Clinical relevance of midline fluid percussion brain injury: Acute deficits, chronic morbidities and the utility of biomarkers.
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ABSTRACT:
SUBMITTER: Lifshitz J
PROVIDER: S-EPMC5303557 | biostudies-other | 2016
REPOSITORIES: biostudies-other
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Project description:Acute trauma involving the anterior cruciate ligament is believed to be a major risk factor for the development of post-traumatic osteoarthritis 10 to 20 years post-injury. In this study, to better understand the early biological changes which occur after acute injury, we investigated synovial fluid and serum biomarkers.We collected serum from 11 patients without pre-existing osteoarthritis from a pilot intervention trial (5 placebo and 6 drug treated) using an intra-articular interleukin-1 receptor antagonist (IL-1Ra) therapy, 9 of which also supplied matched synovial fluid samples at presentation to the clinic after acute knee injury (mean 15.2 ± 7.2 days) and at the follow-up visit for reconstructive surgery (mean 47.6 ± 12.4 days). To exclude patients with pre-existing osteoarthritis (OA), the study was limited to individuals younger than 40 years of age (mean 23 ± 3.5) with no prior history of joint symptoms or trauma. We profiled a total of 21 biomarkers; 20 biomarkers in synovial fluid and 13 in serum with 12 biomarkers measured in both fluids. Biomarkers analyzed in this study were found to be independent of treatment (P > 0.05) as measured by Mann-Whitney and two-way ANOVA.We observed significant decreases in synovial fluid (sf) biomarker concentrations from baseline to follow-up for (sf)C-Reactive protein (CRP) (P = 0.039), (sf)lubricin (P = 0.008) and the proteoglycan biomarkers: (sf)Glycosaminoglycan (GAG) (P = 0.019), and (sf)Alanine-Arginine-Glycine-Serine (ARGS) aggrecan (P = 0.004). In contrast, we observed significant increases in the collagen biomarkers: (sf)C-terminal crosslinked telopeptide type II collagen (CTxII) (P = 0.012), (sf)C1,2C (P = 0.039), (sf)C-terminal crosslinked telopeptide type I collagen (CTxI) (P = 0.004), and (sf)N-terminal telopeptides of type I collagen (NTx) (P = 0.008). The concentrations of seven biomarkers were significantly higher in synovial fluid than serum suggesting release from the signal knee: IL-1? (P < 0.0001), fetal aggrecan FA846 (P = 0.0001), CTxI (P = 0.0002), NTx (P = 0.012), osteocalcin (P = 0.012), Cartilage oligomeric matrix protein (COMP) (P = 0.0001) and matrix metalloproteinase (MMP)-3 (P = 0.0001). For these seven biomarkers we found significant correlations between the serum and synovial fluid concentrations for only CTxI (P = 0.0002), NTx (P < 0.0001), osteocalcin (P = 0.0002) and MMP-3 (P = 0.038).These data strongly suggest that the biology after acute injury reflects that seen in cartilage explant models stimulated with pro-inflammatory cytokines, which are characterized by an initial wave of proteoglycan loss followed by subsequent collagen loss. As the rise of collagen biomarkers in synovial fluid occurs within the first month after injury, and as collagen loss is thought to be irreversible, very early treatment with agents to either reduce inflammation and/or reduce collagen loss may have the potential to reduce the onset of future post-traumatic osteoarthritis.The samples used in this study were derived from a clinical trial NCT00332254 registered with ClinicalTrial.gov.
| S-EPMC3046542 | biostudies-literature
Project description:AimsTo investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery.Materials and methodsIn this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.6 mg/kg/hour for 8 weeks. The dopamine-releasing conditions and metabolism were analyzed sequentially by fast scan cyclic voltammetry (FSCV) and high-pressure liquid chromatography (HPLC). Novel object recognition (NOR) and fixed-speed rotarod (FSRR) behavioral tests were used to determine treatment effects on cognitive and motor deficits after injury.ResultsSequential dopamine-release deficits were revealed in 6-Pa-fluid-percussion cerebral cortical injured animals. The reuptake rate (tau value) of dopamine in injured animals was prolonged, but the tau value became close to the value for the control group after amantadine therapy. Cognitive and motor learning impairments were shown evidenced by the NOR and FSRR behavioral tests after injury. Chronic amantadine therapy reversed dopamine-release deficits, and behavioral impairment after fluid percussion injuries were ameliorated in the rats treated by using amantadine-pumping infusion.ConclusionChronic treatment with amantadine hydrochloride can ameliorate dopamine-release deficits as well as cognitive and motor deficits caused by cerebral fluid-percussion injury.
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Project description:Individual characteristics of pathophysiology and course of depressive episodes are at present not considered in diagnostics. There are no biological markers available that can assist in categorizing subtypes of depression and detecting molecular variances related to disease-causing mechanisms between depressed patients. Identification of such differences is important to create patient subgroups, which will benefit from medications that specifically target the pathophysiology underlying their clinical condition. To detect characteristic biological markers for major depression, we analyzed the cerebrospinal fluid (CSF) proteome of depressed vs control persons, using two-dimensional polyacrylamide gel electrophoresis and time-of-flight (TOF) mass spectrometry peptide profiling. Proteins of interest were identified by matrix-assisted laser desorption ionization TOF mass spectrometry (MALDI-TOF-MS). Validation of protein markers was performed by immunoblotting. We found 11 proteins and 144 peptide features that differed significantly between CSF from depressed patients and controls. In addition, we detected differences in the phosphorylation pattern of several CSF proteins. A subset of the differentially expressed proteins implicated in brain metabolism or central nervous system disease was validated by immunoblotting. The identified proteins are involved in neuroprotection and neuronal development, sleep regulation, and amyloid plaque deposition in the aging brain. This is one of the first hypothesis-free studies that identify characteristic protein expression differences in CSF of depressed patients. Proteomic approaches represent a powerful tool for the identification of disease markers for subgroups of patients with major depression.
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Project description:Acute lung injury (ALI) is characterized by pulmonary edema and acute inflammation leading to pulmonary dysfunction and potentially death. Early medical intervention may ameliorate the severity of ALI, but unfortunately, there are no reliable biomarkers for early diagnosis. We screened for biomarkers in a mouse model of ALI. In this model, inhalation of S. aureus enterotoxin A causes increased capillary permeability, cell damage, and increase protein and cytokine concentration in the lungs. We set out to find predictive biomarkers of ALI in bronchoalveolar lavage (BAL) fluid before the onset of clinical manifestations. A cutting edge proteomic approach was used to compare BAL fluid harvested 16 h post S. aureus enterotoxin A inhalation versus BAL fluid from vehicle alone treated mice. The proteomic PF 2D platform permitted comparative analysis of proteomic maps and mass spectrometry identified cytochrome b5 and cytokeratin 17 in BAL fluid of mice challenged with S. aureus enterotoxin A. Validation of cytochrome b5 showed tropic expression in epithelial cells of the bronchioles. Importantly, S. aureus enterotoxin A inhalation significantly decreased cytochrome b5 during the onset of lung injury. Validation of cytokeratin 17 showed ubiquitous expression in lung tissue and increased presence in BAL fluid after S. aureus enterotoxin A inhalation. Therefore, these new biomarkers may be predictive of ALI onset in patients and could provide insight regarding the basis of lung injury and inflammation.
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Project description:Suffering an acute spinal cord injury (SCI) can result in catastrophic physical and emotional loss. Efforts to translate novel therapies in acute clinical trials are impeded by the SCI community's singular dependence upon functional outcome measures. Therefore, a compelling rationale exists to establish neurochemical biomarkers for the objective classification of injury severity. In this study, CSF and serum samples were obtained at 3 time points (~24, 48, and 72?hours post-injury) from 30 acute SCI patients (10 AIS A, 12 AIS B, and 8 AIS C). A differential chemical isotope labeling liquid chromatography mass spectrometry (CIL LC-MS) with a universal metabolome standard (UMS) was applied to the metabolomic profiling of these samples. This method provided enhanced detection of the amine- and phenol-containing submetabolome. Metabolic pathway analysis revealed dysregulations in arginine-proline metabolism following SCI. Six CSF metabolites were identified as potential biomarkers of baseline injury severity, and good classification performance (AUC?>?0.869) was achieved by using combinations of these metabolites in pair-wise comparisons of AIS A, B and C patients. Using the UMS strategy, the current data set can be expanded to a larger cohort for biomarker validation, as well as discovering biomarkers for predicting neurologic outcome.
| S-EPMC5155264 | biostudies-literature
Project description:It is widely accepted that cerebral pathology can impair ocular motor and manual motor control. This is true in indolent and chronic processes, such as neurodegeneration and in acute processes such as stroke or those secondary to neurotrauma. More recently, it has been suggested that disruptions in these control systems are useful markers for prognostication and longitudinal monitoring. The utility of examining the relationship or the coupling between these systems has yet to be determined. We measured eye and hand-movement control in chronic, middle cerebral artery stroke, relative to healthy controls, in saccade-to-reach paradigms to assess eye-hand coordination. Primary saccades were initiated significantly earlier by stroke participants relative to control participants. However, despite these extremely early initial saccades to the target, reaches were nevertheless initiated at approximately the same time as those of control participants. Control participants minimized the time period between primary saccade onset and reach initiation, demonstrating temporal coupling between eye and hand. In about 90% of all trials, control participants produced no secondary, or corrective, saccades, instead maintaining fixation in the terminal position of the primary saccade until the end of the reach. In contrast, participants with stroke increased the time period between primary saccade onset and reach initiation. During this temporal decoupling, multiple saccades were produced in about 50% of the trials with stroke participants making between one and five additional saccades. Reaches made by participants with stroke were both longer in duration and less accurate. In addition to these increases in spatial reach errors, there were significant increases in saccade endpoint errors. Overall, the magnitude of the endpoint errors for reaches and saccades were correlated across participants. These findings suggest that in individuals with otherwise intact visual function, the spatial and temporal relationships between the eye and hand are disrupted poststroke, and may need to be specifically targeted during neurorehabilitation. Eye-hand coupling may be a useful biomarker in individuals with cerebral pathology in the setting of neurovascular, neurotraumatic, and neurodegenerative pathology.
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Project description:Introduction:Acute kidney injury (AKI) following cardiovascular surgery has been shown to increase costs and overall morbidity and mortality. The incidence, risk factors, and outcomes of AKI following other types of major surgeries have not been as well characterized. We sought to study the incidence of AKI following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) per the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Materials and methods:Patients undergoing CRS and HIPEC between 2013 and 2015 were included. Demographic and perioperative data were compared between patients who experienced AKI versus controls using appropriate statistical analysis between categorical and continuous variables. AKI was recorded by a Certified Professional in Healthcare Quality (CPHQ) and defined as a rise in serum creatinine by???0.3?mg/dL within 48?h (KDIGO criteria). Results:Fifty-eight consecutive patients undergoing CRS and HIPEC were included. Twelve (20.7%) patients were recorded to develop AKI. This was the most common complication recorded by the CPHQ member. There was one 30-day mortality secondary to cerebral infarction. AKI patients had a longer hospitalization period (14.2?±?6.9 vs. 9.5?±?3.3 days, p?=?0.002), and a higher rate of major complications (50.00% vs. 15.21%; p?=?0.018). Readmission rate was similar (p?=?0.626). Multivariate regression identified excessive blood loss during surgery as a major predictor of AKI occurrence, and pre-existing comorbidities and postoperative AKI as predictors of major morbidities following CRS and HIPEC. Conclusion:AKI following CRS and HIPEC appears to be a common complication which is associated with further major morbidities. Current quality improvement programs may be under-reporting this incidence.
| S-EPMC6178214 | biostudies-literature
Project description:Pre-renal acute kidney injury (AKI) is assumed to represent a physiological response to underperfusion. Its diagnosis is retrospective after a transient rise in plasma creatinine, usually associated with evidence of altered tubular transport, particularly that of sodium. In order to test whether pre-renal AKI is reversible because injury is less severe than that of sustained AKI, we measured urinary biomarkers of injury (cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), ?-glutamyl transpeptidase, IL-18, and kidney injury molecule-1 (KIM-1)) at 0, 12, and 24?h following ICU admission. A total of 529 patients were stratified into groups having no AKI, AKI with recovery by 24?h, recovery by 48?h, or the composite of AKI greater than 48?h or dialysis. Pre-renal AKI was identified in 61 patients as acute injury with recovery within 48?h and a fractional sodium excretion <1%. Biomarker concentrations significantly and progressively increased with the duration of AKI. After restricting the AKI recovery within the 48?h cohort to pre-renal AKI, this increase remained significant. The median concentration of KIM-1, cystatin C, and IL-18 were significantly greater in pre-renal AKI compared with no-AKI, while NGAL and ?-glutamyl transpeptidase concentrations were not significant. The median concentration of at least one biomarker was increased in all but three patients with pre-renal AKI. Thus, the reason why some but not all biomarkers were increased requires further study. The results suggest that pre-renal AKI represents a milder form of injury.
| S-EPMC3365288 | biostudies-literature
Project description:BackgroundFluid resuscitation is frequently required for cardiac surgical patients admitted to the intensive care unit. The ideal fluid of choice in regard to efficacy and safety remains uncertain. Compared with crystalloid fluid, colloid fluid may result in less positive fluid balance. However, some synthetic colloids are associated with increased risk of acute kidney injury (AKI). This study compared the effects of succinylated gelatin (4%) (GEL) with compound sodium lactate (CSL) on urinary AKI biomarkers in patients after cardiac surgery.MethodsCardiac surgical patients who required an intravenous fluid bolus of at least 500 mL postoperatively were randomly allocated to receive GEL or CSL as the resuscitation fluid of choice for the subsequent 24 h. Primary outcomes were serial urinary neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C concentrations measured at baseline, 1 h, 5 h and 24 h after enrolment, with higher concentrations indicating greater kidney injury. Secondary biomarker outcomes included urinary clusterin, α1-microglobulin and F2-isoprostanes concentrations. Differences in change of biomarker concentration between the two groups over time were compared with mixed-effects regression models. Statistical significance was set at P < 0.05.ResultsForty cardiac surgical patients (n = 20 per group) with similar baseline characteristics were included. There was no significant difference in the median volume of fluid boluses administered over 24 h between the GEL (1250 mL, Q1-Q3 500-1750) and CSL group (1000 mL, Q1-Q3 500-1375) (P = 0.42). There was a significantly greater increase in urinary cystatin C (P < 0.001), clusterin (P < 0.001), α1-microglobulin (P < 0.001) and F2-isoprostanes (P = 0.020) concentrations over time in the GEL group, compared to the CSL group. Change in urinary NGAL concentration (P = 0.68) over time was not significantly different between the groups. The results were not modified by adjustment for either urinary osmolality or EuroSCORE II predicted risk of mortality.ConclusionsThis preliminary randomised controlled trial showed that use of succinylated gelatin (4%) for fluid resuscitation after cardiac surgery was associated with increased biomarker concentrations of renal tubular injury and dysfunction, compared to crystalloid fluid. These results generate concern that use of intravenous gelatin fluid may contribute to clinically relevant postoperative AKI. Trial registration ANZCTR.org.au, ACTRN12617001461381. Registered on 16th October, 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373619&isReview=true .
| S-EPMC8455786 | biostudies-literature
Project description:Spontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX. Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.
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