Exergame-based rehabilitation for cancer patients undergoing abdominal surgery: Effects on pain, anxiety, depression, and fatigue - A pilot study.

PURPOSE: This study aimed to determine the efficacy of an exergame rehabilitation program on pain, anxiety or depression, and fatigue in oncology patients undergoing abdominal surgery. METHODS: The randomized controlled trial evaluated the efficacy of exergame rehabilitation on Pain, Anxiety, Depression, and Fatigue in oncology patients undergoing abdominal surgery. Patients were recruited from October 2022-March 2023 and were randomly assigned to the intervention group (postoperative traditional rehabilitation plus an exergame rehabilitation program) or control group (postoperative traditional rehabilitation). Data were collected at three different times: on admission, in the first 48 h, and on the 7th day after surgery. Primary outcomes were evaluated and monitored with different validated instruments: numeric rating scale (NRS) for pain, Hospital Anxiety and Depression Scale (HADS) to assess the level of anxiety and depression, and the Fatigue Assessment Scale (FAS) to assess physical and psychological fatigue. The length of stay and program completion were secondary outcomes. RESULTS: A total of 128 postoperative patients were recruited. Of these, 58 patients were excluded from the study due to clinical complications related to the surgical procedure (n = 53) or healthcare staff-related reasons (n = 5). Both the control and intervention groups were the same size (n = 35). Lower pain scores were observed on the 7th postoperative day in the group subject to the "exergame rehabilitation program" (p = 0.006). No statistically significant differences were observed for anxiety and depression between the 2 groups. Regarding fatigue, statistically significant differences were observed on admission (p = 0.03), which disappeared 48 h after surgery (p = 0.143). Differences between the groups were observed again on the 7th day after surgery (p = 0.005). CONCLUSIONS: The intervention using exergames was effective in reducing the postoperative pain of the patient undergoing major abdominal surgery and in restoring the levels of fatigue before surgical intervention. However, no differences were observed for anxiety or depression. Future studies with larger samples should be carried out.

Bipolar Camouflage: A Cerebellar Cognitive Affective Syndrome Case Report.

The cerebellar cognitive affective syndrome is a neuropsychiatric syndrome composed of affective (anxiety, depression, euphoria, and emotional lability) and cognitive symptoms (executive, attentional, and visuospatial deficits) that was described in the 1990s. We present the case of a 49-year-old woman with a history of an acute neurological episode at the age of 28, after which she reported a change in personality, brief and alternating periods of depression, hypomania, and mixed episodes, and cognitive impairment that had a major impact on her personal and occupational level of functioning. She was initially diagnosed with bipolar disorder, but a clinical, neuropsychological, and imaging re-evaluation prompted a diagnostic reconsideration in favor of a cerebellar cognitive affective syndrome. This enabled therapeutical and prognostic refinement. Here, we discuss the diagnostic challenges of this syndrome and the implications that an accurate diagnosis has for patients.

Angiotensin-converting enzymes 1 and 2 in the feces: presence and catalytic activity in the rat 2,4,6-trinitrobenzene sulfonic acid-induced model of colitis.

BACKGROUND AND AIM: Inflammatory bowel disease is challenging to diagnose. Fecal biomarkers offer noninvasive solutions. The renin-angiotensin-aldosterone system is implicated in intestinal inflammation. Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) regulate its activity, but conflicting findings on these enzymes in colitis require further investigation. We aimed to assess ACE and ACE2 presence and activities in the feces, serum, and colon of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rats. METHODS: Colitis was induced in male rats by rectal instillation of a 21% ethanolic TNBS solution. After rats' sacrifice, colonic portions, serum, and feces were collected. ACE and ACE2 presence in the feces was analyzed by western Blot, and colonic and serum enzymes' concentrations were quantified using ELISA kits. ACE activity was assessed using Hippuryl-His-Leu and Z-Phe-His-Leu as substrates. ACE2 activity was assessed using Mca-APK (Dnp) as a substrate in the presence and absence of DX600 (ACE2 inhibitor). RESULTS: An ACE isoform of ~70 kDa was found only in the feces of TNBS-induced rats. ACE concentration was higher than that of ACE2 in the serum and the inflamed colon. ACE N-domain activity was higher than that of the C-domain in all matrices. ACE2 activity was higher in the feces of TNBS-induced animals compared to controls. CONCLUSION: A 70 kDa ACE isoform only detected in the feces of TNBS-induced rats may have translational relevance. ACE N-domain seems to play a significant role in regulating colonic lesions. Further research using human samples is necessary to validate these findings.

Corrigendum: Assessing MR-compatibility of somatosensory stimulation devices: a systematic review on testing methodologies.

[This corrects the article DOI: 10.3389/fnins.2023.1071749.].

Neural inhibition as implemented by an actor-critic model involves the human dorsal striatum and ventral tegmental area.

Inhibition is implicated across virtually all human experiences. As a trade-off of being very efficient, this executive function is also prone to many errors. Rodent and computational studies show that midbrain regions play crucial roles during errors by sending dopaminergic learning signals to the basal ganglia for behavioural adjustment. However, the parallels between animal and human neural anatomy and function are not determined. We scanned human adults while they performed an fMRI inhibitory task requiring trial-and-error learning. Guided by an actor-critic model, our results implicate the dorsal striatum and the ventral tegmental area as the actor and the critic, respectively. Using a multilevel and dimensional approach, we also demonstrate a link between midbrain and striatum circuit activity, inhibitory performance, and self-reported autistic and obsessive-compulsive subclinical traits.

Impact of Exergames on the Rehabilitation of Cancer Patients Undergoing Major Abdominal Surgery: A Randomized Controlled Trial.

BACKGROUND: Exergames can be an appealing strategy that is integrated into post-abdominal surgery rehabilitation. OBJECTIVE: The aim of this study was to assess the effectiveness of exergame rehabilitation in improving independence in activities of daily living (ADLs) and patient balance after abdominal cancer surgery. METHODS: A randomized control-group study was carried out in an oncological hospital in Portugal. Seventy postoperative patients were included, and data collection took place between January 2023 and May 2023. The patients were randomly assigned to either an exergame rehabilitation program (n = 35) or a traditional rehabilitation program (n = 35). The assessed outcomes were the Barthel and Berg scales, and data collection occurred at 3 different time points: admission, 48 hours postoperatively, and on the seventh day after surgery. RESULTS: At the third assessment, a statistically significant difference was observed between the 2 groups for both indicators, ADLs and balance. CONCLUSIONS: There was an improvement in ADLs and balance in the exergames group. By the seventh day after surgery, the intervention group showed improvement in balance and ADLs compared with the control group. IMPLICATIONS FOR PRACTICE: The use of exergames can be a solution to the challenges of traditional rehabilitation methods after abdominal surgery for cancer for postoperative patients. This is the first study carried out in this specific population.

Gender-related differences in cardiometabolic risk factors and oxidative stress among prepubertal children with obesity.

OBJECTIVES: Gender-related differences in oxidative stress, nitric oxide bioavailability, and cardiometabolic risk factors were examined in a cross-sectional study involving 313 prepubertal children (8-9 years old) from the generation XXI birth-cohort. METHODS: Anthropometric measurements, cardiometabolic variables, and redox markers were assessed, including plasma and urinary isoprostanes (P-Isop, U-Isop), plasma total antioxidant status (P-TAS), serum myeloperoxidase (MPO), plasma and urinary nitrates and nitrites (P-NOX, U-NOX), and urinary hydrogen peroxide (U-H2O2). RESULTS: Girls showed higher levels of total/non-HDL cholesterol, triglycerides, and insulin resistance (HOMA-IR) compared to boys. Notably, U-H2O2 values were lower in girls. When stratifying by body mass index (BMI) and gender, both girls and boys exhibited higher MPO concentration and U-Isop values. Uric acid concentration was higher in overweight and obese girls than in normal weight girls, while no significant differences were observed among boys across BMI categories. Furthermore, U-NOX values differed only in boys, with higher levels observed in overweight and obese individuals compared to those with normal weight. Multivariate analysis, adjusted for age and BMI z-score, demonstrated inverse associations between U-H2O2 and pulse wave velocity values, as well as between U-NOX and total or non-HDL cholesterol, exclusively in boys. In girls, a positive association between U-Isop and HOMA-IR values was observed. CONCLUSIONS: In conclusion, gender differentially impacts oxidative stress, nitric oxide bioavailability, and cardiometabolic risk factors in prepubertal children. Prepubertal girls appear more susceptible to oxidative stress-induced metabolic dysfunction, while in boys, elevated levels of redox and nitric oxide bioavailability markers seem to provide protection against arterial stiffness and lipid homeostasis.

A human cortical adaptive mutual inhibition circuit underlying competition for perceptual decision and repetition suppression reversal.

A model based on inhibitory coupling has been proposed to explain perceptual oscillations. This 'adapting reciprocal inhibition' model postulates that it is the strength of inhibitory coupling that determines the fate of competition between percepts. Here, we used an fMRI-based adaptation technique to reveal the influence of neighboring neuronal populations, such as reciprocal inhibition, in motion-selective hMT+/V5. If reciprocal inhibition exists in this region, the following predictions should hold: 1. stimulus-driven response would not simply decrease, as predicted by simple repetition-suppression of neuronal populations, but instead, increase due to the activity from adjacent populations; 2. perceptual decision involving competing representations, should reflect decreased reciprocal inhibition by adaptation; 3. neural activity for the competing percept should also later on increase upon adaptation. Our results confirm these three predictions, showing that a model of perceptual decision based on adapting reciprocal inhibition holds true. Finally, they also show that the net effect of the well-known repetition suppression phenomenon can be reversed by this mechanism.

The pro-resolving lipid mediator Maresin 1 ameliorates pain responses and neuroinflammation in the spared nerve injury-induced neuropathic pain: A study in male and female mice.

Specialized pro-resolving mediators (SPMs) have recently emerged as promising therapeutic approaches for neuropathic pain (NP). We evaluated the effects of oral treatment with the SPM Maresin 1 (MaR1) on behavioral pain responses and spinal neuroinflammation in male and female C57BL/6J mice with spared nerve injury (SNI)-induced NP. MaR1, or vehicle, was administered once daily, on post-surgical days 3 to 5, by voluntary oral intake. Sensory-discriminative and affective-motivational components of pain were evaluated with von Frey and place escape/avoidance paradigm (PEAP) tests, respectively. Spinal microglial and astrocytic activation were assessed by immunofluorescence, and the spinal concentration of cytokines IL-1ß, IL-6, IL-10, and macrophage colony-stimulating factor (M-CSF) were evaluated by multiplex immunoassay. MaR1 treatment reduced SNI-induced mechanical hypersensitivity on days 7 and 11 in both male and female mice, and appeared to ameliorate the affective component of pain in males on day 11. No definitive conclusions could be drawn about the impact of MaR1 on the affective-motivational aspects of pain in female mice, since repeated suprathreshold mechanical stimulation of the affected paw in the dark compartment did not increase the preference of vehicle-treated SNI females for the light side, during the PEAP test session (a fundamental assumption for PAEP's validity). MaR1 treatment also reduced ipsilateral spinal microglial and astrocytic activation in both sexes and marginally increased M-CSF in males, while not affecting cytokines IL-1ß, IL-6 and IL-10 in either sex. In summary, our study has shown that oral treatment with MaR1 (i) produces antinociception even in an already installed peripheral NP mouse model, and (ii) this antinociception may extend for several days beyond the treatment time-frame. These therapeutic effects are associated with attenuated microglial and astrocytic activation in both sexes, and possibly involve modulation of M-CSF action in males.

ACE and ACE2 catalytic activity in the fecal content along the gut.

BACKGROUND: Angiotensin-converting enzyme (ACE) and ACE2 are two major enzymes of the renin-angiotensin-aldosterone system (RAAS), which control the formation/degradation of angiotensin (Ang) II and Ang1-7, regulating their opposite effects. We aimed at evaluating the catalytic activity of ACE and ACE2 in the intestinal content and corresponding intestinal tissue along the gut of Wistar Han rats. METHODS: Portions of the ileum, cecum, proximal colon, and distal colon, and the corresponding intestinal content were collected from Wistar Han rats. Enzyme activity was evaluated by fluorometric assays using different substrates: Hippuryl-His-Leu for ACE-C-domain, Z-Phe-His-Leu for ACE-N-domain, and Mca-APK(Dnp) for ACE2. ACE and ACE2 concentration was assessed by ELISA. Ratios concerning concentrations and activities were calculated to evaluate the balance of the RAAS. Statistical analysis was performed using Friedman test followed by Dunn's multiple comparisons test or Wilcoxon matched-pairs test whenever needed. KEY RESULTS: ACE and ACE2 are catalytically active in the intestinal content along the rat gut. The ACE N-domain shows higher activity than the C-domain both in the intestinal content and in the intestinal tissue. ACE and ACE2 are globally more active in the intestinal content than in the corresponding intestinal tissue. There was a distal-to-proximal prevalence of ACE2 over ACE in the intestinal tissue. CONCLUSIONS & INFERENCES: This work is the first to report the presence of catalytically active ACE and ACE2 in the rat intestinal content, supporting future research on the regulatory role of the intestinal RAAS on gut function and a putative link to the microbiome.

Multimodal assessment of the spatial correspondence between fNIRS and fMRI hemodynamic responses in motor tasks.

Functional near-infrared spectroscopy (fNIRS) provides a cost-efficient and portable alternative to functional magnetic resonance imaging (fMRI) for assessing cortical activity changes based on hemodynamic signals. The spatial and temporal underpinnings of the fMRI blood-oxygen-level-dependent (BOLD) signal and corresponding fNIRS concentration of oxygenated (HbO), deoxygenated (HbR), and total hemoglobin (HbT) measurements are still not completely clear. We aim to analyze the spatial correspondence between these hemodynamic signals, in motor-network regions. To this end, we acquired asynchronous fMRI and fNIRS recordings from 9 healthy participants while performing motor imagery and execution. Using this multimodal approach, we investigated the ability to identify motor-related activation clusters in fMRI data using subject-specific fNIRS-based cortical signals as predictors of interest. Group-level activation was found in fMRI data modeled from corresponding fNIRS measurements, with significant peak activation found overlapping the individually-defined primary and premotor motor cortices, for all chromophores. No statistically significant differences were observed in multimodal spatial correspondence between HbO, HbR, and HbT, for both tasks. This suggests the possibility of translating neuronal information from fMRI into an fNIRS motor-coverage setup with high spatial correspondence using both oxy and deoxyhemoglobin data, with the inherent benefits of translating fMRI paradigms to fNIRS in cognitive and clinical neuroscience.

Assessing MR-compatibility of somatosensory stimulation devices: A systematic review on testing methodologies.

Functional magnetic resonance imaging (fMRI) has been extensively used as a tool to map the brain processes related to somatosensory stimulation. This mapping includes the localization of task-related brain activation and the characterization of brain activity dynamics and neural circuitries related to the processing of somatosensory information. However, the magnetic resonance (MR) environment presents unique challenges regarding participant and equipment safety and compatibility. This study aims to systematically review and analyze the state-of-the-art methodologies to assess the safety and compatibility of somatosensory stimulation devices in the MR environment. A literature search, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines, was performed in PubMed, Scopus, and Web of Science to find original research on the development and testing of devices for somatosensory stimulation in the MR environment. Nineteen records that complied with the inclusion and eligibility criteria were considered. The findings are discussed in the context of the existing international standards available for the safety and compatibility assessment of devices intended to be used in the MR environment. In sum, the results provided evidence for a lack of uniformity in the applied testing methodologies, as well as an in-depth presentation of the testing methodologies and results. Lastly, we suggest an assessment methodology (safety, compatibility, performance, and user acceptability) that can be applied to devices intended to be used in the MR environment. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021257838.

Association between blood pressure and angiotensin-converting enzymes activity in prepubertal children ∗.

OBJECTIVES: Angiotensin-converting enzymes' (ACEs) relationship with blood pressure (BP) during childhood has not been clearly established. We aimed to compare ACE and ACE2 activities between BMI groups in a sample of prepubertal children, and to characterize the association between these enzymes' activities and BP. METHODS: Cross-sectional study of 313 children aged 8-9 years old, included in the birth cohort Generation XXI (Portugal). Anthropometric measurements and 24-h ambulatory BP monitoring were performed. ACE and ACE2 activities were quantified by fluorometric methods. RESULTS: Overweight/obese children demonstrated significantly higher ACE and ACE2 activities, when compared to their normal weight counterparts [median (P25-P75), ACE: 39.48 (30.52-48.97) vs. 42.90 (35.62-47.18) vs. 43.38 (33.49-49.89) mU/ml, P for trend = 0.009; ACE2: 10.41 (7.58-15.47) vs. 21.56 (13.34-29.09) vs. 29.00 (22.91-34.32) pM/min per ml, P for trend < 0.001, in normal weight, overweight and obese children, respectively]. In girls, night-time systolic BP (SBP) and diastolic BP (DBP) increased across tertiles of ACE activity ( P < 0.001 and P  = 0.002, respectively). ACE2 activity was associated with higher night-time SBP and DBP in overweight/obese girls ( P  = 0.037 and P  = 0.048, respectively) and night-time DBP in the BMI z-score girl adjusted model ( P  = 0.018). Median ACE2 levels were significantly higher among nondipper girls (16.7 vs. 11.6 pM/min per ml, P  = 0.009). CONCLUSIONS: Our work shows that obesity is associated with activation of the renin-angiotensin-aldosterone system, with significant increase of ACE and ACE2 activities already in childhood. Also, we report sex differences in the association of ACE and ACE2 activities with BP.

Effects of NADPH Oxidase Isoform-2 (NOX2) Inhibition on Behavioral Responses and Neuroinflammation in a Mouse Model of Neuropathic Pain.

NADPH oxidase isoform-2 (NOX2) has been implicated in the pathophysiology of neuropathic pain (NP), mostly through the modulation of neuroinflammation. Since it is also accepted that some neuroimmune mechanisms underlying NP are sex-dependent, we aimed to evaluate the effects of early systemic treatment with the NOX2-selective inhibitor (NOX2i) GSK2795039 on behavioral responses and spinal neuroinflammation in spared nerve injury (SNI)-induced NP in male and female mice. Mechanical sensitivity was evaluated with the von Frey test, while general well-being and anxiety-like behavior were assessed with burrowing and light/dark box tests. Spinal microglial activation and cytokines IL-1ß, IL-6, and IL-10, as well as macrophage colony-stimulating factor (M-CSF) were evaluated by immunofluorescence and multiplex immunoassay, respectively. NOX2i treatment reduced SNI-induced mechanical hypersensitivity and early SNI-induced microglial activation in both sexes. SNI-females, but not males, showed a transient reduction in burrowing activity. NOX2i treatment did not improve their burrowing activity, but tendentially reduced their anxiety-like behavior. NOX2i marginally decreased IL-6 in females, and increased M-CSF in males. Our findings suggest that NOX2-selective inhibition may be a potential therapeutic strategy for NP in both male and female individuals, with particular interest in females due to its apparent favorable impact in anxiety-like behavior.

Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients.

BACKGROUND: Cysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed. METHODS: Blood and spot urine were collected in "severe" (n = 26), "critically ill" (n = 17) and "critically ill on VV-ECMO" (n = 17) patients with COVID-19 at days 1-2 (admission), 3-4, 5-8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated. RESULTS: U-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients. CONCLUSIONS: U-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.

Exploring the Hypothesis of a Schizophrenia and Bipolar Disorder Continuum: Biological, Genetic and Pharmacologic Data.

Present time nosology has its roots in Kraepelin's demarcation of schizophrenia and bipolar disorder. However, accumulating evidence has shed light on several commonalities between the two disorders, and some authors have advocated for the consideration of a disease continuum. Here, we review previous genetic, biological and pharmacological findings that provide the basis for this conceptualization. There is a cross-disease heritability, and they share single-nucleotide polymorphisms in some common genes. EEG and imaging patterns have a number of similarities, namely reduced white matter integrity and abnormal connectivity. Dopamine, serotonin, GABA and glutamate systems have dysfunctional features, some of which are identical among the disorders. Finally, cellular calcium regulation and mitochondrial function are, also, impaired in the two.

A new error-monitoring brain-computer interface based on reinforcement learning for people with autism spectrum disorders.

Objective.Brain-computer interfaces (BCIs) are emerging as promising cognitive training tools in neurodevelopmental disorders, as they combine the advantages of traditional computerized interventions with real-time tailored feedback. We propose a gamified BCI based on non-volitional neurofeedback for cognitive training, aiming at reaching a neurorehabilitation tool for application in autism spectrum disorders (ASDs).Approach.The BCI consists of an emotional facial expression paradigm controlled by an intelligent agent that makes correct and wrong actions, while the user observes and judges the agent's actions. The agent learns through reinforcement learning (RL) an optimal strategy if the participant generates error-related potentials (ErrPs) upon incorrect agent actions. We hypothesize that this training approach will allow not only the agent to learn but also the BCI user, by participating through implicit error scrutiny in the process of learning through operant conditioning, making it of particular interest for disorders where error monitoring processes are altered/compromised such as in ASD. In this paper, the main goal is to validate the whole methodological BCI approach and assess whether it is feasible enough to move on to clinical experiments. A control group of ten neurotypical participants and one participant with ASD tested the proposed BCI approach.Main results.We achieved an online balanced-accuracy in ErrPs detection of 81.6% and 77.1%, respectively for two different game modes. Additionally, all participants achieved an optimal RL strategy for the agent at least in one of the test sessions.Significance.The ErrP classification results and the possibility of successfully achieving an optimal learning strategy, show the feasibility of the proposed methodology, which allows to move towards clinical experimentation with ASD participants to assess the effectiveness of the approach as hypothesized.

Urinary Cysteinyl Leukotrienes as Biomarkers of Endothelial Activation, Inflammation and Oxidative Stress and Their Relationship with Organ Dysfunction in Human Septic Shock.

Cysteinyl leukotrienes (CysLT) are potent vascular leakage-promoting agents but have been scarcely explored in human septic shock (SS). We evaluated CysLT at admission and during hospitalization and their correlation with endothelial dysfunction, inflammation, oxidative stress, the renin-angiotensin-aldosterone system, and cardiac, renal, respiratory, and hepatic parameters in SS patients. Blood and spot-urine samples were collected at days 1-2 (admission), 3-4, and 5-8 in SS patients (n = 13) and at a single time point in controls (n = 22). Urinary CysLT (u-CysLT) and isoprostanes, plasma, and urinary angiotensinogen, serum myeloperoxidase, and IL-10 were quantified by ELISA. Serum intercellular-adhesion molecule-1, vascular cell-adhesion molecule-1, E-selectin, tumor necrosis factor-α, IL-1ß, and IL-6 were measured by multiplex immunoassays. Routine markers were evaluated using automated analyzers. At admission, SS patients had increased u-CysLT, endothelial activation, inflammation, oxidative stress, and plasma and urinary angiotensinogen, as well as cardiac, respiratory, hepatic, and renal injury/dysfunction. There were no changes in u-CysLT during hospitalization. Both correlation and multivariate analyses showed positive relationships of u-CysLT with endothelial activation, inflammation, oxidative stress, proteinuria, and hepatic injury/dysfunction markers. These results suggest that u-CysLT may be potential non-invasive biomarkers for monitoring the pathophysiological mechanisms underlying SS, as well as putative therapeutic targets.

Endothelitis profile in acute heart failure and cardiogenic shock patients: Endocan as a potential novel biomarker and putative therapeutic target.

Aims: Inflammation-driven endothelitis seems to be a hallmark of acute heart failure (AHF) and cardiogenic shock (CS). Endocan, a soluble proteoglycan secreted by the activated endothelium, contributes to inflammation and endothelial dysfunction, but has been scarcely explored in human AHF. We aimed to evaluate serum (S-Endocan) and urinary endocan (U-Endocan) profiles in AHF and CS patients and to correlate them with biomarkers/parameters of inflammation, endothelial activation, cardiovascular dysfunction and prognosis. Methods: Blood and spot urine were collected from patients with AHF (n = 23) or CS (n = 25) at days 1-2 (admission), 3-4 and 5-8 and from controls (blood donors, n = 22) at a single time point. S-Endocan, U-Endocan, serum IL-1ß, IL-6, tumour necrosis factor-α (S-TNF-α), intercellular adhesion molecule-1 (S-ICAM-1), vascular cell adhesion molecule-1 (S-VCAM-1) and E-selectin were determined by ELISA or multiplex immunoassays. Serum C-reactive protein (S-CRP), plasma B-type natriuretic peptide (P-BNP) and high-sensitivity troponin I (P-hs-trop I), lactate, urea, creatinine and urinary proteins, as well as prognostic scores (APACHE II, SAPS II) and echocardiographic left ventricular ejection fraction (LVEF) were also evaluated. Results: Admission S-Endocan was higher in both patient groups, with CS presenting greater values than AHF (AHF and CS vs. Controls, p < 0.001; CS vs. AHF, p < 0.01). Admission U-Endocan was only higher in CS patients (p < 0.01 vs. Controls). At admission, S-VCAM-1, S-IL-6 and S-TNF-α were also higher in both patient groups but there were no differences in S-E-selectin and S-IL-1ß among the groups, nor in P-BNP, S-CRP or renal function between AHF and CS. Neither endocan nor other endothelial and inflammatory markers were reduced during hospitalization (p > 0.05). S-Endocan positively correlated with S-VCAM-1, S-IL-6, S-CRP, APACHE II and SAPS II scores and was positively associated with P-BNP in multivariate analyses. Admission S-Endocan raised in line with LVEF impairment (p = 0.008 for linear trend). Conclusion: Admission endocan significantly increases across AHF spectrum. The lack of reduction in endothelial and inflammatory markers throughout hospitalization suggests a perpetuation of endothelial dysfunction and inflammation. S-Endocan appears to be a biomarker of endothelitis and a putative therapeutic target in AHF and CS, given its association with LVEF impairment and P-BNP and its positive correlation with prognostic scores.