Lung Sound Analysis Is Useful for Monitoring Therapy in Patients With Bronchial Asthma.

BACKGROUND AND OBJECTIVE: Lung sound analysis (LSA) has been reported to be useful for predicting airway obstruction and inflammation in patients with bronchial asthma. Objectives: We examined whether the exhalation-to-inhalation sound pressure ratio in the middle frequency range (200-400 Hz) (E/I MF) is useful for monitoring therapy in patients with asthma. METHODS: The study population comprised 84 patients with mild to moderate asthma whose LSA data were available before and after 1 year of daily treatment with (budesonide 800 µg). We analyzed whether the E/I MF before and after treatment was associated with the fractional exhaled nitric oxide (FeNO) level, sputum eosinophil percentage, respiratory function, and airway hyperresponsiveness. RESULTS: Prior to treatment with budesonide, the E/I MF was significantly correlated with respiratory function, airway hyperresponsiveness, FeNO, and sputum eosinophil percentage. The cutoff values for the E/I MF to detect the abnormalities of respiratory function, FeNO, and sputum eosinophil percentage were 0.367, 0.358, and 0.363, respectively. With respect to the reference value, the E/I MF improved significantly in patients whose respiratory function and FeNO benefited from therapy with budesonide compared with patients whose respiratory function did not benefit from budesonide (odds ratios of 6.39 and 4.78, respectively). According to the multivariate analysis, patients whose E/I MF did not improve had a longer history of smoking (P=.038), poorer posttreatment respiratory function (P=.028), and higher posttreatment FeNO (P=.0095). CONCLUSIONS: Similar to respiratory function and FeNO, E/I MF based on LSA is a useful indicator for monitoring the efficacy of therapy in asthmatic patients.

Lung sound analysis is useful for monitoring therapy in patients with bronchial asthma

Background: Lung sound analysis (LSA) has been reported to be useful for predicting airway obstruction and inflammation in patients with bronchial asthma. Objectives: We examined whether the exhalation-to-inhalation sound pressure ratio in the middle frequency range (200-400 Hz) (E/I MF) is useful for monitoring therapy in patients with asthma. Methods: The study population comprised 84 patients with mild to moderate asthma whose LSA data were available before and after 1 year of daily treatment with (budesonide 800 μg). We analyzed whether the E/I MF before and after treatment was associated with the fractional exhaled nitric oxide (FeNO) level, sputum eosinophil percentage, respiratory function, and airway hyperresponsiveness. Results: Prior to treatment with budesonide, the E/I MF was significantly correlated with respiratory function, airway hyperresponsiveness, FeNO, and sputum eosinophil percentage. The cutoff values for the E/I MF to detect the abnormalities of respiratory function, FeNO, and sputum eosinophil percentage were 0.367, 0.358, and 0.363, respectively. With respect to the reference value, the E/I MF improved significantly in patients whose respiratory function and FeNO benefited from therapy with budesonide compared with patients whose respiratory function did not benefit from budesonide (odds ratios of 6.39 and 4.78, respectively). According to the multivariate analysis, patients whose E/I MF did not improve had a longer history of smoking (P=.038), poorer posttreatment respiratory function (P=.028), and higher posttreatment FeNO (P=.0095). Conclusion: Similar to respiratory function and FeNO, E/I MF based on LSA is a useful indicator for monitoring the efficacy of therapy in asthmatic patients (AU)

Introducción: El análisis de los sonidos pulmonares ha demostrado ser una prueba de utilidad para objetivar la presencia de obstrucción e inflamación en las vías respiratorias de pacientes con asma bronquial. Objetivos: Hemos evaluado si el cociente sonido inspiración-espiración por presión en el rango de frecuencias medias, de 200 a 400 Hz, (E/I MF) tenía utilidad en la evaluación de la respuesta al tratamiento en pacientes con asma bronquial. Métodos: El estudio incluyó 84 pacientes con asma leve o moderada que tuvieran registros de LSA antes y tras un año de tratamiento con 800 μg de budesonida inhalada. Analizamos si los cambios en E/I MF tras el tratamiento se correlacionaban con los cambios en los niveles de óxido nítrico en aire exhalado (FeNO), el porcentaje de eosinófilos en muestras de esputo inducido, la función pulmonar y la hiperreactividad bronquial. Resultados: Antes de iniciar el tratamiento con budesonida inhalada, el cociente E/I MF se correlacionaba significativamente con la función pulmonar, la hiperreactividad bronquial, los niveles de FeNO y el porcentaje de eosinófilos en las muestras de esputo. Los puntos de corte del cociente E/I MF para detectar valores anómalos en la función pulmonar, los niveles de FeNO, y el porcentaje de eosinófilos en esputo eran 0,367, 0,358 y 0,363 respectivamente. El cociente E/I MF mejoraba significativamente en el grupo de pacientes en los que la budesonida inhalada inducía cambios significativos en la función pulmonar o en los niveles, con respecto a los valores de referencia apropiados comparados con los de los grupos de pacientes que no presentaban mejoría en estos parámetros (odds ratios de 6,39 y 4,78, respectivamente). En un análisis multivariante los pacientes que no presentaban mejoras significativas en el cociente E/I MF presentaban una historia de tabaquismo activo significativamente más larga (p=,038), unos niveles de función pulmonar tras tratamiento significativamente más bajos (p=,028), y paralelamente unos niveles de FeNO, tras tratamiento, más elevados (p=,0095). Conclusiones: Al igual que la función pulmonar y los niveles de FeNO, el cociente E/I MF obtenido mediante el LSA es un indicador útil para evaluar la eficacia del tratamiento en pacientes con asma bronquial (AU)

c-Fos induction in the brainstem following electrical stimulation of the trigeminal ganglion of chronically mandibular nerve-transected rats.

Neuronal excitability in the trigeminal sensory nuclei (TSN) changes after nerve transection. We examined the effects of chronic transection of the trigeminal nerve on the c-Fos-immunoreactivity in the TSN induced 2 h after 10 min of electrical stimulation of the trigeminal ganglion (TG) at C-fiber activating condition (1.0 mA, 5 ms, 5 Hz) in urethane-anesthetized rats. In the non-transected control rats, stimulation of the TG induced c-Fos-immunoreactive cells (c-Fos-IR cells) mostly in superficial layers (VcI/II) of the nucleus caudalis (Vc) in its full extent along the dorsomedial-ventrolateral axis, but modestly in the rostral TSN above the obex, the principal, oral, and interpolar nuclei. Three days, 1, 2, or 3 weeks after transection of the inferior alveolar (IAN), infraorbital, or masseteric nerves, the stimulation of the TG induced c-Fos-IR cells in the central terminal fields of the transected nerve in the rostral TSN and magnocellular zone of the Vc. However, the number of c-Fos-IR cells in the VcI/II decreased inside the central terminal fields of the transected nerve and increased outside the fields. These results indicate that transection of the trigeminal nerve increases the excitability of TSN neurons that receive inputs from injured mechanoreceptors and uninjured nociceptors, but decreases it from injured nociceptors. The altered c-Fos responses may imply mechanisms of neuropathic pain seen after nerve injury.

Total pancreatectomy combined with partial pancreas autotransplantation for recurrent pancreatic cancer: a case report.

We describe a patient presenting with a resectable carcinoma of the remnant pancreas at 3 years after undergoing a pylorus-preserving pancreaticoduodenectomy for invasive ductal carcinoma of the pancreatic head. We also performed a distal pancreas autotransplantation using a part of the resected pancreas to preserve endocrine function. Final histologic findings showed the second tumor to be an invasive ductal carcinoma consisting of a well-differentiated tubular adenocarcinoma with similar histopathologic findings as the first tumor. There were no microscopic lymph node metastases and no evidence of microvascular invasion (pStage IA [pT1, pN0, M0] and R0 according to the International Union Against Cancer TNM classification). The patient was discharged at 20 days after surgery without any trouble and followed by adjuvant chemotherapy with S-1. The carbohydrate antigen 19-9 value was again normalized after the second surgery. Twenty months after the second operation, the patient is alive without cancer recurrence. The pancreas graft is functioning with a blood glucose of 108 mg/dL, HbA1C of 6.2%, and serum C-peptide of 1.4 ng/mL.

Temporal and sequential changes of glial cells and cytokine expression during neuronal degeneration after transient global ischemia in rats.

BACKGROUND: How glial cells and cytokines are associated with the progression of delayed neuronal death induced by transient global ischemia is still unclear. To further clarify this point, we studied morphological changes in glial cells (microglial cells and astrocytes), and cytokine protein levels, during the progression of neuronal cell loss in CA1 (Cornu Ammonis 1) of the hippocampus after transient global ischemia. METHODS: Morphological changes in glial cells were studied immuno-histochemically. Nine cytokines (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-γ and TNF-α) were simultaneously measured by a multiplexed bead-based immunoassay from 6 h to day21 after transient four vessel occlusion (4VO) in rats. RESULTS: During the process of neuronal loss, we observed four distinct phases: (1) lag phase day0-2 (no NeuN+ cell loss observed), (2) exponential phase day2-7 (NeuN+ cells reduced in number exponentially), (3) deceleration phase day7-14 (reduction rate of NeuN+ cells became low), (4) stationary phase day14 onward (NeuN+ cell loss progressed no longer). In the lag phase, activated glial cells were observed in the entire hippocampus but later were gradually restricted to CA1. Cytokine protein levels in the lag and exponential phases were lower than in the deceleration and stationary phases. IL-1α, IL-1ß, IL-4, IL-6 and IFN-γ in 4VO were significantly higher in all four phases than in sham. Compared with sham level, GM-CSF was significantly high in the deceleration phase. TNF-α was significantly high in both the deceleration and stationary phases. CONCLUSION: Ischemic stress in 4VO activated glial cells in areas beyond CA1 in the lag phase. Pyramidal neurons were injured in CA1 from the end of the lag phase and then neuronal cells reduced in CA1 in the exponential phase. After neuronal death began, the influence of dead cells on glial cells and cytokine expression gradually became stronger than the influence by ischemic stress. Therefore, from the deceleration phase, changes in glial cells and cytokine production were likely caused by dead cells. Cytokine interaction in the microenvironment may determine the functions of IL-1α, IL-1ß, IL-4, IL-6 and IFN-γ in all four phases. The function of GM-CSF and TNF-α in the deceleration phase may be neurotrophic.

Tacrolimus is effective for lupus nephritis patients with persistent proteinuria.

OBJECTIVES: To evaluate the safety and potential efficacy of tacrolimus for the treatment of patients with lupus nephritis and persistent proteinuria. METHODS: A total of 23 Japanese patients with lupus nephritis (21 females/2 males) were enrolled in this study. Patients were administered tacrolimus at a dose of 2-3 mg once daily after the evening meal for 6 months. The dose of tacrolimus was unchanged throughout the study period. Concomitant prednisolone therapy was unchanged or gradually tapered, while other immunosuppressants were stopped at the start of tacrolimus treatment. RESULTS: Tacrolimus was well tolerated, and none of the patients developed adverse drug reactions that required discontinuation of the study. Daily urinary protein loss, the U-prot/U-creat ratio, and serum albumin were significantly improved after 4 months, 3 months, and 1 month of treatment with tacrolimus (p<0.05), respectively, and the improvement persisted until 6 months. The serum complement hemolytic activity (CH50), complement C3 level, and CRP level were also significantly improved after treatment with tacrolimus (p<0.05). Improvement of the U-prot/U-creat ratio was most prominent for patients who were in WHO class IV. CONCLUSIONS: Tacrolimus is safe and effective as maintenance therapy for patients with lupus nephritis, at least for 6 months. A larger randomised, controlled trial over a longer period is needed to confirm these results.

Inhibitory effects of antipsychotic and anxiolytic agents on stress-induced degranulation of mouse dermal mast cells.

BACKGROUND: Various psychological stresses induce degranulation of mast cells. It has been confirmed by animal experiments that stress induced by restraint promotes mast-cell degranulation in various organs, and that the degranulation is inhibited by pretreatment with corticotropin-releasing factor (CRF)-neutralizing antibodies, CRF receptor antagonists, and neurotensin (NT) antagonists. Previous studies have suggested that anxiety and fear induced in animals by psychological stressors promote the production and release of various neuropeptides and neurotransmitters, and induce degranulation of mast cells in several organs. AIM: To evaluate the effect of prior treatment with antipsychotic and anxiolytic agents to inhibit foot-shock (FS) stress-induced degranulation of mouse dermal mast cells. METHODS: Using a communication box system, FS was administered to mice and the degranulated dermal mast cells were counted. Chlorpromazine (2 or 4 mg/kg body weight), tandospirone (10 mg/kg body weight) or CRA1000, a selective non-peptidic CRF receptor type 1 antagonist (10 or 100 mg/kg body weight) was injected intraperitoneally 1 h before exposure to FS. RESULTS: After FS was administered, the number of dermal mast cells did not change. However, FS significantly increased the proportion of degranulated mast cells. Pretreatment of mice with chlorpromazine hydrochloride, an antipsychotic agent (2 or 4 mg/kg), or the anxiolytic agents tandospirone citrate (10 mg/kg) or CRA1000 (10 or 100 mg/kg), significantly inhibited the FS-induced mast-cell degranulation (P < 0.05, P < 0.01, P < 0.05, P < 0.05, and P < 0.05, respectively). CONCLUSIONS: Antipsychotic and anxiolytic agents may be effective treatments for stress-aggravated inflammatory skin diseases by inhibition of mast-cell degranulation.

The prognostic impact of isolated tumor cells in lymph nodes of T2N0 gastric cancer: comparison of American and Japanese gastric cancer patients.

BACKGROUND: The clinical significance of immunohistochemically detected isolated tumor cells (ITC) in lymph nodes of gastric cancer patients is controversial. This study examined the prognostic impact of ITC on patients with early-stage gastric cancer in two large volume centers in the United States and Japan. METHODS: Fifty-seven patients with T2N0M0 gastric carcinoma who underwent gastric resection between January 1987 and January 1997 at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York and 107 patients resected at National Cancer Center Hospital (NCCH) in Tokyo between January 1984 and December 1990 were studied. The sections were newly prepared from each lymph node for immunohistochemical staining for cytokeratin. Lymph nodes and original specimens from MSKCC were examined by pathologists in NCCH. The prognostic significance of the presence of ITC in lymph nodes was investigated in patients of both institutions. RESULTS: ITC were identified in 30 of 57 patients (52.6%) at MSKCC and in 38 of 107 patients (35.5%) at NCCH. In both institutions, there was no significant difference in the prognosis of the studied patients with or without ITC (P= .22, .86 respectively). CONCLUSIONS: The presence of ITC detected by immunohistochemistry in the regional lymph nodes did not affect the prognosis of American and Japanese patients with T2N0M0 gastric carcinoma who underwent gastrectomy with D2 lymph node dissection.

Histological diversity in basaloid squamous cell carcinoma of the esophagus.

Basaloid squamous cell carcinoma of the esophagus (BSCCE) is a distinct variant of esophageal cancer. This study investigated histopathological variations of BSCCE. Thirty-eight surgical and two endoscopically resected specimens of BSCCE were examined. Histological features were classified into five components: solid nest (SN), microcyst and/or trabecular nest (MT), ductal differentiation (DD), cribriform pattern (CP), and an invasive squamous cell carcinoma (SCC) component. The immunohistochemical phenotypes of each component were examined using antibodies against cytokeratin (CK) 7, CK14, and alpha smooth muscle actin (SMA). SN, MT, DD, CP, and SCC were present in 95.0, 97.5, 27.5, 32.5, and 82.5% of the cases, respectively, and combinations of SN & MT, SN & DD, SN, MT & DD, SN, MT & CP, and SN, MT, DD & CP were found in 50.0, 2.5, 10.0, 17.5, and 15.0%, respectively. All the intraepithelial lesions observed in 18 (45.0%) cases were SCC. Immunoreactivity for CK7, CK14, and SMA was seen in 10.5, 86.8, and 18.4% of SN; 30.8, 97.4, and 38.5% of MT; 54.5, 100.0, and 54.5% of DD; 7.7, 76.9, and 23.1% of CP; and 6.1, 97.0, and 0.0% of SCC, respectively. CK14 immunoreactivity was seen in the periphery of most of the SN component. CK7, CK14, and SMA immunoreactivity was seen in the inner layer, all layers, and the outer layer of DD, respectively. MT and CP showed partial peripheral positivity for CK14 and SMA in microcystic, trabecular, and cribriform-like pseudoglandular structures. BSCCE demonstrates various histopathological and immunohistochemical features including a ductal and cribriform growth pattern.

Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers.

We previously reported hedgehog (Hh) signal activation in the mucus-secreting pit cell of the stomach and in diffuse-type gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is known to be involved in tumour malignancy. However, little is known about whether and how both signallings cooperatively act in diffuse-type GC. By microarray and reverse transcription-PCR, we investigated the expression of those Hh and EMT signalling molecules in pit cells and in diffuse-type GCs. How both signallings act cooperatively in those cells was also investigated by the treatment of an Hh-signal inhibitor and siRNAs of Hh and EMT transcriptional key regulator genes on a mouse primary culture and on human GC cell lines. Pit cells and diffuse-type GCs co-expressed many Hh and EMT signalling genes. Mesenchymal-related genes (WNT5A, CDH2, PDGFRB, EDNRA, ROBO1, ROR2, and MEF2C) were found to be activated by an EMT regulator, SIP1/ZFHX1B/ZEB2, which was a target of a primary transcriptional regulator GLI1 in Hh signal. Furthermore, we identified two cancer-specific Hh targets, ELK1 and MSX2, which have an essential role in GC cell growth. These findings suggest that the gastric pit cell exhibits mesenchymal-like gene expression, and that diffuse-type GC maintains expression through the Hh-EMT pathway. Our proposed extensive Hh-EMT signal pathway has the potential to an understanding of diffuse-type GC and to the development of new drugs.

Treatment strategy after non-curative endoscopic resection of early gastric cancer.

BACKGROUND: Endoscopic resection (ER) is indicated for patients with early gastric cancer who have a negligible risk of lymph node metastasis (LNM). Histological examination of the resected specimen may indicate a possible risk of LNM or a positive resection margin. These patients are considered to have undergone non-curative ER. The aim of this study was to determine the appropriate treatment strategy for such patients. METHODS: A total of 298 patients who had non-curative ER were classified into those with a positive lateral margin only (group 1; 72 patients) and those with a possible risk of LNM (group 2; 226 patients). RESULTS: Surgery was performed within 6 months of non-curative ER in 19 patients in group 1 and 144 in group 2. In group 1, nine patients were found to have local residual tumours, all limited to the mucosal layer without LNM. In Group 2, 13 patients had residual disease, including four local tumours without LNM, two local tumours with LNM and seven cases of LNM alone. The rate of LNM after surgery was 6.3 per cent in group 2. CONCLUSION: Surgery remains the standard treatment after non-curative ER in patients with a possible risk of LNM.

The effects of MPTP on the activation of microglia/astrocytes and cytokine/chemokine levels in different mice strains.

The effects of MPTP on two mouse strains with different MPTP sensitivities and immunological backgrounds were compared: MPTP-sensitive C57BL/6 mice (B6) with a propensity for Th1 and less MPTP-sensitive BALB/c mice (BALB) with a propensity for Th2. It was found that acute MPTP treatment induced behavioral dysfunction, activated microglia/astrocytes, and increased the levels of IL-10, IL-12(p40) IL-13, IFN-gamma, and MCP-1 in CSF in B6, but not in BALB. This suggests that variances in immunological backgrounds might be a major contributing factor in sensitivity differences to MPTP.

A dose-escalation study of rituximab for treatment of systemic lupus erythematosus and Evans' syndrome: immunological analysis of B cells, T cells and cytokines.

OBJECTIVE: Accumulating evidence suggests that B-cell depletion therapy by rituximab may be effective for autoimmune disorders. However, an optimal dose of rituximab and a mechanism of its action remain to be established. We performed a dose-escalation study for treatment of Japanese patients with autoimmune diseases including eight with SLE and one with Evans' syndrome. METHODS: Rituximab was infused intravenously, weekly 4 times in a dose-escalating fashion at three different doses of 100, 250 or 375 mg/m(2) to three patients each. Immunological parameters were monitored at certain points until 12 months after the treatment. RESULTS: Rituximab was well tolerated and safe in these patients. Seven out of eight SLE patients and one with Evans' syndrome clinically responded completely or partially to the treatment. Four patients achieved long-term remission (18-30 months) without any additional treatment. In these patients, a significant decrease in circulating B cells continued for 6 months after the treatment. The mean fluorescence intensities of CD19, CD21, CD40 and BR3 on the residual B cells as well as the percentage of CD69+ CD4+ T cells decreased significantly. Serum TNF-alpha levels decreased significantly on day 2. The Th1/Th2 balance of CD4+ T cells gradually shifted towards a Th1 type by 6 months. CONCLUSION: In addition to B-cell depletion, modification of B-cell and T-cell phenotypes as well as cytokine profiles may be involved in the action of rituximab.

RCNP polarized (3)He ion source.

We have developed a polarized (3)He ion source named "SEPIS" (spin-exchange polarized ion source) at RCNP, and Department of Physics, Osaka Univeristy. The SEPIS uses a large spin-exchange cross section, sigma(se), and a small electron capture cross section,sigma(ec), for the (3)He(+)+Rb system theoretically expected at low (3)He(+) incident energies. The validity of SEPIS was experimentally proven by observing the (3)He(+) nuclear polarization as a function of the incident (3)He(+) energy.