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OBJECTIVES: Matrix metalloproteinase-9 (MMP-9) is an inducible metalloproteinase that can degrade the cerebrovascular matrix leading to disruption of the blood-brain barrier and exacerbation of oedema in neurotrauma. Therefore, our aim was to determine whether MMP-9 plasma levels were associated with intensive care unit (ICU) mortality after severe traumatic brain injury (TBI) despite the presence of extracerebral injuries. METHODS: This cohort enrolled 80 patients who suffered severe TBI (Glasgow Coma Scale: 3-8 at hospital admission). The plasma MMP-9 level was determined by enzyme-linked immunosorbent assay assay at ICU admission. RESULTS: Severe TBI was associated with a 32.5% ICU mortality rate. There was no association between the presence of extracerebral injuries (72.5% of the patients) and ICU mortality (P = 0.419). Higher plasma MMP-9 concentrations were associated with fatal outcome: 181.1 ± 16.0 ng/mL for survivors and 257.0 ± 23.2 ng/mL for nonsurvivors (mean ± S.E.M., P = 0.009). In contrast, there was no significant difference between MMP-9 levels and associated lesions: 220.8 ± 26.3 ng/mL for isolated TBI and 196.8 ± 15.8 ng/mL for patients with extracerebral injuries (P = 0.397). CONCLUSION: Increased plasma MMP-9 levels predicted short-term fatal outcome following severe TBI, regardless the presence of extracerebral injuries.
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Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/mortalidade , Unidades de Terapia Intensiva , Metaloproteinase 9 da Matriz/sangue , Adolescente , Adulto , Criança , Estudos de Coortes , Escala de Coma de Glasgow , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Adulto JovemRESUMO
Traumatic brain injury (TBI) is a major cause of morbidity and mortality among young individuals worldwide. Understanding the pathophysiology of neurotrauma is crucial for the development of more effective therapeutic strategies. After the trauma occurs, immediate neurologic damage is produced by the traumatic forces; this primary injury triggers a secondary wave of biochemical cascades together with metabolic and cellular changes, called secondary neural injury. In the scenario of the acutely injured brain, the ongoing secondary injury results in ischemia and edema culminating in an uncontrollable increase in intracranial pressure. These areas of secondary injury progression, or areas of "traumatic penumbra", represent crucial targets for therapeutic interventions. Neurotrophins are a class of signaling molecules that promote survival and/or maintenance of neurons. They also stimulate axonal growth, synaptic plasticity, and neurotransmitter synthesis and release. Therefore, this review focuses on the role of neurotrophins in the acute post-injury response. Here, we discuss possible endogenous neuroprotective mechanisms of neurotrophins in the prevailing environment surrounding the injured areas, and highlight the crosstalk between neurotrophins and inflammation with focus on neurovascular unit cells, particularly pericytes. The perspective is that neurotrophins may represent promising targets for research on neuroprotective and neurorestorative processes in the short-term following TBI.
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Lesões Encefálicas/metabolismo , Inflamação/metabolismo , Fatores de Crescimento Neural/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Pressão Intracraniana/fisiologiaRESUMO
OBJECTIVE: Severe traumatic brain injury (TBI) is associated with a 30-70% mortality rate. Nevertheless, in clinical practice there are no effective biomarkers for the prediction of fatal outcome following severe TBI. Therefore, the aim was to determine whether brain-derived neurotrophic factor (BDNF) plasma levels are associated with intensive care unit (ICU) mortality in patients with severe TBI. METHODS: This prospective study enrolled 120 male patients who suffered severe TBI (Glasgow Coma Scale 3-8 at emergency room admission). The plasma BDNF level was determined at ICU admission (mean 6.4 hours after emergency room admission). RESULTS: Severe TBI was associated with a 35% mortality rate and 64% of the patients presented severe TBI with multi-trauma. The mean plasma BDNF concentration among the severe TBI victims was 704.2 ± 63.4 pg ml(-1) (±SEM). Nevertheless, there were no significant differences between BDNF levels in the survivor (700.2 ± 82.8 pg ml(-1)) or non-survivor (711.6 ± 97.4 pg ml(-1)) groups (p = 0.238) or in the isolated TBI (800.4 ± 117.4 pg ml(-1)) or TBI with multi-trauma groups (650.5 ± 73.9 pg ml(-1)) (p = 0.109). CONCLUSIONS: Plasma BDNF concentrations did not correlate with either short-term fatal outcome or type of injury following severe TBI.
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Lesões Encefálicas Traumáticas/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Adulto , Biomarcadores/sangue , Escala de Coma de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Resultado do TratamentoRESUMO
OBJECTIVES: Severe traumatic brain injury (TBI) is associated with a 30-70% mortality rate. Nevertheless, in clinical practice there are no effective biomarkers for the prediction of fatal outcome following severe TBI. Therefore, the aim was to determine whether ferritin serum levels are associated with ICU mortality in patients with severe TBI. METHODS: This prospective study enrolled 69 male patients who suffered severe TBI [Glasgow Coma Scale (GCS) 3-8 at emergency room admission]. The serum ferritin protein level was determined at ICU admission (mean 5.6 ± 2.5 hours after emergency room admission). RESULTS: Severe TBI was associated with a 39% mortality rate. Higher serum ferritin concentrations were significantly associated with lower hospital admission GCS scores (p = 0.049). Further, there was a significant association between higher ferritin concentrations and fatal outcome (289.5 ± 27.1 µg L(-1) for survivors and 376.5 ± 31.5 µg L(-1) for non-survivors, respectively, mean ± SEM, p = 0.032). CONCLUSIONS: Increased serum ferritin levels were associated with lower hospital admission GCS scores and predicted short-term fatal outcome following severe TBI.
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Lesões Encefálicas/sangue , Lesões Encefálicas/mortalidade , Ferritinas/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Brasil/epidemiologia , Resultados de Cuidados Críticos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Despite the involvement of cytokine production in neurotrauma, there is still controversy regarding cytokines levels and clinical outcome following severe traumatic brain injury (TBI). OBJECTIVE: The present study was designed to investigate whether cytokine levels (of IL-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNF-α) are associated with primary outcome (death or survival) after severe TBI. METHODS: This prospective study enrolled 24 male patients, victims of severe TBI. Venous blood samples were taken in the Intensive Care Unit (ICU) (study entry), 24 and 48 hours later. Plasma cytokine levels were assayed by flow cytometry. RESULTS: Severe TBI was associated with a 42% mortality rate. TBI patients had a significant increase in the levels of all cytokines measured, except for IL-1ß, compared to controls. Statistically significant increases in the IL-10, -8 and -6 levels were observed in the non-survivors TBI patients compared to the survivors sub-group measured in the first sample (study entry) and in the subsequent sample (24 hours later). There were no significant differences in IL-1ß, TNF-α and IL-12p70 levels between survivors and non-survivors in any time sampled. CONCLUSIONS: The findings indicate that increased IL-10, -8 and -6 levels may constitute an early predictor of unfavourable outcome in severe TBI patients.
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Lesões Encefálicas/mortalidade , Inflamação/mortalidade , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Lesões Encefálicas/metabolismo , Brasil/epidemiologia , Criança , Feminino , Escala de Coma de Glasgow , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Análise de SobrevidaRESUMO
Brain death (BD) represents the irreversible loss of all brain functions, including the brainstem, and is equivalent to clinical death established by neurological criteria. However, clinical diagnosis, mainly based on the absence of primary reflexes post-acute brain injury, remains a challenge in hospital settings. The S100 calcium-binding protein beta (S100b) is used to monitor brain injuries, as recommended by neurotrauma care guidelines in some countries. Its levels are associated with severity and mortality, particularly after traumatic brain injury (TBI) and cerebral hemorrhage. The evaluation of S100b levels in investigating brain death is promising; however, aspects such as cutoff values remain to be elucidated. This paper reviews the literature on the use of S100b as a biomarker in diagnosing brain death. It is noteworthy that there is still no defined cutoff for S100b levels in confirming brain death. Additionally, when considering the use of S100b in emergency situations, a point-of-care methodology should be established to support clinical decision-making quickly and easily in the early identification of patients who are more likely to progress to brain death. In this context, S100b levels may assist in establishing the diagnosis of brain death, complementing existing clinical evidence. This, in turn, can optimize and qualify the organ donation process, reducing costs with ineffective therapies and minimizing the suffering of the families involved.
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Cultured mesenchymal stromal cells are among the most used cells in clinical trials. Currently, their potential benefits include provision of mature cell types through differentiation, and secretion of various types of paracrine signaling molecules. Even though research on these cells has spanned some decades now, surprisingly, their therapeutic potential has not been fully translated into clinical practice yet, which calls for further understanding of their intrinsic nature and modes of action. In this review, after discussing pieces of evidence that suggest that some perivascular cells may exhibit mesenchymal stem cell characteristics in vivo, we examine the possibility that subpopulations of perivascular and/or adventitial cells activated after tissue injury behave as MSCs and contribute to the resolution of tissue injury by providing cues for the development of regenerative macrophages at injured sites. Under this perspective, an important contribution of cultured MSCs (or their acellular products, such as extracellular vesicles) used in cell therapies would be to instigate the development of M2-like macrophages that support the tissue repair process.
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OBJECTIVE: The aim of this study was to test whether a functional polymorphism (-174C/G) located in the promoter region of the interleukin-6 (IL-6) gene is associated with primary short-term outcome (death or Intensive Care Unit discharge) in patients with severe traumatic brain injury (TBI). METHODS: The study group consisted of 77 male patients who suffered severe TBI. The -174C/G IL-6 polymorphism was analysed by polymerase chain reaction (PCR) followed by restriction digestion. RESULTS: Severe TBI was associated with a 44% mortality rate. The GG genotype was significantly more frequent in the survivor group than in non-surviving patients (67% vs 41%; p =?0.038); similarly, the IL-6 -174G allele was more frequent in the survivor group than in non-surviving patients (81% vs 65%; p =0.031). CONCLUSION: The findings indicate that genetic variation regarding inflammatory response has significant impact on the short-term outcome for patients after acute severe TBI.
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Lesões Encefálicas/genética , Interleucina-6/genética , Regiões Promotoras Genéticas/genética , Adolescente , Adulto , Análise de Variância , Lesões Encefálicas/mortalidade , Criança , Pré-Escolar , Feminino , Escala de Resultado de Glasgow , Humanos , Lactente , Escala de Gravidade do Ferimento , Masculino , Reação em Cadeia da Polimerase , Polimorfismo Genético , Adulto JovemRESUMO
3-nitropropionic acid (3-NP) is a toxin that causes neural damage in the striatum and can lead to the development of Huntington's disease manifestations in animal models. Several studies have shown genotoxicity related to the 3-NP treatment. This study investigated potential genotoxicity and mutagenicity that was induced by a low dose (6.25 mg/kg i. p.) 3-NP subacute treatment (daily, over 6 days) in a rat model. The arterial blood and the frontal cortex were analyzed by the comet assay and the bone marrow by micronucleus. Surprisingly, the 3-NP subacute treatment with the low dose did not show genotoxic or mutagenic effects.
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Dano ao DNA , Mutagênicos , Nitrocompostos/toxicidade , Propionatos/toxicidade , Animais , Ensaio Cometa , Relação Dose-Resposta a Droga , Testes para Micronúcleos , Testes de Mutagenicidade , Mutagênicos/toxicidade , RatosRESUMO
The mitochondrial inhibitor 3-nitropropionic acid (3-NP) induces excitotoxicity. The authors hypothesized that CTK 01512-2, a recombinant peptide calcium channel N-type blocker, and the TRPA1 antagonist, could show neuroprotective effects. The male Wistar rats received 3-NP [25 mg/kg (i.p.) for 7 days], and a treatment of CTK 01512-2 was delivered intrathecally (i.t.), thrice a week. The neuroprotective effects were evaluated by [18F]FDG MicroPET analysis. The CTK 01512-2 toxin was able to reestablish similar glucose uptakes on the control animals. To detect the neurobehavioral effects from 3-NP, three protocols (6.25, 12.5, 18.75 mg/kg of 3-NP (i.p.), for 3, 4, and 6 days, respectively) were evaluated by performance tests (open field test, walk footprint, elevated plus-maze, Y-maze, and the object recognition test). Important disabilities in the gait of the rats were seen, as well as memory deficits, and anxious behavior in the animals that were treated with all 3-NP protocols. The dose of 18.75 mg/kg (for 3 days) showed the most pronounced behavioral effects and lethality, while the rats treated with 12.5 mg/kg (for 4 days) showed behavioral effects similar to the 6.25 mg/kg dose (for 6 days). The third protocol was then repeated and the rats were treated with the CTK 01512-2 toxin to be evaluated behaviorally again. The recombinant peptide prevented all of the gait-evaluated parameters that were induced by 3-NP at a 6.25 mg/kg dose, which displayed an improvement in the exploratory activities. Overall, these results have reinforced the positive effects of CTK 01512-2 against the behavioral changes that were induced by the mitochondrial inhibitor 3-NP.
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Bloqueadores dos Canais de Cálcio , Fármacos Neuroprotetores , Neurotoxinas , Nitrocompostos , Propionatos , Animais , Masculino , Ratos , Bloqueadores dos Canais de Cálcio/farmacologia , Relação Dose-Resposta a Droga , Injeções Espinhais , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/toxicidade , Nitrocompostos/antagonistas & inibidores , Nitrocompostos/toxicidade , Teste de Campo Aberto/efeitos dos fármacos , Propionatos/antagonistas & inibidores , Propionatos/toxicidade , Ratos Wistar , Proteínas Recombinantes , Canal de Cátion TRPA1/antagonistas & inibidoresRESUMO
OBJECTIVE: To determine whether the matrix metalloproteinases-2 and -9 plasma levels were associated with intensive care unit mortality in patients who suffered severe traumatic brain injury, despite the presence of extracerebral injuries. METHODS: This prospective cohort enrolled 39 male patients who suffered severe traumatic brain injury (Glasgow coma scale: 3 - 8 at hospital admission). The plasma matrix metalloproteinase -2 and matix metalloproteinase -9 levels were determined by ELISA at the time of intensive care unit admission. RESULTS: Severe traumatic brain injury was associated with a 46% intensive care unit mortality rate. Higher plasma matrix metalloproteinase -9 concentrations were associated with mortality: 147.94 ± 18.00ng/mL for survivors and 224.23 ± 23.86ng/mL for nonsurvivors (mean ± standard error of the mean, p = 0.022). In contrast, there was no significant association between matrix metalloproteinase -2 levels and intensive care unit mortality: 315.68 ± 22.90ng/mL for survivors and 336.55 ± 24.29ng/mL for nonsurvivors (p = 0.499). Additionally, there were no significant associations between matrix metalloproteinase -2 (p = 0.711) and matrix metalloproteinase -9 (p = 0.092) levels and the presence of associated lesions. CONCLUSION: Increased plasma matrix metalloproteinase -9 levels were associated with intensive care unit mortality following severe traumatic brain injury, regardless of the presence of extracerebral injuries. Conversely, in this same context, plasma matrix metalloproteinase -2 levels were not associated with short-term fatal outcome prediction.
OBJETIVO: Determinar se os níveis plasmáticos das metaloproteinases de matriz -2 e -9 tem associação com a mortalidade na unidade de terapia intensiva em pacientes com trauma craniencefálico grave, independentemente de lesões não cerebrais associadas. MÉTODOS: Esta coorte prospectiva incluiu 39 pacientes do sexo masculino com trauma craniencefálico grave (escore na escala de coma Glasgow na admissão hospitalar: 3 - 8). Os níveis plasmáticos das metaloproteinases -2 e -9 foram determinados por ELISA no momento da admissão na unidade de terapia intensiva. RESULTADOS: O trauma craniencefálico grave apresentou mortalidade de 46% na unidade de terapia intensiva. Concentrações mais elevadas de metaloproteinase -9 apresentaram associação com a mortalidade: 147,94 ± 18,00ng/mL para pacientes que sobreviveram e 224,23 ± 23,86ng/mL para os que não sobreviveram (média ± erro padrão, respectivamente; p = 0,022). Todavia, não houve associação significativa entre os níveis de metaloproteinase -2 e a mortalidade na unidade de terapia intensiva: 315,68 ± 22,90ng/mL para o grupo de sobreviventes e 336,55 ± 24,29ng/mL entre os pacientes que não sobreviveram (p = 0,499). Além disso, não se observaram associações significativas entre os níveis de metaloproteinase -2 (p = 0,711) ou metaloproteinase -9 (p = 0,092) e a presença de lesões não cerebrais associadas. CONCLUSÃO: Em vítimas de traumatismo craniencefálico grave, níveis elevados de metaloproteinase -9 tiveram valor preditivo para o desfecho fatal na unidade de terapia intensiva independentemente da presença de lesões não cerebrais associadas. Por outro lado, no mesmo cenário, os níveis plasmáticos de metaloproteinase -2 não apresentaram associação com a mortalidade na unidade de terapia intensiva.
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Lesões Encefálicas Traumáticas/mortalidade , Unidades de Terapia Intensiva , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Adolescente , Adulto , Lesões Encefálicas Traumáticas/sangue , Estudos de Coortes , Escala de Coma de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Sobreviventes , Adulto JovemRESUMO
BACKGROUND: Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome that impacts negatively patient's daily lives. Its pathogenesis is characterized by a complex relationship between biological and psychosocial factors not fully understood yet. Pain catastrophizing is associated with FM and is an important predictor of outcomes. This study aimed to answer two questions: (i) whether the allele and genotype frequencies of BDNF Val66Met (rs6265) polymorphism differs between FM patients and healthy controls (HC); and (ii) if the BDNF Val66Met polymorphism is a factor that predicts pain catastrophizing in FM. METHODS: In a cross-sectional design, 108 FM patients and 108 HC were included. FM patients responded to the Brazilian Portuguese version of the Pain Catastrophizing Scale (BP-PCS) to assess pain catastrophizing, as well as other validated tools for anxiety (The State-Trait Anxiety Inventory - STAI), depression (Beck Depression Inventory II - BDI-II) and functional aspects (Fibromyalgia Impact Questionnaire - FIQ; Central Sensitization Inventory validated and adapted for Brazilian population - CSI-BP; Pittsburgh Sleep Quality Index - PSQI; and Resilience Scale). All subjects were genotyped for the BDNF Val66Met polymorphism. RESULTS: Val allele was significantly more frequent in FM patients compared to the control group (p < 0.05). Also, FM patients with Val/Val genotype showed more pain catastrophizing thoughts, and this genotype was significantly associated with magnification and rumination dimensions of BP-PCS (p < 0.05). Furthermore, there were significant differences in levels of anxiety and symptoms of depression, years of education, and the functional situation between the FM and control groups. CONCLUSIONS: The findings show an association of BDNF Val66Met polymorphism with pain catastrophizing in FM, which opens new avenues to comprehend the interplay between molecular genetic characteristics and neuroplasticity mechanisms underpinning FM.
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Alelos , Fator Neurotrófico Derivado do Encéfalo/genética , Catastrofização/genética , Fibromialgia/genética , Adulto , Ansiedade/diagnóstico , Estudos de Casos e Controles , Catastrofização/psicologia , Depressão/diagnóstico , Feminino , Fibromialgia/psicologia , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo Genético , Escalas de Graduação Psiquiátrica , Ruminação CognitivaRESUMO
Parkinson disease (PD) is a neurodegenerative disease resulting from the loss of the dopaminergic neurons from the substantia nigra pars compacta (SNpc). It is characterized by bradykinesia, rigidity, resting tremor and/or postural instability. The diagnosis of PD is essentially clinical and there is no reliable biological marker to assess its progression. Recently, investigations have been performed on the potential use of circulating cell-free deoxyribonucleic acid (DNA) in the plasma for clinical diagnosis, prognosis and monitoring of human diseases. The aim of this work was to assess the role of free DNA as a biological marker of PD. Forty-two patients with PD (19 men, 23 women) and 20 healthy (7 men, 13 women) subjects were enrolled in this study. Mean +/- SD plasma DNA concentration in PD patients and control subjects were, respectively, 16,487 +/- 16,378 (range: 100-62,034) kilogenomes-equivalents/L and 37,975 +/- 17,832 (range: 15,143-78,783) kilogenomes-equivalents/L. There was a significant difference between control and PD groups (p < 0.001). There was no correlation between plasma DNA levels and demographic or clinical parameters in PD patients. Free DNA does not seem to be a reliable marker of PD progression. Further research is warranted to confirm the present results to have some value as biomarkers in other neurodegenerative diseases.
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DNA/sangue , Doença de Parkinson/sangue , Plasma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Doença de Parkinson/genética , Estatísticas não ParamétricasRESUMO
The antiproliferative activity of three benzopyrans isolated from the chloroform extract of the aerial parts of Hypericum polyanthemum was analysed in order to determine their effect on the growth and cell cycle in the U-373 MG glioblastoma cell line. Compound 1 was less cytotoxic than compounds 2 and 3. A synergistic effect was noticed when the three benzopyrans were used simultaneously. The cytotoxicity noted could be related to an arrest in G2/M phase, leading to apoptosis in the U-373 MG glioblastoma cell line.
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Antineoplásicos Fitogênicos/farmacologia , Benzopiranos/farmacologia , Ciclo Celular/efeitos dos fármacos , Hypericum/química , Análise de Variância , Linhagem Celular Tumoral , Proliferação de Células , Sinergismo Farmacológico , Humanos , Componentes Aéreos da Planta/química , Extratos Vegetais/farmacologiaRESUMO
INTRODUCTION: Acute brain injuries represent major causes of morbidity and mortality worldwide. Nevertheless, therapeutic options are centered mainly on supportive care, and accurate prognosis prediction following traumatic brain injury (TBI) or stroke remains a challenge in clinical settings. Areas covered: Circulating DNA and RNA have shown potential as predictive molecules in acute brain injuries. In particular, plasma cell-free DNA (cfDNA) levels have been correlated to severity, mortality, and outcome after TBI and stroke. The real-time quantitative polymerase chain reaction (qPCR) is the most widely used technique for determination of cfDNA in brain injuries; however, to consider the use of cfDNA in emergency settings, a quicker and easier methodology for detection should be established. A recent study proposed detection of cfDNA applying a rapid fluorescent test that showed compatible results with qPCR. Expert commentary: As a promising perspective, detection of cfDNA levels using simple, rapid, and cheap methodology has potential to translate to clinic as a point-of-care marker, supporting the clinical decision-making in emergency care settings. Conversely, miRNA profiles may be used as signatures to determine the type and severity of injuries. Additionally, in the future, some miRNAs may constitute innovative neurorestorative therapies without the common hurdles associated with cell therapy.
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Lesões Encefálicas/sangue , Ácidos Nucleicos Livres/sangue , Animais , Biomarcadores/sangue , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Humanos , Valor Preditivo dos TestesRESUMO
The prediction of outcome is one of the major problems associated with traumatic brain injury. Recently, investigations have been performed on the potential use of circulating cell-free DNA in plasma for clinical diagnosis and prognosis of a variety of conditions. In this study, we investigated DNA plasma concentrations after severe traumatic brain injury (TBI) and its correlation with primary outcome. We studied 41 male victims of TBI, with isolated severe TBI or severe TBI with associated exracranial injuries. Control samples were obtained from 13 healthy male volunteers. Plasma DNA was measured by a real-time PCR assay for the beta-globin gene. The mean time for first sampling (study entry) was 11.7 +/- 5.2 h after injury; subsequent DNA determinations were performed 24 h after study entry. Mean plasma DNA concentrations were significantly increased in TBI patients (366,485 and 131,708 kilogenomes-equivalents/L, at study entry and 24 h later, respectively) compared with the control group (3031 kilogenomes-equivalents/L). Additionally, a significant correlation between higher plasma DNA concentrations, determined 24 h after study entry, and fatal outcome was observed. However, at second sampling, there was no significant correlation between plasma DNA concentrations and the presence of associated extracranial injuries. High plasma DNA concentrations at second sampling time predicted fatal outcome with a sensitivity of 67% and specificity of 76%, considering a cut-off value of 77,883 kilogenomes-equivalents/L. Thus, this study showed that severe TBI is associated with elevated DNA plasma levels and suggests that persistent DNA elevations correlate with mortality.
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Lesões Encefálicas/sangue , Lesões Encefálicas/diagnóstico , Traumatismos Craniocerebrais/sangue , Traumatismos Craniocerebrais/diagnóstico , DNA/sangue , Adolescente , Adulto , Biomarcadores/sangue , Globinas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores Sexuais , Taxa de Sobrevida , Regulação para Cima/fisiologiaRESUMO
Biochemical markers of cellular stress/injury have been proposed to indicate outcome after head injury. The aim of the present study was to determine whether plasma von Willebrand factor (VWF) levels correlate with primary outcome and with clinical variables in severe traumatic brain injury (TBI). Forty-four male patients, victims of severe TBI, were analyzed. Clinical outcome variables of severe TBI comprised survival and neurological assessment using the Glasgow Outcome Scale (GOS) at intensive care unit (ICU) discharge. Computerized tomography (CT) scans were analyzed according to Marshall CT classification. Three consecutive venous blood samples were taken: first sample (11.4 +/- 5.2 h after trauma, mean +/- SD), and 24 h and 7 days later. The result of mean plasma VWF concentration was significantly higher in the TBI group (273 U/dL) than in the control group (107 U/dL; p < 0.001). Severe TBI was associated with a 50% mortality rate. Nonsurvivors presented significantly higher APACHE II scores than survivors (nonsurvivors mean, 18.8; survivors mean, 12.7; p < 0.001), and also presented higher scores in Marshall CT classification (nonsurvivors mean, 4.6; survivors mean, 2.7; p < 0.05). There was a significant positive correlation between plasma levels at second plasma sampling and scores in Marshall CT classification (p < 0.05). The sensitivity of plasma VWF concentration in predicting mortality according to the cut-off of 234 U/dL was 64%, with a specificity of 68%. Therefore, VWF increases following severe TBI may be a marker of unfavorable outcome.
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Lesões Encefálicas/sangue , Lesões Encefálicas/mortalidade , Fator de von Willebrand/metabolismo , Adolescente , Adulto , Biomarcadores/sangue , Lesões Encefálicas/diagnóstico por imagem , Seguimentos , Escala de Resultado de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Radiografia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Severe traumatic brain injury (TBI) is associated with a 35-70% mortality rate. Biochemical markers of cellular stress/injury have been proposed to indicate outcome after head injury. Therefore, our aim was to determine whether Hsp70 could be detected in the serum of patients after severe TBI and whether serum levels of Hsp70 correlate with primary outcome in severe TBI. Twenty consecutive male patients, victims of severe TBI (GCS 3-8), were enrolled in this prospective study. Clinical outcome variables of severe TBI comprised: survival, time for ICU discharge, and neurological assessment using the Glasgow Outcome Scale (GOS) at the ICU discharge. Venous blood samples were taken at admission in the ICU (study entry), 24 h later, and 7 days later. A control group consisting of eight healthy male volunteers was also included. Serum Hsp70 levels were measured by an enzyme-linked immunosorbent assay. Mean serum Hsp70 concentrations were significantly increased in the TBI (97.6, 48.1, and 39.2 ng/mL, at study entry, 24 h later, and 7 days later, respectively) compared with the control group (12.2 ng/mL). Severe TBI was associated with a 50% mortality rate. On study entry (mean time 10.8 h after injury), a higher proportion of patients with fatal outcome had elevated serum Hsp70 (mean 143.5 ng/mL) concentrations when compared with survivors (mean 51.6 ng/mL). There was a significant correlation between higher initial serum Hsp70 concentrations and fatal outcome. The sensitivity of serum Hsp70 predicting mortality according to the cutoff of 62 ng/mL is 70% within 20 h after injury. Increased serum Hsp70 levels may constitute an early predictor of unfavorable outcome in severe TBI in males.
Assuntos
Lesões Encefálicas/sangue , Lesões Encefálicas/mortalidade , Proteínas de Choque Térmico HSP70/sangue , APACHE , Adolescente , Adulto , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Escala de Resultado de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Sensibilidade e Especificidade , Taxa de SobrevidaRESUMO
The combination of irinotecan (CPT-11) and 5-fluorouracil (5-FU) is currently used in the treatment of advanced colorectal carcinoma. When compared to both agents alone, CPT-11 followed by 5-FU treatment demonstrated a synergistic effect. This observation can be related to increased in apoptosis induction after caspase activation. Several studies have demonstrated that changes in mitochondrial membrane potential occur earlier in apoptosis. In this study, we verified whether the collapse in mitochondrial membrane and the activation of caspases is responsible for increased apoptosis observed with CPT-11/5-FU treatment. Thus, HT-29 and SNU-C4 human colon carcinoma cell lines were exposed for 24 h to each drug alone, and to various combinations and treatment sequences, and assessed for colony formation, changes in the mitochondrial membrane potential, and the activities of caspase-3, -8, and -9. The CPT-11/5-FU treatment induced apoptosis in both cell lines; however, the most pronounced effect was observed in HT-29 cells. In these cells, both caspase-3 and -9 were involved in the activation of apoptosis after CPT-11/5-FU treatment. Moreover, in these cells, a reduction of 50% in mitochondrial membrane potential was observed with this treatment. On the other hand, in the SNU-C4 cell line in addition to caspase-3 and-9, caspase-8 seems to be important to apoptosis after CPT-11/5-FU treatment. Furthermore, in this cell line we did not observe alterations in mitochondrial membrane potential. In spite of the differences among the cell lines, these results indicated that the increase in apoptosis in HT-29 cells observed with CPT-11 followed by 5-FU treatment could be explained by a disruption in mitochondria membrane potential that induced caspases activation.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Fluoruracila/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Membranas Mitocondriais/fisiologia , Apoptose , Camptotecina/farmacologia , Caspase 3 , Caspase 8 , Caspase 9 , Caspases/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Células HT29 , Humanos , Irinotecano , Membranas Mitocondriais/efeitos dos fármacosRESUMO
RESUMO Objetivo: Determinar se os níveis plasmáticos das metaloproteinases de matriz -2 e -9 tem associação com a mortalidade na unidade de terapia intensiva em pacientes com trauma craniencefálico grave, independentemente de lesões não cerebrais associadas. Métodos: Esta coorte prospectiva incluiu 39 pacientes do sexo masculino com trauma craniencefálico grave (escore na escala de coma Glasgow na admissão hospitalar: 3 - 8). Os níveis plasmáticos das metaloproteinases -2 e -9 foram determinados por ELISA no momento da admissão na unidade de terapia intensiva. Resultados: O trauma craniencefálico grave apresentou mortalidade de 46% na unidade de terapia intensiva. Concentrações mais elevadas de metaloproteinase -9 apresentaram associação com a mortalidade: 147,94 ± 18,00ng/mL para pacientes que sobreviveram e 224,23 ± 23,86ng/mL para os que não sobreviveram (média ± erro padrão, respectivamente; p = 0,022). Todavia, não houve associação significativa entre os níveis de metaloproteinase -2 e a mortalidade na unidade de terapia intensiva: 315,68 ± 22,90ng/mL para o grupo de sobreviventes e 336,55 ± 24,29ng/mL entre os pacientes que não sobreviveram (p = 0,499). Além disso, não se observaram associações significativas entre os níveis de metaloproteinase -2 (p = 0,711) ou metaloproteinase -9 (p = 0,092) e a presença de lesões não cerebrais associadas. Conclusão: Em vítimas de traumatismo craniencefálico grave, níveis elevados de metaloproteinase -9 tiveram valor preditivo para o desfecho fatal na unidade de terapia intensiva independentemente da presença de lesões não cerebrais associadas. Por outro lado, no mesmo cenário, os níveis plasmáticos de metaloproteinase -2 não apresentaram associação com a mortalidade na unidade de terapia intensiva
Abstract Objective: To determine whether the matrix metalloproteinases-2 and -9 plasma levels were associated with intensive care unit mortality in patients who suffered severe traumatic brain injury, despite the presence of extracerebral injuries. Methods: This prospective cohort enrolled 39 male patients who suffered severe traumatic brain injury (Glasgow coma scale: 3 - 8 at hospital admission). The plasma matrix metalloproteinase -2 and matix metalloproteinase -9 levels were determined by ELISA at the time of intensive care unit admission. Results: Severe traumatic brain injury was associated with a 46% intensive care unit mortality rate. Higher plasma matrix metalloproteinase -9 concentrations were associated with mortality: 147.94 ± 18.00ng/mL for survivors and 224.23 ± 23.86ng/mL for nonsurvivors (mean ± standard error of the mean, p = 0.022). In contrast, there was no significant association between matrix metalloproteinase -2 levels and intensive care unit mortality: 315.68 ± 22.90ng/mL for survivors and 336.55 ± 24.29ng/mL for nonsurvivors (p = 0.499). Additionally, there were no significant associations between matrix metalloproteinase -2 (p = 0.711) and matrix metalloproteinase -9 (p = 0.092) levels and the presence of associated lesions. Conclusion: Increased plasma matrix metalloproteinase -9 levels were associated with intensive care unit mortality following severe traumatic brain injury, regardless of the presence of extracerebral injuries. Conversely, in this same context, plasma matrix metalloproteinase -2 levels were not associated with short-term fatal outcome prediction.