A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis, prognosis, early disease ...recognition, risk stratification, appropriate treatment (theranostics), and trial enrichment for patients with sepsis or suspected sepsis. In this narrative review, we aim to answer the question, "Do biomarkers in patients with sepsis or septic shock predict mortality, multiple organ dysfunction syndrome (MODS), or organ dysfunction?" We also discuss the role of pro- and anti-inflammatory biomarkers and biomarkers associated with intestinal permeability, endothelial injury, organ dysfunction, blood-brain barrier (BBB) breakdown, brain injury, and short and long-term mortality. For sepsis, a range of biomarkers is identified, including fluid phase pattern recognition molecules (PRMs), complement system, cytokines, chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, miRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors. We also provide an overview of immune response biomarkers that can help identify or differentiate between systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and sepsis-associated encephalopathy. However, significant work is needed to identify the optimal combinations of biomarkers that can augment diagnosis, treatment, and good patient outcomes.
The present study aimed to evaluate if sepsis sensitizes behavioural and biochemical responses induced by m‐amphetamine. For this, Wistar rats were submitted to the cecal ligation and puncture. After ...30 days of cecal ligation and puncture procedure, the animals were submitted to a single intraperitoneal injection of saline or m‐amphetamine (.25, .50, or 1.0 mg/kg). Locomotor behaviour was assessed 2 h after the administration. Interleukin (IL)‐1β, IL‐6, IL‐10, tumour necrosis factor‐α, dopamine‐cAMP‐regulated phosphoprotein of 32,000 kDa (DARPP‐32) and neuronal calcium sensor (NCS‐1) levels were evaluated in the frontal cortex, hippocampus and striatum. Also, brain‐derived neurotrophic factor (BDNF), neuronal growth factor and glial‐derived neurotrophic factor levels were assessed in the hippocampus. M‐amphetamine alone (.25 and 1.0 mg/kg) increased rats' locomotion and exploratory behaviour compared with the Sham + Sal. Animals from the cecal ligation and puncture + m‐amphetamine (.5 and/or 1.0 mg/kg) group showed an increase in locomotion, exploratory and risk‐like behaviour when compared with the Sham + Saline group and with its respective Sham groups. Cecal ligation and puncture increased interleukin levels compared with the Sham + Sal. However, cecal ligation and puncture animals that received m‐amphetamine (1 mg/kg) increased even more, these inflammatory parameters compared with the Sham + Sal and the cecal ligation and puncture + saline group. M‐amphetamine at lower doses increased neurotrophic factors, but higher doses decreased these parameters in the brain of cecal ligation and puncture rats. M‐amphetamine dose‐dependently increased DARPP‐32 and NCS‐1 levels in cecal ligation and puncture rats in some structures. In conclusion, these results demonstrate that sepsis sensitizes behavioural amphetamine responses while inducing inflammatory and neurotrophic vulnerability in the cecal ligation and puncture model.
Objectives
The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice ...subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD).
Methods
Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels.
Results
The results showed that PSD induced hyperactivity in mice, which is considered a mania‐like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania‐like behavior, oxidative damage and cytokine alterations induced by PSD.
Conclusions
Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system − alterations presented in the animal models of mania – is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers.
We aim to characterize the kinetics of early and late microglial phenotypes after systemic inflammation in an animal model of severe sepsis and the effects of minocycline on these phenotypes. Rats ...were subjected to CLP, and some animals were treated with minocycline (10 ug/kg) by i.c.v. administration. Animals were killed 24 hours, 5, 10 and 30 days after sepsis induction, and serum and hippocampus were collected for subsequent analyses. Real‐time PCR was performed for M1 and M2 markers. TNF‐α, IL‐1β, IL‐6, IL‐10, CCL‐22 and nitrite/nitrate levels were measured. Immunofluorescence for IBA‐1, CD11b and arginase was also performed. We demonstrated that early after sepsis, there was a preponderant up‐regulation of M1 markers, and this was not switched to M2 phenotype markers later on. We found that up‐regulation of both M1 and M2 markers co‐existed up to 30 days after sepsis induction. In addition, minocycline induced a down‐regulation, predominantly, of M1 markers. Our results suggest early activation of M1 microglia that is followed by an overlap of both M1 and M2 phenotypes and that the beneficial effects of minocycline on sepsis‐associated brain dysfunction may be related to its effects predominantly on the M1 phenotype.
The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) are important for the maintenance of brain homeostasis
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During sepsis, peripheral production of proinflammatory ...cytokines and reactive oxygen species are responsible for structural alterations in those brain barriers. Thus, an increasing permeability of these barriers can lead to the activation of glial cells such as microglia and the production of cytotoxic mediators which in turn act on the brain barriers, damaging them further. Thereby, in this review, we try to highlight how the brain barrier’s permeability is not only a cause but a consequence of brain injury in sepsis.
Early detection of cardiovascular dysfunctions directly caused by acute ischemic stroke (AIS) has become paramount. Researchers now generally agree on the existence of a bidirectional interaction ...between the brain and the heart. In support of this theory, AIS patients are extremely vulnerable to severe cardiac complications. Sympathetic hyperactivity, hypothalamic-pituitary-adrenal axis, the immune and inflammatory responses, and gut dysbiosis have been identified as the main pathological mechanisms involved in brain-heart axis dysregulation after AIS. Moreover, evidence has confirmed that the main causes of mortality after AIS include heart attack, congestive heart failure, hemodynamic instability, left ventricular systolic dysfunction, diastolic dysfunction, arrhythmias, electrocardiographic anomalies, and cardiac arrest, all of which are more or less associated with poor outcomes and death. Therefore, intensive care unit admission with continuous hemodynamic monitoring has been proposed as the standard of care for AIS patients at high risk for developing cardiovascular complications. Recent trials have also investigated possible therapies to prevent secondary cardiovascular accidents after AIS. Labetalol, nicardipine, and nitroprusside have been recommended for the control of hypertension during AIS, while beta blockers have been suggested both for preventing chronic remodeling and for treating arrhythmias. Additionally, electrolytic imbalances should be considered, and abnormal rhythms must be treated. Nevertheless, therapeutic targets remain challenging, and further investigations might be essential to complete this complex multi-disciplinary puzzle. This review aims to highlight the pathophysiological mechanisms implicated in the interaction between the brain and the heart and their clinical consequences in AIS patients, as well as to provide specific recommendations for cardiovascular management after AIS.
Pupil reactivity and the Glasgow Coma Scale (GCS) score are the most clinically relevant information to predict the survival of traumatic brain injury (TBI) patients.
We evaluated the accuracy of the ...GCS-Pupil score (GCS-P) as a prognostic index to predict hospital mortality in Brazilian patients with severe TBI and compare it with a model combining GCS and pupil response with additional clinical and radiological prognostic factors.
Data from 1,066 patients with severe TBI from 5 prospective studies were analyzed. We determined the association between hospital mortality and the combination of GCS, pupil reactivity, age, glucose levels, cranial computed tomography (CT), or the GCS-P score by multivariate binary logistic regression.
Eighty-five percent (
= 908) of patients were men. The mean age was 35 years old, and the overall hospital mortality was 32.8%. The area under the receiver operating characteristic curve (AUROC) was 0.73 (0.70-0.77) for the model using the GCS-P score and 0.80 (0.77-0.83) for the model including clinical and radiological variables. The GCS-P score showed similar accuracy in predicting the mortality reported for the patients with severe TBI derived from the International Mission for Prognosis and Clinical Trials in TBI (IMPACT) and the Corticosteroid Randomization After Significant Head Injury (CRASH) studies.
Our results support the external validation of the GCS-P to predict hospital mortality following a severe TBI. The predictive value of the GCS-P for long-term mortality, functional, and neuropsychiatric outcomes in Brazilian patients with mild, moderate, and severe TBI deserves further investigation.
•Blackberry extract prevents the maniac episodes in rat model of mania.•Blackberry extract exhibits neuroprotection in rat model of mania.•Blackberry extract has antioxidant and anti-inflammatory ...effects in rat model of mania.
Bipolar disorder is a chronic mood disorder characterized by episodes of mania and depression. The aim of this study was to investigate the effects of blackberry extract on behavioral parameters, oxidative stress and inflammatory markers in a ketamine-induced model of mania. Animals were pretreated with extract (200 mg/kg, once a day for 14 days), lithium chloride (45 mg/kg, twice a day for 14 days), or vehicle. Between the 8th and 14th days, the animals received an injection of ketamine (25 mg/kg) or vehicle. On the 15th day, thirty minutes after ketamine administration, the animals’ locomotion was assessed using open-field apparatus. After the experiments, the animals were euthanized and cerebral structures were removed for neurochemical analyses. The results showed that ketamine treatment induced hyperlocomotion and oxidative damage in the cerebral cortex, hippocampus and striatum. In contrast, pretreatment with the extract or lithium was able to prevent hyperlocomotion and oxidative damage in the cerebral cortex, hippocampus, and striatum. In addition, IL-6 and IL-10 levels were increased by ketamine, while the extract prevented these effects in the cerebral cortex. Pretreatment with the extract was also effective in decreasing IL-6 and increasing the level of IL-10 in the striatum. In summary, our findings suggest that blackberry consumption could help prevent or reduce manic episodes, since this extract have demonstrated neuroprotective properties as well as antioxidant and anti-inflammatory effects in the ketamine-induced mania model.
The association between triamcinolone hexacetonide (TH) and gold nanoparticles (GNPs) represents a promising treatment due to the potential anti-inflammatory and antioxidant effects of these ...compounds. In this study, we evaluated the effects of intra-articular treatment of TH associated with GNPs in a mechanical model of osteoarthritis (OA).
Fifty Wistar rats were divided into five groups: Sham; OA; OA+TH; OA+GNPs; OA+TH-GNPs. Both applications were performed 30 and 60 days after the model was induced. After 30 days of the last application, the animals were euthanized.
Only the combined treatment with TH and GNPs promoted a reduction in proinflammatory cytokines and an increase in anti-inflammatory cytokines. The OA+TH-GNPs group obtained a significant reduction in the production of oxidants and oxidative damage markers while an increase in antioxidants. Histologically, all treated groups showed results of a significant increase in cartilage thickness and chondrocyte count, the OA+TH-GNPs group had similar behavior to the group without osteoarthritis, with significantly smaller amounts of chondrocytes than the OA group.
The intra-articular use of TH associated with GNPs may be able to prevent the progression of the pathology and minimize joint degradation.
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