTS: Target lesion length was greater (P=0.03), post-procedural minimal lumen diameter was smaller (P<0.01), and serum troponin-I immediately after RA was higher (P=0.01) in 16 patients with a decrease in the AREF of at least 15% than in those without. Stepwise logistic regression analysis identified one independent predictor of such worsening of AREF, troponin-I> or =0.1 ng/ml immediately after the procedure (P<0.01), with sensitivity of 81%, specificity of 79%, and relative risk of 3.8. CONCLUSIONS: Our results suggest that RA can cause substantial deterioration in left ventricular wall motion. Serum troponin-I, a sensitive indicator of myocardial damage, may be useful in predicting reversible LV wall motion abnormalities following RA.

Aged↗
PubMed2006

Drug eruption due to bosentan in a patient with systemic sclerosis.

We present the case of a 60-year-old female patient with systemic sclerosis complicated by pulmonary hypertension. Ten days after the initiation of treatment with bosentan, high fever and skin eruptions were noted. In the previous reports, the frequency of drug-induced skin eruptions has not been well documented. Since the use of bosentan is expected to increase, we should be aware of the previously unknown adverse effects as well as skin eruptions.

Anti-Inflammatory Agents↗
PubMed2006

VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients.

OBJECTIVES: To compare the genetic and clinical factors that cause large interpatient variability and ethnic differences in warfarin efficacy, we investigated variations of the VKORC1, CYP2C9, and CYP2C19 genes in Japanese subjects. Furthermore, we evaluated the genetic variations and clinical data as contributors of variation in warfarin maintenance dose. METHODS: Gene variations of VKORC1, CYP2C9, and CYP2C19 in 125 patients treated with warfarin and 114 healthy subjects were analyzed. The daily dose of warfarin, concentrations of S- and R-warfarin in plasma, and prothrombin time expressed as the international normalized ratio were used as the pharmacokinetic and pharmacodynamic indices. Data were evaluated by a multivariate analysis method. RESULTS: Three missense mutations (47 G>C, 113 A>C, and 1338 A>G) in VKORC1 were newly identified in the Japanese population. The 113 A>C (Asp38Ser) variant decreased the warfarin dose requirement from 3.33 +/- 1.54 mg/d (n = 122) to 1.5 mg/d (n = 1). The variants -1639 G>A in the 5'-upstream region, 1173 C>T in intron 1, and 1542 G>C in intron 2 were in complete linkage disequilibrium, and the frequency of the -1639 G>A variation was only 0.8%, which contrasts with the frequency (39.8%-45.8%) reported previously for white persons. The dose of warfarin was larger in the VKORC1 -1639 GA genotype group (4.55 +/- 1.75 mg/d, P < .001) than in the -1639 AA group (2.94 +/- 1.15 mg/d). The mean daily dose of warfarin was lower in subjects with CYP2C9*1/*3 (1.86 +/- 0.80 mg/d, P = .007) than in subjects with CYP2C9*1/*1 (3.36 +/- 1.43 mg/d). When the relative contributions of the VKORC1 variants, CYP2C9*2, CYP2C9*3, CYP2C19*2, and CYP2C19*3, as well as the clinical characteristics of the patients, diagnoses, and concurrent medications, were compared, the VKORC1 -1639 GA genotype group accounted for 16.5% and CYP2C9 variants accounted for 13.4% of variation in warfarin dose. CONCLUSION: The ethnic difference in warfarin maintenance dose was mainly dependent on the linked VKORC1 variants. Genotyping of -1639 G>A of the VKORC1 gene could be clinically important for predicting individual variability in anticoagulant responses to warfarin.

Adult↗
PubMed2006

Kidney transplantation in pediatric recipients with mental retardation: clinical results of a multicenter experience in Japan.

BACKGROUND: There are few published reports on kidney transplantation (KT) in physically handicapped patients with mental retardation. The aim of this study is to clearly identify the outcome of KT in these patients and clarify whether handicapped patients can be candidates for KT. METHODS: Our study identified 25 multiply handicapped transplant recipients from 8 institutions. Causes of mental retardation were chromosomal abnormality in 5 patients, genetic syndrome in 10 patients, developmental brain anomaly in 2 patients, and other or unknown causes in 8 patients. Primary diseases leading to end-stage renal disease were congenital urinary tract anomaly in 12 patients, focal segmental glomerulosclerosis in 3 patients, cystic kidney disease in 3 patients, and other in 7 patients. RESULTS: Twenty-three patients received living-related transplants from a parent and 2 patients received cadaver transplants. Twenty-two patients were on peritoneal dialysis therapy, 2 patients were on hemodialysis therapy at the time of KT, and 1 patient underwent preemptive KT. Eleven acute rejection episodes occurred in 8 patients. All episodes were completely reversed with treatments that included mainly methylprednisolone pulse therapy. Posttransplantation lymphoproliferative disorder occurred in 2 patients. Follow-up data showed that all grafts were functioning during a mean observation period of 41.1 months (range, 4 to 187 months). All persons providing primary support for patients were satisfied with the KT and believed that quality of life was improved in both transplant recipients and themselves. CONCLUSION: Results indicate that KT is not contraindicated in handicapped patients, but cannot determine which patients are unsuitable to undergo KT.

Adolescent↗
PubMed2006

[Development of a light-polymerized resin for the record base. Part 1 Comparison with autopolymerizing resin].

PURPOSE: The record block for maxillomandibular registration of the denture is absolutely necessary in order to decide the mandibular position. This record block must provide sufficient strength so as not to cause deformation in the oral cavity. It must also fit the alveolar ridge well in order to keep accurate registration. Since most of the conventional materials for this purpose are not sufficient, a new specific light-polymerized resin was experimentally developed for the record base. METHODS: The mechanical strength and suitability of the new material were examined in comparison with a conventional autopolymerizing resin. RESULTS: 1) The transverse strength was equivalent to that of the autopolymerizing resin. 2) Although the shear bond strength was equivalent to the autopolymerizing resin, the intensity was drastically improved by the application of composite primer. 3) The light-polymerized resin and the autopolymerizing resin did not show any difference in suitability, and it was a clinical value without problem. CONCLUSIONS: From these findings, it was confirmed that the new light-polymerized resin had the physical property for clinical application as a material for the record base.

Denture Bases↗
PubMed2005

Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria.

Disorders in enteric bacteria recognition by intestinal macrophages (Mphi) are strongly correlated with the pathogenesis of chronic colitis; however the precise mechanisms remain unclear. The aim of the current study was to elucidate the roles of Mphi in intestinal inflammation by using an IL-10-deficient (IL-10-/-) mouse colitis model. GM-CSF-induced bone marrow-derived Mphi (GM-Mphi) and M-CSF-induced bone marrow-derived Mphi (M-Mphi) were generated from bone marrow CD11b+ cells. M-Mphi from IL-10-/- mice produced abnormally large amounts of IL-12 and IL-23 upon stimulation with heat-killed whole bacteria Ags, whereas M-Mphi from wild-type (WT) mice produced large amounts of IL-10 but not IL-12 or IL-23. In contrast, IL-12 production by GM-Mphi was not significantly different between WT and IL-10-/- mice. In ex vivo experiments, cytokine production ability of colonic lamina propria Mphi (CLPMphi) but not splenic Mphi from WT mice was similar to that of M-Mphi, and CLPMphi but not splenic Mphi from IL-10-/- mice also showed abnormal IL-12p70 hyperproduction upon stimulation with bacteria. Surprisingly, the abnormal IL-12p70 hyperproduction from M-Mphi from IL-10-/- mice was improved by IL-10 supplementation during the differentiation process. These results suggest that CLPMphi and M-Mphi act as anti-inflammatory Mphi and suppress excess inflammation induced by bacteria in WT mice. In IL-10-/- mice, however, such Mphi subsets differentiated into an abnormal phenotype under an IL-10-deficient environment, and bacteria recognition by abnormally differentiated subsets of intestinal Mphi may lead to Th1-dominant colitis via IL-12 and IL-23 hyperproduction. Our data provide new insights into the intestinal Mphi to gut flora relationship in the development of colitis in IL-10-/- mice.

Animals↗
PubMed2005

Disappearance of HCV after cessation of immunosuppression in a patient with ulcerative colitis and renal transplantation.

We report a patient, a 45-year-old Japanese woman, who underwent living-related donor renal transplantation in 1986 and 1988, with the second procedure being successful. Ulcerative colitis (UC) was diagnosed in 1987 while she was receiving immunosuppressive therapy after the renal transplantation. She became positive for serum anti-hepatitis C virus (HCV) in November 1990, although her serum aminotransferase levels were normal. In June 2001, she had frequent episodes of melena with abdominal pain, as control of her UC deteriorated. In July 2001, she was admitted to the Department of Surgery at our hospital, and her daily dose of prednisolone was increased from 40 mg to 80 mg. After 2 weeks of high-dose prednisolone therapy, there was a significant increase of serum aminotransferases, and serum HCV-RNA rose above 850 KIU/ml (by reverse transcription-polymerase chain reaction [RT-PCR]). Control of UC was still poor, so cyclosporine A (CyA) was added at a dose that maintained a high serum concentration. The daily dose of prednisolone was tapered and leukapheresis was performed three times weekly. As result, serum aminotransferases decreased to the normal range. However, total colectomy and colostomy were required because the UC could not be controlled by these therapies. Serum aminotransferase levels increased transiently 2 months after the cessation of immunosuppressive therapy (prednisolone, azathioprine [AZP], and CyA). Subsequently, serum aminotransferases rapidly declined below normal, and the serum level of HCV-RNA (by RT-PCR) fell from 480 KIU/ml to less than 0.5 KIU/ml. She was discharged on April 25, 2002. During follow-up as an outpatient, serum HCV-RNA became negative and remained negative for 7 months. To confirm clearance of HCV, liver biopsy was performed, and no HCV-RNA was detected in the liver tissue by RT-PCR. These findings suggested that HCV was cleared by the cessation of immunosuppressive therapy, as a rebound effect.

Azathioprine↗
PubMed2005

Cholesterol crystal embolization: skin manifestation, gastrointestinal and central nervous symptom treated with corticosteroid.

Cholesterol crystal embolization (CCE) is characterized by tissue ischemia secondary to occlusion of small arteries. It may occur spontaneously but more often follows radiological interventional procedures or vascular surgery. This systemic disease affects multiple organs, including skin, kidney, brain, eye, and gastrointestinal tract. We reported a Japanese male CCE patient with cutaneous manifestations of livedo reticularis, diarrhea, clouding of consciousness, and acute renal failure. Histopathological examination demonstrated multiple biconvex clefts in a vessel of the subcutis. Corticosteroid administration improved his consciousness, diarrhea and skin lesions. Awareness of the skin manifestations of CCE is essential for dermatologists to make an early diagnosis and prescribe appropriate treatment.

Administration, Oral↗
PubMed2005

Significance of subclinical rejection in early renal allograft biopsies for chronic allograft dysfunction.

To determine the significance of early subclinical rejection of renal allografts, we reviewed 127 biopsy specimens obtained soon after transplantation. Histological finding was categorized according to a modification of the Banff scheme as: acute rejection (AR), borderline changes (BL); non-specific inflammatory changes, (NI) and no rejection (NR). Subclinical rejection was defined as AR, BL or NI. Patients with BL or NI were divided into two groups; one was treated with high-dose methylprednisolone (MP), the other remained untreated. Freedom from chronic allograft dysfunction (defined as non-doubling of serum creatinine 5 yr after transplantation) was significantly more frequent in the NR group (89%) than in the BL (70%) and AR (64%) groups. At 1 yr after transplantation, mean serum creatinine had increased significantly only in the untreated group (p < 0.05), and re-biopsy showed that interstitial fibrosis had developed to a significantly greater extent in the untreated group than in the treated group (p < 0.01). Subclinical rejection in the early protocol biopsies correlated closely with subsequent allograft dysfunction. High-dose MP treatment for early subclinical rejection may be effective in suppressing the development of interstitial fibrosis at 1 yr after transplantation.

Adult↗
PubMed2005

Post-transplant early recurrent proteinuria in patients with focal glomerulosclerosis--angiotensin II immunostaining and treatment outcome.

We reviewed the transplantation data and results of histopathological studies with additional angiotensin II (AII) immunostaining of renal graft biopsies of nine cases (10 grafts) with recurrent proteinuria and three controls without recurrent proteinuria that received renal transplantation for primary focal segmental glomerulosclerosis (FSGS) between 1986 and 2002. Recurrent FSGS was confirmed in six grafts from nine cases by light microscopy. In cases with recurrent proteinuria, loss of graft function was noted in all six renal grafts received between 1986 and early 1992 but in none of four grafts received between late 1992 and 2002. Two of four patients of the late group but none of those of the early group received angiotensin converting enzyme (ACEI) or angiotensin II receptor blocker (ARB) with plasma exchange (PE). In control cases without proteinuria, AII immunostaining was detected in tubules but not in glomeruli in 1-hour biopsies as well as later on. In cases with recurrent proteinuria, AII immunostaining was detected in both tubules and glomeruli, although glomerular AII staining was not observed in 1-hour biopsies. Our results suggest that effective treatment of post-transplantation recurrent FSGS requires ACEI or ARB with PE in the absence of another etiology.

Adolescent↗
PubMed2005

A prospective trial of steroid withdrawal after renal transplantation treated with cyclosporine and mizoribine in children: results obtained between 1990 and 2003.

A prospective trial of adrenocorticostertoid (steroid) withdrawal after pediatric renal transplantation was begun in 1990. Ninety-four pediatric renal transplant recipients were enrolled in our multicenter study. Immunosuppressive therapy with cyclosporine (CyA), methylprednisolone (MPL), and mizoribine (MZ) was started after transplantation. MPL was reduced to administration on alternate days in 69 patients (73.4%) and was withdrawn in 27 patients (28.7%). Rejection episodes occurred in nine patients (33.3%) after withdrawal of MPL. It occurred within 3 months after withdrawal of MPL in two patients and more than 6 months in the others. Among them, two patients lost the grafts. Thirteen-year patient survival rate and graft survival rate were 94.6 and 83.1%, respectively. Forty-four of the 94 patients reached their final height. Mean final height was 155.0 cm in males and 146.3 cm in females and their height standard deviation score was -2.6 s.d., the same as that at the time of transplantation. Management of growth retardation before transplantation and further reduction in the steroid dose after transplantation will increase the final height of children with chronic renal failure.

Adolescent↗
PubMed2005

Clinical course of congenital nephrotic syndrome and Denys-Drash syndrome in Japan.

BACKGROUND: The prognosis of Japanese patients with congenital nephrotic syndrome (CNS) and Denys-Drash syndrome (DDS) is not clear. METHODS: Five patients with CNS and four patients with DDS, which causes secondary CNS, were studied retrospectively. RESULTS: Seven patients were sporadic and two DDS patients were identical twins. Five CNS patients presented with edema within 3 months of birth. In four DDS patients, edema was not noted and end-stage renal disease developed between 7 months and 6 years of age. Of these five CNS patients, one patient had cerebral thrombosis and cytomegalovirus pneumonia at the onset and another patient died during dialysis. Frequent intravenous albumin administration required, growth and development during infancy were varied. Of the nine patients with CNS and DDS, seven received renal transplantation and were alive with functioning grafts at the last follow up. Catch-up growth was observed in five patients after transplantation. Five school-aged patients attended school and received adequate grades and two adults worked full-time. Of the DDS patients, dysuria due to hypospadias persisted in one patient and treatment for hypogonadism was needed in one patient. CONCLUSIONS: CNS and DDS were diagnosed early after onset and adequate treatment was started. Growth and development after renal transplantation were relatively good. Thrombotic episodes or severe infection in CNS patients was difficult to manage and complications resulting from DDS affected the quality of life.

Denys-Drash Syndrome↗
PubMed2005

Type 2 diabetes mellitus complicated with smoldering myeloma and non-alcoholic steatohepatitis.

We report a 59-year-old woman with type 2 diabetes mellitus (DM) complicated with smoldering myeloma and non-alcoholic steatohepatitis. A diagnosis of smoldering myeloma was made on the basis of elevation of IgA, M-protein (type:IgA-lambda) and histological findings of bone marrow without bone lesion. As to liver dysfunction, anti-HBV, anti-HCV and a series of auto-immune antibody were negative. She had no alcohol drinking habit and histological findings showed pericellular fibrosis without fatty degeneration, suggesting liver cirrhosis due to non-alcoholic steatohepatitis (NASH). To date, there are no reports of cases with DM, NASH and myeloma. Particular attention may be necessary for these complications.

Diabetes Mellitus, Type 2↗
PubMed2005

[Landiolol does not affect bispectral index scale in off-pump coronary artery bypass surgery in patients under fast-track cardiac anesthesia].

BACKGROUND: We evaluated the effect of landiolol, a novel ultra-short-acting receptor-selective blocker, on bispectral index scale (BIS). METHODS: Ten patients scheduled for off-pump coronary artery bypass (OPCAB) surgery under fast-track cardiac anesthesia were analyzed. Anesthesia was maintained with appropriate additional administration of fentanyl (total dose: 10-15 microg x kg(-1)) and vecuronium under inhalation of a mixture of oxygen, air and sevoflurane (less than 2%). Landiolol was administered continuously for 5 min, when the heart rate (HR) was 80 or more per minute and the BIS values were kept between 40-60. HR, mean arterial pressure (MAP), cardiac index (CI) and BIS values were recorded at 4 time points (after induction of anesthesia, before administration of landiolol, immediately before comple- tion of administration, and 15 minutes after completion of administration). RESULTS: HR decreased significantly by landiolol administration, but there were no significant changes in MAP, CI and BIS. CONCLUSIONS: This study suggests that landiolol does not affect BIS in OPCAB surgery patients under fast-track cardiac anesthesia.

Adrenergic beta-Antagonists↗
PubMed2005

[Recurrence of sarcoidosis in a hemodialysis patient confirmed by abnormal calcium metabolism].

28-year-old man hospitalized for a fever of unknown origin. This patient was already diagnosed as neurosarcoidosis proven by brain biopsy in 1997, then entered chronic hemodialysis therapy in 2002. The data showed hypercalcemia without taking any calcium agent and vitamin D, also showed suppressed intact-parathyroid hormone and normalized 1,25-dihydroxyvitamin D even the condition of end stage renal failure. Recurrence of sarcoidosis was made in this hospitalization. The laboratory data as well as symptom improved after taking oral prednisolone. We reported the case of recurrent sarcoidosis in a hemodialysis patient confirmed by abnormal calcium metabolism.

Adult↗