Background: Prospective studies have shown that cognitive impairment is a strong and consistent risk factor of physical disability. However, cognitive impairment has been based on the result of a single screening tool. Objective: To investigate the role of cognition in the subsequent incidence and decline of functional disability in basic activities of daily living (ADL) and instrumental activities of daily living (IADL) after a full assessment of dementia. Methods: A group of 1,358 Japanese atomic bomb survivors aged 61 years or older who lived in the community or in institutions in Hiroshima City were followed for 4 years. During the baseline survey (1993–1995), subjects were administered a screening test for cognitive impairment. Those suspected of dementia underwent a series of cognitive tests (Hasegawa’s dementia scale, Clinical Dementia Rating) and a neurological examination. The diagnosis of dementia was made according to DSM-III-R criteria. Study subjects were questioned about their reported ADL and their IADL. During the follow-up period, deaths were recorded and a follow-up survey (1997–1999) used to assess ADL and IADL performance. Results: Dementia, even after adjustment for age, sex and history of stroke, was a strong predictor of functional disability, as indicated by ADL (odds ratio, OR = 14.0; confidence interval, CI = 5.4–36.3), IADL (OR = 10.1, CI = 2.2–46.4), and also by assessment of decline in ADL (OR = 9.8, CI = 4.2–22.8) or IADL status (OR = 3.9, CI = 1.8–8.3). Conclusion: Dementia is an important determinant of functional status. Deterioration in ADL is more significant than deterioration in IADL, suggesting that factors other than cognition, such as motivation or perceptual, sensory and motor abilities, may be important in IADL performance. This study confirms previous findings on risk factors that affect functional ability and extends our knowledge by examining several criteria of function that are important in the daily lives of elderly people.
IntroductionProvision for the emergence of an influenza pandemic is an urgent issue. The discovery of a novel anti-influenza therapeutic approach would increase the effectiveness of traditional virus-based strategies. This study was undertaken to evaluate the therapeutic effects of anti-high mobility group box-1 (HMGB1) monoclonal antibody (mAb) treatment on influenza A virus (H1N1)-induced pneumonia in mice.MethodsNine-week-old male C57BL/6 mice were inoculated with H1N1, then anti-HMGB1 mAb or control mAb were administered intravenously at 1, 24 and 48 hours after H1N1 inoculation and the survival rate was analyzed. Lung lavage and histopathological analysis were performed on days 3, 5, 7 and 10 after inoculation.ResultsAnti-HMGB1 mAb significantly improved the survival rate of H1N1-inoculated mice (1 out of 15 versus 8 out of 15 deaths in the anti-HMGB1 mAb-treated group versus the control mAb-treated group, p < 0.01), although the treatment did not affect virus propagation in the lungs. The treatment also significantly attenuated histological changes and neutrophil infiltration in the lungs of H1N1-inoculated mice. This was associated with inhibition of HMGB1 and suppression of inflammatory cytokine/chemokine expression and oxidative stress enhancement, which were observed in H1N1-inoculated mice. The expression of receptor for advanced glycation end products and nuclear factor κB was attenuated by the treatment.ConclusionsAnti-HMGB1 mAb may provide a novel and effective pharmacological strategy for severe influenza virus infection in humans by reducing the inflammatory responses induced by HMGB1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0983-9) contains supplementary material, which is available to authorized users.
Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti‐inflammatory effect of anti‐high‐mobility group box‐1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti‐HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine‐week‐old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post‐infection (dpi). The anti‐HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti‐HMGB1 mAb significantly improved survival rate whereas the anti‐HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti‐HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti‐HMGB1 with conventional anti‐influenza therapy might be useful against severe influenza virus infection.
Objectives: Influenza virus infections can cause severe acute lung injury leading to significant morbidity and mortality. Thioredoxin-1 is a redox-active defensive protein induced in response to stress conditions. Animal experiments have revealed that thioredoxin-1 has protective effects against various severe disorders. This study was undertaken to evaluate the protective effects of recombinant human thioredoxin-1 (rhTRX-1) administration on influenza A virus (H1N1)-induced acute lung injury in mice.Design: Prospective animal trial.
Setting: Research laboratory.Subjects: Nine-week-old male C57BL/6 mice inoculated with H1N1.
Intervention:The mice were divided into vehicle-treated group and rhTRX-1-treated group. For survival rate analysis, the vehicle or rhTRX-1 was administered intraperitoneally every second day from Day -1 to Day 13. For lung lavage and pathological analyses, vehicle or rhTRX-1 was administered intraperitoneally on Day -1, 1, and 3.
Measurements and Main Results:Lung lavage and pathological analyses were performed at 24, 72, and 120 hr after inoculation. The rhTRX-1 treatment significantly improved the survival rate of H1N1-inoculated mice, although the treatment did not affect virus propagation in the lung. The treatment significantly attenuated the histological changes and neutrophil infiltration in the lung of H1N1-inoculated mice. The treatment significantly attenuated the production of TNF-α and CXCL1 in the lung and oxidative stress enhancement which were observed in H1N1-inoculated mice. H1N1 induced expressions of TNF-α and CXCL1 in murine lung epithelial cells MLE-12, which were inhibited by the addition of rhTRX-1. The rhTRX-1 treatment started 30 min after H1N1 inoculation also significantly improved the survival of the mice.
Conclusions:Exogenous administration of rhTRX-1 significantly improved the survival rate and attenuated lung histological changes in the murine model of influenza pneumonia. The protective mechanism of TRX-1 might be explained by its potent antioxidative and anti-inflammatory actions. Consequently, rhTRX-1 might be a possible pharmacological strategy for severe influenza virus infection in humans.
3Influenza virus infections cause a broad array of illnesses that are responsible for significant morbidity and mortality both in children and adults on a yearly basis (1). Influenza can cause periodic global pandemics with even higher penetrance of illness. Highly pathogenic avian influenza virus H5N1 emerged in 1996 in Hong Kong, China (2). Although cases of avian influenza infections have decreased since 2006, the emergence of a pandemic strain remains a threat. In 2009, novel swine-origin influenza virus H1N1 was identified in Mexico. It continues to spread globally (3).Several antiviral compounds have been developed against influenza virus to interfere with specific events in the replication cycle. Under treatment with these drugs, however, influenza virus infection occasionally causes severe pneumonia, necessitating intensive care and mechanical ventilat...
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