検索

CD14 is a pattern recognition receptor on myeloid cells and plays a pivotal role in an innate immune system that is responsible for Gram-negative and Gram-positive bacteria infection. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, can induce production of a large quantity of proinflammatory cytokines into the circulation mediated by CD14-mediated macrophages and monocytes. These cytokines eventually cause septic shock. Several in vitro and in vivo studies have shown that suppression of a CD14 function by a CD14 antibody led to an inhibition of the production of proinflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-8. In the present study, we found that CD14 antisense oligonucleotide (ODN) can prevent lethal LPS shock in D-galactosamine-sensitized mice. This ODN inhibited CD14 expression in a mouse macrophage cell line, RAW264.7, and suppressed production of TNF-alpha in LPS-stimulated RAW264.7 cells. Furthermore, we designed a consensus antisense ODN that could hybridize human and mouse CD14 RNA, and we evaluated its efficacy. The consensus antisense ODN rescued mice primed with Mycobacterium bovis bacillus Calmette-Guerin (BCG) from the LPS-induced lethal shock. In this model, the CD14 antisense ODN down-regulated LPS-elicited CD14 expression in the liver, resulting in a decrease in LPS-induced TNF-alpha production. These findings suggest that the CD14 antisense ODN is distributed in the liver and efficiently suppresses LPS-induced TNF-alpha production by reducing CD14 expression on Kupffer cells. This CD14 antisense ODN may be useful for the development of a therapeutic agent against sepsis and septic shock.

The structure of the human genome is almost completely elucidated and the life sciences will now aim for a general and integrated study of gene expressions and the functional elucidation of proteins. In such a study, various new techniques have been developed, and DNA microarray technology is the most representative one. As for the DNA microarray techniques, several thousands to tens of thousands of gene segments are immobilized on a glass slide at high density, and cDNA probes prepared from specific cells or tissues are hybridized on the slides from which gene expression profiles are obtained at one sweep in a short time. The present development of this technique and its possible application to medicine-related fields are described.</P>

We report a case of retroperitoneal hematoma presenting as femoral nerve pulsy on antiplatelet therapy. The patient, a 78-year-old man who had undergone antiplatelet treatment using ticlopidine, was admitted to our hospital with complaints of sudden-onset low abdominal and back pain. Computed tomography showed an iso-density mass in the right retroperitoneum within the psoas muscle. We made a diagnosis of retroperitoneal hematoma compressing the femoral nerve and performed an operation to remove the hematoma in order to decompress the femoral neuropathy. Postoperatively, the patient rapidly recovered from the femoral neuropathy. In the particular case in which no antagonist against the ticlopidine is available, surgical decompression could produce a good outcome.

In the present investigation, we studied the effect of recombinant human erythropoietin (r-HuEPO) on serum malondialdehyde (MDA) as an index of lipid peroxidation, related to iron-catalyzed free radical reaction and erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities in very-low-birth weight (VLBW) infants. Forty premature infants, at gestational ages were less than 33 weeks and birthweights were less than 1,500 g, were enrolled in the study. The study population was randomly divided into 2 groups. Twenty infants in Group 1 (treatment group) were given r-HuEPO, and 20 infants in Group 2 served as the control. r-HuEPO treatment (750 U/kg a week) was initiated on the 10th day of life and continued for 6 weeks. Preterm infants given erythrocyte transfusions during the study were excluded from the results. Serum ferritin and MDA levels, and erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities were analyzed at the end of the first week of life (at the beginning of the study). Subsequently, serum ferritin, and MDA levels were measured at the end of the 3rd and the 6th week. SOD, CAT, and GPX activities in the hemolysate were analyzed at the end of the 4th week. Six infants in the control group and 1 infant in the r-HuEPO group received transfusions through the end of the study, and these infants were excluded from the results. Significantly decreased serum ferritin concentrations were found in the r-HuEPO group compared to those in the control group both at the end of the 3rd and the 6th week (P < 0.05, and P < 0.01, respectively). In addition, serum MDA levels were also significantly reduced in Group 1 compared to control both at the end of the 3rd and the 6th week (P < 0.01 and P < 0.05, respectively). A good correlation was found between serum MDA and ferritin levels in Group 1. When the 2 groups were compared with respect to activities of SOD, CAT, and GPX at the end of the 4th week, no differences were observed. Our findings in this study show that administration of r-HuEPO significantly decreases lipid peroxidation, but does not affect erythrocyte antioxidant enzyme(s) activities in preterm infants. The mechanism responsible for the r-HuEPO-induced decrease in lipid peroxidation may concern inhibition to iron-catalyzed free radical reactions.</P>

Mutations of the c-KIT gene have been reported not only in gastrointestinal stromal tumors and mast cell tumors, but also in testicular germ cell tumors (TGCTs). In the present study we employed polymerase chain reaction and DNA sequencing analysis to characterize the c-KIT gene in a 29-year-old Japanese patient with bilateral testicular seminomas. Direct sequence analyses revealed a single base substitution in exon 17 in one c-KIT allele, resulting in an amino acid substitution of D816H in this mutated allele. This mutation was found in the left, but not in the right, testicular seminoma. This is the first description of a c-KIT gene mutation in a Japanese patient with bilateral TGCT. The mutational analysis of the c-KIT gene seems to provide crucial information for managing TGCT patients not only in Europe but also in Japan.

The present study was performed to investigate the effects of valerian extract on the sleep-wake cycle using sleep-disturbed model rats. A significant shortening in sleep latency was observed with valerian extract at doses of 1000 and 3000 mg/kg. On the other hand, valerian extract had no significant effects on total times of wakefulness, non-rapid eye movement (non-REM) sleep, or REM sleep, even at a dose of 3000 mg/kg. Valerian extract at doses of 1000 and 3000 mg/kg showed a significant increase in the delta activity during non-REM sleep. In conclusion, valerian extract may be useful as an herbal medicine having not only sleep-inducing effects but also sleep quality-enhancement effects.

Hepatic outflow obstruction created by balloon occlusion of the hepatic vein induces characteristic angiographic findings in the occluded area: prolonged enhancement on hepatogram followed by reversed portal opacification on the hepatic arteriogram and perfusion defect on the arterial portogram. The following induced hepatic hemodynamic changes are suggested: hepatic arterial flow increases, and the portal vein acts as a draining vein with slow reversed flow. These unique hemodynamic changes enhance the effect of hepatic interventional therapies. In transcatheter arterial infusion, increasing hepatic arterial flow and absence of portal inflow can bring about a high concentration of drugs, the presence of which is greatly protracted due to outflow blockage. In transcatheter arterial chemoembolization, reversed portal flow can allow portal embolization in addition to arterial embolization. In microwave coagulation therapy and radiofrequency ablation therapy, decreasing portal flow can cause larger areas of coagulation. Further, the technique of hepatic venous occlusion has potential therapeutic applications.

Apatite-wollastonite containing glass ceramic is considered to be difficult to resorb, but we experienced the disappearance of the porous type of Apatite-wollastonite glass ceramic particles . In this study, the resorption of porous apatite-wollastonite glass-ceramic implanted in the femurs of rabbits was investigated, and the process was compared with beta-tricalcium phosphate, a resorbable ceramics. Porous apatite-wollastonite glass-ceramic (70, 80, and 90% porosity) and beta-tricalcium phosphate (75% porosity) were implanted in the femurs of Japanese white rabbits. Samples were harvested and examined 0, 4, 8, 12, 24 and 36 weeks after implantation. Quantitative analysis of the radiographic and histologic findings was performed with NIH Image software. Radiographic examination demonstrated that the radiopacity and size of the porous apatite-wollastonite glassceramic cylinders decreased gradually after implantation. Histologic examination revealed that the surface area of the apatite-wollastonite glass-ceramic cylinders decreased continuously, and approached 20% of the original area 36 weeks after implantation. However, the resorption rate of porous apatite-wollastonite glass-ceramic was slower than that of beta-tricalcium phosphate. Toluidine blue staining showed abundant new bone formation on the surface of the apatite-wollastonite glassceramic matrix. Considering its mechanical strength, gradual resorption characteristics, and good osteochonductive activity, porous apatite-wollastonite glass-ceramic appears to be a suitable artificial bone substitutes.

This study was undertaken to reveal the trends of prostate cancer and the outcome of treatment modalities for each disease stage in patients in a single institute over a 10-year period. From January 1994 through December 2003, 420 consecutive patients with previously untreated and histologically confirmed prostate cancer were analyzed for annual distributions of disease stages and treatment modalities and for long-term clinical progression-free survival, prostate cancer-specific survival, and prostate-specific antigen (PSA) failure-free survival rates for each stage and treatment modality. Annual trends showed that the number of patients, especially those with clinically localized cancer, increased dramatically. The 5-year disease-specific survival rates for patients with clinically localized disease were 100 percent for all treatment modalities, including hormonal therapy alone. Patients with PSA levels less than 10 ng/ml showed an 81 percent 5-year PSA failure-free survival rate with radical prostatectomy. Stage C patients treated by surgery or radiation-based therapy with concomitant hormonal therapy obtained 93 percent and 100 percent cause-specific survival rates, respectively, and those treated by hormonal therapy alone showed a 79 percent rate. The number of patients with localized prostate cancer was increasing in this decade. While long-term hormonal therapy alone was highly efficient in controlling localized prostate cancer, radical therapies in conjunction with neo-adjuvant hormonal therapy produced better survival rates in cases of locally advanced disease.

It is well known that antecedent term delivery and metastasis to sites other than the lungs and vagina are high risk factors for patients with gestational trophoblastic neoplasia. Here we report on a patient with choriocarcinoma who presented with brain and lung metastases after term delivery and was treated by EMA-CO chemotherapy. A 31-year-old woman delivered a healthy infant at term. Frequent episodes of hemoptysis occurred beginning 3 weeks after the delivery. On admission to our hospital, she had lesions in the uterus, lungs and brain as well as motor aphasia and hemiplagia. The pretreatment beta-hCG level was 21,000 ng/ml and the WHO score was 16 (high-risk group). The EMA-CO regimen was administrated as first-line chemotherapy and the patient achieved complete remission after 7 courses. Treatment was terminated after 11 courses and maintained with etoposide (25 mg/day) for 6 months. The patient has remained in complete remission for more than 16 years without other adjuvant therapies. We believe that EMA-CO can currently be considered the regimen of first choice for most high-risk patients with gestational trophoblastic neoplasia in view of its effectiveness and excellent tolerability.

Lamivudine is widely used to treat patients with hepatitis B. However, the outcomes in patients with hepatocellular carcinoma (HCC) treated with lamivudine have not been established. This study was conducted to evaluate the outcomes of lamivudine treatment for patients with HCC using an untreated, matched control group. Thirty patients with controlled HCC orally received lamivudine. As controls, 40 patients with HCC who were not treated with lamivudine and matched for clinical features were selected. The lamivudine-treated and untreated groups were compared with respect to changes in liver function, HCC recurrence, survival, and cause of death. In the lamivudine-treated group, there was significant improvement in the Child-Pugh score at 24 months after starting treatment, while no improvement was observed in the untreated group. There was no significant difference in the cumulative incidence of HCC recurrence and survival between the groups. However, there was a significant difference in the cumulative incidence of death due to liver failure (P= 0.043). A significant improvement in liver function was achieved by lamivudine treatment, even in patients with HCC. These results suggest that lamivudine treatment for patients with HCC may prevent death due to liver failure. Further prospective randomized studies using a larger number of patients are required.

Changes in brain vascularity in adult rats during adaptation to chronic normobaric hypoxia with or without elevated CO(2) were morphometrically investigated. Immunohistochemistry with anti-rat endothelial cell antigen (RECA-1) antibody was carried out for the vascular analysis. After the rats were subjected to hypoxia for 2 to 8 weeks (wks)(10 percent O(2) in N(2)), the total area of blood vessels was measured in 6 brain regions. After 2 wks of hypoxia, the blood vessel area was found to be significantly increased in the frontal cortex, striatum, hippocampus, thalamus, cerebellum, and medulla oblongata, by 44% , 96% , 65% , 50% , 102% and 97% , respectively. The ratio of large vessels with an area > 500 micro m(2) was also increased in all brain regions. Hypoxic adaptation in brain vascularity did not change during 8 wks of hypoxia, and the hypoxia-induced levels measured in the vasculature returned to control levels 2 wks after the termination of hypoxia in areas of the brain other than the cortex and thalamus. In addition, hypoxia-induced changes in terms of the total vascular area and vessel size distribution were significantly inhibited by the elevation in CO(2), whereas chronic hypercapnia without hypoxia had no effect on brain vascularity. These findings suggested that adaptations in brain vascularity in response to hypoxia are rapidly induced, and there are regional differences in the reversibility of such vascular changes. Carbon dioxide is a potent suppressor of hypoxia-induced vascular changes, and may play an important role in vascular remodeling during the process of adaptation to chronic hypoxia.

We evaluated the visceral adipose tissue accumulation in university students in Okayama prefecture, Japan. Fifty-eight Japanese university students (10 men and 48 women, age 18.4 +/- 0.6 years)were enrolled in this study. Fat distribution was evaluated by visceral fat (V) and subcutaneous fat (S) areas measured with computed tomography (CT) scanning at umbilical levels. Anthropometric parameters,i.e., height, weight, waist circumference, hip circumference, and body fat percentage; blood examination; and blood pressure (BP) were also measured. In 58 subjects, the V area was 23.4 +/- 21.0 cm(2) and the S area was 122.5 +/- 57.9 cm(2). V areas were significantly correlated with hepatic enzymes, uric acid, triglyceride, and BP in men, while they were weakly correlated with hepatic enzymes, triglyceride, and high density lipoprotein (HDL) cholesterol in women. Correlation coefficients between V areas and clinical parameters were comparatively higher than those between other body composition parameters,i.e., S areas, weight, body mass index (BMI), body fat percentage, and clinical parameters. The present study suggests that visceral adipose tissue accumulation is important for hepatic enzymes, uric acid, triglyceride, and BP in university students.

Macrophages and microglia are implicated in spinal cord injury, but their precise role is not clear. In the present study, activation of these cells was examined in a spinal cord injury model using 2 different antibodies against ED1 clone and ionized calcium binding adaptor molecule 1 (Iba1). Activation was observed at 1, 4, 8, and 12 weeks after contusion injury and was compared with sham operated controls. Our results indicate that activation could be observed in both the dorsal funiculus and the ventral white matter area in the spinal cord at 5 mm rostral to the epicenter of injury. For both cells, there was a gradual increase in activation from 1-4 weeks, followed by down-regulation for up to 12 weeks. As a result, we could stain macrophages by ED1 and microglia by Iba1. We concluded that macrophages may play a role in the phagocytosis of denatured dendrites after spinal cord injury, while microglia may have some cooperative functions, as they were found scattered near the macrophages.

Primary aorto-enteric fistula (PAEF)is a serious complication of abdominal aortic aneurysm(AAA). We report a patient with PAEF associated with inflammatory AAA who underwent emergent surgery. A 52-year-old male presented with recurrent hematemesis. A computer tomography scan showed a sealed rupture of the AAA adjacent to the duodenum. At surgery, a coin-sized PAEF was noted. The aorta was replaced with a Dacron graft in situ . Histological examination revealed the characteristics of an inflammatory AAA. The postoperative course was uneventful, and there has been no evidence of infection during a follow-up period of 3 years. We discuss the etiologic and surgical considerations regarding this unusual entity.

Cellular immunity against human bile proteins was investigated by the leukocyte migration inhibition test (LMIT) with 13 primary biliary cirrhosis (PBC) patients, 10 chronic aggressive hepatitis (CAH) patients and 21 healthy adults. Hepatic bile taken from patients operated on for lithiasis of the biliary tract was fractionated into five fractions with Sepharose 6B gel. A subtoxic dose of each fraction was determined in the healthy adults, and used as the antigen for LMIT. Out of the 5 fractions, only the third fraction led to an LMIT positive response in 8 out of 11 (73%) PBC patients and in 1 out of 10 (10%) CAH patients. The difference between PBC and CAH was significant (p less than 0.005). The remaining 3 PBC patients with LMIT negative responses were all under D-penicillamine treatment. Antibody to each fraction was prepared in rabbits. Using the antibodies after absorption with human serum, the localization of the antigens which were present in each fraction was investigated immunohistochemically using human liver sections. The antigen to the anti-first fraction antibody was detected specifically in the epithelial cells of the bile ducts and the ductules, and the antigen to the anti-third fraction antibody was detected specifically on the membrane of the bile canalicules. The third fraction was fractionated into three fractions by Sephadex G-200 gel. Only the first of the 3 fractions showed an LMIT positive response in 3 PBC patients, and its molecular weight was determined to be about 500,000. It is concluded that PBC patients develop cellular immunity against canalicular-antigen-containing fractions but not ductal-antigen-containing ones.

The survival rate of 19 patients who underwent living-related kidney transplantation after donor-specific blood transfusions (DST) was compared with that of 32 historical controls receiving transplants without DST. The graft survival rate of the DST group was 82% after two and three years. The graft survival rate of the DST group was significantly better than the 53% rate after two years obtained with the 32 historical controls (p less than 0.05). We tested sera from 16 DST-treated recipients to study the beneficial effect of DST on kidney allograft survival using the mixed lymphocyte culture (MLC) serum inhibition test. The results demonstrated that MLC inhibitory factors were induced in the serum of the recipient after completion of DST. This inhibition of MLC was observed by treatment of responder lymphocytes with serum obtained three weeks after DST plus rabbit complement. The inhibitory effect was also specific for responder cells in anti-donor MLC. Regarding the correlation with rejection episodes, these MLC inhibitory factors were often observed in the non-rejection group (p less than 0.05). The data suggest that such factors may be anti-idiotypic antibodies and be associated with prolonged graft survival.

In an attempt to evaluate high density lipoprotein (HDL) subfraction levels in liver diseases, HDL was separated by a precipitation method with dextran sulfate-Mg2+ from sera of 289 healthy adults and 50 patients with liver diseases. The HDL was subdivided into HDL2e and HDL3e by Utermann's polyacrylamide gel electrophoresis with lauric acid. Ultracentrifugally separated HDL2 and HDL3 roughly corresponded to HDL2e and HDL3e, respectively. Male and female groups had different distributions of HDL2e/HDL3e ratios. Among healthy males, 121 cases had ratios less than 1.0 (mean +/- SD = 0.72 +/- 0.39, n = 150), while among healthy females, the ratios were generally larger than those of males and varied widely from 0.2 to 6.6 (mean +/- SD = 1.77 +/- 1.05, n = 139). Low levels of HDL-cholesterol were found in patients with liver diseases, except those with mild alcoholic liver injury and intrahepatic cholestasis. Apparent decreases in HDL3e, but not in HDL2e, were found in all cases with liver diseases investigated, even in those who did not show decreases in the total HDL level, when male and female patients were analyzed separately. The analysis of HDL subfractions by the present method is simple and useful for the study on altered lipid metabolism in liver diseases.

Thirteen previously untreated patients aged 70 and above with acute nonlymphocytic leukemia were treated with aclarubicin (ACR) alone. Among 10 cases (3, acute myelocytic leukemia; 4, acute myelomonocytic leukemia; 2, acute monocytic leukemia; and one, acute erythroleukemia) in which an evaluation was possible, 5 cases (3, acute myelomonocytic leukemia; and 2, acute monocytic leukemia) obtained complete remission (CR). The CR rate was 83% in 6 patients with acute myelomonocytic leukemia or acute monocytic leukemia. The median CR duration and survival was 7.5 and 10 + months, respectively. Although side effects of the drug on digestive system such as nausea, vomiting and anorexia were observed in all patients, they were controllable by conventional treatments. The results suggest that ACR is effective for the clinical management of elderly patients with acute nonlymphocytic leukemia, especially those with acute myelomonocytic leukemia or acute monocytic leukemia.

Tissue reactions at the cement-bone and artificial implant-bone interface were examined light and electron microscopically in thirty-six patients who underwent revisory operation of hip or knee replacement. The reactions were classified into three types: inert tissue, active tissue with giant cell proliferation, and active tissue with predominant foamy cell proliferation. The third type of reaction was found only in total hip replacement with bone cement. No evidence of allergic reaction to implanted materials was found in any replacement, though active cellular infiltrations were observed around loosened prostheses especially in cemented arthroplasty. The tissue reactions always occurred around instable or loosened prostheses. Thus, the present study shows that mechanical instability is the primary cause of such undesired tissue reactions.