RESUMO
Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that causes dysfunction of salivation and harmful oral conditions. The association between periodontal disease (PD) and pSS with or without geniquin therapy remains controversial. This study evaluated the association between geniquin therapy and the risk of subsequent development of PD in pSS patients. From Taiwan's National Health Insurance Research Database, we selected a control cohort of 106,818 pSS patients, followed up from 2000 to 2015, matched (1:4) by age and index year with 427,272 non-pSS patients. We also analyzed 15,149 pSS patients receiving geniquin therapy (cohort 1) and 91,669 pSS patients not receiving geniquin therapy (cohort 2). After adjusting for confounding factors, multivariate Cox proportional hazards regression analysis was used to compare the risk of PD over the 15-year follow-up. In the control cohort, 11,941 (11.2%) pSS patients developed PD compared to 39,797 (9.3%) non-pSS patients. In cohorts 1 and 2, 1,914 (12.6%) pSS patients receiving geniquin therapy and 10,027 (10.9%) pSS patients not receiving geniquin therapy developed PD. The adjusted hazard ratio (HR) for subsequent PD in pSS patients was 1.165 (95% confidence interval [CI] = 1.147-1.195, p < 0.001) and in pSS patients receiving geniquin therapy was 1.608 (95% CI = 1.526-1.702, p < 0.001). The adjusted HR for PD treatment was 1.843. Patients diagnosed with pSS showed an increased risk of developing subsequent PD and receiving PD treatment than patients without pSS, while pSS patients receiving geniquin therapy showed even higher risks.
Assuntos
Doenças Periodontais , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/epidemiologia , Síndrome de Sjogren/tratamento farmacológico , Taiwan/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Doenças Periodontais/complicações , Doenças Periodontais/epidemiologia , Estudos de Coortes , Idoso , Fatores de Risco , Modelos de Riscos ProporcionaisRESUMO
Oral squamous cell carcinoma (OSCC) can arise anywhere in the oral cavity. OSCC's molecular pathogenesis is complex, resulting from a wide range of events that involve the interplay between genetic mutations and altered levels of transcripts, proteins, and metabolites. Platinum-based drugs are the first-line treatment for OSCC; however, severe side-effects and resistance are challenging issues. Thus, there is an urgent clinical need to develop novel and/or combinatory therapeutics. In this study, we investigated the cytotoxic effects of pharmacological concentrations of ascorbate on two human oral cell lines, the oral epidermoid carcinoma meng-1 (OECM-1) cell and the Smulow-Glickman (SG) human normal gingival epithelial cell. Our study examined the potential functional impact of pharmacological concentrations of ascorbates on the cell-cycle profiles, mitochondrial-membrane potential, oxidative response, the synergistic effect of cisplatin, and the differential responsiveness between OECM-1 and SG cells. Two forms of ascorbate, free and sodium forms, were applied to examine the cytotoxic effect and it was found that both forms had a similar higher sensitivity to OECM-1 cells than to SG cells. In addition, our study data suggest that the determinant factor of cell density is important for ascorbate-induced cytotoxicity in OECM-1 and SG cells. Our findings further revealed that the cytotoxic effect might be mediated through the induction of mitochondrial reactive oxygen species (ROS) generation and the reduction in cytosolic ROS generation. The combination index supported the agonistic effect between sodium ascorbate and cisplatin in OECM-1 cells, but not in SG cells. In summary, our current findings provide supporting evidence for ascorbate to serve as a sensitizer for platinum-based treatment of OSCC. Hence, our work provides not only repurposing of the drug, ascorbate, but also an opportunity to decrease the side-effects of, and risk of resistance to, platinum-based treatment for OSCC.
Assuntos
Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias Bucais , Humanos , Cisplatino/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Carcinoma de Células Escamosas/patologia , Ácido Ascórbico/farmacologia , Neoplasias Bucais/patologia , Antineoplásicos/farmacologia , Estresse Oxidativo , Linhagem Celular Tumoral , ApoptoseRESUMO
Hyperphosphatemia can occur as a result of reduced phosphate (Pi) excretion in cases of kidney dysfunction, which can induce muscle wasting and suppress myogenic differentiation. Higher Pi suppresses myogenic differentiation and promotes muscle atrophy through canonical (oxidative stress-mediated) and noncanonical (p62-mediated) activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. However, the crosstalk between myogenin and Nrf2/p62 and potential drug(s) for the regulation of myogenin expression needed to be addressed. In this study, we further identified that myogenin may negatively regulate Nrf2 and p62 protein levels in the mouse C2C12 muscle cell line. In the drug screening analysis, we identified N-acetylcysteine, metformin, phenformin, berberine, 4-chloro-3-ethylphenol, cilostazol, and cilomilast as ameliorating the induction of Nrf2 and p62 expression and reduction in myogenin expression that occur due to high Pi. We further elucidated that doxorubicin and hydrogen peroxide reduced the amount of myogenin protein mediated through the Kelch-like ECH-associated protein 1/Nrf2 pathway, differently from the mechanism of high Pi. The dual functional roles of L-ascorbic acid (L-AA) were found to be dependent on the working concentration, where concentrations below 1 mM L-AA reversed the effect of high Pi on myogenin and those above 1 mM L-AA had a similar effect of high Pi on myogenin when used alone. L-AA exacerbated the effect of hydrogen peroxide on myogenin protein and had no further effect of doxorubicin on myogenin protein. In summary, our results further our understanding of the crosstalk between myogenin and Nrf2, with the identification and verification of several potential drugs that can be applied in rescuing the decline of myogenin due to high Pi in muscle cells.
Assuntos
Peróxido de Hidrogênio , Fator 2 Relacionado a NF-E2 , Animais , Camundongos , Ácido Ascórbico/farmacologia , Doxorrubicina/farmacologia , Peróxido de Hidrogênio/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/metabolismo , Miogenina/genética , Miogenina/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais/fisiologiaRESUMO
MYC has a short half-life that is tightly regulated through phosphorylation and proteasomal degradation. Many studies have claimed that treatment with disulfiram (DSF) with or without copper ions can cause cancer cell death in a reactive oxygen species (ROS)-dependent manner in cancer cells. Our previous study showed that the levels of c-Myc protein and the phosphorylation of threonine 58 (T58) and serine 62 (S62) increased in DSF-Cu-complex-treated oral epidermoid carcinoma Meng-1 (OECM-1) cells. These abovementioned patterns were suppressed by pretreatment with an ROS scavenger, N-acetyl cysteine. The overexpression of c-Myc failed to induce hypoxia-inducible factor 1α protein expression, which was stabilized by the DSF-Cu complex. In this study, we further examined the regulatory mechanism behind the induction of the c-Myc of the DSF-Cu complex in an OECM-1 cell compared with a Smulow-Glickman (SG) human normal gingival epithelial cell. Our data showed that the downregulation of c-Myc truncated nick and p62 and the induction of the ratio of H3P/H3 and p-ERK/ERK might not be involved in the increase in the amount of c-Myc via the DSF/copper complexes in OECM-1 cells. Combined with the inhibitors for various signaling pathways and cycloheximde treatment, the increase in the amount of c-Myc with the DSF/copper complexes might be mediated through the increase in the stabilities of c-Myc (T58) and c-Myc (S62) proteins in OECM-1 cells. In SG cells, only the c-Myc (T58) protein was stabilized by the DSF-Cu (I and II) complexes. Hence, our findings could provide novel regulatory insights into the phosphorylation-dependent stability of c-Myc in DSF/copper-complex-treated oral squamous cell carcinoma.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Cobre/metabolismo , Cobre/farmacologia , Dissulfiram/farmacologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Fosforilação , Proteínas Proto-Oncogênicas c-myc/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina/metabolismo , Treonina/metabolismoRESUMO
This study investigates an association between oral cancers and the risk of developing depression. We conducted a total of 3031 patients with newly diagnosed oral cancers and 9093 age-, sex-, and index year-matched controls (1:3) from 2000 to 2013 were selected from the National Health Insurance Research Database (NHIRD) of Taiwan. After adjusting for confounding factors, multivariate Cox proportional hazards analysis was used to compare the risk of depression over a 13-year follow-up. Of the patients with oral cancer, 69 (2.28%, or 288.57 per 105 person-years) developed depression compared to 150 (1.65%, 135.64 per 105 person-years) in the control group. The Cox proportional hazards regression analysis showed that the adjustment hazard ratio (HR) for subsequent depression in patients with oral cancer diagnosed was 2.224 (95% Confidence Interval [CI] 1.641-3.013, p < 0.001). It is noteworthy that in the sensitivity analysis is the adjusted HR in the group with depression diagnosis was 3.392 and in the oral cancer subgroup of "Tongue" was 2.539. This study shows oral cancer was associated with a significantly increased risk for developing subsequent depression and early identification and treatment of depression in oral cancer patients is crucial.
Assuntos
Depressão/etiologia , Neoplasias Bucais/complicações , Neoplasias Bucais/psicologia , Adulto , Idoso , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Análise de Regressão , Fatores de Risco , Taiwan , Adulto JovemRESUMO
Disulfiram (DSF), an irreversible aldehyde dehydrogenase inhibitor, is being used in anticancer therapy, as its effects in humans are known and less adverse than conventional chemotherapy. We explored the potential mechanism behind the cytotoxicity of DSF-Cu+/Cu2+ complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl2 or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu+/Cu2+ induced cell death in OECM-1 cells, but not SG cells. DSF-Cu+/Cu2+ also increased the subG1 population and decreased the G1, S, and G2/M populations in OECM-1 cells, but not SG cells, and suppressed cell proliferation in both OECM-1 and SG cells. ALDH enzyme activity was inhibited by CuCl and DSF-Cu+/Cu2+ in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu+/Cu2+-treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu+/Cu2+ induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl2 increased but DSF- Cu2+ impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl2 stabilized HIF-1α expression under normoxia in OECM-1 cells, and complex with DSF enhanced that effect. Levels of c-Myc protein and its phosphorylation at Tyr58 and Ser62 were increased, while levels of the N-terminal truncated form (Myc-nick) were decreased in DSF-Cu+/Cu2-treated OECM-1 cells. These effects were all suppressed by pretreatment with the ROS scavenger NAC. Overexpression of c-Myc failed to induce HIF-1α expression. These findings provide novel insight into the potential application of DSF-CuCl2 complex as a repurposed agent for OSCC cancer therapy.
Assuntos
Inibidores de Acetaldeído Desidrogenases/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cobre/uso terapêutico , Dissulfiram/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Inibidores de Acetaldeído Desidrogenases/química , Inibidores de Acetaldeído Desidrogenases/farmacologia , Carcinoma de Células Escamosas/metabolismo , Cobre/química , Dissulfiram/química , Dissulfiram/farmacologia , Reposicionamento de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/efeitos dos fármacos , Neoplasias Bucais/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
In recent years, L-ascorbic acid (L-AA), or vitamin C, has been attracting attention as a potential anticancer drug that mediates hydrogen peroxide-induced oxidation and ten-eleven translocation 2-catalyzed DNA demethylation. However, the precise mechanism by which L-AA acts remains unclear. We examined the cytotoxic effects of L-AA or sodium ascorbate in human cervical carcinoma cells by assessing cell viability, expression of cell cycle-related mRNAs and proteins, and mitochondrial functions, and by performing flow cytometric analyses of cell cycle profiles, apoptosis, cell proliferation, and production of reactive oxygen species (ROS). We later tested the effects of ascorbates in combination with two first-line chemotherapeutic drugs, cisplatin, and doxorubicin. At pharmacological concentrations (1-10 mM), L-AA increased ROS levels; decreased levels of several cell cycle-related proteins, including p53, p21, cyclin D1, and phosphorylated histone 3 at serine residue 10; induced DNA damage, as indicated by changes in γH2A.x; decreased levels of the anti-oxidative transcription factor Nrf2; and increased levels of catalase, superoxide dismutase 1, and endoplasmic reticulum stress-related indicators, such as the p-eIF2α/eIF2α ratio and CHOP levels. L-AA also promoted cell proliferation and induced apoptosis and mitochondrial dysfunction. Finally, L-AA increased the susceptibility of HeLa cells to cisplatin and doxorubicin. These findings provide insight into how the adjustment of the cellular ROS status through L-ascorbate (L-AA or sodium ascorbate) administration could potentially synergistically enhance the efficacy of cancer therapies.
RESUMO
OBJECTIVE: Homeostasis of intracellular pH (pHi) plays vital roles in many cell functions, such as proliferation, apoptosis, differentiation and metastasis. Thus far, Na+-H+ exchanger (NHE), Na+-HCO3- co-transporter (NBC), Cl-/HCO3- exchanger (AE) and Cl-/OH- exchanger (CHE) have been identified to co-regulate pHi homeostasis. However, functional and biological pHi-regulators in human dental pulp stem cells (hDPSCs) have yet to be identified. DESIGN: Microspectrofluorimetry technique with pH-sensitive fluorescent dye, BCECF, was used to detect pHi changes. NH4Cl and Na+-acetate pre-pulse were used to induce intracellular acidosis and alkalosis, respectively. Isoforms of pHi-regulators were detected by Western blot technique. RESULTS: The resting pHi was no significant difference between that in HEPES-buffered (nominal HCO3--free) solution or CO2/HCO3-buffered system (7.42 and 7.46, respectively). The pHi recovery following the induced-intracellular acidosis was blocked completely by removing [Na+]o, while only slowed (-63%) by adding HOE694 (a NHE1 specific inhibitor) in HEPES-buffered solution. The pHi recovery was inhibited entirely by removing [Na+]o, while adding HOE 694 pulse DIDS (an anion-transporter inhibitor) only slowed (-55%) the acid extrusion. Both in HEPES-buffered and CO2/HCO3-buffered system solution, the pHi recovery after induced-intracellular alkalosis was entirely blocked by removing [Cl-]o. Western blot analysis showed the isoforms of pHi regulators, including NHE1/2, NBCe1/n1, AE1/2/3/4 and CHE in the hDPSCs. CONCLUSIONS: We demonstrate for the first time that resting pHi is significantly higher than 7.2 and meditates functionally by two Na+-dependent acid extruders (NHE and NBC), two Cl--dependent acid loaders (CHE and AE) and one Na+-independent acid extruder(s) in hDPSCs. These findings provide novel insight for basic and clinical treatment of dentistry.
Assuntos
Equilíbrio Ácido-Base/fisiologia , Citoplasma/metabolismo , Polpa Dentária/metabolismo , Homeostase/fisiologia , Células-Tronco/metabolismo , Desequilíbrio Ácido-Base , Ácidos/farmacologia , Cloreto de Amônio , Antiporters/metabolismo , Apoptose , Soluções Tampão , Diferenciação Celular , Proliferação de Células , Citoplasma/efeitos dos fármacos , Guanidinas/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Bombas de Íon/efeitos dos fármacos , Bombas de Íon/metabolismo , Metástase Neoplásica , Isoformas de Proteínas , Sódio/farmacologia , Simportadores de Sódio-Bicarbonato/metabolismo , Trocador 1 de Sódio-Hidrogênio/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Células-Tronco/efeitos dos fármacos , Sulfonas/farmacologiaRESUMO
Allergic rhinitis (AR) is associated with various developmental issues that affecting dentition. We aimed to determine whether AR is associated with an increased risk of traumatic dental injuries (TDIs) in Taiwanese individuals. We used the Taiwan National Health Insurance Research Database (NHIRD) to conduct a nested case-control study. We compared an AR cohort with a matched cohort of patients without AR. New TDI cases were determined during our study period. To compare TDI risk between our study cohorts, we used Cox proportional regression analysis, and hazard ratios (HR) with 95% confidence intervals (CI) were calculated to quantify the association between AR exposure and TDI risk. In total, 76749 patients with AR (31715 male; 45034 female) were identified. In the AR and the non-AR cohorts, 312 patients in total had TDI. Patients with AR had a significantly higher risk of TDI than those without AR (aHR = 1.92; 95% CI = 1.459-2.525; P < 0.001). The risk of TDI was markedly higher in the AR cohort, except in the 3-12-year-old group, and with a CCI ≥ 1. AR patients had a future risk of TDI, indicating a potentially linked disease pathophysiology. The association between AR and TDI is greater among general patients. Clinicians and caregivers should be aware of potential TDI co-morbidity in patients with AR.
Assuntos
Rinite Alérgica/epidemiologia , Traumatismos Dentários/epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , TaiwanRESUMO
Anxiety is one of the most frequently diagnosed emotional disorders after a mild traumatic brain injury (mTBI); however, predictors of anxiety after an mTBI remain uncertain. Recent research indicated that anxiety is associated with abnormalities in the autonomic nervous system (ANS) which can be evaluated by a power spectral analysis of heart rate variability (HRV). In this study, we investigated whether a frequency-domain analysis of HRV could correlate with the occurrence of anxiety in mTBI patients. We recruited 165 Taiwanese patients diagnosed with an mTBI and 82 volunteer healthy controls from three affiliated hospitals of Taipei Medical University during 2010-2014. The Beck Anxiety Inventory (BAI) was assessed at the 1st, 6th, and 12th weeks. We found that mTBI patients were more vulnerable to anxiety compared to healthy controls. The power spectral density of HRV was significantly lower in mTBI patients than in healthy controls. A correlation analysis indicated that anxiety was negatively significantly correlated with low- and high-frequency power at the 6th week. Our study suggests the clinical usefulness of HRV as a potential noninvasive tool for evaluating later anxiety in mTBI patients.
Assuntos
Ansiedade/diagnóstico , Ansiedade/fisiopatologia , Concussão Encefálica/diagnóstico , Concussão Encefálica/fisiopatologia , Frequência Cardíaca/fisiologia , Adulto , Ansiedade/epidemiologia , Sistema Nervoso Autônomo/fisiopatologia , Concussão Encefálica/epidemiologia , Feminino , Seguimentos , Análise de Fourier , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Patients who have experienced a mild traumatic brain injury (mTBI) are susceptible to symptoms of anxiety or depression. To explore the potential biomarkers for emotional disorders in mTBI patients, we analyzed the frequency domain of heart rate variability (HRV) and serum concentrations of four neurohormones. METHODS: We assessed mTBI patients on their first visit and follow-up. Symptoms were evaluated by the Beck Anxiety Inventory and the Beck Depression Inventory, respectively. Serum levels of adrenocorticotropic hormone (ACTH), melatonin, cortisol, and insulin-like growth factor (IGF)-1 and HRV follow-ups were measured and compared. RESULTS: mTBI patients were more vulnerable to symptoms of anxiety or depression than healthy controls. Reduced HRV was noted in mTBI patients compared to healthy controls. The mTBI patients demonstrated higher serum levels of ACTH, lower IGF-1 compared to healthy controls. In correlation analysis, only IGF-1 was positively correlated with HRV in mTBI patients. Both HRV and IGF-1 were correlated with symptom of depression while only HRV was correlated with symptom of anxiety in mTBI patients. CONCLUSIONS: We infer that HRV may be more significantly correlated with emotional disorders than is IGF-1 in mTBI patients. SIGNIFICANCE: The study is relevant for specific diagnostic markers in mTBI patients.
Assuntos
Ansiedade/sangue , Lesões Encefálicas/sangue , Depressão/sangue , Frequência Cardíaca/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Adulto , Sintomas Afetivos/sangue , Sintomas Afetivos/diagnóstico , Sintomas Afetivos/psicologia , Ansiedade/diagnóstico , Ansiedade/psicologia , Biomarcadores/sangue , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/psicologia , Estudos de Coortes , Depressão/diagnóstico , Depressão/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/sangue , Transtornos do Humor/diagnóstico , Transtornos do Humor/psicologia , Adulto JovemRESUMO
Depression is one of the frequent complications following a mild traumatic brain injury (mTBI). Recent research indicated that abnormalities in the autonomic nervous system (ANS) can be evaluated by a noninvasive power spectral analysis of the heart rate variability (HRV). In this study, we investigated whether a frequency-domain analysis of HRV was correlated with late depression in mTBI patients. In total, 181 patients diagnosed with mTBI and 83 volunteers as healthy controls were recruited in 2010-2014. Beck Depression Inventory (BDI) scores were used to evaluate depression in the 1st week of assessment and at 1.5-, 3-, 6-, 12-, and 18-month follow-ups. Correlation and logistic regression analyses of the 1st week HRV parameters with BDI scores at 18 months were performed in individual female mTBI patients. Female mTBI patients were more vulnerable to depression accompanied by reduced HRV compared to healthy controls. Over time, depression was aggravated in female mTBI patients but was alleviated in male mTBI patients. A significantly lower parasympathetic proportion of the ANS was noted at 18 months with respect to the 1st week in female mTBI patients. In addition, depression in female mTBI patients at 18 months after injury was significantly correlated with a decrease in the parasympathetic proportion of the ANS in the 1st week (ρ = -0.411; p < .05). Dysautonomia resulted in higher risks of depression in female mTBI patients. We concluded that early dysautonomia following an mTBI contributes to late depression in female mTBI patients.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Lesões Encefálicas Traumáticas/complicações , Transtorno Depressivo/etiologia , Frequência Cardíaca/fisiologia , Disautonomias Primárias/diagnóstico , Adulto , Lesões Encefálicas Traumáticas/fisiopatologia , Transtorno Depressivo/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Disautonomias Primárias/complicações , Disautonomias Primárias/fisiopatologia , Fatores Sexuais , Adulto JovemRESUMO
This study determines whether acute respiratory distress syndrome (ARDS) is an independent risk factor for an increased risk of post-traumatic brain injury (TBI) stroke during 3-month, 1-year, and 5-year follow-ups, respectively, after adjusting for other covariates. Clinical data for the analysis were from the National Health Insurance Database 2000, which covered a total of 2121 TBI patients and 101 patients with a diagnosis of TBI complicated with ARDS (TBI-ARDS) hospitalized between January 1, 2001 and December 31, 2005. Each patient was tracked for 5 years to record stroke occurrences after discharge from the hospital. The prognostic value of TBI-ARDS was evaluated using a multivariate Cox proportional hazard model. The main outcome found that stroke occurred in nearly 40% of patients with TBI-ARDS, and the hazard ratio for post-TBI stroke increased fourfold during the 5-year follow-up period after adjusting for other covariates. The increased risk of hemorrhagic stroke in the ARDS group was considerably higher than in the TBI-only cohort. This is the first study to report that post-traumatic ARDS yielded an approximate fourfold increased risk of stroke in TBI-only patients. We suggest intensive and appropriate medical management and intensive follow-up of TBI-ARDS patients during the beginning of the hospital discharge.
Assuntos
Lesões Encefálicas Traumáticas/epidemiologia , Hemorragias Intracranianas/epidemiologia , Síndrome do Desconforto Respiratório/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Adulto , Idoso , Lesões Encefálicas Traumáticas/complicações , Feminino , Seguimentos , Humanos , Hemorragias Intracranianas/etiologia , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/estatística & dados numéricos , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/etiologia , Acidente Vascular Cerebral/etiologia , Taiwan/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The presence of intracellular pH (pHi ) regulators, including Na(+) -H(+) exchanger (NHE), Na(+) -HCO3- co-transporter (NBC), Cl(-) /OH(-) exchanger (CHE), and Cl(-) /HCO3- exchanger (AE), have been confirmed in many mammalian cells. Alcohol consumption is associated with increased risk of cardiovascular disorder. The aims of the study were to identify the possible transmembrane pHi regulators and to explore the effects of ethanol (EtOH) (10 to 300 mM) on the resting pHi and pHi regulators in human aorta smooth muscle cells (HASMCs). METHODS: HASMCs were obtained from patients undergoing heart transplant. The pHi was measured by microspectrofluorimetry with the pH-sensitive dye, BCECF-AM. RESULTS: The following results are obtained. (i) In cultured HASMCs, the resting pHi was 7.19 ± 0.04 and 7.13 ± 0.02 for HEPES- and CO2 /HCO3--buffered solution, respectively. (ii) Two different Na(+) -dependent acid-equivalent extruders, including NHE and Na(+) -coupled HCO3- transporter, functionally coexisted. (iii) Two different Cl(-) -dependent acid loaders (CHE and AE) were functionally identified. (iv) EtOH induced a biphasic, concentration-dependent change in resting pHi (+0.25 pH unit at 100 mM but only +0.05 pH unit at 300 mM) in bicarbonate-buffered solution, while caused a concentration-dependent decrease in resting pHi (-0.06 pH unit at 300 mM) in HEPES-buffered solution. (v) The effect of EtOH on NHE activity was also biphasic: increase of 40% at lower concentration of 10 mM, followed by decrease of 30% at higher concentration of 300 mM. (vi) The increase in Na(+) -coupled HCO3- transporter activity by EtOH was concentration dependent. (vii) The effect of EtOH on CHE and AE activities was both biphasic: increase of ~25% at 30 mM, followed by decrease of 10 to 25% at 100 mM, and finally increase of 15 to 20% at 300 mM. CONCLUSIONS: This study demonstrated that 2 acid extruders and 2 acid loaders coexisted functionally in HASMCs and that EtOH induced a biphasic, concentration-dependent change in resting pHi by altering the activity of the 2 acid extruders, NHE and Na(+) -coupled HCO3- transporter, and the 2 acid loaders, CHE and AE.
Assuntos
Aorta/fisiologia , Etanol/farmacologia , Membranas Intracelulares/fisiologia , Proteínas de Membrana Transportadoras/fisiologia , Miócitos de Músculo Liso/fisiologia , Aorta/efeitos dos fármacos , Células Cultivadas , Antiportadores de Cloreto-Bicarbonato/fisiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Membranas Intracelulares/efeitos dos fármacos , Masculino , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Trocadores de Sódio-Hidrogênio/fisiologiaRESUMO
Acute lung injury (ALI) occurs frequently in patients with severe traumatic brain injury (TBI) and is associated with a poor clinical outcome. Aquaporins (AQPs), particularly AQP1 and AQP4, maintain water balances between the epithelial and microvascular domains of the lung. Since pulmonary edema (PE) usually occurs in the TBI-induced ALI patients, we investigated the effects of a thaliporphine derivative, TM-1, on the expression of AQPs and histological outcomes in the lung following TBI in rats. TM-1 administered (10 mg/kg, intraperitoneal injection) at 3 or 4 h after TBI significantly reduced the elevated mRNA expression and protein levels of AQP1 and AQP4 and diminished the wet/dry weight ratio, which reflects PE, in the lung at 8 and 24 h after TBI. Postinjury TM-1 administration also improved histopathological changes at 8 and 24 h after TBI. PE was accompanied with tissue pathological changes because a positive correlation between the lung injury score and the wet/dry weight ratio in the same animal was observed. Postinjury administration of TM-1 improved ALI and reduced PE at 8 and 24 h following TBI. The pulmonary-protective effect of TM-1 may be attributed to, at least in part, downregulation of AQP1 and AQP4 expression after TBI.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Aporfinas/administração & dosagem , Lesões Encefálicas/tratamento farmacológico , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/fisiopatologia , Animais , Aquaporina 1/biossíntese , Aquaporina 1/genética , Aquaporina 4/biossíntese , Aquaporina 4/genética , Lesões Encefálicas/complicações , Lesões Encefálicas/fisiopatologia , Expressão Gênica/efeitos dos fármacos , Humanos , RatosRESUMO
Surgical brain injury (SBI) is unavoidable during many neurosurgical procedures intrinsically linked to postoperative neurological deficits. We have previously demonstrated that implantation of collagen glycosaminoglycan (CG) following surgical brain injury could significantly promote functional recovery and neurogenesis. In this study we further hypothesized that this scaffold may provide a microenvironment by promoting angiogenesis to favor neurogenesis and subsequent functional recovery. Using the rodent model of surgical brain injury as we previously established, we divided Sprague-Dawley male rats (weighting 300-350 g) into three groups: (1) sham (2) surgical injury with a lesion (L), and (3) L with CG matrix implantation (L + CG). Our results demonstrated that L + CG group showed a statistically significant increase in the density of vascular endothelial cells and blood vessels over time. In addition, tissue concentrations of angiogenic growth factors (such as VEGF, FGF2, and PDGF) significantly increased in L + CG group. These results suggest that implantation of a CG scaffold can promote vascularization accompanied by neurogenesis. This opens prospects for use of CG scaffolds in conditions such as brain injury including trauma and ischemia.
Assuntos
Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Colágeno/farmacologia , Glicosaminoglicanos/farmacologia , Complicações Intraoperatórias/etiologia , Neovascularização Fisiológica/efeitos dos fármacos , Implantação de Prótese , Animais , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Complicações Intraoperatórias/patologia , Imageamento por Ressonância Magnética , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos Sprague-Dawley , Alicerces Teciduais/químicaRESUMO
Neonatal seizures may alter the developing neurocircuitry and cause behavioral abnormalities in adulthood. We found that rats previously subjected to lithium-pilocarpine (LiPC)-induced neonatal status epilepticus (NeoSE) exhibited enhanced behavioral sensitization to methamphetamine (MA) in adolescence. Neurochemically, dopamine (DA) and metabolites were markedly decreased in prefrontal cortex (PFC) and insignificantly changed in striatum by NeoSE, but were increased in both PFC and striatum by NeoSE+MA. Glutamate levels were increased in both PFC and striatum in the NeoSE+MA group. DA turnover, an index of utilization and activity, was increased by NeoSE but reversed by MA in PFC. Gene expression of the regulator of G-protein signaling 4 (RGS4) was downregulated in PFC and striatum by NeoSE and further suppressed by MA. These findings suggest NeoSE affects both dopaminergic and glutamatergic systems in the prefrontal-striatal circuitry that manifests as enhanced behavioral sensitization to MA in adolescence.