Effects of SGLT2 Inhibitors and DPP-4 Inhibitors on Advanced Glycation End Products.

Clinical trials have revealed that sodium glucose cotransporter 2 (SGLT2) inhibitors suppress the onset of heart failure and cardiovascular death in diabetic patients. On the other hand, few reports have been published concerning such effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. We undertook the present study to evaluate the effects of SGLT2 inhibitors and DPP-4 inhibitors on the advanced glycation end products (AGEs), well known as a risk factor for the development of cardiovascular disorders.Type 2 diabetes mellitus were divided into two groups and treated with either SGLT2 inhibitors or DPP-4 inhibitors for 3 months. Before and after the 3-month treatment period with each drug, the AGEs and diabetes-related parameters were measured. Methylglyoxal-derived hydroimidazolone-1 (MG-H1) was measured as one of the AGEs.In the SGLT2 inhibitor group, both the blood HbA1c and MG-H1 levels decreased significantly after the 3-month treatment period. In the DPP-4 inhibitor group, only the blood HbA1c level decreased significantly, with no significant change of the blood MG-H1 level.SGLT2 inhibitor reduced both the blood levels of HbA1c and AGEs (MG-H1). Considering that the blood levels of AGEs are associated with the risk of heart failure and cardiovascular disorders, the results of the present study suggest that the effect of SGLT2 inhibitors in suppressing cardiovascular death might be mediated by the reduction in the blood levels of AGEs induced by this class of drugs. DPP-4 inhibitors showed no significant effects on the blood levels of AGEs.

Estimating Patient Satisfaction Through a Language Processing Model: Model Development and Evaluation.

BACKGROUND: Measuring patient satisfaction is a crucial aspect of medical care. Advanced natural language processing (NLP) techniques enable the extraction and analysis of high-level insights from textual data; nonetheless, data obtained from patients are often limited. OBJECTIVE: This study aimed to create a model that quantifies patient satisfaction based on diverse patient-written textual data. METHODS: We constructed a neural network-based NLP model for this cross-sectional study using the textual content from disease blogs written in Japanese on the Internet between 1994 and 2020. We extracted approximately 20 million sentences from 56,357 patient-authored disease blogs and constructed a model to predict the patient satisfaction index (PSI) using a regression approach. After evaluating the model's effectiveness, PSI was predicted before and after cancer notification to examine the emotional impact of cancer diagnoses on 48 patients with breast cancer. RESULTS: We assessed the correlation between the predicted and actual PSI values, labeled by humans, using the test set of 169 sentences. The model successfully quantified patient satisfaction by detecting nuances in sentences with excellent effectiveness (Spearman correlation coefficient [ρ]=0.832; root-mean-squared error [RMSE]=0.166; P<.001). Furthermore, the PSI was significantly lower in the cancer notification period than in the preceding control period (-0.057 and -0.012, respectively; 2-tailed t47=5.392, P<.001), indicating that the model quantifies the psychological and emotional changes associated with the cancer diagnosis notification. CONCLUSIONS: Our model demonstrates the ability to quantify patient dissatisfaction and identify significant emotional changes during the disease course. This approach may also help detect issues in routine medical practice.

Effects of SGLT2 inhibitors on the intestinal bacterial flora in Japanese patients with type 2 diabetes mellitus.

Selective inhibitors of sodium glucose co-transporter-2 (SGLT2) suppress renal glucose reabsorption and promote urinary glucose excretion, thereby lowering blood glucose. SGLT2 inhibitors have been reported to reduce body weight. However, the mechanism underlying the reduction in the body weight induced by SGLT2 inhibitor treatment remains to be elucidated. In this study, we investigated the effects of SGLT2 inhibitors on the intestinal bacterial flora. A total of 36 Japanese patients with type 2 diabetes mellitus received a SGLT2 inhibitor (luseogliflozin or dapagliflozin) for 3 months, and the prevalences of balance-regulating bacteria and balance-disturbing bacteria in the feces of the patients before and after SGLT2 inhibitor treatment were determined. SGLT2 inhibitor treatment was associated with a significant increase of the overall prevalence of the 12 types of balance-regulating bacteria. In addition, significant increases in the prevalences of the short-chain fatty acid (SCFAs)-producing bacteria among the balance-regulating bacteria were also observed. Individual analyses of the balance-regulating bacteria revealed that the SGLT2 inhibitor treatment was associated with a significant increase in the prevalence of Ruminococci, which are balance-regulating bacteria classified as SCFAs-producing bacteria. However, SGLT2 inhibitor had no effect on the balance-disturbing bacteria. These results suggested that SGLT2 inhibitor treatment was associated with an overall increase in the prevalence of balance-regulating bacteria. Among the balance-regulating bacteria, the prevalences of SCFAs-producing bacteria increased. SCFAs have been reported to prevent obesity. The results of the present study suggest that SGLT2 inhibitors might induce body weight reduction via their actions on the intestinal bacterial flora.

Subnanomolar Sensitive Stable Isotopic Determination in CO2 by Tunable Infrared Laser Absorption Spectroscopy.

Oxygen and carbon stable isotope ratios (18O/16O, 13C/12C, and 17O/16O) of CO2 have been crucial in helping us understand Earth and planetary systems. These ratios have also been used in medicine for the noninvasive diagnosis of diseases from exhaled breath and for quantifying biochemical or metabolic reactions and in determining the production area of agricultural products. The current method for measuring the stable isotope ratios of CO2 is primarily gas-source isotope ratio mass spectroscopy (IRMS). Due to the recent demand for isotopic microanalysis of carbonates and organic compounds, the sample size required for isotopic measurements has been reduced to approximately 2 nmol CO2 (equivalent to 0.2 µg CaCO3 and 24 ng carbon) by using high-precision IRMS. We report a novel method using tunable mid-infrared laser direct absorption spectroscopy (TILDAS) for sensitive measurements of 18O/16O and 13C/12C in subnanomolar CO2. This method can accurately measure 18O/16O and 13C/12C in CO2 with a repeatability of less than 0.03‰ (n = 28) in a range of 0.3 nmol (equivalent to 0.03 µg CaCO3 and 3.8 ng carbon) to 30 nmol. This is a sample size 1 order of magnitude smaller than currently available sensitive analytical techniques. In addition, the TILDAS system measures 17O/16O simultaneously with a repeatability of less than 0.06‰ (n = 28). Our method is a major advance in supersensitive CO2 stable isotopic analyses for various fields.

Transplantation of Fibroblast Sheets with Blood Mononuclear Cell Culture Exerts Cardioprotective Effects by Enhancing Anti-Inflammation and Vasculogenic Potential in Rat Experimental Autoimmune Myocarditis Model.

Fulminant myocarditis causes impaired cardiac function, leading to poor prognosis and heart failure. Cell sheet engineering is an effective therapeutic option for improving cardiac function. Naïve blood mononuclear cells (MNCs) have been previously shown to enhance the quality and quantity of cellular fractions (QQMNCs) with anti-inflammatory and vasculogenic potential using the one culture system. Herein, we investigated whether autologous cell sheet transplant with QQMNCs improves cardiac function in a rat model with experimental autoimmune myocarditis (EAM). Fibroblast sheets (F-sheet), prepared from EAM rats, were co-cultured with or without QQMNCs (QQ+F sheet) on temperature-responsive dishes. QQ+F sheet induced higher expression of anti-inflammatory and vasculogenic genes (Vegf-b, Hgf, Il-10, and Mrc1/Cd206) than the F sheet. EAM rats were transplanted with either QQ+F sheet or F-sheet, and the left ventricular (LV) hemodynamic analysis was performed using cardiac catheterization. Among the three groups (QQ+F sheet, F-sheet, operation control), the QQ+F sheet transplant group showed alleviation of end-diastolic pressure-volume relationship on a volume load to the same level as that in the healthy group. Histological analysis revealed that QQ+F sheet transplantation promoted revascularization and mitigated fibrosis by limiting LV remodeling. Therefore, autologous QQMNC-modified F-sheets may be a beneficial therapeutic option for EAM.

Incorporating Unstructured Patient Narratives and Health Insurance Claims Data in Pharmacovigilance: Natural Language Processing Analysis of Patient-Generated Texts About Systemic Lupus Erythematosus.

BACKGROUND: Gaining insights that cannot be obtained from health care databases from patients has become an important topic in pharmacovigilance. OBJECTIVE: Our objective was to demonstrate a use case, in which patient-generated data were incorporated in pharmacovigilance, to understand the epidemiology and burden of illness in Japanese patients with systemic lupus erythematosus. METHODS: We used data on systemic lupus erythematosus, an autoimmune disease that substantially impairs quality of life, from 2 independent data sets. To understand the disease's epidemiology, we analyzed a Japanese health insurance claims database. To understand the disease's burden, we analyzed text data collected from Japanese disease blogs (tobyoki) written by patients with systemic lupus erythematosus. Natural language processing was applied to these texts to identify frequent patient-level complaints, and term frequency-inverse document frequency was used to explore patient burden during treatment. We explored health-related quality of life based on patient descriptions. RESULTS: We analyzed data from 4694 and 635 patients with systemic lupus erythematosus in the health insurance claims database and tobyoki blogs, respectively. Based on health insurance claims data, the prevalence of systemic lupus erythematosus is 107.70 per 100,000 persons. Tobyoki text data analysis showed that pain-related words (eg, pain, severe pain, arthralgia) became more important after starting treatment. We also found an increase in patients' references to mobility and self-care over time, which indicated increased attention to physical disability due to disease progression. CONCLUSIONS: A classical medical database represents only a part of a patient's entire treatment experience, and analysis using solely such a database cannot represent patient-level symptoms or patient concerns about treatments. This study showed that analysis of tobyoki blogs can provide added information on patient-level details, advancing patient-centric pharmacovigilance.

Jervell and Lange-Nielsen syndrome with novel KCNQ1 and additional gene mutations.

We encountered a boy with Jervell and Lange-Nielsen syndrome (JLNS) with compound heterozygous KCNQ1 mutations, maternal Trp248Phe and a novel paternal mutation, Leu347Arg. His father showed long QT (LQT) and arrhythmia. His mother was asymptomatic with no ECG abnormalities. The proband and his father had an additional mutation (SNTA1 Thr372Met), which is reportedly related to SIDS. These results suggest that multiple gene mutations influence the phenotype of KCNQ1 mutation-related arrhythmia.

Associations among smoking, MGMT hypermethylation, TP53-mutations, and relapse in head and neck squamous cell carcinoma.

BACKGROUND: Epigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair enzyme via promoter hypermethylation (hmMGMT) may increase mutations in the TP53 oncosuppressor gene and contribute to carcinogenesis. The effects of smoking, which is a risk factor for head and neck squamous cell carcinoma (HNSCC), were investigated to determine whether they up- or down-regulate hmMGMT. Additionally, the impact of hmMGMT and disruptive TP53-mutations on relapse was investigated in patients with HNSCC. METHODS: This study included 164 patients with HNSCC who were negative for both p16 protein expression and human papilloma virus infection. The association of smoking and hmMGMT was investigated using multiple logistic regression analysis. Competing risk regression was used to evaluate the effects of hmMGMT and TP53-mutations in exon 2 to 11 on relapse of HNSCC. RESULTS: hmMGMT was observed in 84% of the 164 patients. TP53-mutations, specifically, G:C>A:T transition, were more frequent in patients with hmMGMT (32%) than in those without hmMGMT (8%). The frequency of disruptive TP53-mutations was not significantly different between groups. Compared with nonsmoking, heavy smoking of 20 pack-years or more was significantly associated with decreased hmMGMT (adjusted odds ratio, 0.08; 95% CI, 0.01 to 0.56; P = 0.01). Patients who had both hmMGMT and disruptive TP53-mutations showed a significantly higher relapse rate than all other patients (subdistribution hazard ratio, 1.77; 95% CI, 1.07 to 2.92; P = 0.026). CONCLUSIONS: It was found that hmMGMT was suppressed by heavy smoking, and hmMGMT combined with disruptive TP53-mutations may indicate a poor prognosis in patients with HNSCC.

Differences in Virus Detection and Cytokine Profiles between First Wheeze and Childhood Asthma.

OBJECTIVE: To distinguish between first wheeze and asthma in early childhood, we investigated respiratory viruses and cytokine/chemokine profiles among patients with first wheeze and established asthma. METHODS: We enrolled children with acute exacerbations of wheezing (17 first wheeze and 32 asthma) and 11 controls (no wheezing) aged between 10 months and 6 years. Nasal aspirates were obtained, and virus detection was performed with antigenic assay kits and/or RT-PCR. Serum 27 cytokines/chemokines were assayed by a multi-cytokine detection system. RESULTS: Rhinovirus and respiratory syncytial (RS) virus were dominant in acute exacerbations of asthma. However, many types of viruses were isolated in first wheeze. Serum IL-8 and IL-12 values were significantly higher in first wheeze than in acute asthma or the controls. IL-5 and IP-10 levels in acute asthma and first wheeze cases were higher than in the controls. Both of them were significantly higher in cases of acute asthma than in convalescence stage of asthma cases. Only IP-10 was significantly higher in first wheeze than in convalescence stage of first wheeze cases. CONCLUSIONS: Different profiles in virus detection and production of IL-8 and IL-12 might distinguish between first wheeze and childhood asthma.

The Evaluation of Changes in the Breath Sound Spectrum with Bronchoconstriction and Bronchodilatation in Asthmatic Children.

OBJECTIVE: Focusing on the relative-middle sound area of the breath sound spectrum, the relationship between airway changes and breath sounds in asthmatic children was investigated. METHODS: In Study 1, 77 children (6-16 years old) were included. The breath sound parameters, the ratio of the second area to the third area of the power spectrum (A2/A3) and the ratio of the third area to the fourth area (B3/B4) were evaluated 3 times, before and just after methacholine inhalation and after ß2 agonist inhalation. Other breath sound parameters, the frequency limiting 99% of the power spectrum (F99), the rolloff from 600-1200 Hz (Slope) and the ratio of the third and fourth area to the total area under the curve (A3/AT and B4/AT), and the ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF75 and RPF50), were also evaluated. In Study 2, 91 children (6-16 years old) were included, with evaluations performed twice: before and after ß2 a gonist inhalation. Spirography a nd forced o scillation technique were also performed. RESULTS: In Study 1, A2/A3 and B3/B4 were significantly increased after methacholine inhalation and decreased after ß2 agonist inhalation (p < 0.001, P < 0.001, respectively). In Study 2, A2/A3 and B3/B4 were significantly decreased after ß2 agonist inhalation. These changes in A3/AT and B4/AT were the inverse of those in other spectrum curve indices. CONCLUSIONS: A2/A3 and B3/B4, indicate the breath sound changes after bronchoconstriction and bronchodilatation. These parameters may be useful for assessing bronchial reversibility in asthmatic children.

A Young Patient with Emery-Dreifuss Muscular Dystrophy Treated with Endovascular Therapy for Cardioembolic Stroke: A Case Report.

We had a case of Emery-Dreifuss muscular dystrophy (EDMD) in an 18-year-old woman who underwent endovascular therapy for a cardioembolic stroke. At 5 years old, she showed a high creatine kinase level and atrial fibrillation on electrocardiography in our hospital. Finally, she was diagnosed as having EDMD by genetic screening that revealed mutations in the LMNA gene (c.810+1G>T). Before this event, she received no medications. At 18 years old, she was admitted to our hospital>8 hours after the onset of sudden consciousness disturbance. Neurological examination on admission revealed consciousness disturbance and right hemiplegia. Magnetic resonance imaging revealed a cerebral infarction in the left insular cortex and putamen with left internal carotid artery occlusion. We performed endovascular therapy and completely recanalized her left internal carotid artery. Thereafter, her neurological symptoms improved. She was subsequently transferred to a rehabilitation hospital. EDMD is a rare genetic muscular disease that mainly presents with contractures, weakness, and cardiac conduction abnormalities. Although patients with EDMD are young with low CHADS2 score, they have a disease-specific cardiovascular pathogenesis caused by a fatal risk factor. Therefore, we consider anticoagulant therapy necessary to prevent thrombotic events, even if the CHADS2 score is low, in patients with EDMD.

Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events.

Importance: Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). Objective: To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA. Design, Setting, and Participants: This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. Main Outcomes and Measures: The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, ≥5 to <10; actual internal diameter, <8 mm), and large (z score, ≥10 or ≥8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications. Results: Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1-15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7-4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4-3.6) were significantly associated with CE. Conclusions and Relevance: Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA.

Changes in the breath sound spectrum during methacholine inhalation in children with asthma.

BACKGROUND AND OBJECTIVE: An effort-independent breath sound analysis is expected to be a safe and simple method for clinical assessment of changes in airway function. The effects of bronchoconstriction and bronchodilation on novel breath sound parameters in asthmatic children were investigated. METHODS: The study population included 49 children with atopic asthma (male = 33; mean age: 10.2 years). We evaluated breath sound parameters of the highest frequency of the power spectrum (HFp), frequency limiting 50% and 99% of the power spectrum (F50 and F99 ) and roll-off from 600 Hz to the HFp (Slope). We also assessed new parameters obtained using the ratios of sound spectrum parameters (spectrum curve indices), such as the ratio of the third and fourth power area to the total power area (P3 /PT and P4 /PT ), the ratio of the third and fourth areas to the total area under the curve (A3 /AT and B4 /AT ) and the ratio of power and frequency at 75% of HFp and 50% of HFp (RPF75 and RPF50 ). This was measured before and after methacholine inhalation challenge and after ß2 agonist inhalation. RESULTS: The parameters, F50 and F99 , showed no changes after methacholine inhalation. Conversely, the A3 /AT (12.5-10.0%, P < 0.001), B4 /AT (7.6-5.5%, P < 0.001), RPF75 (6.7-4.0 dBm/Hz, P < 0.001) and RPF50 (5.8-4.3 dBm/Hz, P < 0.001) were significantly decreased. These values returned to the original level after ß2 agonist inhalation. CONCLUSION: Spectrum curve indices indicate bronchoconstriction and bronchodilation. These parameters may play a role in the assessment of airway narrowing in asthmatic children.

Prodromal signs and symptoms of serious infections with tocilizumab treatment for rheumatoid arthritis: Text mining of the Japanese postmarketing adverse event-reporting database.

OBJECTIVE: To search for signs and symptoms before serious infection (SI) occurs in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients. METHODS: Individual case safety reports, including structured (age, sex, adverse event [AE]) and unstructured (clinical narratives) data, were analyzed by automated text mining from a Japanese post-marketing AE-reporting database (16 April 2008-10 April 2015) assuming the following: treated in Japan; TCZ RA treatment; ≥1 SI; unable to exclude causality between TCZ and SIs. RESULTS: The database included 7653 RA patients; 1221 reports met four criteria, encompassing 1591 SIs. Frequent SIs were pneumonia (15.9%), cellulitis (9.9%), and sepsis (5.0%). Reports for 782 patients included SI onset date; 60.7% of patients had signs/symptoms ≤28 days before SI diagnosis, 32.7% had signs/symptoms with date unidentified, 1.7% were asymptomatic, and 4.9% had unknown signs/symptoms. The most frequent signs/symptoms were for skin (swelling and pain) and respiratory (cough and pyrexia) infections. Among 68 patients who had normal laboratory results for C-reactive protein, body temperature, and white blood cell count, 94.1% had signs or symptoms of infection. CONCLUSION: This study identified prodromal signs and symptoms of SIs in RA patients receiving TCZ. Data mining clinical narratives from post-marketing AE databases may be beneficial in characterizing SIs.

High-Precision Simultaneous 18O/16O, 13C/12C, and 17O/16O Analyses for Microgram Quantities of CaCO3 by Tunable Infrared Laser Absorption Spectroscopy.

Stable isotope ratios (18O/16O, 13C/12C, and 17O/16O) in carbonates have contributed greatly to the understanding of Earth and planetary systems, climates, and history. The current method for measuring isotopologues of CO2 derived from CaCO3 is primarily gas-source isotope ratio mass spectroscopy (IRMS). However, IRMS has drawbacks, such as mass overlap by multiple CO2 isotopologues and contaminants, the requirement of careful sample purification, and the use of major instrumentation needing permanent installation and a high power electrical supply. Here, we report simultaneous 18O/16O, 13C/12C, and 17O/16O analyses for microgram quantities of CaCO3 using a tunable mid-infrared laser absorption spectroscopy (TILDAS) system, which has no mass overlap problem and yields high sensitivity/precision measurements on small samples, as small as 0.02 µmol of CO2 (equivalent to 2 µg of CaCO3) with standard errors of less than 0.08 ‰ for 18O/16O and 13C/12C (±0.136 ‰ and ±0.387 ‰ repeatability; n = 10). In larger samples of CO2, 0.68 µmol (or 68 µg of CaCO3), standard error is less than 0.04 ‰ for 18O/16O and 13C/12C (< ±0.1 ‰ repeatability; n = 10) and 0.03 ‰ for 17O/16O (±0.069 ‰ repeatability; n = 10). We also show, for the first time, the relationship between 17O/16O ratios measured using the TILDAS system and published δ17O values of international standard materials (NBS-18 and -19) measured by IRMS. The benchtop TILDAS system, with cryogen-free sample preparation vacuum lines for microgram quantities of carbonates, is therefore a significant advance in carbonate stable isotope ratio geochemistry and is a new alternative to conventional IRMS.

A clinical method for detecting bronchial reversibility using a breath sound spectrum analysis in infants.

BACKGROUND: Using a breath sound analyzer, we investigated clinical parameters for detecting bronchial reversibility in infants. METHODS: A total of 59 infants (4-39 months, mean age 7.8 months) were included. In Study 1, the intra- and inter-observer variability was measured in 23 of 59 infants. Breath sound parameters, the frequency at 99% of the maximum frequency (F99), frequency at 25%, 50%, and 75% of the power spectrum (Q25, Q50, and Q75), and highest frequency of inspiratory breath sounds (HFI), and parameters obtained using the ratio of parameters, i.e. spectrum curve indices, the ratio of the third and fourth area to total area (A3/AT and B4/AT, respectively) and ratio of power and frequency at F75 and F50 (RPF75 and RPF50), were calculated. In Study 2, the relationship between parameters of breath sounds and age and stature were studied. In Study 3, breath sounds were studied before and after ß2 agonist inhalation. RESULTS: In Study 1, the data showed statistical intra- and inter-observer reliability in A3/AT (p=0.042 and 0.034, respectively) and RPF50 (p=0.001 and 0.001, respectively). In Study 2, there were no significant relationships between age, height, weight, and BMI. In Study 3, A3/AT and RPF50 significantly changed after ß2 agonist inhalation (p=0.001 and p<0.001, respectively). CONCLUSIONS: Breath sound analysis can be performed in infants, as in older children, and the spectrum curve indices are not significantly affected by age-related factors. These sound parameters may play a role in the assessment of bronchial reversibility in infants.

A Practical Cryogen-Free CO2 Purification and Freezing Technique for Stable Isotope Analysis.

Since isotopic analysis by mass spectrometry began in the early 1900s, sample gas for light-element isotopic measurements has been purified by the use of cryogens and vacuum-line systems. However, this conventional purification technique can achieve only certain temperatures that depend on the cryogens and can be sustained only as long as there is a continuous cryogen supply. Here, we demonstrate a practical cryogen-free CO2 purification technique using an electrical operated cryocooler for stable isotope analysis. This approach is based on portable free-piston Stirling cooling technology and controls the temperature to an accuracy of 0.1 °C in a range from room temperature to -196 °C (liquid-nitrogen temperature). The lowest temperature can be achieved in as little as 10 min. We successfully purified CO2 gas generated by carbonates and phosphoric acid reaction and found its sublimation point to be -155.6 °C at 0.1 Torr in the vacuum line. This means that the temperature required for CO2 trapping is much higher than the liquid-nitrogen temperature. Our portable cooling system offers the ability to be free from the inconvenience of cryogen use for stable isotope analysis. It also offers a new cooling method applicable to a number of fields that use gas measurements.

Analysis of Patient Narratives in Disease Blogs on the Internet: An Exploratory Study of Social Pharmacovigilance.

BACKGROUND: Although several reports have suggested that patient-generated data from Internet sources could be used to improve drug safety and pharmacovigilance, few studies have identified such data sources in Japan. We introduce a unique Japanese data source: tobyoki, which translates literally as "an account of a struggle with disease." OBJECTIVE: The objective of this study was to evaluate the basic characteristics of the TOBYO database, a collection of tobyoki blogs on the Internet, and discuss potential applications for pharmacovigilance. METHODS: We analyzed the overall gender and age distribution of the patient-generated TOBYO database and compared this with other external databases generated by health care professionals. For detailed analysis, we prepared separate datasets for blogs written by patients with depression and blogs written by patients with rheumatoid arthritis (RA), because these conditions were expected to entail subjective patient symptoms such as discomfort, insomnia, and pain. Frequently appearing medical terms were counted, and their variations were compared with those in an external adverse drug reaction (ADR) reporting database. Frequently appearing words regarding patients with depression and patients with RA were visualized using word clouds and word cooccurrence networks. RESULTS: As of June 4, 2016, the TOBYO database comprised 54,010 blogs representing 1405 disorders. Overall, more entries were written by female bloggers (68.8%) than by male bloggers (30.8%). The most frequently observed disorders were breast cancer (4983 blogs), depression (3556), infertility (2430), RA (1118), and panic disorder (1090). Comparison of medical terms observed in tobyoki blogs with those in an external ADR reporting database showed that subjective and symptomatic events and general terms tended to be frequently observed in tobyoki blogs (eg, anxiety, headache, and pain), whereas events using more technical medical terms (eg, syndrome and abnormal laboratory test result) tended to be observed frequently in the ADR database. We also confirmed the feasibility of using visualization techniques to obtain insights from unstructured text-based tobyoki blog data. Word clouds described the characteristics of each disorder, such as "sleeping" and "anxiety" in depression and "pain" and "painful" in RA. CONCLUSIONS: Pharmacovigilance should maintain a strong focus on patients' actual experiences, concerns, and outcomes, and this approach can be expected to uncover hidden adverse event signals earlier and to help us understand adverse events in a patient-centered way. Patient-generated tobyoki blogs in the TOBYO database showed unique characteristics that were different from the data in existing sources generated by health care professionals. Analysis of tobyoki blogs would add value to the assessment of disorders with a high prevalence in women, psychiatric disorders in which subjective symptoms have important clinical meaning, refractory disorders, and other chronic disorders.

Losartan attenuates the coronary perivasculitis through its local and systemic anti-inflammatory properties in a murine model of Kawasaki disease.

BACKGROUND: Kawasaki disease is a common systemic vasculitis that leads to coronary artery lesions. Besides its antihypertensive effects, losartan can modulate inflammation in cardiovascular disease. We examined whether losartan can attenuate coronary inflammation in a murine model of Kawasaki disease. METHODS AND RESULTS: Five-wk-old C57/BL6J male mice were intraperitoneally injected with Lactobacillus casei cell wall extract to induce coronary inflammation and divided into four groups: placebo, intravenous immunoglobulin (IVIG), losartan, and IVIG+losartan. After 2 wk, mice were harvested. The coronary perivasculitis was significantly attenuated by losartan but not by IVIG alone, and further dramatic attenuation by IVIG+losartan was observed. The frequency of Lactobacillus casei cell wall extract-induced myocarditis (80%) was markedly lowered by losartan (22%) and IVIG+losartan (0%). Furthermore, interleukin (IL)-6 mRNA was markedly attenuated by IVIG+losartan. Serum levels of IL-6, TNF-α, MCP-1, and IL-10 after Lactobacillus casei cell wall extract injection were slightly decreased by IVIG or losartan. Moreover, IL-1ß, IL-10, and MCP-1 levels were significantly decreased by IVIG+losartan. CONCLUSION: The addition of losartan to IVIG strongly attenuated the severity of coronary perivasculitis and the incidence of myocarditis, along with suppressing systemic/local cytokines as well as the activated macrophage infiltration. Therefore, losartan may be a potentially useful additive drug for the acute phase of Kawasaki disease to minimize coronary artery lesions.

IP-10 Is Elevated in Virus-Induced Acute Exacerbations in Childhood Asthma.

OBJECTIVE: Viral infections and sensitization to aeroallergens are major factors in the exacerbation of asthma and its development during early childhood. However, the cytokine profiles and eosinophil activation status linked to the association between viral infections and sensitization to aeroallergens are incompletely understood. Here we investigated respiratory viruses, serum eosinophil cationic protein (ECP), and various cytokines/chemokines in acute exacerbation of childhood asthma. METHODS: We analyzed peripheral eosinophil counts, serum ECP, and 27 cytokines/chemokines in 76 virus-induced acute asthma cases with or without aeroallergen sensitization. Asthma due to sensitization was defined by a positive reaction to at least one aeroallergen in serum specific IgE antibody tests. Virus detection was performed using antigen detection kits and/or RT-PCR, followed by direct DNA sequencing analysis. Serum cytokines/chemokines were measured using a multi-cytokine detection system. RESULTS: Peripheral eosinophil counts and serum ECP and IL-5 levels were significantly elevated in sensitized cases compared with nonsensitized cases. Conversely, IP-10 values were significantly higher in nonsensitized cases. An inverse correlation between IP-10 and IL-5 production was identified in virus-induced acute exacerbations of asthma but not in controls. CONCLUSIONS: Cytokine profiles and eosinophil activation status might be different between sensitized and nonsensitized cases of virus-induced acute exacerbations of asthma.