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Tomomi Tanigai,
Shigeharu Ueki,
Junko Kihara,
Rie Kamada,
Yumiko Yamauchi,
Andrei Sokal,
Masahide Takeda,
Wataru Ito,
Hiroyuki Kayaba, Tetsuya Adachi,
Ken Ohta,
Junichi Chihara
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ABSTRACT: Despite the fact that previous studies have indicated the significant roles of polyunsaturated fatty acids (PUFAs) in the immune system through peroxisome proliferator-activated receptor alpha (PPARα) and PPARγ, the biological functions and the mechanisms of action in eosinophils are poorly understood.
We investigated the functional effects of docosahexaenoic acid (DHA, n-3 PUFA) on human peripheral blood eosinophils, using in vitro systems to test the hypothesis that DHA negatively regulates eosinophil mechanisms through PPARα and PPARγ.
Eosinophil apoptosis that spontaneously occurs under normal culture conditions was accelerated in the presence of DHA. In addition, eotaxin-directed eosinophil chemotactic responses were inhibited by pretreatment with DHA, disturbing both the velocity and the directionality of the cell movement. Pharmacological manipulations with specific antagonists indicated that the effects of DHA were not mediated through PPARα and PPARγ, despite the presence of these nuclear receptors. DHA also induced Fas receptor expression and caspase-3 activation that appears to be associated with a proapoptotic effect of DHA. Further, DHA rapidly inhibited the expression of eotaxin receptor C-C chemokine receptor 3 and eotaxin-induced calcium influx and phosphorylation of extracellular signal-regulated kinase. Interestingly, these inhibitory effects were not observed with linoleic acid (n-6 PUFA).
The data might explain one of the mechanisms found in previous research showing the favorable effects of n-3 PUFA supplementation on allergic diseases, and provide novel therapeutic strategies to treat eosinophilic disorders.
International Archives of Allergy and Immunology 04/2012; 158(4):375-86. · 2.40 Impact Factor
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ABSTRACT: We report a case of bronchopleural fistula in a patient with allergic bronchopulmonary aspergillosis. A 25-year-old man was admitted with high fever and chest pain. Although his chest CT in a previous hospital showed pulmonary infiltrate suggesting the existence of a mucous plug, a mass shadow in the right upper lobe was recognized on admission to our hospital. Based on the presence of eosinophilia, elevated levels of total IgE and Aspergillus-specific IgE, positive precipitating antibody to Aspergillus, and detection of A. fumigatus in bronchial washing fluid, we diagnosed this case as ABPA complicated with lung abscess. Although we treated by antibiotics and antifungal drugs, the lung abscess did not improve and led to bronchopleural fistula. After addition of nebulised liposomal amphotericin B, his symptoms improved and treatment was successful.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 06/2009; 47(5):432-7.
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ABSTRACT: Eosinophils play a pivotal role in the pathogenesis of asthma. Thus, it is of paramount importance to investigate the mechanism of eosinophil activation. Although a number of factors including cytokines/chemokines activate eosinophils, the potency of each stimulus to phosphorylate intracellular molecules and activate eosinophils remains to be elucidated. In the present study, we performed inclusive analyses of protein phosphorylation in eosinophils and studied the functional relevance of such phosphorylation in cytokine production.
Blood eosinophils were purified using Percoll and anti-CD16 antibody-coated magnetic beads. Purified eosinophils were stimulated with various stimuli. The eosinophil lysates were subjected to phosphoprotein analysis using the Luminex system. In some of these experiments, we studied the effect of a few signaling inhibitors on cytokine production from eosinophils.
We found that several factors such as IL-5, eotaxin, platelet-activating factor (PAF), and PGD2 phosphorylated Akt, ERK1/2, p38 MAPK, and glycogen synthase kinase-3 (GSK-3) in the eosinophils. Because eotaxin most potently induced the production of various cytokines, we performed the inhibition study using eotaxin-stimulated eosinophils. Eotaxin-induced production of IL-1beta, IL-6, and MIP-1beta was significantly reduced by the MEK inhibitor PD98059, p38 MAPK inhibitor SB203580, or PI3K inhibitor LY294002. In contrast, the GSK-3 inhibitor SB216763 blocked only IL-1beta production from the eosinophils.
In terms of the phosphorylation of intracellular signaling molecules, we could quantify the potency of various stimuli that activate eosinophils. We are the first to demonstrate the role of GSK-3 in cytokine production from eosinophils. The Luminex system aids in examining the mechanism of eosinophil activation.
International Archives of Allergy and Immunology 02/2009; 149 Suppl 1:45-50. · 2.40 Impact Factor
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Kumiya Sugiyama,
Hironori Sagara,
Mitsuru Adachi,
Kenji Minoguchi,
Akihiko Tanaka,
Hiroshi Inoue,
Kouhei Yamauchi,
Hitoshi Kobayashi,
Kazuo Akiyama,
Naomi Tsurikisawa, [......],
Michiaki Mishima,
Akio Niimi,
Hisako Matsumoto,
Ken Ohta, Tetsuya Adachi,
Hiroyuki Nagase,
Hiroshi Nakajima,
Shin-ichiro Kagami,
Itsuo Iwamoto,
Takeshi Fukuda
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ABSTRACT: In asthmatic patients, first asthmatic symptoms are not often typical. In those cases, it takes long time before asthma diagnosis, and the severities are progressed in some patients. For early intervention, we tried to make the diagnostic criteria for asthma, which are useful to diagnose as early stage of asthma.
Three hundred and eighty eight of asthmatic patients, who were recorded first their symptoms in asthma, were enrolled. Their first symptoms and examinations were analyzed.
In first asthmatic symptoms, 79% of patients had cough, 68% patients had wheezing, 49% patients had dyspnoea, and 15% of patients did not have typical asthmatic symptoms in the early stage. The percentages of abnormal in first examinations were 99% in airway hypersensitivity, 92% of low %V25, 82% of eosinophila in sputum and 77% of low %V50. Low FEV1% and reversible airway obstruction were not seen in a lot of patients.
We advocate that the diagnostic criteria for early stage of asthma are the following three elements. First criterion is spasmodic cough, wheezing and dyspnoea. Second criterion is airway hypersensitivity, or over 3% of eosinophils in sputum, or under 70% of %V50, or under 50% of %V25, or effect of bronchodilator. Effect of bronchodilator will be required, when the symptom is cough only. Third criterion is the exclusion of other lung and heart diseases.
Arerugī = [Allergy] 01/2009; 57(12):1275-83.
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ABSTRACT: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is part of a complex signaling system that affects a variety of important cell functions. PTEN antagonizes the action of PI3K by dephosphorylating the signaling lipid phosphatidylinositol 3,4,5-triphosphate. In the present study, we used a TAT fusion protein transduction system to elucidate the role of PTEN in eosinophils and airway inflammation. A small region of the HIV TAT protein (YGRKKRRQRRR), a protein transduction domain known to enter mammalian cells efficiently, was fused to the N terminus of PTEN. Flow cytometric analysis of annexin V- and propidium iodide-stained cells was used to assess eosinophil survival. A chemotaxis assay was performed using a Boyden chamber. Cell analysis in bronchoalveolar lavage fluid and histological examinations were performed using OVA-challenged A/J mice. We found that TAT-PTEN was successfully internalized into eosinophils and functioned as a phosphatase in situ. TAT-PTEN, but not a TAT-GFP control protein, blocked the ability of IL-5 to prevent the apoptosis of eosinophils from allergic subjects. The eotaxin-induced eosinophil chemotaxis was inhibited by TAT-PTEN in a dose-dependent manner. Intranasal pretreatment with TAT-PTEN, but not TAT-GFP, significantly inhibited the OVA-induced eosinophil infiltration in bronchoalveolar lavage fluid. Histological examination of the lung, including H&E and Alcian blue/periodic acid-Schiff staining, revealed that TAT-PTEN, but not TAT-GFP, abrogated eosinophilic inflammation and mucus production. Our results suggest that PTEN negatively regulates eosinophil survival, chemotaxis, and allergic inflammation. The pharmacological targeting of PTEN may constitute a new strategy for the treatment of eosinophilic disorders.
The Journal of Immunology 12/2007; 179(12):8105-11. · 5.79 Impact Factor
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ABSTRACT: beta-agonists are frequently used as bronchodilators for asthma as not only a reliever but also a controller, and their utility has increased with the development of long-acting beta(2) selective drugs. Although anti-inflammatory effects of beta(2) selective-agonists have been reported in vitro, side effects on augmentation of airway hyperresponsiveness by chronic use of beta(2) selective-agonists have been described in several reports. In this study, we investigated the effects of procaterol, a second-generation beta(2)-agonist, on airway inflammation in vivo using an antigen-specific murine model of asthma.
Mice immunized with ovalbumin (OVA) + alum and challenged with inhaled ovalbumin were orally administered procaterol during the challenge. After inhalation, the mice were tracheostomized and placed in a body box under controlled ventilation to measure airway resistance before and after acetylcholine inhalation.
Administration of procaterol at a clinical dose equivalent did not augment airway hyperresponsiveness, inflammation of the airway wall, or subsequent airway wall thickening induced by OVA inhalation. BALF cell analysis revealed that the eosinophil number in the BALF was significantly reduced in procaterol-treated mice compared to untreated mice.
Oral administration of procaterol at a clinical dose did not augment airway responsiveness, but did reduce eosinophil inflammation.
Allergology International 10/2007; 56(3):241-7.
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ABSTRACT: The cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is recognized as a potent lipid mediator that is derived from PGD(2), which is produced abundantly in allergic inflammatory sites. It is now established that 15d-PGJ(2) negatively regulates cellular functions through its intracellular targets such as peroxisome proliferator-activated receptor-gamma (PPARgamma). However, recent studies revealed that 15d-PGJ(2) appears to possess not only anti-inflammatory activities but also a proinflammatory potential depending on its concentration and the activation state of the target cell. For instance, at low concentrations, 15d-PGJ(2) enhances eotaxin-induced chemotaxis, shape change, and actin reorganization in eosinophils through its ligation with PPARgamma. Moreover, 15d-PGJ(2) itself is a potent chemoattractant, and it induces calcium mobilization, and up-regulates CD11b expression through its membrane receptor--chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Conversely, at high concentrations, 15d-PGJ(2) inhibits eosinophil survival by inducing apoptosis in a PPARgamma-independent manner. Here, we discuss the pathophysiological roles of 15d-PGJ(2) that could act as a paracrine, autocrine, and intracrine substance to regulate eosinophil functions.
International Archives of Allergy and Immunology 02/2007; 143 Suppl 1:15-22. · 2.40 Impact Factor
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ABSTRACT: Receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) are capable of eliciting kinase activity after ligand binding. In several cells, RTKs are activated via the G-protein-coupled receptor independent of the ligand-RTK interaction. We have previously found that EGFR is transactivated via CC chemokine receptor 3 in bronchial epithelial cells and that this pathway is important for mitogen-activated protein (MAP) kinase activation and cytokine production. It has recently been suggested that hypereosinophilic syndrome results from the fusion tyrosine kinase FIP1L1-PDGFRA. Although it is possible that the PDGFR signal is involved in eosinophil function, the details are still unclear.
Blood eosinophils were purified using Percoll and anti-CD16 antibody-coated magnetic beads. Expression of PDGFR mRNA was examined by RT-PCR. After stimulating eosinophils with eotaxin, the phosphorylation of MAP kinases was examined by Western blotting with the antiphosphospecific MAP kinase antibody. The eotaxin-induced eosinophil chemotaxis was studied using Boyden chambers.
Eosinophils expressed PDGFRbeta mRNA in 4 out of 8 donors, while PDGFRalpha mRNA was expressed in only 1 donor. Protein expression of PDGFR was also detectable in eosinophils from some donors. AG1295, a specific inhibitor of PDGFR, showed dose-dependent inhibition of eotaxin-induced MAP kinase phosphorylation in the eosinophils expressing PDGFRbeta mRNA. The chemotaxis of these eosinophils was significantly inhibited by AG1295 (n = 3).
Our results suggest that PDGFR modifies the CCR3-MAP kinase signaling pathway and chemotactic response in some donors. The pharmacological targeting of PDGFR may be a new strategy to treat eosinophilic disorders.
International Archives of Allergy and Immunology 02/2006; 140 Suppl 1:28-34. · 2.40 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that regulates lipid metabolism. Recently, PPARgamma was reported to be a negative regulator in the immune system. Eosinophils also express PPARgamma, however, the role of PPARgamma in eosinophil functions is not well understood. Surface expression of CD69 and eosinophil-derived neurotoxin (EDN) release are well-known activation markers of eosinophils. We investigated the effect of a PPARgamma agonist on human eosinophil functions such as IL-5-induced CD69 surface expression and EDN release. IL-5 significantly induced eosinophil CD69 surface expression analyzed using flow cytometry and EDN release measured by ELISA. IL-5-induced eosinophil CD69 surface expression and EDN release were significantly inhibited by the synthetic PPARgamma agonist troglitazone, and these effects were reversed by a PPARgamma antagonist. The PPARgamma agonist troglitazone has a potent inhibitory effect on activation and degranulation of eosinophils, and it may be a therapeutic modality for the treatment of allergic diseases.
Pharmacology 08/2005; 74(4):169-73. · 1.79 Impact Factor
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ABSTRACT: Insulin-like growth factor (IGF)-I is known to act on fibroblasts as a progression factor to push cells toward proliferation and activation to synthesize collagen. Subepithelial fibrosis, collagen deposition at the lamina reticularis, is part of the process of so-called remodeling and is a characteristic finding in the asthmatic airway. To study the role of IGF in the evolution of asthma, we used a model that involved immunization of mice with ovalbumin and alum, followed by an inhaled challenge of ovalbumin. IGF-I neutralizing antibody was continuously infused with an osmotic pump. Pulmonary function was analyzed using whole-body plethysmography before and after acetylcholine administration. It was found that OVA inhalation induced IGF-I expression at the site of the airway. IGF-I neutralizing Ab inhibited the elevation of airway resistance, airway inflammation, and an increase in airway wall thickening. The depression of ICAM-1 expression was accompanied by a diminution in airway inflammation. In conclusion, these results suggest that IGF-I is likely to be an important mediator of inflammation and remodeling in the asthmatic airway.
Cellular Immunology 07/2005; 235(2):85-91. · 1.97 Impact Factor
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Hiroyuki Kayaba,
Hitomi Meguro,
Hajime Muto,
Yumiko Kamada, Tetsuya Adachi,
Yoshiyuki Yamada,
Akira Kanda,
Kazutoshi Yamaguchi,
Kazuyuki Hamada,
Shigeharu Ueki,
Junichi Chihara
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ABSTRACT: Grain dust and other irritants affect the airway of allergic patients in rice-growing area during the harvest. The aim of this study was to elucidate the mechanism of airway hypersensitivity in rice-growing areas during the harvest. Firstly, the effect of rice-husk dust on eosinophil activation was studied. Secondary, the concentration of lipopolysaccharides (LPS), a potent activator of inflammatory cells, in rice-husk dust was measured. Since it is possible for LPS, a component of gram-negative bacterial cell wall, to adhere to the particle of smoke generated from rice-husk dust, LPS contained in the smoke was also measured. Furthermore, chemical irritants contained in the smoke generated from the rice-husk dust were analyzed. Microscopically, the dust contained fine thorns dropped off from the outer sheath of the rice, and irritated the skin, throat and eyes. The grain dust extract increased the expressions of eosinophil activation markers. These up-regulatory effects were largely dependent on LPS. The smoke contained LPS and several chemical irritants such as formaldehyde and acetaldehyde. Rice-husk dust and its smoke, hazardous air pollutants, probably play a major role in the aggravation of airway diseases in agricultural areas.
The Tohoku Journal of Experimental Medicine 10/2004; 204(1):27-36. · 1.24 Impact Factor
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ABSTRACT: We have previously found that bronchial epithelial cells express CCR3 whose signaling elicits mitogen-activated protein (MAP) kinase activation and cytokine production. Several investigators have focused on the signaling crosstalk between G protein-coupled receptors (GPCRs) and epidermal growth factor receptor (EGFR) in cancer cells. In this study, we investigated the role of EGFR in CCR3 signaling in the bronchial epithelial cell line NCI-H292. Eotaxin (1-100 nM) induced dose-dependent tyrosine phosphorylation of EGFR in NCI-H292 cells. Pretreatment of the cells with the EGFR inhibitor (AG1478) significantly inhibited the MAP kinase phosphorylation induced by eotaxin. Eotaxin stimulated IL-8 production, which was inhibited by AG1478. The transactivation of EGFR through CCR3 is a critical pathway that elicits MAP kinase activation and cytokine production in bronchial epithelial cells. The delineation of the signaling pathway of chemokines will help to develop a new therapeutic strategy to allergic diseases including bronchial asthma.
Biochemical and Biophysical Research Communications 08/2004; 320(2):292-6. · 2.48 Impact Factor
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Yoshiyuki Yamada,
Satoshi Sannohe,
Norihiro Saito,
Chang-Hao Cui,
Shigeharu Ueki,
Hajime Oyamada,
Akira Kanda,
Kazutoshi Yamaguchi,
Kazuyuki Hamada, Tetsuya Adachi,
Hiroyuki Kayaba,
Junichi Chihara
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ABSTRACT: Ketotifen is an antiallergic drug and may have direct inhibitory effects on eosinophils. To investigate the anti-eosinophilic effect of ketotifen, we examined the effect of ketotifen on the production of reactive oxygen species (ROS) from eotaxin-primed human eosinophils. Ketotifen at 10(-10)-10(-6) mol/l significantly reduced the production of ROS evoked by A23187 from eosinophils primed by eotaxin. In contrast, ketotifen at 10(-5) mol/l significantly augmented the production in the absence of eotaxin. We demonstrated that appropriate concentrations of ketotifen may have direct inhibitory effects on eosinophil oxidative metabolism primed by eotaxin. Ketotifen may contribute to the treatment of allergic disease through its anti-eosinophilic effects.
Pharmacology 12/2003; 69(3):138-41. · 1.79 Impact Factor
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ABSTRACT: Idiopathic chronic constipation (ICC) is one of the most common clinical conditions in children. The pathophysiology is multifactorial and differs from case to case. To investigate the relationship between anorectal motility (ARM) and clinical course in children with ICC, anorectal function was evaluated using fecoflowmetry in nine children aged 2-14 years (mean 6.1). Three were boys and six were girls. Pressure fluctuations in the rectum and anal canal were simultaneously recorded during saline (250-500 ml) infusion into the rectum. The dynamics of defecation were evaluated using recordings of the saline evacuation curve from the rectum in each patient. Seven patients showed periodic contractions of the rectum accompanied (five) or unaccompanied (two) by relaxations of the anal canal during saline infusion. These patients achieved comfortable spontaneous defecation during follow-up periods ranging from 5 to 20 months. The other two exhibited no rectal contractions in spite of relaxations of the anal canal, and did not respond well to long-term medical management. In eight patients segmental fecoflowmetric curves showed a significantly lower flow rate and longer evacuation time than those of controls. Fecoflowmetry is a simple and non-invasive technique for evaluation of the ability to defecate. Disturbances of ARM may play an important role in patients with severe ICC. When evaluating anorectal function in children with chronic constipation, more attention should be paid to ARM and fecodynamics.
Pediatric Surgery International 07/2003; 19(4):251-5. · 1.25 Impact Factor
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ABSTRACT: Eosinophils play a pivotal role in the mechanism of allergic diseases including asthma. Interleukin-5 (IL-5) and eotaxin are critical cytokines/chemokines for eosinophil activation. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates lipid metabolism. Recent evidence has suggested that PPARgamma serves as a negative regulator in the immune system. In the present study, we investigated the expression of PPARgamma and effect of PPARgamma agonist on human eosinophils. We demonstrated that purified eosinophils and Eol-1 cells express PPARgamma at the mRNA and protein levels. The PPARgamma agonist troglitazone reduced the IL-5-stimulated, but not spontaneous, eosinophil survival in a concentration-dependent manner. Moreover, the eotaxin-directed eosinophil chemotaxis was dose-dependently inhibited by troglitazone. Our results suggest that the administration of the PPARgamma agonists thiazolidinediones could be a new therapeutic modality for the treatment of allergic diseases such as asthma.
Immunology Letters 05/2003; 86(2):183-9. · 2.53 Impact Factor
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ABSTRACT: The pathogenesis of bronchial asthma is chronic airway inflammation caused by immune cells such as T lymphocytes and eosinophils. Eosinophils release cytotoxic products including reactive oxygen species at the site of inflammation, leading to epithelial damage. Human thioredoxin (TRX), a redox-regulating protein with antioxidant activity, is induced and secreted from cells by oxidative stress. This study was undertaken to investigate the clinical significance of TRX in the pathogenesis of asthma. We collected blood samples from 48 patients with bronchial asthma with or without attack, and measured serum ECP and pulmonary function as well as serum TRX. The serum TRX levels in patients with asthma were significantly increased in patients with mild (34.63 [28.40-42.73] ng/ml, medians with 25 and 75% interquartiles, P=0.0064) and moderate (38.83 [35.14-50.80] ng/ml, P=0.0017) asthma attacks compared with those during the asymptomatic period. The serum TRX levels were inversely correlated with FEV(1.0)% (r=-0.44, P=0.039) and %PEF (r=-0.49, P=0.020) during attack. There was a significant correlation between the serum TRX and the serum eosinophil cationic protein (rs=0.32, P=0.016). These findings suggest that serum TRX is related to the state of asthma exacerbation and allergic inflammation.
Immunology Letters 05/2003; 86(2):199-205. · 2.53 Impact Factor
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ABSTRACT: Disturbance in anorectal function is a major factor restricting the activities of daily living in patients with spinal cord disorders. To detect changes in anorectal motilities due to a tethered spinal cord, anorectal functions were evaluated using a saline enema test and fecoflowmetry before and after patients underwent untethering surgery.
The bowel functions in five patients with a tethered cord syndrome (TCS) were evaluated by performing a saline enema test and fecoflowmetry. The contractile activity of the rectum, the volume of infused saline tolerated in the rectum, anal canal pressure, and the ability to evacuate rectal content were examined. The characteristic findings in anorectal motility studies conducted in patients with TCS were a hyperactive rectum, diminished rectal saline-retention ability, and diminished maximal flow in saline evacuation. A hyperactive rectum was considered to be a major contributing factor to fecal incontinence. In one asymptomatic patient diminished anal squeezing pressure was exhibited and was incontinent to liquid preoperatively, but recovered after surgery. Two patients who underwent surgery for myeloschisis as infants complained of progressive fecal incontinence when they became adolescents. In one patient fecal incontinence improved but in another patient no improvement was observed after untethering surgery.
Fecodynamic studies allow the detection of neurogenic disturbances of the anorectum in symptomatic and also in asymptomatic patients with TCS. More attention should be paid to the anorectal functions of patients with TCS.
Journal of Neurosurgery 05/2003; 98(3 Suppl):251-7. · 2.96 Impact Factor
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ABSTRACT: Eosinophil migration in the tissue is one characteristic feature of allergic diseases. The CC chemokine eotaxin plays a pivotal role in local accumulation of eosinophils. Myosin light chain kinase (MLCK) is known to regulate cytoskeletal rearrangement and cell motility by means of phosphorylation of myosin light chain (MLC).
We have previously shown that mitogen-activated protein (MAP) kinases are important for eosinophil migration. In the present study we hypothesized that MLCK is downstream of MAP kinases, thereby linking the MAP kinase pathway to the activation of cytoskeletal components required for eosinophil chemotaxis.
Blood eosinophils were purified by using Percoll and anti-CD16 antibody-coated magnetic beads. We investigated the phosphorylation of MLCK and MLC by using the phosphorous 32-orthophosphates-labeled eosinophils. The kinase activity of MLCK was determined by measuring the phosphotransferase activity for the MLCK-specific peptide substrate. The chemotaxis assay was performed in a 48-well Boyden microchamber.
The phosphotransferase activity of MLCK for a substrate peptide was enhanced in eotaxin-stimulated eosinophils. We also found that eotaxin induced phosphorylation of MLCK in vivo in phosphorous 32-orthophosphate-labeled eosinophils. PD98059 (MAP/extracellular signal-regulated kinase inhibitor) or SB202190 (p38 MAP kinase inhibitor) abrogated the eotaxin-induced phosphorylation of MLCK. The phosphorylation of MLC was upregulated by eotaxin. Eosinophil chemotaxis was inhibited by means of pretreatment of the MLCK inhibitor ML-7.
These results suggest that eotaxin regulates MLCK through both extracellular signal-regulated kinase 1/2 and p38 MAP kinase. MLCK activation is a critical step in the cytoskeletal rearrangements leading to eosinophil migration.
Journal of Allergy and Clinical Immunology 02/2003; 111(1):113-6. · 11.00 Impact Factor
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ABSTRACT: Nontyphoidal salmonellosis has a wide variety of clinical presentations. With the aim of describing the detailed clinical presentations of gastroenteritis caused by nontyphoidal Salmonella spp., findings for 126 patients (1-94 years of age; 37.0 years on average) were analyzed. Nontyphoidal salmonellosis is prevalent from April to October in Akita, when the mean atmospheric temperature exceeds 10 degrees C. On physical examination, 3 patients had rebound tenderness and muscle guarding on their abdominal wall; 1 of these patients underwent surgery for associated acute appendicitis. Elderly patients tended to be more seriously affected, resulting in severe dehydration. Elevation of the serum C-reactive protein (CRP) level correlated well with a decline in the platelet count. Although nontyphoidal salmonellosis is a common cause of acute gastroenteritis, thorough investigation and meticulous care are required so that conditions requiring surgical treatment or those that are potentially fatal are not overlooked.
Journal of Infection and Chemotherapy 10/2002; 8(3):232-6. · 1.80 Impact Factor
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ABSTRACT: Eotaxin is a critical chemokine eliciting migration of eosinophils and basophils in the pathogenesis of bronchial asthma. Recent studies have shown that the specific receptor for eotaxin, CCR3, is expressed in bronchial epithelial cells. Although mitogen-activated protein (MAP) kinases are involved in diverse cell functions of bronchial epithelial cells, their role in eotaxin signaling is unknown. In this study, we studied the activation and functional relevance of MAP kinases in bronchial epithelial cells stimulated with eotaxin. Eotaxin (1-100 nM) induced tyrosine/threonine phosphorylation and activation of extracellular regulated kinase (ERK) 1/2 and p38 in NCI-H(292) cells and normal human bronchial epithelial cells. The phosphorylation of these MAP kinases was detectable after 30 s, and peaked at 5 min. Eotaxin stimulated production of interleukin-8 and granulocyte macrophage colony-stimulating factor. Pretreatment of Compound X (a specific CCR3 antagonist), pertussis toxin, genistein, and wortmannin reduced the MAP kinase phosphorylation and cytokine production. The eotaxin-induced cytokine production was inhibited by specific inhibitors for MAP/ERK kinase (PD98059) and p38 MAP kinase (SB202190). These results suggest that both ERK1/2 and p38 MAP kinase activated by eotaxin have a critical role in the pathogenesis of asthma.
American Journal of Respiratory Cell and Molecular Biology 10/2002; 27(3):329-35. · 5.13 Impact Factor
