Pneumococcal vaccination, but not influenza vaccination, is negatively associated with incident dementia among Japanese older adults: The JAGES 2013-2022 prospective cohort study.

BACKGROUND: It is unclear whether inactivated influenza vaccination (IIV) or pneumococcal vaccination are associated with the risk of dementia; however, both types of vaccination are recommended for older adults. Studies have shown that the IIV is negatively associated with incident dementia; however, the uptake of pneumococcal vaccinations has not been considered. We investigated the independent associations of IIV and 23-valent pneumococcal polysaccharide vaccine (PPSV23) with incident dementia in older adults. METHODS: Health-related information on older Japanese adults was obtained through a baseline survey conducted in 2013 (baseline survey). The uptake of IIV and PPSV23 was determined in a second survey conducted in 2016 (second wave). Both surveys were conducted among independent Japanese older adults aged ≥ 65 years at the two surveys and who had not been certified as needing long-term care (LTC). In the second wave, 9,865 participants were followed up for 3.5 years (short-term follow-up), and 6,995 participants were followed up for six years and five months (long-term follow-up) until they required LTC due to dementia onset (incident dementia). A competing risk model with stabilized inverse probability weighting (SIPW) was constructed to calculate the hazard ratios (HRs) and 95 % confidence intervals (CIs) of incident dementia. RESULTS: PPSV23 uptake was negatively associated with incident dementia among participants in both the short- and long-term follow-up periods after SIPW (short-term follow-up: HR: 0.77, 95 % CI: 0.63 - 0.95; long-term follow-up: HR: 0.83, 95 % CI: 0.70 - 0.97). Conversely, IIV uptake was not associated with incident dementia among participants in either follow-up group (short-term follow-up: HR: 0.86, 95 % CI: 0.63-1.16; long-term follow-up: HR: 0.99, 95 % CI: 0.76-1.29). The PPSV23 uptake was negatively associated with incident dementia in participants without the IIV uptake (short-term follow-up: HR: 0.44, 95 % CI: 0.24 - 0.81; long-term follow-up: HR: 0.47, 95 % CI: 0.29 - 0.76). Conversely, the IIV uptake was not associated with incident dementia regardless of the PPSV23 status (short-term follow-up: HR: 0.87, 95 % CI: 0.62 - 1.23; long-term follow-up: HR: 1.00, 95 % CI: 0.74 - 1.35). CONCLUSION: Our results suggest that the PPSV23 uptake was independently associated with the incidence of dementia. However, the IIV uptake was not associated with the incidence of dementia.

Oral Self-Care, Pneumococcal Vaccination, and Pneumonia Among Japanese Older People, Assessed With Machine Learning.

BACKGROUND: Pneumonia is a leading cause of death worldwide. It is a particularly serious burden in older people, as they tend to have a weakened immune response. Identifying the role of oral self-care and pneumococcal vaccination in healthy, independent older people can aid pneumonia prevention among them. This study investigated the associations between oral self-care, pneumococcal vaccination, and pneumonia experience among independent older people. METHODS: This cross-sectional study used data from the 2016 Japan Gerontological Evaluation Study. We used machine learning to examine the association between oral self-care and the experience of pneumonia over the previous year, stratified by pneumococcal vaccination. The covariates were sex, age, years of education, equivalent annual income, medical history of stroke, oral health status (choking, dryness, number of teeth), and smoking status. The analysis included 17 217 independent older people aged 65 and over. RESULTS: The prevalence of pneumonia experienced among those who brushed their teeth once or less per day was 4.5% and 5.3% for those with and those without pneumococcal vaccinations, respectively. In the unvaccinated group, the odds ratio of pneumonia experience for those who brushed their teeth once or less a day was 1.57 (95% confidence interval: 1.15-2.14) compared to those who brushed their teeth 3 or more times a day. By contrast, there was no significant association between the frequency of toothbrushing and the experience of pneumonia among people who received pneumococcal vaccination. CONCLUSIONS: Oral care influenced the experience of pneumonia among independent older people who did not receive pneumococcal vaccination.

Association of frailty with influenza and hospitalization due to influenza among independent older adults: a longitudinal study of Japan Gerontological Evaluation Study (JAGES).

BACKGROUND: It is unknown that whether frailty is a risk factor of influenza and the hospitalization among older adults, although it has been shown that frailty was associated with poor recovery from the hospitalization among those. We examined the association of frailty with influenza and the hospitalization and the effect by sex among independent older adults. METHODS: We used the longitudinal data from the Japan Gerontological Evaluation Study (JAGES), performed in 2016 and 2019 and conducted in 28 municipalities in Japan. The target population comprised 77,103 persons aged ≥ 65 years who did not need assistance from the public long-term care insurance. Primary outcome measures were influenza and hospitalization due to influenza. Frailty was evaluated with the Kihon check list. We estimated the risk of influenza, the hospitalization, those risks by sex, and the interaction for frailty and sex using Poisson regression adjusting for covariates. RESULTS: Frailty was associated with both influenza and the hospitalization among the older adults compared with nonfrail individuals after adjusting for covariates (influenza, frail: risk ratio {RR}: 1.36, 95% confidence interval {95% CI}: 1.20 - 1.53, and prefrail: RR: 1.16, 95% CI: 1.09 - 1.23; the hospitalization, frail: RR: 3.18, 95% CI: 1.84 - 5.57, and prefrail: RR: 2.13, 95% CI: 1.44 - 3.16). Male was associated with the hospitalization, but not associated with influenza compared to female (the hospitalization: RR: 1.70, 95% CI: 1.15 - 2.52 and influenza: RR: 1.01, 95% CI: 0.95 - 1.08). The interaction for frailty and sex was significant neither in influenza nor in the hospitalization. CONCLUSION: These results suggest that frailty is a risk of influenza and the hospitalization, that risks of the hospitalization are different by sex, but that the sex difference does not cause the effect heterogeneity of frailty on the susceptibility and severity among independent older adults.

Associations of influenza and pneumococcal vaccinations with burdens of older family caregivers: The Japan Gerontological Evaluation study (JAGES) cross-sectional study.

BACKGROUND: Influenza and pneumonia tend to be severe in older adults; thus, vaccination is necessary to prevent these illnesses. Vaccination is especially important for older family caregivers (OFCs) not only to prevent them from becoming ill, but also to prevent secondary infections in the family care receivers (FCRs), who are mostly frail older adults and have a higher risk of severe illness. Thus, we investigated whether caregiving burdens were associated with the vaccinations among older adults. METHODS: We used cross-sectional data from the Japan Gerontological Evaluation Study (JAGES), which was conducted in 64 Japanese municipalities from November 2019 to January 2020. The target population consisted of 26,177 individuals aged 65 years or older who were independent and did not need public long-term care. The primary outcome was the uptakes of either or both influenza and pneumococcal vaccinations. Multinomial logistic regressions were performed, setting those who underwent neither vaccinations as the reference group. RESULTS: Among the participants, 23.3 %, 25.8 %, 9.4 %, or 41.5 % underwent neither, only influenza, only pneumococcal, or the both vaccinations, respectively. The caregiving frequency, time length in a day, or dementia of FCR were negatively associated with influenza vaccination (caregiving almost every day: relative risk ratio {RRR}: 0.39, 95 % confident interval {95 % CI} [0.24-0.63]; caregiving almost all day: 0.44, 95 % CI: 0.23-0.85; caregiving for FCR: RRR:0.55, 95 % CI: 0.34-0.91). On the other hand, those caregiving burdens were not associated with pneumococcal only or the both vaccinations. Having a family physician mitigated all the negative effect of the caregiving burdens on the vaccinations. CONCLUSION: Our results suggest that the caregiving burden is a barrier to influenza vaccination but not to pneumococcal vaccination and that having a physician mitigates the negative effect regardless of the burden kind.

Association of functional competencies with vaccination among older adults: a JAGES cross-sectional study.

It is unknown whether higher functions in sublevels of competence other than instrumental activities of daily living (IADL) are associated with vaccinations. This study examined whether higher functions, including intellectual activity (IA) and social role (SR), were associated with vaccinations among 26,177 older adults. Older adults with incapable activities in IA and SR had increased risks for non-receipt of influenza vaccinations (IA: for one incapable task/activity: incident rate ratio (IRR) = 1.05, 95% confidence interval (CI) = 1.02-1.09; SR: for two incapable tasks: IRR = 1.12, 95% CI = 1.08-1.16). Those with incapable activities in IADL and IA had increased risks for non-receipt of pneumococcal vaccination (IADL: for two incapable tasks: IRR = 1.13, 95% CI = 1.05-1.23; IA: for two incapable tasks: IRR = 1.10, 95% CI = 1.08-1.12). Those with incapable activities in IADL, IA, and SR had increased risks for non-receipt of both of the two vaccinations (IADL: for two incapable tasks: IRR = 1.17, 95% CI = 1.03-1.33; IA: for two incapable tasks: IRR = 1.18, 95% CI = 1.11-1.25; SR: for two incapable tasks: IRR = 1.13, 95% CI = 1.07-1.20). Having a family physician mitigated associations for non-receipt, regardless of competency. Our results suggest-maintaining the higher functions are important for older adults to undergo recommended vaccinations as scheduled; also, having a family physician to promote vaccinations is beneficial even for older adults with limited functions.

Association of Pneumococcal and Influenza Vaccination With Patient-Physician Communication in Older Adults: A Nationwide Cross-sectional Study From the JAGES 2016.

BACKGROUND: Increasing the coverage of vaccinations recommended by the World Health Organization in the older adult population is an urgent issue, especially in the context of avoiding co-epidemics during the current coronavirus disease 2019 crisis. The aim of this study was to examine factors associated with the quality of perceived patient-physician communication and whether this variable was associated with increased odds of vaccination. METHODS: We used cross-sectional data from the Japan Gerontological Evaluation Study conducted from October 2016 to January 2017. The participants were 22,253 physically and cognitively independent individuals aged 65 or older living in 39 municipalities in Japan. Multilevel logit models were used to estimate the odds of vaccination. RESULTS: Among the participants, 40.0% and 58.8% had received pneumococcal and influenza vaccinations as per the recommended schedule, respectively. People with low educational levels were more likely to have a family physician but rate their experience in asking questions lower than those with higher educational levels. Having a family physician and high rating for physicians' listening attitude were positively associated with increased odds of pneumococcal and influenza vaccinations. High rating for patients' questioning attitude and shared decision-making, compared to an ambiguous attitude toward medical decision-making, were positively associated with increased odds of pneumococcal vaccination. CONCLUSION: The results suggest that promotion of having a family physician, better patient-physician communication, and shared decision-making may encourage older adults to undergo recommended vaccinations.

Social capital and pneumococcal vaccination (PPSV23) in community-dwelling older Japanese: a JAGES multilevel cross-sectional study.

OBJECTIVE: Inequalities exist between the 23-valent pneumococcal polysaccharide vaccination (PPSV23) rate in each municipality among Japanese older adults. Exploring individual-level and community-level intervenable factors is necessary to improve the vaccination rates. We examined the associations between community-level and individual-level social capital and the PPSV23 vaccination among older Japanese adults using multilevel Poisson regression analyses. DESIGN: Cross-sectional study. SETTING: We used data from the Japan Gerontological Evaluation Study, conducted between 3 October 2016 and 10 January 2017 in 631 districts, 39 municipalities and 18 prefectures. PARTICIPANTS: The target population comprised persons aged 65 years or older who are physically and cognitively independent (that is, not certified as needing long-term care). Further, 180 021 older adults from 39 Japanese municipalities were enrolled. PRIMARY OUTCOME MEASURE: The primary outcome was the PPSV23 vaccination among the Japanese older adults aged 65 years or older who did not have physical or cognitive disabilities. RESULTS: After adjusting for municipality-, community-, individual-levels effects with multiple imputation, 137 075 individuals who participated in one/more of the civic participation (participation of social groups), social cohesion (social tie), or reciprocity (mutual exchange of social support) were significantly associated with more vaccinations than those without the three social capitals among the 137 075 older adults (13.0% (95% CI 11.0% to 14.9%), 5.0% (95% CI 2.4% to 7.6%) or 33.9% (95% CI23.6% to 44.2%) increase, respectively, p>0.001 for all). The rich (≥+1 SD) community-level civic participation was significantly associated with 3.4% increase [95% CI 0.02% to 6.78%, p<0.05] of the PPSV23 vaccination among the older adults compared to those with the poor or standard one. CONCLUSIONS: Older adults with one/more of the three social capitals at the both levels received more PPSV23 vaccinations than those without those social capitals. Therefore, fostering of those social capitals may improve the inequality of the PPSV23 vaccination rate among older adults in each municipality.

Frailty is associated with susceptibility and severity of pneumonia in older adults (A JAGES multilevel cross-sectional study).

Pneumonia is a leading cause of mortality among older adults worldwide. Recently, several studies reported that frailty was associated with mortality among older adults hospitalized due to respiratory infectious diseases, including pneumonia. However, it is unknown whether frailty is associated with susceptibility to and severity of pneumonia in functionally-independent community-dwelling older adults. In this study, we examined whether frailty increased the susceptibility to pneumonia and hospitalization in older adults. We used cross-sectional data from the Japan Gerontological Evaluation Study; the data was collected by using mail-based, self-reported questionnaires from 177,991 functionally-independent community-dwelling older adults aged ≥ 65 years. Our results showed that frailty was significantly associated with both occurrence of and hospitalization due to pneumonia after adjustments with covariates; (Preference ratio {PR} 1.92, 95% confidence interval {95% CI} [1.66-2.22] and PR 1.80, 95% CI [1.42-2.28], respectively, p < 0.001 for the both). Pre-frailty was associated only with the occurrence of pneumonia. Besides, the instrumental activity of daily living, physical strength, nutrition status, oral function, homeboundness, and depression status in frail older adults were associated with either or both occurrence of and hospitalization due to pneumonia. Our results suggest that frailty influenced the susceptibility to and severity of pneumonia in older adults.

Development of cycling probe based real-time PCR methodology for influenza A viruses possessing the PA/I38T amino acid substitution associated with reduced baloxavir susceptibility.

Baloxavir marboxil has been used for influenza treatment since March 2018 in Japan. After baloxavir treatment, the most frequently detected substitution is Ile38Thr in polymerase acidic protein (PA/I38T), and this substitution reduces baloxavir susceptibility in influenza A viruses. To rapidly investigate the frequency of PA/I38T in influenza A (H1N1)pdm09 and A (H3N2) viruses in clinical samples, we established a rapid real-time system to detect single nucleotide polymorphisms in PA, using cycling probe real-time PCR. We designed two sets of probes that were labeled with either 6-carboxyfluorescein (FAM) or 6-carboxy-X-rhodamine (ROX) to identify PA/I38 (wild type strain) or PA/I38T, respectively. The established cycling probe real-time PCR system showed a dynamic linear range of 101 to 106 copies with high sensitivity in plasmid DNA controls. This real-time PCR system discriminated between PA/I38T and wild type viruses well. During the 2018/19 season, 377 influenza A-positive clinical samples were collected in Japan before antiviral treatment. Using our cycling probe real-time PCR system, we detected no (0/129, 0.0%) influenza A (H1N1)pdm09 viruses with PA/I38T substitutions and four A (H3N2) (4/229, 1.7%) with PA/I38T substitution prior to treatment. In addition, we found PA/I38T variant in siblings who did not received baloxavir treatment during an infection caused by A (H3N2) that afflicted the entire family. Although human-to-human transmission of PA/I38T variant may have occurred in a closed environment, the prevalence of this variant in influenza A viruses was still limited. Our cycling probe-PCR system is thus useful for antiviral surveillance of influenza A viruses possessing PA/I38T.

MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia.

Membrane-associated guanylate kinase with inverted orientation protein 1 (MAGI-1) is a cytoplasmic scaffold protein that interacts with various signaling molecules; it negatively controls the cell growth of various types of cells and positively controls cell-cell interaction. In T cells, MAGI-1 has been shown to inhibit Akt activity through its interaction with PTEN and MEK1. In this study we found that MAGI-1 expression is decreased in multiple (9 out of 15) human T-cell leukemia cell lines, including adult T-cell leukemia (ATL), T-cell acute lymphoblastic leukemia and chronic T-cell lymphocytic leukemia. The overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced cellular growth. While the overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced the Akt and MEK activities, the knockdown of MAGI-1 in a MAGI-1-high ATL cell line augmented the Akt and MEK activities. Collectively, the findings of the present study suggest that the decreased expression of MAGI-1 in human T cells contributes to the development of several types of T-cell leukemia, partly through the stimulation of the Akt and MEK pathways.

USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells.

Self-renewal, replication, and differentiation of hematopoietic stem cells (HSCs) are regulated by cytokines produced by niche cells in fetal liver and bone marrow. HSCs must overcome stresses induced by cytokine deprivation during normal development. In this study, we found that ubiquitin-specific peptidase 10 (USP10) is a crucial deubiquitinase for mouse hematopoiesis. All USP10 knockout (KO) mice died within 1 year because of bone marrow failure with pancytopenia. Bone marrow failure in these USP10-KO mice was associated with remarkable reductions of long-term HSCs (LT-HSCs) in bone marrow and fetal liver. Such USP10-KO fetal liver exhibited enhanced apoptosis of hematopoietic stem/progenitor cells (HSPCs) including LT-HSCs but not of lineage-committed progenitor cells. Transplantation of USP10-competent bone marrow cells into USP10-KO mice reconstituted multilineage hematopoiesis. These results suggest that USP10 is an essential deubiquitinase in hematopoiesis and functions by inhibiting apoptosis of HSPCs including LT-HSCs.

The effects of neuraminidase inhibitors on the release of oseltamivir-sensitive and oseltamivir-resistant influenza viruses from primary cultures of human tracheal epithelium.

Defining the effects of neuraminidase inhibitors on influenza virus infection may provide important information for the treatment of patients. The effects of neuraminidase inhibitors have been examined using various methods, including viral release from kidney cells. However, the effects of neuraminidase inhibitors on viral release from primary cultures of human tracheal epithelial cells, which retain functions of the original tissues, have not been studied. The effects of neuraminidase inhibitors on the replication of the pandemic influenza virus [A/Sendai-H/N0633/2009 (H1N1) pdm09] and the seasonal influenza virus [A/Sendai-H/216/2009 (H1N1)] that was isolated during the 2008-2009 season were examined. The virus stocks were generated by infecting tracheal cells with the pandemic or seasonal influenza virus. Four types of inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) reduced pandemic viral titers and concentrations of the cytokines interleukin-6 and tumor necrosis factor-α in supernatants and viral RNA in cells. However, oseltamivir did not reduce seasonal viral titers, cytokine concentrations and viral RNA, and the 50% inhibitory concentration (IC50 ) of oseltamivir for neuraminidase activity in the seasonal virus was 300-fold higher than that observed for the pandemic influenza virus. The seasonal influenza virus had an oseltamivir-resistant genotype. The magnitude of the IC50 values of the neuraminidase inhibitors for the seasonal influenza virus was inversely related to the magnitude of the inhibitory effects on viral release. These methods for measuring the release of virus and inflammatory cytokines from primary cultures of human tracheal epithelium may provide useful information regarding the effects of neuraminidase inhibitors on influenza viruses.

Characterization of human Influenza Viruses in Lebanon during 2010-2011 and 2011-2012 post-pandemic seasons.

OBJECTIVE: To genetically characterize human influenza viruses and their susceptibilities to antivirals during two post-pandemic seasons in Lebanon. METHODS: Influenza virus was isolated from nasopharyngeal swabs that were obtained from patients with influenza-like illness during 2010-2012 and further analyzed both phenotypically and genotypically. RESULTS: During the 2010-2011 season, both 2009 pandemic H1N1 (H1N1p) and B viruses co-circulated with equal prevalence, while the H3N2 virus predominated during the 2011-2012 season. All H3N2 and H1N1 viruses were resistant to amantadine. Importantly, all viruses of the influenza A and B types were susceptible to the neuraminidase (NA) inhibitors oseltamivir, zanamivir, peramivir, and laninamivir. Nonetheless, all 2011-2012 H1N1p isolates had three mutations (V241I, N369K, and N386S) in the NA gene that were suggested to be permissive of the H275Y mutation, which confers resistance to oseltamivir. We also detected one H1N1p virus during the 2010-2011 season with a 4-fold decrease in susceptibility to oseltamivir due to an NA-S247N mutation. This isolate was phylogenetically distinct from other H1N1p viruses that were isolated in other regions. CONCLUSIONS: Influenza A viruses with reduced susceptibility to oseltamivir and mutations permissive for acquiring NA resistance-conferring mutation with minimal burden on their fitness were isolated in Lebanon.

Effectiveness of trivalent influenza vaccine among children in two consecutive seasons in a community in Japan.

Influenza vaccination is considered the single most important medical intervention for the prevention of influenza. The dose of trivalent influenza vaccine in children was increased almost double since 2011/12 season in Japan. We estimated the influenza vaccine effectiveness for children 1-11 years of age using rapid test kits in Isahaya City, involving 28,884 children-years, over two consecutive influenza seasons (2011/12 and 2012/13). Children were divided into two groups, vaccinated and unvaccinated, according to their vaccination record, which was obtained from an influenza registration program organized by the Isahaya Medical Association for all pediatric facilities in the city. There were 14,562 and 14,282 children aged from 1-11 years in the city in 2011 and 2012 respectively. In the 2011/12 season, the overall vaccine effectiveness in children from 1-11 years of age, against influenza A and B were 23% [95% confidence interval (CI): 14%-31%] and 20% [95% CI: 8%-31%], respectively. In the 2012/13 season, vaccine effectiveness against influenza A and B was 13% (95% CI: 4%-20%) and 9% (95% CI: -4%-21%), respectively. The vaccine effectiveness was estimated using the rapid diagnosis test kits. Age-stratified estimation showed that vaccine effectiveness was superior in younger children over both seasons and for both virus types. In conclusion, the trivalent influenza vaccine has a significant protective effect for children 1-11 years of age against influenza A and B infection in the 2011/12 season and against influenza A infection in the 2012/13 season in a community in Japan.

Neuraminidase inhibitor susceptibility profile of pandemic and seasonal influenza viruses during the 2009-2010 and 2010-2011 influenza seasons in Japan.

Two new influenza virus neuraminidase inhibitors (NAIs), peramivir and laninamivir, were approved in 2010 which resulted to four NAIs that were used during the 2010-2011 influenza season in Japan. This study aims to monitor the susceptibility of influenza virus isolates in 2009-2010 and 2010-2011 influenza seasons in Japan to the four NAIs using the fluorescence-based 50% inhibitory concentration (IC50) method. Outliers were identified using box-and-whisker plot analysis and full NA gene sequencing was performed to determine the mutations that are associated with reduction of susceptibility to NAIs. A total of 117 influenza A(H1N1)pdm09, 59 A(H3N2), and 18 type B viruses were tested before NAI treatment and eight A(H1N1)pdm09 and 1 type B viruses were examined from patients after NAI treatment in the two seasons. NA inhibition assay showed type A influenza viruses were more susceptible to NAIs than type B viruses. The peramivir and laninamivir IC50 values of both type A and B viruses were significantly lower than the oseltamivir and zanamivir IC50 values. Among influenza A(H1N1)pdm09 viruses, the prevalence of H274Y viruses increased from 0% in the 2009-2010 season to 3% in the 2010-2011 season. These H274Y viruses were resistant to oseltamivir and peramivir with 200-300 fold increase in IC50 values but remained sensitive to zanamivir and laninamivir. Other mutations in NA, such as I222T and M241I were identified among the outliers. Among influenza A(H3N2) viruses, two outliers were identified with D151G and T148I mutations, which exhibited a reduction in susceptibility to oseltamivir and zanamivir, respectively. Among type B viruses, no outliers were identified to the four NAIs. For paired samples that were collected before and after drug treatment, three (3/11; 27.3%) H274Y viruses were identified among A(H1N1)pdm09 viruses after oseltamivir treatment but no outliers were found in the laninamivir-treatment group (n=3). Despite widespread use of NAIs in Japan, the prevalence of NAI-resistant influenza viruses is still low.

Clinical effectiveness of neuraminidase inhibitors--oseltamivir, zanamivir, laninamivir, and peramivir--for treatment of influenza A(H3N2) and A(H1N1)pdm09 infection: an observational study in the 2010-2011 influenza season in Japan.

The clinical effectiveness of the newly released neuraminidase inhibitors (NAIs) laninamivir and peramivir has not been sufficiently evaluated in influenza-infected patients in clinical and practical settings. In this study, we analyzed the clinical data of 211 patients infected with influenza A virus subtype H3N2 (A(H3N2)) and 45 patients infected with influenza A virus subtype H1N1pdm (A(H1N1)pdm09) who received the NAIs oseltamivir, zanamivir, laninamivir, or peramivir during the 2010-2011 influenza season. The duration of fever from the first dose of the NAI to fever alleviation to <37.5 °C was evaluated as an indicator of the clinical effectiveness of the NAIs in the influenza-infected patients. For the A(H3N2)-infected patients, Kaplan-Meier analysis showed the peramivir treatment group had the fastest time of fever alleviation to <37.5 °C (median 17.0 h, 95 % confidence interval [CI] 7.2-26.8 h) of the four treatment groups. No significant difference was found in the time to fever alleviation among the other antivirals, oseltamivir, zanamivir, and laninamivir. Results of multivariate analysis, using a Cox proportional-hazards model (hazard ratio 3.321) adjusted for the factors age, sex, body weight, vaccination status, time from onset to the clinic visit, and body temperature showed significantly faster fever alleviation in the peramivir treatment group compared with the oseltamivir treatment group. For the A(H1N1)pdm09-infected patients, only the oseltamivir and zanamivir treatment groups were compared, and no significant difference in time to alleviation of fever was observed between the two groups. Based on a cycling probe real-time polymerase chain reaction (PCR) assay, none of the A(H1N1)pdm09 strains in this study had the H275Y mutation conferring oseltamivir resistance. Further evaluation of the clinical effectiveness of the newly released NAIs for influenza-infected patients, including those infected with A(H1N1)pdm09, is needed.

Activation of the PI3K-Akt pathway by human T cell leukemia virus type 1 (HTLV-1) oncoprotein Tax increases Bcl3 expression, which is associated with enhanced growth of HTLV-1-infected T cells.

Bcl3 is a member of the IkappaB family that regulates genes involved in cell proliferation and apoptosis. Recent reports indicated that Bcl3 is overexpressed in HTLV-1-infected T cells via Tax-mediated transactivation, and acts as a negative regulator of viral transcription. However, the role of Bcl3 in cellular signal transduction and the growth of HTLV-1-infected T cells have not been reported. In this study, we showed that the knockdown of Bcl3 by short hairpin RNA inhibited the growth of HTLV-1-infected T cells. Although phosphatidylinositol-3 kinase (PI3K) inhibitor reduced Bcl3 expression, inactivation of glycogen synthase kinase 3 (GSK3), an effector kinase of the PI3K/Akt signaling pathway, restored Bcl3 expression in Tax-negative but not in Tax-positive T cells. Our results indicate that the overexpression of Bcl3 in HTLV-1-infected T cells is regulated not only by transcriptional but also by post-transcriptional mechanisms, and is involved in overgrowth of HTLV-1-infected T cells.

X-ray polarimeter with a transmission multilayer.

We fabricated a novel x-ray polarimeter with a transmission multilayer and measured its performance with synchrotron radiation. A self standing multilayer with seven Mo/Si bilayers was installed with an incident angle of 45 degrees in front of a back-illuminated CCD. The multilayer can be rotated around the normal direction of the CCD keeping an incident angle of 45 degrees. This polarimeter can be easily installed along the optical axis of x-ray optics. By using the CCD as a photon counting detector with a moderate energy resolution, the polarization of photons in a designed energy band can be measured along with the image. At high photon energies, where the multilayer is transparent, the polarimeter can be used for imaging and spectroscopic observations. We confirmed a modulation factor of 45% with 45% and 17% transmission for P- and S-polarization, respectively.

Hepatitis C virus core protein interacts with fibrinogen-beta and attenuates cytokine stimulated acute-phase response.

UNLABELLED: Fibrinogen-beta (FBG-beta), an important acute-phase protein (APP), is generated by the liver as a target for inflammatory mediators. Here we identified FBG-beta as a hepatitis C virus (HCV) core interacting protein by screening a human liver complementary DNA (cDNA) library using mammalian two-hybrid analysis. An association between FBG-beta and HCV core protein was verified by confocal microscopy and coimmunoprecipitation from the transfected human hepatocyte (Huh-7) cell line. HCV core or genomic RNA transfected Huh-7 cells modestly increased FBG-beta protein expression when compared to the basal level in control hepatocytes. Transfection of HCV core or full-length (FL) gene into Huh-7 cells up-regulated basal FBG-beta promoter activity. Exogenous addition of IL-6 stimulates FBG-beta promoter activity in hepatocytes. However, ectopic expression of HCV core or FL in hepatocytes inhibited IL-6-stimulated FBG-beta promoter activation. Inhibition of endogenous FBG-beta expression following introduction of small interfering RNA (siRNA) into cells displayed a gain of function of promoter regulation by HCV core protein. Further studies suggested that HCV core gene expression in stable transfectants of Huh-7 cells resulted in a basal up-regulation of FBG-beta and other APPs. However, treatment with cytokines, interleukin-6 (IL-6), or tumor necrosis factor-alpha repressed FBG-beta and other acute-phase response (APR) genes. CONCLUSION: Our results reveal that the core/FBG-beta interaction may act as a regulatory feedback, allowing repression of IL-6-stimulated APR genes. Together, these data suggested a network of interactions between HCV core and the hepatic APR genes, and may contribute to impaired innate immunity for viral persistence.

Analysis of the mechanism by which BALB/c mice having prior immunization with nucleocapsid protein of SARS-CoV develop severe pneumonia after SARS-CoV infection.

The precise mechanism of severe acute respiratory syndrome (SARS), which is caused by SARS-associated coronavirus (SARS-CoV), is still unclear. We generated recombinant vaccinia virus (rVV) LC16m8 strain which simultaneously expresses four structural proteins of SARS-CoV, including nucleocapsid (N), membrane (M), envelop (E), spike (S) proteins (rVV-NMES) and reported that old BALB/c mice having prior immunization with rVV-NMES develop severe pneumonia similar to those of control mice though rVV-NMES-immunized mice showed lower pulmonary viral titer than in the control mice. Furthermore, we determined which SARS-CoV structural protein for the prior rVV-immunization is responsible for the severe pneumonia after the SARS-CoV infection as observed in the rVV-NMES-immunized mice. Old BALB/c mice were inoculated intradermally with rVV that expressed each structural proteins of SARS-CoV (rVV-N, -M, -E, or -S) with or without rVV-S and then infected intranasally with SARS-CoV more than 4 weeks later. At 9 days after SARS-CoV infection, the rVV-N-immunized mice show more severe pneumonia than in other groups. Furthermore, significant up-regulation of Th1 (IL-2)- and Th2 (IL-4 and IL-5)-bias cytokines and down-regulation of anti-inflammatory cytokine (IL-10 and TGF-ß) were observed in rVV-N-immunized mice, resulting in the intensive infiltration of immunocompetent cells into the lung. In contrast, rVV-S-immunized mice showed only low pulmonary viral tier and slight pneumonia. However, the mice having co-immunization with both rVV-N and rVV-S showed severe pneumonia though their pulmonary viral titer was low. These results suggest that an excessive host immune response against the N protein of SARS-CoV is involved in severe pneumonia caused by SARS-CoV infection. These findings increase our understanding of the pathogenesis of SARS.