Biomedical subjects
Publications and source records attributed to T Sugaya.
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BACKGROUND AND OBJECTIVE: Recent studies have shown that bone morphogenetic protein-2 (BMP-2) stimulates mineralization and osteoclast differentiation. Osteoclastic resorption by BMP-2 application may play an important role in the regulation of new cementum-like tissue formation on the dentin surfaces. Therefore, this study aimed to examine the effect of BMP-2 application on dentin resorption and cementum-like tissue formation at the dentin surfaces. MATERIAL AND METHODS: Seventy-two flat dentin blocks were prepared from rat roots and treated with 24% EDTA. Each block was assigned to group 0, group 100, or group 400, and immersed correspondingly in 0, 100, or 400 microg/ml BMP-2. The dentin blocks were then implanted into palatal connective tissue of rats, and specimens were prepared 2, 4 and 8 wk after surgery for histologic and histomorphometric analyses. RESULTS: BMP-2 caused a dose-dependent increase in dentin resorption by osteoclastic cells. New cementum-like tissue was randomly formed on parts of the nonresorbed and resorbed dentin surfaces in groups 100 and 400. Dentin resorption in groups 100 and 400 was significantly greater than group 0 (p < 0.01). However, at 8 wk, new cementum-like tissue formed in 41.8% of group 100, as compared with 16.2% of group 400 (p < 0.05). CONCLUSION: Dentin resorption was stimulated by a high dose of BMP-2, and cementum-like tissue was induced by a low dose of BMP-2, effectively suggesting that BMP-2 application, at an appropriate dose, to a dentin surface may enhance periodontal regeneration.
AIMS: Focal glomerulosclerosis (FGS) and minor glomerular abnormalities are kidney diseases characterized by massive proteinuria. Urinary liver-type fatty acid-binding protein (L-FABP), an intracellular carrier protein of free fatty acids, is expressed in proximal tubules of the human kidney. Patients with FGS show significant improvement with low-density lipoprotein (LDL) apheresis. The aim of the present study was to determine whether urinary L-FABP levels differ between patients with FGS and those with minor glomerular abnormalities and whether levels are altered by LDL apheresis. PATIENTS AND METHODS: There were 24 patients with minor glomerular abnormalities (nephrotic stage, n = 14, remission stage, n = 10), 17 patients with FGS, and 20 healthy age-matched subjects were included in the present study. Urinary L-FABP levels were measured by enzyme-linked immunosorbent assay and compared. All patients with minor glomerular abnormalities at the nephrotic stage received prednisolone for 6 months, and all FGS patients received some form of immunosuppression therapy with prednisolone, cyclophosphamide or mizoribine for 12 months. LDL apheresis was performed in eight FGS patients with drug-resistant nephrotic syndrome. RESULTS: Urinary L-FABP levels were significantly higher in the 17 FGS patients (82.0 +/- 44.4 microg/g.Cr) than in the 24 patients with minor glomerular abnormalities (10.2 +/- 8.4 microg/g.Cr) (p < 0.01) and in the 20 healthy subjects (7.4 +/- 4.2 microg/g.Cr) (p < 0.01). Urinary L-FABP levels differed little between nephrotic stage and remission stage in patients with minor glomerular abnormalities. Urinary L-FABP levels were significantly higher in the eight drug-resistant FGS patients (122.6 +/- 78.4 microg/g.Cr) than in the nine drug-sensitive FGS patients (45.9 +/- 32.0 microg/g.Cr). Urinary L-FABP levels did not correlate with levels of other clinical markers including serum creatinine, urinary protein, and urinary N-acetyl-beta-D- glucosaminidase. In the eight drug-resistant FGS patients, LDL-apheresis significantly reduced urinary protein excretion (p < 0.01) and urinary L-FABP levels (p < 0.01). CONCLUSIONS: Urinary L-FABP may be a useful diagnostic indicator for differentiation between FGS and minor glomerular abnormalities. LDL apheresis may be effective in ameliorating tubulointerstitial lesions associated with FGS.
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Using angiotensin II (AngII) type 1A receptor-deficient mice [AT1(-/-)], in which we induced protein overload nephropathy, we explored the potential implication of AngII and endothelin-1 (ET-1) in the tubulointerstitial damage because of persistent proteinuria. At day 7, AT1(-/-) showed marked proteinuria to a similar extent to that of wild-type mice (WT). However, at day14, AT1(-/-) had significantly less proteinuria, renal damage, transforming growth factor-beta, and matrix mRNA expression and mortality. AT1(-/-) also showed a significant diminution in the activation of the transcriptional factors nuclear factor-kappaB and AP-1. Unexpectedly, AT1(-/-) had a higher interstitial infiltration than WT. The administration of the angiotensin-converting enzyme inhibitor quinapril to WT caused a marked improvement in proteinuria and renal lesions, resembling that seen in untreated AT1(-/-). However, the interstitial infiltration persisted in AT1(-/-) when treated with quinapril. Because ET-1 may participate in the recruitment of mononuclear cells, we also studied the implication of this peptide. AT1(-/-) had a significantly higher ET-1 expression in tubular epithelial cells than WT. The administration of the dual ETA/ETB antagonist bosentan to AT1(-/-) considerably reduced the interstitial infiltrates. Bosentan also exerted a beneficial effect on proteinuria, renal lesions, and mortality in WT. These data show that in overload nephropathy, proteinuria and renal lesions are, to a large extent, AngII-dependent. The up-regulation of ET-1 in tubular epithelial cells in AT1(-/-), associated with interstitial infiltrates, suggests that the combination of drugs interfering with both vasopeptides may be of therapeutic interest in renal diseases with severe proteinuria and tubulointerstitial damage.
The purpose of the study was to evaluate periodontal healing after replantation of intentionally rotated teeth with healthy and denuded root surfaces. Ten teeth with hopeless prognoses because of extensive alveolar bone loss and deep pockets extending to the apexes only on one or two surfaces, but with a healthy periodontal apparatus on the other surfaces, were selected. A mucogingival flap was elevated and the teeth were extracted carefully so as not to damage the healthy remnant of the periodontal membrane remaining on the root surfaces. Thorough extra-oral debridement was performed on the contaminated root surface and the remnant was carefully conserved. Retrofilling was also done to eliminate an endodontic cause of attachment loss. The teeth were horizontally rotated and then replanted so that the healthy root would face the connective tissue at the initially periodontally involved sites, and the root planed surfaces, which had been periodontally involved, would face the surfaces of the alveolar sockets at initially healthy sites. The teeth were splinted with adjacent teeth. Clinical parameters and radiographic examination were performed pre-operatively, and at 3 or 6 months, 1, 2, and 3 years postoperatively. One tooth was extracted 1.5 years postoperatively due to reduced support and the treatment strategy of the patient. The other nine teeth were well maintained without any discomfort for the whole maintenance period of 3 years. In all teeth, areas that previously had no pocketing but were now against denuded root surfaces maintained the previous pocket depth readings. In areas where a deep pocket was present but now had a root surface with healthy periodontium, a distinct decrease of mean pocket depth was observed at the first reexamination 3 months postoperatively. The mean radiographic alveolar bone level increased from 0.3% to 45.3% in 2 years and was thereafter maintained for the entire observation period. Loss of periodontal space and possible root resorption were observed in only one case without other ankylotic symptoms. These results suggest that the healing without ankylosis of an extensive denuded root surface may occur by mechanisms other than the maintenance of a viable periodontal ligament on the root surface.
Vertical root fractures lead to advanced periodontal breakdown with deep periodontal pockets and vertical bone defects. The purpose of this study is to evaluate clinically the periodontal healing of root fracture treatment using adhesive resin cement. In 22 patients, 23 teeth with vertical root fractures were treated with 4-META/MMA-TBB resin cement. Eleven fractured roots were bonded through the root canal (group A) and 12 fractured roots were bonded extra-orally and replanted (group B). All teeth were then restored with full cast crowns (n=20) or coping (n=3). Mean probing depth was 6.6 mm at pre-treatment and 4.4 mm 6 months after the treatment in group A, and 7.4 mm and 4.6 mm, respectively, in group B. Bleeding scores were 100% at pre-treatment and 36.4% after 6 months in group A and 91.7% and 8.3%, respectively in group B. Radiographic bone level was 56.8% at pretreatment and 59.1% after 6 months in group A, and 18.8% and 29.2%, respectively, in group B. Two roots of group A and three roots of group B were extracted due to refracture, deterioration of periodontal inflammation, mobility, and luxation. The remaining roots (n=18) presented no discomfort to the patients and there was no deterioration of periodontal conditions over a mean period of 33 months (range 14-74 months) in group A and over a mean period of 22 months (range 6-48 months) in group B. There was no ankylosed teeth nor was any root resorption detected. The results suggested that the treatment of vertical root fracture using 4-META/MMA-TBB resin has good prognostic possibilities.
Despite an intensive effort of elucidating the pathogenic role of angiotensin II (AII) in immune-mediated renal injury, the precise mechanisms are poorly understood. In the present study, we examined the site of AII action, peripheral blood leukocytes or resident renal cells, in immune-mediated renal injury using AII type 1a receptor (AT1a)-deficient homozygous (AT1a -/-) mice and wild-type (AT1a +/+) mice. The AT1a -/- mice showed delayed-type hypersensitivity similar to that of the AT1a +/+ mice, suggesting that the lack of AT1a does not impair a Th1-type cellular immune response of peripheral blood leukocytes involved in immune-mediated renal injury. We then generated the radiation bone marrow chimera mice, WA and AW, which have transplanted peripheral blood leukocytes from the AT1a +/+ and AT1a -/- mice into the AT1a -/- and AT1a +/+ mice, respectively. As controls, WW and AA, the AT1a +/+ and AT1a -/- mice given bone marrow cells from the AT1a +/+ and AT1a -/- mice, respectively, were generated. Seven days after induction of antiglomerular basement membrane nephritis, glomerulosclerosis observed in the WW mice was markedly ameliorated in the WA mice, but not in the AW mice. In addition, the recruitment of monocytes/macrophages and the expressions of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 in the glomeruli of the AW and WW mice was evident, but such significant phenotypes were not seen in the WA and AA mice, showing a marked amelioration of renal injury dependent on the host AT1a genotype. These results demonstrate an essential role of AT1a in intrinsic renal cells for progressive immune-mediated renal injury and indicate a beneficial effect of blocking the renin-angiotensin system in the treatment of such diseases.
BACKGROUND: Angiotensin II (Ang II), which contracts vascular smooth muscle cells (VSMCs), has been reported to regulate VSMC growth. Recently formed transgenic mice without angiotensinogen or Ang II receptors showed vascular alterations. However, it is still unclear how their VSMCs alter. We explored the role of Ang II via the Ang II type 1a receptor (AT1a) in VSMCs in vivo using AT1a null mutant mice. METHODS: We analyzed the ultrastructure of the intrarenal arteries in AT1a null mutant mice that were homozygous for a targeted disruption of AT1a receptor gene using light and electron microscopy. RESULTS: The structural changes of the intrarenal arteries in AT1a null mutant mice showed the wall thickening, which in the interlobar, arcuate, and proximal interlobular arteries consisted of two additional populations of VSMCs, on the luminal and abluminal sides of the media. The luminal overpopulation of smooth muscle cells (SMCs) was arranged in a longitudinal direction separated by increased interposed elastic laminae. The abluminal overpopulation of SMCs ran in circumferential directions separated from the main population. The cytological structure of VSMCs in AT1a null mutant mice was smaller in size, contained more organelles for protein synthesis and secretion than in control mice, and had poorly developed contractile apparatus. CONCLUSIONS: The lack of AT1a signaling causes structural abnormalities in the renal vascular system and transforms the phenotype of VSMCs into cell proliferation, induces the escape of VSMCs from the circular mechanical integrity, and results in increased synthesis of extracellular matrices.
We have earlier reported that diverse collagen vascular diseases, including arthritis, arteritis, thrombosis, myocarditis, myositis, sialo-/dacryoadenitis and dermatitis develop with the advent of autoantibodies in transgenic rats carrying the LTR-env-pX gene of human T lymphocyte virus type I (LTR-env-pX rats). To clarify the pathogenesis of these collagen vascular diseases, immunological features of LTR-env-pX rats were examined. In LTR-env-pX rats affected with these diseases, expression of CD80/86 on both tissue-infiltrating and peripheral T cells increased, compared with findings in non-transgenic rats with experimental inflammatory diseases. CD80/86 was also upregulated on peripheral T cells in LTR-env-pX rats prior to the development of diseases. Lymphocytes from LTR-env-pX rats showed an increase in autologous proliferation and were hyperreactive against several mitogens, including concanavalin A, immobilized anti-CD3 antibodies, and superantigens in vitro. Antigen-specific immune response was also enhanced in LTR-env-pX rats. The collective evidence indicates that lymphocytes of LTR-env-pX rats constitutively express surface molecules related to T cell activation and are immunologically hyperresponsive. Bone marrow cell transfer from LTR-env-pX rats to lethally irradiated non-transgenic rats revealed that these immunologically pre-activated and hyperresponsive lymphocytes play a critical role in the pathogenesis of several collagen vascular diseases, especially of dermatitis in LTR-env-pX rats.
Classification of the relationship between electronic structures and biological activities of endocrine disruptors (so-called environmental hormones) was attempted using the parameters of absolute hardness (eta), absolute electronegativity (chi), and global softness (S), approximately defined as eta=1/2(epsilonLUMO-epsilonHOMO), chi=-1/2(epsilonHOMO+ epsilonLUMO), and S=1/eta, respectively, based on the hardness concept. The strength of binding affinity and toxicity of the chemicals were approximately proportional to the absolute hardness, and laterally toxic chlorinated PCDDs, PCBs, and DDTs are classified as chemically soft. Here we found that the electronic structures of environmental hormones can be classified into four main groups: 17beta-estradiol type (group I), testosterone type (group II), thyroxine type (group III), and HCH (hexachlorocyclohexane) type (group IV). Therefore, if we can predict the coordinate (chi, eta) of the electronic structure of one chemical on the eta-chi activity diagram, we would be able to predict the receptor with which the chemicals (environmental hormones) interact. For instance, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is classified in group II, therefore, it would bind with the thyroid receptor more than the estrogen receptor (group I). It appears that dibutyl phthalate would not interact with estrogen receptor because it does not belong to group I. In addition, the coordinates of these four groups do not complementarily overlap with the electronic structures of 20 natural amino acid residues. The eta-chi activity diagram is a new tool for the prediction of the toxicity and biological activity of environmental hormones.
A 44-year-old woman noticed edema of the lower limbs in May 1999 and visited our hospital in September 1999 to undergo further examination. On admission, severe hypoalbuminemia (1.9 g/dl) was detected with a negative urinary protein level. Protein leakage into the gastrointestinal tract and deposition of immune complex in the colonic mucosa were shown by the fluorescent antibody method. In addition, anti-centromere antibody, sclerodactyly, and findings indicative of histological sclerotic changes on a skin biopsy were observed. These findings supported a diagnosis of protein-losing gastroenteropathy complicated by scleroderma. Administration of oral corticosteroids was begun one month after admission and the patient experienced diminished visual acuity immediately after steroid pulse therapy in November. Central serous chorioretinopathy (CSC) was diagnosed at the Department of Ophthalmology of our hospital, and the administration of corticosteroids was suspected as a possible cause of CSC. Considering the severity of hypoproteinemia, the corticosteroid treatment was continued despite corticosteroids being strogly suspected as the primary cause of CSC. A complete disappearance of CSC was achieved in 30 days after the onset of symptoms despite continuation of the steroid therapy, and her serum albumin and complement levels both normalized. We concluded that damage to the retinal pigment epithelium secondary to the vascular lesion at the choroidal level plays a causative role in CSC. In the present case, the findings suggested that the deposition of immune complex in choroidal tissues as well as the gastrointestinal tract caused hyperpermeability of choroidal vessels and led to the development of CSC.
Human T-cell leukemia virus type I(HTLV-I) is known to be associated with a number of disorders, inducing adult T cell leukemia, myelopathy, arthropathy, uveitis, and probably Sjögren's syndrome, T cell alveolitis, polymyositis, and infective dermatitis. To investigate the pathogenetic role of HTLV-I in these clinical disorders, we established a transgenic rat model carrying the env-pX gene of HTLV-I(env-pX rat), which develops arthritis, myocarditis, dermatitis, necrotizing arteritis, myositis and sialoadenitis. Several autoantibodies, such as anti-nuclear and anti-cardiolipin antibodies and rheumatoid factor, were detected in the sera. Peripheral T lymphocytes of env-pX rats expressed co-stimulatory molecules and showed hyper-immune reactivity to various stimulation in vitro. In this study, to characterize major pathogenic autoantigens in the affected lesions, the author examined the clonalities of T cells in the spleen and of infiltrating T cells in the skin lesions as well as affected joints of env-pX rats by single strand conformation polymorphism (SSCP) of polymerase chain reaction-amplified cDNA fragments of T cell receptor (TCR) V beta. No specific expansion of particular T cell clones was evident in the spleen of env-pX rats. Oligoclonal T cell expansions were observed in both infiltrating T cells of the affected joints and skin lesions, but no specific T cell clones common in the two lesions expanded in env-pX rats. Also, no specific amino acid motif in the complementarity determining region 3 of TCR V beta was evident in the affected joints. Those results suggest that the locally expanded T cell clones against various autoantigens of the joint or skin induced by the transgene may play major pathogenetic roles in development of autoimmune diseases in env-pX rats. On the other hand, env-pX rats easily developed arthritis by immunization of type II collagen and the SSCP patterns of accumulated T cell clonotypes in the arthritis were similar to those of arthritis developed in env-pX rats without immunization. The evidence suggests that the type II collagen-immunization may be a trigger to develop the inherent arthritis of env-pX rats.
The interaction between mesangial cells (MCs) and monocytes/macrophages (Mo/Mo) is an important pathogenic feature of glomerulonephritis. However, its mechanism is not fully elucidated. Studies to date have focused on the interactions through mediators. In the present study, to obtain insight into the mechanism of the interaction between MCs and Mo/Mo, we examined the significance of the cell to cell interaction of these cells in the context of monocyte chemoattractant protein-1 (MCP-1) expression using cell contact cultures or co-culture without contact. Our results revealed that the cellular adhesion of cultured macrophages to MCs induced the expression of MCP-1, which was mainly observed in the MCs. In addition, the induction of MCP-1 was, at least in part, mediated by nuclear factor kappa-B activation which occurs preferentially in the MCs. Because MCP-1 is suggested to play an important role in glomerulonephritis, this novel cell to cell interaction between the MCs and Mo/Mo could be important in glomerulonephritis.
We compared a viscous fingering formation of hydrochloric acid (HCl) in rabbit corpus, antral and duodenal mucins and with dextran under neutral and acidic conditions with respect to relative viscosity, molecular mass, and carbohydrate composition. The effect of desialyzation of duodenal mucin on the viscous fingering formation of HCl was also examined. HCl (0.1 N) was injected into 1% solutions of mucins and dextran and a subsequent viscous fingering formation was assessed based on an influx volume rate of HCl. A low influx volume rate indicates a high ability of the solutions to produce viscous fingers. The influx volume rate of HCl was lowest in duodenal mucin followed bl corpus mucin, antral mucin, and dextran at pH 7. The influx volume rate of HCl was inversely correlated with the relative viscosity of the solution. Maximum molecular masses were large in the order of corpus, antral, and duodenal mucins, and they were larger than dextran T2000. Rabbit gastrointestinal mucins were very polydisperse system. Duodenal mucin contains more sialic acid than gastric mucins; the influx volume rate of HCl increased in desialylated duodenal mucin. It is suggested that the higher ability of gastric mucins to prevent HCl diffusion than dextran were due to the differences in the molecular mass. The ability of duodenal mucin to prevent HCl diffusion was probably attributed to its high sialic acid content, which may reflect a physiological role of duodenal mucin in the duodenum that has to deal with HCl influx from the stomach.
BACKGROUND: This study aimed to evaluate quantitatively the migrated, attached, and oriented human periodontal ligament cells (HPLC) to periodontally diseased cementum and dentin after demineralization with low and neutral pH etching solution. METHODS: Human teeth, extracted due to periodontal diseases, were scaled and root planed so that cementum remained on one longitudinal half of the root and dentin was exposed on the other half. Forty root slices of 200 microm thickness, obtained from the mid-third of these roots, were divided into four groups: group 1, demineralized with a saturated solution of citric acid (pH 1.20); group 2, with 24% EDTA (pH 7.04); group 3, with tetracycline HCl 100 mg/ml (pH 2.00); and group 4, only scaled and root planed (control). Root slices were placed over the confluent HPLC in 35 mm culture dishes and incubated. Phase contrast microscopic photographs of attached and oriented refractile HPLC to root surfaces were taken at days 1, 3, and 7. Quantitative analysis of attached and oriented HPLC from these photographs was done using special software. RESULTS: The results showed no significant difference in the attachment and orientation index of HPLC to cementum compared to dentin in any method of demineralization at each time point (P >0.05), although there was a significantly higher cell attachment and orientation index to demineralized dentin with EDTA and citric acid than to non-etched dentin and to all 3 demineralized cementum surfaces compared to non-etched cementum (P<0.05). CONCLUSIONS: EDTA and citric acid demineralization may enhance HPLC attachment and orientation to the root surface, and it is not always necessary to remove excessive cementum when the demineralizing procedure is used.
A 43-year-old male patient was admitted to our hospital because of left heel pain and fever. He had had swelling of the left ankle joint and pain 4 years prior to this, and 4 years later, he was admitted to another hospital when left heel ulcer and fever developed. The ulcer was diagnosed and treated as a diabetic ulcer because of hyperglycemia. In spite of good control of blood sugar, the ulcer became enlarged and the pain deteriorated, so he was transferred to orthopedics. Antibiotics produced no response, and culture from a specimen of the ulcer was negative. However, severe inflammatory response was seen in blood examination. MRI and scintigram of his left foot showed disseminated low intensity areas and accumulation in the tarsal bone area, so osteomyelitis was suspected. A biopsy of the ulcer showed infiltration of inflammatory cells into the dermis. We considered amputation of the left lower leg at first. However the biopsy result suggested an autoimmune mechanism, so prednisolone was administered. As a result, the ulcer and pain both diminished. This case was similar to pyoderma gangenosum, however this diagnosis cannot explain osteomyelitis or all its symptoms. We expect that there must be other case report with the same symptoms.
A 57-year-old man, employed as a taxi driver, noticed arthralgia of his fingers beginning in May 1999. He was unable to work due to the arthralgia and the accompanying general malaise and anorexia, and was thus admitted to a local hospital in July 1999. Since a diagnosis of rheumatic disease was suspected due to elevated inflammatory reactions and joint symptoms, he was referred to our hospital in September 1999. Although no joint swelling was observed, severe tenderness was present in both the fingers and wrists. His grasping power had decreased markedly and fever was intermittently observed. All autoantibodies aside from antinuclear antibody were negative. Given that hyponatremia (126 mEq/l) and fasting hypoglycemia were demonstrated, an endocrinological examination, in particular for hypopituitary-adrenal function, was performed. Both plasma and urinary cortisol concentrations were very low, and an associated low concentration of plasma ACTH (6.0 pg/ml) was noted. The ACTH circadian rhythm was absent and there was no response to the administration of corticotropin releasing hormone. All other pituitary hormones were secreted at normal levels and brain MRI revealed a normal appearance of a pituitary gland. Based on these findings, the patient was diagnosed as having isolated ACTH deficiency. Arthralgia and general malaise both improved soon after replacement of glucocorticoid, and CRP levels were normalized. Isolated ACTH deficiency should be considered in the differential diagnosis of patients suffering from polyarthralgia, given that fever and increased inflammatory reactions occasionally develop and that rheumatic symptoms are also present, as in the present case.