Aerobic Exercise and Neuropathic Pain: Insights from Animal Models and Implications for Human Therapy.

This narrative review explores the complex relationship between aerobic exercise (AE) and neuropathic pain (NP), particularly focusing on peripheral neuropathies of mechanical origin. Pain, a multifaceted phenomenon, significantly impacts functionality and distress. The International Association for the Study of Pain's definition highlights pain's biopsychosocial nature, emphasizing the importance of patient articulation. Neuropathic pain, arising from various underlying processes, presents unique challenges in diagnosis and treatment. Our methodology involved a comprehensive literature search in the PubMed and SCOPUS databases, focusing on studies relating AE to NP, specifically in peripheral neuropathies caused by mechanical forces. The search yielded 28 articles and 1 book, primarily animal model studies, providing insights into the efficacy of AE in NP management. Results from animal models demonstrate that AE, particularly in forms like no-incline treadmill and swimming, effectively reduces mechanical allodynia and thermal hypersensitivity associated with NP. AE influences neurophysiological mechanisms underlying NP, modulating neurotrophins, cytokines, and glial cell activity. These findings suggest AE's potential in attenuating neurophysiological alterations in NP. However, human model studies are scarce, limiting the direct extrapolation of these findings to human neuropathic conditions. The few available studies indicate AE's potential benefits in peripheral NP, but a lack of specificity in these studies necessitates further research. In conclusion, while animal models show promising results regarding AE's role in mitigating NP symptoms and influencing underlying neurophysiological mechanisms, more human-centric research is required. This review underscores the need for targeted clinical trials to fully understand and harness AE's therapeutic potential in human neuropathic pain, especially of mechanical origin.

End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine.

Heparin is the most common anticoagulant used in clinical practice but shows some downsides such as short half-life (for the high molecular weight heparin) and secondary effects. On the other hand, its low molecular weight analogue cannot be neutralized with protamine, and therefore cannot be used in some treatments. To address these issues, we conjugated polyethylene glycol (PEG) to heparin reducing end (end-on) via oxime ligation and studied the interactions of the conjugate (Hep-b-PEG) with antithrombin III (AT) and protamine. Isothermal titration calorimetry showed that Hep-b-PEG maintains the affinity to AT. Dynamic light scattering demonstrated that the Hep-b-PEG formed colloidal stable nanocomplexes with protamine instead of large multi-molecular aggregates, associated with heparin side effects. The in vitro (human plasma) and in vivo experiments (Sprague Dawley rats) evidenced an extended half-life and higher anticoagulant activity of the conjugate when compared to unmodified heparin.

Learning to suppress a distractor may not be unconscious.

The additional singleton task has become a popular paradigm to explore visual statistical learning and selective attention. In this task, participants are instructed to find a different-shaped target among a series of distractors as fast as possible. In some trials, the search display includes a singleton distractor with a different color, making search more difficult. This singleton distractor appears more often in one location than in the remaining locations. The typical results of these experiments show that participants learn to ignore the area of the screen that is more likely to contain the singleton distractor. It is often claimed that this learning takes place unconsciously, because at the end of the experiment participants seem to be unable to identify the location where the singleton distractor appeared most frequently during the task. In the present study, we tested participants' awareness in three high-powered experiments using alternative measures. Contrary to previous studies, the results show clear evidence of explicit knowledge about which area of the display was more likely to contain the singleton distractor, suggesting that this type of learning might not be unconscious.

The role of working memory in probabilistic cuing of visual search.

In a typical probabilistic cuing experiment, participants are asked to find a visual target among a series of distractors. Although participants are not informed about this, the target appears more frequently in one region of the display, resulting in faster search times for targets located in this region. This bias is thought to depend on a habit-like attentional control mechanism, unconstrained by the availability of working memory (WM) resources. However, the only study that has explored this feature in the past suffers from methodological shortcomings that leave the results open to alternative explanations. In three experiments, we aimed to confirm whether probabilistic cuing is unaffected by visual, spatial, and spatiotemporal WM load. For each experiment, one group of participants performed the visual search task during the retention interval of a WM task (high-load group), whereas another group of participants (no-load group) carried out the visual search task after the WM task. We hypothesized that the probabilistic cuing effect would be larger for the no-load group compared to the high-load group. This hypothesis was confirmed in one experiment, but exploratory analyses suggest that the results can be highly dependent on the analytic approach, casting doubts on its robustness. Overall, our results provide partial support for the hypothesis that probabilistic cuing is not affected by a secondary task. However, given that some analyses reveal an effect of WM load, we conclude that it might be premature to rule out the possibility that the expression of this attentional bias requires WM resources. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Association between Gray-Scale Ultrasound Imaging and Serological Creatine Kinase for Quantifying Exercise-Induced Muscle Damage: An Observational Study.

Limited evidence has verified if ultrasound imaging (US) can detect post-exercise muscle damage based on size, shape, and brightness metrics. This study aimed to analyze the correlation between creatine kinase (CK) concentration and (as a biomarker of muscle damage) changes in US gray-scale metrics after an exercise-induced muscle damage protocol. An observational study was conducted at a private university lab located in Madrid. Twenty-five untrained and asymptomatic volunteers were enrolled in this study. Baseline demographic data and body composition metrics were collected. In addition, the rectus femoris US data and CK concentration were assessed at baseline and after inducing muscle damage (24 and 48 h later). After calculating time differences for all the outcomes, the correlation between the changes observed with US and biomarkers was assessed. Significant CK concentration increases were found 24 h (p = 0.003) and 48 h (p < 0.001) after exercise. However, no significant changes in muscle size, shape, or brightness were found in any location (p > 0.05 for all). In addition, no significant associations were found between CK changes and US changes (p > 0.05 for all). Gray-scale US is not a sensitive tool for detecting muscle damage, as a protocol of exercise-induced muscle damage confirmed with CK produced no significant gray-scale US changes after 24 or 48 h. In addition, US and CK changes after 24 and 48 h were not associated with each other.

Pearls & Oy-sters: Challenges and Controversies in Wilson Disease.

Wilson disease (WD) is a genetic disorder of copper metabolism caused by variants in the ATP7B gene, which are inherited in an autosomal recessive pattern. Despite all the advances made on pathogenesis, cellular biology, and genetics, to date, WD remains a diagnostic and therapeutic challenge. With this series of cases, we aim to illustrate the main challenges that clinicians may encounter when dealing with patients with WD: the difficulties with clinical diagnosis, the therapeutic management of WD and the indication for advanced therapies, management during pregnancy, and genotype-phenotype correlations.

Highly Emitting Perovskite Nanocrystals with 2-Year Stability in Water through an Automated Polymer Encapsulation for Bioimaging.

Lead-based halide perovskite nanocrystals are highly luminescent materials, but their sensitivity to humid environments and their biotoxicity are still important challenges to solve. Here, we develop a stepwise approach to encapsulate representative CsPbBr3 nanocrystals into water-soluble polymer capsules. We show that our protocol can be extended to nanocrystals coated with different ligands, enabling an outstanding high photoluminescence quantum yield of ∼60% that is preserved over two years in capsules dispersed in water. We demonstrate that this on-bench strategy can be implemented on an automated platform with slight modifications, granting access to a faster and more reproducible fabrication process. Also, we reveal that the capsules can be exploited as photoluminescent probes for cell imaging at a dose as low as 0.3 µgPb/mL that is well below the toxicity threshold for Pb and Cs ions. Our approach contributes to expanding significantly the fields of applications of these luminescent materials including biology and biomedicine.

Exogenous Attention to Emotional Stimuli Presenting Realistic (3D) Looming Motion.

Previous research shows that dynamic stimuli, on the one hand, and emotional stimuli, on the other, capture exogenous attention due to their biological relevance. Through neural (ERPs) and behavioral measures (reaction times and errors), the present study explored the combined effect of looming motion and emotional content on attentional capture. To this end, 3D-recreated static and dynamic animals assessed as emotional (positive or negative) or neutral were presented as distractors while 71 volunteers performed a line orientation task. We observed a two-phase effect: firstly (before 300 ms), early components of ERPs (P1p and N2po) showed enhanced exogenous attentional capture by looming positive distractors and static threatening animals. Thereafter, dynamic and static threatening distractors received enhanced endogenous attention as revealed by both late ERP activity (LPC) and behavioral (errors) responses. These effects are likely explained by both the emotional valence and the distance of the stimulus at each moment.

The role of working memory in contextual cueing of visual attention.

It is usually easier to find objects in familiar contexts that we have seen before. The type of learning that underlies this facilitation, known as contextual cueing, has been understood as an incidental and automatic process given that, among other reasons, it seems to be independent of working memory (WM) resources. This claim has found support in previous research showing that contextual cueing can be acquired latently, while participants perform a demanding WM task. However, previous studies have not always found this pattern of results and, in general, the available evidence is far from conclusive. The aim of the present study was to clarify the role of WM in contextual learning with two large-sample, confirmatory experiments. Our results show a robust contextual cueing effect even when visuospatial working memory resources were recruited by a demanding secondary task.

Routine flow cytometry approach for the evaluation of solid tumor neoplasms and immune cells in minimally invasive samples.

BACKGROUND: Multidimensional flow cytometry (MFC) is routinely used for the diagnosis and follow-up of hematolymphoid neoplasms but its contribution to the identification of non-hematolymphoid malignant tumors is limited. METHODS: The presence of non-hematolymphoid cells in clinical samples obtained via minimally invasive methods was ascertained by using a panel of monoclonal antibodies previously developed in our laboratory comprising a mixture of antibodies: CD9-PacB/CD45-OC515/CD57-FITC/CD56-PE/CD3-PerCP-Cy5.5/CD117-PE-Cy7/CD326-APC/CD81-APC-C750. Histopathological studies were performed using standard techniques. RESULTS: 164 specimens of different origins were included. Malignancy was finally confirmed in 142 (86.5%), while 22 non neoplastic samples were identified. The most frequent diagnosis was small cell lung carcinoma (SCLC) (50%). High sensitivity (S = 98.6%) was reached combining MFC and conventional pathology. Individual markers differed according to the cellular origin of the neoplasm, with neuroendocrine tumors showing a unique immunophenotypic profile (CD56+ CD326+ CD117-/+ and variable tetraspanins expression). Principal component analysis efficiently distinguished SCLC from other tumor samples. In immune cell populations, differences between reactive and malignant biopsies were found in different cell compartments, especially in B cells and Plasma cells. Differences also emerged in the percentage of CD4+ CD8- T cells, CD4-CD8+ T cells and NK cells and these were dependent on the origin of the tumor cells. CONCLUSIONS: These results support the use of MFC as a rapid and valuable technique to detect non-hematolymphoid tumoral cells in clinical specimens, providing an initial orientation to complement hystopathological studies and allow a more precise diagnosis, especially in neuroendocrine neoplasms. The impact of different immune cell patterns warrants further research.

Evaluation of Celiac Disease by Minimally Invasive Biomarkers in a Spanish Pediatric Population.

BACKGROUND: The diagnosis of celiac disease (CD) has been substantially improved with the availability of highly sensitive CD-specific IgA-TG2, Ig-GDP, and IgA-EMA. The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) published (2012) and updated (2020) diagnostic criteria for CD in order to simplify CD diagnosis and to avoid biopsies in selected patients. METHODS: A prospective study including 5641 pediatric patients (0-16 years old) from January 2012 to January 2019 was performed. CD diagnosis was made according to the ESPGHAN algorithm. The objective of this study was to evaluate the utility of biomarkers and the relationship between TGA-IgA and EMA titers. RESULTS: CD diagnoses were confirmed in 113 patients, 110 were IgA-TG2-positive and 3 (2.7%) had IgA deficiency. The diagnosis was made by serologic tests in 95 (84.1%) patients. Only 18 (15.9%) patients underwent intestinal biopsy. We obtained 100% concordance between IgA-EMA and positive results for IgA-TG2 ≥ 10 ULN with IgA-EMA antibody titer ≥ 1:80. CONCLUSIONS: This study provides evidence of a positive correlation between IgA-TG2 antibody serum levels and IgA-EMA. The diagnosis could be guaranteed with strict application of IgA-TG2 values ≥ 10 ULN (confirmed by subsequent testing) plus the serological response to the gluten-free diet (GFD).

Heart-brain synchronization breakdown in Parkinson's disease.

Heart rate variability (HRV) abnormalities are potential early biomarkers in Parkinson's disease (PD) but their relationship with central autonomic network (CAN) activity is not fully understood. We analyzed the synchronization between HRV and brain activity in 31 PD patients and 21 age-matched healthy controls using blood-oxygen-level-dependent (BOLD) signals from resting-state functional brain MRI and HRV metrics from finger plethysmography recorded for 7.40 min. We additionally quantified autonomic symptoms (SCOPA-AUT) and objective autonomic cardiovascular parameters (blood pressure and heart rate) during deep breathing, Valsalva, and head-up tilt, which were used to classify the clinical severity of dysautonomia. We evaluated HRV and BOLD signals synchronization (HRV-BOLD-sync) with Pearson lagged cross-correlations and Fisher's statistics for combining window-length-dependent HRV-BOLD-Sync Maps and assessed their association with clinical dysautonomia. HRV-BOLD-sync was lower significantly in PD than in controls in various brain regions within CAN or in networks involved in autonomic modulation. Moreover, heart-brain synchronization index (HBSI), which quantifies heart-brain synchronization at a single-subject level, showed an inverse exposure-response relationship with dysautonomia severity, finding the lowest HBSI in patients with severe dysautonomia, followed by moderate, mild, and, lastly, controls. Importantly, HBSI was associated in PD, but not in controls, with Valsalva pressure recovery time (sympathetic), deep breathing E/I ratio (cardiovagal), and SCOPA-AUT. Our findings support the existence of heart-brain de-synchronization in PD with an impact on clinically relevant autonomic outcomes.

Clinical Response After Treatment of Knee Osteoarthritis With a Standardized, Closed-System, Low-Cost Platelet-Rich Plasma Product: 1-Year Outcomes.

Background: Intra-articular infiltration of platelet-rich plasma (PRP) is an alternative therapeutic option to classic hyaluronic acid for the treatment of symptomatic knee osteoarthritis (KOA). However, variation in preparation methods and quality assessment of PRP makes the study of its real clinical efficacy difficult. Purpose: To (1) evaluate the clinical efficacy of a characterized PRP product prepared in a standardized manner and in a closed-system for the treatment of KOA and to (2) evaluate the association of the clinical response to PRP-related variables. Study Design: Case series; Level of evidence, 4. Methods: We recruited 130 patients with nonoperative KOA and evaluated them for 1 year. PRP was prepared from a donation of autologous blood, obtaining 3 aliquots of approximately 10mL of product, which were frozen, allowing platelet disruption, platelet factor release, and long-term storage, until administration. Patients were treated 3 consecutive times every 4 weeks with an intra-articular PRP knee injection under sterile conditions. Complete blood count was performed on the whole-blood sample and the processed PRP before freezing it, for product quality assessment. Patients were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and basic satisfaction scale at 3 months, 6 months, and 1 year after intervention. Results: Quality assessment confirmed a leukocyte-poor PRP product (white blood cell count, 0.09 ± 0.09 × 109/L) with a high platelet purity (platelet count, 630.86 ± 191.75 × 109/L). WOMAC scores improved, and basic satisfaction was achieved in 70% of patients. No adverse events were reported. No correlations were observed between PRP quality parameters and clinical results. PRP complete treatment production costs were €108/US$125 (€36/US$41.6 per injection). Conclusion: This standardized PRP production method resulted in improved WOMAC scores at 1 year postoperatively in 70% of patients with KOA. This technique was safe and affordable and ensured consecutive infiltrations with the same product to each patient.

Red Cell Distribution Width as a Predictive Factor of Celiac Disease in Middle and Late Adulthood and Its Potential Utility as Celiac Disease Screening Criterion.

Red cell distribution width (RDW) could be of interest by its potential use in the assessment of celiac disorder (CD). The main objective of this study was to evaluate the case positive rate of CD and the utility of red cell distribution width (RDW) in the CD diagnosis. This prospective study included 9.066 middle adult (≥45 years old) and elderly patients (≥60 years old) from 2012 to 2021. CD diagnosis was performed by CD antibody tests (serology and Human Leucocyte Antigen genotype (HLA)) and biopsy. Gastrointestinal and extra-intestinal manifestations as well as hematological and biochemical parameters were analyzed. CD diagnoses were confirmed in 101 patients (median (IQR) age = 62 (52.3−73); 68.32% women) by serologic tests (100%) and intestinal biopsy (88.12%), showing mainly marked or complete atrophy (76.24%, MARSH 3a−c). Anemia was the most commonly presenting extra-intestinal manifestation (28.57%). Among 8975 individuals without CD, 168 age and sex matched were included. By comparison of CD and no CD individuals, we observed that high >14.3% RDW was exhibited by 58.40% and 35.2% individuals with CD and without CD, respectively. Furthermore, high RDW is associated with CD and grade III atrophy. We suggest that RDW could be used as a CD screening criterion.

Is probabilistic cuing of visual search an inflexible attentional habit? A meta-analytic review.

In studies on probabilistic cuing of visual search, participants search for a target among several distractors and report some feature of the target. In a biased stage the target appears more frequently in one specific area of the search display. Eventually, participants become faster at finding the target in that rich region compared to the sparse region. In some experiments, this stage is followed by an unbiased stage, where the target is evenly located across all regions of the display. Despite this change in the spatial distribution of targets, search speed usually remains faster when the target is located in the previously rich region. The persistence of the bias even when it is no longer advantageous has been taken as evidence that this phenomenon is an attentional habit. The aim of this meta-analysis was to test whether the magnitude of probabilistic cuing decreases from the biased to the unbiased stage. A meta-analysis of 42 studies confirmed that probabilistic cuing during the unbiased stage was roughly half the size of cuing during the biased stage, and this decrease persisted even after correcting for publication bias. Thus, the evidence supporting the claim that probabilistic cuing is an attentional habit might not be as compelling as previously thought.

Clinical long-term nocturnal sleeping disturbances and excessive daytime sleepiness in Parkinson's disease.

OBJECTIVE: To prospectively evaluate nocturnal sleep problems and excessive daytime sleepiness (EDS) in Parkinson's disease (PD) patients, and analyze the influence of motor symptoms, treatment, and sex differences on sleep problems in PD. METHODS: Sleep disturbances of 103 PD patients were assessed with Parkinson's Disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale (ESS). Student's t-test for related samples, one-way ANOVA with Tukey's HSD post hoc test were used to assess group differences. Bivariate correlations and mixed-effects linear regression models were used to analyze the association between clinical aspects and sleep disturbances over time. RESULTS: At baseline, 48.5% of PD patients presented nocturnal problems and 40% of patients presented EDS. The PDSS and ESS total score slightly improve over time. Nocturnal problems were associated with age and motor impartment, explaining the 51% of the variance of the PDSS model. Males presented less nocturnal disturbances and more EDS than females. Higher motor impairment and combined treatment (L-dopa and agonist) were related to more EDS, while disease duration and L-dopa in monotherapy were related to lower scores, explaining the 59% of the model. CONCLUSIONS: Sleep disturbances changed over time and age, diseases duration, motor impairment, treatment and sex were associated with nocturnal sleep problems and EDS. Agonist treatment alone or in combination with L-dopa might predict worse daytime sleepiness, while L-dopa in monotherapy is related to lower EDS, which significantly affects the quality of life of PD patients.

Magnetic Nanoparticle-Based Hyperthermia Mediates Drug Delivery and Impairs the Tumorigenic Capacity of Quiescent Colorectal Cancer Stem Cells.

Cancer stem cells (CSCs) are the tumor cell subpopulation responsible for resistance to chemotherapy, tumor recurrence, and metastasis. An efficient therapy must act on low proliferating quiescent-CSCs (q-CSCs). We here investigate the effect of magnetic hyperthermia (MHT) in combination with local chemotherapy as a dual therapy to inhibit patient-derived colorectal qCR-CSCs. We apply iron oxide nanocubes as MHT heat mediators, coated with a thermoresponsive polymer (TR-Cubes) and loaded with DOXO (TR-DOXO) as a chemotherapeutic agent. The thermoresponsive polymer releases DOXO only at a temperature above 44 °C. In colony-forming assays, the cells exposed to TR-Cubes with MHT reveal that qCR-CSCs struggle to survive the heat damage and, with a due delay, restart the division of dormant cells. The eradication of qCR-CSCs with a complete stop of the colony formation was achieved only with TR-DOXO when exposed to MHT. The in vivo tumor formation study confirms the combined effects of MHT with heat-mediated drug release: only the group of animals that received the CR-CSCs pretreated, in vitro, with TR-DOXO and MHT lacked the formation of tumor even after several months. For DOXO-resistant CR-CSCs cells, the same results were shown, in vitro, when choosing the drug oxaliplatin rather than DOXO and applying MHT. These findings emphasize the potential of our nanoplatforms as an effective patient-personalized cancer treatment against qCR-CSCs.

Realistic (3D) looming of emotional visual stimuli: Attentional effects at neural and behavioral levels.

Previous research shows that endogenous attention (the controlled selection of certain aspects of our environment) is enhanced toward emotional stimuli due to its biological relevance. Although looming affective stimuli such as threat seem even more critical for survival, little is known about their effect on endogenous attention. Here, we recorded neural (event-related potentials, ERPs) and behavioral responses (errors and reaction times) to explore the combined effect of emotion and looming motion. 3D-recreated static and moving animals assessed as emotionally positive, negative, and neutral, were presented to participants (n = 71), who performed an indirect categorization task (vertebrate vs. invertebrate). Behavioral results showed better task performance, as reflected by lower number of errors and reaction times, in response to threatening stimuli. Neural indices revealed significant early (P1p, 150 milliseconds), intermediate (P2p, 240), and late (LPP, 450) effects, the latter being more intensely associated with behavior, as revealed by regression analyses. In general, neural indexes of attention to both static and dynamic stimuli showed a positivity offset in early stages and a negativity bias in subsequent phases. However, and importantly, the progressive inclusion of negative stimuli in the attentional focus is produced earlier in the case of dynamic (at P2p latency) than in static versions (at LPP). These results point to an enhancement of attention, particularly in temporal terms, toward stimuli combining motion and biological significance.

Quantitative analysis of dysautonomia in patients with autonomic dysreflexia.

Autonomic dysreflexia (AD) is a life-threatening condition for individuals with cervical or high-thoracic spinal cord injury (SCI). The profile of autonomic dysfunction in AD using validated clinical autonomic tests has not been described so far, although it could be useful to identify SCI patients at greater risk of developing AD non-invasively. With this objective, 37 SCI patients (27% female) were recruited, and hemodynamic and cardiac parameters were continuously monitored to determine the presence of AD, defined as an increase of systolic blood pressure of 20 mmHg or higher after bladder filling with saline. Then, standard autonomic function testing was performed, including Deep Breathing, Valsalva Manoeuvre and Tilt Table Test. Finally, baroreflex sensitivity (BRS), and spectral analysis of heart rate and blood pressure variability were measured at rest. Catecholamines and vasopressin levels were also measured at supine and upright positions. The severity of SCI was assessed through clinical and radiological examinations. AD was observed in 73.3% of SCI patients, being 63.6% of them asymptomatic during the dysreflexive episode. AD patients displayed a drop in sympathetic outflow, as determined by decreased noradrenalin plasma levels, reduced sympathovagal balance and increased BRS. In line with decreased sympathetic activity, the incidence of neurogenic orthostatic hypotension was higher in AD patients. Our results provide novel evidence regarding the autonomic dysfunction in SCI patients with AD compared to non-AD patients, posing non-invasively measured autonomic parameters as a powerful clinical tool to predict AD in SCI patients.