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BACKGROUND: Thrombomodulin (TM) exerts anticoagulant and anti-inflammatory effects to improve the survival of patients with septic shock. Heat stroke resembles septic shock in many aspects. We tested whether TM would improve cognitive deficits and related causative factors in heat-stressed (HS) mice. METHODS: Adult male mice were exposed to HS (33°C for 2 hours daily for 7 consecutive days) to induce cognitive deficits. Recombinant human soluble TM (1 mg/kg, i.p.) was administered immediately after the first HS trial and then once daily for 7 consecutive days. We performed the Y-maze, novel objective recognition, and passive avoidance tests to evaluate cognitive function. Plasma levels of lipopolysaccharide (LPS), high-mobility group box 1 (HMGB1), coagulation parameters, and both plasma and tissue levels of inflammatory and oxidative stress markers were biochemically measured. The duodenum and hippocampus sections were immunohistochemically stained. The intestinal and blood-brain barrier permeability were determined. RESULTS: Compared with controls, HS mice treated with TM had lesser extents of cognitive deficits, exacerbated stress reactions, gut barrier disruption, endotoxemia, blood-brain barrier disruption, and inflammatory, oxidative, and coagulatory injury to heart, duodenum, and hippocampal tissues, and increased plasma HMGB1. In addition to reducing cognitive deficits, TM therapy alleviated all the abovementioned complications in heat-stressed mice. CONCLUSIONS: The findings suggest that HS can lead to exacerbated stress reactions, endotoxemia, gut barrier disruption, blood-brain barrier disruption, hippocampal inflammation, coagulopathy, and oxidative stress, which may act as causative factors for cognitive deficits. TM, an anti-inflammatory, antioxidant, and anti-coagulatory agent, inhibited heat stress-induced cognitive deficits in mice.
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Disfunção Cognitiva , Proteína HMGB1 , Trombomodulina , Animais , Masculino , Proteína HMGB1/metabolismo , Proteína HMGB1/sangue , Camundongos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Modelos Animais de Doenças , Aprendizagem da Esquiva/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Resposta ao Choque Térmico/efeitos dos fármacos , Resposta ao Choque Térmico/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacosRESUMO
Retinal ischemia followed by reperfusion (IR) is a common cause of many ocular disorders, such as age-related macular degeneration (AMD), which leads to blindness in the elderly population, and proper therapies remain unavailable. Retinal pigment epithelial (RPE) cell death is a hallmark of AMD. Hyperbaric oxygen (HBO) therapy can improve IR tissue survival by inducing ischemic preconditioning responses. We conducted an in vitro study to examine the effects of HBO preconditioning on oxygen-glucose deprivation (OGD)-induced IR-injured RPE cells. RPE cells were treated with HBO (100% O2 at 3 atmospheres absolute for 90 min) once a day for three consecutive days before retinal IR onset. Compared with normal cells, the IR-injured RPE cells had lower cell viability, lower peroxisome proliferator activator receptor-alpha (PPAR-α) expression, more severe oxidation status, higher blood-retinal barrier disruption and more elevated apoptosis and autophagy rates. HBO preconditioning increased PPAR-α expression, improved cell viability, decreased oxidative stress, blood-retinal barrier disruption and cellular apoptosis and autophagy. A specific PPAR-α antagonist, GW6471, antagonized all the protective effects of HBO preconditioning in IR-injured RPE cells. Combining these observations, HBO therapy can reverse OGD-induced RPE cell injury by activating PPAR-α signalling.
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BACKGROUND: Adjuvant chemotherapy is recommended as the standard treatment for patients with stage II/III resected gastric cancer. However, it is unclear whether older patients also benefit from an adjuvant chemotherapy strategy. This study aimed to investigate the clinical impact of adjuvant chemotherapy in older patients with stage II/III gastric cancer. METHODS: This retrospective, real-world study analyzed 404 patients with stage II/III gastric cancer visited at our institute between January 2009 and December 2019. The clinical characteristics and outcomes of patients aged 70 years or older who received adjuvant chemotherapy were compared with those who did not receive this type of treatment. Propensity score analysis was performed to mitigate selection bias. RESULTS: Of the 404 patients analyzed, 179 were aged 70 years or older. Fewer older patients received adjuvant chemotherapy than did younger patients (60.9% vs. 94.7%, respectively; P < 0.001). Among patients aged 70 years or older, those who received adjuvant chemotherapy had improved disease-free survival (DFS) (5-year DFS rate, 53.1% vs. 30.4%; P < 0.001) and overall survival (OS) (5-year OS rate, 68.7% vs. 52.1%; P = 0.002) compared to those who did not receive adjuvant chemotherapy. A similar survival benefit was observed in the propensity-matched cohort. Multivariate analysis showed that more advanced stage was associated with poorer OS. Receipt of adjuvant chemotherapy was independently associated with a decreased hazard of death (hazard ratio (HR), 0.37; 95% confidence intervals (CI), 0.20-0.68; P = 0.002). CONCLUSIONS: Adjuvant chemotherapy may benefit older stage II/III gastric cancer patients aged ≥ 70 years. Further prospective studies are needed to confirm these findings.
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Neoplasias Gástricas , Humanos , Idoso , Neoplasias Gástricas/tratamento farmacológico , Estudos Retrospectivos , Quimioterapia Adjuvante , Intervalo Livre de Doença , Análise MultivariadaRESUMO
Oxidative stress is identified as a major inducer of retinal pigment epithelium (RPE) cell dysregulation and is associated with age-related macular degeneration (AMD). The protection of RPE disorders plays an essential role in the pathological progress of retinal degeneration diseases. The pharmacological functions of fucoxanthin, a characteristic carotenoid, including anti-inflammatory and antioxidant properties, may ameliorate an outstanding bioactivity against premature senescence and cellular dysfunction. This study demonstrates that fucoxanthin protects RPE cells from oxidative stress-induced premature senescence and decreased photoreceptor cell loss in a sodium iodate-induced AMD animal model. Similarly, oxidative stress induced by hydrogen peroxide, nuclear phosphorylated histone (γH2AX) deposition and premature senescence-associated ß-galactosidase staining were inhibited by fucoxanthin pretreatment in a human RPE cell line, ARPE-19 cells. Results reveal that fucoxanthin treatment significantly inhibited reactive oxygen species (ROS) generation, reduced malondialdehyde (MDA) concentrations and increased the mitochondrial metabolic rate in oxidative stress-induced RPE cell damage. Moreover, atrophy of apical microvilli was inhibited in cells treated with fucoxanthin after oxidative stress. During aging, the RPE undergoes well-characterized pathological changes, including amyloid beta (Aß) deposition, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression and tight junction disruption, which were also reduced in fucoxanthin-treated groups by immunofluorescence. Altogether, pretreatment with fucoxanthin may protect against premature senescence and cellular dysfunction in retinal cells by oxidative stress in experimental AMD animal and human RPE cell models.
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Degeneração Macular/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Xantofilas/farmacologia , Animais , Antioxidantes/farmacologia , Linhagem Celular , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Degeneração Macular/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/citologiaRESUMO
BACKGROUND/PURPOSE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative therapy for acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), but advanced age with multiple comorbidities limits the eligibility for allo-HSCT. We conducted a retrospective study to investigate the comorbidities assessments and prognostic factors that predict outcomes for these patients. METHODS: Clinical data of patients older than 50 years who had received diagnoses of AML or MDS and underwent allo-HSCT were obtained. Information on patient characteristics, including age, gender, allogeneic transplant type, conditioning regimens, Charlson comorbidity index (CCI), and presence of acute graft-versus-host disease (GVHD) or chronic GVHD, were collected and analyzed. RESULTS: Two hundred fifty-five elderly patients with a median age at allo-HSCT of 57 years were included. The significant prognostic factors associated with worse overall survival (OS) were CCI ≥3 (hazard ratio: 1.88) and grade III-IV acute GVHD (3.18). Similar findings were noted in the non-relapse mortality analysis. To investigate the effects of chronic GVHD on patient outcomes, OS analysis was performed for those with survival >100 days after transplantation. The results revealed CCI ≥3 (1.88) and grade III-IV acute GVHD (2.73) remained poor prognostic factors for OS, whereas mild chronic GVHD (0.43) was associated with better OS. CONCLUSION: This cohort study suggests that CCI ≥3 predicts poor outcomes, primarily due to a higher NRM risk. Careful management of GVHD after transplantation could improve outcomes in elderly patients with AML or MDS after allo-HSCT.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Idoso , Estudos de Coortes , Comorbidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Condicionamento Pré-TransplanteRESUMO
We aimed to ascertain whether therapeutic hypothermia (TH) acts as cardioprotective management for heat stroke (HS). Adult male rats under general anesthesia were exposed to whole-body heating (43°C for 70 min) to induce HS. Rats with HS displayed hyperthermia (core body temperature 42°C vs. 36°C); hypotension (30 mmHg vs. 90 mmHg mean arterial blood pressure); suppressed left ventricular (LV) performance (stroke volume 52 µl/min vs. 125 µl/min), ejection fraction (0.29% vs. 0.69%), relaxation factor (72 ms vs. 12 ms), and arterial elastance (0.31 mmHg/ µl vs. 10 mmHg/ µl); increased myocardial injury markers (e.g., creatine kinase-MB: 86 U/L vs. 24 U/L, cardiac troponin I: 3.08 ng/ml vs. 0.57 ng/ml); increased myocardial oxidative stress markers (e.g., malondialdehyde: 6.52 nmol/mg vs. 1.06 nmol/mg, thiobarbituric acid-reactive substances: 29 nmol/g vs. 2 nmol/g); decreased myocardial antioxidants (e.g., superoxide dismutase: 6 unit/mg vs. 17 unit/mg, reduced glutathione: 0.64 nmol/mg vs. 2.53 nmol/mg); increased myocardial proinflammatory cytokines (e.g., tumor necrosis factor-α 3200 pg/ml vs. 1000 pg/ml, interleukin-6: 668 pg/ml vs. 102 pg/ml); and increased cardiac damage scores (2.2 vs. 0.3). TH therapy significantly reversed the following conditions: HS-induced hyperthermia (37.5°C core body temperature), hypotension (71 mmHg), suppressed LV performance (stroke volume: 97 µl/min, ejection fraction: 0.65%, relaxation factor: 39 ms, and arterial elastance: 0.99 mmHg/µl), increased myocardial injury markers (e.g., creatine kinase-MB: 37 U/L, cardiac troponin I: 1.06 ng/ml), increased myocardial oxidative stress markers (e.g., malondialdehyde: 2.68 nmol/mg, thiobarbituric acid-reactive substances: 12.3 nmol/g), decreased myocardial antioxidants (e.g., superoxide dismutase: 13.3 unit/mg, reduced glutathione: 2.71 mmol/mg), increased myocardial proinflammatory cytokines (e.g., tumor necrosis factor-α 1500 pg/ml, interleukin-6: 108 ng/ml); and increased cardiac damage scores (0.9). We thus conclude that TH protects against HS-induced arterial hypotension by promoting LV performance in rats. These results add to the literature regarding the use of TH as cardioprotective management for HS.
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Artérias/fisiopatologia , Golpe de Calor/terapia , Hipotensão/prevenção & controle , Hipotermia Induzida , Estresse Oxidativo , Função Ventricular , Anestesia Geral , Animais , Antioxidantes/metabolismo , Elasticidade , Traumatismos Cardíacos/fisiopatologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica , Temperatura Alta , Inflamação , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Estimativa de Kaplan-Meier , Masculino , Miocárdio , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo , Função Ventricular EsquerdaRESUMO
Background: Hypoxia-inducible factor-1α (HIF-1α), heat shock protein-72 (HSP-72), hemeoxygenase-1 (HO-1), and matrix metalloproteinase-9 (MMP-9) have been identified as potential therapeutic targets in the brain for cerebral ischemia. To elucidate their underlying mechanisms, we first aimed to ascertain whether these proteins participate in the pathogenesis of heat-induced ischemic damage to the hypothalamus of rats. Second, we investigated whether hypobaric hypoxia preconditioning (HHP) attenuates heat-induced hypothalamic ischemic/hypoxic injury by modulating these proteins in situ. Methods: Anesthetized rats treated with or without HHP were subjected to heat stress. Hypothalamic ischemic/hypoxic damage was evaluated by measuring hypothalamic levels of cerebral blood flow (CBF), partial oxygen pressure (PO2), and hypothalamic temperature via an implanted probe. Hypothalamic apoptotic neurons were counted by measuring the number of NeuN/caspase-3/DAPI triple-stained cells. Hypothalamic protein expression of HIF-1α, HSP-72, HO-1, and MMP-9 was determined biochemically. Results: Before the start of the thermal experiments, rats were subjected to 5 hours of HHP (0.66 ATA or 18.3% O2) daily for 5 consecutive days per week for 2 weeks, which led to significant loss of body weight, reduced brown adipose tissue (BAT) wet weight and decreased body temperature. The animals were then subjected to thermal studies. Twenty minutes after heat stress, heat-exposed rats not treated with HHP displayed significantly higher core and hypothalamic temperatures, hypothalamic MMP-9 levels, and numbers of hypothalamic apoptotic neurons but significantly lower mean blood pressure, hypothalamic blood flow, and PO2 values than control rats not exposed to heat. In heat-exposed rats, HHP significantly increased the hypothalamic levels of HIF-1α, HSP-72, and HO-1 but significantly alleviated body and hypothalamic hyperthermia, hypotension, hypothalamic ischemia, hypoxia, neuronal apoptosis and degeneration. Conclusions: HHP may protect against hypothalamic ischemic/hypoxic injury and overexpression of MMP-9 by upregulating the hypothalamic expression of HIF-1α, HSP-72, and HO-1 in rats subjected to heatstroke.
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Isquemia Encefálica/terapia , Golpe de Calor/terapia , Hipotálamo/patologia , Hipóxia/fisiopatologia , Metaloproteinase 9 da Matriz/metabolismo , Animais , Apoptose , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Golpe de Calor/complicações , Golpe de Calor/patologia , Golpe de Calor/fisiopatologia , Humanos , Hipotálamo/citologia , Hipotálamo/fisiopatologia , Masculino , Neurônios/patologia , RatosRESUMO
We aimed to elucidate the role of cortical and hippocampal dendritic spines on neurological deficits associated with hippocampal microgliosis, hippocampal neurogenesis, and neuroinflammation in mice with cortical compact impact (CCI) injury. In the present study, we found that CCI reduced spatial memory mean latency (10 s. vs 50 s) and motor dysfunction (130 s. vs 150 s.) in mice, as determined by Morris water maze and rotarod test, respectively. Golgi staining of cortical pyramidal neurons revealed that, compared to the controls, the CCI group treated with vehicle solution had significantly lower values of dendritic order (or dendritic branch number) (4.0 vs 6.2), total spine length (400 µm vs 620 µm) and spine density (40 spines/µm vs 60 spines/µm), but had significantly higher values of dendritic beading (40 beadings/mm vs 20 beadings/mm). Additionally, Sholl analysis showed that, compared to controls, the CCI + NS group mice had significantly lower values of dendritic intersections (1.0 vs 2.0). Immunofluorescence assay also revealed that, compared to controls, the CCI + NS group mice had significantly higher values of the newly formed hippocampal cells (1250/mm2 vs 1000/mm2) but significantly lower values of dendritic order (2.0 branch # vs 4.2 branch #), total spine length (180 µm vs 320 µm) and intersection (1.0 vs 3.0). The CCI + NS group mice further showed significantly higher numbers of microglia in the dentate gyrus of the hippocampus and higher concentrations of pro-inflammatory cytokines in the cerebrospinal fluids. All the CCI-induced spatial memory (40 s) and motor (150 s) dysfunction, deranged dendritic and spine morphology of cortical pyramidal neurons or hippocampal newly formed cells, hippocampal microgliosis, and central neuroinflammation were all significantly reduced by melatonin administration during post-CCI. Simultaneously, melatonin therapy caused an enhancement in the compensatory hippocampal neurogenesis and neurotrophic growth factors (e.g., doublecortin-1) and compensatory central anti-inflammatory cytokines. Our results indicate that melatonin attenuates the spatial memory and motor deficits via the modification of cortical and hippocampal dendritic spine morphology, hippocampal microgliosis and neurogenesis, and neuroinflammation in mice with traumatic brain injury.
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Lesões Encefálicas Traumáticas/tratamento farmacológico , Espinhas Dendríticas/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Melatonina/farmacologia , Córtex Motor/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Owing to the shortage of hematopoietic stem cells from matched sibling donors (MSD) and matched unrelated donors (MUD), the number of patients undergoing haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT) has rapidly increased. Despite a comparable overall survival (OS) and leukemia-free survival using this approach, some evidence suggests that haploidentical allo-HSCT recipients have a higher incidence of cytomegalovirus (CMV) infection, though this has not been clearly established. METHODS: This study retrospectively compared the cumulative incidence of CMV DNAemia, 2-year OS, and leukemia-free survival rates in acute leukemia patients with MSD (n = 41), MUD (n = 18), and haploidentical donor allografts (n = 21). RESULTS: The cumulative incidences of CMV DNAemia at day 180 in the MSD, MUD, and haploidentical groups were 39.0, 55.6, and 85.7%, respectively (P < 0.000). As less than 50% of patients in the MSD group were detected to have CMV DNAemia, the median time to CMV DNAemia detection in patients allografted with MSD could not be obtained. However, it was 42 and 29 days, respectively, for the MUD and haploidentical groups. Multivariate analysis revealed that haploidentical allo-HSCT (MSD vs. haploidentical: HR: 0.26; 95% CI: 0.09-0.78; P = 0.017) and age (HR: 1.03; 95% CI: 1.01-1.06; P = 0.011) increased CMV infection. Finally, MSD, MUD, and haploidentical allo-HSCT provided comparable 2-year OS rates (52.1%, 65.5%, and 65.6%; P = 0.425) and 2-year leukemia-free survival rates (67.1%, 68.3%, and 80.7%, P = 0.837). CONCLUSION: The CMV incidence was higher for haploidentical allo-HSCT than for MSD and MUD allo-HSCT; this could be explained by graft-versus-host disease prophylaxis by multiple immunosuppressants.
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Infecções por Citomegalovirus/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/complicações , Adulto , Idoso , Infecções por Citomegalovirus/mortalidade , Feminino , Humanos , Leucemia Mieloide Aguda/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Irmãos , Condicionamento Pré-Transplante , Transplante Haploidêntico/efeitos adversos , Doadores não RelacionadosRESUMO
Background: Exercise preconditioning (EP+) is a useful and important procedure for the prevention of stroke. We aimed to ascertain whether EP+ protects against ischemic brain injury by preserving heat shock protein (HSP) 72-containing neurons in ischemic brain tissues. Methods: Adult male Sprague-Dawley rats (n=240) were used to assess the contribution of HSP72-containing neurons to the neuroprotective effects of EP+ on ischemic brain injury caused by transient middle cerebral artery occlusion. Results: Significant (P<0.05) increases in the percentages of both old HSP72-containing neurons (NeuN+HSP72 double positive cells) (18~20% vs. 40~50%) and newly formed HSP72-containing neurons (BrdU+NeuN+HSP72 triple positive cells); (2~3% vs. 16~20%) after 3 weeks of exercise coincided with significant (P<0.05) reductions in brain ischemia volume (250 mm3 vs. 100 mm3), brain edema (78% vs. 74% brain water content), blood-brain barrier disruption (1.5 µg/g vs. 0.7 µg/g tissue Evans Blue dye extravasation) and neurological motor deficits (neurological severity scores of 12 vs. 6 and maximal angles of 60° vs. 20°) in brain ischemia rats. Reductions in the percentages of both old (from 40~50% to 10~12%) and newly formed (from 18~20% to 5~7%) HSP72-containing neurons by gene silencing with an intracerebral injection of pSUPER small interfering RNA showed a significant (P<0.05) reversal in the neuroprotective outcomes. Our data provide an inverse correlation between the EP+-mediated increases in both old and newly formed HSP72-containing neurons and the extent of cerebral ischemic injury. Conclusions: The percentages of both old and newly formed HSP72-containing neurons are inversely correlated with the outcomes of ischemic brain injury. Additionally, preischemic treadmill exercise improves the outcomes of ischemic brain injury by preserving both the old and newly formed HSP72-containing neurons in rats.
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Lesões Encefálicas/terapia , Isquemia Encefálica/terapia , Proteínas de Choque Térmico HSP72/genética , Condicionamento Físico Animal , Animais , Encéfalo/fisiopatologia , Lesões Encefálicas/etiologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores , Ratos , Ratos Sprague-DawleyRESUMO
In this paper, a hierarchical prosody model (HPM)-based method for Mandarin spontaneous speech is proposed. First, an HPM is designed for describing relations among acoustic features of utterances, linguistic features of texts, and prosodic tags representing the underlying hierarchical prosodic structures of utterances. Subsequently, a sequential optimization algorithm is employed to train the HPM based on a large conversational speech corpus, the Mandarin Conversational Dialogue Corpus (MCDC), which features orthographic transcriptions and prosodic event annotations. In this unsupervised training method, all utterances of the MCDC are labeled with two types of prosodic tags, namely, break and prosodic states, automatically and simultaneously. After training, the HPM parameters are examined to identify critical prosodic properties of Mandarin spontaneous speech, which are then compared with their counterparts in the read-speech HPM. The prosodic tags on the studied utterances enable mapping of various prosodic events onto the hierarchical prosodic structures of the utterances. Prosodic analyses of some disfluent events are conducted using the prosodic tags affixed to the MCDC. Finally, an application of the HPM to assist in Mandarin spontaneous-speech recognition is discussed. Significant relative error rate reductions of 9.0%, 9.2%, 15.6%, and 7.3% are obtained for base-syllable, character, tone, and word recognition, respectively.
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BACKGROUND/PURPOSE: Calycosin-7-O-ß-D-glucoside (CG), a calycosin derivative compound derived from Astragali Radix, has protective effect against ischemia/reperfusion injury as well as bacterial endotoxin-induced vascular cell injury. In the present study, we ascertained whether CG could reduce myocardial injury in heatstroke rats. METHODS: Heat stroke was induced by exposing anaesthetized rats to heat stress (43 °C for 70 min). Rats were given an i.p. dose of CG (26.8 mg/ml/kg) or vehicle solution (ml/kg) 15 min before the start of heat stress and immediately after termination of heat stress. Left ventricular performance, myocardial injury markers in the blood, and myocardial damage scores were assessed in heat stroke rats treated with or without CG. Additionally, cardiac levels of oxidative stress and inflammatory status were estimated simultaneously. RESULTS: At the time point of heat stroke onset, compared with normothermic controls, group rats with vehicle solution had significantly decreased survival rate, increased hyperthermia, decreased left ventricular stress markers, and increased cardiac damage scores. Compared with group rats with vehicle solution, group rats with CG had significantly improved survival rate, decreased hyperthermia, decreased cardiac ischemic, inflammatory, and oxidative damage. CONCLUSION: We thus conclude that myocardial injury can be a pressing need for the design of diagnostic and therapeutic modalities for heat stroke. In particular, our data indicate that CG protects against heat stroke in rats by mitigating myocardial injury.
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Medicamentos de Ervas Chinesas/farmacologia , Golpe de Calor/complicações , Isoflavonas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Astragalus propinquus , Medicamentos de Ervas Chinesas/química , Febre/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND & PURPOSE: Following traumatic brain injury (TBI), primary mechanical injury to the brain may cause blood-brain-barrier damage followed by secondary injury, ultimately culminating in cell death. We aimed to test whether one injection of mesenchymal stem cells (MSC) derived from the human umbilical cord can modulate brain cytokine and chemokine gene profiles and attenuate neurological injury in rats with TBI. METHODS: One-day post-TBI, the injured rats were treated with one injection of MSC (4 × 106/rat, i.v.). Three days later, immediately after assessment of neurobehavioral function, animals were sacrificed for analysis of neurological injury (evidenced by both brain contusion volume and neurological deficits) and parietal genes encoding 84 cytokines and chemokines in the injured brain by qPCR methods. RESULTS: Three days post-TBI, rats displayed both neurological injury and upgrade of 11 parietal genes in the ipsilateral brain. One set of 8 parietal genes (e.g., chemokine [C-X-C motif] ligand 12, platelet factor 4, interleukin-7, chemokine [C-C motif] ligand (CCL)19, CCL 22, secreted phosphoprotein 1, pro-platelet basic protein 1, and CCL 2) differentially upgraded by TBI was related to pro-inflammatory and/or neurodegenerative processes. Another set of 3 parietal genes up-graded by TBI (e.g., glucose-6-phosphate isomerase, bone morphogenetic protein (BMP) 2, and BMP 4) was related to anti-inflammatory/neuroregenerative events. Administration of MSC attenuated neurological injury, down-regulated these 8 parietal pro-inflammatory genes, and up-regulated these 3 parietal anti-inflammatory genes in the rats with TBI. CONCLUSION: Our data suggest that modulation of parietal cytokines and chemokines gene profiles by MSC as a basis for neurotrauma recovery.
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Lesões Encefálicas Traumáticas/terapia , Quimiocinas/genética , Citocinas/genética , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/genética , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Transcriptoma , Cordão Umbilical/citologiaRESUMO
BACKGROUND: Despite previous evidence for a potent inflammatory response after a traumatic brain injury (TBI), it is unknown whether exercise preconditioning (EP) improves outcomes after a TBI by modulating inflammatory responses. METHODS: We performed quantitative real-time PCR (qPCR) to quantify the genes encoding 84 cytokines and chemokines in the peripheral blood and used ELISA to determine both the cerebral and blood levels of interleukin-6 (IL-6). We also performed the chromatin immunoprecipitation (ChIP) assay to evaluate the extent of nuclear factor kappa-B (NF-κB) binding to the DNA elements in the IL-6 promoter regions. Also, we adopted the Western blotting assay to measure the cerebral levels of heat shock protein (HSP) 70, synapsin I, and ß-actin. Finally, we performed both histoimmunological and behavioral assessment to measure brain injury and neurological deficits, respectively. RESULTS: We first demonstrated that TBI upregulated nine pro-inflammatory and/or neurodegenerative messenger RNAs (mRNAs) in the peripheral blood such as CXCL10, IL-18, IL-16, Cd-70, Mif, Ppbp, Ltd, Tnfrsf 11b, and Faslg. In addition to causing neurological injuries, TBI also upregulated the following 14 anti-inflammatory and/or neuroregenerative mRNAs in the peripheral blood such as Ccl19, Ccl3, Cxcl19, IL-10, IL-22, IL-6, Bmp6, Ccl22, IL-7, Bmp7, Ccl2, Ccl17, IL-1rn, and Gpi. Second, we observed that EP inhibited both neurological injuries and six pro-inflammatory and/or neurodegenerative genes (Cxcl10, IL-18, IL-16, Cd70, Mif, and Faslg) but potentiated four anti-inflammatory and/or neuroregenerative genes (Bmp6, IL-10, IL-22, and IL-6). Prior depletion of cerebral HSP70 with gene silence significantly reversed the beneficial effects of EP in reducing neurological injuries and altered gene profiles after a TBI. A positive Pearson correlation exists between IL-6 and HSP70 in the peripheral blood or in the cerebral levels. In addition, gene silence of cerebral HSP70 significantly reduced the overexpression of NF-κB, IL-6, and synapsin I in the ipsilateral brain regions after an EP in rats. CONCLUSIONS: TBI causes neurological deficits associated with stimulating several pro-inflammatory gene profiles but inhibiting several anti-inflammatory gene profiles of cytokines and chemokines. Exercise protects against neurological injuries via stimulating an anti-inflammatory HSP70/NF-κB/IL-6/synapsin I axis in the injured brains.
Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Condicionamento Físico Animal/fisiologia , Sinapsinas/metabolismo , Animais , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/prevenção & controle , Masculino , Condicionamento Físico Animal/métodos , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
Cathepsin B is one of the major lysosomal cysteine proteases that plays an important role in apoptosis. Herein, we investigated whether Cathepsin B is involved in cardiomyocyte apoptosis caused by hyperthermic injury (HI) and heat shock protein (HSP)-70 protects these cells from HI-induced apoptosis mediated by Cathepsin. HI was produced in H9C2 cells by putting them in a circulating 43 °C water bath for 120 min, whereas preinduction of HSP-70 was produced in H9C2 cells by mild heat preconditioning (or putting them in 42 °C water bath for 30 min) 8 h before the start of HI. It was found that HI caused both cardiomyocyte apoptosis and increased Cathepsin B activity in H9C2 cells. E-64-c, in addition to reducing Cathepsin B activity, significantly attenuated HI-induced cardiomyocyte apoptosis (evidenced by increased apoptotic cell numbers, increased tuncated Bid (t-Bid), increased cytochrome C, increased caspase-9/-3, and decreased Bcl-2/Bax) in H9C2 cells. In addition, preinduction of HSP-70 by mild heat preconditioning or inhibition of HSP-70 by Tripolide significantly attenuated or exacerbated respectively both the cardiomyocyte apoptosis and increased Cathepsin B activity in H9C2 cells. Furthermore, the beneficial effects of pre-induction of HSP-70 by mild heat production in reducing both cardiomyocyte apoptosis and increased Cathepsin B activity caused by HI can be significantly reduced by Triptolide preconditioning. These results indicate that Cathepsin B is involved in HI-induced cardiomyocyte apoptosis in H9C2 cells and HSP-70 protects these cells from HI-induced cardiomyocyte apoptosis through Cathepsin B pathways.
Assuntos
Apoptose , Catepsina B/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Resposta ao Choque Térmico , Miócitos Cardíacos/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Temperatura Alta , Miócitos Cardíacos/citologia , Fenantrenos/farmacologia , RatosRESUMO
Intolerance to heat exposure is believed to be associated with hypothalamo-pituitary-adrenocortical (HPA) axis impairment [reflected by decreases in blood concentrations of both adrenocorticotrophic-hormone (ACTH) and corticosterone]. The purpose of this study was to determine the effect of human recombinant factor VIIa (rfVIIa) on heat intolerance, HPA axis impairment, and hypothalamic inflammation, ischemic and oxidative damage, and apoptosis in mice under heat stress. Immediately after heat stress (41.2 °C for 1 h), mice were treated with vehicle (1 mL/kg of body weight) or rfVIIa (65-270 µg/kg of body weight) and then returned to room temperature (26 °C). Mice still alive on day 4 of heat exposure were considered survivors. Cellular ischemia markers (e.g., glutamate, lactate-to-pyruvate ratio), oxidative damage markers (e.g., nitric oxide metabolite, hydroxyl radials), and pro-inflammatory cytokines (e.g., interleukin-6, interleukin-1ß, tumor necrosis factor-α) in hypothalamus were determined. In addition, blood concentrations of both ACTH and corticosterone were measured. Hypothalamic cell damage was assessed by determing the neuronal damage scores, whereas the hypothalamic cell apoptosis was determined by assessing the numbers of cells stained with terminal deoxynucleotidyl transferase-mediated αUTP nick-end labeling, caspase-3-positive cells, and platelet endothelial cell adhesion molecula-1-positive cells in hypothalamus. Compared with vehicle-treated heated mice, rfVIIa-treated heated mice had significantly higher fractional survival (8/10 vs 1/10), lesser thermoregulatory deficit (34.1 vs 24.8 °C), lesser extents of ischemic, oxidative, and inflammatory markers in hypothalamus, lesser neuronal damage scores and apoptosis in hypothalamus, and lesser HPA axis impairment. Human recombinant factor VIIa appears to exert a protective effect against heatstroke by attenuating hypothalamic cell apoptosis (due to ischemic, inflammatory, and oxidative damage) in mice.
Assuntos
Apoptose , Fator VIIa/metabolismo , Golpe de Calor/enzimologia , Hipotálamo/citologia , Neurônios/citologia , Animais , Caspase 3/metabolismo , Fator VIIa/genética , Golpe de Calor/genética , Golpe de Calor/fisiopatologia , Temperatura Alta , Humanos , Hipotálamo/enzimologia , Masculino , Camundongos , Neurônios/enzimologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND/PURPOSE: Repetitive hyperbaric oxygen (HBO2) therapy may cause excessive generation of reactive oxygen species. This study assessed whether repetitive or 2-4-day trials of HBO2 therapy (2 treatments daily for 2-4 consecutive days) provides better effects in reducing brain inflammation and oxidative stress caused by middle cerebral artery occlusion (MCAO) in rats than did a 1-day trial of HBO2 therapy (2 treatments for 1 day). METHODS: Rats were randomly divided into four groups: sham; MCAO without HBO2 treatment; MCAO treated with 1-day trial of HBO2; and MCAO treated with 2-4-day trials of HBO2. One treatment of HBO2 (100% O2 at 253 kPa) lasted for 1 hour in a hyperbaric chamber. RESULTS: Therapy with the 2-4-day trials of HBO2 significantly and dose-dependently attenuated the MCAO-induced cerebral infarction and neurological deficits more than the 1-day trial of HBO2 therapy. The beneficial effects of repetitive HBO2 therapy were associated with: (1) reduced inflammatory status in ischemic brain tissues (evidenced by decreased levels of tumor necrosis factor-α, interleukin-1ß, and myeloperoxidase activity); (2) decreased oxidative damage in ischemic brain tissues (evidenced by decreased levels of reactive oxygen and nitrogen species, lipid peroxidation, and enzymatic pro-oxidants, but increased levels of enzymatic antioxidant defenses); and (3) increased production of an anti-inflammatory cytokine, interleukin-10. CONCLUSION: The results provide the apparently contradictory finding that heightened oxygen tension reduced oxidative stress (and inflammation), which was reflected by increased antioxidant and decreased oxidant contents under focal cerebral ischemia.
Assuntos
Isquemia Encefálica/terapia , Encefalite/terapia , Oxigenoterapia Hiperbárica/métodos , Estresse Oxidativo , Animais , Isquemia Encefálica/metabolismo , Modelos Animais de Doenças , Encefalite/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Testicular hyperthermia has been noted in men who work in high ambient temperatures. Scrotal temperatures above the normal range caused germ cell loss in the testes and resulted in male subfertility. In adult male rats, exercising at a higher environmental temperature (36 °C with relative humidity of 50%, 52 min) caused exertional heat stroke (EHS) characterized by scrotal hyperthermia, impaired sperm quality, dysmorphology in testes, prostates and bladders, and erectile dysfunction. Here, we aim to ascertain whether hyperbaric oxygen preconditioning (HBOP: 100% O2 at 2.0 atm absolute [ATA] for 2 h daily for 14 days consequently before the onset of EHS) is able to prevent the problem of EHS-induced sterility, testes, prostates, and bladders dysmorphology and erectile dysfunction. At the end of exertional heat stress compared to normobaric air (NBA or non-HBOP) rats, the HBOP rats exhibited lower body core temperature (40 °C vs. 43 °C), lower scrotal temperature (34 °C vs. 36 °C), lower neurological severity scores (2.8 vs. 5.8), higher erectile ability, (5984 mmHg-sec vs. 3788 mmHg-sec), higher plasma testosterone (6.8 ng/mL vs. 3.5 ng/mL), lower plasma follicle stimulating hormone (196.3 mIU/mL vs. 513.8 mIU/mL), lower plasma luteinizing hormone (131 IU/L vs. 189 IU/L), lower plasma adrenocorticotropic hormone (5136 pg/mL vs. 6129 pg/mL), lower plasma corticosterone (0.56 ng/mL vs. 1.18 ng/mL), lower sperm loss and lower values of histopathological scores for epididymis, testis, seminal vesicle, prostate, and bladder. Our data suggest that HBOP reduces body core and scrotal hyperthermia and improves sperm loss, testis/prostate/bladder dysmorphology, and erectile dysfunction after EHS in rats.
Assuntos
Disfunção Erétil , Golpe de Calor , Oxigenoterapia Hiperbárica , Humanos , Adulto , Masculino , Ratos , Animais , Testículo/patologia , Temperatura , Disfunção Erétil/patologia , Sêmen , Espermatozoides , Golpe de Calor/complicações , Golpe de Calor/terapiaRESUMO
OBJECTIVE: Dasatinib and quercetin (D & Q) have demonstrated promise in improving aged-related pathophysiological dysfunctions in humans and mice. Herein we aimed to ascertain whether the heat stress (HS)-induced cognitive deficits in aged or even young adult male mice can be reduced by D & Q therapy. METHODS: Before the onset of HS, animals were pre-treated with D & Q or placebo for 3 consecutive days every 2 weeks over a 10-week period. Cognitive function, intestinal barrier permeability, and blood-brain barrier permeability were assessed. RESULTS: Compared to the non-HS young adult male mice, the HS young adult male mice or the aged male mice had significantly lesser extents of the exacerbated stress reactions, intestinal barrier disruption, endotoxemia, systemic inflammation and oxidative stress, blood-brain barrier disruption, hippocampal inflammation and oxidative stress, and cognitive deficits evaluated at 7 days post-HS. All the cognitive deficits and other syndromes that occurred in young adult HS mice or in aged HS mice were significantly attenuated by D & Q therapy (P < 0.01). Compared to the young adult HS mice, the aged HS mice had significantly (P < 0.01) higher severity of cognitive deficits and other related syndromes. CONCLUSIONS: First, our data show that aged male mice are more vulnerable to HS-induced cognitive deficits than those of the young adult male mice. Second, we demonstrate that a combination of D and Q therapy attenuates cognitive deficits in heat stressed aged or young adult male mice via broad normalization of the brain-gut-endotoxin axis function.
Assuntos
Barreira Hematoencefálica , Dasatinibe , Estresse Oxidativo , Quercetina , Animais , Masculino , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Quercetina/farmacologia , Quercetina/uso terapêutico , Camundongos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Resposta ao Choque Térmico/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Quimioterapia Combinada , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Cognição/efeitos dos fármacosRESUMO
BACKGROUND AND OBJECTIVES: Huddles among members of interdisciplinary medical teams involve short stand-up sessions and allow team members to focus on existing or emerging patient safety issues, thereby facilitating team communication. Hospital managers are able to recognize the current situation of the organization through patient safety attitudes, strengthen team members' awareness of patient safety, and improve the quality of health care. The purpose of this study was to determine the effects of huddles on improving team members' attitudes toward patient safety. METHODS: We used a quasi-experimental design and selected 2 adult wards with similar properties as the experimental and comparison groups by convenience sampling. Data collection was from December 1, 2021, to June 30, 2022, at a teaching hospital in central Taiwan. Team members of the ward performing huddles formed the experimental group, and they participated 2 times per week in 15-minute huddles from 8:15 to 8:30 am for a total of 4 weeks. The comparison group adopted the routine team care process. Both groups completed the Safety Attitudes Questionnaire during the pre- and post-tests of the study. RESULTS: The experimental group scored significantly higher in the post-test than in the pre-test in all aspects of safety attitudes, with the exception of stress recognition. These improved aspects were teamwork climate (76.47 ± 15.90 vs 83.29 ± 13.52, P < .001), safety climate (75.94 ± 16.14 vs 82.81 ± 13.74, P < .001), job satisfaction (74.34 ± 20.22 vs 84.40 ± 17.22, P <.001), perceptions of management (78.02 ± 19.99 vs 85.51 ± 15.97, P < .001), and working conditions (78.85 ± 17.87 vs 86.81 ± 14.74, P < .001). CONCLUSION: Through the huddles, clinical team members improved their understanding of different aspects of safety attitudes. Such a study provided ward units with real-time improvement and adjustment in terms of patient safety during their medical work processes with better patient safety.