Clinical and Pathological Correlations in Chronic Venous Disease.

BACKGROUND: Chronic Venous Disease (CVD) has a high prevalence in the western world. Varicose veins (VVs) are the main signs of this disease that is characterized by important pathological vessel wall changes. The aim of this study is to correlate the main histopathological abnormalities with related clinical issues of CVD. METHODS: A cohort of patients with VVs scheduled for open surgical treatment namely stab avulsion of VVs was recruited. Subsequently, venous tissue from stab avulsion was collected in order to evaluate the following biomarkers: Vascular-Endothelial Growth Factor (VEGF), Protein Gene Product 9.5 (PGP 9.5), Fibronectin (FN), and Matrix Metalloproteinase-9 (MMP-9). The Clinical-Etiology-Anatomy-Pathophysiology (CEAP) criteria were used to classify CVD. RESULTS: Fourteen tissue fragments were processed for histological and immunohistochemical studies. Of these, 43% were from CEAP C2 patients, 36% from CEAP C3 patients, and 21% from CEAP C4 patients. CEAP Class C2 had few to moderate structures positive to VEGF; occasional structures positive to Fibronectin, numerous structures positive to MMP9, few to moderate structures positive to PGP 9.5. CEAP Class C3 had moderate structures positive to VEGF; few to moderate structures positive to Fibronectin; many structures positive to MMP9; few to moderate structures positive to PGP 9.5. CEAP Class C4 had numerous structures positive to VEGF; numerous structures positive to Fibronectin; abundant structures positive to MMP-9; few structures positive to PGP 9.5. CONCLUSIONS: In this study, positive VEGF, FN, and MMP-9 structures were found with increasing trends in relation to the disease staging. VEGF and FN are associated with a progressive increase from C2 to C4. The MMP-9 marker has an important positivity even at early stage of the disease, being higher in CEAP C4 patients. PGP 9.5 decreases in CEAP C4 patients and this is concordant to decreased vein wall innervation.

Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post-Cardiac Arrest.

[Figure: see text].

Progesterone Treatment Does Not Decrease Serum Levels of Biomarkers of Glial and Neuronal Cell Injury in Moderate and Severe Traumatic Brain Injury Subjects: A Secondary Analysis of the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECT) III Trial.

Early treatment of moderate/severe traumatic brain injury (TBI) with progesterone does not improve clinical outcomes. This is in contrast with findings from pre-clinical studies of progesterone in TBI. To understand the reasons for the negative clinical trial, we investigated whether progesterone treatment has the desired biological effect of decreasing brain cell death. We quantified brain cell death using serum levels of biomarkers of glial and neuronal cell death (glial fibrillary acidic protein [GFAP], ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], and Alpha II Spectrin Breakdown Product 150 [SBDP]) in the Biomarkers of Injury and Outcome-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (BIO-ProTECT) study. Serum levels of GFAP, UCHL1, S100B, and SBDP were measured at baseline (≤4 h post-injury and before administration of study drug) and at 24 and 48 h post-injury. Serum progesterone levels were measured at 24 and 48 h post-injury. The primary outcome of ProTECT was based on the Glasgow Outcome Scale-Extended assessed at 6 months post-randomization. We found that at baseline, there were no differences in biomarker levels between subjects randomized to progesterone treatment and those randomized to placebo (p > 0.10). Similarly, at 24 and 48 h post-injury, there were no differences in biomarker levels in the progesterone versus placebo groups (p > 0.15). There was no statistically significant correlation between serum progesterone concentrations and biomarker values obtained at 24 and 48 h. When examined as a continuous variable, baseline biomarker levels did not modify the association between progesterone treatment and neurological outcome (p of interaction term >0.39 for all biomarkers). We conclude that progesterone treatment does not decrease levels of biomarkers of glial and neuronal cell death during the first 48 h post-injury.

Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI.

Serum biomarkers are promising tools for evaluating patients following traumatic brain injury (TBI). However, their relationship with diffuse histopathology remains unclear. Additionally, translatability is a focus of neurotrauma research, however, studies using translational animal models are limited. Here, we evaluated associations between circulating biomarkers and acute thalamic histopathology in a translational micro pig model of mTBI. Serum samples were collected pre-injury, and 1 min-6 h following mTBI. Markers of neuronal injury (Ubiquitin Carboxy-terminal Hydrolase L1 [UCH-L1]), microglial/macrophage activation (Ionized calcium binding adaptor molecule-1 [Iba-1]) and interleukin-6 [IL-6]) and astrogliosis/astrocyte damage (glial fibrillary acidic protein [GFAP]) were measured. Axonal injury and histological features of neurons and glia were also investigated using immunofluorescent labeling and correlated to serum levels of the associated biomarkers. Consistent with prior experimental and human studies, GFAP, was highest at 6 h post-injury, while no substantial changes were observed in UCH-L1, Iba-1 or IL-6 over 6 h. This study also found promising associations between thalamic glial histological signatures and ensuing release of Iba-1 and GFAP into the circulation. Our findings suggest that in diffuse injury, monitoring serum Iba-1 and GFAP levels can provide clinically relevant insight into the underlying acute pathophysiology and biomarker release kinetics following mTBI, providing previously underappreciated diagnostic capability.

Evaluation of ubiquitin C-terminal hydrolase-L1 enzyme levels in patients with epilepsy / Avaliação dos níveis de enzima ubiquitina C-terminal hidrolase-L1 em pacientes com epilepsia

ABSTRACT Objective: Ubiquitin C-terminal Hydrolase-L1 (UCH-L1) enzyme levels were investigated in patients with epilepsy, epileptic seizure, remission period, and healthy individuals. Methods: Three main groups were evaluated, including epileptic seizure, patients with epilepsy in the non-seizure period, and healthy volunteers. The patients having a seizure in the Emergency department or brought by a postictal confusion were included in the epileptic attack group. The patients having a seizure attack or presenting to the Neurology outpatient department for follow up were included in the non-seizure (remission period) group. Results: The UCH-L1 enzyme levels of 160 patients with epilepsy (80 patients with epileptic attack and 80 patients with epilepsy in the non-seizure period) and 100 healthy volunteers were compared. Whereas the UCH-L1 enzyme levels were 8.30 (IQR=6.57‒11.40) ng/mL in all patients with epilepsy, they were detected as 3.90 (IQR=3.31‒7.22) ng/mL in healthy volunteers, and significantly increased in numbers for those with epilepsy (p<0.001). However, whereas the UCH-L1 levels were 8.50 (IQR=6.93‒11.16) ng/mL in the patients with epileptic seizures, they were 8.10 (IQR=6.22‒11.93) ng/mL in the non-seizure period, and no significant difference was detected (p=0.6123). When the UCH-L1 cut-off value was taken as 4.34 mg/mL in Receiver Operating Characteristic (ROC) Curve analysis, the sensitivity and specificity detected were 93.75 and 66.00%, respectively (AUG=0.801; p<0.0001; 95%CI 0.747‒0.848) for patients with epilepsy. Conclusion: Even though UCH-L1 levels significantly increased more in patients with epilepsy than in healthy individuals, there was no difference between epileptic seizure and non-seizure periods.

RESUMO Objetivo: Níveis da enzima ubiquitina C-terminal hidrolase-L1 (UCH-L1) foram investigados em pacientes com epilepsia, crise epiléptica, período de remissão e indivíduos saudáveis. Método: Foram avaliados três grupos principais, incluindo crise epiléptica, epilepsia no período não convulsivo e voluntários saudáveis. Pacientes com convulsão no departamento de emergência ou trazidos por confusão pós-ictal foram incluídos no grupo de crise epiléptica. Os pacientes que tiveram crise epiléptica ou foram ao ambulatório de Neurologia para acompanhamento foram incluídos no grupo não convulsivo (período de remissão). Resultados: Os níveis da enzima UCH-L1 de 160 pacientes com epilepsia (80 pacientes com crise epiléptica e 80 pacientes com epilepsia no período não convulsivo) e 100 voluntários saudáveis foram comparados. Enquanto os níveis da enzima UCH-L1 foram 8,30 (IQR=6,57‒11,40) ng/mL em todos os pacientes com epilepsia, os níveis detectados foram de 3,90 (IQR=3,31‒7,22) ng/mL em voluntários saudáveis e aumentaram significativamente na epilepsia (p<0,001). No entanto, ao passo que os níveis de UCH-L1 foram 8,50 (IQR=6,93‒11,16) ng/mL nos pacientes com crise epiléptica, foram 8,10 (IQR=6,22‒11,93) ng/mL no período não convulsivo, e nenhuma diferença significativa foi detectada (p=0,6123). Quando o valor de corte de UCH-L1 foi considerado 4,34 mg/mL com base na análise da curva ROC, sensibilidade e especificidade foram detectadas como 93,75 e 66,00%, respectivamente (AUG=0,801; p<0,0001; IC95% 0,747‒0,848) para os pacientes com epilepsia. Conclusão: Embora os níveis de UCH-L1 tenham aumentado significativamente nos pacientes com epilepsia em relação aos indivíduos saudáveis, não foi observada diferença entre crise epiléptica e períodos não convulsivos.

Blood-based biomarkers for prediction of intracranial hemorrhage and outcome in patients with moderate or severe traumatic brain injury.

BACKGROUND: Early identification of traumatic intracranial hemorrhage (ICH) has implications for triage and intervention. Blood-based biomarkers were recently approved by the Food and Drug Administration (FDA) for prediction of ICH in patients with mild traumatic brain injury (TBI). We sought to determine if biomarkers measured early after injury improve prediction of mortality and clinical/radiologic outcomes compared with Glasgow Coma Scale (GCS) alone in patients with moderate or severe TBI (MS-TBI). METHODS: We measured glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein-2 (MAP-2) on arrival to the emergency department (ED) in patients with blunt TBI enrolled in the placebo arm of the Prehospital TXA for TBI Trial (prehospital GCS score, 3-12; SPB, > 90). Biomarkers were modeled individually and together with prehospital predictor variables [PH] (GCS score, age, sex). Data were divided into a training data set and test data set for model derivation and evaluation. Models were evaluated for prediction of ICH, mass lesion, 48-hour and 28-day mortality, and 6-month Glasgow Outcome Scale-Extended (GOS-E) and Disability Rating Scale (DRS). Area under the curve (AUC) was evaluated in test data for PH alone, PH + individual biomarkers, and PH + three biomarkers. RESULTS: Of 243 patients with baseline samples (obtained a median of 84 minutes after injury), prehospital GCS score was 8 (interquartile range, 5-10), 55% had ICH, and 48-hour and 28-day mortality were 7% and 13%, respectively. Poor neurologic outcome at 6 months was observed in 34% based on GOS-E of 4 or less, and 24% based on DRS greater than or equal to7. Addition of each biomarker to PH improved AUC in the majority of predictive models. GFAP+PH compared with PH alone significantly improved AUC in all models (ICH, 0.82 vs. 0.64; 48-hour mortality, 0.84 vs. 0.71; 28-day mortality, 0.84 vs. 0.66; GOS-E, 0.78 vs. 0.69; DRS, 0.84 vs. 0.81, all p < 0.001). CONCLUSION: Circulating blood-based biomarkers may improve prediction of neurological outcomes and mortality in patients with MS-TBI over prehospital characteristics alone. Glial fibrillary acidic protein appears to be the most promising. Future evaluation in the prehospital setting is warranted. LEVEL OF EVIDENCE: Prospective, Prognostic and Epidemiological, level II.

Prediagnostic circulating inflammation biomarkers and esophageal squamous cell carcinoma: A case-cohort study in Japan.

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype of esophageal cancer worldwide. Measurements of circulating inflammation-related biomarkers may inform etiology or provide noninvasive signatures for early diagnosis. We therefore examined levels of inflammation molecules for associations with ESCC risk. Using a case-cohort study designed within the Japan Public Health Center-based Prospective Study, we measured baseline plasma levels of 92 biomarkers using a multiplex assay in a subcohort of 410 randomly selected participants and 66 participants with incident ESCC (including four cases that occurred in the subcohort). ESCC hazard ratios (HRs) were calculated for 2-4 quantiles of each biomarker by Cox proportional hazards regression models with age as the time metric, adjusted for sex, smoking and alcohol use. Twenty analytes were undetectable in nearly all samples. Of the remaining 72, 12 biomarkers (FGF19, ST1A1, STAMBP, AXIN1, CASP8, NT3, CD6, CDCP1, CD5, SLAMF1, OPG and CSF1) were associated with increased ESCC risk (ptrend < 0.05) with HRs per quantile 1.28-1.65. Seven biomarkers (CXCL6, CCL23, CXCL5, TGFA, CXCL1, OSM and CCL4) were inversely associated with HRs 0.57-0.72. FGF19, CASP8, STAMBP, ST1A1 and CCL-4 met statistical significance with false discovery rate correction. Associations did not differ <5 vs. ≥5 years between blood collection and ESCC diagnosis. CASP8, STAMBP and ST1A1 were strongly correlated (p < 0.05). Our study expands the range of inflammation molecules associated with the development of this highly lethal neoplasia. Correlations among these novel biomarkers suggest a possible shared pathway. These findings need replication and could further delineate ESCCs molecular mechanisms of carcinogenesis.

Intraoperative Oxidative Damage and Delirium after Cardiac Surgery.

BACKGROUND: Mechanisms of postoperative delirium remain poorly understood, limiting development of effective treatments. We tested the hypothesis that intraoperative oxidative damage is associated with delirium and neuronal injury and that disruption of the blood-brain barrier modifies these associations. METHODS: In a prespecified cohort study of 400 cardiac surgery patients enrolled in a clinical trial of atorvastatin to reduce kidney injury and delirium, we measured plasma concentrations of F2-isoprostanes and isofurans using gas chromatography-mass spectrometry to quantify oxidative damage, ubiquitin carboxyl-terminal hydrolase isozyme L1 to quantify neuronal injury, and S100 calcium-binding protein B using enzyme-linked immunosorbent assays to quantify blood-brain barrier disruption before, during, and after surgery. We performed the Confusion Assessment Method for the Intensive Care Unit twice daily to diagnose delirium. We measured the independent associations between intraoperative F2-isoprostanes and isofurans and delirium (primary outcome) and postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (secondary outcome), and we assessed if S100 calcium-binding protein B modified these associations. RESULTS: Delirium occurred in 109 of 400 (27.3%) patients for a median (10th, 90th percentile) of 1.0 (0.5, 3.0) days. In the total cohort, plasma ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was 6.3 ng/ml (2.7, 14.9) at baseline and 12.4 ng/ml (7.9, 31.2) on postoperative day 1. F2-isoprostanes and isofurans increased throughout surgery, and the log-transformed sum of intraoperative F2-isoprostanes and isofurans was independently associated with increased odds of postoperative delirium (odds ratio, 3.70 [95% CI, 1.41 to 9.70]; P = 0.008) and with increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (ratio of geometric means, 1.42 [1.11 to 1.81]; P = 0.005). The association between increased intraoperative F2-isoprostanes and isofurans and increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 was amplified in patients with elevated S100 calcium-binding protein B (P = 0.049). CONCLUSIONS: Intraoperative oxidative damage was associated with increased postoperative delirium and neuronal injury, and the association between oxidative damage and neuronal injury was stronger among patients with increased blood-brain barrier disruption.

Observational study of long-term persistent elevation of neurodegeneration markers after cardiac surgery.

Surgery and anesthesia induce inflammatory changes in the central nervous system, which ultimately lead to neuronal damage concomitant with an increase in the level of neurodegeneration markers. Despite some experimental data showing prolonged activation of the immune system post-surgery, no study has determined the extent of long-term elevation of neurodegeneration markers. The purpose of this study was to investigate the serum levels of tau protein, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NF-L), and glial fibrillary acidic protein (GFAP) after elective cardiac surgery with the implementation of cardiopulmonary bypass (CPB). The serum levels of these markers from 30 patients were compared longitudinally to the baseline (pre-surgery or t0), at 24 hours (t+24), at 7 days (t+7d), and at 3 months (t+3m). The secondary outcome was the production of macrophage-colony stimulating factor (M-CSF) and tumor necrosis factor-α (TNF-α) in vitro by isolated monocytes in response to lipopolysaccharide (LPS) as the measure of immune system activation. The tertiary outcome was the serum level of C-reactive protein (CRP), serum amyloid P (SAP), and α-2-macroglobulin (A2M). Serum levels of tau protein increased 24 hours after surgery (p = 0.0015) and remained elevated at 7 days (p = 0.0017) and three months (p = 0.036). Serum levels of UCH-L1 peaked at 24 hours (p = 0.00055) and normalized at 3 months. In vitro secretion of M-CSF by LPS-stimulated peripheral monocytes, but not TNFα, correlated highly (r = 0.58; p = 0.04) with persistent elevation of serum tau levels at 3 months. The serum CRP and SAP increases correlated with tau post-CPB levels significantly at 3 months. We demonstrated that elevation of serum tau levels at 24 hours, 7 days, and 3 months after heart surgery is concomitant with some traits of inflammation after CPB. The elevation of tau several weeks into recovery is significantly longer than expected.

Glial Fibrillary Acidic Protein (GFAP) Outperforms S100 Calcium-Binding Protein B (S100B) and Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) as Predictor for Positive Computed Tomography of the Head in Trauma Subjects.

OBJECTIVE: Traumatic brain injuries (TBIs) are largely underdiagnosed and may have persistent refractory consequences. Current assessments for acute TBI are limited to physical examination and imaging. Biomarkers such as glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and S100 calcium-binding protein B (S100B) have shown predictive value as indicators of TBI and potential screening tools. METHODS: In total, 37 controls and 118 unique trauma subjects who received a clinically ordered head computed tomography (CT) in the emergency department of a level 1 trauma center were evaluated. Blood samples collected at 0-8 hours (initial) and 12-32 hours (delayed) postinjury were analyzed for GFAP, UCH-L1, and S100B concentrations. These were then compared in CT-negative and CT-positive subjects. RESULTS: Median GFAP, UCH-L1, and S100B concentrations were greater in CT-positive subjects at both timepoints compared with CT-negative subjects. In addition, median UCH-L1 and S100B concentrations were lower at the delayed timepoint, whereas median GFAP concentrations were increased. As predictors of a positive CT of the head, GFAP outperformed UCH-L1 and S100B at both timepoints (initial: 0.89 sensitivity, 0.62 specificity; delayed: 0.94 sensitivity, 0.67 specificity). GFAP alone also outperformed all possible combinations of biomarkers. CONCLUSIONS: GFAP, UCH-L1, and S100B demonstrated utility for rapid prediction of a CT-positive TBI within 0-8 hours of injury. GFAP exhibited the greatest predictive power at 12-32 hours. Furthermore, these results suggest that GFAP alone has greater utility for predicting a positive CT of the head than UCH-L1, S100B, or any combination of the 3.

The role of UCH-L1, MMP-9, and GFAP as peripheral markers of different susceptibility to seizure development in a preclinical model of epilepsy.

In our study, we assessed the potency of the brain-derived proteins ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), matrix metalloproteinase 9 (MMP-9), glial fibrillary acidic protein (GFAP) and the immune activation indicators interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) as peripheral biomarkers of different susceptibilities to kindling in a preclinical model. We observed increased plasma UCH-L1 levels in kindled vs. control animals. Furthermore, MMP-9 and IL-1ß concentrations were the lowest in rats resistant to kindling. In summary, UCH-L1 is an indicator of neuronal loss and BBB disruption after seizure. MMP-9 and IL-1ß may indicate resistance to kindling. UCH-L1, MMP-9 and IL-1ß may have utility as peripheral biomarkers with translational potency in the clinic.

Association of Very Early Serum Levels of S100B, Glial Fibrillary Acidic Protein, Ubiquitin C-Terminal Hydrolase-L1, and Spectrin Breakdown Product with Outcome in ProTECT III.

Rapid risk-stratification of patients with acute traumatic brain injury (TBI) would inform management decisions and prognostication. The objective of this serum biomarker study (Biomarkers of Injury and Outcome [BIO]-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment [ProTECT]) was to test the hypothesis that serum biomarkers of structural brain injury, measured at a single, very early time-point, add value beyond relevant clinical covariates when predicting unfavorable outcome 6 months after moderate-to-severe acute TBI. BIO-ProTECT utilized prospectively collected samples obtained from subjects with moderate-to-severe TBI enrolled in the ProTECT III clinical trial of progesterone. Serum samples were obtained within 4 h after injury. Glial fibrillary acidic protein (GFAP), S100B, αII-spectrin breakdown product of molecular weight 150 (SBDP150), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) were measured. The association between log-transformed biomarker levels and poor outcome, defined by a Glasgow Outcome Scale-Extended (GOS-E) score of 1-4 at 6 months post-injury, were estimated via logistic regression. Prognostic models and a biomarker risk score were developed using bootstrapping techniques. Of 882 ProTECT III subjects, samples were available for 566. Each biomarker was associated with 6-month GOS-E (p < 0.001). Compared with a model containing baseline patient variables/characteristics, inclusion of S100B and GFAP significantly improved prognostic capacity (p ≤ 0.05 both comparisons); conversely, UCH-L1 and SBDP did not. A final predictive model incorporating baseline patient variables/characteristics and biomarker data (S100B and GFAP) had the best prognostic capability (area under the curve [AUC] = 0.85, 95% confidence interval [CI]: CI 0.81-0.89). Very early measurements of brain-specific biomarkers are independently associated with 6-month outcome after moderate-to-severe TBI and enhance outcome prediction.

Ubiquitin C-Terminal Hydrolase 1 and Phosphorylated Axonal Neurofilament Heavy Chain in Infants Undergoing Cardiac Surgery: Preliminary Assessment as Potential Biomarkers of Brain Injury.

BACKGROUND: There are no reliable markers to assess brain injury in neonates following cardiac surgery. We examine ubiquitin C-terminal hydrolase 1 (UCHL1) and phosphorylated axonal neurofilament heavy chain (pNF-H), neuronal-specific biomarkers released following axonal and cortical injury, in neonates undergoing cardiac surgery involving cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). METHODS: Twenty-six patients younger than three months were prospectively enrolled (CPB only, n = 12 and DHCA, n = 14). Healthy newborns (n = 22) served as the control. Blood samples were collected preoperatively and postoperatively upon intensive care unit admission (hour 0) and subsequently at 12, 24, 36, and 48 hours. Serum was tested for UCHL1 and pNF-H using enzyme-linked immunosorbent assay. Concomitant arterial blood gas, lactate, and cerebral near-infrared spectroscopy (NIRS) monitoring were performed. RESULTS: Ubiquitin C-terminal hydrolase 1 showed a significant rise at 0 hours in the DHCA group compared to baseline (74.9 ± 13.7 pg/mL vs 33.9 ± 37.3 pg/mL, P < .0001). Levels returned to baseline at 12 hours. There was an early rise in UCHL1 at 0 hours in the CPB group, P = .09. Phosphorylated axonal neurofilament heavy chain was decreased at 0 hours in both the CPB and DHCA groups compared to baseline, P = .06. There was no difference between control and baseline levels of UCHL1 ( P = .9) or pNF-H ( P = .77). Decreased NIRS was observed in the DHCA group at 0 hours (57.3 ± 10.5) versus baseline (64.2 ± 12.3), but not significant ( P = .21). There was no correlation between biomarkers and NIRS at 0 hours. CONCLUSION: A rapid rise in UCHL1 levels was observed in the DHCA group, suggesting that it may be a marker for acute brain injury. Follow-up with neurodevelopmental studies is ongoing.

Correlating Oxygen Delivery During Cardiopulmonary Bypass With the Neurologic Injury Biomarker Ubiquitin C-Terminal Hydrolase L1 (UCH-L1).

OBJECTIVE: The authors sought to assess the relationship between low oxygen delivery (DO2) during cardiopulmonary bypass (CPB) and a neuron-specific biomarker of neurologic injury, ubiquitin C-terminal hydrolase L1 (UCH-L1). DESIGN: Retrospective analysis of patient charts and prospectively collected blood samples. SETTING: University-affiliated tertiary care hospital. PARTICIPANTS: Adult patients undergoing cardiac surgery on CPB. INTERVENTIONS: Serum UCH-L1 levels were drawn at baseline and 6 and 24 hours after CPB cessation. DO2 was computed from perfusion records, with area-under-the-curve (AUC) computations performed to account for distance of DO2 excursions below predefined DO2 thresholds and the amount of time spent below them. Strokes were defined radiographically using computed tomography and magnetic resonance imaging. MEASUREMENTS AND MAIN RESULTS: Forty-three adults were included (median age 65 y, interquartile range 59-72). Three patients experienced strokes (imaged at 2, 7, and 8 d postoperatively). Most patients underwent isolated coronary artery bypass grafting (41%, 18 patients) or isolated aortic valve replacement (30%, 13). Median UCH-L1 levels differed from baseline to 6 and 24 hours after CPB (40, 232, and 166 pg/mL, respectively; p < 0.001). On multivariable linear regression analysis controlling for baseline and surgical variables, only DO2 AUC <225 was significantly associated with 6-hour UCH-L1 levels (p = 0.001), whereas only DO2 AUC <300 was significantly associated with 24- hour levels (p < 0.001). The 3 patients who experienced radiographic strokes had nonsignificantly elevated 24-hour UCH-L1 levels compared with control patients (585 v 151 pg/mL, p = 0.11). CONCLUSIONS: This is the first study to demonstrate an independent association between DO2 during CPB and elevations of a brain injury biomarker; additional study is needed to clarify the clinical significance of these results.

Operation Brain Trauma Therapy: 2016 Update.

Operation brain trauma therapy (OBTT) is a multi-center, pre-clinical drug and biomarker screening consortium for traumatic brain injury (TBI). Therapies are screened across three rat models (parasagittal fluid percussion injury, controlled cortical impact [CCI], and penetrating ballistic-like brain injury). Operation brain trauma therapy seeks to define therapies that show efficacy across models that should have the best chance in randomized clinical trials (RCTs) and/or to define model-dependent therapeutic effects, including TBI protein biomarker responses, to guide precision medicine-based clinical trials in targeted pathologies. The results of the first five therapies tested by OBTT (nicotinamide, erythropoietin, cyclosporine [CsA], simvastatin, and levetiracetam) were published in the Journal of Neurotrauma. Operation brain trauma therapy now describes preliminary results on four additional therapies (glibenclamide, kollidon-VA64, AER-271, and amantadine). To date, levetiracetam was beneficial on cognitive outcome, histology, and/or biomarkers in two models. The second most successful drug, glibenclamide, improved motor function and histology in CCI. Other therapies showed model-dependent effects (amantadine and CsA). Critically, glial fibrillary acidic protein levels predicted treatment effects. Operation brain trauma therapy suggests that levetiracetam merits additional pre-clinical and clinical evaluation and that glibenclamide and amantadine merit testing in specific TBI phenotypes. Operation brain trauma therapy has established that rigorous, multi-center consortia could revolutionize TBI therapy and biomarker development.

Immunoproteasome in the blood plasma of children with acute appendicitis, and its correlation with proteasome and UCHL1 measured by SPR imaging biosensors.

The aim of this study was to determinate the immunoproteasome concentration in the blood plasma of children with appendicitis, and its correlation with circulating proteasome and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1). Twenty-seven children with acute appendicitis, managed at the Paediatric Surgery Department, were included randomly into the study (age 2 years 9 months up to 14 years, mean age 9·5 ± 1 years). There were 10 girls and 17 boys; 18 healthy, age-matched subjects, admitted for planned surgeries served as controls. Mean concentrations of immunoproteasome, 20S proteasome and UCHL1 in the blood plasma of children with appendicitis before surgery 24 h and 72 h after the appendectomy were higher than in the control group. The immunoproteasome, 20S proteasome and UCHL1 concentrations in the blood plasma of patients with acute appendicitis were highest before surgery. The immunoproteasome, 20S proteasome and UCHL1 concentration measured 24 and 72 h after the operation decreased slowly over time and still did not reach the normal range (P < 0·05). There was no statistical difference between immunoproteasome, 20S proteasome and UCHL1 concentrations in children operated on laparoscopically and children after classic appendectomy. The immunoproteasome concentration may reflect the metabolic response to acute state inflammation, and the process of gradual ebbing of the inflammation may thus be helpful in the assessment of the efficacy of treatment. The method of operation - classic open appendectomy or laparoscopic appendectomy - does not influence the general trend in immunoproteasome concentration in children with appendicitis.

Concentration of UHCL1 in the Serum of Children with Acute Appendicitis, Before and After Surgery, and Its Correlation with CRP and Prealbumin.

Ubiquitin-mediated protein degradation plays a crucial role in various cellular processes, including signal transduction, cell differentiation, and stress response. Ubiquitin C-terminal hydrolase 1 (UCHL1) is a unique deubiquitinating enzyme that has both hydrolase and ligase activities. The aim of this study was the determination of UCHL1 concentration in serum of children with appendicitis, before and after the surgery. MATERIAL AND METHODS: 42 children with acute appendicitis, who were managed at the Pediatric Surgery Department, between 2013 and 2014, were randomly included into the study (age 9 months up to 14 years, mean age 2.5 + 1 years). There were 15 girls and 27 boys. 18 healthy, age-matched subjects, admitted for planned surgeries served as controls. Exclusion criteria were: severe preexisting infections, immunological or cardiovascular diseases that required long-term medication, and complicated cases of appendicitis with perforation of appendix and/or peritonitis. RESULTS: The UCHL1 concentrations in the blood plasma of patients with acute appendicitis, were highest before the surgery, and were above the range of concentrations measured in controls, the difference was statistically significant. The UCHL1 concentration measured 24 and 72 h after the operation, slowly decreased over time, and still did not reach the normal range, when compared with the concentration measured in controls (p < 0.05). CONCLUSIONS: UCHL1 concentration may reflect the metabolic response to acute state inflammation, and the process of gradual ebbing of the inflammation. The method of operation-classic open appendectomy, or laparoscopic appendectomy, does not influence the general trend in UCHL1 concentration in children with appendicitis. There is strong negative correlation between prealbumin and UCHL1 concentrations.

[Expression levels of ubiquitin C-terminal hydrolase-L1 and serum glial fibrillary acidic protein and its clinical significance in patients with acute cerebral infarction].

OBJECTIVE: To determine expression levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and serum glial fibrillary acidic protein (GFAP) in patients with acute cerebral infarction and their clinical significance.
 Methods: A total of 80 patients with acute cerebral infarction in Chongqing Cancer Hospital from January 2014 to February 2016 were enrolled as an observation group. Another 80 healthy people served as a control group. The expression levels of UCH-L1 and GFAP in the 2 groups were detected.
 Results: Sensibility and specificity for UCH-L1 and GFAP were 75.0%, 87.5% and 81.3%, 90.0%, respectively. Receiver operating characteristic curve areas of UCH-L1 and GFAP were 0.670 and 0.757, respectively. There were no significant significance in age, gender, drinking, smoke, diabetes, and hyperlipidemia in the 2 groups (P>0.05). High blood pressure rate in the observation group was higher than that in the control group (P<0.05). Spearson/Pearson analysis showed that serum UCH-L1 and GFAP levels were positively correlated with hypertension, but they were negatively correlated with sex, age, diabetes, hyperlipidemia, alcohol consumption, smoking, and other factors. General data at different time in the observation group was not statistically different (P>0.05). The expression levels of UCH-L1 and GFAP in the observation group was higher than that in the control group (P<0.05). UCH-L1 and GFAP levels at different time in the 2 groups were not statistically different (P>0.05). UCH-L1 and GFAP levels in the light, medium, and heavy groups were higher than those in the control group (P<0.05), while UCH-L1 and GFAP levels in the medium and heavy groups were higher than those in the light group (P<0.05). There was significant difference between levels of UCH-L1 or GFAP and infarction size at different time in the observation group (P<0.05). The results of Pearson correlation analysis showed that the levels of serum UCH-L1 and GFAP were positively correlated (r=0.634, P=0.001).
 Conclusion: The levels of serum UCH-L1 and GFAP are significantly increased at the early stage of acute cerebral infarction, and they have a certain correlation with the severity of cerebral infarction, which can provide a basis for early clinical diagnosis and treatment.

Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in serum of children after thermal injury.

PURPOSE: The study aims to determinate concentrations of ubiquitin C-terminal hydrolase 1 (UCHL1), which hydrolyzes amino acids from ubiquitin and cleave di-ubiquitins, in serum of children after thermal injury. PATIENTS/METHODS: 42 children scalded by hot water, managed at the Department of Pediatric Surgery, with burns in 4-20% TBSA were included into the study (age 9 months up to 14 years, mean age 2.5±1 years). Blood plasma UCHL1 concentration was assessed in 2-6h, 12-16h, 3d, 5d, and 7d after injury using surface plasmon resonance imaging biosensor. 18 healthy subjects admitted for planned surgeries served as controls. RESULTS: The UCHL1 concentration in the blood plasma of patients with thermal injuries reached its peak 12-16h after thermal injury and slowly decreased over time, and still did not reach the normal range on the 7th day after thermal injury. Mean concentrations of UCHL1 after thermal injury were above the range measured in controls (0.12ng/ml): 2-6h after injury - 5.59ng/dl, 12-16h after injury - 9.16ng/dl, 3 days after injury - 6.94ng/dl, 5 days after 5.41ng/dl, 7 days after injury - 4.09ng/dl. CONCLUSIONS: We observed sudden increase in the concentration of UCHL1 2-16h after thermal injury with the slow decrease in the UCHL1 concentration over the time. UCHL1 concentration was proportional to the severity of the burn. Further studies are needed to determine the mechanisms by which UCHL1 contributes to metabolic response following thermal injury.

Influence of exposure to coarse, fine and ultrafine urban particulate matter and their biological constituents on neural biomarkers in a randomized controlled crossover study.

BACKGROUND: Epidemiological studies have reported associations between air pollution and neuro-psychological conditions. Biological mechanisms behind these findings are still not clear. OBJECTIVES: We examined changes in blood and urinary neural biomarkers following exposure to concentrated ambient coarse, fine and ultrafine particles. METHODS: Fifty healthy non-smoking volunteers, mean age 28years, were exposed to coarse (2.5-10µm, mean 213µg/m3) and fine (0.15-2.5µm, mean 238µg/m3) concentrated ambient particles (CAPs), and filtered ambient and/or medical air. Twenty-five participants were exposed to ultrafine CAP (mean size 59.6nm, range 47.0-69.8nm), mean (136µg/m3) and filtered medical air. Exposures lasted 130min, separated by ≥2weeks, and the biological constituents endotoxin and ß-1,3-d-glucan of each particle size fraction were measured. Blood and urine samples were collected pre-exposure, and 1-hour and 21-hour post-exposure to determine neural biomarker levels. Mixed-model regressions assessed associations between exposures and changes in biomarker levels. RESULTS: Results were expressed as percent change from daily pre-exposure biomarker levels. Exposure to coarse CAP was significantly associated with increased urinary levels of the stress-related biomarkers vanillylmandelic acid (VMA) and cortisol when compared with exposure to filtered medical air [20% (95% confidence interval: 1.0%, 38%) and 64% (0.2%, 127%), respectively] 21hours post-exposure. However exposure to coarse CAP was significantly associated with decreases in blood cortisol [-26.0% (-42.4%, -9.6%) and -22.4% (-43.7%, -1.1%) at 1h and 21h post-exposure, respectively]. Biological molecules present in coarse CAP were significantly associated with blood biomarkers indicative of blood brain barrier integrity. Endotoxin content was significantly associated with increased blood ubiquitin C-terminal hydrolase L1 [UCHL1, 11% (5.3%, 16%) per ln(ng/m3+1)] 1-hour post-exposure, while ß-1,3-d-glucan was significantly associated with increased blood S100B [6.3% (3.2%, 9.4%) per ln(ng/m3+1)], as well as UCHL1 [3.1% (0.4%, 5.9%) per ln(ng/m3+1)], one-hour post-exposure. Fine CAP was marginally associated with increased blood UCHL1 when compared with exposure to filtered medical air [17.7% (-1.7%, 37.2%), p=0.07] 21hours post-exposure. Ultrafine CAP was not significantly associated with changes in any blood and urinary neural biomarkers examined. CONCLUSION: Ambient coarse particulate matter and its biological constituents may influence neural biomarker levels that reflect perturbations of blood-brain barrier integrity and systemic stress response.