Biomedical subjects
Publications and source records attributed to Y Ikuta.
The treatment of the mutilated hand with more than one digit missing and a metacarpal defect is challenging. We used double-toe transfer after temporary insertion of a block of silicone to fill the bony defect.
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MDP-Lys (N2-[(N-acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine), a macrophage activator, is a lipophilic derivative of muramyl dipeptide (MDP). Multilamellar liposome incorporated MDP-Lys was prepared using phosphatidylcholine and phosphatidylserine by conventional film method, and its inhibitory effect on lung metastasis was compared with MDP-Lys as a solution in hamster's osteosarcoma. The lung metastatic rates after transplantation of the tumor to a lower extremity, in which the extremity was amputated 3 weeks later, were 50% and 100% 3 and 7 weeks, respectively, after transplantation. The rates after amputation were reduced by the treatment with MDP-Lys proportionally to the logarithmic MDP-Lys dose, and the rates 7 weeks after transplantation were 55% and 60%, respectively, in the MDP-Lys solution (50 microg/day) and liposomal MDP-Lys (20 microg twice/week) groups. Fifty percent of hamsters treated with liposomal MDP-Lys survived for more than 6 months. Considering that hamsters had a lung metastasis rate of 50% before MDP-Lys treatment, liposomal MDP-Lys given at a dose of 20 microg twice/week was effective for inhibiting lung metastasis at a far lower dose of MDP-Lys than that given as a solution (40 microg vs. 350 microg per week). No significant side effect of liposomal MDP-Lys, as evaluated by the comparison of body weight changes among differently treated hamsters, was detected. This greater inhibitory effect of liposomal MDP-Lys can be considered to be due to the longer retention of the liposomal form in the lung.
Although active targeting of anticancer drugs using magnetically responsive carriers is a very attractive treatment approach for solid tumors, successful results are limited. In particular, the therapeutic utility of intravenously administered magnetically responsive carriers has to date not been clearly established. The present study investigates magnetic liposomes designed to act as anticancer drug carriers, which can be effectively delivered to solid tumors via intravenous administration. Magnetic liposomes with incorporated adriamycin (magnetic ADR liposomes) were prepared by the reverse-phase evaporation method, and an in vivo study was carried out to assess the magnetic targeting of these liposomes to hamster osteosarcoma. The average diameter of liposomes thus prepared was 146 nm. Syrian male hamsters inoculated with osteosarcoma, Os515, in the right hind limb were studied 7 days after inoculation. After the hamsters had received an intravenous administration of either magnetic ADR liposomes or ADR solution (corresponding to 5 mg ADR/kg), the ADR concentrations in plasma, tumor, liver, lung, heart, and kidney were determined at designated time intervals. Administration of magnetic ADR liposomes under magnetic force using a permanent magnet (0.4 tesla) implanted in solid tumor produced an approximately 4-fold higher maximum ADR concentration in the tumor than did administration of ADR solution. The former administration modality induced an increase in ADR concentration in the liver and lung and a decrease in the heart compared with concentrations produced by the latter. The present results indicated that intravenously administered magnetic ADR liposomes can be used to effectively deliver ADR to osteosarcoma implanted with a magnet, as well as to the lung, a common site of metastases for osteosarcoma. Our results also suggest that this new treatment approach, which involves a combination of magnet implantation at the target site and intravenous administration of magnetic liposomes, can improve the clinical chemotherapy of solid tumors.
Cutaneous branches of radial nerves in patients with lepromatous leprosy (LL) and borderline lepromatous (BL) were studied by light and electron microscopy. Foamy macrophages were found more or less in the nerve fibers of all leprosy patients and distributed in the epineurial, perineurial and endoneurial areas. In the endoneurium, the foamy macrophages were mainly located in the subperineurial and perivascular spaces. Vacuolated Schwann cells were also found in the nerve fasciculus. In electron microscopy, these foamy macrophages and vacuolated Schwann cells contained numerous small dense materials, irregular in size and shape, considered to be degenerated and fragmented mycobacterium leprae. These dense materials were found also in the cytoplasm of vascular endothelial cells. These findings suggest that mycobacteria enter into the endoneurium via the blood vessels. In our present study, on the other hand, it was very difficult to find the intact mycobacteria in the cytoplasm of the foamy macrophages, Schwann cells or endothelial cells, as well as in the Ziehl-Neelsen staining of paraffin sections. The disappearance of intact bacilli in our present study might have been caused by multi drug therapy. The myelinated nerve fibers were degenerated and disappeared in variable degrees. Degenerative changes of the myelin sheath developed from the outer layer to the inner layer with disarrangement of the lamellar structure. These findings were different from myelin destruction of peripheral nerves in Wallerian degeneration. The degenerative changes of the myelin sheath are caused by degeneration and destruction of Schwann cells in leprosy patients. Fibrosis surrounding myelinated and unmyelinated nerve fibers, i.e., periaxonal fibrosis, was found to a greater or lesser extent in the endoneurium. In the present study, it is still unclear whether the periaxonal fibrosis was due to necrosis of the Schwann cells by infection of mycobacteria or to an autoimmune mechanism such as antiperipheral nerve antibody. However, lamellated concentric fibrosis surrounding regenerative myelinated and unmyelinated nerve fibers with the disappearance of mycobacteria suggests that degenerations and regenerations of nerve axons were repeated during clinical cause. These findings indicated that autoimmune mechanisms play an important role in the pathogenesis of periaxonal fibrosis.
In the rabbit, posterior facial vein segments were grafted to the femoral arteries using either conventional suture technique or a mechanical absorbable pinned-ring device. The purpose of this study was to compare patency rates and anastomotic times for the two different methods. The anastomoses were evaluated macroscopically and using light and scanning electron microscopy. The grafts anastomosed with the absorbable rings exhibited 100% patency, while only 83% of the sutured grafts were patent. The mean anastomotic time using the mechanical pinned-ring device was 18.1 min (range 9.8-30 min). The conventionally sutured anastomoses were completed in a mean time of 60 min (range 50-75 min). The experiment has confirmed that the absorbable pinned-ring device provides a safe and fast way to perform microvascular anastomosis.
Eight patients with ganglion cysts arising from the cruciate ligaments of the knee joint underwent arthroscopic excision after the MR examination. The MR findings, clinical features and arthroscopic findings were evaluated comparatively.
The effects of exogenous basic fibroblast growth factor (bFGF) on the repair of full-thickness cartilage defects were examined. Four-millimeter diameter, cylindrical defects were made in rabbit articular cartilage and were filled with human recombinant bFGF. The addition of bFGF to the defect induced the formation of a thick cartilage layer composed of chondrocytes and a metachromatic-stained matrix after 6 weeks. The score of the bFGF-treated tissue, as evaluated by a semiquantitative histological scale, was significantly higher than that of the untreated tissue. At 24 weeks, the cartilage-like matrix that contained the proteoglycans and type II collagen was thicker in the bFGF-treated tissue than in the untreated tissue. Immunohistochemical analysis of the tissues at 6-12 weeks with an anti-bFGF monoclonal antibody suggested that a single application of bFGF increased the number of differentiating chondrocytes that synthesized bFGF at a high level. In contrast, immunostaining of the tissues at 6-12 weeks with a monoclonal antibody against proliferating cell nuclear antigen showed that the number of proliferating cells in the bFGF-treated tissue was fewer than in the untreated tissue. These findings suggest that administration of bFGF into cartilagenous defects promotes the differentiation of chondrocytes and their matrix synthesis, and that this growth factor is useful for improving cartilage repair.
Clinical and radiological studies were done on the results of rotational acetabular osteotomy for advanced osteoarthrosis secondary to dysplasia of 29 adult hips followed up for 6 to 11 years postoperatively (mean 8 years). Clinical evaluation by Merle d'Aubigne and Postel's system showed improvement from a preoperative mean of 12.8 to a follow-up mean of 14.8, with aggravation being observed in 8 joints. Radiologically, this procedure produced adequated improvement regarding femoral head coverage, but improvement in joint congruency could not necessarily be obtained due to joint deformity and progression of arthrosis, with aggravation of joint congruency being observed in 6 joints. The most important factor influencing the postoperative results of this procedure was postoperative joint congruency. If the postoperative joint congruency is satisfactory, with the joint congruent index being more than 6.0, progression of arthrosis can be prevented in the long term by this procedure, even in advanced cases.
After replacement of a bicuspid aortic valve with a Freestyle stentless xenograft, right coronary leaflet dysfunction and an elevated pressure gradient developed. Attempts to match the right and left ostia of the prosthesis, which were located at an angle of less than 120 degrees, to the native right and left ostia, which were located at 180 degrees, may have resulted in the leaflet distension. This is a suggestive finding about its implantation technique.
Tissue inhibitors of metalloproteinases (TIMPs) are involved in liver fibrosis through impaired matrix degradation. Previous studies showed that the serum level of TIMP-1 was increased in patients with chronic liver disease, reflecting the liver TIMP-1 level, and that it is useful for assessing liver fibrosis. An enzyme immunoassay for TIMP-2 is now available. In this study, we examined the clinical usefulness of this serum TIMP-2 test for liver fibrosis in patients with chronic liver disease, in comparison with the serum TIMP-1 test. The serum TIMP-2 concentration was 61 +/- 13 ng/ml in healthy controls (n = 32), and 18% higher in the group of chronic active hepatitis (CAH) patients (n = 34), 64% higher in the liver cirrhosis (LC) group (n = 33) and 44% higher in the hepatocellular carcinoma (HCC) group (n = 61), and similar to the control level in the chronic persistent hepatitis (CPH) group (n = 23). In contrast, the serum TIMP-1 concentration was 155 +/- 17 ng/ml in the healthy controls, 18% higher in CPH, 35% in CAH, 63% higher in LC and 92% higher in HCC. The serum TIMP-2 level was related to the histological degrees of both periportal necrosis and liver fibrosis, as well as to the serum TIMP-1 level. However, the relationships for TIMP-2 were weaker compared to those of serum TIMP-1. These results suggest that compared to the serum TIMP-1 level, changes in the serum TIMP-2 level in chronic liver disease are less liver-specific, and the serum TIMP-2 level is less useful in the assessment of liver fibrosis in chronic liver disease.
From the dried roots of Cephaelis acuminata, five ipecac alkaloids, neocephaeline, 7'-O-demethylcephaeline, 10-O-demethylcephaeline, 2'-N-(1"-deoxy-1"-beta-D-fructopyranosyl)cephaeline and 2'-N-(1"-deoxy-1"-beta-D-fructopyranosyl)neocephaeline, were isolated, along with emetine, cephaeline, psychotrine, protoemetine, 9-demethylprotoemetinol and isocephaeline. Structures were determined by spectroscopic and chemical means.
BACKGROUND/AIMS: Matrix metalloproteinase (MMP)-3 plays an important role in extracellular matrix degradation, because of its broad substrate specificity and its activation of other proMMPs. Our aims in the present study were to determine whether the measurement of serum MMP-3 is clinically useful for assessing ongoing liver fibrolysis in patients with chronic liver disease. METHODS: We measured the serum MMP-3 concentrations with a sandwich enzyme immunoassay in 58 patients with chronic hepatitis, 22 patients with liver cirrhosis, 45 patients with hepatocellular carcinoma and 124 healthy individuals. The liver MMP-3 content was also measured in autopsied livers. RESULTS: Among the healthy controls, the serum levels of MMP-3 were about 2-fold higher in the males than in the females. In this study, the serum MMP-3 results of mainly the male group were analyzed because of the large number of male subjects. Compared to the control level, the mean serum MMP-3 concentration was 55% lower in chronic hepatitis, 53% lower in liver cirrhosis and 46% lower in hepatocellular carcinoma. There was no significant difference in the serum MMP-3 levels among the chronic hepatitis, liver cirrhosis and hepatocellular carcinoma groups. The serum MMP-3 levels were not related to the histological degree of necroinflammation or of liver fibrosis in the patients with chronic hepatitis. No significant difference in serum MMP-3 levels was observed among three Child's subgroups in the group of cirrhotic patients. In the group of patients with hepatocellular carcinoma, the serum MMP-3 levels were not related to the severity of liver function, the HCC tumor size, or the histological differentiation. The serum MMP-3 level was not correlated with serum markers for connective tissue turnover, i.e. procollagen type III peptide, 7S fragment of type IV collagen, hyaluronan and tissue inhibitor of metalloproteinase-1 in the patients with chronic liver disease or hepatocellular carcinoma. CONCLUSIONS: The measurement of serum MMP-3 is of little use for assessing fibrolysis in chronically diseased livers.
BACKGROUND/AIMS: The production of matrix metalloproteinase (MMP)-2 was reported to be increased in chronically diseased livers. Our aims in the present study were to elucidate the clinical usefulness of the serum MMP-2 concentration in chronic viral liver disease. METHODS: We measured serum MMP-2 concentrations with a sandwich enzyme immunoassay in 62 patients with chronic hepatitis, 35 patients with liver cirrhosis, 55 patients with hepatocellular carcinoma and 24 healthy individuals. The assay detects proMMP-2 and proMMP-2 complexed with tissue inhibitor of metalloproteinase-2, but not active forms of MMP-2. The liver MMP-2 content was also measured in autopsied cirrhotic and non-cirrhotic livers. Gelatin zymography and gel filtration chromatography were carried out using the serum. RESULTS: The serum MMP-2 concentration was significantly increased in the liver cirrhosis and hepatocellular carcinoma patients, but not in the patients with chronic hepatitis. There was no significant difference in the serum MMP-2 level between the liver cirrhosis and hepatocellular carcinoma groups. In the patients with chronic viral liver disease, serum MMP-2 concentration showed the best correlation with the degree of liver fibrosis and with serum hyaluronate level. The zymography of serum showed the majority of MMP-2 in serum exists as a proMMP-2. The chromatography of serum revealed a single peak at the position of about 90 kDa corresponding to an MMP-2 complexed with tissue inhibitor of metalloproteinases-2. The liver MMP-2 content was markedly increased in the cirrhotic livers compared with the non-cirrhotic livers, and was positively correlated with the liver collagen content. When investigating the utility of the serum MMP-2 test for differentiating liver cirrhosis from chronic hepatitis, the utility of serum MMP-2 was equal to that of serum hyaluronate, which is known as the best current test for diagnosing liver cirrhosis. CONCLUSIONS: The serum MMP-2 concentration reflects mainly the amount of proMMP-2 complexed with tissue inhibitor of metalloproteinase-2. The serum MMP-2 level was markedly increased in cirrhotic patients, and may be explained by an overproduction in the cirrhotic liver. In the clinical state, the measurement of serum MMP-2 was as useful a test for diagnosing liver cirrhosis as is the serum hyaluronate level.
The objective of this study was to observe the changing appearance of human anterior cruciate ligament (ACL) grafts in their tibial bone tunnels by MRI using oblique axial images. One-hundred and eight knees in 75 patients were studied by MRI at 1-33 months after arthroscopic ACL reconstructions using double-looped, autogenous semitendinosus and/or gracilis tendons. Knees with poor stability were excluded from this study. The examinations were performed at 0.2T with spin echo proton density and T2-weighted oblique axial images. Appearances of grafts were mainly described on spin echo proton density images based upon time after surgery. The grafts appeared as homogeneous, low signal intensity areas in the bone tunnels at 1 month after the surgery. Ring-shaped low signal intensity areas were observed along the wall of the bone tunnels in the 2- to 3-month group. In many grafts from this group, each tendinous bundle appeared as a low signal area separated by a high signal intensity area. In all cases in the 4- to 6-month group, the thickness of the ring-shaped low signal intensity area had increased, whereas the thickness of the high signal intensity area had decreased. In almost all of the cases, the interior of the bone tunnel gradually became a homologous low signal intensity region by 7 to 12 months after the surgery. According to these results, it is suggested that the maturation of the tendon-bone interface was completed from 6 to 12 months after the ACL reconstruction.
BACKGROUND AND AIMS: Previously we found that serum matrix metalloproteinase (MMP)-1 activity decreased with progression of chronic liver disease. Our objectives in the present study were to observe the change in the serum MMP-1 protein concentration using recently developed specific enzyme immunoassays for MMP-1 and MMP-1 complexed with tissue inhibitor of metalloproteinases (TIMP)-1 and to elucidate the clinical usefulness of the serum MMP-1 test in chronic viral hepatitis. We measured the serum concentrations of MMP-1 and MMP-1/TIMP-1 complex using these immunoassays in 64 patients with histologically characterized chronic viral hepatitis. RESULTS: Serum MMP-1 concentration was inversely related to the histological severity of chronic hepatitis (P< 0.0001). It was closely associated with the histological degree of periportal necrosis (P< 0.0001), intralobular necrosis (P< 0.005), portal inflammation (P<0.0001) and liver fibrosis (P< 0.05). The serum concentration of MMP-1/TIMP-1 complex was also related to the histological severity of chronic hepatitis (P< 0.0001). It was associated with the degree of portal inflammation (P< 0.05), but not with the degree of periportal necrosis, intralobular necrosis or liver fibrosis. As serum MMP-1 level was closely associated with the histological degree of necroinflammation, we examined the ability of the serum MMP-1 test to differentiate active and inactive forms of hepatitis with a receiver operating curve. The results were compared with those of serum procollagen type III N-peptide (PIIINP) test. We found that the serum MMP-1 test was superior to the serum PIIINP test in assessing liver necroinflammation. CONCLUSIONS: In addition to the previously reported changes in enzyme activity, MMP-1 proteins in serum decreased during histological progression of chronic hepatitis. The serum MMP-1 test may be useful clinically to differentiate active and inactive types of hepatitis in patients with chronic viral hepatitis.
The commercially available mechanical vascular anastomotic device with ring-pin technique employs polyethylene rings and stainless steel pins, but even after healing of the anastomotic site, the ring remains. To resolve this disadvantage, the ring material was replaced by biodegradable material, and a ring coupling device was fabricated. This new ring was used to anastomose the femoral vein of rabbits, and morphological observations were made macroscopically and by light and scanning electron microscopy. Of the 58 anastomosed veins, 54 were patent, giving a patency rate of 92.9%. The ring was largely absorbed 15 weeks after anastomosis and completely after 30 weeks. Histologically, re-endothelialisation was observed in 1 week. Infiltration of inflammatory cells was significant around the ring at 3 weeks, but inflammation subsided within 6 weeks. There were no findings indicating adverse effects of the stainless steel pins remaining outside the vascular wall.
An absorbable ring for vascular anastomosis was developed, composed of a copolymer of L-lactic acid and glycolic acid (7:3 mole percent). It has an external diameter of 3.0 mm, a thickness of 1.0 mm, and an inner diameter of 1.0 mm, with six stainless steel pins and six opposed holes. With this ring, femoral artery anastomoses were performed in 27 rabbits. One, 2, 6, and 30 weeks after anastomosis, the femoral artery was harvested and patency was evaluated by light and scanning electron microscopy. Absorption of the ring occurred within 30 weeks. Of the 27 animals, the anastomosed vessel was patent in 24 cases, for a patency rate of about 89 percent. Vascular anastomosis with the absorbable ring is useful, and the device may compensate for some of the drawbacks of manual suturing and the conventional non-absorbable ring.