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Biomedical subjects

M Nawata

Publications and source records attributed to M Nawata.

At least 19 recordsLinked to original sources
PubMed2004

Down-regulation of CD40 and CD80 on B cells in patients with life-threatening systemic lupus erythematosus after successful treatment with rituximab.

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoreactive T cells and polyclonally activated B cells that produce autoantibodies. Five SLE patients who failed to respond to conventional immunosuppressants were treated with anti-CD20 antibody (rituximab) and their clinical manifestations and laboratory data were evaluated, including phenotypic analysis of B cells. METHODS: Rituximab (375 mg/m(2)) was administered weekly for 2 weeks in five SLE patients who developed severe manifestations despite intensive treatment. RESULTS: Rituximab resulted in rapid improvement (within several days) in clinical manifestations such as consciousness disorder, seizures, progressive sensory disorder, haemolytic crisis, cardiac function and laboratory data. The effects lasted 20 months in one patient; other patients were in remission for more than 6 months. Flow cytometric analysis revealed down-regulation of CD40 and CD80 expression on CD19-positive B cells 1 week after infusion of rituximab, and such down-regulation was seen for more than 7 months in two patients. CONCLUSIONS: Our pilot study provides sufficient evidence of excellent tolerability and high efficacy of rituximab therapy in refractory SLE. Rituximab not only reduced B-cell number and IgG levels but down-regulated CD40 and CD80 on B cells, suggesting possible disturbance of T-cell activation through these costimulatory molecules. Reduction of both quantity and quality of B cells suggests that rituximab could improve the disease course in patients with refractory SLE.

Adult↗
PubMed2003

Trabecular minimodeling in human iliac bone.

In adult human beings, remodeling creates nearly all of new bone tissue. However, Frost hypothesized that modeling can go on in trabeculae throughout life. As this hypothesis has not been verified, we looked for histologic evidence of trabecular modeling (minimodeling) during bone histomorphometry of transiliac bone biopsy specimens obtained from 34 patients (age range, 38-81 years; mean age, 58.4 years; female, 31/34) at the time of total hip arthroplasty. Before the bone biopsy study, we performed quantitative bone scintigraphy of bilateral hip joints and bilateral iliac crests in 10 other patients with unilateral hip disease and confirmed that the bone biopsy site was not affected by ipsilateral hip joint disease. Patients who had metabolic bone diseases or who had taken medications known to affect bone metabolism were excluded from the study. During modeling where bone formation and bone resorption are not coupled, bone formation can occur on quiescent bone surfaces without preceding bone resorption and create smooth cement lines. Therefore, the combination of fluorochrome labeling and a smooth cement line without interruption of surrounding collagen fibers was regarded as evidence of minimodeling. Histologic evidence of minimodeling was detected in 21 of the entire 34 specimens (62%) and 17 of 27 specimens obtained from postmenopausal patients (63%). Bone volume of minimodeling sites was less than 1% of the trabecular bone volume, and these sites accounted for less than 2% of the entire bone surface on average. However, osteoid volume of minimodeling sites comprised approximately one-tenth of the entire osteoid volume, and their labeled surface constituted one-fourth to half of the entire labeled surface on average. Therefore, when performing bone histomorphometry of adult cancellous bone, minimodeling should be taken into account when dealing with parameters related to osteoid volume and mineralization. A comparison of specimens with and without minimodeling demonstrated that the presence of minimodeling was correlated with smaller physique of patients, accelerated mineralization (as indicated by the higher mean MS/BS and MAR values and the shorter mean Omt), and higher metabolic turn-over of bone (as indicated by the higher mean BFR/BV value). Although the findings still need to be verified in a larger number of normal subjects without hip joint disease, they support Frost's hypothesis that minimodeling can continue throughout human life.

Adult↗
PubMed2003

Local bone formation by injection of recombinant human bone morphogenetic protein-2 contained in polymer carriers.

The regenerating potential of human bone is limited. The repair of large bone defects often associated with bone tumor resections is not observed, and nonunion or delayed union of bone is a serious problem for fracture treatment. In these cases, autogeneic or allogeneic bone grafting has been routinely indicated, but these approaches require invasive surgical procedures. An alternative approach described in this paper involves the injection of bone morphogenetic proteins (BMPs) in a polymeric delivery system. We demonstrate that synthetic biodegradable polymers, poly-D,L-lactic acid-polyethylene glycol (PLA-PEG) block copolymers, which exhibit an exquisite temperature-dependent liquid-semisolid transition, work well as an injectable delivery system for recombinant human (rh) BMP-2. The thermosensitive property of the PLA-PEG/rhBMP-2 composite is permissive to percutaneous injection when heated. The fluidity of this composite decreases as it cools down to body temperature and the resultant semisolid form provides a scaffold for bone formation through the gradual local release of the rhBMP-2. This new type of injectable osteoinductive material will enable a less invasive approach to surgeries involving the restoration or repair of bone tissues.

Animals↗
PubMed2001

Morphological characteristics of the bony birth canal in patients with developmental dysplasia of the hip (DDH): investigation by three-dimensional CT.

We investigated the three-dimensional morphological characteristics of the pelvis in adult female patients with developmental dysplasia of the hip (DDH), using computerized tomography (CT) images. Forty-two subjects with normal hips and 40 DDH patients were recruited for the study. In the DDH group, the average transverse diameter of the pelvic inlet was significantly less and the average transverse diameter of the pelvic outlet was significantly greater than the measurements in the normal group. Further, the bony birth canal in DDH patients exhibited a higher incidence of anthropoid-type geometry, as defined by a longer sagittal diameter relative to the transverse diameter of the pelvic inlet. These findings indicate a characteristic pelvic geometry and suggest different development of the pelvis in the transverse direction in DDH patients. In addition, the obstetric conjugate length/transverse diameter of the pelvic inlet ratio was correlated to the degree of severity of acetabular dysplasia. This finding suggests that DDH is a manifestation of a developmental characteristic of the pelvis.

Adult↗
PubMed2001

A biodegradable polymer as a cytokine delivery system for inducing bone formation.

Bone morphogenetic proteins (BMPs) that have the potential to elicit new bone in vivo have been used in a tissue-engineering approach for the repair of bone injuries and bone defects. Although it is now possible to generate large amounts of recombinant human (rh) BMPs for medical use, the major challenge remains in the development of optimal local delivery systems for these proteins. Here we describe the development of a synthetic biodegradable polymer, poly-d,l-lactic acid-p-dioxanone-polyethylene glycol block copolymer (PLA-DX-PEG). This polymer exhibits promising degradation characteristics for BMP delivery systems and good biocompatibility under test conditions. PLA-DX-PEG/rhBMP-2 composite implants induced ectopic new bone formation effectively when tested in vivo, and can repair large bone defects orthotopically. This polymeric delivery system represents an advance in the technology for the enhancement of bone repair.

Animals↗
PubMed2001

Possible triggering effect of cytomegalovirus infection on systemic lupus erythematosus.

We report on a patient with systemic lupus erythematosus (SLE) who showed elevated titers of IgM antibodies to cytomegalovirus (CMV), suggesting CMV infection at the onset of SLE. Serum CMV antigens were also detected in the patient. These findings raise the possibility that CMV infection may be related to the onset of SLE in certain patients.

Adolescent↗
PubMed2001

Biodegradable poly-D,L-lactic acid-polyethylene glycol block copolymers as a BMP delivery system for inducing bone.

BACKGROUND: Bone morphogenetic proteins (BMPs) are biologically active molecules capable of eliciting new bone formation. In combination with biomaterials, these proteins can be used in a clinical setting as bone-graft substitutes to promote bone repair. Collagen from animal sources has previously been the preferred carrier material in animal experiments. More recently, synthetic biodegradable polymers have been tested as a delivery vehicle for osteoinductive agents. In earlier studies performed in our laboratory, it was found that the polylactic acid homopolymers (PLA650) and poly-D,L-lactic acid-polyethylene glycol block copolymers (PLA650-PEG200) are viscous liquids that can be used as BMP delivery systems. METHODS: To obtain new PLA-PEG polymers that exhibit greater plasticity, the molecular sizes of PLA and PEG segments in the copolymer chains were increased. Plastic PLA-PEG polymers with various molecular sizes and PLA/PEG ratios were synthesized, mixed with recombinant human (rh) BMP-2, and implanted into the dorsal muscles of mice for 3 weeks to evaluate their capacity to elicit new bone formation. To compare the plastic PLA-PEG polymer with the liquid PLA650-PEG200 polymer, these two polymers were combined with rhBMP-2, implanted, and harvested after 3 weeks. Bone mineral content (BMC), bone area, and bone mineral density (BMD) of the ectopic new bone were measured by means of single energy X-ray absorptiometry (SXA). RESULTS: All of the PLA6,500-PEG3,000 implants with 10 or 20 microg of rhBMP-2 showed new bone formation. In contrast, little or no bone formation was seen in other plastic PLA-PEG implants with rhBMP-2. Control implants that lacked rhBMP-2 did not show new bone formation. Radiographic and histologic examinations showed that the PLA6,500-PEG3,000 implants with rhBMP-2 harvested 3 weeks after implantation had normal bone characteristics with hematopoietic marrow and osseous trabeculae. SXA analysis showed that the values for bone mineral content (BMC), bone area, and bone mineral density (BMD) of new bone resulting from the use of plastic PLA6,500-PEG3,000 polymers with rhBMP-2 were significantly higher than those obtained with the liquid PLA650-PEG200 polymers (p < 0.001 for each of the three values). CONCLUSIONS: These results indicate that the PLA6,500-PEG3000 block copolymer with plastic properties works effectively as a BMP delivery system. These data suggest that the total molecular size and ratio of PLA size to PEG size is an essential factor in determining the efficacy of a BMP delivery system. After implantation, it is possible that the PLA6,500-PEG3,000 pellets might have absorbed tissue fluids and become swollen, resulting in bone formation that exceeded the size of the original implants. This expansion characteristic is a potentially beneficial property, given the intended practical application of the polymer in the repair of bone defects. CLINICAL RELEVANCE: New synthetic biodegradable delivery systems will play an important role in the clinical applications of rhBMPs in which local formation of bone via an osteoinductive graft material is needed. Further pre-clinical and clinical work is necessary to establish the safety of these implants before they are adopted for widespread clinical use.

Animals↗
PubMed1999

Advantages of concurrent use of anabolic and antiresorptive agents over single use of these agents in increasing trabecular bone volume, connectivity, and biomechanical competence of rat vertebrae.

The purpose of this study was to evaluate the usefulness of a combination regimen of anabolic and antiresorptive agents in increasing skeletal quantity and quality in comparison to a single-drug regimen with these agents. We examined histomorphometrically and biomechanically the effects of separate and combined administration of intermittent parathyroid hormone (PTH) and estrogen or bisphosphonate on both axial and appendicular skeletons of male Wistar rats, which were 4 months old and weighed approximately 300 g at the beginning of the treatment. The animals were untreated or injected with vehicle, recombinant human PTH(1-84) (PTH; 100 microg/kg daily), 17beta-estradiol (E2, 500 microg/kg every other day), incadronate disodium (YM175, 80 microg/kg every other day), combined PTH and E2 (PTH + E2), or a combination of PTH and YM175 (PTH + YM175). After 1 month of treatment, the three groups in which PTH was administered (PTH, PTH + E2, and PTH + YM175) had significantly higher trabecular bone volume and connectivity in the proximal tibial metaphyses (PTMs) compared with the untreated and vehicle-treated groups, whereas only combination groups (PTH + E2 and PTH + YM175) showed significant increases in these indices in the lumbar vertebrae. This site-related discrepancy was attributed to the fact that PTH significantly elevated bone resorption not in the PTMs but in the vertebrae. This increased bone resorption in the vertebrae was suppressed by the addition of an antiresorptive agent. As a result, trabecular bone mass, connectivity, and mechanical strength of the vertebrae were significantly increased from control levels only in the concurrent treatment groups (PTH + E2 and PTH + YM175). The superior skeletal effects of PTH cotherapy over PTH monotherapy were not seen with regard to bone mass, but with increased connectivity and mechanical strength. The concurrent use of PTH and an antiresorptive agent has been shown to be superior to the single use of PTH for enhancing these properties of rat vertebrae, which encourages future research, especially in larger animals.

Animals↗
PubMed1996

Size and asymmetry of the planum temporale. A new three-dimensional method for analysis of the supratemporal plane using MR imaging and computer-aided graphics.

The planum temporale of the supratemporal plane is important for language function and shows left-right asymmetry in most brains. To estimate the size and allow side comparison of the planum temporale, we developed a new technique for 3-D MR analysis of the supratemporal plane using a personal computer and computer-aided graphics. The temporal lobes of 5 human cadavers were imaged by MR in the sagittal plane, at a slice thickness of 2 mm. The images of the supratemporal plane were entered into a personal computer using the original software to determine the positions of anatomic landmarks and the size of the planum temporale. The data were then transferred to a supercomputer to reconstruct the 3-D surface image of the supratemporal plane. Computer images of the supratemporal plane agreed with macroscopic observations. The positions of anatomic landmarks and the size of the planum temporale also agreed with macroscopic measurements. Thus, the present technique provides valuable anatomic data on the supratemporal plane which should be useful for further clarification of the anatomic basis of language function.

Adult↗
PubMed1995

[Application of quantitative assay for endotoxin using immobilized histidine and filtration plate to parenteral drugs].

We improved the Limulus amebocyte lysate (LAL) test for endotoxins in parenteral drugs using immobilized histidine and a filtration plate. In order to deal with many samples at the same time and to apply to a routine assay, we used a filtration plate having 96 wells instead of a filter unit with a working volume of 2 ml. LAL test-affecting substances which are contained in a parenteral drug were separated from endotoxins by adsorbing endotoxins on immobilized histidine in the well of a filtration plate. Then the absorbed endotoxins were allowed to react with LAL reagent in the same well. We defined that this method had the higher precision than conventional methods and was not influenced by the concentrations of endotoxin and parenteral drugs. Hence we examined the recovery of endotoxin spiked to 23 kinds of parenteral drugs by this method, as a result, 100 +/- 25% of recovery was obtained from 17 kinds of them.

Endotoxins↗
PubMed1994

[Specific assay for endotoxin using immobilized histidine. Application to serum sample].

The amount of endotoxin in the serum was measured by the new assay method of endotoxin using a filtercup, Limulus amebocyte lysate, and immobilized histidine which is a specific adsorbent for endotoxin. The maximum recovery of endotoxin in the rabbit serum was obtained using acetate buffer (pH 5.5, mu = 0.1) for the adsorption. Using this buffer, various kinds of endotoxin in water were adsorbed quantitatively on immobilized histidine, and the activity of the adsorbed endotoxin was well recovered. The value of the amount of endotoxin in the bovine serum measured by the new assay method, which includes heat treatment (70 degrees C, 10 min) after separation followed by washing, was closer to that calculated from pyrogenic activities in rabbits than that measured by the PCA-Toxicolor method.

Animals↗
PubMed1994

Assay of endotoxin in human plasma using immobilized histidine, Limulus amoebocyte lysate and chromogenic substrate.

The Limulus amoebocyte lysate test for endotoxin is inhibited or enhanced by many substances. It is particularly difficult to determine endotoxin in plasma. In order to overcome this problem, we have modified the specific endotoxin assay method by using a membrane filter unit, a chromogenic Limulus amoebocyte lysate reagent, and immobilized histidine (which is a specific adsorbent for endotoxins). This immobilized histidine method consists of the endotoxin adsorption step on immobilized histidine, the separation step, in which Limulus amoebocyte lysate-interfering substances are removed, and the Limulus amoebocyte lysate test. Preheating of plasma samples (40-fold dilution with distilled water, at 100 degrees C for 7.5 min) was necessary, and it was necessary to dilute the sample more than 100-fold for the adsorption step. Under these conditions, the fraction of endotoxin recovered from plasma by the immobilized histidine method was almost 1. Moreover, by increasing the sample volume and extending the Limulus amoebocyte lysate reaction time, the sensitivity could be increased. By using the immobilized histidine method, 50-200 units/l of endotoxin in plasma samples can be accurately assayed. The method was used for the determination of plasma endotoxin in rabbits.

Animals↗