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Biomedical subjects

Hitoshi Yokoyama

Publications and source records attributed to Hitoshi Yokoyama.

At least 19 recordsLinked to original sources
PubMed2006

Remission of IgA nephropathy after allogeneic peripheral blood stem cell transplantation followed by immunosuppression for acute lymphocytic leukemia.

We report a case with immunoglobulin A (IgA) nephropathy, showing IgA deposition which disappeared after peripheral blood stem cell transplantation (PBSCT) for acute lymphocytic leukemia (ALL). In 1996, a 28-year-old man was diagnosed with IgA nephropathy by renal biopsy. Steroid therapy improved proteinuria from 3 g/day to 1 g/day. In 2003, he received PBSCT following the initial therapy for ALL. After complete remission, urinary protein and hematuria remained at between (-) and (+/-). In 2004, the second renal biopsy specimen revealed no deposit of IgA or C3. These findings suggested that immune reconstruction with PBSCT following immunosuppression therapy was of benefit to IgA nephropathy.

Adult↗
PubMed2006

Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.

Fibrocytes are a distinct population of bloodborne cells that share markers of leukocytes as well as mesenchymal cells. We hypothesized that CCR7-positive fibrocytes migrate into the kidney in response to secondary lymphoid tissue chemokine (SLC/CCL21) and contribute to renal fibrosis. To investigate this hypothesis, renal fibrosis was induced by unilateral ureteral obstruction in mice. A considerable number of fibrocytes dual-positive for CD45 and type I collagen (ColI) or CD34 and ColI infiltrated the interstitium, reaching a peak on day 7. Most fibrocytes were positive for CCR7, and CCL21/CCR7 blockade reduced the number of infiltrating fibrocytes. CCL21 and MECA79 dual-positive vessels were also detected in the interstitium. The blockade of CCL21/CCR7 signaling by anti-CCL21 antibodies reduced renal fibrosis, which was confirmed by a decrease in fibrosis in CCR7-null mice with concomitant reduction in renal transcripts of pro alpha1 chain of ColI and TGF-beta1. The number of F4/80-positive macrophages decreased along with renal transcripts of monocyte chemoattractant protein 1 (MCP-1/CCL2) after the blockade of CCL21/CCR7 signaling. These findings suggest that CCR7-positive fibrocytes infiltrate the kidney via CCL21-positive vessels, thereby contributing to the pathogenesis of renal fibrosis. Thus, the CCL21/CCR7 signaling of fibrocytes may provide therapeutic targets for combating renal fibrosis.

Animals↗
PubMed2006

Virological effects and safety of combined double filtration plasmapheresis (DFPP) and interferon therapy in patients with chronic hepatitis C: A preliminary study.

PURPOSE: In patients with chronic genotype 1b hepatitis C and a high viral load, the viral load was reduced by double filtration plasmapheresis (DFPP), followed by combined interferon and ribavirin therapy. The safety and virological effects of this treatment method were preliminarily investigated. METHODS: In nine patients with chronic hepatitis C, DFPP was performed three times on days 1, 2, and 4, and the administration of interferon and ribavirin was initiated immediately after DFPP on day 1. RESULT: The HCV RNA was undetectable in all patients after the plasma was passed through a plasma fractionator (second filter) in the DFPP circuit. After 2 weeks, the HCV RNA tended to decrease in the DFPP group more than in the control group (-2.45+/-1.12 versus -1.57+/-0.95, P=0.073). However, this decrease was not attributable to a sustained virological response (SVR) (22.2% versus 18.2%, P=0.822). Most of the adverse events were caused by the interferon and ribavirin combination therapy. CONCLUSION: DFPP can be safely performed concomitantly with interferon and ribavirin combination therapy in chronic hepatitis C patients. The combination may contribute to an early virological response. The effect of DFPP on the SVR and its significance remain to be clarified.

Journal Article↗
PubMed2006

TAK-603, an anti-inflammatory compound, reduces crescentic glomerulonephritis and preserves renal function in WKY rats.

BACKGROUND: The therapeutic efficacy of the regulation of T helper (Th)-1-predominant immune responses remains to be investigated. Therefore, the effects of the anti-inflammatory compound TAK-603 were investigated in a model of crescentic glomerulonephritis induced by a small dose of nephrotoxic serum in Wistar-Kyoto rats. METHODS: TAK-603 (50 mg/kg body weight) was administered orally, starting at the time of induction of glomerulonephritis. In group 1, the drug was administered daily for the initial 6 days. TAK-603 was administered on day 0 only in group 2, and from day 3 to 5 in group 3. In each group, nephritic rats were killed on days 6 and 56. RESULTS: In group 1 consisting of rats treated with TAK-603 daily from day 0 to 5, glomerular damage, including crescent formation, was improved on day 6, with reductions in the numbers of CD4, CD8 and ED-1 positive cells, as well as in urinary protein excretion. Protein and transcript levels of Th1 cytokines in the diseased kidneys were markedly decreased by TAK-603 treatment. Renal pathology, including glomerulosclerosis and interstitial fibrosis, was ameliorated and proteinuria was markedly decreased. Elevated levels of serum creatinine showed concomitant improvement. In group 3, in which treatment was initiated shortly after the appearance of glomerular abnormalities, glomerular damage was also diminished, resulting in a decrease in urinary protein excretion. Treatment only on the first day in group 2, partially rescued renal dysfunction. CONCLUSIONS: These results suggest the possible therapeutic application of inhibition of Th1-predominant immune responses in progressive crescentic glomerulosclerosis.

Animals↗
PubMed2006

Proteomic analysis of serum, outflow dialysate and adsorbed protein onto dialysis membranes (polysulfone and pmma) during hemodialysis treatment using SELDI-TOF-MS.

AIMS: Alterations in the profiling of peptides and proteins in the serum, outflow dialysate and adsorbed protein on the dialysis membrane were investigated. METHODS: Alterations in the protein profiling of routine hemodialysis using polysulfone (TS-UL) and PMMA (moderate flux membrane of polymethylmethacrylate: BK-U) in 8 patients and that of adsorption onto polysulfone and PMMA membranes in 4 patients were evaluated by SELDI-TOF-MS and ProteinChip array. Mass-to-charge ratios (m/z) between 2,000 and 120,000 were analyzed. RESULTS: The protein with a relative intensity of m/z 11,730 measured by SELDI-TOF-MS was present in a small amount in the outflow dialysate and in a large amount in adsorption (identified as beta2-microglobulin) onto PMMA membrane. Unexpectedly, 68 molecular masses of peptides that were adsorbed more onto polysulfone than onto PMMA membrane were observed. There were more peptides less than m/z 11,730 adsorbed onto polysulfone membrane than onto PMMA membrane. Dominant peaks, m/z 6,629 and 6,431 adsorbed onto polysulfone membrane were identified as apolipoprotein CI and truncated apolipoprotein CI, respectively. 37 proteins with molecular weights larger than m/z 11,730 showed greater filtration through PMMA membrane than through polysulfone membrane. 149 molecular masses that were adsorbed onto PMMA or more onto PMMA membrane than onto polysulfone membrane were observed. CONCLUSION: This experiment suggests that membrane adsorption is an important mechanism for the removal of middle-molecular-weight proteins by hemodialysis using not only PMMA membrane but also polysulfone membrane. Adsorption of peptide or protein onto a dialysis membrane may depend not only on the membrane material, but also on the peptide or protein.

Adsorption↗
PubMed2006

Reduction in chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase.

BACKGROUND: Chronic allograft nephropathy (CAN) is the major cause for late graft loss and is therefore a key target for therapy. METHODS: The impact of p38 mitogen-activated kinase (MAPK) on CAN was investigated by administering FR167653 (32 mg/kg/day), a specific inhibitor of p38 MAPK, for 4 weeks in addition to conventional cyclosporine therapy (1.5 mg/kg/day for 5 days) in an established experimental rat transplantation model. RESULTS: Transplanted rats develop glomerulosclerosis, arterial obliteration, interstitial fibrosis and tubular atrophy, all of which are characteristic of CAN, resulting in shortened survival on 32 weeks. However, the inhibition of p38 MAPK by daily subcutaneous treatment with FR167653 resulted in reduced CAN with preserved renal function and prolonged survival. The FR167653-treated rats had fewer phosphorylated p38 MAPK-positive cells in treated kidneys. Concomitantly, the expression of monocyte chemoattractant protein-1/CCL2 and transforming growth factor-beta(1) was markedly reduced. CONCLUSION: These results suggest that p38 MAPK phosphorylation is involved in the pathogenesis of CAN and provide evidence that p38 MAPK is a novel, appealing therapeutic target for combating CAN.

Animals↗
PubMed2006

MCP-1/CCR2-dependent loop for fibrogenesis in human peripheral CD14-positive monocytes.

Monocyte/macrophage (Momicron) migration to sites of inflammation is a prerequisite cause of organ fibrosis. The recruitment and activation of Mo are regulated by C-C chemokines, especially monocyte chemoattractant protein-1 [(MCP-1)/CC chemokine ligand 2], which interacts with CC chemokine receptor 2 (CCR2). However, the mechanisms leading to fibrosis via MCP-1/CCR2 signaling in Mo remain to be investigated. The effect of MCP-1 on the expression of MCP-1, CCR2, transforming growth factor-beta1 (TGF-beta1), and type I collagen in circulating human CD14-positive Mo was investigated. In addition, the impact of MCP-1-specific or TGF-beta1-specific antisense (AS) phosphorothioate oligodeoxynucleotides (ODN) was examined to explore the involvement of autocrine/paracrine production of MCP-1 and TGF-beta1 by human CD14-positive Mo. Furthermore, specific CCR2 inhibitors were applied to examine the involvement of CCR2 signaling for the promotion of a fibrogenic response. The stimulation of Mo with MCP-1 increased mRNA levels of TGF-beta1 and a pro-alpha1 chain of type I collagen (COL1A1) as well as protein synthesis. Similarly, the expression of MCP-1 and CCR2 was enhanced by the stimulation with MCP-1 in dose- and time-dependent manners. This positive loop via MCP-1 was reduced by pretreatment with MCP-1-specific AS-ODN. It was also noted that pretreatment with TGF-beta1-specific AS-ODN partially reduced COL1A1 mRNA levels. Finally, transcripts of these molecules were suppressed by pretreatment with specific CCR2 inhibitors. The present study demonstrated that human peripheral CD14-positive Mo contribute directly to fibrogenesis by a MCP-1/CCR2-dependent amplification loop. These data suggest that fibrogenic processes in Mo regulated by MCP-1/CCR2 may be novel, therapeutic targets for combating organ fibrosis.

Cells, Cultured↗
PubMed2006

Deoxyspergualin, an immunosuppressant, in patients suffering from nephropathies with crescent formation: an open-label trial to evaluate safety and efficacy.

BACKGROUND: Crescent formation in glomeruli means an acute active lesion that develops a rapidly progressive course. Therapies using pulse methylprednisolone, oral corticosteroids, and cyclophosphamide are recommended, but no agreement has been reached on the optimal therapy. There have been no controlled trials, because of the severity of this condition and because withholding treatment would become an ethical issue. METHODS: We evaluated the safety and efficacy of deoxyspergualin (DSG), an immunosuppressant, in a multicenter, prospective trial of 44 patients with crescent formation in over 10% of glomeruli, who were randomly placed into groups that received daily doses of 0.1 mg/kg (n = 21) and 0.2 mg/kg (n = 23) of DSG, given by a 1-h infusion for 4 weeks, and who were then monitored for 3 months. All patients received DSG in this open-label prospective study. We evaluated the levels of urinary protein and hematuria, and examined renal function after the DSG treatment. RESULTS: Urinary protein significantly decreased with each dose after starting the DSG administration and this efficacy was sustained for 2 months after the discontinuation of DSG. In the groups receiving 0.1 mg/kg and 0.2 mg/kg, mean urinary protein levels were 2.1 g/day and 2.3 g/day at the initiation of the DSG administration, 1.4 g/day and 1.6 g/day at week 4, and 1.5 g/day and 1.3 g/day at week 12, respectively. Hematuria was markedly improved by a dose of 0.2 mg/kg and was not exacerbated following the termination of DSG. Exacerbation of renal dysfunction, as measured by creatinine clearance, serum creatinine, and blood urea nitrogen was prevented by both doses of DSG. The most common adverse reaction was reversible neutropenia. CONCLUSIONS: Short-term treatment with DSG may be effective and tolerated in patients suffering from nephropathies with crescent formation.

Creatinine↗
PubMed2006

Three-dimensional quantification of cardiac surface motion: a newly developed three-dimensional digital motion-capture and reconstruction system for beating heart surgery.

OBJECTIVE: This study aimed to evaluate our newly developed 3-dimensional digital motion-capture and reconstruction system in an animal experiment setting and to characterize quantitatively the three regional cardiac surface motions, in the left anterior descending artery, right coronary artery, and left circumflex artery, before and after stabilization using a stabilizer. METHODS: Six pigs underwent a full sternotomy. Three tiny metallic markers (diameter 2 mm) coated with a reflective material were attached on three regional cardiac surfaces (left anterior descending, right coronary, and left circumflex coronary artery regions). These markers were captured by two high-speed digital video cameras (955 frames per second) as 2-dimensional coordinates and reconstructed to 3-dimensional data points (about 480 xyz-position data per second) by a newly developed computer program. RESULTS: The remaining motion after stabilization ranged from 0.4 to 1.01 mm at the left anterior descending, 0.91 to 1.52 mm at the right coronary artery, and 0.53 to 1.14 mm at the left circumflex regions. Significant differences before and after stabilization were evaluated in maximum moving velocity (left anterior descending 456.7 +/- 178.7 vs 306.5 +/- 207.4 mm/s; right coronary artery 574.9 +/- 161.7 vs 446.9 +/- 170.7 mm/s; left circumflex 578.7 +/- 226.7 vs 398.9 +/- 192.6 mm/s; P < .0001) and maximum acceleration (left anterior descending 238.8 +/- 137.4 vs 169.4 +/- 132.7 m/s2; right coronary artery 315.0 +/- 123.9 vs 242.9 +/- 120.6 m/s2; left circumflex 307.9 +/- 151.0 vs 217.2 +/- 132.3 m/s2; P < .0001). CONCLUSIONS: This system is useful for a precise quantification of the heart surface movement. This helps us better understand the complexity of the heart, its motion, and the need for developing a better stabilizer for beating heart surgery.

Animals↗
PubMed2006

Rituximab therapy for Epstein-Barr virus-related chronic hepatitis following living donor kidney transplantation.

A patient who underwent living donor kidney transplantation was infected with Epstein-Barr virus (EBV) that resulted in persistent EBV infection and EBV-associated chronic hepatitis, determined by abnormally elevated anti-EBV antibody titers and high frequency of EBV-infected B lymphocytes. Despite decreases in immunosuppressant doses, persistent EBV infection and chronic hepatitis persisted for several years. Therapy using anti-CD20 monoclonal antibody (rituximab) virtually eliminated peripheral B lymphocytes and EBV-encoded small RNA 1 (EBER-1)-positive cells. Moreover, hepatic enzyme levels normalized and histological findings indicated marked improvement in hepatic inflammation. Although peripheral CD20(+) B lymphocyte and EBER-1-positive cell levels began to increase 4 months after the end of therapy, the number of EBER-1-positive cells remained very low, and liver function test results remained within normal ranges. The present case illustrates the significance of early diagnosis, monitoring of viral load, and vigorous management of EBV-related disorders associated with organ transplantation.

Adolescent↗
PubMed2006

Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury.

OBJECTIVE: Ischemia-reperfusion injury is known to cause organ failure, but the mechanisms of pathogenesis remain unclear. Inflammation is a factor in tissue destruction in ischemia reperfusion injury, and interleukin (IL)-1 is a key promoter of inflammation. DESIGN: Prospective, randomized, and controlled study. SETTING: University laboratory. SUBJECTS: Male mice 6-8 wks of age, in which genes for IL-1alpha and IL-1beta (IL-1alpha/beta deficient) and IL-1 receptor antagonist (IL-1RA deficient) are deleted by homologous recombination, and wild-type controls on a Balb/c background. INTERVENTIONS: In this study, the role of IL-1 on inflammatory cascades, including chemokine expression, inflammatory cell infiltration, and tissue destruction, was investigated in 45 mins of unilateral renal ischemic injury using IL-1alpha/beta-deficient mice and IL-1RA-deficient mice. In addition, the effects of IL-1 on chemokine expression in cultured tubular epithelial cells were investigated. MEASUREMENTS AND MAIN RESULTS: In vivo study revealed that the number of interstitial infiltrated neutrophils and macrophages, which accompanied the increase of the serum levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-1alpha, respectively, significantly increased in IL-1RA-deficient mice. The number of interstitial infiltrated neutrophils correlated well with serum levels of KC at 24 hrs after reperfusion, whereas the number of interstitial infiltrated macrophages correlated well with the serum levels of MIP-1alpha and monocyte chemoattractant protein (MCP)-1 at 24 and 48 hrs after reperfusion, respectively. Likewise, in vitro study revealed that stimulation of tubular epithelial cells by IL-1beta and/or H2O2 sequentially induced KC, MIP-1alpha, and MCP-1 in both protein and messenger RNA levels, which is consistent with in vivo results. CONCLUSION: IL-1-dependent inflammatory cascades, followed by inflammatory cell infiltration and subsequent tissue destruction, may affect pathogenesis of renal ischemia-reperfusion injury.

Animals↗
PubMed2006

Prolapse of aortic intimal flap into the left ventricle: a rare cause of global myocardial ischemia in acute type A aortic dissection.

A 62-year-old woman experienced an acute type A aortic dissection complicated with profound shock caused by acute myocardial ischemia. Intraoperative transesophageal echocardiography (TEE) identified a circumferentially dissected intimal flap at 5.5 cm above the aortic valve, prolapsing into the left ventricle through the aortic valve during diastole and obstructing both coronary ostia. Acute aortic dissection must be kept in mind when presented with myocardial ischemia and TEE is the most useful method for detecting a prolapsing cylindrical intimal flap.

Aortic Dissection↗
PubMed2006

Interferon-gamma plays protective roles in sodium arsenite-induced renal injury by up-regulating intrarenal multidrug resistance-associated protein 1 expression.

Subcutaneous injection of sodium arsenite (NaAs, 12.5 mg/kg) into BALB/c [wild-type (WT)] mice causes acute renal dysfunction characterized by severe hemorrhages, acute tubular necrosis, and cast formation, with increases in serum blood urea nitrogen and creatinine levels. Concomitant enhancement in intrarenal interferon (IFN)-gamma expression prompted us to examine its roles in this pathology. IFN-gamma-deficient (IFN-gamma-/-) mice exhibited higher serum blood urea nitrogen and creatinine levels and exaggerated histopathological changes, compared with WT mice. Eventually, IFN-gamma-/- mice exhibited a high mortality (87.5%) within 24 hours after NaAs challenge, whereas most WT mice survived. The intrarenal arsenic concentration was significantly higher in IFN-gamma-/- mice later than 10 hours after NaAs treatment, with attenuated intrarenal expression of multidrug resistance-associated protein (MRP) 1, a main transporter for NaAs efflux, compared with WT mice. NF-E2-related factor (Nrf) 2 protein, a transcription factor crucial for MRP1 gene expression, was similarly increased in the kidneys of both strains of mice after NaAs treatment. In contrast, the absence of IFN-gamma augmented transforming growth factor-beta-Smad3 signal pathway and eventually enhanced the expression of activating transcription factor 3, which is presumed to repress Nrf2-mediated MRP1 gene expression. Thus, IFN-gamma can protect against NaAs-induced acute renal injury, probably by maintaining Nrf2-mediated intrarenal MRP1 gene expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice.

To clarify the pathophysiological mechanism underlying acute renal injury caused by acute exposure to arsenic, we subcutaneously injected both BALB/c and C57BL/6 mice with sodium arsenite (NaAs; 13.5 mg/kg). BALB/c mice exhibited exaggerated elevation of serum blood urea nitrogen (BUN) and creatinine (CRE) levels, compared with C57BL/6 mice. Moreover, half of BALB/c mice died by 24 h, whereas all C57BL/6 mice survived. Histopathological examination on kidney revealed severe hemorrhages, acute tubular necrosis, neutrophil infiltration, cast formation, and disappearance of PAS-positive brush borders in BALB/c mice, later than 10 h. These pathological changes were remarkably attenuated in C57BL/6 mice, accompanied with lower intrarenal arsenic concentrations, compared with BALB/c mice. Among heavy metal inducible proteins including multidrug resistance-associated protein (MRP)-1, multidrug resistance gene (MDR)-1, metallothionein (MT)-1, and arsenite inducible, cysteine- and histidine-rich RNA-associated protein (AIRAP), intrarenal MDR-1, MT-1, and AIRAP gene expression was enhanced to a similar extent in both strains, whereas NaAs challenge augmented intrarenal MRP-1 mRNA and protein expression levels in C57BL/6 but not BALB/c mice. Moreover, the administration of a specific inhibitor of MRP-1, MK-571, significantly exaggerated acute renal injury in C57BL/6 mice. Thus, MRP-1 is crucially involved in arsenic efflux and eventually prevention of acute renal injury upon acute exposure to NaAs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Changes in platelet aggregation during cardiopulmonary bypass: comparison of poly-2-methoxyethylacrylate and heparin as a circuit coating material.

At present, there are various biomaterials that have high biocompatibility. In particular, there are many types of coated circuits in cardiopulmonary bypass (CPB) systems. However, only a few clinical studies have investigated platelet aggregation caused by these coated circuits. In this study, a CPB system coated with poly-2-methoxyethylacrylate (X coating) was used to ascertain whether platelet aggregation could be suppressed during CPB, and a comparison was made between X coating and ordinary (covalently bonded) heparin coating. The subjects were 19 adult patients who were scheduled to undergo valve replacement or valvuloplasty. They were divided into two groups: group X (X coating) and group H (heparin coating). The platelet aggregation threshold index (PATI, grading curve) and beta-thromboglobulin and plalelet factor IV levels were assessed preoperatively (control), 5 min after heparin administration, 10 and 60 min after the start of CPB, and 0 and 2 h after the end of CPB. The results indicated that platelet aggregation was reduced during CPB and that platelets were activated. The changes in platelet aggregation associated with the X coating were shown to be similar to those associated with heparin coating.

Acrylates↗
PubMed2005

Long-term results of endoluminal grafting for descending thoracic aortic aneurysms.

OBJECTIVE: This paper describes the long-term results of endoluminal grafting (EG) for the treatment of descending thoracic aortic aneurysms (dTAA). METHODS: Until July 2004, EG for dTAA has been applied in 45 cases (male/female, 29/16, 49-86 years old, mean age 67 years old). Locations included the proximal dTAA in 24 cases, and middle or distal dTAA in 21 cases. The stent-grafts (SGs) were constructed of Gianturco Z-stents covered with woven polyester grafts. RESULTS: Deployment of the SGs was successful in 43 of 45 cases (96%) and complete thrombosis of the aneurysm was achieved in 39 cases (87%). Six minor endoleaks (13%), one migration (2%) and one conversion to surgery (2%) occurred. There was no instance of paraplegia nor hospital death. Over a mean 48 month follow-up (range 3 to 90), there were three persistent endoleaks (6%), four secondary endoleaks (8%), one breakage of wire frame (2%). Four cases were converted to open surgery due to secondary endoleak. There were two aneurysmal ruptures at the site where EG was not performed. The cumulative survival rate was 95.6 +/- 4.4% at 12 months, 85.7 +/- 5.4% at 24 months, and 82.4 +/- 6.1% at 36 and 60 months. CONCLUSION: These results demonstrated that EG is safe and effective in selected dTAA patients. Improvements in patients selection, surgical techniques and equipment will reduce EG related complications and conversion to open repair over the course of the evaluation.

Aged↗