Roles of cytokines and T cells in the pathogenesis of myasthenia gravis.

Myasthenia gravis (MG) is characterized by muscle weakness and fatigue caused by the presence of autoantibodies against the acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase (MuSK). Activated T, B and plasma cells, as well as cytokines, play important roles in the production of pathogenic autoantibodies and the induction of inflammation at the neuromuscular junction in MG. Many studies have focused on the role of cytokines and lymphocytes in anti-AChR antibody-positive MG. Chronic inflammation mediated by T helper type 17 (Th17) cells, the promotion of autoantibody production from B cells and plasma cells by follicular Th (Tfh) cells and the activation of the immune response by dysfunction of regulatory T (Treg ) cells may contribute to the exacerbation of the MG pathogenesis. In fact, an increased number of Th17 cells and Tfh cells and dysfunction of Treg cells have been reported in patients with anti-AChR antibody-positive MG; moreover, the number of these cells was correlated with clinical parameters in patients with MG. Regarding cytokines, interleukin (IL)-17; a Th17-related cytokine, IL-21 (a Tfh-related cytokine), the B-cell-activating factor (BAFF; a B cell-related cytokine) and a proliferation-inducing ligand (APRIL; a B cell-related cytokine) have been reported to be up-regulated and associated with clinical parameters of MG. This review focuses on the current understanding of the involvement of cytokines and lymphocytes in the immunological pathogenesis of MG, which may lead to the development of novel therapies for this disease in the near future.

Skin inflammation exacerbates food allergy symptoms in epicutaneously sensitized mice.

BACKGROUND: Cutaneous exposure to food antigen through impaired skin barrier has been shown to induce epicutaneous sensitization, thereby causing IgE-mediated food allergies. OBJECTIVE: We examined whether skin barrier impairment following epicutaneous sensitization exacerbates food allergies. METHODS: BALB/c mice were epicutaneously sensitized by repeated application of ovalbumin (OVA) to MC903-pretreated ear skin for 48 hours weekly and then intragastrically challenged with OVA. After the first oral challenge, the skin barrier was disrupted with topical application of MC903 or by tape-stripping. Mice were monitored for changes in body temperature and the occurrence of diarrhea after undergoing the second oral challenge. Serum levels of mouse mast cell protease-1 (mmcp1) and OVA-specific IgE, IgG1, IgG2a antibodies and OVA-specific IgA levels in intestinal lavage fluid were measured by ELISA. Tissue accumulation of eosinophils was determined histologically. RESULTS: Epicutaneously sensitized mice developed anaphylaxis after intragastric challenge, as evidenced by diarrhea, decreased body temperature, and increased serum mmcp1 levels. Skin barrier disruption by MC903 treatment or tape-stripping exacerbated allergic reactions induced by oral challenge. MC903 treatment increased serum baseline and postchallenge mmcp1 levels. Topical pretreatment with dexamethasone alleviated allergic reactions that were exacerbated by MC903 treatment. CONCLUSION: Even after eliminating exposure to the antigen, inflammation from skin barrier disruption can exacerbate the severity of food allergy symptoms. Serum baseline mmcp1 levels might be an effective marker for predicting the severity of antigen-induced allergic symptoms.

The Biomarker Salivary SP-D May Indicate Small Airway Inflammation and Asthma Exacerbation.

BACKGROUND: Noninvasive and child-friendly biomarkers are important tools for understanding the various phenotypes of childhood asthma. Objective: The aim of this study was to examine the usefulness of salivary surfactant protein (SP) D in assessing the pathophysiology of childhood asthma. METHODS: We measured salivary concentrations of SP-D and forced oscillation technique (FOT) indexes in 19 healthy controls and 21 asthmatic children. Regression equations for the predictive values of FOT indexes were generated from healthy controls. We analyzed the correlations between salivary SP-D concentration and percentages of the predictive values of FOT indexes, as well as the severity of exacerbation. RESULTS: We found that salivary SP-D levels were higher in asthmatic children than in healthy controls. In the asthmatic children, salivary SP-D levels correlated with the percentages of predicted differences in resistance between 5 Hz and 20 Hz (%R5-R20), which represented the resistance of peripheral airways, and with the severity of asthma exacerbation. CONCLUSIONS: Salivary SP-D may reflect asthmatic inflammation in peripheral small airways and may be a useful marker for monitoring the degree of exacerbation in childhood asthma.

The biomarker salivary SP-D may indicate small airway inflammation and asthma exacerbation

Background: Noninvasive and child-friendly biomarkers are important tools for understanding the various phenotypes of childhood asthma. Objective: The aim of this study was to examine the usefulness of salivary surfactant protein (SP) D in assessing the pathophysiology of childhood asthma. Methods: We measured salivary concentrations of SP-D and forced oscillation technique (FOT) indexes in 19 healthy controls and 21 asthmatic children. Regression equations for the predictive values of FOT indexes were generated from healthy controls. We analyzed the correlations between salivary SP-D concentration and percentages of the predictive values of FOT indexes, as well as the severity of exacerbation. Results: We found that salivary SP-D levels were higher in asthmatic children than in healthy controls. In the asthmatic children, salivary SP-D levels correlated with the percentages of predicted differences in resistance between 5 Hz and 20 Hz (%R5-R20), which represented the resistance of peripheral airways, and with the severity of asthma exacerbation. Conclusion: Salivary SP-D may reflect asthmatic inflammation in peripheral small airways and may be a useful marker for monitoring the degree of exacerbation in childhood asthma (AU)

Antecedentes: El empleo de biomarcadores no invasivos es una buena herramienta para estudiar la fisiopatología de los diferentes fenotipos del asma infantil. Objetivo: El objetivo de este estudio fue examinar la utilidad de la proteína salival surfactante (SP) D en la evaluación de la fisiopatología del asma infantil. Métodos: Se midieron las concentraciones en la saliva de SP-D y se realizaron oscilometrías forzadas de impulsos (FOT) en 21 niños asmáticos y 19 controles sanos. Las ecuaciones de regresión para los valores predictivos de los índices FOT se generaron a partir de controles sanos. Se analizaron las correlaciones entre la concentración de SP-D salival y los porcentajes de los valores predictivos de los índices FOT, así como la gravedad de las exacerbaciones. Resultados: Se encontró que los niveles en la saliva de la SP-D fueron más elevados en los niños asmáticos en comparación con los controles sanos. En los niños asmáticos, los niveles de SP-D salival se correlacionaron con los porcentajes de las diferencias predichas en la resistencia entre 5Hz y 20Hz (% R5-R20), que representan la resistencia de las vías respiratorias periféricas y la gravedad de la exacerbación del asma. Conclusión: La SP-D salival puede reflejar la inflamación asmática en las vías respiratorias pequeñas y puede ser un marcador útil para monitorizar el grado de exacerbación en el asma infantil (AU)

Electron impact excitation of the low-lying 3s[3∕2]1 and 3s'[1∕2]1 levels in neon for incident energies between 20 and 300 eV.

Absolute differential cross sections (DCSs) for electron impact of the two lower-lying 3s[3∕2]1 ((3)P0) and 3s(')[1∕2]1 ((1)P1) electronic states in neon (Ne) have been determined for eight incident electron energies in the range 20-300 eV. Comparisons between our results and previous measurements and calculations, where possible, are provided with best agreement being found with the recent large-scale B-spline R-matrix computations [O. Zatsarinny and K. Bartschat, Phys. Rev. A 86, 022717 (2012)]. Based on these DCSs at 100, 200, and 300 eV, a generalised oscillator strength analysis enabled us to determine estimates for the optical oscillator strengths of the 3s[3∕2]1 and 3s(')[1∕2]1 levels. In this case, excellent agreement was found with a range of independent experiments and calculations, giving us some confidence in the validity of our measurement and analysis procedures. Integral cross sections, derived from the present DCSs, were presented graphically and discussed elsewhere [M. Hoshino, H. Murai, H. Kato, Y. Itikawa, M. J. Brunger, and H. Tanaka, Chem. Phys. Lett. 585, 33 (2013)], but are tabulated here for completeness.

Characteristics of inspiratory and expiratory reactance in interstitial lung disease.

BACKGROUND: Forced oscillometry is a non-invasive method to measure respiratory resistance and reactance. In this study, we investigated the characteristics of measurements obtained with an impulse oscillation system (IOS) for patients with interstitial lung disease (ILD). METHOD: IOS and spirometry were performed in 64 ILD patients, 54 asthma patients, 49 chronic obstructive pulmonary disease (COPD) patients, and 29 controls. Respiratory resistance and reactance were assessed as measurements averaged over several tidal breaths (whole-breath analysis) and as measurements separately averaged during inspiration and expiration (inspiratory-expiratory analysis). RESULTS: Whole-breath IOS analyses for ILD patients showed increased resistance at 5 Hz and decreased reactance at 5 Hz (X5) compared with controls, although these features were also found in asthma and COPD patients. Inspiratory-expiratory analysis demonstrated that the changes in X5 and reactance area (AX) between inspiration and expiration (ΔX5 and ΔAX, respectively) were significantly different from those in asthma patients, COPD patients, and controls. However, multiple linear regression analysis showed that the presence of ILD was independently associated with ΔX5, but not with ΔAX. Furthermore, ΔX5 was inversely correlated with vital capacity and diffusing capacity of carbon monoxide in ILD patients. CONCLUSIONS: Our results suggest that ΔX5 is a characteristic feature of IOS measurements in ILD patients, which is clearly different from those in asthma and COPD patients. This within-breath X5 change in ILD might be associated with its severity and physiological abnormality, although further studies are needed to investigate its cause.

A comprehensive and comparative study of elastic electron scattering from OCS and CS2 in the energy region from 1.2 to 200 eV.

We report absolute differential cross sections (DCSs) for elastic electron scattering from OCS (carbonyl sulphide) and CS(2) (carbon disulphide) in the impact energy range of 1.2-200 eV and for scattering angles from 10° to 150°. Above 10 eV, the angular distributions are found to agree quite well with our present calculations using two semi-phenomenological theoretical approaches. One employs the independent-atom model with the screening-corrected additivity rule (IAM-SCAR), while the other uses the continuum-multiple-scattering method in conjunction with a parameter-free exchange-polarization approximation. Since OCS is a polar molecule, further dipole-induced rotational excitation cross sections have been calculated in the framework of the first Born approximation and incoherently added to the IAM-SCAR results. In comparison with the calculated DCS for the S atom, atomic-like behavior for the angular distributions in both the OCS and CS(2) scattering systems is observed. Integrated elastic cross sections are obtained by extrapolating the experimental measurements, with the aid of the theoretical calculations, for those scattering angles below 10° and above 150°. These values are then compared with the available total cross sections.

Distinct CSF cytokine/chemokine profiles in atopic myelitis and other causes of myelitis.

BACKGROUND: We reported the emergence of a distinct myelitis in patients with atopic diathesis (atopic myelitis [AM]) by a nationwide survey throughout Japan. Similar cases have recently been reported in Caucasians. Pathologic studies of biopsied spinal cord specimens revealed chronic active inflammation with eosinophilic infiltration. OBJECTIVE: To clarify the cytokine/chemokine alterations in CSF from patients with AM in comparison to other causes of myelitis. METHODS: We measured 27 cytokines, chemokines, and growth factors simultaneously in CSF from 22 patients with AM, 20 with opticospinal multiple sclerosis (OSMS), 11 with HTLV-1-associated myelopathy (HAM), 9 with Sjögren syndrome-related myelitis (SM), and 20 with other noninflammatory neurologic diseases (OND), using a fluorescent bead-based immunoassay. RESULTS: In patients with AM, CCL11 and interleukin (IL)-9 were significantly increased as compared with patients with OND and other myelitis while in patients with OSMS interferon-gamma and granulocyte-colony stimulating factor levels were significantly higher than in patients with OND and other causes of myelitis. Significant increase of IL-17 in comparison to patients with OND was found only in patients with OSMS, irrespective of presence or absence of anti-aquaporin-4 (AQP4) antibody. In patients with HAM, CXCL10 and CCL5 were higher than in patients with OND and other myelitis. In patients with SM, CCL3 and CCL4 were higher than in patients with OND. In patients with AM, CCL11, IL-9, and IL-1 receptor antagonist (IL-1ra) showed positive correlations with the final Kurtzke Expanded Disability Status Scale scores while IL-1ra and IL-12(p70) had positive correlations with disease duration. CONCLUSION: Intrathecal upregulation of CCL11 and Th2 cytokines is characteristic of atopic myelitis, which is distinct from interleukin-17/interferon-gamma-related autoimmune condition of opticospinal multiple sclerosis.

Ganglioglioma originating in the cerebellum with a large cyst--a case report and review of the literature.

Here we report a rare case of cerebellar ganglioglioma accompanied by a large cyst, and present a review of the reported 28 cases with cerebellar ganglioglioma. An otherwise healthy 46-year-old woman complained of gradual headache and truncal ataxia. MRI revealed a huge cystic lesion with a mural nodule in the left cerebellar hemisphere. The tumor was resected totally. Histologically, it was composed of neuronal and glial elements, and was accordingly diagnosed as ganglioglioma.

Osmotic shock-induced neurite extension via activation of p38 mitogen-activated protein kinase and CREB.

Although it is known that sustained activation of classical mitogen-induced protein kinase (MAPK, also known as ERK) induced by nerve growth factor (NGF) plays an important role in the induction of neurite outgrowth, the role of p38 MAPK in neural cell function is still not clear. We developed two neuronal cell lines from PC12 cells, PC12m3 and PC12m32, in which NGF-induced neurite outgrowth is impaired and that show neurite outgrowth in response to hyperosmotic shock. The frequencies of neurite outgrowth of PC12m3 and PC12m32 cells induced by osmotic shock were approximately 10- and 12-fold greater, respectively, than that in PC12 parental cells. The p38 MAPK pathway inhibitor SB203580 but not the ERK pathway blocker U0126 inhibited the ability of PC12m3 and PC12m32 cells to induce neurite outgrowth in response to osmotic shock. Furthermore, expression of a nonactivable form of p38 but not that of wild-type p38 significantly blocked neurite outgrowth induced by osmotic shock. The extent of phosphorylation of p38 MAPK induced by osmotic shock in PC12m32 cells was much greater than that in PC12 parental cells. The upstream kinases MKK3 and MKK6, which phosphorylate and activate p38 MAPK, also showed higher levels in PC12m32 cells than in PC12 parental cells when treated with osmotic shock. Inhibition of p38 MAPK by SB203580 resulted in inhibition of the activity of the transcription factor CREB, which is activated by osmotic shock. These findings indicate that activation of CREB mediated by a p38 pathway distinct from the NGF signaling pathway may be required for neurite outgrowth.

[Intralobar pulmonary sequestration with high level of serum CEA; report of a case].

We reported a case of intralobar pulmonary sequestration with a high level of the serum CEA. A 53-year-old woman whose chief complaint was cough was admitted to our hospital. Enhanced chest computed tomography (CT) revealed the mass in the left lower lung, lymph-nodes swelling, and the aberrant artery. Magnetic resonance angiography (MRA) conformed the aberrant artery from the descending aorta. The level of serum CEA elevated at 9.6 ng/ml. Left lower lobectomy was performed. A diagnosis of intralobar pulmonary sequestration (Pryce type II) was established in this case. Histopathologically, the peribronchial epithelial cells in pulmonary sequestration showed weak positive for anti-CEA monoclonal antibody. Postoperative course was uneventful and the serum CEA level was 3.5 ng/ml in the normal range at the postoperative 17th day.

Electromagnetic fields inhibit endothelin-1 production stimulated by thrombin in endothelial cells.

Electromagnetic field (EMF) radiation has been found to induce arteriolar dilatation, but the mechanism of action remains largely unknown. This study investigated the effect of EMF radiation on the production of endothelin-1 (ET-1), a potent vasoconstrictor, by cultured endothelial cells. EMF radiation reduced ET-1 basal levels in human umbilical vein and microvascular endothelial cells, but failed to reduce ET-1 basal levels in bovine and human aortic endothelial cells. EMF radiation significantly inhibited thrombin-stimulated ET-1 production in all four endothelial cell types in a dose-dependent manner. EMF radiation significantly inhibited thrombin-induced endothelin-1 mRNA expression in all four cell types. The inhibitory effect of EMF radiation on ET-1 production was abolished by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (10(-3) mol/1). These results demonstrate that EMF radiation modulates ET-1 production in cultured vascular endothelial cells and the inhibitory effect of EMF radiation is, at least partly, mediated through a nitric oxide-related pathway.

[Chronic hemorrhagic pyothorax treated with preoperative internal thoracic and intercostal arterial embolization and perioperative non-invasive positive pressure ventilation].

We reported successful surgery for chronic hemorrhagic empyema with severe right heart insufficiency. The preoperative embolization of right internal thoracic artery and intercostals arteries was effective for the control of intraoperative bleeding. Non-invasive positive pressure ventilation (NIPPV) was useful for the perioperative respiratory management. A 62-year-old female with a history of right pneumonectomy and thoracoplasty for pulmonary tuberculosis was admitted because of dyspnea on effort on Dec 5th 2002. Her right heart insufficiency was worsened gradually. On May 20th 2003, we performed the transcatheter embolization of right internal thoracic and intercostals arteries for the control of intraoperative bleeding. The next day, the curettage and fenestration was performed for intraoperative cardiac dysfunction. The intraoperative bleeding was 1,596 ml and operative time was 2 hours 24 minutes. Due to CO2 narcosis, the ventilator under the intratracheal tube was needed for respiratory management in the postoperative course. The switching of the respiratory management with NIPPV from the intratracheal tube during 8 days, her respiratory and general conditions had been improved gradually. Because of methicillin-resistant Staphylococcus aureus (MRSA) infection of thoracic cavity, the radical thoracoplasty following the latissimus dorsi muscules flap and the omentopexy was performed. The operative course was uneventful and she needed overnight NIPPV without O2 inhalation and was discharged.

Infrasternal mediastinoscopic surgery for anterior mediastinal masses.

BACKGROUND: Infrasternal mediastinoscopic surgery is a new alternative to the thoracoscopic approach for patients with anterior mediastinal masses. METHODS: We applied this technique to 18 thymectomies, one thymomectomy, and one cystectomy in a total of 20 patients with anterior mediastinal masses and then assessed the surgical results. RESULTS: Infrasternal mediastinoscopic surgery was accomplished in 18 of the 20 patients (90%). The pathological diagnoses included 13 Masaoka stage I thymomas, one stage II thymoma, two stage III thymomas, one thymic cyst, one pericardial cyst, one thymic granuloma, and one mature teratoma. Two patients with stage III thymoma required conversion to sternotomy, one for invasion into the innominate vein and the other for invasion into the pericardium. There was no surgically related mortality or complications in any patients. CONCLUSION: Infrasternal mediastinoscopic surgery is safe and feasible for stage I thymoma and other benign tumors in the anterior mediastinum.

MRI of ectopic posterior pituitary bright spot with large adenomas: appearances and relationship to transient postoperative diabetes insipidus.

MRI of large pituitary adenomas has revealed that a posterior pituitary bright spot (PPBS), comprising ADH-containing neurosecretory granules, is commonly ectopic before surgery and attached to the tip of the pituitary stalk late after surgery. Although the PPBS indicates functional integrity of the posterior lobe, transient diabetes insipidus (DI), caused by deficiency of ADH, is frequent early after surgery. We attempted to clarify how the shape, signal intensity and site of the PPBS before surgery are related to transient DI in the early postoperative period. We carried out MRI on 15 patients with a large adenoma and an ectopic PPBS before surgery and then within 1 week (early), 1-2 months (intermediate) and 6 or more months (late) after the operation. There were nine who had transient DI, which subsided by the intermediate study; none had permanent DI. Regardless of transient DI, the PPBS was visible, and its signal intensity was similar, on all postoperative studies. Although 11 did not change in shape, four showed a remarkable change from a flat shape before surgery to a rounded one postoperatively. On the intermediate MRI, the PPBS had descended to the level of the diaphragma as mass effect disappeared.