Biomedical subjects

Junji Uchida

Publications and source records attributed to Junji Uchida.

At least 19 recordsLinked to original sources

PubMed2005

Increased antitumor activity in combined treatment TS-1 and docetaxel. A preclinical study using gastric cancer xenografts.

As TS-1 and docetaxel (TXT) have different mechanisms of antitumor activity, the combination therapy is expected to have a higher response. Human gastric cancer xenografts SC-2, St-40, and SC-4 inoculated into nude rats were treated with TS-1 alone (TS-1 12 mg/kg/day, day 1-14), TXT alone (TXT 2 mg/kg/day, day 1 or day 8), and combination of both drugs. TS-1 alone showed antitumor activity against three tumors (growth inhibition rate (IR): SC-2 (38.6 and 40.5%), St-40 (54.5%), SC-4 (55.1%)). TXT was effective with minimal toxicity, especially on day 1 of administration (IR at day 1 administration: SC-2 (51.7%), St-40 (42.1%), SC-4 (46.3%)). In the combined TS-1 and TXT group, antitumor activity increased at day 1 and at day 8 TXT administration (IR at day 1 administration: SC-2 (68.4%), St-40 (72.5%), SC-4 (76.0%)). Weight loss of TS-1 and day 1 TXT administration was the same as that of TS-1 alone. TS-1 and TXT showed no pharmacokinetic interaction. Compared with 5-fluorouracil and cisplatin treatment, combined therapy with TS-1 and TXT showed the same antitumor activity and toxicity. Combined therapy with TS-1 and TXT showed enhanced antitumor activity compared with monotherapy of each drug. The outpatient-based treatment of this combination is worth investigating.

Animals↗

PubMed2005

The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice.

Although anti-CD20 immunotherapy effectively treats human lymphoma and autoimmune disease, the in vivo effect of immunotherapy on tissue B cells and their subsets is generally unknown. To address this, anti-mouse CD20 mAbs were used in a mouse model in which the extent and kinetics of tissue B cell depletion could be assessed in vivo. CD20 mAb treatment depleted most mature B cells within 2 days, with 95-98% of B cells in the bone marrow, blood, spleen, lymph nodes, and gut-associated lymphoid tissues depleted by day 7, including marginal zone and follicular B cells. The few spleen B cells remaining after CD20 mAb treatment included pre-B, immature, transitional, and some B1 B cells that expressed CD20 at low levels. By contrast, peritoneal cavity B cells expressed normal CD20 densities and were coated with CD20 mAb, but only 30-43% of B1 cells and 43-78% of B2 cells were depleted by day 7. Spleen B cells adoptively transferred into the peritoneal cavity were similarly resistant to mAb-induced depletion, while transferred B cells that had migrated to the spleen were depleted. However, peritoneal B1 and B2 cells were effectively depleted in mAb-treated wild-type and C3-deficient mice by thioglycolate-induced monocyte migration into this otherwise privileged niche. Inflammation-elicited effector cells did not promote peritoneal cavity B cell depletion in FcR-deficient mice treated with CD20 mAb. Thus, the majority of CD20(+) cells and B cell subsets within lymphoid tissues and the peritoneum could be depleted efficiently in vivo through Fc-dependent, but C-independent pathways during anti-CD20 immunotherapy.

Animals↗

PubMed2005

Silent cerebral infarction predicts vascular events in hemodialysis patients.

BACKGROUND: Cardiovascular disease is the leading cause of death in hemodialysis (HD) patients. We have previously reported a higher incidence of silent cerebral infarction (SCI) in HD patients compared with the control group using MRI studies. In the present study, we examined whether or not SCI could predict vascular events in HD patients. METHODS: Cranial magnetic resonance imaging (MRI) was performed on 119 HD patients without symptomatic cerebrovascular disease. SCI was detected by MRI, and the patients were prospectively followed up. The end points of the study were the incidence of major events related to vascular events (cerebral events, cardiac events, and sudden deaths). We investigated the prognostic role of SCI in cerebral, cardiac, and vascular events by using the Kaplan-Meier method and Cox proportional hazards analysis. RESULTS: The prevalence of SCI was 49.6% in HD patients. During a follow-up period of maximum 60 months, vascular events, which included 13 cerebral events, 5 cardiac events, and 3 sudden deaths, occurred in 21 patients. The presence of SCI was predictive for a higher cerebral and vascular morbidity compared to the absence of SCI [18.6% (N= 11) vs. 3.3% (N= 2), P= 0.0169, and 30.5% (N= 18) vs. 5.0% (N= 3), P= 0.0006, respectively]. By multivariate Cox proportional hazards analysis, SCI remained a powerful independent predictor of cerebral and vascular events (hazard ratio for cerebral events 7.33, 95% CI 1.27-42.25: for vascular events 4.48, 95% CI 1.09-18.41). CONCLUSION: The findings of the present study indicate that the presence of SCI is a new risk factor for vascular events in HD patients.

Adult↗

PubMed2004

The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy.

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell-, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti-mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcgammaRI- and FcgammaRIII-dependent pathways, whereas B cells were not eliminated in FcR common gamma chain-deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcgammaR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.

Animals↗

PubMed2004

Severely impaired B lymphocyte proliferation, survival, and induction of the c-Myc:Cullin 1 ubiquitin ligase pathway resulting from CD22 deficiency on the C57BL/6 genetic background.

Understanding the molecular mechanisms through which CD22 regulates B lymphocyte homeostasis, signal transduction, and tolerance is critical to defining normal B cell function and understanding the role of CD22 in autoimmunity. Therefore, CD22 function was examined in vivo and in vitro using B cells from CD22-deficient (CD22(-/-)) mice. Backcrossing of founder CD22(-/-) mice onto the C57BL/6 (B6) genetic background from a B6/129 mixed background resulted in a dramatically reduced B cell proliferative response following IgM ligation, characterized by a paucity of lymphoblasts and augmented apoptosis. Also, the phenotype of splenic B6 CD22(-/-) B cells was uniquely HSA(high) and IgD(low)/CD21(low) with intermediate levels of CD5 expression, although the percentages of mature and transitional B cells were normal. That B6 CD22(-/-) B cells predominantly underwent apoptosis following IgM ligation correlated with this unique tolerant phenotype, as well as defective induction of the c-Myc:Cullin 1 (CUL1) ubiquitin ligase pathway that is necessary for progression to the S phase of cell cycle. CD40 ligation compensated for CD22 deficiency by restoring lymphoblast development, proliferation, c-Myc and CUL1 expression, and protein ubiquitination/degradation in IgM-stimulated B6 CD22(-/-) B cell cultures. Thereby, this study expands our current understanding of the complex role of CD22 during B cell homeostasis and Ag responsiveness, and reveals that the impact of CD22 deficiency is dictated by the genetic background on which it is rendered. Moreover, this study defines CD22 and CD40 as the first examples of lymphocyte coreceptors that influence induction of the c-Myc:CUL1 ubiquitin ligase pathway.

Adjuvants, Immunologic↗

PubMed2004

Mouse CD20 expression and function.

CD20 plays a role in human B cell proliferation and is an effective target for immunotherapy. In this study, mouse CD20 expression and biochemistry were assessed for the first time using a new panel of CD20-specific mAb, with CD20 function assessed using CD20-deficient (CD20(-/-)) mice. CD20 expression was B cell restricted and was initiated during late pre-B cell development. The frequency and density of CD20 expression increased during B cell maturation in the bone marrow, with a subpopulation of transitional IgM(hi) B cells expressing higher CD20 levels than the majority of mature recirculating B cells. Transitional T1 B cells in the spleen also expressed high CD20 levels, providing a useful new marker for this B cell subset. In CD20(-/-) mice, immature and mature B cell IgM expression was approximately 20-30% lower relative to B cells from wild-type littermates. In addition, CD19-induced intracellular calcium responses were significantly reduced in CD20(-/-) B cells, with a less dramatic effect on IgM-induced responses. These results reveal a role for CD20 in transmembrane Ca(2+) movement in mouse primary B cells that complements previous results obtained using human CD20 cDNA-transfected cell lines. Otherwise, B cell development, tissue localization, signal transduction, proliferation, T cell-dependent antibody responses and affinity maturation were normal in CD20(-/-) mice. Thus, mouse and human CD20 share similar patterns of expression and function. These studies thereby provide an animal model for studying CD20 function in vivo and the molecular mechanisms that influence anti-CD20 immunotherapy.

Animals↗

PubMed2004

Kidney transplants from living related donors having double inferior vena cava.

We performed four living related kidney transplantations from donors with double inferior vena cava (D-IVC), in which the left kidney was selected in two cases and the right in two cases. By dissecting the right internal iliac vein and isolating the right external iliac vein, the surgical procedure of the recipient side was so devised as to avoid any complications. In one patient, the surgical procedure of the donor side was modified to extend the donor left renal vein by anastomosis of part of the donor IVC to the renal vein. In the other case, no special treatment was necessary due to the patient's slender physique. In all four cases, transplants were successfully performed. The following conclusions can be made from these results: If the donor has D-IVC, it is essential to carefully conduct pre-operative examinations including angiography and venography to investigate other possible anomalies and blood flow of the renal vein. In addition, the graft must be carefully selected so that it is not disadvantageous to the donor. If there is no disadvantage to the donor as to which kidney is selected, the kidney with the longer renal vein should be transplanted.

Adolescent↗

PubMed2003

Renal transplantation for the hemodialysis patient with axillofemoral bypass.

BACKGROUND: Axillofemoral bypass grafts are used in the treatment of aortoiliac occlusive disease caused by atherosclerosis. There have been no previous reports on renal transplantation used as treatment for chronic renal failure after an axillofemoral bypass graft being placed because of atypical coarctation of the aorta. METHODS: The patient was a 47-year-old woman who had received regular hemodialysis for 15 years. Axillofemoral bypass surgery was performed because of atypical coarctation of the aorta in October 1999. Three years after surgery, she underwent renal transplantation. RESULTS: Renal transplantation was successful, and helical computed tomography demonstrated patent graft bypass and good nephrographic effects of the renal artery. CONCLUSIONS: Even though dialysis patients with atypical coarctation of the aorta are treated with an axillofemoral bypass, it is possible for them to undergo regular renal transplantation, if part of the external or internal iliac artery is intact.

Aortic Coarctation↗

PubMed2003

Renal allograft arteriovenous fistula and large pseudoaneurysm.

The patient was a 51-year-old female. Post-biopsy arteriovenous fistula (AVF) and pseudoaneurysm in a renal allograft were diagnosed 5 yr and 4 months after she received a renal transplantation. Four years after the diagnosis, interventional treatment for the AVF and pseudoaneurysm was performed because of a high risk of pseudoaneurysm rupture. Although the longitudinal diameter of the pseudoaneurysm was more than 5 cm, this AVF and pseudoaneurysm were treated successfully by a percutaneous transluminal embolization, and renal function has remained stable after embolization. A selective interventional procedure proved effective for the large pseudoaneurysm in the renal allograft. Therefore, when a transcutaneous needle biopsy of the renal allograft is performed, although there are no apparent symptoms or signs of vascular complications during the clinical course, periodical examinations such as echo-Doppler imaging should be made on the allograft.

Aneurysm, False↗

PubMed2003

Xanthogranulomatous pyelonephritis with acquired cystic disease of the kidney in a haemodialysis patient.

A 54-year-old-female patient who had received regular haemodialysis therapy for 12 years was referred to our hospital for evaluation of a left renal mass. Imaging examinations revealed acquired cystic disease of the kidney (ACDK) and a tumour-like lesion in the left kidney. Because of the preoperative diagnosis of the left renal cell carcinoma, the patient underwent a left nephrectomy. Pathological examination revealed xanthogranulomatous pyelonephritis. It was difficult to distinguish xanthogranulomatous pyelonephritis from renal cell carcinoma in our case, because it is very rare for xanthogranulomatous pyelonephritis to occur in ACDK.

Female↗

PubMed2003

Unruptured intracranial aneurysms in haemodialysis patients.

While the mortality rate of subarachnoid haemorrhage is very high in haemodialysis (HD) patients, the prevalence of unruptured intracranial aneurysms in HD patients has not yet been elucidated. We performed cerebral magnetic resonance angiography (MRA) on 123 HD patients who did not have symptomatic cerebrovascular disease, and on 52 control subjects. On the basis of these images, the prevalence of unruptured intracranial aneurysms was evaluated. Unruptured aneurysms were found in three HD patients (2.4%). There were no aneurysms found in the healthy control group. There was no significant difference in the prevalence of unruptured aneurysms between HD patients and healthy controls. Therefore, the incidence of intracranial aneurysms is not associated with chronic renal failure.

Adult↗

PubMed2003

Advanced ureteral cancer with complete remission achieved by taxan containing systemic chemotherapy.

We report a case of advanced ureteral cancer successfully treated with systemic chemotherapy combined with irradiation. A 47-year-old man was diagnosed as having a right ureteral cancer at the clinical stage of T4, N2 and M1 (liver). A papillary tumor was also found in the bladder and the resected specimen showed a grade 1 transitional cell carcinoma. Although three cycles of methotrexate, vinblastine, pirarubicin and cisplatin (MVAC) gave partial response to the ureteral tumor, new metastases to the lung and pelvic bone were observed. The patient received 50 Gy external irradiation to the pelvis, 11 cycles of paclitaxel (270 mg) and cisplatin (60-80 mg) followed by four cycles of docetaxel (100 mg) and cisplatin. Thereafter, he underwent bone biopsy, partial hepatectomy, total nephroureterectomy and lymph node resection, by which a complete response was achieved pathologically. The patient has been alive without evidence of disease for 12 months.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Asymptomatic occlusive lesions of cerebral arteries in Japanese hemodialysis patients.

While cerebrovascular diseases (CVD) are very common in hemodialysis (HD) patients, the prevalence and risk factors of asymptomatic occlusive lesions (AOL) of cerebral arteries in HD patients have not yet been elucidated. We performed cerebral magnetic resonance angiography (MRA) on 123 HD patients without symptomatic cerebrovascular disease and on 52 control subjects. On the basis of these images, we investigated the prevalence and risk factors of AOL. Stenosis greater than 25% narrowing of the cerebral arteries was found in 27 HD patients. The prevalence of AOL of cerebral arteries in HD patients was significantly higher than in the control group [27 (22.0%) versus 4 patients (7.7%), chi.2=4.2, p=0.0411]. Multiple logistic regression analysis showed that independent risk factors of AOL of cerebral arteries were uremic state, dyslipidemia, and age in all subjects and dyslipidemia and age in HD patients (R.2=0.162, p=0.0004; R.2 =0.138, p=0.0145, respectively). Our findings suggest that chronic renal failure maintained by hemodialysis increases the prevalence of AOL, and that age and dyslipidemia are also significantly associated with AOL in HD patients.

Adult↗

PubMed2003

Cadaveric renal transplantation from a non-heart-beating pediatric donor into adult recipients.

INTRODUCTION: The use of cadaveric pediatric kidneys has been suggested as a means to overcome organ shortage, but is debated because of technical complications and an increased incidence of functional allograft impairment. METHODS: We experienced 2 cases of cadaveric renal transplantation from a non-heart-beating pediatric donor. RESULTS: In our cases, transplanted kidneys achieved good graft function and proteinuria due to glomerulosclerosis was not recognized. CONCLUSION: Previous reports indicate that in transplantation from pediatric donors into adults recipients, glomerular sclerosis occurs as the reason for impairment of grafts. Further, cadaveric renal transplantation from a non-heart-beating donor has a warm ischemia time and an increased risk of hyperfiltrated injury and graft failure. If transplantation of pediatric kidneys into adults from a non-heart-beating donor is performed, BMI and BSA must be carefully considered in the selection of recipients in order to avoid imbalance between nephron supply and metabolic demands and to insure successful, healthy grafts.

Body Mass Index↗

PubMed2003

Results of cadaver kidney transplantation with right renal vein extension.

INTRODUCTION: Several methods to lengthen the renal vein of the allografts have been proposed in order to secure the surgeon's field of vision and to allow appropriate positioning of the graft. However, its safety and complications have not been clarified. Furthermore, its long- and short-term results have not been investigated. Therefore, we studied the results of this operative procedure to confirm the safety of the technique. METHODS: The right renal vein extension was utilized when the donated right kidney from a cadaver donor had sufficient length of the inferior vena cava wall. The results of 10 patients who received kidney transplantation with renal vein extension were examined. RESULTS: None of the patients had vascular complications. The transplanted kidney functioned in all patients; 3- and 5-year graft survival was 100 and 75.0%, respectively. CONCLUSIONS: The results confirmed that this technique was safe and without complications and did not affect the long- and short- term results of patients who received cadaver kidneys. Therefore, we conclude that it is appropriate to adapt this technique when the physician judges the long renal vein suitable for the procedure.

Adult↗

PubMed2003

The prognostic role of atrial natriuretic peptides in hemodialysis patients.

BACKGROUND: It is well known that plasma atrial natriuretic peptide (ANP) is an indicator of extracellular fluid volume expansion and that plasma ANP is considered to be a marker for setting the proper dry weight of HD patients. Although the plasma ANP is a prognostic predictor of cardiac death, the prognostic role of ANP in HD patients has yet to be elucidated. In this study, we investigated the prognostic role of ANP in HD patients. METHODS: Plasma ANP concentrations were measured in 105 HD patients after HD. Multiple regression analysis was performed to determine the major factors causing increased plasma ANP concentrations. Cardiac mortality was monitored for 24 months after baseline analysis, and the prognostic role of ANP was examined by Cox proportional hazards regression analysis. RESULTS: Multiple regression analysis showed that cardiovascular disease (CD) and age were independent factors for elevated ANP (R2 = 0.298, p < 0.0001). During a 24-month follow-up period, cardiac death occurred in 11 patients. Kaplan- Meier survival estimates of patients from varying plasma ANP levels (<50 and >50 pg/ml) differed between the two groups (p < 0.0001). The group with the higher ANP level (>50 pg/ml) had the lower survival. When compared with patients with ANP <50, the hazard ratios for cardiac death of patients with ANP of >50 pg/ml were 32.0 (95% confidence interval (CI) 4.1 to 252.4). Univariate Cox proportional hazards model showed that ANP, left ventricular ejection fraction (LVEF), LVMI, age, serum albumin and C-reactive protein (CRP) were significantly associated with the risk of cardiac mortality. By stepwise multivariate Cox proportional hazards analysis, only ANP, LVMI and CRP remained powerful independent predictors of cardiac death. The relative risk ratios were 3.483 (95% CI 1.640-7.397) for ln ANP, 1.023 (1.008-1.038) for LVMI, and 1.379 (1.115-1.705) for CRP. CONCLUSION: High plasma ANP level of post-HD were strongly associated with CD and age. Post-HD ANP level may be a reliable parameter for assessing the risk for cardiac death in HD patients by providing prognostic information independent of other variables previously reported.

Aged↗

PubMed2003

Renin mRNA expression and renal dysfunction in tacrolimus-induced acute nephrotoxicity.

Tacrolimus is a superior immunosuppressive agent and has markedly improved the short-term outcome of renal allografts. Despite the beneficial effects of maintaining immunotolerance in organ transplant recipients, it has well-characterized side effects on renal hemodynamics in the early phase. The mechanism of tacrolimus-induced acute nephrotoxicity is still unclear. The purpose of this study was to elucidate the role of renin-angiotensin system (RAS) in tacrolimus-induced acute nephrotoxicity. We examined the renal mRNA levels of renin in order to elucidate the relationship between plasma renin activity (PRA) and tacrolimus-induced renal dysfunction. Daily administration of tacrolimus (4 mg/kg/day) for 2 weeks in spontaneously hypertensive rats (SHR) significantly increased BUN and plasma creatinine (P-Cr) level, while endogenous creatinine clearance (Ccr) significantly decreased in tacrolimus treated rats. Regarding tubular function data, fractional excretion of Na (FENa) and fractional excretion of K were higher in the tacrolimus treated group. Renin mRNA levels in the renal cortex in tacrolimus treated rats significantly increased when compared to the vehicle-treated rats. Ccr level was inversely proportional to PRA, with a high correlation coeffecient. The rise in PRA significantly correlated with increase in FENa by liner regression. Therefore, the results indicate that RAS is involved in the tacrolimus-induced acute nephrotoxicity.

Animals↗

PubMed2002

Dissection of B cell differentiation during primary immune responses in mice with altered CD40 signals.

CD40 is essential for efficient humoral immune responses. CD40 has two cytoplasmic domains required for binding of tumor necrosis factor receptor-associated factors (TRAF). The TRAF6-binding site is within the membrane proximal cytoplasmic (Cmp) region, while a PXQXT motif in the membrane distal cytoplasmic (Cmd) region needs to engage TRAF2/3/5. To dissect CD40 signals necessary for B cell differentiation, we generated transgenic mice expressing wild-type and mutant human CD40 (hCD40) molecules in a mouse CD40-deficient (mCD40(-/-)) background. The B cell-specific expression of hCD40 in mCD40(-/-) mice resulted in T-dependent antibody responses including germinal center (GC) formation. Mutant hCD40 molecules that carry either a point mutation of the TRAF2/3/5-binding site or a deletion of the Cmd region rescued extrafollicular B cell differentiation but not GC formation. A mutant hCD40 that comprises of only the TRAF2/3/5-binding site in the cytoplasmic region also rescued low but significant titers of antigen-specific IgG1 without GC formation. These results demonstrated that two distinct signals either from the Cmp or from the Cmd region induced the extrafollicular B cell differentiation and Ig class switching; however, GC formation required both. We conclude that combinations of these two signals determine which of the extrafollicular or the follicular (GC) differentiation pathway B cells enter.

Animals↗