Biomedical subjects
Publications and source records attributed to Y Iwamoto.
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OBJECTIVE: To review the subchondral changes on MR imaging in transient osteoporosis of the hip (TOH) and to consider the pathophysiology. DESIGN AND PATIENTS: MR images of 12 hips of 11 consecutive patients with TOH were retrospectively studied. The diagnoses of TOH were confirmed on the basis of previously published criteria, including decreased bone density of the femoral head and/or neck on radiographs, bone marrow edema (BME) pattern on MR images, spontaneous resolution of the symptoms and a return to normal radiodensity. RESULTS: All 12 hips showed a BME pattern in the femoral head and/or neck. Linear patterns of very low signal intensity were identified on T1-weighted images in the subchondral area within the diffuse low signal intensity area in all 12 hips. On T2-weighted images, a low signal intensity line was observed in the corresponding area in eight hips only. These linear patterns were thought to represent subchondral fracture lines. CONCLUSIONS: The presence of a subchondral fracture may be important when considering the pathophysiology of TOH.
We report on a case of primary leiomyosarcoma of the patella in a 59-year-old woman. To our knowledge, this is the first report of this rare tumor in a bone where malignant lesions rarely occur.
The case of a male infant is reported who had club foot on the right side and pes adductus on the left side in combination with acrofacial dysostosis; he also demonstrated preaxial anomalies of the upper limbs indicative of Nager syndrome. In addition, an unusual aberrant muscle was discovered during surgical correction of the right club foot.
A 47-year-old woman suffered from gait disturbance due to back pain and muscle weakness. Laboratory data showed serum hypophosphatemia, elevated alkaline phosphatase, and a normal level of ionized calcium. Radiological examinations revealed multiple pathologic fractures in the ribs and pubic rami. She had had no episode of familial or any other notable disorder, and so she was initially treated with medication for adult-onset osteomalacia. However, 19 years later (when she was 66 years old), she noticed a soft-tissue tumor in her buttock. The tumor was excised. The histological features were those of glomangiopericytoma characterized by both glomus tumor-like and hemangiopericytoma-like structures. After removal of the tumor, her symptoms disappeared immediately. Laboratory data normalized 8 months later. To our knowledge, this is the first report of oncogenic osteomalacia caused by glomangiopericytoma.
In order to obtain high reproducibility and sensitivity in the evaluation of joint space in osteoarthritic knees, we used new equipment, and established an anteroposterior weight-bearing radiograph with both knees in semiflexion taking into account our investigation of the posterior slope angle. We compared our method with the Rosenberg method, and the coefficient of variation of our method showed higher reproducibility than that of the Rosenberg method. The most essential issue is whether the bilateral leg loading radiograph can show the same sensitivity as the homolateral leg loading radiograph. We compared standing radiographs of the knee in 26 degrees flexion with those of 26 degrees flexion in both knees. We assessed the widths of the narrowest points of the joint spaces in the medial and lateral compartments, the condylar plateau angle, and the femorotibial angle, in 47 knees in 24 patients. The data were analyzed statistically by single regression and each correlation was of statistical significance. Our method has better reproducibility and is more comfortable for the subject than conventional methods.
We report an 81-year-old man with late recurrent multiple metastases in skeletal muscles 15 years after radical nephrectomy was carried out for stage IV renal cell carcinoma (RCC). The tumors were located in the left triceps muscle and the brachioradial muscle. We performed surgical resections of both tumors, and histological analysis revealed that they were both metastatic RCC of the clear-cell type. In this case report, we discuss the characteristics and differential diagnosis of this tumor on magnetic resonance imaging, and we also refer to the rarity of muscle metastasis and the unpredictable tendency of this tumor to remain dormant for long periods.
The A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene (mt.3243A>G) is associated with both diabetes mellitus and myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Recently, this mutation was found in three diabetic subjects with progressive kidney disease, suggesting that it may be a contributing factor in the development of kidney disease in patients with diabetes. The aim of this study was to evaluate the contribution of this mutation to the development of end stage renal disease (ESRD) in patients with diabetes. The study group consisted of 135 patients with diabetes and ESRD. The control group consisted of 92 non-diabetic subjects with ESRD who were receiving hemodialysis. The mt.3243A>G mutation was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We found the mt.3243A>G mutation in eight patients (8/135; 5.9%), all of whom were initially diagnosed with type II diabetes. Five of the eight patients were subsequently also diagnosed with MELAS. We did not find the mutation in any of the 92 nondiabetic subjects with ESRD. The prevalence of this mutation was 6.5-fold higher in patients with diabetes and ESRD than in those with diabetes alone (8/135 vs 5/550, respectively; chi2 = 13.704; P = 0.0002). The mt.3243A>G mutation may be a contributing genetic factor in the development of ESRD in Japanese patients with diabetes.
We screened the protein-coding region of the peroxisome proliferator-activated receptor alpha gene (PPARA) and the flanking intron sequences for mutations in 57 unrelated Japanese subjects with maturity-onset diabetes of the young (MODY). We found three missense mutations, designated P22R, D140Y, and V227A. The D140Y and V227A mutations were found at similar frequencies in MODY and in nondiabetic Japanese subjects, suggesting that they were unlikely to be pathogenic. The P22R mutation was found in a single female subject with MODY. Two of her four siblings, all of whom were diagnosed with diabetes before age 35 years, also inherited the P22R mutation. However, two other diabetic siblings had not inherited the mutant allele, implying that the P22R mutation was not the cause of MODY in this family. Variation in the coding region of PPARA is unlikely to be a major cause of MODY in Japanese people.
Synovial sarcoma is a mesenchymal tumor that has an epithelial character and two major histological subtypes, the biphasic type and the monophasic fibrous type. However, the mechanisms involved in its epithelial differentiation are unknown, and furthermore, the determinants for histological subtype in synovial sarcoma remain unclear. In this study, we immunohistochemically examined E-cadherin expression and screened for genetic alterations in the E-cadherin gene from exon 4 to exon 9 in 49 cases of synovial sarcoma. In addition, we also examined the mRNA expressions of E-cadherin and Snail, a direct repressor of E-cadherin gene expression, by reverse transcriptase-polymerase chain reaction in 20 samples of frozen material. Immunohistochemical E-cadherin membranous expression was observed in 12 cases (24.5%), and was predominant in biphasic tumors. Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed 15 missense E-cadherin mutations in 12 cases (24.5%: monophasic, 11 of 42; biphasic, 1 of 6; poorly, 0 of 1) and 7 silent mutations (14.3%) in 7 cases. Ten of the 12 cases with E-cadherin missense mutations did not show E-cadherin membranous expression. Reverse transcriptase-polymerase chain reaction demonstrated E-cadherin and Snail mRNA expressions in 14 cases (70%) and in all cases, respectively. E-cadherin gene expression was inactivated by missense mutations in three of the eight cases (37.5%) of monophasic fibrous tumors that showed E-cadherin mRNA expressions. The E-cadherin gene was potentially inactivated in a significant number of synovial sarcomas. E-cadherin dysfunction because of its mutation in the central region of the molecule was associated with its decreased immunohistochemical expression and histological fibroblastic and spindle-shaped features of monophasic tumors. Thus, E-cadherin gene mutation may be one of the determinants of histological subtype in synovial sarcoma.
Troglitazone is effective in approximately 50% in patients with type 2 diabetes (NIDDM). In this study, we investigated the relations between serum leptin levels and clinical efficacy of troglitazone. Forty-five type 2 diabetic patients (23 men and 22 women) from our outpatient clinic were treated with troglitazone 400 mg daily for 12 weeks. Fasting plasma glucose (FPG), HbA1c, body weight, serum insulin and leptin concentrations were measured before and after troglitazone treatment. After 12 weeks of troglitazone treatment, FPG (before versus after, 179+/-33 vs. 138+/-26 mg/dl, mean+/-SD), HbA1c (7.8+/-1.3 vs. 6.9+/-1.0%), IRI (8.3+/-4.3 vs. 6.3+/-3.4 microU/ml) and HOMA-R index (homeostasis model assessment of insulin resistance) (3.8+/-2.4 vs. 2.2+/-1.3) decreased significantly, while body mass index (BMI) slightly increased (26.3+/-3.5 vs. 26.6+/- 3.6 kg/m(2)), and serum leptin remained unchanged (8.5+/-7.2 vs. 9.1+/-8.7 ng/ml). Reduction in FPG (DeltaFPG) after troglitazone treatment were correlated with reduction in HOMA-R (DeltaHOMA-R) (r=0.721, P<0.0001). DeltaFPG was correlated with serum leptin (r=0.441, P<0.01), HOMA-R (r=0.460, P<0.01) and FPG (r=-0.781, P<0.0001) at baseline, but not with BMI and serum IRI at baseline. Furthermore, serum leptin at baseline was significantly correlated with DeltaHOMA-R (r=0.634, P<0.01). Leptin concentration before treatment therefore, can be used as an predictor for clinical efficacy of troglitazone in patients with type 2 diabetes.
Vinorelbine (Navelbine, KW-2307), a semisynthetic vinca alkaloid, is a potent inhibitor of mitotic microtubule polymerization. The aims of this study were to demonstrate radiosensitization produced by vinorelbine in human non-small cell lung cancer (NSCLC) PC-9 cells and to elucidate the cellular mechanism of radiosensitization. A clonogenic assay demonstrated that PC-9 cells were sensitized to radiation by vinorelbine with a maximal sensitizer enhancement ratio at a 10% cell survival level of 1.35 after 24-h exposure to vinorelbine at 20 nM. After 24-h exposure to vinorelbine at 20 nM, the approximately 67% of the cells that had accumulated in the G2/M-phase were cultured in the absence of vinorelbine and then irradiated at a dose of 8 Gy. Flow cytometric analyses showed prolonged G2/M accumulation concomitant with continuous polyploidization, and induction of apoptosis was observed in the cells subjected to the combination of vinorelbine-pretreatment and radiation. Polyploidization and induction of apoptosis were confirmed by morphological examination and a DNA fragmentation assay, respectively. We concluded that vinorelbine at a minimally toxic concentration moderately sensitizes human NSCLC cells to radiation by causing accumulation of cells in the G2/M-phase of the cell cycle. Prolonged G2/M accumulation concomitant with continuous polyploidization and increased susceptibility to induction of apoptosis may be associated with the cellular mechanism of radiosensitization produced by vinorelbine.
Chondrocytes produce several local regulatory factors such as basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta) and insulin-like growth factor-I (IGF-I). In this study, we examined the effect of bFGF on the expressions of both mRNA and protein of the growth factors synthesized by chondrocytes. Treatment of chondrocytes with bFGF (1-100 ng/ml) stimulated the mRNA expression of bFGF and TGF-beta up to 121-604% and 130-220% at 12 h compared with the controls, respectively. On the other hand, the treatment of chondrocytes with bFGF (1-100 ng/ml) suppressed IGF-I mRNA expression to 79-47% at 12 h compared with the controls. An enzyme-linked immunosorbent assay (ELISA) revealed that the treatment of chondrocytes with bFGF (1-100 ng/ml) also enhanced the production of TGF-beta proteins in the chondrocytes up to 299-508% at 24 h compared with controls. We conclude that bFGF influenced the local expression of growth factors by chondrocytes, suggesting autoregulation of growth factor expression during chondrogenesis.
Type XI collagen is predominantly found in cartilage. However, expression of the pro-alpha2(XI) collagen gene (COL11A2) has recently been detected in various non-cartilaginous tissues. We identified the differentiation stage at which COL11A2 was expressed in cultured fetal rat calvarial (FRC) cells and in rat femoral fracture calluses in order to investigate the involvement of COL11A2 during bone formation in vitro and in vivo. We also studied the alternative splicing of exons 6-8 in FRC cells and fracture calluses. In FRC cells, mineralized nodules stained with von Kossa stain were observed from day 9 after confluence. COL11A2 was highly expressed on days 0 and 5, but the expression levels were rapidly decreased on day 9 by Northern blot analysis. During rat femoral fracture repair, intramembranous ossification proceeded and newly formed woven bone was observed on the cortex on day 7 after fracture. In situ hybridization showed that COL11A2 signals were detected in osteoblastic cells in the newly formed woven bone. According to the maturation and remodeling of the woven bone into the trabecular bone, the distribution of the signal for COL11A2 mRNA was limited to the superficial osteoblastic cells of the newly formed trabecular bone. These results demonstrated that COL11A2 was expressed in relatively immature osteoblastic cells during bone formation in vitro and in vivo. RT-PCR showed that the shortest band corresponding to mRNA lacking exons 6-8 was clearly detected when using RNA from soft calluses. In contrast, the largest band corresponding to mRNA with exons 6-8 was predominant when using RNA from FRC cells or from hard calluses on days 7 and 14. These results indicate that the splicing pattern of exons 6-8 in osteoblastic cells is different from the pattern in chondrocytes.
We succeeded in developing a novel rabbit model of nonsteroid and nontraumatic osteonecrosis (ON) by use of a single- and low-dose lipopolysaccharide (LPS) injection. This model is simple and highly reproducible for the frequent development of multifocal and widespread ON lesions. Male adult Japanese white rabbits intravenously injected with a single injection of 10 microg/kg body weight of LPS were histopathologically examined in the early phase (3 [n = 3], 5 [n = 3], and 24 h [n = 3]) and at 4 weeks (n = 22). Seventy-seven percent of the rabbits developed multifocal ON 4 weeks after LPS injection. ON was also observed in the femoral and humeral condyle. The average percentage of necrotic area/total area examined was 86.7 +/- 29.1% and 78.8 +/- 16.7% in the proximal one third of both the femoral and humeral bones, respectively. Organized thrombi in the intraosseous small-sized arteries and arterioles were frequently seen in and around the necrotic tissues. In the early phase, LPS treatment prominently induced thrombocytopenia, hyperlipidemia, and increased plasma levels of plasminogen activator inhibitor-1 (PAI-1). The plasma level of PAI-1 was significantly higher in the rabbits with ON than in those without ON (p < 0.01). The immunohistochemical expression of tissue factor was exaggerated in monocytes/macrophages and adipocytes in both the femoral and humeral bones of the LPS-treated rabbits. Histologically, marrow necrosis and fibrin thrombi could be observed at 24 h. In addition, pretreatment with an anticoagulant, warfarin potassium, significantly decreased the incidence of LPS-induced ON (33%, n = 9, p < 0.05) associated with elongation of prothrombin time. The results of our study show that a single administration of low-dose lipopolysaccharide induces multifocal and widespread ON characterized by the pathophysiological participation of hypercoagulability in ON development. Therefore, this model would be useful for elucidating the pathogenesis of nonsteroid ON in humans especially inflammatory hypercoagulability-induced as well as for developing preventive and therapeutic strategies.
Three novel bisabolane-type sesquiterpenoids, phyllaemblic acids B (1) and C (2) and phyllaemblicin D (3), together with two new phenolic glycosides, 2-carboxylmethylphenol 1-O-beta-D-glucopyranoside (4) and 2,6-dimethoxy-4-(2-hydroxyethyl)phenol 1-O-beta-D-glucopyranoside (5), were isolated from the roots of Phyllanthus emblica. The structures of 1-5 were established by spectral and chemical methods. The absolute stereochemistry of 1 and 2 was determined by applying the PGME method.
E7070 is a novel sulfonamide antitumor agent that exhibits potent antitumor activity in vitro and in vivo. This compound affects cell cycle progression in human tumor cells. To elucidate the mechanisms by which E7070 inhibits tumor cell growth, we established and characterized an E7070-resistant subline, A549/ER, from a human non-small cell lung cancer cell line A549. Flow cytometric analyses demonstrated an increase in G0/G1 and a decrease in S phase populations in cells treated with E7070 at 20 or 100 microg/ml for 24 h. Longer exposure to E7070, i.e. 48 and 72 h, increased the G2/M phase fraction in A549 cells. These inhibitory actions of E7070 on cell cycle progression were not observed in A549/ER cells. E7070 inhibited the phosphorylation of pRb, decreased expressions of cyclin A, B1, CDK2, and CDC2 proteins, and suppressed CDK2 catalytic activity with the induction of p53 and p21 proteins in A549 cells but not in A549/ER cells. Taken together, these results suggest that E7070 exerts its antitumor effects by disturbing the cell cycle at multiple points, including both the G1/S and the G2/M transition, in human lung cancer cells.