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Rantakari P.,University of Turku | Auvinen K.,University of Turku | Jappinen N.,University of Turku | Kapraali M.,University of Turku | And 12 more authors.
Nature Immunology | Year: 2015

In the lymphatic sinuses of draining lymph nodes, soluble lymph-borne antigens enter the reticular conduits in a size-selective manner and lymphocytes transmigrate to the parenchyma. The molecular mechanisms that control these processes are unknown. Here we unexpectedly found that PLVAP, a prototypic endothelial protein of blood vessels, was synthesized in the sinus-lining lymphatic endothelial cells covering the distal conduits. In PLVAP-deficient mice, both small antigens and large antigens entered the conduit system, and the transmigration of lymphocytes through the sinus floor was augmented. Mechanistically, the filtering function of the lymphatic sinus endothelium was dependent on diaphragms formed by PLVAP fibrils in transendothelial channels. Thus, in the lymphatic sinus, PLVAP forms a physical sieve that regulates the parenchymal entry of lymphocytes and soluble antigens. © 2015 Nature America, Inc. All rights reserved.


Niitsu N.,Saitama University | Okamoto M.,Fujita Health University Hospital | Nakamine H.,Kansai University of Health Sciences | Hirano M.,Fujita Health University Hospital
Cancer Science | Year: 2010

Among methotrexate (MTX)-related lymphoproliferative disorders (MTX-LPD), diffuse large B-cell lymphoma (DLBCL) accounts for about half. We studied the clinicopathological characteristics and prognosis of patients with DLBCL in MTX-LPD. This study included 29 patients who developed DLBCL after receiving MTX for rheumatoid arthritis. MTX was discontinued in all patients. Their median age was 62 years. Elevated lactate dehydrogenase (LDH) level was observed in 97% of the patients, bone marrow involvement in 17%, and involvement of extranodal sites in 41%. As for the cellular immunophenotype, CD20 was positive in 93%, CD5 in 3%, CD10 in 31%, BCL2 in 21%, BCL6 in 69%, and Epstein-Barr virus (EBV)-encoded small non-polyadenylated RNA (EBER) in 24%. Chemotherapy was started within 2 months after MTX withdrawal in 23 patients, of whom 12 patients received combination with rituximab. Spontaneous remission occurred in the remaining six patients. The EEBV-positive rate was 67% (4/6), and the four EBV-positive patients achieved complete response. Among the 23 DLBCL patients treated with chemotherapy, 20 patients achieved complete response. The 5-year overall survival was 74% and the 5-year progression-free survival was 65%. After the development of DLBCL, withdrawal of MTX was the first choice of treatment. Germinal center B-cell type and EBER-positive patients tended to show spontaneous remission. The utility of rituximab should be examined in future studies. © 2010 Japanese Cancer Association.


Tsuda K.,Kansai University of Health Sciences | Tsuda K.,Wakayama Medical University
International Journal of Hypertension | Year: 2012

Many Studies suggest that changes in sympathetic nerve activity in the central nervous system might have a crucial role in blood pressure control. The present paper discusses evidence in support of the concept that the brain renin-angiotensin system (RAS) might be linked to sympathetic nerve activity in hypertension. The amount of neurotransmitter release from sympathetic nerve endings can be regulated by presynaptic receptors located on nerve terminals. It has been proposed that alterations in sympathetic nervous activity in the central nervous system of hypertension might be partially due to abnormalities in presynaptic modulation of neurotransmitter release. Recent evidence indicates that all components of the RAS have been identified in the brain. It has been proposed that the brain RAS may actively participate in the modulation of neurotransmitter release and influence the central sympathetic outflow to the periphery. This paper summarizes the results of studies to evaluate the possible relationship between the brain RAS and sympathetic neurotransmitter release in the central nervous system of hypertension. © 2012 Kazushi Tsuda.


Tsuda K.,Kansai University of Health Sciences | Tsuda K.,Wakayama Medical University
Journal of Obesity | Year: 2011

This study was undertaken to investigate possible relationships among plasma adiponectin, 8-iso-prostaglandin F2α (8-iso-PG F2α: an index of oxidative stress), and membrane fluidity (a reciprocal value of microviscosity) in hypertensive and normotensive men using an electron spin resonance-method. The order parameter (S) for the spin-label agent (5-nitroxide stearate) in red blood cell (RBC) membranes was higher in hypertensive men than in normotensive men, indicating that membrane fluidity was decreased in hypertension. Plasma adiponectin and NO metabolites levels were lower in hypertensive men than in normotensive men. In contrast, plasma 8-iso-PG F2α levels were increased in hypertensive men compared with normotensive men. Plasma adiponectin concentration was correlated with plasma NO-metabolites, and inversely correlated with plasma 8-iso-PG F2α. The order parameter (S) of RBCs was inversely correlated with plasma adiponectin and plasma NO metabolite levels, and positively correlated with plasma 8-iso-PG F2α, suggesting that the reduced membrane fluidity of RBCs might be associated with hypoadiponectinemia, endothelial dysfunction, and increased oxidative stress. In a multivariate regression analysis, adiponectin and 8-iso-PG F2α were significant determinants of membrane fluidity of RBCs after adjustment for general risk factors. These results suggest that adiponectin and oxidative stress might have a close correlation with rheologic behavior and microcirculation in hypertension. © 2011 Kazushi Tsuda.


Tsuda K.,Kansai University of Health Sciences | Tsuda K.,Wakayama Medical University
International Journal of Hypertension | Year: 2012

Recent evidence indicates that high-sensitivity C-reactive protein (hs-CRP), an acute phase of an inflammatory marker, might be associated with atherosclerosis, hypertension, and other cardiovascular diseases. The present study was performed to assess the possible link between plasma hs-CRP and membrane fluidity (a reciprocal value of membrane microviscosity) in hypertensive elderly men. We measured the membrane fluidity of red blood cells (RBCs) in hypertensive and normotensive elderly men using an electron spin resonance and spin-labeling method. Membrane fluidity of RBCs was decreased in hypertensive elderly men compared with normotensive elderly men. Plasma hs-CRP levels were significantly higher in hypertensive elderly men than in normotensive elderly men. In contrast, plasma nitric-oxide- (NO-) metabolite levels were lower in hypertensive elderly men than in normotensive elderly men. The reduced membrane fluidity of RBCs was associated with increased plasma hs-CRP and decreased plasma NO-metabolite levels. In a multivariate regression analysis, plasma hs-CRP was an independent determinant of membrane fluidity of RBCs after adjustment for general risk factors. The results suggest that CRP might have a close correlation with the rheologic behavior of RBCs and the microcirculation and would contribute, at least in part, to the circulatory dysfunction and vascular complications in hypertensive elderly men. © 2012 Kazushi Tsuda.


Tsuda K.,Kansai University of Health Sciences | Tsuda K.,Wakayama Medical University
International Heart Journal | Year: 2013

Current evidence indicates that abnormalities in physical properties of the cell membranes may be strongly linked to hypertension and other circulatory disorders. Recent studies have shown that chronic kidney disease (CKD) might be a risk factor for cardiovascular and cerebrovascular outcomes. The purpose of the present study was to examine the possible relationship between kidney function and membrane fluidity (a reciprocal value of membrane microviscosity) of red blood cells (RBCs) in hypertensive and normotensive subjects using an electron spin resonance (ESR) and spin-labeling method. The order parameter (S) for the ESR spin-label agent (5-nitroxide stearate) in RBC membranes was significantly higher in hypertensive subjects than in normotensive subjects, indicating that membrane fluidity was decreased in hypertension. The order parameter (S) of RBCs was inversely correlated with estimated glomerular filtration rate (eGFR), suggesting that a decreased eGFR value might be associated with reduced membrane fluidity of RBCs. Multi-variate regression analysis also demonstrated that, after adjustment for general risk factors, eGFR might be a significant predictor of membrane fluidity of RBCs. The reduced levels of both membrane fluidity of RBCs and eGFR were associated with increased plasma 8-iso-prostaglandin F2α (an index of oxidative stress) and decreased plasma nitric oxide (NO)-metabolites, suggesting that kidney function could be a determinant of membrane microviscosity of RBCs, at least in part, via oxidative stress- and NO-dependent mechanisms. The ESR study suggests that CKD might have a close correlation with impaired rheologic behavior of RBCs and microcirculatory disorders in hypertensive subjects.


Tsuda K.,Kansai University of Health Sciences | Tsuda K.,Wakayama Medical University
International Heart Journal | Year: 2010

Recent evidence indicates that oxidative stress might actively participate in the pathophysiology of hypertension, atherosclerosis, and other cardiovascular diseases. The purpose of the present study was to assess the possible link between oxidative stress and membrane fluidity in hypertensive and normotensive men. We measured the membrane fluidity (a reciprocal value of membrane microviscosity) of red blood cells (RBCs) in hypertensive and normotensive men using an electron spin resonance (ESR) and spin-labeling method. Membrane fluidity of RBCs was decreased in hypertensive men compared with normotensive men. The levels of plasma 8-Iso-prostaglandin F2α (8-Iso-PG F2α: an index of oxidative stress) were significantly higher in hypertensive men than in normotensive men. In contrast, plasma nitric oxide (NO)-metabolite levels were significantly lower in hypertensive men than in normotensive men. In the overall analysis of hypertensive and normotensive men, plasma 8-Iso-PG F2α levels were inversely correlated with plasma NO-metabolites. Furthermore, the reduced membrane fluidity of RBCs was associated with increased plasma 8-Iso-PG F2α and decreased plasma NO-metabolite levels. In a multivariate regression analysis, plasma 8-Iso-PG F2α was found to be an independent determinant of membrane fluidity of RBCs. The results of the present study suggest that oxidative stress might have a close correlation with the rheologic behavior of RBCs and the microcirculation in hypertensive men.


Sakurai Y.,Matsubara Tokushukai Hospital | Takeda T.,Kansai University of Health Sciences
Journal of Immunology Research | Year: 2014

Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed. © 2014 Yoshihiko Sakurai and Tomohiro Takeda.


Toda S.,Kansai University of Health Sciences
Evidence-based Complementary and Alternative Medicine | Year: 2011

Electroacupuncture (EA) and manual acupuncture (MA) have therapeutic effects on muscle fatigue in muscle disease. The deficiencies of carnitine and glutathione induce muscle fatigue. This report investigated the effects of EA and MA on carnitine and glutathione in muscle. After the mice of EA group were fixed in the animal cage, right Zusanli (ST36) and Jiexi (ST41) were acupunctured and stimulated with uniform reinforcing and reducing method by twirling the acupuncture needle for 15 min. And then, the needle handles were connected to an electric stimulator for stimulating the acupoint with dense-sparse waves. After the mice of MA group were fixed in an animal cage, right ST36 and ST41 were acupunctured and allowed for 15 min. The mice of normal control group were not acupunctured and stimulated for 15 min. The mice of all groups were killed for collecting muscle tissue 1 h after the final treatment. Carnitine and glutathione in homogenate of muscle tissue were determined with carnitine (Kainos Laboratories Co., Tokyo, Japan) and glutathione assay kit (Dojin Chemicals Co., Kumamoto, Japan). Carnitine level in muscle tissue of MA group was significantly higher than those of EA group and normal control group. Carnitine level in muscle tissue of EA group was not significantly different from that of normal control group. Glutathione levels in muscle tissue of EA group and MA group were significantly higher than that of normal control group. This report presented that carnitine in muscle is increased by MA, and not increased by EA, and that glutathione in muscle is increased by EA and MA. Copyright © 2011 Shizuo Toda.


Kondo T.,Kansai University of Health Sciences | Kawamoto M.,Kansai University of Health Sciences
BioPsychoSocial Medicine | Year: 2014

Acupuncture and moxibustion, which medical doctors are licensed by the government of Japan to perform, can improve the psychological relationship between doctors and patients, especially when it is disturbed by a " game" , a dysfunctional interpersonal interaction that is repeated unintentionally. This advantage is due to the essential properties of acupuncture and moxibustion. Acupuncture and moxibustion are helpful in treating somatoform disorders, especially musculoskeletal symptoms. In Japan, a holistic acupuncture and moxibustion therapy called Sawada-style has been developed. This is based on fundamental meridian points that are considered to have effects on central, autonomic nervous, immune, metabolic, and endocrine systems to regulate the whole body balance. In addition, some of the fundamental points have effects on Qi, blood, and water patterns associated with major depression, generalized anxiety disorder, eating disorders, and somatoform disorders. The fixed protocol of Sawada-style would be suitable for large-scale, randomized, controlled studies in the future. Recent systematic reviews indicate that electroacupuncture would be a useful addition to antidepressant therapy for some symptoms accompanying fibromyalgia. Acupuncture and moxibustion are also recommended for irritable bowel syndrome, instead of Western drug therapy. Surprisingly, the dorsal prefrontal cerebral cortex, which is associated with a method of scalp acupuncture applied for gastrointestinal disorders, has been found to be activated in patients with irritable bowel syndrome. It is quite possible that regulation of this cortical area is related to the effect of scalp acupuncture. This acupuncture method can be effective not only for irritable bowel syndrome but also for other stress-related gastrointestinal disorders. © 2014 Kondo and Kawamoto; licensee BioMed Central Ltd.

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