Sustained effects of intralymphatic pollen-specific immunotherapy on Japanese cedar pollinosis.

BACKGROUND: Intralymphatic immunotherapy (ILIT) for allergic patients requires only a few intralymphatic injections of the allergen. However, the effectiveness and safety for Japanese cedar pollinosis are unclear. The objectives of this study were to clarify whether and how long ILIT is effective for pollinosis, and its safety. METHODS: In an open pilot investigation followed by a double-blind, placebo-controlled study, patients with Japanese cedar pollinosis received 3 intralymphatic inguinal injections of the pollen extracts before the first pollen season. The symptom medication score (SMS), nasal provocation testing and scoring visual analogue scale (VAS) were assessed after the first-third seasons. RESULTS: (1) Although mild adverse events were induced at the injected site, severe adverse events were not noted. (2) During the latter part of the first season, ILIT-treated patients (n=12) tended to show improved SMS compared to placebo-treated (n=6) without statistical significance. When assessed by nasal provocation testing and VAS scoring after the first season, the effectiveness of ILIT was significant. (3) The effects of ILIT continued until the second or third season. (4) Neither allergen-specific antibodies nor Treg/Breg cells changed in the peripheral blood. CONCLUSIONS: ILIT was safe and effective for Japanese cedar pollinosis. The clinical effects remained for 1-2 years.

Metal-ion-induced expression of gene fragments from subseafloor micro-organisms in the Kumano forearc basin, Nankai Trough.

AIMS: Using substrate-induced gene-expression (SIGEX) screening on subseafloor sediment samples from the Nankai Trough, Japan, we identified gene fragments showing an induction response to metal ions. METHODS AND RESULTS: Environmental DNA libraries in Escherichia coli host cells were tested by the addition of metal ions (Ni2+ , Co2+ , Ga3+ or Mo6+ ), followed by cell sorting of clones exhibiting green fluorescence upon co-expression of green fluorescence protein downstream of the inserted gene fragments. One clone displayed Ni2+ -specific induction, three clones displayed Ga3+ -specific induction and three clones displayed an induction response to multiple metal ions. DNA sequence analysis showed that a variety of genes showed induction responses in the screened clones. CONCLUSIONS: Using the SIGEX approach, we retrieved gene fragments with no previously identified response to metal ions that exhibited metal-ion-induced expression. This method has the potential to promote exploration of gene function through gene-induction response. SIGNIFICANCE AND IMPACT OF THE STUDY: We successfully linked gene-induction response with sequence information for gene fragments of previously unknown function. The SIGEX-based approach exhibited the potential to identify genetic function in unknown gene pools from the deep subseafloor biosphere, as well as novel genetic components for future biotechnological applications.

Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study.

BACKGROUND: Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS. METHODS: This was a retrospective study conducted by 15 institutions participating in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC). We evaluated patients with CRS treated with endoscopic sinus surgery (ESS), and risk of recurrence was estimated using Cox proportional hazard models. Multiple logistic regression models and receiver operating characteristics curves were constructed to create the diagnostic criterion for ECRS. RESULTS: We analyzed 1716 patients treated with ESS. To diagnose ECRS, the JESREC scoring system assessed unilateral or bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in computed tomography (CT) scans. The cutoff value of the score was 11 points (sensitivity: 83%, specificity: 66%). Blood eosinophilia (>5%), ethmoid sinus disease detected by CT scan, bronchial asthma, aspirin, and nonsteroidal anti-inflammatory drugs intolerance were associated significantly with recurrence. CONCLUSION: We subdivided CRSwNP in non-ECRS, mild, moderate, and severe ECRS according to our algorithm. This classification was significantly correlated with prognosis. It is notable that this algorithm may give useful information to clinicians in the refractoriness of CRS before ESS or biopsy.

Continuous Vocalization during Kendo Exercises Suppresses Expiration of CO2.

One distinctive trait of kendo, the Japanese martial art of fencing, is the execution of sustained, high-effort vocalizations during actions. The purpose of this study was to determine the effect of these vocalizations on respiratory functions. First, the intensity of 3 kendo exercises was quantified by measuring oxygen uptake (V̇O2) and comparing it with V̇O2max measured during treadmill tests of 8 university kendo athletes. Respiratory variables of these 8 athletes were then analyzed using a portable breath gas analyzer during the most intensive kendo exercise, kakari-keiko, with and without vocalization. Breathing frequency (fB) increased regardless of vocalization, but in trials with vocalization, fB and ventilation were significantly lower, and expiration time was significantly longer. Components of expired gases were also affected by vocalization. Although there was no significant difference in oxygen uptake, vocalization yielded a reduction in carbon dioxide output (V̇CO2) and an increase in fraction of end-tidal carbon dioxide (FetCO2). We thus conclude that these vocalizations greatly affect expiration breathing patterns in kendo. Moreover, repetition of kakari-keiko caused a reduction in V̇CO2 and an increase in FetCO2 and CO2 storage. We consider the possibility that the sustained high-effort vocalizations of kendo also increase cerebral blood flow.

Exercise lowers postprandial glucose but not fasting glucose in type 2 diabetes: a meta-analysis of studies using continuous glucose monitoring.

Exercise has repeatedly been shown to improve glycemic control as assessed by glycated hemoglobin. However, changes in glycated hemoglobin do not provide information regarding which aspects of glycemic control have been altered. The purpose of this systematic review was to examine the effect of exercise as assessed by continuous glucose monitoring systems (CGMS) in type 2 diabetes. Databases (PubMed, Medline, EMBASE) were searched up to February 2013. Eligible studies had participants with type 2 diabetes complete standardized exercise protocols and used CGMS to measure changes in glycemic control. Randomized controlled trials, crossover trials and studies with pre-post designs were included. Average glucose concentration, daily time spent in hyperglycemia or hypoglycemia, and fasting glucose concentration were compared between exercise and control conditions. Eleven studies met the inclusion criteria and were included in the review. Eight studies had short-term (≤2 weeks) exercise interventions, whereas three studies had a longer-term intervention (all >2 months). The types of exercises utilized included aerobic, resistance and a combination of the two. The eight short-term studies were included in quantitative analysis. Exercise significantly decreased average glucose concentrations (-0.8 mmol/L, p < 0.01) and daily time spent in hyperglycemia (-129 minutes, p < 0.01), but did not significantly affect daily time spent in hypoglycemia (-3 minutes, p = 0.47) or fasting glucose (-0.3 mmol/L, p = 0.13). The four randomized crossover trials had similar findings compared to studies with pre-post designs. Exercise consistently reduced average glucose concentrations and time spent in hyperglycemia despite not significantly affecting outcomes such as fasting glucose and hypoglycemia.

A novel clinical role for angiopoietin-1 in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour associated with asbestos exposure that has only a limited response to conventional therapy; therefore, diagnosing MPM early is very important. We have previously reported that angiopoietin (Ang)-1 was correlated with bleomycin-induced pulmonary fibrosis. Here, we investigated the association of Ang-1 with the development of MPM cells, which originate from mesenchymal cells similar to lung fibroblasts, and demonstrated that Ang-1 stimulated the growth and migration of MPM cells in vitro. We also demonstrated that patients with MPM had significantly higher serum levels of Ang-1 in comparison to a population who had been exposed to asbestos but had not developed MPM. The patients with advanced-stage MPM showed higher levels of Ang-1 than the early-stage MPM patients and the Kaplan-Meier method revealed a significant correlation between serum Ang-1 levels and survival. We propose the possibility that Ang-1 plays an important role in MPM tumour growth and our data suggest that the serum concentration of Ang-1 could be useful as prognostic factor.

Less protease-resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulphate.

Treatment with intraventricular pentosan polysulphate (PPS) might be beneficial in patients with Creutzfeldt-Jakob disease. We report a 68-year-old woman with sporadic Creutzfeldt-Jakob disease who received continuous intraventricular PPS infusion (1-120 microg/kg/day) for 17 months starting 10 months after the onset of clinical symptoms. Treatment with PPS was well tolerated but was associated with a minor, transient intraventricular hemorrhage and a non-progressive collection of subdural fluid. The patient's overall survival time was well above the mean time expected for the illness but still within the normal range. Post-mortem examination revealed that the level of abnormal protease-resistant prion protein in the brain was markedly decreased compared with levels in brains without PPS treatment. These findings suggest that intraventricular PPS infusion might modify the accumulation of abnormal prion proteins in the brains of patients with sporadic Creutzfeldt-Jakob disease.

Isolated spinal neurosarcoidosis: an autopsy case.

STUDY DESIGN: Autopsy cases of isolated spinal neurosarcoidosis are extremely rare or none. OBJECTIVES: To report an autopsy case of isolated spinal neurosarcoidosis without the involvement of other organs. SUMMARY OF BACKGROUND DATA: A few reports of isolated spinal neurosarcoidosis are present, but no autopsy cases of isolated spinal neurosarcoidosis are present in the English literature. SETTING: Japan. METHODS: An autopsy case of isolated spinal neurosarcoidosis was examined pathologically. RESULTS: A 54-year-old woman was admitted to our hospital because of leg numbness and muscle weakness. Imaging modalities showed an irregular contour and a mass-like lesion in the spinal cord. No biopsies were performed. Clinical diagnoses were suspected sarcoidosis and malignant lymphoma. The patient was treated by steroids and anti-cancer drugs, but she suddenly died of unknown cause. An autopsy revealed fibrosis and non-caseating granulomata in the spinal cord. No acid-fast bacteria or fungi were recognized by special stains. A PCR revealed no acid-fast bacteria including tuberculosis. Other organs including the brain and lung showed no sarcoidosis lesions. A pathological diagnosis of isolated spinal neurosarcoidosis was made. Other pathological diagnoses were systemic congestion, lung emphysema, food impaction in the upper esophagus and larynx, cardiac hypertrophy and marked dilation of the colon. The cause of death was thought to be respiratory failure. CONCLUSION: We have reported a very rare autopsy case of isolated spinal neurosarcoidosis, with an emphasis on pathological findings.

Effect of antibiotic treatment on microbial composition and expression of antimicrobial peptides and cytokines in the chick cecum.

The aim of this study was to confirm whether the expression of innate immune molecules in the chick cecum is altered in association with changes in the composition of the intestinal microbiome that are regulated by treatment with antibiotics. Broiler chicks were administered with antibiotics (penicillin and streptomycin) daily, and the composition of the microbiota, expression of innate immune molecules, and localization of antimicrobial peptides in the chick cecum were examined at day 7 and day 14 using real-time PCR and immunohistochemistry. The oral administration of antibiotics caused an increase in the relative frequency of the Enterobacteriaceae family and a decrease in some gram-negative (Barnesiellaceae) and gram-positive bacterial (Clostridiaceae and Erysipelotrichaceae) families. The gene expression levels of immune molecules, including 4 Toll-like receptors (TLR) (TLR 2, 4, 5, and 21), inflammation-related cytokines (IL-1ß, TGFß3, TGFß4, and IL-8), and antimicrobial peptides (avian ß-defensins and cathelicidins) showed a tendency to decrease with antibiotic treatment at day 7. However, expression levels of TLR21 and some cytokines (IL-1ß, TGFß3, and IL-8) were higher in the cecum or cecal tonsils of the antibiotic-treated group than in those of the control at day 14. The immunoreactive avian ß-defensin 2 and cathelicidin 1 proteins were localized in the leukocyte-like cells in the lamina propria, and they were aggregated in the form of small islands. We conclude that the expression of innate immune molecules, including TLR, inflammation-related cytokines, and antimicrobial peptides, in the cecum are altered in association with changes in the density or composition of the luminal microbiota during the early phase of life in chicks.

All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumour of mesothelial origin associated with asbestos exposure. Because MPM has limited response to conventional chemotherapy and radiotherapy, the prognosis is very poor. Several researchers have reported that cytokines such as interleukin (IL)-6 play an important role in the growth of MPM. Previously, it was reported that all-trans-retinoic acid (ATRA) inhibited the production and function of IL-6 and transforming growth factor (TGF)-beta1 in experiments using lung fibroblasts. We investigated whether ATRA had an inhibitory effect on the cell growth of MPM, the origin of which was mesenchymal cells similar to lung fibroblasts, using a subcutaneous xenograft mouse model. We estimated the tumour growth and performed quantitative measurements of IL-6, TGF-beta1 and platelet-derived growth factor (PDGF) receptor (PDGFR)-beta mRNA levels both of cultured MPM cells and cells grown in mice with or without the administration of ATRA. ATRA significantly inhibited MPM tumour growth. In vitro studies disclosed that the administration of ATRA reduced 1) mRNA levels of TGF-beta1, TGF-beta1 receptors and PDGFR-beta, and 2) TGF-beta1-dependent proliferation and PDGF-BB-dependent migration of MPM cells. These data may provide a rationale to explore the clinical use of ATRA for the treatment of MPM.

Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation.

BACKGROUND: The association between gastro-oesophageal reflux disease (GORD) and chronic obstructive pulmonary disease (COPD) exacerbation has so far remained unclear. OBJECTIVE: To prospectively establish the clinical significance of GORD symptoms on exacerbation. METHODS: 82 patients with COPD and 40 age matched controls were enrolled in this study. Symptoms were evaluated by a questionnaire using the Frequency Scale for the Symptoms of GORD (FSSG). Patients with COPD were prospectively surveyed for 6 months, and episodes of exacerbation were identified using a diary based on modified Anthonisen's criteria. Exhaled breath condensate (EBC) pH was measured in both groups, and induced sputum was evaluated in patients with COPD. RESULTS: Positive GORD symptoms were reported in 22 (26.8%) patients with COPD and in five (12.5%) controls (p = 0.10). The frequency of exacerbations was significantly associated with the FSSG score (p = 0.03, r = 0.24, 95% CI 0.02 to 0.43). Multiple regression analysis revealed that GORD symptoms were significantly associated with the occurrence of exacerbations (p<0.01; relative risk 6.55, 95% CI 1.86 to 23.11). EBC pH was inversely correlated with FSSG score in both groups (p = 0.01, r = -0.37, 95% CI -0.55 to -0.14 in patients with COPD, and p<0.01, r = -0.45, 95% CI -0.67 to -0.16 in control subjects). CONCLUSIONS: GORD symptoms were identified as an important factor associated with COPD exacerbation.

Innate antiviral immune response against infectious bronchitis virus and involvement of prostaglandin E2 in the uterine mucosa of laying hens.

Infectious bronchitis virus (IBV) is an enveloped RNA virus that causes deformities in eggshells. The aim of this study was to investigate the innate immune response to IBV, and to determine whether prostaglandin (PG) E2, which is synthesized during inflammation, is involved in the innate immune response in the uterine mucosa. The effects of intra-oviductal inoculation with attenuated IBV (aIBV) on the expression of viral RNA recognition receptors and innate antiviral factors were examined by real-time PCR and immunohistochemistry, and on PGE2 levels by ELISA. Then, the effects of PGE2 on the expression of innate antiviral factors in cultured uterine mucosal cells were examined. The results showed that the expression of RNA virus pattern recognition receptors (TLR3, 7, and MDA5), antimicrobial peptides (avian ß-defensins, including AvBD1, 2, 4-6 and cathelicidins, including CATH1 and 3), and interferons (IFNα, ß, γ, λ) were upregulated, and the expression of cyclooxygenase 2 (PG synthase) and the level of PGE2 were increased in the uterine mucosa following aIBV inoculation. The number of AvBD2-positive cells in the mucosa also increased in response to aIBV. In cultured mucosal cells (mainly epithelial), the expression of AvBD4, 10-13 and IFNα, ß, and λ was upregulated following incubation with 500 nM PGE2. These results suggest that the expression of viral RNA-recognition receptors, AvBDs, CATHs, and IFNs and PGE2 are induced by the IBV antigen, and that the expression of a different set of AvBDs is also induced by PGE2 in the cultured uterine mucosal cells. These antiviral factors may play a role in the protection of the uterine mucosa from IBV infection.

Relationship between Eustachian tube dysfunction and otitis media with effusion in radiotherapy patients.

OBJECTIVE: This study evaluated the relationship between radiation and Eustachian tube dysfunction, and examined the radiation dose required to induce otitis media with effusion. METHODS: The function of 36 Eustachian tubes in 18 patients with head and neck cancer were examined sonotubometrically before, during, and 1, 2 and 3 months after, intensity-modulated radiotherapy. Patients with an increase of 5 dB or less in sound pressure level (dB) during swallowing were categorised as being in the dysfunction group. Additionally, radiation dose distributions were assessed in all Eustachian tubes using three dose-volume histogram parameters. RESULTS: Twenty-two of 25 normally functioning Eustachian tubes before radiotherapy (88.0 per cent) shifted to the dysfunction group after therapy. All ears that developed otitis media with effusion belonged to the dysfunction group. The radiation dose threshold evaluation revealed that ears with otitis media with effusion received significantly higher doses to the Eustachian tubes. CONCLUSION: The results indicate a relationship between radiation dose and Eustachian tube dysfunction and otitis media with effusion.

Evaluation of efficacy and indications of surgical fixation for multiple rib fractures: a propensity-score matched analysis.

PURPOSE: The purpose of this study was to assess the effects of recent surgical rib fixation and establish its indications not only for flail chest but also for multiple rib fractures. METHODS: Between 2007 and 2015, 187 patients were diagnosed as having multiple rib fractures in our institution. After the propensity score matching was performed, ten patients who had performed surgical rib fixation and ten patients who had treated with non-operative management were included. Categorical variables were analyzed with Fischer's exact test and non-parametric numerical data were compared using the Mann-Whitney U test. Wilcoxon signed-rank test was performed for comparison of pre- and postoperative variables. All statistical data are presented as median (25-75 % interquartile range [IQR]) or number. RESULTS: The surgically treated patients extubated significantly earlier than non-operative management patients (5.5 [1-8] vs 9 [7-12] days: p = 0.019). The duration of continuous intravenous narcotic agents infusion days (4.5 [3-6] vs 12 [9-14] days: p = 0.002) and the duration of intensive care unit stay (6.5 [3-9] vs 12 [8-14] days: p = 0.008) were also significantly shorter in surgically treated patients. Under the same ventilating conditions, the postoperative values of tidal volume and respiratory rate improved significantly compared to those values measured just before the surgery. The incidence of pneumonia as a complication was significantly higher in non-operative management group (p = 0.05). CONCLUSIONS: From the viewpoints of early respiratory stabilization and intensive care unit disposition without any complications, surgical rib fixation is a sufficiently acceptable procedure not only for flail chest but also for repair of severe multiple rib fractures.