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1.
J Crit Care ; 57: 1-4, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31991332

RESUMO

PURPOSE: Previously our team found higher serum substance P concentrations at day 1 of a malignant middle cerebral artery infarction (MMCAI) in non-surviving than in surviving patients. Thus, the objective of this study was to determine whether serum substance P levels during the first week of MMCAI could predict mortality. METHODS: We included patients with MMCAI defined as computed tomography findings of acute infarction in at least of 50% of the territory and Glasgow Coma Scale ≤8. We determined serum concentrations of substance P on days 1, 4 and 8 of MMCAI. Thirty-day mortality was the study end-point. RESULTS: Serum substance P concentrations at days 1 (p < .001), 4 (p < .001), and 8 (p = .001) of MMCAI in non-surviving (n = 34) were higher than in surviving patients (n = 34). Receiver operating characteristic analyses showed that serum substance P concentrations at days 1, 4, and 8 of MMCAI had an area under curve (95% confidence intervals) to predict 30-day mortality of 0.77 (0.66-0.87; p < .001), 0.82 (0.69-0.91; p < .001) and 0.85 (0.72-0.94; p < .001) respectively. CONCLUSIONS: The two new findings of our study are that non-surviving MMCAI patients showed higher serum substance P levels at day 1, 4 and 8 than surviving, and that those levels could predict 30-day mortality.

2.
Brain Sci ; 9(12)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795260

RESUMO

OBJECTIVE: The activation of different physiopathological pathways (neuroinflammation, apoptosis, and oxidation) can lead to secondary brain injury in ischemic stroke, and in animal models the administration of melatonin has reduced that secondary injury. Lower levels of serum melatonin were found at the time of admission of cerebral infarction in surviving patients than in non-surviving patients. Thus, we carried out this prospective and observational study with the aim of exploring serum melatonin levels in the first week of a malignant middle cerebral artery infarction (MMCAI) in surviving and non-surviving patients, and to explore the capacity of those levels to predict mortality. METHODS: Patients with severe MMCAI, defined as computed tomography showing acute infarction in more than 50% of the territory and Glasgow Coma Scale (GCS) lower than 9, were included in the study. We measured serum melatonin concentrations at days 1, 4, and 8 of MMCAI. Mortality at 30 days was the endpoint of our study. RESULTS: Non-surviving patients (n = 34) compared to surviving patients (n = 34) showed higher serum melatonin levels at days 1 (p < 0.001), 4 (p < 0.001), and 8 (p = 0.001) of MMCAI. Serum melatonin concentrations at days 1, 4, and 8 of MMCAI had an area under the curve (AUC) (95% confidence interval (CI)) in the prediction of mortality of 0.89 (0.80-0.96; p < 0.001), 0.81 (0.68-0.91; p < 0.001), and 0.82 (0.68-0.92; p < 0.001), respectively. CONCLUSIONS: The novel findings of our study were that serum melatonin levels in the first week of MMCAI were higher in non-surviving patients, and were able to predict mortality.

3.
BMC Res Notes ; 12(1): 789, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796118

RESUMO

OBJECTIVE: Higher blood malondialdehyde (biomarker of lipid peroxidation) levels in the first hours of traumatic brain injury (TBI) have been found in patients with a worst prognosis. The objective of this study was to determine whether serum malondialdehyde levels during the first week of severe TBI could be used as mortality biomarkers. This was a multicenter, prospective and observational study performed in six Spanish Intensive Care Units. We included patients with severe TBI (defined as Glasgow Coma Scale < 9), and with Injury Severity Score in non-cranial aspects < 9. We determined serum malondialdehyde concentrations at days 1, 4 and 8 of TBI. We stablished 30-day mortality as the end-point study. RESULTS: We found that serum malondialdehyde concentrations at days 1 (p < 0.001), 4 (p < 0.001), and 8 (p < 0.001) of TBI were higher in non-survivor (n = 34) than in survivor (n = 90) patients. We found an area under curve of serum malondialdehyde concentrations at days 1, 4, and 8 of TBI to predict 30-day mortality of 77% (p < 0.001), 87% (p < 0.001) and 84% (p < 0.001) respectively. Thus, the new and most relevant findings of our study were serum malondialdehyde levels during the first week of TBI could be used as mortality biomarkers.

4.
World Neurosurg ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31669537

RESUMO

BACKGROUND: Matrix metalloproteinase (MMP)-9, a member of the endoproteinase family, is involved in the neuroinflammation of spontaneous intracerebral hemorrhage (SIH). High circulating MMP-9 levels have been associated with poor functional outcome in patients with SIH. The objectives of this study were to determine whether serum MMP-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1 levels in SIH patients were higher in nonsurviving than surviving patients, if they were associated with early mortality, and if they could be used as biomarkers of prognosis. METHODS: This observational prospective study included patients with severe supratentorial SIH (defined as Glasgow Coma Scale <9) from 6 Spanish Intensive Care Units. Serum MMP-9 and TIMP-1 levels were determined at the time of severe SIH diagnosis. Thirty-day mortality was the endpoint study. RESULTS: Nonsurviving patients (n = 46) showed higher serum TIMP-1 (P < 0.001) and MMP-9 levels (P = 0.01) than surviving patients (n = 54). The area under the curve by serum TIMP-1 levels for the prediction of 30-day mortality was 74% (95% confidence interval = 64%-82%; P < 0.001). Multiple logistic regression analysis showed an association between serum TIMP-1 levels >223 ng/mL and 30-day mortality (odds ratio = 13.993; 95% confidence interval = 2.864-68.356; P = 0.001) after controlling for intracerebral hemorrhage score, glycemia, midline shift, and early evacuation of SIH. There was an association between circulating levels of TIMP-1 and MMP-9 (rho = 0.25; P = 0.01). CONCLUSIONS: The novel aspects our study include that serum TIMP-1 and MMP-9 levels in SIH patients were higher in nonsurviving than in surviving patients and that serum TIMP-1 levels were associated with early mortality and could be used as biomarkers for predicting mortality.

5.
Brain Sci ; 9(10)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658711

RESUMO

OBJECTIVE: Apoptosis increases in traumatic brain injury (TBI). Caspase-cleaved cytokeratin (CCCK)-18 in blood during apoptosis could appear. At the time of admission due to TBI, higher blood CCCK-18 levels were found in non-surviving than in surviving patients. Therefore, the objective of our study was to analyze whether serum CCCK-18 levels determined during the first week after TBI could predict early mortality (at 30 days). METHODS: Severe TBI patients were included (considering severe when Glasgow Coma Scale < 9) in this observational and multicentre study. Serum CCCK-18 levels were determined at day 1 of TBI, and at days 4 and 8 after TBI. RESULTS: Serum CCCK-18 levels at day 1 of TBI, and in the days 4 and 8 after TBI were higher (p < 0.001) in non-surviving than in surviving patients (34 and 90 patients, respectively) and could predict early mortality (p < 0.001 in the area under the curve). CONCLUSIONS: The new findings from our study were that serum CCCK-18 levels at any moment of the first week of TBI were higher in non-surviving patients and were able to predict early mortality.

6.
Neurocrit Care ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31598840

RESUMO

PURPOSE: One study found higher leukocytes 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in patients with spontaneous intracerebral hemorrhage (ICH) than in healthy subjects due to the oxidation of guanosine from deoxyribonucleic acid (DNA). The objective of this study was to determine whether there is an association between oxidative damage of serum DNA and ribonucleic acid (RNA) and mortality in patients with ICH. METHODS: In this observational and prospective study, patients with severe supratentorial ICH (defined as Glasgow Coma Scale < 9) were included from six Intensive Care Units of Spanish hospitals. At the time of severe ICH diagnosis, concentrations in serum of malondialdehyde (as lipid peroxidation biomarker) and of the three oxidized guanine species (OGS) (8-hydroxyguanosine from RNA, 8-hydroxyguanine from DNA or RNA, and 8-OHdG from DNA) were determined. Thirty-day mortality was considered the end-point study. RESULTS: Serum levels of OGS (p < 0.001) and malondialdehyde (p = 0.002) were higher in non-surviving (n = 46) than in surviving patients (n = 54). There was an association of serum OGS levels with serum malondialdehyde levels (rho = 0.36; p = 0.001) and 30-day mortality (OR = 1.568; 95% CI 1.183-2.078; p = 0.002). CONCLUSIONS: The novel and most important finding of our study was that serum OGS levels in ICH patients are associated with mortality.

7.
BMC Neurol ; 19(1): 238, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623565

RESUMO

OBJECTIVE: Previously there have been found higher circulating malondialdehyde levels during the first week of ischemic stroke in patients with worst neurological functional outcome, and at moment of ischemic stroke in non-survivor patients. Thus, the aim of our study was to determine the potential role of serum malondialdehyde levels during the first week of a severe cerebral infarction to mortality prediction. METHODS: This study was observational, prospective, and multicenter. We included patients with a severe malignant middle cerebral artery infarction (MMCAI) defined as patients with computed tomography showing acute infarction in more than of 50% of the territory and Glasgow Coma Scale (GCS) lower than 9. We determined serum concentrations of malondialdehyde on days 1, 4 and 8 of MMCAI. RESULTS: Serum malondialdehyde concentrations at days 1 (p < 0.001), 4 (p < 0.001), and 8 (p = 0.001) of MMCAI in non-survivor patients (n = 34) were higher than in survivor patients (n = 34). ROC curve analyses showed that serum malondialdehyde concentrations at days 1, 4, and 8 of MMCAI had an AUC (95% CI) to predict 30-day mortality of 0.77 (0.65-0.86; p < 0.001), 0.82 (0.69-0.91; p < 0.001) and 0.84 (0.70-0.93; p < 0.001) respectively. CONCLUSIONS: The new findings of our study were that serum malondialdehyde levels during the first week of MMCAI could be used as biomarkers to mortality prediction.


Assuntos
Biomarcadores/sangue , Infarto da Artéria Cerebral Média/sangue , Malondialdeído/sangue , Idoso , Feminino , Humanos , Infarto da Artéria Cerebral Média/mortalidade , Infarto da Artéria Cerebral Média/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC
8.
Brain Sci ; 9(10)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581589

RESUMO

Objective: Providing melatonin in animal models with spontaneous intracerebral hemorrhage (SIH) has been associated with beneficial effects. However, to our knowledge, there are no published data on circulating melatonin levels regarding the prognosis of SIH patients. Therefore, the objectives of this study were to determine whether serum melatonin levels in SIH patients were associated with early mortality and whether they could be used as prognostic biomarkers. Methods: This observational and prospective study included patients with supratentorial and clinically severe SIH (defined as Glasgow Coma Scale GCS <9) admitted to the Intensive Care Units of six Spanish hospitals. Serum melatonin levels were determined at the time of severe SIH diagnosis. Mortality at 30 days was the study end-point. Results: Non-surviving patients (n = 46) showed higher serum melatonin levels (p < 0.001) than surviving (n = 54) patients. An area under the curve was found for the prediction of 30-day mortality by serum melatonin levels of 0.89 (95% CI = 0.81-0.94; p < 0.001). Multiple logistic regression analysis showed an association of serum melatonin levels with 30-day mortality (Odds Ratio = 8.16; 95% CI = 2.30-28.95; p = 0.001) after controlling for midline shift, glycemia, early evacuation of SIH, and Intracerebral hemorrhage(ICH) score. Conclusions: The novel findings by our study were the presence of higher serum melatonin levels in non-surviving patients than in surviving patients and the association of these levels with mortality.

9.
Neurocrit Care ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31385181

RESUMO

BACKGROUND: The hyperoxidative state in traumatic brain injury (TBI) could produce oxidative damage on the ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Oxidative damage to nucleic acids in TBI patients has been studied, and higher concentrations of 8-OHdG were found in postmortem brain samples of subjects who died following TBI than in subjects who died from sudden cardiac death. Thus, the objective of this study was to determine whether there is an association between serum DNA and RNA oxidative damage and mortality in TBI patients. METHODS: We included patients with severe isolated TBI defined as a lower score than 9 points in the Glasgow Coma Scale (GCS) and lower than 9 points in non-cranial aspects in the Injury Severity Score. We determined serum concentrations of the three oxidized guanine species (OGS) (8-OHdG from DNA, 8-hydroxyguanosine from RNA, and 8-hydroxyguanine from DNA or RNA) and malondialdehyde (to estimate lipid peroxidation) on the day of TBI. Mortality at 30 days was the end-point study. RESULTS: We found higher serum concentrations of OGS (p < 0.001) and malondialdehyde (p < 0.001) in non-surviving (n = 34) than in surviving patients (n = 90), an association between serum OGS levels and 30-day mortality after control for CGS, age, and computed tomography findings (OR = 1.397; 95% CI = 1.137-1.716; p = 0.001), and a positive correlation between serum levels of OGS and malondialdehyde (rho = 0.24; p = 0.01). CONCLUSIONS: To our knowledge, our study is the largest series reporting data on DNA oxidative damage in TBI patients and is the first reporting DNA and RNA oxidative damage in TBI patients associating lipid peroxidation and mortality.

10.
World Neurosurg ; 132: e613-e617, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31442647

RESUMO

BACKGROUND: Substance P is a neuropeptide belonging to the tachykinin family and is involved in neuroinflammation. In a previous study by our team, we found higher serum substance P levels on day 1 of traumatic brain injury (TBI) in nonsurviving than in surviving patients. Thus, the objective of this study was to determine whether serum substance P levels during the first week of TBI could predict early mortality. METHODS: This was a multicenter, observational, and prospective study. We included patients with an isolated severe TBI, defining isolated as <9 points in non-cranial aspects of Injury Severity Score and severe as <9 points of Glasgow Coma Scale. We determined serum substance P concentrations at days 1, 4, and 8 of TBI. We performed receiver operating characteristic analyses to determine the capacity of serum substance P levels at day 1, 4, and 8 of TBI to predict 30-day mortality. RESULTS: Nonsurviving (n = 34) compared with surviving patients (n = 90) had greater serum substance P levels on day 1 (P < 0.001), 4 (P < 0.001), and 8 (P < 0.001) of TBI. The areas under curve of serum substance P concentrations at days 1, 4, and 8 of TBI to predict 30-day mortality were 76% (P < 0.001), 87% (P < 0.001), and 89% (P < 0.001), respectively. CONCLUSIONS: The new finding of our study is that the presence of elevated serum substance P levels during the first week of TBI is associated with increased mortality.


Assuntos
Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/mortalidade , Substância P/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
World Neurosurg ; 132: e630-e636, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31442656

RESUMO

BACKGROUND: Higher circulating soluble cluster of differentiation 40 ligand (sCD40L) levels at admission of an ischemic stroke have been found in nonsurvivor than in survivor patients. The objectives of this study were to determine whether serum sCD40L levels during the first week of a severe malignant middle cerebral artery infarction (MMCAI) are higher in nonsurvivor than in survivor patients and whether they could be used as biomarker of mortality prediction. METHODS: This multicenter study included patients with severe MMCAI (defined as Glasgow Coma Scale score <9). We determined serum sCD40L concentrations at days 1, 4, and 8 and performed receiver operating characteristic analyses to determine their capacity for 30-day mortality prediction. RESULTS: Nonsurvivors (n = 34) showed higher sCD40L levels on days 1 (P < 0.001), 4 (P = 0.004), and 8 (P < 0.001) than did survivor patients (n = 34). Areas under the curve of serum sCD40L concentrations at days 1, 4, and 8 of severe MMCAI for 30-day mortality prediction were 83% (P < 0.001), 89% (P < 0.001), and 87% (P < 0.001), respectively. CONCLUSIONS: The findings that nonsurvivors showed higher serum sCD40L levels during the first week of MMCAI than did survivors and that serum sCD40L levels during the first week of MMCAI could be used as a mortality predictor biomarker are 2 novel findings.


Assuntos
Biomarcadores/sangue , Ligante de CD40/sangue , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/mortalidade , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
BMC Neurol ; 19(1): 167, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319804

RESUMO

BACKGROUND: Higher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 early after ischemic stroke have been associated with lower survival. The objectives of this study were to determine serum TIMP-1 levels during the first week of a severe cerebral infarction in surviving and non-surviving patients, and whether those levels during the first week could be used as a mortality biomarker for these patients. METHODS: We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as computer tomography showing ischaemic changes in more than 50% of the middle cerebral artery territory and Glasgow Coma Scale (GCS) ≤ 8. We measured serum levels of matrix metalloproteinases (MMP)-9 and TIMP-1. End-point study was 30-day mortality. RESULTS: We found higher TIMP-1 concentrations at days 1 (p < 0.001), 4 (p = 0.001), and 8 (p = 0.03) of MMCAI in non- urviving (n = 34) than in surviving (n = 34) patients. We found lower serum MMP-9 concentrations at day 1 (p = 0.03) of MMCAI and no significant differences at days 4 and 8. ROC curve analysis of TIMP-1 concentrations performed at days 1, 4, and 8 of MMCAI showed an area under curve to predict 30-day mortality of 81% (p < 0.001), 80% (p < 0.001) and 72% (p = 0.07) respectively. CONCLUSIONS: The new findings of our study were that non-surviving MMCAI patients showed higher serum TIMP-1 levels during the first week of MMCAI that surviving patients, and those levels during the first week of MMCAI could be used as mortality biomarkers.


Assuntos
Infarto da Artéria Cerebral Média/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Idoso , Biomarcadores/sangue , Feminino , Escala de Coma de Glasgow , Humanos , Infarto da Artéria Cerebral Média/mortalidade , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Acidente Vascular Cerebral/sangue
13.
PLoS Comput Biol ; 15(7): e1007078, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31276496

RESUMO

Network medicine approaches have been largely successful at increasing our knowledge of molecularly characterized diseases. Given a set of disease genes associated with a disease, neighbourhood-based methods and random walkers exploit the interactome allowing the prediction of further genes for that disease. In general, however, diseases with no known molecular basis constitute a challenge. Here we present a novel network approach to prioritize gene-disease associations that is able to also predict genes for diseases with no known molecular basis. Our method, which we have called Cardigan (ChARting DIsease Gene AssociatioNs), uses semi-supervised learning and exploits a measure of similarity between disease phenotypes. We evaluated its performance at predicting genes for both molecularly characterized and uncharacterized diseases in OMIM, using both weighted and binary interactomes, and compared it with state-of-the-art methods. Our tests, which use datasets collected at different points in time to replicate the dynamics of the disease gene discovery process, prove that Cardigan is able to accurately predict disease genes for molecularly uncharacterized diseases. Additionally, standard leave-one-out cross validation tests show how our approach outperforms state-of-the-art methods at predicting genes for molecularly characterized diseases by 14%-65%. Cardigan can also be used for disease module prediction, where it outperforms state-of-the-art methods by 87%-299%.


Assuntos
Doenças Genéticas Inatas/genética , Biologia Computacional/métodos , Bases de Dados Genéticas , Doenças Genéticas Inatas/diagnóstico , Humanos , Fenótipo
14.
Neurocrit Care ; 31(3): 486-493, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31115825

RESUMO

PURPOSE: Circulating caspase-3 levels at 24 h of ischemic stroke were found to be associated with poorer functional neurological outcome in a previous study. The aim of this study was to determine whether there is an association between serum caspase-3 levels and early mortality in patients with malignant middle cerebral artery infarction (MMCAI). METHODS: We included patients with MMCAI defined as computer tomography showing ischemic changes in more than 50% of the middle cerebral artery territory and Glasgow Coma Scale ≤ 8. Serum caspase-3 levels at days 1, 4, and 8 of MMCAI were determined. RESULTS: Non-surviving MMCAI (n = 34) showed higher serum caspase-3 levels at days 1 (p < 0.001), 4 (p = 0.001), and 8 (p = 0.01) than surviving patients (n = 34). We found that the area under the curve of serum caspase-3 levels for prediction of mortality at 30 days was 88% (95% CI = 78-95%; p < 0.001). Multiple logistic regression showed that serum caspase-3 levels were associated with 30-day mortality (OR = 51.25; 95% CI = 8.30-316.31; p < 0.001). CONCLUSIONS: The novel and more important findings of our study were that high serum caspase-3 levels were associated with mortality in MMCAI patients.

15.
Nat Commun ; 10(1): 1167, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842421

RESUMO

The original version of this Article contained an error in the hyperlink for the online repository http://mulvdb.org which was incorrectly given as http://mulv.lms.mrc.ac.uk. This has been corrected in both the PDF and HTML versions of the Article.

16.
World Neurosurg ; 126: e1537-e1541, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30926559

RESUMO

BACKGROUND: Soluble cluster of differentiation 40 ligand (sCD40L) is a member of the tumor necrosis factor family with proinflamatory and procoagulant effects. A previous study found higher serum sCD40L levels at day 1 of traumatic brain injury (TBI) in nonsurviving than surviving patients. Thus the objective of this study was to compare serum sCD40L levels during the first week of a severe TBI between surviving and nonsurviving patients and to determine whether it could be used as a mortality predictor biomarker. METHODS: In this multicenter study severe TBI patients (with Glasgow Coma Scale score <9) with an Injury Severity Score in noncranial item <9 were included. Serum sCD40L concentrations at days 1, 4, and 8 of TBI were determined. We performed receiver operating characteristic analyses to determine the capacity of 30-day TBI mortality prediction by serum sCD40L levels at days 1, 4, and 8 of TBI. RESULTS: We found that nonsurviving (n = 34) patients in comparison with surviving (n = 90) patients had higher sCD40L levels on days 1 (P < 0.001), 4 (P = 0.004), and 8 (P < 0.001) of TBI. We also found that the areas under curve of serum sCD40L concentrations at days 1, 4, and 8 of TBI to 30-day mortality prediction were 82% (P < 0.001), 72% (P = 0.01) and 83% (P < 0.001), respectively. CONCLUSIONS: The existence of higher serum sCD40L levels in nonsurviving than surviving patients during the first week of TBI and fact that serum sCD40L levels during the first week of TBI can be used as a mortality predictor biomarker are the new findings of our study.


Assuntos
Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/mortalidade , Ligante de CD40/sangue , Adulto , Idoso , Biomarcadores , Feminino , Escala de Coma de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Análise de Sobrevida
17.
J Crit Care ; 51: 117-121, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30802757

RESUMO

PURPOSE: Previously, higher circulating levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor matrix metalloproteinases (TIMP)-1 were reported in the first hours after TBI in blood samples from patients with poor prognosis. Thus, the objectives of this study were to determine whether MMP-9 and TIMP-1 levels during the first week of a severe TBI could be used as biomarker predictive of mortality. METHODS: We included patients with severe TBI (defined as Glasgow Coma Scale lower than 9), and with Injury Severity Score in non-cranial aspects lower than 9. We determined serum concentrations of MMP-9 and TIMP-1 at days 1, 4 and 8 of TBI. RESULTS: TIMP-1 concentrations at days 1 (p < .001), 4 (p = .001), and 8 (p = .01) of TBI were higher in non-surviving (n = 34) than in surviving (n = 90) patients. ROC curve analyses showed an area under curve of TIMP-1 concentrations at days 1, 4, and 8 of TBI to predict 30-day mortality of 78% (p < .001), 76% (p < .001) and 71% (p = .02) respectively. CONCLUSIONS: The most relevant new findings of our study were that TIMP-1 levels during the first week of a severe TBI were higher in non-surviving than in surviving patients and that could be used as biomarker predictive of mortality.

18.
Nat Commun ; 9(1): 2649, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985390

RESUMO

Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of murine leukemia virus-driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This scale of data allows novel statistical approaches for identifying selected mutations and yields a high-resolution, genome-wide map of the selective forces surrounding cancer gene loci. We also demonstrate negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Screening of two BCL2 transgenic models confirmed known drivers of human non-Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance and MHC loci. Correlating mutations with genotypic and phenotypic features independently of local variance in mutation density also provides support for weakly evidenced cancer genes. An online resource http://mulv.lms.mrc.ac.uk allows customized queries of the entire dataset.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Linfoma/genética , Mutação , Animais , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Vírus da Leucemia Murina/genética , Vírus da Leucemia Murina/fisiologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Insercional
19.
J Int Med Res ; 46(8): 3268-3277, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29848129

RESUMO

Objectives Lower serum melatonin levels are found in patients with ischaemic stroke compared with healthy controls. This study aimed to determine whether serum melatonin levels are associated with peroxidation status, antioxidant status, and mortality in patients with ischaemic stroke. Methods Patients with severe malignant middle cerebral artery infarction (MMCAI), defined as a Glasgow coma scale (GCS) score lower than 9, were included. Serum levels of melatonin, malondialdehyde (to assess lipid peroxidation), and total antioxidant capacity at the time of diagnosing MMCAI were determined. We chose 30-day mortality as the endpoint of the study. Results We found significantly higher serum levels of melatonin, total antioxidant capacity, and malondialdehyde in non-survivors (n = 32) than in survivors (n = 32) with MMCAI. Serum melatonin levels were associated with 30-day mortality (odds ratio = 2.205; 95% confidence interval = 1.294-3.759) after controlling for GCS score and age. We found a positive association between serum melatonin levels and total antioxidant capacity (rho = 0.36), and between serum melatonin and malondialdehyde levels (rho = 0.35). Conclusions Our study shows that serum melatonin levels are associated with peroxidation status, antioxidant status, and mortality in patients with MMCAI.


Assuntos
Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/mortalidade , Melatonina/sangue , Idoso , Antioxidantes/análise , Feminino , Humanos , Infarto da Artéria Cerebral Média/diagnóstico , Infarto da Artéria Cerebral Média/fisiopatologia , Malondialdeído/sangue , Pessoa de Meia-Idade , Estresse Oxidativo , Prognóstico , Estudos Prospectivos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/fisiopatologia
20.
BMC Neurosci ; 19(1): 23, 2018 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-29661155

RESUMO

BACKGROUND: Apoptotic changes after cerebral hemorrhage in brain samples of humans have been found. Caspase-cleaved cytokeratin (CCCK)-18 could be detected in the bloodstream during apoptosis. Higher circulating CCCK-18 levels have been associated with 6-month mortality in patients with basal ganglia hemorrhage. The aim of our study was to determine whether there is an association between serum CCCK-18 levels and early mortality of spontaneous intracerebral hemorrhage (SIH) patients. We performed an observational, prospective and multicentre study. There were included patients with severe SIH defined as Glasgow Coma Scale (GCS) lower than 9. We determined serum CCCK-18 levels at the severe SIH diagnosis moment. RESULTS: We found that non-surviving SIH patients (n = 46) showed lower GCS, and higher serum CCCK-18 levels and APACHE-II score than survivor ones (n = 54). In ROC analysis was found that the area under the curve of serum CCCK-18 levels for 30-day mortality prediction was 90% (95% CI 82-95%; p < 0.001). In the multiple logistic regression analysis, we found an association between serum CCCK-18 levels and 30-day mortality (OR 1.034; 95% CI 1.013-1.055; p = 0.002). CONCLUSIONS: The novel finding of our study was that there is an association between high serum CCCK-18 levels and 30-day mortality in severe SIH patients.


Assuntos
Biomarcadores/sangue , Caspases/sangue , Hemorragia Cerebral/mortalidade , Queratina-18/sangue , Idoso , Hemorragia Cerebral/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Curva ROC
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