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Background: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma. Methods: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS). Results: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1–5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p

Abstract Electric dipole (E1) and spin-magnetic dipole (spin-M1) responses of nuclei have been studied by proton inelastic scattering experiments at forward angles, including zero degrees, at the Research Center for Nuclear Physics (RCNP) by employing a proton beam 295 or 392 MeV and the high-resolution magnetic spectrometer Grand Raiden. The E1 response of nuclei is the most fundamental nuclear response to the external field and is relevant to photo-nuclear reactions. After introducing the relevant nuclear matrix elements and the experimental methods, several recent experimental works are highlighted that include (E1) polarizability and the extraction of the symmetry energy parameters, pygmy dipole resonance, gamma-coincidence measurements, isoscalar and isovector spin-M1 excitations and the np spin correlation in the ground state, and gamma-emission probability for neutral current neutrino detection. A project, PANDORA, is introduced that aims at a systematic study of photo-nuclear reactions and decay branching ratios for light nuclei.

Summary: The heritability of major depressive disorder (MDD) is reportedly 30–50%. However, the genetic basis of its heritability remains unknown. Within SITH-1, a risk factor for MDD in human herpesvirus 6B (HHV-6B), we discovered a gene polymorphism with a large odds ratio for an association with MDD. It was a sequence whose number of repeats was inversely correlated with SITH-1 expression. This number was significantly lower in MDD patients. Rates for 17 or fewer repeats of the sequence were 67.9% for MDD and 28.6% for normal controls, with an odds ratio of 5.28. For patients with 17 or less repeats, the rate for presence of another MDD patient in their families was 47.4%, whereas there were no MDD patients in the families of patients with more than 17 repeats. Since HHV-6B is transmitted primarily mother to child and within families and persists for life, this gene polymorphism could potentially influence heritability of MDD.

Abstract Objective Inflammatory bowel disease (IBD) is closely related to stress and fatigue. Human herpesvirus 6B (HHV‐6B) is reactivated by stress and fatigue and is associated with IBD. This study aimed to clarify the relationship between IBD and HHV‐6B. Methods Antibody titers to SITH‐1, a protein specific to HHV‐6B latent infection, were measured in 163 patients with IBD (107 with ulcerative colitis [UC] and 56 with Crohn's disease [CD]); clinical and endoscopic scores and depression scores of UC and CD were analyzed to examine the relationship between SITH‐1 and IBD. The SITH‐1 cut‐off value was set as 1.96, according to known reports. Results In patients with UC, C‐reactive protein (CRP) level was significantly higher (1.5 vs 0.6 mg/L, P = 0.006) and disease exacerbation within 6 months after entry was significantly more common in the SITH‐1 (+) group (20% vs 0%, P

Background: Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is characterized by concurrent features of asthma and COPD. Since disease pathogenesis, severities, and treatments differ between asthma and ACO, it is important to differentiate them. Objective: To clarify and compare the characteristics of ACO and asthma and identify the serum biomarkers for differentiating them, especially in older patients. Methods: This study used the data of 639 participants from the nationwide cohort study, the NHOM-Asthma study, an asthma registry in Japan, with complete information on smoking history, respiratory function, and serum biomarkers. ACO was defined as the self-reported comorbidity of COPD or emphysema, or with obstructive pulmonary function and smoking history (pack-years≥10). The clinical characteristics of patients with ACO and asthma without COPD were compared. The serum biomarkers for differentiation were examined using receiver operating characteristic curves and multivariable analysis. The associations between the biomarkers and age were also analyzed. Results: Of the 639 asthma patients, 125 (19.6%) were diagnosed with ACO; these patients were older and male-dominant and had a higher prevalence of comorbidities such as hypertension, diabetes, and stroke. Among the serum biomarkers that were significantly different between ACO and asthma without COPD, the YKL-40/CHI3L1, MMP3, and IL-1RA levels showed a high area under the curve for discriminating ACO. Only the MMP3 and IL-1RA levels were significantly higher among ACO patients, regardless of age and sex; the YKL-40/CHI3L1 levels were not different due to the effect of age. Conclusion: MMP3 and IL-1RA may be useful serum biomarkers for distinguishing ACO from asthma.

Background: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes. Methods: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1–3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal–Wallis, and chi-square tests were used to compare cluster differences. Results: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV1; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV1, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes. Conclusions: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.)

An 84-year-old woman who had been diagnosed as having dementia with Lewy body (DLB) upon initial examination exhibited cognitive impairments and person delusional misidentification (DMS): she transiently claimed that her spouse was a stranger. She was re-examined at the age of 89 years; her frequency of speech and activities of daily living had both decreased, leading to verbal communication difficulties complicated by sensory aphasia, and brain diffusion-weighted (DW) magnetic resonance imaging (MRI) showed cortical hyperintensities in some areas of both hemispheres. About 4 months later, the DW high-intensity areas were observed to have expanded into diffuse cortical areas. While the clinical features of Creutzfeldt Jakob disease (CJD) (myoclonus; ataxia; parkinsonism; rapidly progressive cognitive impairments; periodic sharp discharges on electroencephalograms) were not observed, a genetic analysis of the prion protein (PRNP) gene, which was performed because of a family history of dementia, revealed a V180I mutation (heterozygosis: valine/isoleucine) suggesting genetic CJD (g-CJD). Her activity progressively decreased, reaching akinetic mutism about 11 months after the re-examination. Finally, she suffered from severe bedsores and died from aspiration pneumonia at the age of 90 years. The present report describes the first case of person DMS as an initial neuropsychiatric symptom for V180I g-CJD; the typical long-term clinical symptoms of CJD were not observed in this patient. The inclusion of person DMS as an initial clinical symptom and the presence of expansive cortical hyperintensity areas may be useful for clinicians attempting to diagnosis V180I g-CJD in patients with elusive symptoms.

IntroductionIt is assumed that host defense systems eliminating the pathogen and regulating tissue damage make a strong impact on the outcome of tuberculosis (TB) disease and that these processes are affected by rifampicin (RIF) resistance–conferring mutations of Mycobacterium tuberculosis (Mtb). However, the host responses to the pathogen harboring different mutations have not been studied comprehensively in clinical settings. We analyzed clinico-epidemiological factors and blood transcriptomic signatures associated with major rpoB mutations conferring RIF resistance in a cohort study.MethodsDemographic data were collected from 295 active pulmonary TB patients with treatment history in Hanoi, Vietnam. When recruited, drug resistance–conferring mutations and lineage-specific variations were identified using whole-genome sequencing of clinical Mtb isolates. Before starting retreatment, total RNA was extracted from the whole blood of HIV-negative patients infected with Mtb that carried either the rpoB H445Y or rpoB S450L mutation, and the total RNA was subjected to RNA sequencing after age-gender matching. The individual RNA expression levels in the blood sample set were also measured using real-time RT-PCR. Logistic and linear regression models were used to assess possible associations.ResultsIn our cohort, rpoB S450L and rpoB H445Y were major RIF resistance–conferring mutations [32/87 (36.8%) and 15/87 (17.2%), respectively]. H445Y was enriched in the ancient Beijing genotype and was associated with nonsynonymous mutations of Rv1830 that has been reported to regulate antibiotic resilience. H445Y was also more frequently observed in genetically clustered strains and in samples from patients who had received more than one TB treatment episode. According to the RNA sequencing, gene sets involved in the interferon-γ and-α pathways were downregulated in H445Y compared with S450L. The qRT-PCR analysis also confirmed the low expression levels of interferon-inducible genes, including BATF2 and SERPING1, in the H445Y group, particularly in patients with extensive lesions on chest X-ray.DiscussionOur study results showed that rpoB mutations as well as Mtb sublineage with additional genetic variants may have significant effects on host response. These findings strengthen the rationale for investigation of host-pathogen interactions to develop countermeasures against epidemics of drug-resistant TB.

Summary: Neurological complications that occur in SARS-CoV-2 infection, such as olfactory dysfunction, brain inflammation, malaise, and depressive symptoms, are thought to contribute to long COVID. However, in autopsies of patients who have died from COVID-19, there is normally no direct evidence that central nervous system damage is due to proliferation of SARS-CoV-2. For this reason, many aspects of the pathogenesis mechanisms of such symptoms remain unknown. Expressing SARS-CoV-2 S1 protein in the nasal cavity of mice was associated with increased apoptosis of the olfactory system and decreased intracerebral acetylcholine production. The decrease in acetylcholine production was associated with brain inflammation, malaise, depressive clinical signs, and decreased expression of the cytokine degrading factor ZFP36. Administering the cholinesterase inhibitor donepezil to the mice improved brain inflammation, malaise and depressive clinical signs. These findings could contribute to the elucidation of the pathogenesis mechanisms of neurological complications associated with COVID-19 and long COVID.

Abstract With the widespread increase in elderly populations, the quality of life and mental health in old age are issues of great interest. The human brain changes with age, and the brain aging process is biologically complex and varies widely among individuals. In this cross-sectional study, to clarify the effects of mental health, as well as common metabolic factors (e.g., diabetes) on healthy brain aging in late life, we analyzed structural brain MRI findings to examine the relationship between predicted brain age and life satisfaction, depressive symptoms, resilience, and lifestyle-related factors in elderly community-living individuals with unimpaired cognitive function. We extracted data from a community-based cohort study in Arakawa Ward, Tokyo. T1-weighted images of 773 elderly participants aged ≥65 years were analyzed, and the predicted brain age of each subject was calculated by machine learning from anatomically standardized gray-matter images. Specifically, we examined the relationships between the brain-predicted age difference (Brain-PAD: real age subtracted from predicted age) and life satisfaction, depressive symptoms, resilience, alcohol consumption, smoking, diabetes, hypertension, and dyslipidemia. Brain-PAD showed significant negative correlations with life satisfaction (Spearman’s rs= −0.102, p = 0.005) and resilience (rs= −0.105, p = 0.004). In a multiple regression analysis, life satisfaction (p = 0.038), alcohol use (p = 0.040), and diabetes (p = 0.002) were independently correlated with Brain-PAD. Thus, in the cognitively unimpaired elderly, higher life satisfaction was associated with a ‘younger’ brain, whereas diabetes and alcohol use had negative impacts on life satisfaction. Subjective life satisfaction, as well as the prevention of diabetes and alcohol use, may protect the brain from accelerated aging.

AbstractEnhancing forage production through organic fertilization is an important option for smallholder farmers. In north-western Ethiopia, a field experiment was conducted to assess the effects of farmyard manure (FYM) and Desmodium intortum intercropping on the morphological characteristics, dry matter yield, and crude protein yield of Napier and desho grass, as well as their effects on soil physicochemical properties. The experiment was carried out in three replications using randomized complete block design with factorial arrangements at the Aba Gerima and Guder watersheds, which represent midland and highland agro-ecologies, respectively. The treatments used were Napier or desho grass alone [control], Napier or desho with Desmodium, Napier or desho with FYM, and Napier or desho combined with Desmodium and FYM. The results showed that fertilizer treatments had positive influence on morphological characteristics in both watersheds. The dry matter yield and crude protein yield were higher (p

It has been reported that some specific changes in DNA methylation can be due to aging or infection by tumor-related viruses but the effect of herpes simplex virus type 1 (HSV-1) in this regard is unknown. HSV-1 is a well-known virus that causes cold sores. After the primary infection, the virus switches to latent infection and remains in the body for the whole life. As the location of DNA methylation, we focused on the promoter region of the COASY gene, which codes for coenzyme A synthase, because methylation in this region is reportedly associated with Alzheimer's disease (AD). During HSV-1 lytic infection, compared to non-infected cells, COASY DNA methylation decreased but when HSV-1 replication was inhibited by acyclovir, an anti-herpes agent, COASY DNA methylation increased. In addition, for expression of immediate early protein only, there was no significant change in COASY DNA methylation, while for expression of the capsid protein VP26, a late protein known to bind with DNA methyltransferase DNMT3A, in the nucleus only, COASY DNA methylation significantly increased compared to the control, without changes in DNMT3A mRNA. Our results suggested that DNA methylation occurred not due to transcriptional changes in DNMT3A but through translational regulation. In this research, we showed that host COASY DNA methylation is altered by HSV-1 infection, in particular by HSV-1 VP26. It is a potential cause of various diseases, and this is particularly relevant for AD.

Objective Portable laser methane detectors (LMDs) may be an economical means of estimating CH4 emissions from ruminants. We validated an LMD-based approach and then used that approach to evaluate CH4 emissions from indigenous dairy cows in a dryland area of Ethiopia. Methods First, we validated our LMD-based approach in Simmental crossbred beef cattle (n = 2) housed in respiration chambers and fed either a high- or low-concentrate diet. From the results of the validation, we constructed an estimation equation to determine CH4 emissions from LMD CH4 concentrations. Next, we used our validated LMD approach to examine CH4 emissions in Fogera dairy cows grazed for 8 h/d (GG, n = 4), fed indoors on natural-grassland hay (CG1, n = 4), or fed indoors on Napier-grass (Pennisetum purpureum) hay (CG2, n = 4). All the cows were supplemented with concentrate feed. Results The exhaled CH4 concentrations measured by LMD were linearly correlated with the CH4 emissions determined by infrared-absorption-based gas analyzer (r2 = 0.55). The estimation equation used to determine CH4 emissions (y, mg/min) from LMD CH4 concentrations (x, ppm m) was y = 0.4259x+38.61. Daily CH4 emissions of Fogera cows estimated by using the equation did not differ among the three groups; however, a numerically greater milk yield was obtained from the CG2 cows than from the GG cows, suggesting that Napier-grass hay might be better than natural-grassland hay for indoor feeding. The CG1 cows had higher CH4 emissions per feed intake than the other groups, without significant increases in milk yield and body-weight gain, suggesting that natural-grassland hay cannot be recommended for indoor-fed cows. Conclusion These findings demonstrate the potential of using LMDs to valuate feeding regimens rapidly and economically for dairy cows in areas under financial constraint, while taking CH4 emissions into consideration.

Optical remote sensing is one of the most attractive options for generating crop cover maps because it enables computation of vegetation indices, which are useful for assessing the condition of vegetation. The Sentinel-2A Multispectral Instrument (MSI), which is a multispectral sensor with 13 bands covering the visible, near infrared and short-wave infrared (SWIR) wavelength regions, offers a vast number of vegetation indices. Spectral indices, which are combinations of spectral measurements at different wavelengths, have been used in the previous studies and they sometimes contributed to improve classification accuracies. In this study, 91 published spectral indices were calculated from the MSI data. Additionally, classification algorithms are essential for generating accurate maps and the random forests classifier is one of which possesses the five hyperparameters were applied. The improvements in classification accuracies were confirmed achieving an overall accuracy of 93.1% based on the reflectance at 4 bands and 8 spectral indices.

Integrating farmyard manure (FYM) and legume intercropping improves soil chemical and microbial properties, thereby increasing forage productivity and nutritional value. The purpose of this study was to evaluate how fertilizer treatments affected the chemical composition, in vitro gas production and organic matter digestibility (IVOMD), and volatile fatty acid production (VFA) of Napier and desho grasses in the upper Blue Nile basin of Ethiopia. Apart from ether extract content, the chemical composition of the fertilizer treatments in the Aba Gerima watershed did not differ significantly, whereas significant differences were observed in acid detergent fiber and crude protein contents at the Guder watershed. In both watersheds, Napier grass had significantly higher crude protein levels than desho grass. In Aba Gerima, ash content was significantly higher in 2018 than in 2019, but not in Guder. For Napier and desho grasses, there were an increment in IVOMD (6.7 vs 4.7%), metabolizable energy (5.5 vs 4.5%), and VFA production (23.1 vs 3.0%) in the Desmodium intortum plus FYM treatment than in the control in Aba Gerima. In Guder, however, IVOMD (13.7 vs 4.6%), metabolizable energy (13.3 vs 3.3%), and VFA production (11.2 vs 5.6%) increased in the same treatment for Napier and desho grasses than in the control. This study suggests that the Desmodium intortum plus FYM improves the nutritional value, IVOMD, and VFA production of Napier and desho grasses in dryland areas of the upper Blue Nile basin, facilitating their growth as alternative livestock feed for better production in these areas.

The incidence rate of tuberculosis (TB) in Japan was 11.5 per 100,000 of the population in 2019. Of TB patients in Japan, 61.1% were aged >70 years, and 10.7% were born outside Japan, mostly in Asian countries with a high burden of tuberculosis.

Objective In dryland areas of China, alfalfa hay (AH) is a possible substitute for concentrate feed for beef cattle. To evaluate the potential benefits of this substitution, we studied the effect of the ratio of AH intake to total dry matter (DM) intake on average daily body-weight gain (ADG), dietary energy utilization status, and economic benefit in Gansu province. Methods In each of two feeding trials in 2016 (trial 1 [T1], July 3 to 17; trial 2 [T2], August 15 to September 23), crossbred male Simmental calves were allocated to low AH (LA), medium AH (MA), and high AH (HA) feeding groups (n = 4 per group). The target ADG was set as 1 kg for both trials. In a one-way-layout design based on conventional feeding practices in the province, calves received diets containing the different AH amounts, with a constant ratio of corn stover:total DM and decreasing rations of concentrate feed proportional to the increase in AH. Calves in T1 received AH at 15% (T1-LA), 23% (T1-MA), or 31% (T1-HA) of their dietary DM allowances; those in T2 received 9% (T2-LA), 24% (T2-MA), or 34% (T2-HA) AH. Results Among the T1 groups, both ADG and economic benefit were highest in T1-LA; whereas in T2, they were higher in the T2-LA and T2-MA groups than in T2-HA. Energy digestibility did not significantly differ among the groups in either trial. The dietary AH inclusion ratios of 14% in the warm season and 8% to 21% in the cool season appeared to yield optimal ADG, metabolizable energy intake, and economic benefit. Conclusion Low-level inclusion of AH, ranging from 8% to 21%, is a practical approach for beef cattle feeding. This modified feeding regimen likely will promote increased growth performance during the fattening stage of beef steers in dryland areas of Gansu province, China.

Introduction: Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract. Known types are Crohn’s disease (CD) and ulcerative colitis (UC), but their cause remains unclear and there is no convenient biomarker for IBD. The present study aimed to demonstrate an association between the onset of CD and activating transcription factor 3 (ATF3); as a new biomarker, measurement of blood ATF3 mRNA would be useful for distinguishing between CD and UC. Methods: First, in a mouse model of IBD in which damage to the intestinal mucosa was chemically induced with dextran sulfate sodium (DSS), intestinal ATF3 mRNA was evaluated. Next, in human subjects, CD and UC patients, blood ATF3 mRNA and intestinal ATF3 protein production were evaluated. Results: In the mouse model of IBD, intestinal ATF3 mRNA was elevated compared with the control ( P

Summary: Little is known about the effect of latent-phase herpesviruses on their host. Human herpesvirus 6B (HHV-6B) is one of the most ubiquitous herpesviruses, and olfactory astrocytes are one of the most important sites of its latency. Here, we identified SITH-1, an HHV-6B latent protein specifically expressed in astrocytes. Mice induced to produce SITH-1 in their olfactory astrocytes exhibited olfactory bulb apoptosis, a hyper-activated hypothalamic-pituitary-adrenal (HPA) axis and depressive symptoms. The binding of SITH-1 to the host protein calcium-modulating ligand (CAML) to form an activated complex promoted the influx of extracellular calcium. The serum antibody titers for depressive patients with respect to this activated complex were significantly higher than for normal controls (p = 1.78 × 10−15), when the antibody positive rates were 79.8% and 24.4%, respectively, and the odds ratio was 12.2. These results suggest that, in the latent phase, HHV-6B may be involved in the onset of depression.

Abstract Background Sleep-related eating disorder is characterized by parasomnia with recurrent episodes of nocturnal eating or drinking during the main sleep period. Several drugs, including atypical antipsychotics, induce sleep-related eating disorder. However, aripiprazole has not previously been associated with sleep-related eating disorder. Case presentation A 41-year-old Japanese man visited our clinic complaining of depression. The patient was treated with sertraline, which was titrated up to 100 mg for 4 weeks. A sleep inducer and an anxiolytic were coadministered. His depressive mood slightly improved, but it continued for an additional 4 months. Subsequently, aripiprazole (3 mg) was added as an adjunctive therapy. After 3 weeks, the patient’s mother found that the patient woke up and ate food at night. The next morning, the patient was amnesic for this event, felt full, and wondered why the bags of food were empty. This episode lasted for 2 days. The patient gained 5 kg during these 3 weeks. After the aripiprazole dose was reduced to 1.5 mg, the patient’s nocturnal eating episodes rapidly and completely disappeared. Conclusions To the best of our knowledge, this is first report of sleep-related eating disorder induced by aripiprazole, and it indicates that this disorder should be considered a possible side effect of aripiprazole. Although aripiprazole is used mainly in patients with schizophrenia, its recently documented use as an adjunctive therapy in patients with depression might induce hitherto unknown side effects.

Sentinel-1A C-SAR and Sentinel-2A MultiSpectral Instrument (MSI) provide data applicable to the remote identification of crop type. In this study, six crop types (beans, beetroot, grass, maize, potato, and winter wheat) were identified using five C-SAR images and one MSI image acquired during the 2016 growing season. To assess the potential for accurate crop classification with existing supervised learning models, the four different approaches namely kernel-based extreme learning machine (KELM), multilayer feedforward neural networks, random forests, and support vector machine were compared. Algorithm hyperparameters were tuned using Bayesian optimization. Overall, KELM yielded the highest performance, achieving an overall classification accuracy of 96.8%. Evaluation of the sensitivity of classification models and relative importance of data types using data-based sensitivity analysis showed that the set of VV polarization data acquired on 24 July (Sentinel-1A) and band 4 data (Sentinel-2A) had the greatest potential for use in crop classification.

Background/Aims: Mutations in the presenilin 2 (PSEN2) gene cause familial Alzheimer's disease (AD). Common polymorphisms affect gene activity and increase the risk of AD. Nonsynonymous polymorphisms in the PSEN2 gene showed Lewy body dementia (LBD) phenotypes clinically. Therefore, we aimed to investigate whether PSEN2 gene polymorphisms were associated with AD or LBD. Methods: Seven single nucleotide polymorphisms (SNPs) of the gene were analyzed using a case-control study design comprising 288 AD patients, 76 LBD patients, and 105 age-matched controls. Results: Linkage disequilibrium (LD) examination showed strong LD from rs1295645 to rs8383 on the gene in our cases from Japan. There were no associations between the SNPs studied here and AD onset, and haplotypic analyses did not detect genetic associations between AD and the PSEN2 gene. Although the number of the cases was small, the SNPs studied did not modify the risk of developing LBD in a Japanese population. Conclusion: The common SNPs of the PSEN2 gene did not affect the risk of AD or LBD in a Japanese population. Because genetic variability of the PSEN2 gene is associated with behavioral and psychological symptoms of dementia (BPSD) in AD and LBD, further detailed analyses considering BPSD of both diseases would be required.

The nutritionally imbalanced poor-quality diet feeding is the major constraint of dairy production in tropical regions. Hence, alternative high-quality roughage-based diets are required to improve milk yield and reduce methane emission (CH4). Thus, we tested the effects of feeding natural pasture hay, improved forage grass hays (Napier and Brachiaria Hybrid), and treated crop residues (Eragrostis tef straw) on nutrient digestibility, milk yield, nitrogen balance, and methane emission. The eight lactating Fogera cows selected for the experiment were assigned randomly to a 4 × 4 Latin square design. Cows were housed in well-ventilated individual pens and fed a total mixed ration (TMR) comprising 70% roughage and 30% concentrate. The four roughage-based basal dietary treatments supplemented with formulated concentrate were: Control (natural pasture hay (NPH)); treated teff straw silage (TTS); Napier grass hay (NGH); and Brachiaria hybrid grass hay (BhH). Compared with the control diet, the daily milk yield increased (p < 0.01) by 31.9%, 52.9%, and 71.6% with TTS, NGH, and BhH diets, respectively. Cows fed BhH had the highest dry matter intake (8.84 kg/d), followed by NGH (8.10 kg/d) and TTS (7.71 kg/d); all of these intakes were greater (p = 0.01) than that of NPH (6.21 kg/d). Nitrogen digestibility increased (p < 0.01) from the NPH diet to TTS (by 27.7%), NGH (21.7%), and BhH (39.5%). The concentration of ruminal ammonia nitrogen was higher for cows fed NGH than other diets (p = 0.01) and positively correlated with plasma urea nitrogen concentration (R² = 0.45). Feeding TTS, NGH, and BhH hay as a basal diet changed the nitrogen excretion pathway from urine to feces, which can help protect against environmental pollution. Estimated methane yields per dry matter intake and milk yield were decreased in dairy cows fed BhH, NGH, and TTS diets when compared to cows fed an NPH diet (p < 0.05). In conclusion, feeding of TTS, NGH, and BhH roughages as a basal diet to lactating dairy cows in tropical regions improved nutrient intake and digestibility, milk yield, nitrogen utilization efficiency, and reduced enteric methane emission.

As described in Japanese essay (Hojoki), written around 1200, various disasters such as big fires, earthquakes, and famines have occurred in Japan. Asian countries have been suffering from the disasters; furthermore, natural disasters are increasing due to global warming. Because tropical-infectious diseases are often disaster-related infectious diseases (DRIDs), the strategies against the former kind of disease could be applicable to DRIDs. Meteorological analysis of the occurrence of DRIDs using a method of time series analysis is important. In situations of disasters, it is desirable if you can identify the pathogen and identify disease severity simultaneously. A dipstick DNA chromatography assay termed as Single-Tag Hybridization—Printed Array Strip (STH—PAS) system was developed based on the DNA sequences of various mosquito-borne diseases. The plasma levels of matricellular proteins including galectin-9 (Gal-9) and osteopontin (OPN) were found to reflect the disease severities in the dengue virus and other DIRDs. Because both proteins have been reported to be immune-check molecules, their inhibition might enhance the immune system against pathogens. We found that brefelamide derivatives could inhibit OPN and other inflammatory molecules synthesis. Very recently, different derivatives were found to inhibit PD-L1 transcription. Applications of these agents should be considered as multi-step strategies against DRIDs.

Objectives: In the performance of interferon gamma release assays (IGRA) for the diagnosis of tuberculosis (TB) infection, false-negative results are a major obstacle. In active TB patients, treatment-dependent changes of the negative test results remain unknown. Methods: The treatment course of 19 smear-positive/culture-confirmed TB patients who had IGRA-negative results by QuantiFERON-TB in-tube (QFT-IT) method at the time of diagnosis (month 0) in a previous study, were monitored in the present study. Blood was further collected at months 2 and 7, and the concentrations of 27 immune molecules were measured in the plasma supernatants remaining after performing the IGRA, using a suspension array system. Results: After initiating treatment, eight of the 19 QFT-IT-negative patients showed positive conversion, whereas the remaining 11 (58%) did not; the interferon gamma (IFN-γ) response was restored to levels higher than 1 IU/ml in only three of the eight patients with positive conversion. Plasma concentrations of interleukin 1 receptor antagonist, interleukin 2, and interferon gamma-induced protein 10 remained low after Mycobacterium tuberculosis-specific antigen stimulation at months 2 and 7 in the continuously QFT-IT-negative group, whereas the parameters were elevated only in the transiently QFT-IT-negative group. Conclusions: It was demonstrated that a majority of active TB patients showing negative IGRA results did not regain sufficient levels of immune responsiveness despite successful treatment.

Background/Aims: In the present study, we examined whether DNA methylation of the brain-derived neurotrophic factor (BDNF) promoter is associated with the manifestation and clinical presentation of Alzheimer's disease (AD). Methods: Of 20 patients with AD and 20 age-matched normal controls (NCs), the DNA methylation of the BDNF promoter (measured using peripheral blood samples) was completely analyzed in 12 patients with AD and 6 NCs. The resulting methylation levels were compared statistically. Next, we investigated the correlation between the DNA methylation levels and the clinical presentation of AD. Results: The total methylation ratio (in %) of the 20 CpG sites was significantly higher in the AD patients (5.08 ± 5.52%) than in the NCs (2.09 ± 0.81%; p Conclusion: These results suggest that the DNA methylation of the BDNF promoter may significantly influence the manifestation of AD and might be associated with its neurocognitive presentation.

Influenza viruses have acquired resistance to approved neuraminidase-targeting drugs, increasing the need for new drug targets for the development of novel anti-influenza drugs. Nucleoprotein (NP) is an attractive target since it has an indispensable role in virus replication and its amino acid sequence is well conserved. In this study, we aimed to identify new inhibitors of the NP using a structure-based drug discovery algorithm, named Nagasaki University Docking Engine (NUDE), which has been established especially for the Destination for GPU Intensive Machine (DEGIMA) supercomputer. The hit compounds that showed high binding scores during in silico screening were subsequently evaluated for anti-influenza virus effects using a cell-based assay. A 4-hydroxyquinolinone compound, designated as NUD-1, was found to inhibit the replication of influenza virus in cultured cells. Analysis of binding between NUD-1 and NP using surface plasmon resonance assay and fragment molecular orbital calculations confirmed that NUD-1 binds to NP and could interfere with NP-NP interactions essential for virus replication. Time-of-addition experiments showed that the compound inhibited the mid-stage of infection, corresponding to assembly of the NP and other viral proteins. Moreover, NUD-1 was also effective against various types of influenza A viruses including a clinical isolate of A(H1N1)pdm09 influenza with a 50% inhibitory concentration range of 1.8-2.1 μM. Our data demonstrate that the combined use of NUDE system followed by the cell-based assay is useful to obtain lead compounds for the development of novel anti-influenza drugs.

The influenza virus replicates in the host cell nucleus, and the progeny viral ribonucleoprotein complex (vRNP) is exported to the cytoplasm prior to maturation. NS2 has a nuclear export signal that mediates the nuclear export of vRNP by the vRNP–M1–NS2 complex. We previously reported that the heat shock cognate 70 (Hsc70) protein binds to M1 protein and mediates vRNP export. However, the interactions among M1, NS2, and Hsc70 are poorly understood. In the present study, we demonstrate that Hsc70 interacts with M1 more strongly than with NS2 and competes with NS2 for M1 binding, suggesting an important role of Hsc70 in the nuclear export of vRNP.

A low nitrogen utilization efficiency (NUE, the ratio of retained N to N intake) and high methane (CH4) emissions of ruminants can lead to potentially high diet protein wastage and directly contribute to global warming. Diet manipulation is the most effective way to improve NUE or reduce CH4 emissions. This study investigated how replacing oat hay with alfalfa hay (AH) or common vetch hay (CVH) with different proportions (20% (20) and 40% (40) of the total dry matter (DM) allowance) affects the body weight gain (BWG), NUE, and CH4 emissions of crossbred Simmental cattle. The forage dry matter intake (DMI) and the total DMI of cattle fed on a CVH40 diet were significantly higher than the values for those fed on AH20 or AH40 diets (p < 0.05). There were no differences in the BWG for the four treatments observed, however, nutrient digestibility significantly decreased in the AH40 diet as compared with the AH20 diet (p < 0.05). The NUE was significantly lower in AH40 than in CVH20. The CH4 emissions were significantly lower for the CVH40 diet than with the AH20 diet (p < 0.05). Our findings suggest that a 20% AH and 40% CVH substitution for oat hay are the optimal proportions to maintain the BWG, NUE, nutrient digestibility, and reduce the CH4 emissions of crossbred Simmental cattle. Overall, CVH has a greater potential to reduce CH4 emissions than AH.

On our quest for new bioactive molecules from marine sources, two cyclic imines (1, 2) were isolated from a dinoflagellate extract, inhibiting the growth of the respiratory syncytial virus (RSV). Compound 1 was identified as a known molecule portimine, while 2 was elucidated to be a new cyclic imine, named kabirimine. The absolute stereochemistry of 1 was determined by crystallographic work and chiral derivatization, whereas the structure of 2 was elucidated by means of spectroscopic analysis and computational study on all the possible isomers. Compound 1 showed potent cytotoxicity (CC50 < 0.097 µM) against HEp2 cells, while 2 exhibited moderate antiviral activity against RSV with IC50 = 4.20 µM (95% CI 3.31−5.33).

Background: In cases using a budesonide/formoterol combination inhaler, many patients are started on fixed-dose treatment at 640/18 μg (4 puffs) daily, but there are no guidelines yet regarding the step-down method when control has been maintained. Methods: Patients with moderate asthma treated with either budesonide 400 μg and salmeterol 100 μg (GINA step3 group) or salmeterol/fluticasone 250 at 2 puffs (GINA step4 group) were enrolled and started on therapy of budesonide/formoterol 4 puffs. Thereafter, step-down to 2 puffs was performed if either of the following criteria was met at 8-week intervals: fractional exhaled nitric oxide (FeNO)≤28 ppb plus asthma control test (ACT) score≥22, or ACT score≥24 at 3 consecutive visits regardless of FeNO level. Thereafter, changes in ACT score, the number of acute exacerbations and reliever use, and FeNO level were monitored through 48th week. Results: Fifty-one patients, 27 in step3 group and 24 in step4 group, underwent step-down. ACT scores and the number of reliever use remained stable in both groups even after step-down. In contrast, FeNO levels increased gradually in step4 group, whereas in the step3 group they increased immediately after step-down. Step-down was considered to be safely performed because the numbers of reliever use and those of moderate or more severe exacerbations during the 48-week period has not changed significantly compared to before step-down. Conclusions: If complete control of asthma, not only of clinical symptoms but also airway inflammation, is achieved by 3-6 months of fixed-dose budesonide/formoterol 4 puffs/day, it should be possible to safely perform step-down to 2 puffs/day.

From the standpoint of early interventions for dementia, a convenient method of diagnosis using biomarkers is required for Alzheimer's disease (AD) in the early stage as well as amnesic mild cognitive impairment (aMCI). Focusing on differences in DNA methylation due to AD and aMCI, in the present study, we first conducted genome-wide screening, measuring blood DNA methylation levels by the Illumina Infinium HD Methylation Assay in 3 small age-and gender-matched groups consisting of 4 subjects each: normal controls (NC), aMCI and AD. The genome-wide analysis produced 11 DNA methylation loci that distinguished the 3 groups. For confirmation, we increased group sizes and examined samples by pyrosequencing which revealed that DNA methylation in the NCAPH2/LMF2 promoter region was significantly decreased in the AD (n = 30) and aMCI (n = 28) groups as compared to the NC group (n = 30) (P < 0.0001, ANCOVA). No association was found between methylation levels and APOE genotype. NCAPH2/LMF2 methylation levels were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI.

In order to conduct early therapeutic interventions for Alzheimer's disease (AD), convenient, early diagnosis markers are required. We previously reported that changes in DNA methylation levels were associated with amnestic mild cognitive impairment (aMCI) and AD. As the results suggested changes in DNA methylation levels in the COASY and SPINT1 gene promoter regions, in the present study we examined DNA methylation in these regions in normal controls (NCs, n = 30), aMCI subjects (n = 28) and AD subjects (n = 30) using methylation-sensitive high resolution melting (MS-HRM) analysis. The results indicated that DNA methylation in the two regions was significantly increased in AD and aMCI as compared to NCs (P < 0.0001, P < 0.0001, ANOVA). Further analysis suggested that DNA methylation in the COASY gene promoter region in particular could be a high sensitivity, high specificity diagnosis biomarker (COASY: sensitivity 96.6%, specificity 96.7%; SPINT1: sensitivity 63.8%, specificity 83.3%). DNA methylation in the COASY promoter region was associated with CDR Scale Sum of Boxes (CDR-SB), an indicator of dementia severity. In the SPINT1 promoter region, DNA methylation was negatively associated with age in NCs and elevated in aMCI and AD subjects positive for antibodies to Herpes simplex virus type 1 (HSV-1). These findings suggested that changes in DNA methylation in the COASY and SPINT1 promoter regions are influenced by various factors. In conclusion, DNA methylation levels in the COASY and SPINT1 promoter regions were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI.

Background: The particle distribution might differ between nebulizer therapy and metered-dose inhaler (MDI) or dry powder inhaler (DPI) therapy because the particles repeatedly enter/re-enter the airways with the nebulizer. Inhaled corticosteroids (ICS) were administered with a nebulizer to assess the benefit of changes in the distribution of particles in patients with cough variant asthma (CVA) and cough-predominant asthma (CPA). Methods: Patients whose symptoms were not controlled by their current therapy were enrolled. In patients receiving high-dose ICS by MDI or DPI (ICS-MDI/DPI), steroid therapy was switched to 1,320 μg/day of nebulized dexamethasone (1,600 μg as dexamethasone sodium phosphate) (chronic steroid-independent group). In patients receiving systemic steroids regardless of their ICS-MDI/DPI therapy, nebulized dexamethasone was added and any concurrent ICS-MDI/DPI therapy was halted to detect a steroid-sparing effect (chronic steroid-dependent group). In patients with acute exacerbation of CVA or CPA and persistent symptoms despite systemic corticosteroids, nebulized dexamethasone was added to assess its effect (acute group). Results: Superior symptom control was achieved in 10 out of 12 steroid-independent patients, 3 out of 6 steroid-dependent patients, and all 7 acute patients. Conclusions: Delivery of ICS via a nebulizer has advantages over ICS-MDI/DPI in some patients with CVA or CPA.

Significant fire and explosion accident on spherical tanks for Liquefied Petroleum Gas (LPG) storage was induced by the strong ground motion of the 2011 Great East Japan Earthquake. Steel pipe braces were broken due to the strong seismic inertia force, and then buckling of support legs occurred. To prevent recurrence, reinforcing the intersection of braces was needed. Currently, in the Japanese seismic resistance design standard for high pressure equipment including spherical tanks for storage, when subjected to a large earthquake, it is allowed to occur a certain degree of plastic deformation, witch way not lead to release high pressure gases. When receiving a high-level seismic motion, seismic response of high pressure equipment could be non-linear due to plastic deformation and the mechanical damping could be increased as well. On the other hand, a vibration test for spherical tank has not conducted in the past. Deformation behavior of the spherical tank and pipe braces was not clear against real ground motion. In addition, there are not many precedent studies done on the effectiveness of the reinforcement of pipe braced supporting frame against high-level ground motion. In this study, we conducted vibration tests using small models of spherical tank and examined non-linear response characteristics and failure mode due to plastic deformation. From the test results, it was concluded the effectiveness of reinforcement and the response characteristic of the pipe braced supporting frame of a spherical tank as follows; (1) The natural frequency indicates substantially the same value with or without reinforcement, because a large difference in the response characteristics of the whole structure was not observed. (2) In a case of brace intersection was reinforced, the maximum response acceleration increased at collapse. (3) In a case of brace intersection was reinforced there is no reinforcement to brace intersection, structural strength indicated the lowest at the load direction acting tensile force on long brace, cross section of long brace were deformed largely.

A significant fire and explosion accident on spherical tanks for Liquefied Petroleum Gas (LPG) storage at Chiba prefecture in Japan were induced by the strong ground motion of the 2011 Great East Japan Earthquake and its aftershock. The braces made by steel pipe, of which ends were connected to support legs of one spherical tank filled with water, were broken due to the strong seismic inertia force, and then buckling of support legs were caused. To clarify the failure mechanism of the pipe braced supporting frame of a spherical tank, we performed the elastic and elastic-plastic finite element analysis. From FEA results, it was concluded the fracture mechanism of the pipe braced supporting frame of a spherical tank as follows; (1) high stress was generated in the cross point of two braces due to the structural discontinuities, (2) the generated high stress triggered for the failure initiation of the supporting frame damage, (3) resulting the spherical tank overturn during the aftershock of predominant earthquake. In this paper, the fracture mechanism of the spherical storage tank was clarified for heading off the same type accident, and the effective reinforcement of spherical tanks were proposed for securing safety.

An 80-year-old woman was admitted to our hospital with pneumonia and exacerbation of sinobronchial syndrome (SBS). She presented with yellow discoloration of the nail beds of all fingers and toes, and her nails were recognized as growing slowly. Chest X-ray revealed bronchiectasis in the bilateral lower lobe and bilateral pleural effusion. We diagnosed her as having yellow nail syndrome (YNS), based on the triad of yellow nails, lymphedema, and lung disease. After treatment with antibiotics [ampicillin/sulbactam and clarithromycin (CAM)] for pneumonia and SBS, her general condition improved, and the yellow nails disappeared in some fingers. When she was previously treated with 200 mg CAM for SBS, her yellow nails had not shown improvement. This time, her yellow nails improved after treatment with 400 mg CAM. The literature reports vitamin E, zinc, and topical corticosteroid plus active vitamin D3 to be effective in the treatment of yellow nails. Two studies have reported treatment for YNS using CAM, though they found a lack of efficacy. Thus, the present case is the first to report improved yellow nails using CAM alone. We conclude that not only SBS and lung disease but also YNS were improved by treatment with 400 mg CAM.

Background: Treatment strategy that reduces dependence on long-term medication for chronic asthma is preferable. The purpose of the study is to investigate the efficacy of an early intensive intervention for inducing inactive asthma in adults and identify factors that affect the efficacy. Methods: A prospective study was conducted on subjects who had asthma for two years or less. An intensive intervention consisting of systemic corticosteroid treatment for two weeks followed by inhaled corticosteroid for further 16 weeks with concomitant administration of bronchodilator(s) was administrated on 109 subjects. As a control group, 33 subjects were treated according to the current asthma treatment guidelines for 18 weeks. The primary outcome of the intervention was assessed with symptomatology and use of medication during 12 months after the cessation of treatment period. Results: At one year after the intervention, significantly more patients in the intensive intervention group (41%) than in the control group (24%) had no respiratory symptoms and were medication-free or had experienced minor upper respiratory symptoms (inactive asthma) (P = 0.01). The intensive intervention maintained a significant factor associated with one-year inactive asthma (adjusted odds ratio: 3.61, 95% confidence interval: 1.2010.84; P = 0.02). Infection as onset cause, asthma duration and pre-treatment %FEV1.0 were also identified independently associated with inactive asthma. As the limitation, the study was not randomized trial. Conclusions: Intensive therapy in the early stage is very likely to contribute to increasing one-year asthma inactivity, which may reduce patients' dependence on long-term management by medical treatment.

The antioxidant properties of different low molecular weight (LMW) chitosans (CS1; 22 kDa, CS2; 38 kDa, CS3; 52 kDa, CS4; 81 kDa) were examined for possible use in extended-release tablets. The criteria used were the ability of the chitosans to reduce Cu2+, and hydroxyl and superoxide radicals and N-centered radicals derived from 1,1'-diphenyl-2-picrylhydrazyl, via the use of ESR spectrometry. CS2 showed the highest scavenging activity. CS1 and CS3, however, were much less effective and CS4 was not a viable antioxidant. The results suggest that CS2 could be useful in combating the development of oxidative stress. A series of chitosan tablets were prepared using a spray drying method and evaluated as an extended-release matrix tablet using theophylline (TPH) as a model drug. The release of TPH from the different MW chitosan tablets increased with increasing MW of the chitosan used. CS2, CS3 and CS4 showed a reasonable release activity, but CS1 showed the shortest release activity. Moreover, the CS2-TPH tablet showed the highest scavenging activity of the three chitosan tablets (CS2-CS4) using 2,2’-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radicals. These results suggest that a CS2-TPH tablet could be potentially useful in an extended-release matrix tablet with a high antioxidant activity.

This article presents a multi dynamic absorber for suppressing liquid sloshing in a floating roof tank. The presented multi dynamic absorber uses U-tubes set on the floating roof. Many seismic damages on floating roof tanks by the sloshing of the contained liquid in the tank due to long periodic components of earthquake were reported. Since the natural period of sloshing varies according to the liquid height, robustness for parameters variances such as natural period is required for the sloshing suppression device to obtain a good performance. From this point of view, a multi dynamic absorber is developed instead of the single dynamic absorber which is sensitive to the parameter variance. A multi degree of freedom mechanical model for sloshing of the contained liquid and the presented multi dynamic absorber on the floating roof of the tank is derived to design the optimal tuning and optimal damping for parameters of the multi dynamic absorber and to evaluate the sloshing suppression performance. Numerical simulations on two kinds of actual size floating roof tank are conducted to examine seismic response of the present device as well as the transfer function characteristics. As the result the presented multi dynamic absorber is effective to suppress the sloshing of the floating roof.

This paper discusses the parametric resonance of the metallic bellows which is connected to the fluid filled pipe subjected to the seismic excitation. The axial stiffness of the metallic bellows varies due to the internal fluid pressure variation, and this stiffness variation by the pressure variation excites the parametric resonance in the metallic bellows. Finite element model of the metallic bellows that is connected to the fluid filled pipe was developed to investigate that parametric resonance is excited in the metallic bellows or not when the piping system is subjected to the seismic excitation. Numerical simulations were carried out assuming that the metallic bellows was connected to the L-shaped pipe to examine the parametric resonance was induced due to the seismic excitation. The L-shaped piping system with a metallic bellows was excited by the shaking table to verify the numerical simulation results. As the results, it is clarified from both numerical simulations results and experiment result that the parametric resonance was excited in the metallic bellows when the natural frequency of the pipe is close to the twice of the bending natural frequency of the bellows and the piping system is resonant with the predominant frequency component of the earthquake though earthquake motion is unsteady.

Absolute Nodal Coordinate Formulation (ANCF) is a kind of finite element method for the flexible multibody system with large deformation and large rotation. While there are few studies which extract controllers from the mathematical expressions derived by ANCF, a robust controller design procedure using ANCF model was proposed by author. The proposed controller design method has a drawback that the controller performance depends on number of elements used in ANCF model, and larger number of the elements leads to inefficient design procedure. Therefore, the main aim of this study is to propose a dimension reduction method of a controller design procedure proposed by author's previous study. A flexible beam is introduced as a controlled object and the control torque is applied to one end of the beam. Control objective is to rotate the beam to the desired position as well as to suppress the residual vibration of the beam. In the proposed method, dimension reduction based on component mode synthesis is employed, and some modifications of the ANCF model are introduced for the effective application of dimension reduction. The validity of the proposed method is demonstrated by numerical simulations.

In endemic areas with high transmission intensities, malaria infections are very often composed of multiple genetically distinct strains of malaria parasites. It has been hypothesised that this leads to intra-host competition, in which parasite strains compete for resources such as space and nutrients. This competition may have repercussions for the host, the parasite, and the vector in terms of disease severity, vector fitness, and parasite transmission potential and fitness. It has also been argued that within-host competition could lead to selection for more virulent parasites. Here we use the rodent malaria parasite Plasmodium yoelii to assess the consequences of mixed strain infections on disease severity and parasite fitness. Three isogenic strains with dramatically different growth rates (and hence virulence) were maintained in mice in single infections or in mixed strain infections with a genetically distinct strain. We compared the virulence (defined as harm to the mammalian host) of mixed strain infections with that of single infections, and assessed whether competition impacted on parasite fitness, assessed by transmission potential. We found that mixed infections were associated with a higher degree of disease severity and a prolonged infection time. In the mixed infections, the strain with the slower growth rate was often responsible for the competitive exclusion of the faster growing strain, presumably through host immune-mediated mechanisms. Importantly, and in contrast to previous work conducted with Plasmodium chabaudi, we found no correlation between parasite virulence and transmission potential to mosquitoes, suggesting that within-host competition would not drive the evolution of parasite virulence in P. yoelii.

Viral infection is one of the risk factors for asthma exacerbation. However, which pathogens are related to asthma exacerbation in adults remains unclear.The relation between various infections and adult asthma exacerbations was investigated in clinical practice.The study subjects included 50 adult inpatients due to asthma exacerbations and 20 stable outpatients for comparison. The pathogens from a nasopharyngeal swab were measured by multiplex PCR analysis.Asthma exacerbations occurred after a common cold in 48 inpatients. The numbers of patients with viral, bacterial, or both infections were 16, 9, and 9, respectively. The dominant viruses were rhinoviruses, respiratory syncytial virus, influenza virus, and metapneumovirus. The major bacteria were S. pneumoniae and H. influenzae. Compared to pathogen-free patients, the patients with pathogens were older and non-atopic and had later onset of disease, lower FeNO levels, lower IgE titers, and a higher incidence of comorbid sinusitis, COPD, or pneumonia. Compared to stable outpatients, asthma exacerbation inpatients had a higher incidence of smoking and comorbid sinusitis, COPD, or pneumonia. Viruses were detected in 50% of stable outpatients, but a higher incidence of rhinovirus, respiratory syncytial virus, and metapneumovirus infections was observed in asthma exacerbation inpatients. H. influenzae was observed in stable asthmatic patients. Other bacteria, especially S. pneumoniae, were important in asthma exacerbation inpatients.Viral or bacterial infections were observed in 70% of inpatients with an asthma exacerbation in clinical practice. Infection with S. pneumoniae was related to adult asthma exacerbation.

Background: Although the prevalence of pulmonary tuberculosis (TB) and HIV infection in Japan is low, careful monitoring of these two diseases is necessary. We conducted a nationwide survey on multidrug resistant (MDR)-TB (2011–2013) and HIV-TB (2007–2014) to understand the mode of prevention and the effect of therapy. A study on MDR-TB and HIV in San Lazaro Hospital (SLH) in the Philippines was also conducted. These studies introduced an international collaborative study against the global epidemics of HIV-TB/MDR-TB. Methods: The nationwide survey of MDR-TB was done in hospitals that treat TB patients in Japan from 2011 to 2013. The HIV-TB survey has been done every year since 2007. Classic information such as chest X-ray (CXR) as well as computed tomography (CT) results for each patient were analyzed. Likewise, the presence of a cavity, involved segments, and patterns of parenchymal lesion were assessed. Finally, tentative diagnosis and disease activity, bronchogenic spread of the lesion with CT, and bronchiectasis were recorded. At SLH, sputa of suspected cases were subjected to GeneXpert testing and HIV testing was performed on all TB patients. Results: In the nationwide MDR survey in Japan, 171 patients were diagnosed as pulmonary MDR-TB (0.2% of total Mycobacterium tuberculosis (MTB) in Japan). Among them, 48 (28%) were foreigners and most were living in big cities. In Tokyo metropolitan areas, 27 out of 53 MDR-TB patients were foreigners: 13 were from China, 4 from the Philippines, and 3 from Myanmar. Thirty nine among 53 MDR-TB patients were cured or treatment was completed with favorable prognosis. Five deaths (9.4%) and six departures from Japan (11.3%) were noted. In the HIV-TB survey in National Hospitals, the HIV-positive rates on MTB were constantly low (0.23–0.46%) from 2007 to 2014. Among the reported 114 HIV-TB patients (0.37% of total MTB in National Hospitals), 17 were foreigners and 3 (2.6%) were MDR-TB cases (2 Chinese, 1 Japanese). Half of the HIV-TB patients have low CD4 cell numbers (

This paper describes how to reduce degrees of freedom for the absolute nodal coordinate formulation (ANCF) of three-dimensional beam made up of 24 degrees of freedom beam elements by applying the component mode synthesis. The stiffness matrix of the ANCF Bernoulli-Euler beam is introduced to the equation of motion of 24 dof ANCF beam element. Since the bending stiffness matrix of the ANCF Bernoulli-Euler beam is constant, the Craig-Bampton method is applicable to the equation of motion to reduce degrees of freedom of beam structure which is composed of 24 dof ANCF elements. To examine the effectiveness and the efficiency of the presented method, three numerical examples were performed with comparing the results obtained by the conventional ANCF beam elements. In examples of the pure torsional deformation and the free-fall behavior under the gravity field, the presented method was verified to be capable of expressing the torsional deformation and large deformation precisely as well as the conventional ANCF, in spite of the dof of the presented method being reduced to be the half of the conventional ANCF. In the example of the cantilevered beam subjected by the screw driving constraint under the gravity, the presented method was also verified to express the large bending and torsion coupled deformation well.

In this paper, we present a reduction method of the system matrix of a flexible thin plate element of 48 degrees of freedom, which is formulated on the basis of the absolute nodal coordinate method (ANCF) by use of the component mode synthesis method. We focus that the bending stiffness matrix expressed by the ANCF plate element is constant when the continuum mechanics approach is adopted and the in-plane strain is not so large. This feature allows applying the Craig-Bampton method to the equation of motion of the plate expressed by ANCF, and then it enable to reduce the dimension size of the system matrix of the plate. Three numerical examples that compare the presented method and the conventional ANCF plate are demonstrated to examine the performance and the accuracy of the presented method. From these examples, it is verified that the presented method can describe the large deformation and rotation effects as well as the conventional ANCF plate does. The use of the presented method is also verified to be able to reduce the computing time against the conventional ANCF plate. This feature is effective for carrying out numerical simulations for the structure composed of multiple plate elements when the number of elements increases.

BACKGROUND: The avoidance of inhaled allergens or tobacco smoke has been known to have favorable effects on asthma control. However, it remains unclear whether other lifestyle-related factors are also related to asthma control. Therefore, a comprehensive study to examine the associations between various lifestyle factors and asthma control was conducted in Japanese asthmatic patients. METHODS: The study subjects included 437 stable asthmatic patients recruited from our outpatient clinic over a one-year period. A written, informed consent was obtained from each participant. Asthma control was assessed using the asthma control test (ACT), and a structured questionnaire was administered to obtain information regarding lifestyle factors, including tobacco smoking, alcohol drinking, physical exercise, and diet. Both bivariate and multivariate analyses were conducted. RESULTS: The proportions of total control (ACT = 25), well controlled (ACT = 20-24), and poorly controlled (ACT < 20) were 27.5%, 48.1%, and 24.5%, respectively. The proportions of patients in the asthma treatment steps as measured by Global Initiative for Asthma 2007 in step 1, step 2, step 3, step 4, and step 5 were 5.5%, 17.4%, 7.6%, 60.2%, and 9.4%, respectively. Body mass index, direct tobacco smoking status and alcohol drinking were not associated with asthma control. On the other hand, younger age (< 65 years old), passive smoking, periodical exercise (> 3 metabolic equivalents-h/week), and raw vegetable intake (> 5 units/week) were significantly associated with good asthma control by bivariate analysis. Younger age, periodical exercise, and raw vegetable intake were significantly associated with good asthma control by multiple linear regression analysis. CONCLUSIONS: Periodical exercise and raw vegetable intake are associated with good asthma control in Japanese patients.

Despite the use of retroviral vectors, efficiently introducing target genes into immunocytes such as T cells is difficult. In addition, retroviral vectors carry risks associated with the oncogenicity of the native virus and the potential for introducing malignancy in recipients due to genetic carryover from immortalized cells used during vector production. To address these issues, we have established a new virus vector that is based on human herpesvirus 6 (HHV-6), a non-oncogenic lymphotropic herpesvirus that infects CD4(+) T cells, macrophages, and dendritic cells. In the present study, we have altered the cell specificity of the resulting recombinant HHV-6 by knocking out the U2-U8 genes. The resulting virus proliferated only in activated cord blood cells and not in peripheral blood cells. Umbilical cord blood cells produced replication-defective recombinant virus in sufficiently high titer to omit the use of immortalized cells during vector production. HHV-6 vectors led to high rates (>90%) of gene transduction in both CD4(+) and CD8(+) T cells. These viruses showed low-level replication of viral DNA that supported greater expression of the induced genes than that of other methods but that was insufficient to support the production of replication-competent virus. Furthermore, HHV-6 vectors containing short hairpin RNAs against CD4 and HIV Gag remarkably inhibited the production of these proteins and HIV particles. Here we demonstrate the utility of HHV-6 as a new non-carcinogenic viral vector for immunologic diseases and immunotherapy.

Sleep-related eating disorder (SRED) is characterized by recurrent episodes of involuntary eating during sleep period and is often associated with restless legs syndrome (RLS). Although pharmacotherapy is recommended for SRED patients, no drug have shown promising effects so far. The patient, a 48-year-old Japanese housewife, first visited our clinic and complained about nighttime eating. She had a history of hypertension, diabetes mellitus, sleep apnea syndrome, and depression. Insomnia appeared 10 years before the first visit and she often received hypnosedatives; at the same time, she developed nocturnal eating episodes. She had amnesia for these episodes, and she felt urge to move her legs while sleeping. The patient was diagnosed with SRED and RLS. Reduction in the doses of triazolam decreased her nighttime eating frequency, and her complete amnesia changed to vague recall of eating during night. Clonazepam 1.0 mg at bedtime decreased nocturnal eating frequency from 1 to 2 times per month, though sleepwalking remained. Administration of pramipexole 0.125 mg relieved all symptoms including SRED, RLS, and sleepwalking. This is the first paper to report that the combination of clonazepam and pramipexole therapy-reduced SRED episodes and RLS symptoms.