In JoVE (1)

Other Publications (66)

Articles by Hideki Nakano in JoVE

Other articles by Hideki Nakano on PubMed

Balanced Responsiveness to Chemoattractants from Adjacent Zones Determines B-cell Position

Nature. Mar, 2002  |  Pubmed ID: 11882900

B lymphocytes re-circulate between B-cell-rich compartments (follicles or B zones) in secondary lymphoid organs, surveying for antigen. After antigen binding, B cells move to the boundary of B and T zones to interact with T-helper cells. Despite the importance of B--T-cell interactions for the induction of antibody responses, the mechanism causing B-cell movement to the T zone has not been defined. Here we show that antigen-engaged B cells have increased expression of CCR7, the receptor for the T-zone chemokines CCL19 and CCL21, and that they exhibit increased responsiveness to both chemoattractants. In mice lacking lymphoid CCL19 and CCL21 chemokines, or with B cells that lack CCR7, antigen engagement fails to cause movement to the T zone. Using retroviral-mediated gene transfer we demonstrate that increased expression of CCR7 is sufficient to direct B cells to the T zone. Reciprocally, overexpression of CXCR5, the receptor for the B-zone chemokine CXCL13, is sufficient to overcome antigen-induced B-cell movement to the T zone. These findings define the mechanism of B-cell relocalization in response to antigen, and establish that cell position in vivo can be determined by the balance of responsiveness to chemoattractants made in separate but adjacent zones.

Antiviral Immune Responses in the Absence of Organized Lymphoid T Cell Zones in Plt/plt Mice

Journal of Immunology (Baltimore, Md. : 1950). Jun, 2002  |  Pubmed ID: 12055211

The paucity of lymph node (LN) T cells (plt) mutation in mice results in strongly reduced T cell numbers in LNs and homing defects of both dendritic cells (DCs) and naive T cells. In this study, we investigated the functional significance of the plt phenotype for the generation of antiviral immune responses against cytopathic and noncytopathic viruses. We found that DC-CD8(+) T cell contacts and the initial priming of virus-specific T cells in plt/plt mice occurred mainly in the marginal zone of the spleen and in the superficial cortex of LNs. The magnitude of the initial response and the maintenance of protective memory responses in plt/plt mice was only slightly reduced compared with plt/+ controls. Furthermore, plt/plt mice mounted rapid neutralizing antiviral B cell responses and displayed normal Ig class switch. Our data indicate that the defective homing of DCs and naive T cells resulting from the plt/plt mutation results in a small, but not significant, effect on the induction of protective antiviral T and B cell immunity. Overall, we conclude that the spatial organization of secondary lymphoid T cell zones via the CCR7-CC chemokine ligand 19/CC chemokine ligand 21 pathway is not an absolute requirement for the initial priming and the maintenance of protective antiviral T and B cell responses.

Irradiation Up-regulates CD80 Expression Through Induction of Tumour Necrosis Factor-alpha and CD40 Ligand Expression on B Lymphoma Cells

Immunology. Jul, 2002  |  Pubmed ID: 12100723

Previously, we reported that 100 Gy X-ray irradiation followed by 24 hr incubation up-regulates CD80 expression in murine B lymphoma cells, A20-2J. In the present study, we analysed the underlying mechanisms of such up-regulation using A20-HL cells derived from A20-2J cells. Irradiation of A20-HL cells with 100 Gy enhanced CD80 expression. Incubation of untreated A20-HL cells with those 100 Gy irradiated induced up-regulation of CD80 expression. Irradiation of A20-HL cells also up-regulated the expression of tumour necrosis factor-alpha (TNF-alpha) and CD40 ligand (CD40L), and the amount of immunoprecipitable TNF-alpha and CD40L in cell lysates. The addition of anti-TNF-alpha or anti-CD40L monoclonal antibody (mAb) to the incubation of irradiated A20-HL cells partially inhibited up-regulation of CD80 expression, and the addition of both antibodies together almost completely inhibited the up-regulation, suggesting that irradiation up-regulated the CD80 expression through the induction of TNF-alpha and CD40L expression. Irradiation also increased the accumulation of CD80, TNF-alpha and CD40L mRNA. n-tosyl-l-phenylalanine chloromethyl ketone (TPCK), a nuclear factor (NF)-kappaB inhibitor, markedly decreased irradiation-induced accumulation of CD80 mRNA and CD80 expression. FK506, a calcineurin inhibitor, and nifedipine, a calcium channel inhibitor, inhibited not only the expression of TNF-alpha and CD40L, but also the up-regulation of CD80 on irradiated A20-HL cells. These results strongly suggested that irradiation induced TNF-alpha and CD40L expression, which then up-regulated CD80 mRNA and CD80 expression through activation of NF-kappaB transcription factor in A20-HL cells.

[Eosinophilic Pleural Effusion Associated with Dantrolene Administration]

Nihon Kokyuki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. Jun, 2002  |  Pubmed ID: 12325337

A 42-year old man was admitted to our hospital for evaluation of pleural effusion in the right hemithorax. He had been treated for spastic paraplegia with dantrolene sodium for 28 months. The pleural fluid consisted of sterile exudates with a very high eosinophil count, and peripheral blood eosinophilia was noted. Thoracoscopy revealed no apparent abnormalities and a pleural biopsy specimen showed only non-specific inflammation. Two weeks after discontinuing dantrolene therapy, the pleural effusion disappeared. The toxicity of dantrolene in patients with pleural effusion must be taken into consideration when long-term dantrolene therapy is given.

[Secondary Pulmonary Alveolar Proteinosis Associated with Myelodysplastic Syndrome]

Nihon Kokyuki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. Jul, 2002  |  Pubmed ID: 12382426

A 51-year-old man with myelodysplastic syndrome (MDS) was admitted to our hospital because of dyspnea on exertion in December 1999. Chest radiography showed ground-glass shadows in the middle and lower fields of both lungs, and chest computed tomography revealed a typical "crazy paving appearance". The bronchoalveolar lavage fluid was milky in appearance, and so secondary pulmonary alveolar proteinosis associated with MDS was diagnosed. Because there was no need to treat his MDS, we twice performed whole-lung lavage under general anesthesia in January and February 2000. The treatments were effective, and his abnormal chest radiography findings, laboratory data and pulmonary function were normalized. This was a rare case of secondary pulmonary alveolar proteinosis associated with MDS successfully treated with whole-lung lavage.

[Chemokines and Lymphocyte Homing]

Tanpakushitsu Kakusan Koso. Protein, Nucleic Acid, Enzyme. Dec, 2002  |  Pubmed ID: 12518440

[Clinical Analysis of Chronic Hypersensitivity Pneumonitis]

Nihon Kokyuki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. Sep, 2002  |  Pubmed ID: 12607297

Chronic hypersensitivity pneumonitis (CHP) has a poor prognosis because of the difficulties in its diagnosis and treatment. Recently, we have encountered six cases of CHP (4 patients with the home-related type, a patient with bird fancier's lung, and one with flour-induced CHP), and we examined the clinical characteristics of these cases. Environmental provocation testing has been considered useful for diagnosing HP, but all patients gave negative results in short-term environmental exposure tests performed routinely for the diagnosis of HP. However, 5 patients had a positive response in long-term environmental exposure tests. Two patients died of respiratory failure after ten years' observation despite improvement of the causative environment, and were given steroid therapy. Radiographically and pathologically, the process of progressive and irreversible lesions were recognized in our series of CHP patients. The diagnosis of CHP should be carried out on the basis of the comprehensive findings including the detailed history, clinical course, radiography, and histology.

[An Autopsy Case of Cor Pulmonale Due to a Pulmonary Tumor Embolism As the First Clinical Manifestation of Occult Gastric Cancer]

Nihon Kokyuki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. Nov, 2002  |  Pubmed ID: 12645114

A 47-year-old man was admitted to our hospital because of progressive dyspnea and cough. Physical examination and chest radiographs showed the signs of cor pulmonale. A lung scan using perfused radionuclide revealed multiple peripheral perfusion defects and catheterization of the right heart showed severe pulmonary hypertension. A diagnosis of severe pulmonary embolism was made. Despite intensive care with anti-coagulation therapy, the patient died on the third-hospital day. Autopsy disclosed gastric cancer in the pylorus with metastases to the regional lymph nodes. There were no macroscopic pulmonary artery emboli or parenchymal lesions, but more than 60% of the small arteries and arterioles were occluded by casts of tumor cells. Cor pulmonale due to a pulmonary tumor embolism is a rare complication of cancer. This case is particularly unusual because the embolus-caused cor pulmonale was the initial manifestation of clinically occult, but pathologically advanced, gastric cancer.

Distinct Antigen Trafficking from Skin in the Steady and Active States

International Immunology. Jun, 2003  |  Pubmed ID: 12750361

In antigen trafficking from the skin, it has been postulated that Langerhans cells/dendritic cells are activated after capturing exogenous antigens, up-regulate the expression of the chemokine receptor, CCR7, and migrate into lymphoid organs in response to the signaling of a chemokine, CCL21, which is expressed in lymphatic vessels and T cell zone stromal cells. Here we demonstrate that there is a distinct pathway of antigen trafficking from skin in the steady state that is independent of CCL21-CCR7 signaling. Employing melanin granules as an endogenous traceable antigen, we developed a system for visualizing antigen trafficking using mice with melanocytosis in the skin. We found the abrogation of antigen trafficking into regional lymph nodes (LN) in CCL21-Ser-deficient paucity of lymph node T cells (plt) mice in the active state induced by lipopolysaccharide injection, corresponding with previous reports, but normal accumulation of antigen in regional LN under steady-state conditions. These findings suggest that self-antigen is trafficking constitutively using pathway(s) other than that of the active state and the constitutive trafficking might regulate self-reactivity of the immune system.

Increased Regional Cerebral Blood Flow but Normal Distribution of GABAA Receptor in the Visual Cortex of Subjects with Early-onset Blindness

NeuroImage. May, 2003  |  Pubmed ID: 12781732

Before the completion of visual development, visual deprivation impairs synaptic elimination in the visual cortex. The purpose of this study was to determine whether the distribution of central benzodiazepine receptor (BZR) is also altered in the visual cortex in subjects with early-onset blindness. Positron emission tomography was carried out with [(15)O]water and [(11)C]flumazenil on six blind subjects and seven sighted controls at rest. We found that the CBF was significantly higher in the visual cortex for the early-onset blind subjects than for the sighted control subjects. However, there was no significant difference in the BZR distribution in the visual cortex for the subject with early-onset blindness than for the sighted control subjects. These results demonstrated that early visual deprivation does not affect the distribution of GABA(A) receptors in the visual cortex with the sensitivity of our measurements. Synaptic elimination may be independent of visual experience in the GABAergic system of the human visual cortex during visual development.

High-dose Intravenous Glucocorticoid Therapy Abrogates Circulating Dendritic Cells

The Journal of Allergy and Clinical Immunology. Dec, 2003  |  Pubmed ID: 14657889

[A Case of Adenocarcinoma of the Lung Presenting Symptoms of Choroidal Metastasis As the Initial Clinical Manifestation]

Nihon Kokyuki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. May, 2004  |  Pubmed ID: 15168458

A 51-year-old woman was referred to our hospital with a complaint of disturbance in vision. Ophthalmologic examination revealed multiple choroidal tumors. High-resolution CT showed a nodular shadow in the left lower lobe. Transbronchial biopsy and right supraclavicular lymph node biopsy specimens showed a poorly-differentiated adenocarcinoma. We concluded that the choroidal tumors had metastasized from the lung. Combined chemotherapy (CDDP + CPT-11) followed by irradiation of both eyes and brain were performed. Nevertheless, she died 6 months after the initial presentation. It is important to notice ophthalmologic symptoms because lung cancer may metastasize to the choroids.

Symptomatological and Cognitive Predictors of Insight in Chronic Schizophrenia

Psychiatry Research. Jun, 2004  |  Pubmed ID: 15261706

Studies of schizophrenia show lack of agreement about the relationship of symptomatological and cognitive factors to insight. In this study, positive and negative symptomatology and cognitive function were assessed by the Positive and Negative Syndrome Scale (PANSS), the Wisconsin Card Sorting Test (WCST), and the Wechsler Adult Intelligence Scale Revised (WAIS-R) in male chronic schizophrenic patients in relation to level of insight measured with the Japanese version of the Schedule for the Assessment of Insight (SAI-J). Negative symptoms were significantly and negatively associated with overall insight, particularly with treatment compliance and recognition of mental illness. The present findings suggest that aspects of insight such as treatment compliance and recognition of mental illness are negatively associated with negative symptoms.

CCR7 Signals Are Essential for Cortex-medulla Migration of Developing Thymocytes

The Journal of Experimental Medicine. Aug, 2004  |  Pubmed ID: 15302902

Upon TCR-mediated positive selection, developing thymocytes relocate within the thymus from the cortex to the medulla for further differentiation and selection. However, it is unknown how this cortex-medulla migration of thymocytes is controlled and how it controls T cell development. Here we show that in mice deficient for CCR7 or its ligands mature single-positive thymocytes are arrested in the cortex and do not accumulate in the medulla. These mutant mice are defective in forming the medullary region of the thymus. Thymic export of T cells in these mice is compromised during the neonatal period but not in adulthood. Thymocytes in these mice show no defects in maturation, survival, and negative selection to ubiquitous antigens. TCR engagement of immature cortical thymocytes elevates the cell surface expression of CCR7. These results indicate that CCR7 signals are essential for the migration of positively selected thymocytes from the cortex to the medulla. CCR7-dependent cortex-medulla migration of thymocytes plays a crucial role in medulla formation and neonatal T cell export but is not essential for maturation, survival, negative selection, and adult export of thymocytes.

Localization of Marginal Zone Macrophages is Regulated by C-C Chemokine Ligands 21/19

Journal of Immunology (Baltimore, Md. : 1950). Oct, 2004  |  Pubmed ID: 15470021

The marginal zone (MZ) of the spleen is an important site for the capture of blood-borne pathogens and a gateway for lymphocytes entering the white pulp. We have recently reported that Leishmania donovani infection results in a remarkably selective loss of MZ macrophages (MZM) from the MZ. To understand the basis of this observation, we have investigated how MZM maintain their anatomical distribution in the steady state in uninfected mice. We now report that plt/plt mice, which lack functional CCL19 and CCL21, have significantly reduced numbers of MZM compared with normal C57BL/6 (B6) mice. Similarly, in B6.CD45.1-->plt/plt chimeras, donor-derived MZM were rare compared with the number observed in reciprocal plt/plt-->B6.CD45.1 chimeras. Moreover, we show that administration of pertussis toxin, an inhibitor of chemokine receptor signaling, to B6 mice results in exit of MZM from the MZ, that MZM can migrate in response to CCL19 and CCL21 in vitro, and that MZM colocalize with CD31+CCL21+ endothelial cells. Collectively, these data indicate that CCL21 and, to a lesser extent, CCL19 play significant roles in the distinctive localization of MZM within the splenic MZ. Deficiency of CCL19 and CCL21, as also previously observed in mice infected with L. donovani, may thus account for the selective loss of MZM seen during this infection.

Predicting Denial Function of Schizophrenic Patients by the Picture Completion Subtest of WAIS-R

Progress in Neuro-psychopharmacology & Biological Psychiatry. Nov, 2004  |  Pubmed ID: 15610932

In the previous study, picture completion (PC) test scores of Wechsler Adult Intelligence Scale Revised (WAIS-R) were negatively associated with recognition of mental illness measured by Schedule for the Assessment of Insight (SAI). Therefore, it can be hypothesized that function measured by the PC test is positively associated with denial function. To investigate this hypothesis, we investigated the relationship between two picture tests (picture completion and picture arrangement) of the WAIS-R and denial function tests (lie scale, frequency scale and correction scale) of the Minnesota Multiphasic Personality Inventory (MMPI) in 26 schizophrenic patients. As a result, the lie scale score and the correction scale score were positively and significantly associated with picture completion whereas no scale score was significantly associated with picture arrangement. The present findings suggest that the positive association between function measured by the PC test and denial function measured by lie and correction scale scores. Further studies are warranted to investigate the usefulness of the PC test for the measurement of denial function in schizophrenia.

[Cyclosporin Treatment of Interstitial Pneumonia and Monitoring of Serum Concentration]

Nihon Kokyuki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. Nov, 2004  |  Pubmed ID: 15651272

Recently, cyclosporin has been reported to be a promising drug for the treatment of interstitial pneumonia. Monitoring of the serum cyclosporin concentration is important for the safety and efficacy of treatment. We measured the concentrations of this drug just before (C0) and 2 hours after (C2) administration, and the area under the concentration-time curve from the start of administration for 5 hours (AUC 0-5) in 58 patients. We found that C2 has the strongest correlation with AUC 0-5, which indicates the efficacy of cyclosporin. In 11 cases of interstitial pneumonia, 5 showed deterioration despite cyclosporin treatment. Three of those 5 cases had low C2 and AUC 0-5 levels, indicating that they were low absorbers and slow absorbers, which may be associated with a poor response. Therefore, the monitoring of the cyclosporin concentration is important especially in progressive cases of interstitial pneumonia that deteriorate despite cyclosporin treatment.

The Role of CCL21 in Recruitment of T-precursor Cells to Fetal Thymi

Blood. Jan, 2005  |  Pubmed ID: 15358618

During embryonic development, T-lymphoid precursor cells colonize the thymus. Chemoattraction by the fetal thymus is thought to mediate T-precursor cell colonization. However, the molecules that attract T-precursor cells to the thymus remain unclear. By devising time-lapse visualization in culture, the present results show that alymphoid fetal thymus lobes attract T-precursor cells from fetal liver or fetal blood. CD4(-)CD8(-)CD25(-)CD44+ fetal thymocytes retained the activity to specifically re-enter the thymus. The attraction was predominantly due to I-A-expressing thymic epithelial cells and was mediated by pertussis toxin-sensitive G-protein signals. Among the chemokines produced by the fetal thymus, CCL21, CCL25, and CXCL12 could attract CD4(-)CD8(-)CD25(-)CD44+ fetal thymocytes. However, fetal thymus colonization was markedly diminished by neutralizing antibodies specific for CCL21 and CCL25, but not affected by anti-CXCL12 antibody. Fetal thymus colonization was partially defective in CCL21-deficient plt/plt mice and was further diminished by anti-CCL25 antibody. These results indicate that CCL21 is involved in the recruitment of T-cell precursors to the fetal thymus and suggest that the combination of CCL21 and CCL25 plays a major role in fetal thymus colonization.

[Analysis of CD1 Molecules in the Process of Granuloma Formation with Sarcoidosis]

Nihon Kokyuki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. Jan, 2005  |  Pubmed ID: 15704447

There have been many reports studying the presentation for lipid antigen by CD1 molecules on dendritic cells (DC), mainly in the infection of acid-fast bacilli. But little is known about the expression of CD1 molecules in sarcoidosis. In this study, we analyzed the expression of CD1 molecules by immunohistochemical stain with monoclonal anti-CD1a, CD1b and CD1c antibody for the specimens of nine sarcoidosis patients (sarcoidosis group) and seven control cases (control group). Aggregation of CD1 positive cells was present adjacent to granulomas in five cases of the sarcoidosis group, but was absent in all cases of the control group. There were no differences in the results of laboratory findings or disease activity between CD1-positive and negative cases in the sarcoidosis group. These data suggest that the presentation of lipid antigens mediated by CD1 molecules on DC is involved in granuloma formation in sarcoidosis.

CCL19 and CCL21 Induce a Potent Proinflammatory Differentiation Program in Licensed Dendritic Cells

Immunity. Apr, 2005  |  Pubmed ID: 15845453

Dendritic cells (DCs) are key instigators of adaptive immune responses. Using an alphaviral expression cloning technology, we have identified the chemokine CCL19 as a potent inducer of T cell proliferation in a DC-T cell coculture system. Subsequent studies showed that CCL19 enhanced T cell proliferation by inducing maturation of DCs, resulting in upregulation of costimulatory molecules and the production of proinflammatory cytokines. Moreover, CCL19 programmed DCs for the induction of T helper type (Th) 1 rather than Th2 responses. Importantly, only activated DCs that migrated from the periphery to draining lymph nodes, but not resting steady-state DCs residing within lymph nodes, expressed high levels of CCR7 in vivo and responded to CCL19 with the production of proinflammatory cytokines. Migrating DCs isolated from mice genetically deficient in CCL19 and CCL21 (plt/plt) presented an only partially mature phenotype, highlighting the importance of these chemokines for full DC maturation in vivo. Our findings indicate that CCL19 and CCL21 are potent natural adjuvants for terminal activation of DCs and suggest that chemokines not only orchestrate DC migration but also regulate their immunogenic potential for the induction of T cell responses.

CXCL9 Antagonism Further Extends Prolonged Cardiac Allograft Survival in CCL19/CCL21-deficient Mice

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Sep, 2005  |  Pubmed ID: 16095489

CCL19/MIP-3beta and CCL21/SLC are essential for chemotactic recruitment of mature dendritic cells (DC) to T-cell areas of secondary lymphoid tissue. Paucity of lymph node T-cells (plt/plt) mice lack CCL21-serine (ser) and CCL19 expression. We tested plt/plt and wild type (wt) BALB/c (H2d) mice as recipients of heart or skin allografts from C57BL/10J (H2b) donors. Donor DC trafficking to secondary lymphoid tissue was markedly reduced in plt heart but not skin allograft recipients. Heart, but not skin grafts survived significantly longer in plt recipients. Accordingly, T cells from plt heart transplant recipients demonstrated poor anti-donor responses in ex vivo MLR, compared to wt heart or wt and plt skin recipients. Moreover, donor-reactive T cells from plt heart recipients exhibited Th2-skewing in comparison to T cells from wt heart or skin graft recipients. Anti-CXCL9/Mig was administered for 2 weeks post-transplant to determine whether impairment of activated T-cell migration could further prolong cardiac allograft survival in plt recipients. CXCL9-antagonism extended graft survival significantly only in plt mice, likely due, in part, to retention of alloactivated T cells in secondary lymphoid tissue/reduction of graft-infiltrating T cells. Thus, targeting DC and activated T-cell migration concomitantly has additive effects in prolonging heart graft survival with potential for therapeutic application.

Role of CXC Chemokine Ligand 13, CC Chemokine Ligand (CCL) 19, and CCL21 in the Organization and Function of Nasal-associated Lymphoid Tissue

Journal of Immunology (Baltimore, Md. : 1950). Oct, 2005  |  Pubmed ID: 16210592

Nasal-associated lymphoid tissue (NALT) orchestrates immune responses to Ags in the upper respiratory tract. Unlike other lymphoid organs, NALT develops independently of lymphotoxin-alpha (LTalpha). However, the structure and function of NALT are impaired in Ltalpha(-/-) mice, suggesting a link between LTalpha and chemokine expression. In this study we show that the expression of CXCL13, CCL19, CCL21, and CCL20 is impaired in the NALT of Ltalpha(-/-) mice. We also show that the NALT of Cxcl13(-/-) and plt/plt mice exhibits some, but not all, of the structural and functional defects observed in the NALT of Ltalpha(-/-) mice. Like the NALT of Ltalpha(-/-) mice, the NALT in Cxcl13(-/-) mice lacks follicular dendritic cells, BP3(+) stromal cells, and ERTR7(+) lymphoreticular cells. However, unlike the NALT of Ltalpha(-/-) mice, the NALT of Cxcl13(-/-) mice has peripheral node addressin(+) high endothelial venules (HEVs). In contrast, the NALT of plt/plt mice is nearly normal, with follicular dendritic cells, BP3(+) stromal cells, ERTR7(+) lymphoreticular cells, and peripheral node addressin(+) HEVs. Functionally, germinal center formation and switching to IgA are defective in the NALT of Ltalpha(-/-) and Cxcl13(-/-) mice. In contrast, CD8 T cell responses to influenza are impaired in Ltalpha(-/-) mice and plt/plt mice. Finally, the B and T cell defects in the NALT of Ltalpha(-/-) mice lead to delayed clearance of influenza from the nasal mucosa. Thus, the B and T cell defects in the NALT of Ltalpha(-/-) mice can be attributed to the impaired expression of CXCL13 and CCL19/CCL21, respectively, whereas impaired HEV development is directly due to the loss of LTalpha.

[An Adult Case of Asymptomatic Congenital Tracheal Stenosis]

Nihon Kokyuki Gakkai Zasshi = the Journal of the Japanese Respiratory Society. Nov, 2005  |  Pubmed ID: 16366366

A 42-year-old woman was admitted with abnormal chest radiographs. Though interstitial pneumonia associated with dermatomyositis was diagnosed, her chest radiograph also revealed a narrowed trachea about 6 mm in diameter. Bronchoscopy showed that her trachea lacked a membranous posterior segment and O-shaped complete tracheal rings were present throughout the trachea, indicating congenital tracheal stenosis. Congenital tracheal stenosis is a rare disorder and is usually recognized in the first few weeks of life, but the patient had no history of dyspnea or recurrent pneumonia. This case suggests that among healthy people there are a very few who have asymptomatic congenital tracheal stenosis.

Immunization with Dendritic Cells Retrovirally Transduced with Mycobacterial Antigen 85A Gene Elicits the Specific Cellular Immunity Including Cytotoxic T-lymphocyte Activity Specific to an Epitope on Antigen 85A

Vaccine. Mar, 2006  |  Pubmed ID: 16352377

In the present study, we evaluated antigen 85A (Ag85A) gene-transduced dendritic cells (DCs) vaccine against Mycobacterium tuberculosis. Murine bone marrow-derived DCs were retrovirally transduced with mycobacterial Ag85A gene and injected to BALB/c mice intravenously. The DC vaccine was capable of inducing purified protein derivative (PPD)- and the antigen-specific spleen cell proliferation and IFN-gamma production from both CD4+ and CD8+ T cells in spleens of the immune mice. In addition, the DC vaccination induced cytotoxic T-lymphocytes (CTL) and IFN-gamma-producing cells specific for a 9-mer CTL epitope on Ag85A molecule. This eliciting cellular immunity led to protection against wasting disease due to M. tuberculosis infection and induction of moderate bacterial clearance.

[Risk Factors for Suicide: a Questionnaire Survey by Psychiatrists in Fukuoka Prefecture]

Seishin Shinkeigaku Zasshi = Psychiatria Et Neurologia Japonica. 2006  |  Pubmed ID: 16532697

In our previous study, we demonstrated a preliminary questionnaire survey to psychiatrists from university hospitals, psychiatric hospitals, psychiatric clinics, and departments of psychiatry in general hospitals in Fukuoka Prefecture. In that study, 324 psychiatric patients who committed suicide between January 1, 1998 and December 31, 2001 were ascertained. In the present study, we have recruited matched control patients from the same clinics/hospitals and further demonstrated a secondary questionnaire survey to the psychiatrists in order to reveal the various risk factors for suicide suggested by the literature. Associations between completed suicide and possible risk factors were examined in 192 completed suicide psychiatric patients and 356 non-suicidal psychiatric patients (controls). Significant association was found for history of admission to psychiatric hospitals, history of suicide attempts, history of substance abuse, cluster B personality disorders, and hopelessness in our sample. In male samples, history of suicide attempts, cluster B personality disorders, recent loss, and hopelessness were significantly associated with suicide. In females, history of admission to psychiatric hospitals, history of suicide attempts, and hopelessness were significant.

Loss of Dendritic Cell Migration and Impaired Resistance to Leishmania Donovani Infection in Mice Deficient in CCL19 and CCL21

Journal of Immunology (Baltimore, Md. : 1950). May, 2006  |  Pubmed ID: 16622017

The encounter between APC and T cells is crucial for initiating immune responses to infectious microorganisms. In the spleen, interaction between dendritic cells (DC) and T cells occurs in the periarteriolar lymphoid sheath (PALS) into which DC and T cells migrate from the marginal zone (MZ) along chemokine gradients. However, the importance of DC migration from the MZ into the PALS for immune responses and host resistance to microbial infection has not yet been elucidated. In this study, we report that following Leishmania donovani infection of mice, the migration of splenic DC is regulated by the CCR7 ligands CCL19/CCL21. DC in plt/plt mutant mice that lack these chemokines are less activated and produce less IL-12, compared with those in wild-type mice. Similar findings are seen when mice are treated with pertussis toxin, which blocks chemokine signaling in vivo. plt/plt mice had increased susceptibility to L. donovani infection compared with wild-type mice, as determined by spleen and liver parasite burden. Analysis of splenic cytokine profiles at day 14 postinfection demonstrated that IFN-gamma and IL-4 mRNA accumulation was comparable in wild-type and plt/plt mice. In contrast, accumulation of mRNA for IL-10 was elevated in plt/plt mice. In addition, plt/plt mice mounted a delayed hepatic granulomatous response and fewer effector T cells migrated into the liver. Taken together, we conclude that DC migration from the MZ to the PALS is necessary for full activation of DC and the optimal induction of protective immunity against L. donovani.

TLR4 Signaling Attenuates Ongoing Allergic Inflammation

Journal of Immunology (Baltimore, Md. : 1950). May, 2006  |  Pubmed ID: 16670292

The relationship between LPS exposure and allergic asthma is poorly understood. Epidemiologic studies in humans have found that exposure to LPS can protect, have no effect, or exacerbate allergic asthma. Similarly, LPS has had variable effects on allergic pulmonary inflammation in the mouse, depending on the model used. In the present study, we studied the effect of very low doses of LPS in models of both short-term and long-term allergen challenge. When challenged with allergen for short periods, wild-type and tlr4-deficient mice had similar responses. However, when challenged for periods of 1 wk or longer, tlr4-deficient mice developed dramatically increased airway eosinophils, serum IgE, and Th2 cytokines compared with similarly challenged, genetically matched C57BL/6 mice. The relative attenuation of allergic responses seen in C57BL/6 mice was dependent on bone marrow-derived cell-specific expression of tlr4, and was not associated with an increase in Th1 responses. The number of dendritic cells in lungs of challenged tlr4-deficient mice was significantly increased compared with those in challenged C57BL/6 mice. No differences were seen in the abilities of naive C57BL/6 and tlr4-deficient mice to develop allergen-specific tolerance after exposure to similar preparations of OVA, suggesting that tolerance and regulation of existing inflammation develop through different mechanisms. The attenuation of eosinophilic inflammation in C57BL/6 mice was abolished when these mice were challenged with OVA supplemented with additional LPS. Together, these findings show that low doses of endotoxin can have regulatory effects on allergic inflammation, particularly in the setting of ongoing allergen exposure.

Lithium and Dementia: a Preliminary Study

Progress in Neuro-psychopharmacology & Biological Psychiatry. Aug, 2006  |  Pubmed ID: 16753246

Recent studies have shown that lithium may block the accumulation of amyloid-beta (Abeta) peptides and to inhibit the hyperphosphorylation of tau via the inhibition of GSK-3alpha in the brain of mice. The purpose of the present study is to examine whether lithium could potentially be effective for the prevention of Alzheimer's disease. We investigated the clinical records of 1,423 outpatients at a university psychiatric outpatient clinic and classified patients according to the following criteria: (a) absence of a diagnosis of dementia, (b) age 60 years or older, and (c) lithium had been prescribed and/or was currently prescribed. We compared these patients with randomly selected age and gender matched control group who had never been prescribed lithium. Despite no significant difference in MMSE scores between the lithium group, which consisted of patients receiving lithium treatment, and the control group, those who had previously received lithium and/or were currently prescribed lithium had significantly better MMSE scores than the control patients. The findings provide partial evidence to support the contention that lithium could offer hope as a preventive treatment for Alzheimer's disease. Further prospective studies with a large number of patients are warranted to investigate this potentially important effect.

Global Estimates of Shark Catches Using Trade Records from Commercial Markets

Ecology Letters. Oct, 2006  |  Pubmed ID: 16972875

Despite growing concerns about overexploitation of sharks, lack of accurate, species-specific harvest data often hampers quantitative stock assessment. In such cases, trade studies can provide insights into exploitation unavailable from traditional monitoring. We applied Bayesian statistical methods to trade data in combination with genetic identification to estimate by species, the annual number of globally traded shark fins, the most commercially valuable product from a group of species often unrecorded in harvest statistics. Our results provide the first fishery-independent estimate of the scale of shark catches worldwide and indicate that shark biomass in the fin trade is three to four times higher than shark catch figures reported in the only global data base. Comparison of our estimates to approximated stock assessment reference points for one of the most commonly traded species, blue shark, suggests that current trade volumes in numbers of sharks are close to or possibly exceeding the maximum sustainable yield levels.

Enhanced Allergen-induced Airway Inflammation in Paucity of Lymph Node T Cell (plt) Mutant Mice

The Journal of Allergy and Clinical Immunology. Dec, 2006  |  Pubmed ID: 17157652

Dendritic cells and lymphocytes play a central role in allergic asthma. Chemokines for these cells include the CCR7 agonists secondary lymphoid chemokine/CCL21 and EBV-induced lymphoid chemokine/CCL19, but their role in allergic asthma is poorly understood.

Chemokines CCL19 and CCL21 Promote Activation-induced Cell Death of Antigen-responding T Cells

Blood. Jan, 2007  |  Pubmed ID: 16973962

Secondary lymphoid organs (SLOs) provide a niche for the initiation and regulation of T-cell responses, but the mechanisms have been poorly understood. We investigated the influence of chemokines CCL19 and CCL21 constitutively expressed in SLOs on activation-induced cell death (AICD) of CD4+ T cells. When paucity of lymph node T cells (plt) mutant mice lacking expression of CCL19/CCL21 were primed with OVA/CFA, both expansion of OVA-responding CD4+ T cells in the draining lymph nodes and an in vitro recall response were prolonged as compared with responses in wild-type (WT) mice. The apoptotic cell frequency among OVA-responding CD4+ T cells was similarly low in plt/plt and WT mice during the clonal expansion phase. However, during the clonal contraction phase, the frequency never increased in plt/plt mice, whereas in WT mice it continuously increased to a peak 18 days after immunization. The presence of CCL19/CCL21 during the in vitro stimulation of CD4+ T cells with anti-CD3 plus anti-CD28 significantly enhanced in vitro AICD induction of the restimulated T cells, partially through enhancing expression of Fas ligand. Our results suggest that CCL19/CCL21 produced by stromal cells and antigen-presenting cells regulate CD4+ T-cell immune responses in SLOs by promoting AICD.

Experimental Scrapie in 'plt' Mice: an Assessment of the Role of Dendritic-cell Migration in the Pathogenesis of Prion Diseases

The Journal of General Virology. Aug, 2007  |  Pubmed ID: 17622642

Peripherally acquired transmissible spongiform encephalopathies display strikingly long incubation periods, during which increasing amounts of prions can be detected in lymphoid tissues. While precise sites of peripheral accumulation have been described, the mechanisms of prion transport from mucosa and skin to lymphoid and nervous tissues remain unknown. Because of unique functional abilities, dendritic cells (DCs) have been suspected to participate in prion pathogenesis. In mice inoculated subcutaneously with scrapie-infected DCs, the incubation was shorter when cells were alive as compared with killed cells, suggesting that DC functions may facilitate prion neuroinvasion. However, early propagation in lymphoid tissues seemed not importantly affected by DC vitality. Mutant (plt) mice that have deficient CCL19/CCL21 expression and DC migration displayed similar infection of secondary lymphoid organs as normal mice, regardless of the route of inoculation and scrapie strain. Under certain conditions of transcutaneous inoculation, the incubation and duration of disease were moderately prolonged in plt mice. This was not related to a milder neuropathogenesis, since plt and normal mice were equally susceptible to intracerebral prion challenge. We conclude that peripheral spreading of prions appears poorly dependent on cell migration through the chemokine/receptor system CCL19/CCL21/CCR7, although DCs might be able to help prions reach sites of neuroinvasion.

Stress at Work Alters Serum Brain-derived Neurotrophic Factor (BDNF) Levels and Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) Levels in Healthy Volunteers: BDNF and MHPG As Possible Biological Markers of Mental Stress?

Progress in Neuro-psychopharmacology & Biological Psychiatry. Apr, 2008  |  Pubmed ID: 18160197

There is growing evidence that blood levels of brain-derived neurotrophic factor (BDNF) and catecholamine, and cytokines are related to not only to depressive, suicidal, and anxious states but also to depression-associated personality traits. Psychological job stress is well known to lead to symptoms of depression and anxiety. In the present study, we examined effects of psychological job stress on serum levels of BDNF and plasma levels of catecholamine metabolites, and cytokines in healthy volunteers (n=106, male/female=42/64, age=36+/-12 yr) working in a hospital setting. The values (mean+/-SD) of scores for stress items in the Stress and Arousal Check List (s-SACL), plasma MHPG levels, and, serum BDNF levels in all participants were 7.2+/-3.3, 5.2+/-3.4 ng/mL, and 23.3+/-14.7 ng/mL, respectively. A negative correlation was found between scores for s-SACL and serum BDNF levels (rho=-0.211, p=0.022). A positive correlation was also found between scores on the s-SACL and plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) (rho=0.416, p=0.01), but not homovanillic acid (HVA). No relationship was found between s-SACL scores and plasma levels of interleukin-6 (IL-6) or tumor necrosis factor alpha (TNFalpha). These results suggest that serum BDNF levels and plasma MHPG levels might be biological markers reflective of psychological job stress in hospital employees.

CCR2+ Monocyte-derived Dendritic Cells and Exudate Macrophages Produce Influenza-induced Pulmonary Immune Pathology and Mortality

Journal of Immunology (Baltimore, Md. : 1950). Feb, 2008  |  Pubmed ID: 18250467

Infection with pathogenic influenza virus induces severe pulmonary immune pathology, but the specific cell types that cause this have not been determined. We characterized inflammatory cell types in mice that overexpress MCP-1 (CCL2) in the lungs, then examined those cells during influenza infection of wild-type (WT) mice. Lungs of both naive surfactant protein C-MCP mice and influenza-infected WT mice contain increased numbers of CCR2(+) monocytes, monocyte-derived DC (moDC), and exudate macrophages (exMACs). Adoptively transferred Gr-1(+) monocytes give rise to both moDC and exMACs in influenza-infected lungs. MoDC, the most common inflammatory cell type in infected lungs, induce robust naive T cell proliferation and produce NO synthase 2 (NOS2), whereas exMACs produce high levels of TNF-alpha and NOS2 and stimulate the proliferation of memory T cells. Relative to WT mice, influenza-infected CCR2-deficient mice display marked reductions in the accumulation of monocyte-derived inflammatory cells, cells producing NOS2, the expression of costimulatory molecules, markers of lung injury, weight loss, and mortality. We conclude that CCR2(+) monocyte-derived cells are the predominant cause of immune pathology during influenza infection and that such pathology is markedly abrogated in the absence of CCR2.

Two Cases of Burning Mouth Syndrome Treated with Olanzapine

Psychiatry and Clinical Neurosciences. Jun, 2008  |  Pubmed ID: 18588600

Two case reports of patients suffering from burning mouth syndrome (BMS), a type of somatoform disorder, who were treated with olanzapine are discussed. One case was a 54-year-old female with BMS who failed to respond to milnacipran treatment. Olanzapine (2.5 mg/day) brought about dramatic improvement in the patient's symptoms, and thereafter milnacipran withdrawal further eliminated her symptoms. The second case was a 51-year-old male with BMS who failed to respond to paroxetine treatment. Olanzapine (2.5 mg/day) was added to the treatment regimen and increased to 5.0 mg/day the following week. The patient noted a reduction in symptoms and continued to live normally thereafter without experiencing severe symptoms. These findings suggest that olanzapine may be useful in the treatment of BMS.

Blood Levels of Catecholamine Metabolites and Brain-derived Neurotrophic Factor in a Case of Sydenham's Chorea

The World Journal of Biological Psychiatry : the Official Journal of the World Federation of Societies of Biological Psychiatry. 2009  |  Pubmed ID: 17965987

We report a case of Sydenham's chorea with neuropsychiatric symptoms who was successfully treated with low-dose risperidone. We also longitudinally investigated serum BDNF levels and plasma levels of catecholamine metabolite in the patient. Serum BDNF levels were increased and plasma levels of HVA and MHPG were decreased according to the recovery from the active phase of the disease. These results suggest that dysfunctions of catecholaminergic neurons and neurotrophic factors might exist in Sydenham's chorea, and the decreasing catecholamine activities in response to risperidone might be associated with the improvement of the disease.

Blood-derived Inflammatory Dendritic Cells in Lymph Nodes Stimulate Acute T Helper Type 1 Immune Responses

Nature Immunology. Apr, 2009  |  Pubmed ID: 19252492

T helper type 1 (T(H)1)-polarized immune responses, which confer protection against intracellular pathogens, are thought to be initiated by dendritic cells (DCs) that enter lymph nodes from peripheral tissues. Here we found after viral infection or immunization, inflammatory monocytes were recruited into lymph nodes directly from the blood to become CD11c(+)CD11b(hi)Gr-1(+) inflammatory DCs, which produced abundant interleukin 12p70 and potently stimulated T(H)1 responses. This monocyte extravasation required the chemokine receptor CCR2 but not the chemokine CCL2 or receptor CCR7. Thus, the accumulation of inflammatory DCs and T(H)1 responses were much lower in Ccr2(-/-) mice, were preserved in Ccl2(-/-) mice and were relatively higher in CCL19-CCL21-Ser-deficient plt mutant mice, in which all other lymph node DC types were fewer in number. We conclude that blood-derived inflammatory DCs are important in the development of T(H)1 immune responses.

CCR7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis Through Generating IL-23-dependent Th17 Cells

Journal of Immunology (Baltimore, Md. : 1950). Aug, 2009  |  Pubmed ID: 19625643

CCL19 and CCL21 are thought to be critical for experimental autoimmune encephalomyelitis (EAE) induction, but their precise role is unknown. We examined the role of these chemokines in inducing EAE. C57BL/6 mice lacking expression of these chemokines (plt/plt mice) or their receptor CCR7 were resistant to EAE induced with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55)) and pertussis toxin. However, passive transfer of pathogenic T cells from wild-type mice induced EAE in plt/plt mice, suggesting a defect independent of the role of CCR7 ligands in the migration of immune cells. Examination of draining lymph node (DLN) cells from MOG(35-55)-immunized plt/plt mice found decreased IL-23 and IL-12 production by plt/plt dendritic cells (DCs) and a concomitant defect in Th17 cell and Th1 cell generation. In contrast, production of the Th17 lineage commitment factors IL-6 and TGF-beta were unaffected by loss of CCR7 ligands. The adoptive transfer of in vitro-generated Th17 cells from DLN cells of MOG(35-55)-immunized plt/plt mice developed EAE in wild-type recipient mice, whereas that of Th1 cells did not. Pathogenic Th17 cell generation was restored in plt/plt DLNs with the addition of exogenous IL-23 or CCL19/CCL21 and could be reversed by inclusion of anti-IL-23 mAb in cultures. Exogenous CCL19/CCL21 induced IL-23p19 expression and IL-23 production by plt/plt or wild-type DCs. Therefore, CCR7 ligands have a novel function in stimulating DCs to produce IL-23 and are important in the IL-23-dependent generation of pathogenic Th17 cells in EAE induction.

Allergic Sensitization Through the Airway Primes Th17-dependent Neutrophilia and Airway Hyperresponsiveness

American Journal of Respiratory and Critical Care Medicine. Oct, 2009  |  Pubmed ID: 19661246

In humans, immune responses to inhaled aeroallergens develop in the lung and draining lymph nodes. Many animal models of asthma bypass this route and instead use intraperitoneal injections of allergen using aluminum hydroxide as an adjuvant.

Mast Cells Augment Adaptive Immunity by Orchestrating Dendritic Cell Trafficking Through Infected Tissues

Cell Host & Microbe. Oct, 2009  |  Pubmed ID: 19837373

Mast cells (MCs) are best known for eliciting harmful reactions, mostly after primary immunity has been established. Here, we report that, during footpad infection with E. coli in MC-deficient mice, as compared to their MC-sufficient counterparts, the serum antibody response is significantly diminished and less protective following passive immunization in a urinary tract infection (UTI) model in wild-type mice. MCs were found to recruit large numbers of dendritic cells (DCs) into the infected tissue site, which eventually migrated into draining lymph nodes (DLNs) during a prolonged time course. This pattern of trafficking was facilitated by MC-generated TNF, which increased the expression of E-selectin on local blood vessels. Antibody blockade of E-selectin inhibited DC recruitment into the site of infection and DLNs and consequently impaired the primary humoral immune response. Thus, during infection, resident MCs contribute to the primary protective adaptive response through recruitment of DCs from the circulation into infected sites.

Induction of Targeted Cell Migration by Cutaneous Administration of a DNA Vector Encoding a Biologically Active Chemokine CCL21

The Journal of Investigative Dermatology. Jun, 2010  |  Pubmed ID: 20182442

Skin inflammation can induce local expression of CCL21, which is subsequently drained to lymph nodes (LNs) influencing their cellular composition. To determine whether the same can be achieved by dermal administration of a plasmid DNA (pDNA) encoding CCL21, we generated a pDNA-based gene construct allowing high-level expression of CCL21. Expression and secretion of biologically active CCL21 were confirmed in vitro by immunohistochemistry, western blot analysis, ELISA, and transwell chemotactic assays. In vivo experiments showed cellular expression of transgenic CCL21 after particle-mediated gene gun delivery of pDNA into skin. CCL21 was expressed in the epidermis, consequently secreted into the upper dermis, and transported into the draining LNs, which resulted in increased CCL21 concentration, total cell number, and frequencies of CD11c(+) DCs and CD4(+)/CD62L(+) naïve, CD4(+)/CD62L(-), and CD8(+)/CD62L(-) effector memory T-cells (expressing CCL21 receptors CCR7 or CXCR3), as well as retention of adoptively transferred T-lymphocytes, in the draining LNs of plt/plt mice (lacking endogenous expression of CCL21). Our studies show that biologically active CCL21 can be overexpressed by genetic means in vitro and in vivo. This strategy allows reconstitution of a genetic defect and colocalization of different cell types in the secondary lymphoid organs, an important prerequisite for targeted cell migration.

Association Between Plasma Nitric Oxide Metabolites Levels and Negative Symptoms of Schizophrenia: a Pilot Study

Human Psychopharmacology. Mar, 2010  |  Pubmed ID: 20196178

Nitric oxide (NO) is involved in pathophysiology of psychiatric disorders such as depression and schizophrenia. We hypothesize that plasma levels of NO and its metabolites (NO(x)) are decreased in patients with schizophrenia. To examine the hypothesis, we compared plasma NO(x) levels between 30 schizophrenic patients (M/F: 18/12, age: 38 +/- 15 years) and age- and sex-matched 30 healthy controls (M/F: 18/12, age: 41 +/- 19 years), and we also examined the effects of risperidone on plasma NO(x) levels in schizophrenic patients. The baseline plasma NO(x) levels were significantly lower in the schizophrenia group (1.85 +/- 0.70 microM) than those in control group (3.37 +/- 2.27 microM). A significantly negative correlation was found between plasma NO(x) levels and PANSS-N scores before risperidone administration (rho = -0.385, p = 0.0416). Treatment with risperidone significantly increased the plasma NO(x) levels by 8 weeks (before; 1.85 +/- 0.70 microM, after; 2.25 +/- 1.00 microM, p = 0.0491). These results suggest that NO might be one of the candidates factors which are associated with the pathophysiology of negative symptoms of schizophrenia.

Ozone Activates Pulmonary Dendritic Cells and Promotes Allergic Sensitization Through a Toll-like Receptor 4-dependent Mechanism

The Journal of Allergy and Clinical Immunology. May, 2010  |  Pubmed ID: 20394980

Altered Antibody Production and Helper T Cell Function in Mice Lacking Chemokines CCL19 and CCL21-Ser

Microbiology and Immunology. Nov, 2010  |  Pubmed ID: 21044143

The roles of chemokines CCL19 and CCL21 in Ab production were investigated using plt mutant mice, which lack expression of CCL19 and CCL21-ser in their lymphoid organs. In these mice, the Th response has been shown to tend towards the Th1 type because of accumulation of inflammatory dendritic cells. When plt mice were immunized with 100 μg OVA in CFA, the number of Ab-forming cells in the draining LN, and serum concentrations of OVA-specific IgM and IgG Ab, were very close to those of the control, yet IgG2a Ab in plt mice was increased. In vitro IFN-γ production by the draining LN cells of plt mice was increased. In addition, the ability of helper T cells from plt mice to stimulate Ab production in vitro was prolonged. Also, in the plt mice, in vivo challenge with OVA in incomplete Freund's adjuvant elicited a stronger IgG2a response and a weaker IgG1 response, which is suggestive of a Th1-dominant response. Similar findings were obtained when mice were immunized with 100 μg OVA in alum, except that with alum the increases observed in plt mice were IgG1 produced in vivo and IL-4 produced in vitro by draining LN cells. Furthermore, immunization with alum adjuvant also induced a prolonged in vitro recall response of IFN-γ and IL-4. These findings indicate that plt mice mount an anti-OVA Ab response, and suggest that CCL19 and CCL21 induce prompt Ab responses to antigen, and negatively regulate helper T cell responses in vivo.

[Case Report: a Case of Pulmonary Arteriovenous Fistula Benefited by Transcatheter Embolotherapy]

Nihon Naika Gakkai Zasshi. The Journal of the Japanese Society of Internal Medicine. Jul, 2011  |  Pubmed ID: 21863774

Reliability, Validity and Clinical Utility of a Japanese Version of the Social Adaptation Self-evaluation Scale As Calibrated Using the Beck Depression Inventory

Psychiatry and Clinical Neurosciences. Dec, 2011  |  Pubmed ID: 22176281

The Social Adaptation Self-evaluation Scale (SASS) was developed to assess the social impairment caused by depression. The purposes of this study were to develop a Japanese version of the SASS (SASS-J) and to evaluate its reliability and validity.

IL-35 Production by Inducible Costimulator (ICOS)-positive Regulatory T Cells Reverses Established IL-17-dependent Allergic Airways Disease

The Journal of Allergy and Clinical Immunology. Jan, 2012  |  Pubmed ID: 21906794

Recent evidence suggests that IL-17 contributes to airway hyperresponsiveness (AHR); however, the mechanisms that suppress the production of this cytokine remain poorly defined.

ATP Binding Cassette Transporter G1 Deletion Induces IL-17-dependent Dysregulation of Pulmonary Adaptive Immunity

Journal of Immunology (Baltimore, Md. : 1950). Jun, 2012  |  Pubmed ID: 22539789

Mice with genetic deletion of the cholesterol transporter ATP binding cassette G1 (ABCG1) have pulmonary lipidosis and enhanced innate immune responses in the airway. Whether ABCG1 regulates adaptive immune responses to the environment is unknown. To this end, Abcg1(+/+) and Abcg1(-/-) mice were sensitized to OVA via the airway using low-dose LPS as an adjuvant, and then challenged with OVA aerosol. Naive Abcg1(-/-) mice displayed increased B cells, CD4(+) T cells, CD8(+) T cells, and dendritic cells (DCs) in lung and lung-draining mediastinal lymph nodes, with lung CD11b(+) DCs displaying increased CD80 and CD86. Upon allergen sensitization and challenge, the Abcg1(-/-) airway, compared with Abcg1(+/+), displayed reduced Th2 responses (IL-4, IL-5, eosinophils), increased neutrophils and IL-17, but equivalent airway hyperresponsiveness. Reduced Th2 responses were also found using standard i.p. OVA sensitization with aluminum hydroxide adjuvant. Mediastinal lymph nodes from airway-sensitized Abcg1(-/-) mice produced reduced IL-5 upon ex vivo OVA challenge. Abcg1(-/-) CD4(+) T cells displayed normal ex vivo differentiation, whereas Abcg1(-/-) DCs were found paradoxically to promote Th2 polarization. Th17 cells, IL-17(+) γδT cells, and IL-17(+) neutrophils were all increased in Abcg1(-/-) lungs, suggesting Th17 and non-Th17 sources of IL-17 excess. Neutralization of IL-17 prior to challenge normalized eosinophils and reduced neutrophilia in the Abcg1(-/-) airway. We conclude that Abcg1(-/-) mice display IL-17-mediated suppression of eosinophilia and enhancement of neutrophilia in the airway following allergen sensitization and challenge. These findings identify ABCG1 as a novel integrator of cholesterol homeostasis and adaptive immune programs.

The Toll-like Receptor 5 Ligand Flagellin Promotes Asthma by Priming Allergic Responses to Indoor Allergens

Nature Medicine. Nov, 2012  |  Pubmed ID: 23064463

Allergic asthma is a complex disease characterized by eosinophilic pulmonary inflammation, mucus production and reversible airway obstruction. Exposure to indoor allergens is a risk factor for asthma, but this disease is also associated with high household levels of total and particularly Gram-negative bacteria. The ability of bacterial products to act as adjuvants suggests they might promote asthma by priming allergic sensitization to inhaled allergens. In support of this idea, house dust extracts (HDEs) can activate antigen-presenting dendritic cells (DCs) in vitro and promote allergic sensitization to inhaled innocuous proteins in vivo. It is unknown which microbial products provide most of the adjuvant activity in HDEs. A screen for adjuvant activity of microbial products revealed that the bacterial protein flagellin (FLA) stimulated strong allergic airway responses to an innocuous inhaled protein, ovalbumin (OVA). Moreover, Toll-like receptor 5 (TLR5), the mammalian receptor for FLA, was required for priming strong allergic responses to natural indoor allergens present in HDEs. In addition, individuals with asthma have higher serum levels of FLA-specific antibodies as compared to nonasthmatic individuals. Together, these findings suggest that household FLA promotes the development of allergic asthma by TLR5-dependent priming of allergic responses to indoor allergens.

Effect of a Plantar Perceptual Learning Task on Walking Stability in the Elderly: a Randomized Controlled Trial

Clinical Rehabilitation. Jul, 2013  |  Pubmed ID: 23405022

To determine whether the plantar perceptual learning task, using a hardness discrimination training, efficiently improves walking stability in the elderly.

Current Smoking Rate in Patients with Psychiatric Disorders in Japan: Questionnaire Survey

Psychiatry Research. Nov, 2013  |  Pubmed ID: 23601794

The association between smoking and psychiatric disorders (PD) has been known for many years. Support for smoking cessation among patients with PD is provided in advanced nations, but there is a little support for smoking cessation among patients with PD in Japan, where few studies have investigated the smoking rate. The aim of the present study is to determine the smoking rate and smoking habits of Japanese patients with PD. The subjects included outpatients who visited the outpatient psychiatric clinic at a University hospital between January and March of 2011. They answered a questionnaire consisting of questions about their sociodemographic background and smoking habits. In an analysis of 733 subjects, the overall smoking rate was 25.1%. The smoking rates among the patients with schizophrenia and depression were 17.3% and 23.9%, respectively, and these rates were lower than the results of previous studies. Among the current smokers, 43.4% had experienced smoking cessation, and only 26.1% were not interested in smoking cessation. Of the current smokers, 37.5% spent between US$128.88 and US$257 per month on cigarettes.

Changes in Electroencephalographic Activity During Observation, Preparation, and Execution of a Motor Learning Task

The International Journal of Neuroscience. Dec, 2013  |  Pubmed ID: 23768018

This study aimed to compare electroencephalographic (EEG) activity between high- and low-motor learning groups (n = 10 each) during observation of, preparation for, and execution of a motor learning task. The subjects performed a ball rotation task in which two balls were rotated clockwise with the right hand. Each trial started with a rest period (5 s), subjects then observed the task action on a computer screen (30 s), this was followed by another rest (5 s), preparation for performing the action (5 s), and finally action execution (30 s); five trials were performed. The number of rotations during execution and EEG activities during observation, preparation, and execution were recorded. The EEG data of the high-motor learning group were compared with those of the low-motor learning group and were analyzed using exact low-resolution electromagnetic tomography (eLORETA). The left sensorimotor and parietal areas of the high-motor learning group showed a greater decrease in the alpha-2 (10.5-12.0 Hz) and beta-2 (18.5-21.0 Hz) rhythms than those of the low-motor learning group during all three phases of the trials. The study results suggest that the decreases in the alpha-2 and beta-2 rhythms in these areas during observation, preparation, and execution are associated with motor skill improvement.

Pulmonary Antigen Presenting Cells: Isolation, Purification, and Culture

Methods in Molecular Biology (Clifton, N.J.). 2013  |  Pubmed ID: 23943441

Antigen presenting cells (APCs) such as dendritic cells (DCs) and macrophages comprise a relatively small fraction of leukocytes residing in lymphoid and non-lymphoid tissues. Accordingly, functional analyses of these cells have been hampered by low cell yields. Also, alveolar macrophages share several physical properties with DCs, and this has complicated efforts to prepare pure populations of lung APCs. To overcome these difficulties, we have developed improved flow cytometry-based methods to analyze and purify APCs from the lung and its draining lymph nodes (LNs). In this chapter, we describe these methods in detail, as well as methods for culturing APCs and characterizing their interactions with T cells.

Central Neural Mechanisms of Interindividual Difference in Discomfort During Sensorimotor Incongruence in Healthy Volunteers: an Experimental Study

Rheumatology (Oxford, England). Jul, 2014  |  Pubmed ID: 24591698

It has been reported that disturbance in sensory and motor function may induce sensorimotor incongruence and produce pain, discomfort and other sensations in healthy volunteers. One study suggested that sensorimotor incongruent information to healthy subjects results in increased neuronal activity in the posterior parietal cortex (PPC) and dorsolateral prefrontal cortex; however, this study did not take into consideration the discomfort induced by sensorimotor incongruence. The present study attempted to characterize intracortical electrical activities for sensorimotor incongruence in the frequency domain. In our study, electroencephalogram (EEG) cortical sources were compared between sensorimotor congruence and sensorimotor incongruence. In addition, high and no discomfort subgroups were compared during sensorimotor incongruence.

Factors Associated with the Modulation of Pain by Visual Distortion of Body Size

Frontiers in Human Neuroscience. 2014  |  Pubmed ID: 24688463

Modulation of pain using visual distortion of body size (VDBS) has been the subject of various reports. However, the mechanism underlying the effect of VDBS on pain has been less often studied. In the present study, factors associated with modulation of pain threshold by VDBS were investigated. Visual feedback in the form of a magnified image of the hand was provided to 44 healthy adults to examine changes in pain. In participants with a higher pain threshold when visual feedback of a magnified image of the hand was provided, the two-point discrimination threshold decreased. In contrast, participants with a lower pain threshold with visual feedback of a magnified image of the hand experienced unpleasant emotions toward the magnified image of the hand. Interestingly, this emotional reaction was strongly associated with negative body consciousness in several subjects. These data suggested an analgesic effect of visual feedback in the form of a magnified image of the hand is only when tactile perception is vivid and the emotional reaction toward the magnified image is moderate. The results also suggested that negative body consciousness is important for the modulation of pain using VDBS.

Aprepitant in Patients with Advanced Non-small-cell Lung Cancer Receiving Carboplatin-based Chemotherapy

Lung Cancer (Amsterdam, Netherlands). Jun, 2014  |  Pubmed ID: 24746177

Chemotherapy-induced nausea and vomiting (CINV) is an unanswered problem in cancer therapy. We evaluated the efficacy and safety of triple antiemetic therapy with aprepitant, a 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonist, and dexamethasone in patients with advanced non-small-cell lung cancer (NSCLC) who received carboplatin-based first-line chemotherapy.

Activation of the Serotonergic System by Pedaling Exercise Changes Anterior Cingulate Cortex Activity and Improves Negative Emotion

Behavioural Brain Research. Aug, 2014  |  Pubmed ID: 24815213

Pedaling exercise (PE) of moderate intensity has been shown to ease anxiety and discomfort; however, little is known of the changes that occur in brain activities and in the serotonergic (5-HT) system after PE. Therefore, this study was conducted for the following reasons: (1) to localize the changes in the brain activities induced by PE using a distributed source localization algorithm, (2) to examine the changes in frontal asymmetry, as used in the Davidson model, with electroencephalography (EEG) activity, and (3) to examine the effect of PE on the 5-HT system. A 32-channel EEG was used to record before and after PE. Profile of Mood States tests indicated that there was a significant decrease in tension-anxiety and a significant increase in vigor after PE. A standardized low-resolution brain electromagnetic tomography analysis showed a significant decrease in brain activities after PE in the alpha-2 band (10-12.5 Hz) in the anterior cingulate cortex (ACC). Moreover, a significant increase in frontal EEG asymmetry was observed after PE in the alpha-1 band (7.5-10 Hz). Urine 5-HT levels significantly increased after PE. Urine 5-HT levels positively correlated with the degree of frontal EEG asymmetry in the alpha-1 band and negatively correlated with brain activity in ACC. Our results suggested that PE activates the 5-HT system and consequently induces increases in frontal EEG asymmetry in the alpha-1 band and reductions of brain activity in the alpha-2 band in the ACC region.

Brain Activity Associated with the Illusion of Motion Evoked by Different Vibration Stimulation Devices: An FNIRS Study

Journal of Physical Therapy Science. Jul, 2014  |  Pubmed ID: 25140108

[Purpose] A number of different stimulation devices are used in basic and clinical research studies, and their frequencies of use vary. However, whether or not they are equally effective has not been investigated. The purpose of the present study was to investigate neural activity in the brain during the illusion of motion evoked by stimulating the tendons of the wrist extensor muscles using various vibration devices. [Subjects] Twelve right-handed university students with no history of nervous system disorder or orthopedic disease participated in the study. [Methods] The wrist extensor tendon was stimulated using 3 different devices: 1) a vibration stimulation device (SL-0105 LP; Asahi Seisakusho Co., Ltd., Saitama, Japan), frequency 80 Hz; 2) a handy massager (YCM-20; Yamazen Corporation, Osaka, Japan), frequency 70 Hz; and 3) a handy massager (Thrive MD-01; Thrive Co., Ltd., Osaka, Japan), frequency 91.7 Hz. Brain activity was recorded during stimulation by using functional near-infrared spectroscopy. [Results] Increased neural activity was observed in both the premotor cortices and the parietal region in both hemispheres in all 3 cases. The level and localization of neural activity was comparable for all 3 stimulation devices used. [Conclusion] This suggests that subjects experience the illusion of motion while the tendon is being stimulated using any vibration device.

Epigenetic Control of Ccr7 Expression in Distinct Lineages of Lung Dendritic Cells

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2014  |  Pubmed ID: 25297875

Adaptive immune responses to inhaled allergens are induced following CCR7-dependent migration of precursor of dendritic cell (pre-DC)-derived conventional DCs (cDCs) from the lung to regional lymph nodes. However, monocyte-derived (moDCs) in the lung express very low levels of Ccr7 and consequently do not migrate efficiently to LN. To investigate the molecular mechanisms that underlie this dichotomy, we studied epigenetic modifications at the Ccr7 locus of murine cDCs and moDCs. When expanded from bone marrow precursors, moDCs were enriched at the Ccr7 locus for trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with transcriptional repression. Similarly, moDCs prepared from the lung also displayed increased levels of H3K27me3 at the Ccr7 promoter compared with migratory cDCs from that organ. Analysis of DC progenitors revealed that epigenetic modification of Ccr7 does not occur early during DC lineage commitment because monocytes and pre-DCs both had low levels of Ccr7-associated H3K27me3. Rather, Ccr7 is gradually silenced during the differentiation of monocytes to moDCs. Thus, epigenetic modifications of the Ccr7 locus control the migration and therefore the function of DCs in vivo. These findings suggest that manipulating epigenetic mechanisms might be a novel approach to control DC migration and thereby improve DC-based vaccines and treat inflammatory diseases of the lung.

Effects of Voluntary and Automatic Control of Center of Pressure Sway During Quiet Standing

Journal of Motor Behavior. 2015  |  Pubmed ID: 25425422

The authors investigated the effects of voluntary and automatic control on the spatial variables (envelope area, maximal amplitude, and root mean square [RMS]) of center of pressure (COP) displacement during quiet standing and identified differences in their postural control strategies (mean velocity [MV], mean power frequency [MPF], and power density). COP data were recorded under relaxed (experimental control), still (voluntary control), and dual (automatic control) conditions. RMS was significantly lower in the still and dual conditions than in the relaxed condition. MV, MPF, and power density were significantly higher in the still condition than in the dual condition. These results indicate that both voluntary and automatic control decrease the spatial variables of COP displacement; however, their postural control strategies are different.

Effects of Voluntary and Automatic Control of Center of Pressure Sway During Quiet Standing

Journal of Motor Behavior. 2015  |  Pubmed ID: 25649050

Complement Receptor C5aR1/CD88 and Dipeptidyl Peptidase-4/CD26 Define Distinct Hematopoietic Lineages of Dendritic Cells

Journal of Immunology (Baltimore, Md. : 1950). Apr, 2015  |  Pubmed ID: 25769922

Differential display of the integrins CD103 and CD11b are widely used to distinguish two major dendritic cell (DC) subsets in nonlymphoid tissues. CD103(+) DCs arise from FLT3-dependent DC precursors (preDCs), whereas CD11b(hi) DCs can arise either from preDCs or FLT3-independent monocytes. Functional characterization of these two lineages of CD11b(hi) DCs has been hindered by the lack of a widely applicable method to distinguish between them. We performed gene expression analysis of fractionated lung DCs from C57BL/6 mice and found that monocyte-derived DCs (moDCs), including CD11b(hi)Ly-6C(lo) tissue-resident and CD11b(hi)Ly-6C(hi) inflammatory moDCs, express the complement 5a receptor 1/CD88, whereas preDC-derived conventional DCs (cDCs), including CD103(+) and CD11b(hi) cDCs, express dipeptidyl peptidase-4/CD26. Flow cytometric analysis of multiple organs, including the kidney, liver, lung, lymph nodes, small intestine, and spleen, confirmed that reciprocal display of CD88 and CD26 can reliably distinguish FLT3-independent moDCs from FLT3-dependent cDCs in C57BL/6 mice. Similar results were obtained when DCs from BALB/c mice were analyzed. Using this novel approach to study DCs in mediastinal lymph nodes, we observed that most blood-derived lymph node-resident DCs, as well as tissue-derived migratory DCs, are cDCs. Furthermore, cDCs, but not moDCs, stimulated naive T cell proliferation. We anticipate that the use of Abs against CD88 and CD26 to distinguish moDCs and cDCs in multiple organs and mouse strains will facilitate studies aimed at assigning specific functions to distinct DC lineages in immune responses.

Effect of Anticipation Triggered by a Prior Dyspnea Experience on Brain Activity

Journal of Physical Therapy Science. Mar, 2015  |  Pubmed ID: 25931697

[Purpose] Oxygenated hemoglobin (oxy-Hb) concentrations in the prefrontal cortex are closely associated with dyspnea. Dyspnea is influenced not only by physical activity, but also by visual stimuli, and several studies suggest that oxy-Hb concentrations change in response to certain external stimuli. However, the effects of internal psychological states on dyspnea have not been reported. This study explored the influence of anticipation triggered by previous episodes of dyspnea on brain activity. [Subjects] The subjects were 15 healthy volunteers with a mean age of 25.0 ± 3.0 years. [Methods] The subjects were shown a variety of photographs and instructed to expect breathing resistance matched to the affective nature of the particular photograph. After viewing the images, varying intensities of breathing resistance that were identical to, easier than, or harder than those shown in the images were randomly administered to the subjects; in fact, the image and resistance were identical 33% of the time and discordant 66% of the time. [Results] The concentrations of oxy-Hb in the right medial prefrontal cortex (rMPFC) increased significantly with an inspiratory pressure that was 30% of the maximum intensity in the subjects shown a pleasant image compared to the concentrations in subjects shown an unpleasant image. Moreover, rMPFC activity was significantly correlated with the magnitude of the dyspnea experienced. [Conclusion] These results suggest that a correlation exists between increased oxy-Hb in the rMPFC and the effects of expectations on dyspnea.

Inhaled House Dust Programs Pulmonary Dendritic Cells to Promote Type 2 T-cell Responses by an Indirect Mechanism

American Journal of Physiology. Lung Cellular and Molecular Physiology. Nov, 2015  |  Pubmed ID: 26386119

The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.

Effects of Vibratory Stimulation-induced Kinesthetic Illusions on the Neural Activities of Patients with Stroke

Journal of Physical Therapy Science. Jan, 2016  |  Pubmed ID: 27065525

[Purpose] This study evaluated the influence of vibratory stimulation-induced kinesthetic illusion on brain function after stroke. [Subjects] Twelve healthy individuals and 13 stroke patients without motor or sensory loss participated. [Methods] Electroencephalograms were taken at rest and during vibratory stimulation. As a neurophysiological index of brain function, we measured the μ-rhythm, which is present mainly in the kinesthetic cortex and is attenuated by movement or motor imagery and compared the data using source localization analyses in the Standardized Low Resolution Brain Electromagnetic Tomography (sLORETA) program. [Results] At rest, μ-rhythms appeared in the sensorimotor and supplementary motor cortices in both healthy controls and stroke patients. Under vibratory stimulation, no μ-rhythm appeared in the sensorimotor cortex of either group. Moreover, in the supplementary motor area, which stores the motor imagery required for kinesthetic illusions, the μ-rhythms of patients were significantly stronger than those of the controls, although the μ-rhythms of both groups were reduced. Thus, differences in neural activity in the supplementary motor area were apparent between the subject groups. [Conclusion] Kinesthetic illusions do occur in patients with motor deficits due to stroke. The neural basis of the supplementary motor area in stroke patients may be functionally different from that found in healthy controls.

Distinct Functions of CXCR4, CCR2, and CX3CR1 Direct Dendritic Cell Precursors from the Bone Marrow to the Lung

Journal of Leukocyte Biology. Feb, 2017  |  Pubmed ID: 28148720

Precursors of dendritic cells (pre-DCs) arise in the bone marrow (BM), egress to the blood, and finally migrate to peripheral tissue, where they differentiate to conventional dendritic cells (cDCs). Upon their activation, antigen-bearing cDCs migrate from peripheral tissue to regional lymph nodes (LNs) in a manner dependent on the chemokine receptor, CCR7. To maintain immune homeostasis, these departing cDCs must be replenished by new cDCs that develop from pre-DCs, but the molecular signals that direct pre-DC trafficking from the BM to the blood and peripheral tissues remain poorly understood. In the present study, we found that pre-DCs express the chemokine receptors CXCR4, CCR2, and CX3CR1, and that each of these receptors has a distinct role in pre-DC trafficking. Flow cytometric analysis of pre-DCs lacking CXCR4 revealed that this receptor is required for the retention of pre-DCs in the BM. Analyses of mice lacking CCR2 or CX3CR1, or both, revealed that they promote pre-DC migration to the lung at steady state. CCR2, but not CX3CR1, was required for pre-DC migration to the inflamed lung. Thus, these multiple chemokine receptors cooperate in a step-wise fashion to coordinate the trafficking of pre-DCs from the BM to the circulation and peripheral tissues.

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