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K Kawada

Publications and source records attributed to K Kawada.

At least 19 recordsLinked to original sources
PubMed2001

Lupus anticoagulant-like activity observed in a dimeric lambda protein produced by myeloma cells.

We report here a lupus anticoagulant (LA)-like activity observed in a 45-year-old man with Bence-Jones protein (BJP) lambda-type multiple myeloma. This patient showed no clinical symptoms of thrombosis or bleeding diathesis. Laboratory examination on admission showed mild anemia, prolongation of activated partial thromboplastin time (APTT) (APTT, 56.2 seconds; control, 29.1 seconds), normal prothrombin time, normal thrombin time, and massive proteinuria (2.3 g/d). The mix test with normal plasma showed the presence of circulating anticoagulant. Based on the assumption that the lambda-type BJP may have been responsible for the prolongation of APTT, we purified the BJP from the patient's urine using column works. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting showed that the purified protein was a 48-kd homodimer of immunoglobulin lambda-chains. Addition of the purified dimeric lambda-type BJP to the normal plasma prolonged both APTT and dilute Russell's viper venom time (DRVVT) in a dose-dependent manner, and the negatively charged phospholipid-dependent prothrombinase activity was significantly inhibited in the presence of this protein. Furthermore, both the prolongation of DRVVT and the inhibition of the prothrombinase activity were almost completely abrogated under the condition of high ionic strength. These findings collectively suggest that the dimeric lambda-type BJP showed LA-like activity via the mechanism of ionic charge.

Bence Jones Protein↗
PubMed2000

The roles of carbohydrate chains of the beta-subunit on the functional expression of gastric H(+),K(+)-ATPase.

Gastric H(+),K(+)-ATPase consists of alpha and beta-subunits. The alpha-subunit is the catalytic subunit, and the beta-subunit is a glycoprotein stabilizing the alpha/beta complex in the membrane as a functional enzyme. There are seven putative N-glycosylation sites on the beta-subunit. In this study, we examined the roles of the carbohydrate chains of the beta-subunit by expressing the alpha-subunit together with the beta-subunit in which one, several, or all of the asparagine residues in the N-glycosylation sites were replaced by glutamine. Removing any one of seven carbohydrate chains from the beta-subunit retained the H(+),K(+)-ATPase activity. The effects of a series of progressive removals of carbohydrate chains on the H(+),K(+)-ATPase activity were cumulative, and removal of all carbohydrate chains resulted in the complete loss of H(+), K(+)-ATPase activity. Removal of any single carbohydrate chain did not affect the alpha/beta assembly; however, little alpha/beta assembly was observed after removal of all the carbohydrate chains from the beta-subunit. In contrast, removal of three carbohydrate chains inhibited the surface delivery of the beta-subunit and the alpha-subunit assembled with the beta-subunit, indicating that the surface delivery mechanism is more dependent on the carbohydrate chains than the expression of the H(+),K(+)-ATPase activity and alpha/beta assembly.

Animals↗
PubMed2000

New gamma-fluoromethotrexates modified in the pteridine ring: synthesis and in vitro immunosuppressive activity.

Our continuing program to develop new antifolate drugs useful against rheumatoid arthritis led us to modify the pteridine ring of gamma-fluoromethotrexate. Pyrrolopyrimidine derivatives 1e and 1t were found to exhibit potent suppressive effects on the responses of both T and B cells to mitogens, although tetrahydropyridopyrimidine derivatives 2e and 2t and quinazoline derivatives 3e, 3t and 4e showed very weak suppressive activities. Thus, conversion of the pteridine ring of gamma-fluoromethotrexate to a pyrrolopyrimidine ring led to a new potential antirheumatic compound.

Antirheumatic Agents↗
PubMed2000

High viral eradication with a daily 12-week natural interferon-beta treatment regimen in chronic hepatitis C patients with low viral load. IFN-beta Research Group.

Virological sustained response (SR) is achieved in 31-49% of patients with chronic hepatitis C with combination therapy using interferon (IFN)-alpha and ribavirin for 24-48 weeks. However, as a period of 24-48 weeks is a burden for patients, we investigated the effect of daily intravenous administration of natural IFN-beta for 12 weeks in this study. In all, 112 patients were enrolled and received a daily administration of 6 MU of natural IFN-beta intravenously for 12 weeks. Serum HCV-RNA before treatment was assessed by the competitive reverse-transcription polymerase chain reaction assay. The patients were divided into two groups according to pretreatment viral load: the low viral load group (N = 25, <6.3 x 10(5) copies/ml), and the high viral load group (N = 87, > or =6.3 x 10(5) copies/ml) who were additionally administered IFN-beta thrice weekly for subsequent 14 weeks at the patients' request. Virological SR was obtained in 37% (41/112) of all the patients; 88% of those with a low viral load, and 22% of patients with a high viral load. Virological SR was attained in 21% of patients with HCV subtype 1, and in 67% of those with subtype 2a. In patients with HCV subtype 1b, virological SR was obtained in patients with the mutant-type (> or =4 amino acid mutations in the NSSA2209-48) having a low viral load (4/4), but not in those having a high viral load (0/3). The results suggest that a daily intravenous administration of natural IFN-beta for 12 weeks showed high therapeutic efficacy in patients with a low viral load despite the shorter treatment period and that the therapeutic efficacy depends on viral load rather than on the number of NS5A2209-48 amino acid mutations.

Adolescent↗
PubMed2000

Different role of IL-4 in the onset of hapten-induced contact hypersensitivity in BALB/c and C57BL/6 mice.

1. To study the role of interleukin (IL)-4 in the onset of contact hypersensitivity (CH) in mice, the effect of IL-4 gene-depletion and anti-IL-4 monoclonal antibody treatment on dinitrofluorobenzene (DNFB)-induced CH was examined. Simultaneously, to clarify the effect of background gene, DNFB-induced CH in BALB/c and C57BL/6 mice was compared. 2. Five repeated topical applications of DNFB to the ears of mice resulted in CH of the ears in terms of increases in ear thickness and histopathological changes. The magnitude of ear thickness increase in BALB/c mice was almost three times greater than that in C57BL/6 mice. 3. The CH in BALB/c mice was significantly suppressed by IL-4 gene-depletion and anti-IL-4 monoclonal antibody treatment. In contrast, the symptoms of dermatitis in C57BL/6 mice were slightly affected by the same treatment. These changes corresponded well to the production of specific IgE antibody. 4. Total IgE antibody production and the expression of productive Cepsilon mRNA were dramatically suppressed by IL-4 gene-depletion and anti-IL-4 treatment in BALB/c and C57BL/6 mice. Neither total IgG nor IgM levels in either strain of mice was altered by depletion of IL-4. 5. The expression of IFN-gamma in the skin lesion was dramatically suppressed by IL-4 gene-depletion in BALB/c mice, but not in C57BL/6 mice. 6. These findings indicate that IL-4 plays an important role in the onset of DNFB-induced CH in BALB/c mice, but not in C57BL/6 mice.

Animals↗
PubMed2000

Allergen-induced airway inflammation and bronchial responsiveness in interleukin-5 receptor alpha chain-deficient mice.

OBJECTIVE: The role of IL-5 receptor alpha chain (IL-5Ralpha) in the onset of bronchial hyperresponsiveness (BHR) to acetylcholine was investigated by testing IL-5Ralpha knockout (IL-5Ralpha KO) mice. METHODS: Mice were immunized with antigen at intervals of 12 days. Starting 10 days after the secondary immunization, mice were exposed to antigen three times every fourth day. Twenty-four hours after the last antigen challenge, bronchial responsiveness to acetylcholine was measured and bronchoalveolar lavage was carried out. RESULTS: Twenty-four hours after the last antigen inhalation, total and differential cells counts of bronchoalveolar lavage revealed a significant increase in eosinophils and lymphocytes in ovalbumin-exposed wild-type mice. In IL-5Ralpha KO mice, there was little increase of eosinophils in bronchoalveolar lavage fluid (BALF). The production of IL-5 in BALF increased in both mice after repeated antigen challenge, and there was no significant difference between wild-type and IL-5Ralpha KO mice. Similar to the BAL study, histological sections of lung tissue from ovalbumin-exposed wild-type mice exhibited airway eosinophilic inflammation, which was attenuated by the deficiency of IL-5Ralpha chain. There was no significant difference in serum antigen-specific IgE levels between wild-type and IL-5Ralpha KO mice after immunization nor antigen inhalation. Repeated antigen provocation caused BHR to acetylcholine in wild-type mice. In contrast, no BHR was observed in IL-5Ralpha KO mice after repeated inhalation of antigen. CONCLUSION: These findings indicate that IL-5Ralpha plays an important role in the development of antigen-induced airway eosinophilia and BHR in mice.

Acetylcholine↗
PubMed2000

Nitric oxide induces a decrease in the mitochondrial membrane potential of peripheral blood lymphocytes, especially in natural killer cells.

Increased levels of nitric oxide (NO) at an inflammatory site may affect the biological activity of lymphoid cells. To investigate the effects of NO on the immune system, we measured the mitochondrial membrane potential (delta psi m) of the peripheral blood lymphocytes (PBL) cultured with a chemical NO donor. PBL from healthy volunteers were cultured with NOC18, a NO-generating compound, at various concentrations. The delta psi m of the PBL was measured by flow-cytometry using 3,3-dihexyloxacarbocyanine iodide (DiOC6(3)). NOC18 induced a decrease in the delta psi m of the PBL in a dose-dependent fashion, induced an increase in the levels of reactive oxygen species (ROS), and caused these cells to undergo apoptosis. Dual-color staining of the delta psi m and lymphocyte surface markers demonstrated that CD3-CD56+ natural killer (NK) cells were responsive to NO. Trolox, a vitamin E analog, partially reversed the NO-induced decrease in the delta psi m of the PBL. We showed that the delta psi m of peripheral NK cells were decreased by NO, which suggests that abundant NO at an inflammatory site may impair NK cell function.

Antioxidants↗
PubMed2000

Changes in cerebral hemoglobin concentration and oxygen saturation immediately after birth in the human neonate using full-spectrum near infrared spectroscopy.

Using full-spectrum near infrared spectroscopy (fsNIRS), we measured changes in oxy- and deoxyhemoglobin (HbO2 and Hb), total hemoglobin (T-Hb) concentration, and hemoglobin oxygen saturation (SbO2) in the brain tissue of seven neonates immediately following birth. It was found that HbO2 rose rapidly within 2-3 min after birth. During the same time, there was a transient increase in T-Hb concentration, after which it decreased together with Hb. SbO2 increased rapidly after birth, from 18% at 1.5 min to about 55% at 5-6 min, followed by a gradual increase of about 10%. Oxygenation in the brain occurred much sooner in three subjects given oxygen for a short time immediately after birth than in those who did not receive oxygen. This preliminary study indicated that dynamic changes occur in cerebral circulation and oxygenation as part of the physiological changes taking place soon after birth.

Brain↗
PubMed1999

Correlation of antiangiogenic and antitumor efficacy of N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrix metalloproteinase inhibitor.

The antiangiogenic activity and antitumor efficacy of a newly developed matrix metalloproteinase (MMP) inhibitor were examined. N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA) potently inhibits MMP-2, -9, and -14, but not MMP-1, -3, or -7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMPs tested. Daily oral administration of 200 mg/kg BPHA, but not (-)BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth, and liver metastasis. The growth inhibition activity of BPHA was 48% and 45% in a B16-BL6 melanoma and F2 hemangio-endothelioma model, respectively. BPHA also showed 42% inhibition of the liver metastasis of C-1H human colon carcinoma cells. These results indicate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential.

Animals↗
PubMed1999

Prevalence of microalbuminuria and relationship to the risk of cardiovascular disease in the Japanese population.

The prevalence of microalbuminuria and its relationship to cardiovascular disease risk factors were examined in subjects participating in an annual physical and laboratory examination program. The urinary albumin concentration and the urinary albumin/creatinine ratio were determined in morning urine specimens. A turbidimetric immunoassay was used for the measurement of urinary albumin. Of the 731 subjects, 41 (5.6%) who were weakly positive or positive on a routine dipstick test for protein were excluded from the final analysis of data. Microalbuminuria was present in 14.5% of the men, in 12.4% of the women, and in 13.2% of the entire subject population when defined as a urinary albumin concentration of 30-299 microgram/ml. The prevalence of microalbuminuria was significantly higher in subjects with a high normal blood pressure (15.0%) or hypertension (26.2%) as compared with normotensive subjects (6.5%). Subjects with impaired glucose tolerance (24.3%) or hyperglycemic subjects (50.0%) had a significantly higher prevalence of microalbuminuria than normoglycemic subjects (11.3%). The prevalence of microalbuminuria was significantly higher in subjects with left ventricular hypertrophy (47.1%) as compared with those with normal electrocardiograms (11.3%). A good correlation was observed between urinary albumin concentration and albumin/creatinine ratio, and both showed a significant positive correlation with age, systolic and diastolic blood pressures, and fasting plasma glucose, total serum protein, albumin, and triglyceride levels, but not with angiotensin-converting enzyme activity. Multiple regression analysis demonstrated that both the urinary albumin concentration and the albumin/creatinine ratio show a significant positive correlation with systolic blood pressure and fasting plasma glucose. The prevalence of microalbuminuria was about 13% in this Japanese cohort, and the systolic blood pressure and the fasting plasma glucose level were demonstrated as independent risk indicators for both urinary microalbumin level and urinary microalbumin/creatinine ratio.

Adult↗
PubMed1999

Magnetic resonance imaging of pseudotumors of the craniovertebral junction in long-term hemodialysis patients.

BACKGROUND/AIMS: Pseudotumors of the craniovertebral junction (PTCVJ) are observed in long-term hemodialysis (HD) patients. There are neither criteria for diagnosis nor guidelines for screening. We attempted to determine magnetic resonance imaging (MRI) findings that could be used to detect PTCVJ, to determine the prevalence of PTCVJ, and to evaluate whether destructive spondyloarthropathy (DSA) might be a yardstick for selection of patients for MRI examination for PTCVJ. METHODS: MRI were examined in 19 DSA patients (8 males, 11 females, age 61.4 +/- 7.3 years, HD duration 17.0 +/- 4.4 years) and in 20 sex-, age-, and HD-duration-matched non-DSA patients (9 males, 11 females, age 57.5 +/- 6.6 years, HD duration 17.7 +/- 4.9 years). We evaluated MRI characteristics of PTCVJ according those which occur due to rheumatoid arthritis. RESULTS: PTCVJ were characterized as follows: disappearance of fat pads in the upper region (supradental PTCVJ), intensity change of the 'predental triangle' in the anterior region (predental PTCVJ), and thickening of cruciform ligaments (retrodental PTCVJ). The prevalence of PTCVJ among patients undergoing HD more than 10 years was high (26 out of 39; 66.7%). The prevalence of PTCVJ was not different between DSA and non-DSA groups. CONCLUSION: We verified that the above MRI findings might be helpful in the detection of PTCVJ. These findings were observed frequently and independently also in patients with DSA.

Amyloidosis↗
PubMed1999

Effect of overproduction of interleukin 5 on dinitrofluorobenzene-induced allergic cutaneous response in mice.

The effect of overproduction of interleukin (IL) 5 on the allergic cutaneous response was investigated in transgenic mice overexpressing IL-5. Five repeated topical applications of 2, 4-dinitrofluorobenzene (DNFB) to the ears of mice resulted in allergic dermatitis on the ears as well as significant elevation in dinitrophenol-specific IgE antibody and total IgE in the serum in both wild-type and transgenic mice. The development of dermatitis as measured by skin thickness and histopathological changes were potentiated in the transgenic mice. In IL-5 transgenic mice, significant accumulation of eosinophils in skin lesions was observed after five paintings of DNFB, and the magnitudes of eosinophilia and IL-5 messenger RNA expression were significantly higher than in wild-type mice. The dinitrophenol-specific and total IgE in the serum were higher in IL-5 transgenic mice. The late phase reaction of IgE antibody-mediated biphasic cutaneous response was potentiated in IL-5 transgenic mice. The magnitudes of vasopermeability increase by passive cutaneous anaphylaxis, serotonin, and platelet-activating factor were similar in both mice. These results indicate that overproduction of IL-5 resulted in the potentiation of DNFB-induced dermatitis by elevation of IgE production, IgE-mediated allergic late-phase cutaneous reaction, and eosinophilia in the skin lesion.

Animals↗
PubMed1998

Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives.

Various N-sulfonylamino acid derivatives were synthesized and evaluated for their in vitro and in vivo activities to inhibit type IV collagenase (MMP-9 and MMP-2). When the amino acid residue and the sulfonamide moiety were modified, their inhibitory activities were greatly affected by the structure of the sulfonamide moiety. A series of aryl sulfonamide derivatives containing biaryl, tetrazole, amide, and triple bond were found to be potent and highly selective inhibitors of MMP-9 and MMP-2. In addition, these compounds were orally active in animal models of tumor growth and metastasis. These results revealed the potential of the N-sulfonylamino acid derivatives as a new type of candidate drug for the treatment of cancer.

Administration, Oral↗
PubMed1998

Cyclosporin A and FK-506 inhibit development of superantigen-potentiated collagen-induced arthritis in mice.

1. Staphylococcal enterotoxine B (SEB; superantigen) accelerated the onset of arthritis in mice preimmunized with type II collagen (SEB-potentiated collagen-induced arthritis). Cyclosporin A and FK-506 inhibited the induction and development of clinical signs and histopathological changes of SEB-potentiated collagen-induced arthritis in mice. 2. Simultaneously, both cyclosporin A and FK-506 inhibited the development of humoral and cellular immunity to type II collagen. 3. The expression of IL-2 receptor (CD25) by SEB on splenocyte T cells from collagen-preimmunized mice was inhibited by both agents in ex vivo experimentation.

Animals↗
PubMed1998

[Attributable factors to the emergence of multidrug-resistant Mycobacterium tuberculosis based on the observation of consecutive drug resistance test results].

Thirty six cases with multidrug-resistant tuberculosis were retrospectively studied to define the causes attributable to the emergence of multidrug-resistant M. tuberculosis. All these tuberculosis cases were microbiologically confirmed and resistant to at least isoniazid and rifampicin. Data analysis using matched-pair sampling methods (1:3) demonstrated that the followings are the significant risk factors for the emergence of multidrug-resistant tuberculosis; incompliance to treatment (Odds ratio 21.0: 95% CI 4.10-107.63), alcohol abuse (Odds ratio 15.0: 95% CI 2.34-96.1) and the history of previous treatment (Odds ratio 5.0: 95% CI 2.04-12.21), while diabetes mellitus is not statistically significant. The incompliance to treatment which is primarily thought to be patient's responsibility results in non-optimal administration of antituberculous agents, leading to the multidrug-resistant tuberculosis. Other factors that may have contributed to the emergence of resistance included the unnecessary change of regimen before completion of chemotherapy. This is patient-unrelated situation where responsibility lies in the medical side. A clinical case presented here is an example. In this case RFP was replaced with ethambutol 3-months after the initiation of regimen including SM, INH and RFP because of abnormal elevation of GOT and GPT without any supporting evidence that RFP was causative. The readministration of RFP after 1-year cessation did not induce liver dysfunction, while the drug resistance was observed not only to RFP but also to INH. This case suggests unnecessary interruption of RFP could lead to the emergence of resistance to INH as well as RFP. One known mechanism of drug resistance is random mutation and the selection by drugs administered during the course of chemotherapy. The cases with advanced cavitary lesions would have a higher probability of the occurrence of mutation. The more the number of mutant bacilli, the higher the probability of emergence of multidrug resistance. Those cases in which longer period of time is needed for the negative conversion of M. tuberculosis should be treated with potent chemotherapy regimens under the intense supervision. Since both INH and RFP are the most potent among currently available antituberculous agents. It is crucial to preserve the potency of these essential agents before novel antituberculous are developed.

Antitubercular Agents↗
PubMed1997

Synthesis and evaluation of novel fluorinated methotrexate derivatives for application to rheumatoid arthritis treatment.

An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure L-erythro- or L-threo-gamma-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3'-substituted phenyl or methylthiophene ring showed potent immunosuppressive activities, including in vitro inhibition of mitogen responses to both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong electronegativity of fluorine, which increases the acidity of the gamma-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.

Animals↗
PubMed1997

Immunoglobulin E production in mice by means of contact sensitization with a simple chemical, hapten.

Production of IgE caused by repeated topical application of 2,4-dinitrofluorobenzene (DNFB) to the ears of BALB/c mice was investigated. Ear thickness increased in proportion to the number of applications. Eczematous changes of the skin included marked infiltration of neutrophils, eosinophils, and monocytes and hypertrophy of the epidermis. Ear thickness due to inflammation reached a maximum 24 hours after the second, third, fourth, and fifth applications. The strong expression of interferon-gamma and IL-2 messenger RNA (mRNA) in the skin lesions indicated the participation of Th1 type helper T cells in the delayed-type hypersensitivity reaction. After the fifth application, the mice showed an immediate cutaneous reaction in addition to the delayed-type hypersensitivity reaction. The immediate reaction appeared within 1 hour of application. Hapten-specific IgE also was detected in serum from the mice, and the expression of germline and productive Cepsilon mRNA was detected in cervical lymph nodes, whereas productive Cepsilon mRNA was detected in the spleen. These results indicate that five topical applications of DNFB to the ear produce local eczematous dermatitis and increase serum hapten-specific IgE level in mice. Eczematous dermatitis is mainly caused by Th1 type T cells, and IgE production is mediated by Th2 type T cells in the cervical lymph nodes. In addition, IgE class switching occurs in the cervical nodes and IgE production occurs in both lymph nodes and spleen.

Animals↗