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Biomedical subjects

Minoru Hasegawa

Publications and source records attributed to Minoru Hasegawa.

At least 55 records · Page 3Linked to original sources
PubMed2004

Mouse CD20 expression and function.

CD20 plays a role in human B cell proliferation and is an effective target for immunotherapy. In this study, mouse CD20 expression and biochemistry were assessed for the first time using a new panel of CD20-specific mAb, with CD20 function assessed using CD20-deficient (CD20(-/-)) mice. CD20 expression was B cell restricted and was initiated during late pre-B cell development. The frequency and density of CD20 expression increased during B cell maturation in the bone marrow, with a subpopulation of transitional IgM(hi) B cells expressing higher CD20 levels than the majority of mature recirculating B cells. Transitional T1 B cells in the spleen also expressed high CD20 levels, providing a useful new marker for this B cell subset. In CD20(-/-) mice, immature and mature B cell IgM expression was approximately 20-30% lower relative to B cells from wild-type littermates. In addition, CD19-induced intracellular calcium responses were significantly reduced in CD20(-/-) B cells, with a less dramatic effect on IgM-induced responses. These results reveal a role for CD20 in transmembrane Ca(2+) movement in mouse primary B cells that complements previous results obtained using human CD20 cDNA-transfected cell lines. Otherwise, B cell development, tissue localization, signal transduction, proliferation, T cell-dependent antibody responses and affinity maturation were normal in CD20(-/-) mice. Thus, mouse and human CD20 share similar patterns of expression and function. These studies thereby provide an animal model for studying CD20 function in vivo and the molecular mechanisms that influence anti-CD20 immunotherapy.

Animals↗
PubMed2004

Novel autoantibody to Cu/Zn superoxide dismutase in patients with localized scleroderma.

Abnormal production of reactive oxygen species (ROS) induces tissue damage and superoxide dismutase (SOD) that converts superoxide radicals to hydrogen peroxide functions as defense against ROS. Cu/Zn SOD administration has been shown to be effective for various fibrotic conditions by inhibiting the fibrogenic effects of ROS. We hypothesized that autoimmune background in localized scleroderma induced anti-Cu/Zn SOD autoantibodies that inhibited SOD activity and thereby contributed to fibrosis by increasing ROS. ELISA using human purified Cu/Zn SOD revealed that IgG or IgM anti-Cu/Zn SOD Ab was detected in the serum of 89% of localized scleroderma patients, especially 100% of patients with generalized morphea, the severest form of localized scleroderma, but was positive only in the serum of less than 15% of patients with other autoimmune disorders, including systemic sclerosis, systemic lupus erythematosus, dermatomyositis, and autoimmune bullous disorders. The immunoblotting analysis confirmed the presence of IgG anti-Cu/Zn SOD Ab in sera from localized scleroderma patients. Remarkably, anti-Cu/Zn SOD autoantibody could inhibit Cu/Zn SOD enzymatic activity. Collectively, these results indicate that anti-Cu/Zn SOD Ab is a novel, major autoantibody in localized scleroderma, and also suggest that the autoantibody may play a role in the development of fibrosis by directly inhibiting SOD activity.

Adult↗
PubMed2004

High potassium treatment resets the circadian oscillator in Xenopus retinal photoreceptors.

In vertebrate retina, light hyperpolarizes the photoreceptor membrane, and this is an essential cellular signal for vision. Cellular signals responsible for photic entrainment of some circadian oscillators appear to be distinct from those for vision, but it is not known whether changes in photoreceptor membrane potential play roles in photic entrainment of the photoreceptor circadian oscillator. The authors show that a depolarizing exposure to high potassium resets the circadian oscillator in cultured Xenopus retinal photoreceptor layers. A 4-h pulse of high [K(+)] (34 mM higher than in normal culture medium) caused phase shifts of the melatonin rhythm. This treatment caused phase delays during the early subjective day and phase advances during the late subjective day. In addition to the phase-shifting effect, high potassium pulses stimulated melatonin release acutely at all times. High [K(+)] therefore mimicked dark in its effects on oscillator phase and melatonin synthesis. These results suggest that membrane potential may play a role in photic entrainment of the photoreceptor circadian oscillator and in regulation of melatonin release.

Animals↗
PubMed2004

Elevated circulating CD40L concentrations in patients with systemic sclerosis.

OBJECTIVE: B cell activation, fibrosis, and expression of adhesion molecules on endothelial cells are regulated by soluble CD40L (sCD40L)/CD40 interactions. Since these effects are characteristic in patients with systemic sclerosis (SSc), serum concentrations of sCD40L were determined in patients with SSc. METHODS: Fifty-two Japanese patients with SSc were examined. They were grouped into 24 patients with limited cutaneous SSc (lSSc) and 28 with diffuse cutaneous SSc (dSSc). Serum sCD40L levels were examined by ELISA. As a disease control, serum samples from 20 patients with systemic lupus erythematosus (SLE) were also examined. In addition, a retrospective longitudinal study was performed in 71 serum samples from 18 patients with SSc. RESULTS: Serum sCD40L levels were elevated in SSc patients compared with healthy controls (p < 0.001). Levels of sCD40L in patients with SSc were higher than in patients with SLE (p < 0.001) that had elevated sCD40L levels compared with healthy controls. Among SSc subsets, there were no differences in sCD40L levels between lSSc and dSSc. sCD40L levels correlated positively with C-reactive protein levels in SSc patients (p < 0.0001, r = 0.449). In a cross-sectional study and a longitudinal study, serum sCD40L levels in dSSc patients were persistently elevated, although those in lSSc patients were temporarily elevated at the early phase of the disease process. CONCLUSION: Patients with SSc exhibited elevated sCD40L levels that may correlate with disease activity. These results suggest that CD40/CD40L interactions may be potential therapeutic targets in SSc.

Adolescent↗
PubMed2004

Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis.

OBJECTIVE: To clarify the clinical significance of surfactant protein-D (SP-D) and KL-6 in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc), and to evaluate the differences between SP-D and KL-6. METHODS: Serum SP-D and KL-6 concentrations were determined by ELISA in 42 SSc patients. In a retrospective longitudinal study, 83 serum samples from 6 SSc patients were analyzed during a followup period of 0.6-6.3 years. RESULTS: SP-D and KL-6 concentrations at the first visit were higher in patients with SSc, especially those with PF, compared with healthy controls. Increased concentrations of SP-D were associated with decreased DLCO and decreased vital capacity in SSc patients more strongly than those of KL-6. The sensitivity and specificity for PF were 91% and 88% for SP-D and 39% and 100% for KL-6, respectively. In the longitudinal study, both SP-D and KL-6 concentrations were associated with activity of PF in patients with SSc. SP-D concentrations changed more rapidly than KL-6 concentrations, in parallel with the PF activity. CONCLUSION: SP-D was a more sensitive marker for PF than KL-6. By contrast, KL-6 showed higher specificity than SP-D. Combined use of these 2 serum markers would be more helpful to diagnose and monitor the PF activity in patients with SSc than single use of each marker.

Adult↗
PubMed2003

Ultraviolet light exposure suppresses contact hypersensitivity by abrogating endothelial intercellular adhesion molecule-1 up-regulation at the elicitation site.

Hapten sensitization through UV-exposed skin induces systemic immune suppression, which is experimentally demonstrated by inhibition of contact hypersensitivity (CHS). Although this UV-induced effect has been shown to be mediated by inhibition of the afferent phase of the CHS, the UV effects on the efferent (elicitation) phase remain unknown. In this study, UV effects on endothelial ICAM-1 expression at elicitation sites were first examined. Mice were sensitized by hapten application onto UV-exposed back skin, and ears were challenged 5 days later. ICAM-1 up-regulation at nonirradiated elicitation sites following hapten challenge was eliminated by UV exposure on sensitization sites distant from elicitation sites. To assess whether loss of the ICAM-1 up-regulation at elicitation sites contributed to UV-induced immunosuppression, we examined CHS responses in UV-exposed ICAM-1-deficient (ICAM-1(-/-)) mice that genetically lacked the ICAM-1 up-regulation. ICAM-1(-/-) mice exhibited reduced CHS responses without UV exposure, but UV exposure did not further reduce CHS responses in ICAM-1(-/-) mice. Furthermore, ICAM-1 deficiency did not affect the afferent limb, because ICAM-1(-/-) mice had normal generation of hapten-specific suppressor and effector T cells. This UV-induced immunosuppression was associated with a lack of TNF-alpha production after Ag challenge at elicitation sites. Local TNF-alpha injection before elicitation abrogated the UV-induced CHS inhibition with increased endothelial ICAM-1 expression. TNF-alpha production at elicitation sites was down-regulated by IL-10, a possible mediator produced by hapten-specific suppressor T cells that are generated by UV exposure. These results indicate that UV exposure inhibits CHS by abrogating up-regulation of endothelial ICAM-1 expression after Ag challenge at elicitation sites.

Animals↗
PubMed2003

L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity.

Repeated Ag exposure results in a shift in the time course of contact hypersensitivity (CH) from a typical delayed-type to an immediate-type response followed by a late phase reaction. Chronic CH responses are clinically relevant to human skin allergic diseases, such as atopic dermatitis, that are usually caused by repeated stimulation with environmental Ags. Chronic inflammatory responses result in part from infiltrating leukocytes. To determine the role of leukocyte adhesion molecules in chronic inflammation, chronic CH responses were assessed in mice lacking L-selectin, ICAM-1, or both adhesion molecules. Following repeated hapten sensitization for 24 days at 2-day intervals, wild-type littermates developed an immediate-type response at 30 min after elicitation, followed by a late phase reaction. By contrast, loss of ICAM-1, L-selectin, or both, eliminated the immediate-type response and inhibited the late phase reaction. Similar results were obtained when wild-type littermates repeatedly exposed to hapten for 22 days were treated with mAbs to L-selectin and/or ICAM-1 before the elicitation on day 24. The lack of an immediate-type response on day 24 paralleled a lack of mast cell accumulation after 30 min of elicitation and decreased serum IgE production. Repeated Ag exposure in wild-type littermates resulted in increased levels of serum L-selectin, a finding also observed in atopic dermatitis patients. The current study demonstrates that L-selectin and ICAM-1 cooperatively regulate the induction of the immediate-type response by mediating mast cell accumulation into inflammatory sites and suggests that L-selectin and ICAM-1 are potential therapeutic targets for regulating human allergic reactions.

Administration, Cutaneous↗
PubMed2003

Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis.

Systemic sclerosis is characterized by fibrosis and systemic autoimmunity; however, roles of autoantibodies in the development of fibrosis remain unknown in systemic sclerosis. The net accumulation of extracellular matrix is dependent on the balance between the synthesis and degradation of extracellular matrix components, the latter process regulated by matrix metalloproteinases. Matrix metalloproteinase-1 (interstitial collagenase-1) can initiate degradation of collagen types I-III that are major extracellular matrix constituents in affected skin of systemic sclerosis. In this study, we tested the hypothesis that systemic autoimmunity in systemic sclerosis induced anti-matrix metalloproteinase-1 autoantibodies that inhibited matrix metallo-proteinase-1 activity, resulting in collagen accumulation. Enzyme-linked immunosorbent assay using human recombinant matrix metalloproteinase-1 revealed that IgG anti-matrix metalloproteinase-1 autoantibody levels were significantly elevated in sera from patients with systemic sclerosis, but not patients with active systemic lupus erythematosus or dermatomyositis, relative to normal controls. IgG anti-matrix metalloproteinase-1 autoantibody levels were significantly higher in patients with diffuse cutaneous systemic sclerosis than those found in patients with limited cutaneous systemic sclerosis. Furthermore, IgG anti-matrix metalloproteinase-1 antibody levels significantly correlated with the extent of fibrosis in the skin, lung, and renal blood vessels. The presence of IgG anti-matrix metalloproteinase-1 autoantibody in sera from systemic sclerosis patients was confirmed by immunoblotting analysis. Remarkably, IgG anti-matrix metalloproteinase-1 autoantibody in sera from systemic sclerosis patients inhibited matrix metalloproteinase-1 collagenase activity. Collectively, the results of this study suggest that anti-matrix metalloproteinase-1 autoantibody contributes to the development of fibrosis by inhibiting matrix metalloproteinase-1 collagenase activity and reducing the extracellular matrix turnover and suggest that the presence of anti-matrix metalloproteinase-1 autoantibody in systemic sclerosis is the link between systemic autoimmunity and fibrosis.

Adult↗
PubMed2003

Serum levels of tumor necrosis factor and interleukin-13 are elevated in patients with localized scleroderma.

BACKGROUND: The enhanced production of some cytokines may be related to the pathogenesis of localized scleroderma (LSc). OBJECTIVE: To determine whether serum levels of tumor necrosis factor (TNF) and interleukin (IL)-13 are elevated, and whether they correlated with clinical or serological features in patients with LSc. METHODS: Serum levels of TNF and IL-13 were examined by ELISA in 45 patients with LSc and in 20 healthy controls. RESULTS: The frequency of serum TNF detection was significantly higher in patients with LSc (24%) compared with that in healthy controls (0%). The frequency of serum IL-13 detection was also significantly higher in patients with LSc (29%) compared with that in controls (0%). In patients with LSc, elevated TNF levels significantly correlated with the presence of IgM antihistone antibodies, anti-single-stranded DNA antibodies, elevated serum IL-6 levels, the number of linear lesions, and muscle involvement. Elevated IL-13 levels were significantly associated with the number of plaque lesions and the total number of lesions. CONCLUSIONS: These results suggest that TNF and IL-13 may be associated with the development of LSc.

Adolescent↗
PubMed2003

CT findings and progression of small peripheral lung neoplasms having a replacement growth pattern.

OBJECTIVE: We investigated the imaging findings and progression of replacement lung neoplasms that were revealed on thin-section CT and serial CT. MATERIALS AND METHODS: We evaluated the age of patients and thin-section CT findings (lesion size; percentage of ground-glass opacity areas; and presence or absence of solid portions, lobulation, coarse spiculation, air bronchogram, cavity, multiplicity, and pleural tags) in 73 lesions (11 atypical adenomatous hyperplasias, 17 type A [Noguchi's classification], 18 type B, and 27 type C small peripheral adenocarcinomas). We compared the serial findings of 48 of 73 lesions on low-dose screening CT (n = 21) or thin-section CT (n = 27) obtained at a mean interval of 450 days (range, 85-951 days). Progression from atypical adenomatous hyperplasia through type A to type B and then to type C tumor was studied using trend tests. RESULTS: A significant linear trend was seen for lesion size (r = 0.55; p < 0.001), percentages of ground-glass opacity areas (r = 0.75; p < 0.001), and the prevalence of lobulation (p < 0.001), spiculation (p = 0.001), air bronchogram (p = 0.023), cavity (p = 0.046), pleural tag (p < 0.001), and solid portions (p < 0.001). In general from serial CT assessment, lesions were recognized first as a ground-glass opacity nodule (56% of 48 lesions) with subsequent increase in size (75%), then solid portions appeared in the nodule (17%), and finally solid portions increased (23%) with occasional augmentation of tissue contraction (6%). CONCLUSIONS: CT analysis revealed stepwise progression of replacement-type lung neoplasms.

Adenocarcinoma↗
PubMed2003

Small solitary pulmonary nodules (< or =1 cm) detected at population-based CT screening for lung cancer: Reliable high-resolution CT features of benign lesions.

OBJECTIVE: We assessed thin-section CT features specific to benignity in solitary pulmonary nodules of 1 cm or smaller that were detected at population-based CT screening for lung cancer. MATERIALS AND METHODS: Two reviewers independently made qualitative (presence or absence of lobulation, spiculation, air bronchogram, cavity, satellite lesions, pleural tag, concave margins, polygonal shape, and peripheral subpleural lesion) and quantitative (lesion size, percentage of ground-glass opacity areas, and two- and three-dimensional ratios of lesion) assessments in CT images of 72 nodules (25 lung cancers, seven atypical adenomatous hyperplasias, and 40 benign lesions). Optimal criteria specific to benignity were studied. RESULTS: The prevalence of polygonal shape (p = 0.005 and p = 0.019, reviewer 1 and reviewer 2), peripheral subpleural lesion (p = 0.011 and p = 0.033), a predominantly solid lesion (p < 0.001 and p < 0.001), and three-dimensional ratios (p < 0.001 and p < 0.001) were greater in benign lesions than in malignancies. The prevalence of a predominantly solid lesion (p < 0.001 and p < 0.001) was greater in benign lesions than in atypical adenomatous hyperplasias, and the prevalence of a peripheral subpleural lesion (p = 0.004 and p = 0.012) was greater in atypical adenomatous hyperplasias than in malignancies. Using a single CT feature, polygonal shape and a three-dimensional ratio of greater than 1.78 showed 100% specificity for both reviewers. Among all combinations of CT findings specific to benignity, a combined criterion of a predominantly solid lesion and peripheral subpleural lesion or polygonal shape or the three-dimensional ratio attained the highest sensitivity (63% and 60%) for both reviewers. CONCLUSION: A combined criterion of CT features was optimal for predicting benign pulmonary lesions.

Adenocarcinoma↗
PubMed2003

Indeterminate solitary pulmonary nodules revealed at population-based CT screening of the lung: using first follow-up diagnostic CT to differentiate benign and malignant lesions.

OBJECTIVE: We studied the role of the first follow-up diagnostic CT for differentiating benign and malignant lesions in indeterminate solitary pulmonary nodules revealed at CT screening for lung cancer in which a total of 13,786 CT examinations (46% in women and 54% in men; 46% were smokers; mean age, 62 years) were performed. MATERIALS AND METHODS: We reviewed thin-section CT findings on the initial diagnostic CT (lesion size; percentages of ground-glass-opacity areas of lesion; and presence or absence of lobulation, spiculation, air bronchogram, cavity, satellite lesions, pleural tag, concave margins, polygonal shape, and peripheral subpleural lesion) in 80 pulmonary nodules (36 malignancies and 44 benign lesions) of 80 patients. We evaluated changes in size (regression, no change, or growth) on the first follow-up CT performed 42-120 days (mean, 93 days) after the initial CT. RESULTS: The greatest accuracy (81%) with 89% sensitivity and 75% specificity for determining malignancy was attained with a combined criterion of growth of lesions or predominantly ground-glass-opacity lesions. Of all criteria that were specific to malignancy, the greatest sensitivity (50%) was achieved with a combination of growth or no change in size of lesions and predominantly ground-glass opacity and no concave margins. Of all criteria that were specific to benign lesions, the greatest sensitivity (45%) was attained with a combination of lesion regression or polygonal shape. CONCLUSION: Follow-up CT findings were useful, and a combination of findings on initial CT and follow-up CT was optimal for differentiating benign and malignant pulmonary nodules.

Adult↗
PubMed2003

[Imaging of gastrointestinal stromal tumor (GIST): relation between CT findings and grade of malignancy].

PURPOSE: To report the relation between CT findings and the grade of malignancy in gastrointestinal stromal tumor (GIST), especially the uncommitted type of GIST. MATERIALS AND METHODS: A total of 14 patients with histologically proven GIST (uncommitted type) underwent CT. Tumors were divided into three grades. HISTOLOGICALLY: Benign (mitotic index [MI] < 2/10 high-power fields [HPF]), borderline (2/10 HPF < or = MI < or = 5/10 HPF), and malignant (5/10 HPF < MI). We evaluated tumor size, cystic component, margin, and early enhancement. RESULTS: All benign tumors were smaller than 5 cm, and most malignant tumors reached 5 cm. The size of borderline tumors was between the sizes of benign and malignant tumors. No benign tumors had cystic components, whereas all borderline and malignant tumors except for one case had cystic components. Only two huge malignant tumors had unclear margins. The relation between early enhancement and the grade of malignancy showed no tendency, but all duodenal tumors showed marked early enhancement irrespective of grade. CONCLUSION: The grade of malignancy of GIST (uncommitted type) and size, presence of cystic components, and margin were highly correlated. That is, 1) tumors smaller than 5 cm with no cystic components can be diagnosed as benign, whereas 2) tumors that have cystic components are borderline or malignant. 3) Tumors that have cystic components and unclear margin can be diagnosed as actively malignant.

Aged↗
PubMed2003

Serum concentrations of the CXC chemokines interleukin 8 and growth-regulated oncogene-alpha are elevated in patients with systemic sclerosis.

OBJECTIVE: To determine whether serum concentrations of 2 CXC chemokines, interleukin 8 (IL-8) and growth-regulated oncogene-alpha (GRO-alpha), which are potent chemoattractants and activators for neutrophils, are elevated and whether they correlate with clinical features in patients with systemic sclerosis (SSc). METHODS: Serum samples from patients with diffuse cutaneous SSc (dSSc; n = 36), limited cutaneous SSc (lSSc; n = 42), systemic lupus erythematosus (SLE; n = 15), dermatomyositis (DM; n = 15), and healthy controls (n = 35) were examined by ELISA. RESULTS: Serum IL-8 was detected significantly more frequently in patients with dSSc (61%) and lSSc (55%) relative to healthy controls (6%), patients with SLE (7%), and those with DM (13%). Similarly, serum GRO-alpha concentrations in SSc patients were significantly increased compared with controls, patients with SLE, or those with DM. Elevated IL-8 concentrations significantly correlated with decreased % DLCO and rheumatoid factor positivity, while increased GRO-alpha levels were significantly associated with decreased % DLCO and % vital capacity, involvement of kidney and muscle, the presence of anti-topoisomerase I antibody, and increased serum IgG levels. CONCLUSION: Our results suggest that the elevation of serum levels of the CXC chemokines IL-8 and GRO-alpha is specific to SSc and that the elevation of CXC chemokines, particularly GRO-alpha, correlates with the involvement of internal organs, especially pulmonary damage.

Adolescent↗
PubMed2003

[Acquired inhibitor against coagulation factor V with severe hematuria].

A 42-year-old man was admitted with hematuria after a common cold. No purpura could be observed but there was oozing on the site of the forearm where blood had been taken in a previous hospital. Platelet count was 292 x 10(3)/microliter, examination of coagulation system showed abnormalities; prolonged prothrombin time: PT (99.7 sec) and activated partial thromboplastin time: APTT (more than 200 sec), which suggested deficiency of coagulation factor II (FII), factor V (FV) or factor X (FX). In fact, the FV activity was only 2% of the pooled normal plasma. Mixing test of patient's plasma with normal pooled plasma revealed the existence of an FV inhibitor (FVI), which was IgA with an activity levels of 3 Bethesda unit/ml. Although hematuria stopped soon after beginning treatment with steroids (PSL), the abnormalities in PT and APTT improved very slowly and incompletely. At the time of writing, FVI is still observed ten months after onset. The patient had no underlying disease, and in this case FVI appeared following a common cold. Previous reports have said that FVI can cause mild bleeding, and it disappear in a short time. This case showed the possibility of the hidden presence of FVI in patients with hematuria.

Adult↗