Moritoshi Itoman

Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis

It was reported that angiotensin II stimulates angiogenesis in vivo, and angiotensin-converting enzyme (ACE) inhibitors inhibit angiogenesis. We found that an AT1-receptor (AT1-R) antagonist, TCV-116, inhibited tumor growth, tumor-associated angiogenesis, and metastasis in a murine model. Tumor growth of Sarcoma 180 (S-180) cells and of fibrosarcoma (NFSA) cells was strongly inhibited by administration of TCV-116 in the diet at a dose of approximately 100 mg/kg/day. This reduction was accompanied with a marked reduction in tumor-associated angiogenesis. The same treatment also reduced the lung metastasis of intravenously injected Lewis lung carcinoma cells. These effects of TCV-116 were equivalent to those of the ACE inhibitor, lisinopril. In S-180 and NFSA tumor tissues, ACE and AT1a receptor (AT1a-R) mRNAs were expressed when assessed with RT-PCR. AT1b receptor and AT2 receptor, however, were not detected. Immunoreactive AT1-R was detected mainly on the neovascularized vascular endothelial cells in which expression was reduced by TCV-116 and lisinopril. These results suggested that TCV-116 inhibits the angiogenesis, growth, and metastasis of tumors highly dependent on AT1a-R blockade. Blockade of AT1a-R signaling may therefore become an effective novel strategy for tumor chemoprevention.

Distinct Anabolic Response of Osteoblast to Low‐Intensity Pulsed Ultrasound

Low‐intensity pulsed ultrasound, a form of mechanical energy transmitted as high‐frequency acoustical pressure waves, provides noninvasive therapeutic treatment for accelerating fracture repair and distraction osteogenesis. Relatively young osteoblasts respond to ultrasound by transiently upregulating message levels of immediate‐early genes as well as that of osteocalcin and insulin‐like growth factor I (IGF‐I). Osteocytes derived from newborn rat tibia and calvaria responded to a lesser extent only in c‐fos and cyclooxygenase‐2 (COX‐2) messages. Compared with the stretched osteocytes, which use stretch‐activated and parathyroid hormone (PTH)‐potentiated Ca2+ influx as an entry route to the protein kinase A (PKA) signal transduction pathways, there was no evidence of Ca2+ internalization by any of the cells tested on exposure to the ultrasound. On the other hand, inhibitors of p38 mitogen‐activated protein kinase (MAPK) and upstream phosphoinositide 3‐kinase (PI3K) blocked COX‐2 and osteocalcin upregulation by the ultrasound‐exposed ST2, murine bone marrow‐derived cells. This is distinct from the aforementioned osteocytic response to low‐frequency stretching and implies the involvement of integrins. Our findings suggested that accelerated fracture repair and distraction osteogenesis by the low‐intensity pulsed ultrasound depend, at least in part, on the stimulation of osteoblastic cells at relatively early stages of osteogenic lineage. Bone is under control of multiple regulatory mechanisms so that diverse physical forces can be reflected to the microenvironment of each cell, in turn, to the entire bone.

Attenuation of monosodium urate crystal‐induced arthritis in rabbits by a neutralizing antibody against interleukin‐8

Accumulating evidence implicates interleukin‐8 (IL‐8) as an essential mediator in neutrophil‐mediated acute inflammation. Neutrophils have also been shown to have a crucial role in the pathogenesis of acute gouty arthritis. Thus, we investigate the pathophysiological role of IL‐8 in an experimental model of acute gout, monosodium urate (MSU) crystal‐induced arthritis in rabbits. The injection of MSU crystals into knee joints caused a marked swelling of joints. Concomitantly, the infiltration of leukocytes, mostly neutrophils, was observed in synovial membrane and synovial fluids. The injection of MSU crystals also induced an elevation in synovial fluid IL‐8 levels preceding neutrophil infiltration into synovial fluids, without an accompanying increase in plasma IL‐8 levels. Immunoreactive IL‐8 protein was detected in synovial lining cells at 12–24 h after the injection. IL‐8 protein was also observed in infiltrated leukocytes in synovium as early as 3–24 h after the injection. Finally, the intraarticular injection of a neutralizing anti‐IL‐8 antibody significantly attenuated the crystal‐induced joint swelling that occurred at 12 h, and neutrophil infiltration into arthritic joints at 12 and 24 h after the induction. These results provide evidence on the pathogenic roles of locally produced IL‐8 in MSU crystal‐induced gouty arthritis. J. Leukoc. Biol. 62: 444–449; 1997.

Gluteal muscle necrosis following transcatheter angiographic embolisation for retroperitoneal haemorrhage associated with pelvic fracture

Transcatheter angiographic emobilisation has been used as an effective control of haemorrhage associated with pelvic fracture. Although few complications of this procedure have been reported, gluteal muscle necrosis occurs occasionally. We assessed the type of pelvic fracture, concomitant injury, embolic site, embolic materials, and outcome in cases of gluteal muscle necrosis associated with angiographic embolisation for pelvic fracture-related haemorrhage, and investigated the factors associated with the development of gluteal muscle necrosis, one of the fatal complications of transcatheter angiographic embolisation. Five out of the 151 patients (incidence, 3.3%) who underwent transcatheter angiographic embolisation for haemorrhagic shock due to pelvic fracture developed gluteal muscle necrosis after embolisation. The five cases had injury severity scores ranging from 26 to 59 (mean 46.4). Three patients died (mortality, 60%) of subsequent sepsis and disseminated intravascular coagulation. These cases showed that transcatheter angiographic embolisation with gelatin sponge and/or steel coil, while effectively controlling bleeding, may also result in gluteal muscle necrosis. Aggressive management including intraarterial antibiotic treatment may have a role, but our numbers are too small to confirm this.

Growth factor expression in the osteophytes of the human femoral head in osteoarthritis.

Osteoarthritis is characterized by marked osteophyte formation consisting of new cartilage and bone. Because several growth factors are known to be involved in chondrogenesis and osteogenesis, the expression of transforming growth factor-β1 and basic fibroblast growth factor in the osteophytes of the human femoral heads in osteoarthritis were examined. Transforming growth factor-β1 messenger ribonucleic acid was detected in the osteophytes by reverse transcription-polymerase chain reaction. All of the nine examined osteophytes expressed transforming growth factor-β1 messenger ribonucleic acid, whereas one of four osteoarthritic femoral heads and none of four osteonecrotic femoral heads expressed transforming growth factor-β1 messenger ribonucleic acid. The extent of transforming growth factor-β1 messenger ribonucleic acid expression varied among the osteophytes. Transforming growth factor-β1 or basic fibroblast growth factor was analyzed in osteophytes immunohistochemically. Transforming growth factor-β1 was localized in the superficial cells in the osteophyte cartilage, but it was scarcely detected in the superficial cells in the degenerative articular cartilage. Basic fibroblast growth factor was detected in the cells in the whole layer of osteophyte cartilage and in the articular cartilage. There was a difference in the localization, which suggests the different roles of transforming growth factor-β1 and basic fibroblast growth factor in bone and cartilage metabolism in osteophyte formation.

Ganglion causing paralysis of the suprascapular nerve: Diagnosis by MRI and ultrasonography

A 26-year-old man had a right infraspinatus muscle weakness and aching of the shoulder due to suprascapular nerve entrapment confirmed by electromyography. MRI revealed a well-defined area of increased signal intensity over the suprascapular notch. An ultrasonogram showed a homogeneous hypoechogenic area at the base of the scapular spine. A diagnosis was made of a ganglion compressing the inferior branch of the suprascapular nerve. After removal of several ganglia, the patient had immediate pain relief, and normal electromyographic findings were obtained 5 months postoperatively.

Morphologic differences of the distal femur between Caucasian and Japanese women

Purpose. To compare the morphology of the distal femur between Caucasian and Japanese women. Methods. 30 Caucasian women aged 41 to 84 (mean, 67) years and 70 Japanese women aged 54 to 86 (mean, 70) years who underwent total knee arthroplasty for osteoarthritis were randomly selected. Morphologic measurements of the distal femur were compared using lateral radiographs. Both race and height influenced the morphology. To adjust for the influence of height on morphology, each measurement was divided by the patients height and the ratios were compared. Results. Caucasian women were generally taller and heavier (p<0.001) and had higher body mass index (p=0.03) than the Japanese women. Each morphologic measurement of the distal femur was significantly longer in the Caucasian women. In both groups, anteroposterior width of the condyle correlated more with height than weight. In women of equal height, the anteroposterior and metaphyseal widths of the femur and the anterior and resected condyles were longer in Caucasian women, but the posterior condyle was longer in Japanese women. Conclusion. Both the size of the femur and the anterior and posterior condyles are significantly larger in Caucasian than Japanese women.

Involvement of Cyclins in Cell Proliferation and Their Clinical Implications in Soft Tissue Smooth Muscle Tumors

Expression of cyclins A and E and cyclin-dependent kinase 2 (cdk2) was examined immunohistochemically in 55 cases of soft tissue smooth muscle tumors, including vascular leiomyoma, and compared to expression of Ki-67 and proliferating cell nuclear antigen. Cyclin A was expressed in 70% of the leiomyoma cases, but with much lower labeling indexes than in leiomyosarcoma. Cyclin E was expressed exclusively in leiomyosarcoma. Although the differences of cyclin A- and cyclin E-labeling indexes between leiomyoma and leiomyosarcoma were statistically significant, no significant differences were found in the other markers. Furthermore, cyclin A- and/or E-positivity predicted a poor prognosis in recurrence- or metastasis-free survivals and overall survival. Immunoblotting revealed that cyclins A and E were expressed, in complex with cdk2, exclusively in tumors. In addition, not only leiomyosarcoma, but also leiomyoma specimens that exhibited negligible levels of complex expression, manifested detectable cdk2 activity. These results suggest 1) up-regulation of active cyclin A/cdk2 expression and associated kinase activity is critical for unrestrained cell proliferation; 2) cyclin E/cdk2 complexes may play a crucial role in leiomyosarcoma; 3) immunohistochemical detection of cyclins can be a more reliable tool for differential diagnosis between leiomyoma versus leiomyosarcoma than that of Ki-67 or proliferating cell nuclear antigen, and be a possible prognostic indicator.

Multiinstitutional epidemiological study regarding osteoarthritis of the hip in Japan

Background. Osteoarthritis (OA) of the hip is a major disease that affects the healthy lifespan of a population. It is necessary to fully understand the patients’ conditions before a systematic treatment can be applied. However, a nationwide epidemiological study regarding hip OA has not yet been conducted in Japan. The present study examined the current status of patients with hip OA, including the disease etiology. Methods. This is a multiinstitutional study of new patients presenting with hip OA at the orthopedic outpatient clinics of 15 institutions in fi ve geographical areas of Japan. The collected data from each patient included the sex, age, treatment history for developmental dysplasia of the hip (DDH), the clinical score of the hip joints based on the Japanese Orthopaedic Association (JOA) scoring system, and the pelvic inclination according to anteroposterior radiographs. In addition, the etiology was determined from the following 17 options: primary OA, acetabular dysplasia, intragluteal dislocation, osteonecrosis, trauma, Perthes disease, slipped capital femoral epiphysis, infection, rheumatoid arthritis, ankylosing spondylitis, neuroarthropathy, endocrine diseases, metabolic diseases, hereditary bone diseases, synovial chondromatosis, generalized OA, and others. Results. There were a substantially larger number of female patients than male patients. This difference regarding sex was present in each generation. The mean age of the patients was 58 ± 14 years. The peak age at presentation was approximately 50 years. Most patients had no history of therapy for DDH. The older patients had lower gait and activities of daily living scores. The etiology was assessed to be acetabular dysplasia in most of the patients. A lower frequency of elderly patients demonstrated acetabular dysplasia. The patients who had a pelvic posterior inclination increased with increasing age. Conclusions. The patients with hip OA in Japan were unique in regard to age distribution, sexual heterogeneity, and disease

Isolated paralysis of the infraspinatus muscle

We report six patients with isolated paralysis of the infraspinatus and discuss the diagnosis, pathology, treatment, and outcome over a mean follow-up period of 33 months. Four patients were shown to have space-occupying lesions at the spinoglenoid notch by MRI or ultrasonography or both, and ganglia were confirmed and removed surgically in three, with good results. Ganglia at this site are not uncommon and should be included in the differential diagnosis of patients presenting with shoulder pain and weakness.