Search Results (437)

Bullying is increasingly understood as a group-based phenomenon in which bystanders play a critical role, yet little is known about how witnessing bullying affects bystanders’ self-esteem and academic motivation. The aim of this study was to explore adolescents’ perspectives on how witnessing bullying in school may be linked to their self-esteem and academic motivation. This qualitative study explored these experiences among 35 Swedish adolescents (22 girls and 13 boys, aged 14–16) using focus group interviews analyzed through constructivist grounded theory. The analysis generated a core category, Authenticity in witnessing bullying, reflecting how adolescents balanced empathic responses, self-image, and academic motivation when confronted with bullying. In addition, six interrelated categories emerged: (1) sympathetic wounding, (2) relationship buffering, (3) fear-driven avoidance, (4) academic shielding, (5) academic draining, and (6) normalization of bullying. Witnessing bullying affected participants’ feelings of authenticity, self-esteem, coping strategies, and academic focus. Academic motivation was shaped divergently: some students withdrew and lost motivation, while others increased focus on grades to secure transfer to a safer school environment. The theory offers a framework that is grounded in participants’ accounts that helps the understanding of how authenticity shapes the social context, emotional experience, and academic engagement. Interventions that address the emotional and motivational consequences of witnessing bullying and foster supportive school climates, empowering students to act constructively, are needed. Full article

β-blockers (BBs) remain a cornerstone therapy for cardiovascular disorders, reducing heart rate, blood pressure, and arrhythmia risk. Yet, their influence extends well beyond the heart, impacting renal function, inflammatory responses, metabolism, and endocrine balance. Although cardio-selective BBs are designed to minimize off-target effects, they still modulate immune signaling and hormonal pathways, producing paradoxical outcomes. Suppression of sympathetic tone and RAAS activity underpins therapeutic benefit but may also contribute to renal hypoperfusion, electrolyte imbalance, and pro-inflammatory changes, especially in patients receiving combination therapy with RAAS inhibitors or diuretics. Genetic polymorphisms (e.g., ADRB1, GRK5, eNOS, CYP2D6) and comorbidities further shape individual responses. This review integrates cardiovascular, renal, and immune perspectives to map the pathways by which BBs influence systemic homeostasis, highlighting cytokine interactions and disease-specific remodeling. We emphasize the need for personalized, biomarker-guided strategies, leveraging pharmacogenomics, multi-omics, and machine learning tools to optimize BB selection and dosing. By reframing BBs as dynamic modulators of the cardio-renal-immune axis, this review advances their role in precision cardiovascular medicine. Full article

Post-occlusive reactive hyperemia (PORH) is widely used to assess microvascular reactivity, but its systemic impact on contralateral neurovascular function remains unclear. This study quantified bilateral synchrony and asymmetry of cutaneous signals during unilateral PORH in healthy subjects using a novel multidimensional framework of inter-limb coherence. Twelve young adults underwent a standard suprasystolic occlusion (5 min at 200 mmHg) on the upper limb, while photoplethysmography (PPG), skin temperature, and electrodermal activity (EDA) were recorded bilaterally in the fingers. Coherence was characterized by profile similarity (Cross-Signal Similarity Index, CSSI), temporal lag (τ*), magnitude asymmetry (Bilateral Magnitude Difference Index, BDMI), directional concordance (Signal Direction Index, SDI; Directional Concordance Index, DCI), and integrated indices (IBIL, IBIS). At baseline, all signals showed high bilateral synchrony (CSSI ≈ 0.9; τ* < 20 ms). Occlusion markedly reduced CSSI for blood flow (0.89 to 0.07, p = 0.002) and temperature (0.93 to −0.03, p = 0.06), while EDA coherence remained preserved (0.95 to 0.82). Integrated indices decreased significantly (IBIL 0.84 to 0.17, p = 0.005; IBIS 0.84 to 0.18, p = 0.004) and recovered only partially during hyperemia (IBIL 0.20, p = 0.003). Directional concordance was heterogeneous: during hyperemia, 9 of 12 subjects showed concordant EDA changes but only 7 of 12 for perfusion. BDMI was largest for perfusion (≈0.8), moderate for temperature (≈0.5), and minimal for EDA (≈0.3). Unilateral PORH thus induces a marked loss of bilateral coherence in microvascular signals, whereas sympathetic-driven responses remain strongly synchronized. This dissociation reveals that occlusion evokes systemic autonomic adjustments beyond local hemodynamics. The proposed framework captures hidden aspects of neurovascular integration and may provide new markers for autonomic imbalance or perfusion asymmetry. Full article

Catecholamines are fundamental mediators of the stress response, regulating arousal, vigilance, and adaptive behavior. However, their dynamics under extreme real-life conditions remain insufficiently explored. Survival, Evasion, Resistance, and Escape (SERE) training provides a unique model for examining neuroendocrine mechanisms of adaptation during both the acute phase and the recovery period following intense psychological and physical stress. Serum norepinephrine (NE) and dopamine (DA) were measured in 47 special forces soldiers during peak stress in SERE and one month later, compared with 17 healthy controls. Samples were collected under standardized conditions and analyzed using validated ELISA kits. NE levels differed significantly among groups (p = 0.003), being higher during SERE training and in controls compared to the post-recovery condition. DA also showed a significant group effect (p < 0.001), with increased levels during recovery and in soldiers during SERE relative to controls. The post-recovery decline in norepinephrine suggests adaptive habituation of sympathetic activity following extreme stress exposure. Conversely, the sustained elevation of dopamine during recovery may reflect neuroadaptive mechanisms that promote motivational and cognitive restoration. Together, these findings indicate coordinated catecholaminergic regulation supporting long-term resilience in elite military personnel. Full article

Background/Objectives: One of the neurotoxic components from the sea trumpet polyps, Protopalythoa variabilis (Cnidaria, Anthozoa), is a 26-residue, V-shape helical peptide (PpVα). Its synthetic versions, i.e., the linear, the single-disulfide-bonded analog, and the chimeric peptide with a 6-residue stretch of the N-terminal native homologous peptide covalently linked to the linear sequence, were investigated for their activity on ion channels responsible for cellular excitability and synaptic transmission. Methods: Molecular docking analyses and dynamic simulations focused on the ability of PpVα peptides to bind ion channels selectively through interaction with critical residues at their binding sites. Results: Electrophysiological studies using the patch clamp technique with sympathetic bovine chromaffin cells from the adrenal medulla confirmed that PpVα analogs can block both sodium and calcium currents, which are responsible for initiating and propagating action potentials, respectively, and for neurotransmitter release. Additionally, the peptides displayed neuroprotective effects, attenuating cellular damage induced by veratridine, which interferes with sodium channel activity, and by oligomycin and rotenone (O/R), which affect mitochondrial function. Conclusions: The block of calcium and sodium channels and the neuroprotective effects against oxidative stress make the PpVα peptide scaffold an attractive template for developing agents that has significant clinical potential in several areas, such as the treatment of neurological diseases (epilepsy, multiple sclerosis, and neurodegenerative diseases), neuroprotection in acute events (stroke and traumatic brain or spinal cord injuries), the management of neuropathic pain, the prevention of ischemic damage, and psychiatric disorders (anxiety and bipolar disorder). Full article

Background/Objectives: Postural orthostatic tachycardia syndrome (POTS) is a form of dysautonomia characterized by excessive tachycardia during orthostatic stress. It is frequently observed in patients with syncope, Chronic Fatigue Syndrome (CFS), and post-COVID-19 syndrome (PCS), yet the underlying mechanisms may differ across these conditions. This study aimed to assess autonomic nervous system (ANS) function in patients with syncope, CFS of insidious onset, and CFS post-COVID-19 who presented with POTS, and to compare them with age- and sex-matched patients without POTS. Methods: In this retrospective cross-sectional study, 138 patients over 18 years of age were included following head-up tilt testing (HUTT). Patients were divided into six groups: syncope with and without POTS, CFS with insidious onset with and without POTS, and CFS post-COVID-19 with and without POTS. All participants underwent HUTT, cardiovascular reflex testing (CART) by Ewing, five-minute resting ECG with short-term Heart Rate Variability (HRV) analysis, and 24 h Holter ECG monitoring. Results: The prevalence of POTS across groups ranged from 5% to 7%. Female predominance was consistent across all subgroups. In syncope with POTS, hypertensive responses during HUTT, lower rates of normal Valsalva maneuver results, and reduced HF values in short-term HRV suggested baroreceptor dysfunction with sympathetic overdrive. In both CFS subgroups with POTS, CART revealed higher rates of definite parasympathetic dysfunction, along with more frequent extreme blood pressure variation during HUTT and reduced vagally mediated HRV parameters (rMSSD, pNN50). Across groups, no significant differences were observed with regard to long-term HRV across groups. Conclusions: Distinct autonomic profiles were identified in POTS patients depending on the underlying condition. Syncope-related POTS was associated with baroreceptor dysfunction and sympathetic predominance, whereas CFS-related POTS was characterized by parasympathetic impairment and impaired short-term baroreflex regulation. Evaluating dysautonomia patterns across disease contexts may inform tailored therapeutic strategies and improve management of patients with POTS. Full article

Early-life feeding strategies are known to affect growth, behavior, and stress physiology in dairy calves. This study examined the effects of different milk feeding regimes on heart rate (HR) and heart rate variability (HRV) during feeding and rehousing as indicators of autonomic activity. Dairy calves were fed either a restrictive milk allowance twice per day (6 L/d; RES; n = 21) or an unlimited amount of milk (ad libitum; ADL; n = 24) during the first three weeks of life. All calves were housed in individual straw bedded hutches from d 1 to 23 of life and were moved to a group pen on d 23 ± 2 of life. Starting at least one day before rehousing until one hour after the rehousing process HR, HRV, and variables in the time and frequency domain were measured continuously using a portable recording system. To study the cardiac response to the feeding process, six time windows of 5 min each were chosen as follows: resting time at 5.00 a.m., start of personnel activity in the barn, 15 min before feeding, during feeding, 15 min after feeding, and 1 h after feeding. For the evaluation of cardiac response to an unknown stressor such as rehousing, four time windows of 5 min each were selected as follows: resting time at 5.00 a.m., during rehousing, 30 min after rehousing, and 1 h after rehousing. During resting as well as before feeding and rehousing, HR was higher in ADL calves compared with RES calves. During feeding and rehousing, HR reached peak values which were comparable in both groups. HRV variables of the time and frequency domain indicated a shift towards a sympathetic dominance in the balance of the autonomic nervous system during feeding time, particularly in RES calves. Differences between resting and feeding values were demonstrated in RES calves at low-frequency and high-frequency power, whereas no differences were observed in ADL calves which did not react to the feeding process. The cardiac response of calves to rehousing was inconsistent in both groups. An increase in RMSSD and SD1 in ADL calves indicated that the vagal component in the vegetative neurological control was increased in these calves during rehousing. In conclusion, our findings indicate that restrictive milk feeding alters autonomic regulation and may increase physiological stress responses in calves. Full article

The blood–brain barrier (BBB) restricts the entry of therapeutic agents into the brain cardiovascular regulatory region, potentially contributing to drug-resistant hypertension. Objective: The objective of this study was to overcome this limitation by modifying PEGylated liposomes with transferrin (Tf) to facilitate Tf receptor binding at the BBB and penetratin (Pen), a cell-penetrating peptide, to enhance neuronal uptake. Methods: This study evaluated the efficacy of Tf-Pen-liposomes in delivering angiotensin-converting enzyme 2 (ACE2) or EGFP (control) genes across the BBB in rats. In addition, the therapeutic effect of intravenous administration of Tf-Pen-Lip carrying plasmid DNA encoding ACE2 (Tf-Pen-Lip-pACE2) was tested in a neurogenic hypertension model induced by intracerebroventricular (ICV) infusion of angiotensin II (Ang II) via osmotic pump implantation and brain cannulation. Results: Conjugation with Tf and Pen significantly enhanced liposome-mediated gene transfection in cultured cells and increased transport across an in vitro BBB model. In vivo, intravenous administration of Tf-Pen-Lip-pACE2 or Tf-Pen-Lip-pGFP successfully elevated ACE2 or EGFP expression, respectively, in the hypothalamic paraventricular nucleus (PVN). Chronic ICV infusion of Ang II produced a sustained increase in blood pressure and heart rate, accompanied by sympathetic overactivation and elevated arginine vasopressin (AVP) secretion, hallmarks of neurogenic hypertension. Notably, intravenous Tf-Pen-Lip-pACE2 treatment dramatically attenuated Ang II–induced neurogenic hypertension, whereas Tf-Pen-Lip-pGFP had no effect on pressor responses, sympathetic activity, or AVP secretion. Conclusions: This dual-functionalized liposomal delivery system effectively transported the ACE2 gene across the BBB into the brain, increased ACE2 expression, and markedly attenuated neurogenic hypertension following systemic administration. Full article

Bone immunity represents a dynamic interface where skeletal homeostasis intersects with systemic immune regulation. We synthesize emerging paradigms by contrasting two functionally distinct microenvironments: the marrow cavity, a hematopoietic and immune cell reservoir, and cancellous bone, a metabolically active hub orchestrating osteoimmune interactions. The marrow cavity not only generates innate and adaptive immune cells but also preserves long-term immune memory through stromal-derived chemokines and survival factors, while cancellous bone regulates bone remodeling via macrophage-osteoclast crosstalk and cytokine gradients. Breakthroughs in lymphatic vasculature identification challenge traditional views, revealing cortical and lymphatic networks in cancellous bone that mediate immune surveillance and pathological processes such as cancer metastasis. Central to bone immunity is the neuro–immune–endocrine axis, where sympathetic and parasympathetic signaling bidirectionally modulate osteoclastogenesis and macrophage polarization. Gut microbiota-derived metabolites, including short-chain fatty acids and polyamines, reshape bone immunity through epigenetic and receptor-mediated pathways, bridging systemic metabolism with local immune responses. In disease contexts, dysregulated immune dynamics drive osteoporosis via RANKL/IL-17 hyperactivity and promote leukemic evasion through microenvironmental immunosuppression. We further propose the “brain–gut–bone axis” as a systemic regulatory framework, wherein vagus nerve-mediated gut signaling enhances osteogenic pathways, while leptin and adipokine circuits link marrow adiposity to inflammatory bone loss. These insights redefine bone as a multidimensional immunometabolic organ, integrating neural, endocrine, and microbial inputs to maintain homeostasis. By elucidating the mechanisms of immune-driven bone pathologies, this work highlights therapeutic opportunities through biomaterial-mediated immunomodulation and microbiota-targeted interventions, paving the way for next-generation treatments in osteoimmune disorders. Full article

Cardiomyopathies affect over 3 million individuals globally, with conventional treatments exhibiting up to 60% resistance and 25% 30-day readmission rates. This review synthesizes the current evidence on the role of neuro-immune interactions in the pathogenesis of cardiomyopathy and evaluates emerging therapies targeting this axis. We systematically examined clinical trials and mechanistic and multi-omics data across cardiomyopathy phenotypes, focusing on autonomic-immune dysregulation. Sympathetic overactivation, present in approximately 85% of patients, correlates with elevated pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and contributes significantly to therapeutic non-response. Concurrent parasympathetic withdrawal impairs cholinergic anti-inflammatory pathways, as reflected by reduced heart rate variability and baroreflex sensitivity. At the molecular level, shared mechanisms include inflammasome activation, neuroimmune synaptic signaling, and neurogenic inflammation. Emerging therapies targeting this axis are promising. Vagus nerve stimulation, as demonstrated in the INOVATE-HF trial, improves functional outcomes, whereas IL-1β antagonists reduce cardiovascular events by 15–20% in the context of inflammatory diseases. Bioelectronic interventions, such as transcutaneous vagal nerve stimulation and baroreflex activation therapy, offer noninvasive dual-modulatory strategies that address both neural and immune pathways, positioning the neuroimmune axis as a central driver of cardiomyopathy, regardless of etiology. The integration of genetic and metabolomic profiling may enable precision therapies targeting neuroimmune circuits, thereby overcoming the limitations of hemodynamic-focused care. This mechanistic framework shifts the therapeutic paradigm from symptomatic relief to targeted modulation of pathogenic pathways, with implications for millions of patients with cardiomyopathy and broader inflammatory cardiovascular disorders. Full article

The vascular 5-HT sympatho-modulation may involve inhibitory or potentiating pathways: nitric oxide (NO), endothelium-dependent hyperpolarization (EDH)-K⁺ channels, prostanoids, angiotensin II (Ang-II), or endothelin. Compared to males, female rats show differences in the serotonergic sympatho-regulation; therefore, we aimed to study the involvement of indirect pathways via 5-HT_1D-mediated inhibition and 5-HT_2A/3-mediated potentiation of vascular noradrenergic neurotransmission in females. An i.v. bolus of different inhibitors/blockers of modulators/mediators (NO, K⁺ channels, prostanoids, Ang-II, or endothelin) was administered prior to the infusion of the agonists, L-694,247 (5-HT_1D), TCB-2 (5-HT_2A), or 1-PBG (5-HT₃), in female pithed rats. In these conditions, the vascular sympathetic outflow was electrically stimulated to assess the vasopressor responses. The L-694,247 vascular sympatho-inhibition was abolished by a non-selective K⁺ channel blocker, tetraethylammonium. The 1-PBG sympatho-excitatory vascular effect was not modified by any of the inhibitors tested, whereas TCB-2 sympatho-potentiation was blocked solely by losartan (Ang-II type 1 receptor antagonist). Moreover, Ang-II levels were increased after TCB-2 infusion in females. The EDH pathway mediates the 5-HT_1D-induced sympatho-inhibition, while the 5-HT_2A-evoked sympatho-excitatory effect is associated with Ang-II. In contrast, the 5-HT₃ sympatho-potentiation does not involve any indirect pathway. These findings advance current understanding of the complex interactions between 5-HT and vascular homeostasis in female rats. Full article

Background: As we age, our autonomic function declines, resulting in altered autonomic balance during postural transitions. These changes can affect the dynamic interplay between sympathetic and parasympathetic modulation, compromising short-term compensatory responses to active standing. Objectives: This study aimed to compare heart rate variability (HRV) at baseline, cardiac parasympathetic modulation (CPM), and cardiac baroreflex gain (CRG) between younger adults (YA) and older adults (OA) following active standing orthostatic stress. A secondary objective was to analyze the incidence of orthostatic intolerance (OI) symptoms. Methods: Participants (n = 76) completed sit-to-stand and lie-to-stand maneuvers with continuous beat-to-beat blood pressure and heart rate (HR, electrocardiogram). HRV at baseline was analyzed in both time and frequency domains. CPM was measured by the HR 30:15 ratio on standing. CBG was determined as the ratio of HR and SBP changes (ΔHR/ΔSBP) at specific phase time points (30 s, 60 s, 180 s, and 420 s). Results: At baseline, OA showed reduced Standard Deviation of RR intervals (SDRR), Root Mean Square of Successive Differences (RMSSD), low-frequency (LF), and high-frequency (HF) power, and elevated LF/HF ratio (all p < 0.05), indicating a shift toward sympathetic dominance. During active standing orthostatic stress, OA demonstrated a lower HR30:15 ratio and CBG in later phases (phases 2–4) (all p < 0.05). Also, OA reported more symptoms (14%) of OI than YA (0%) (p = 0.041). Conclusions: These findings indicate that older adults have impaired autonomic function characterized by reduced HRV, CPM and CBG responses. These impairments lead to diminished autonomic regulation under active-standing orthostatic stress and a higher incidence of OI symptoms. Full article

Background: Temperature regulation is impaired in iron-deficient anemic humans and rats at rest during cold exposure. However, there is a paucity of data regarding the interplay of cold exposure, anemia, and exercise on thermal and cardiovascular responses. Therefore, we aimed to explore thermal and cardiovascular responses of individuals with chronic mild iron-deficiency anemia during exercise in the cold compared to controls. Methods: Nine anemic (5 F, 4 M) and nine control (5 F, 4 M) individuals, matched for body fat, size, and mass but different by design in hematological parameters and physical fitness, participated in the study. The participants cycled in cold 11 °C with 40% relative humidity (RH) and neutral (22 °C, 40% RH) conditions at an intensity ~10% below the respiratory threshold until 1 °C increase in rectal temperature (T_re) or 1 h of exercise, whichever occurred first. Results: In the cold, the anemic individuals showed a lower rate of T_re rise (p = 0.047) and lower mean skin temperature (T_sk) (p = 0.03) compared to controls, while only controls increased heat production compared to the neutral condition (p = 0.035). Moreover, the anemic group exhibited an exaggerated blood pressure response in the cold compared to the neutral environment (p < 0.05), due to heightened total peripheral resistance (p < 0.05) and vasomotor response (p < 0.001). Conclusions: In summary, chronic mild iron-deficiency anemia impaired temperature regulation as judged from the lower rate of T_re rise and an inability to activate further the metabolism at cold. Concomitantly, the anemic participants demonstrated increased cardiovascular strain. This is notable because anemia and these environmental conditions are encountered in the workplace, recreational activities, and athletic endeavors. These findings may inform safety guidelines for athletes, workers, and patients exposed to cold environments. Full article

Brown adipose tissue (BAT) has shifted from being considered a transient thermogenic organ of infancy to a metabolically dynamic and multifunctional tissue throughout life. Histologically and developmentally distinct from white and beige adipocytes, BAT originates from a myogenic lineage and is characterised by a high mitochondrial density, multilocular lipid droplets, and abundant sympathetic innervation. Its defining function, non-shivering thermogenesis, is mediated by uncoupling protein 1 (UCP1) and complemented by alternative mechanisms such as futile creatine and calcium cycling. Beyond heat production, thermogenic fat is crucial in regulating whole-body metabolism. It contributes to glucose, lipid, and branched-chain amino acid homeostasis, and engages in endocrine and paracrine signalling through a rich secretome of batokines, lipid mediators, and extracellular vesicle-bound microRNAs. These signals orchestrate crosstalk with the liver, skeletal muscle, pancreas, and immune system, enhancing insulin sensitivity, vascularisation, and anti-inflammatory responses. Brown/Beige fat also exhibits notable anti-fibrotic properties and supports adipose tissue remodelling, maintaining structural and functional plasticity under metabolic stress. This review offers a comprehensive synthesis of thermogenic adipose tissue biology, integrating its structural, developmental, and molecular features with its expanding physiological functions, highlighting its pivotal role in energy balance as well as its emerging therapeutic potential in obesity, type 2 diabetes, and related metabolic disorders. Full article

Background/Objectives: Syncope is a common clinical problem often requiring pharmacological treatment, yet evidence-based therapies remain limited. Midodrine, a vasopressor agent, is frequently used, though its autonomic effects over time remain unclear. This study aimed to assess autonomic nervous system changes and blood pressure response in syncope patients treated with Midodrine, placebo, or their combination. Additionally, the structural properties of the Midodrine placebo were analyzed using nanotechnological methods. Methods: A total of 67 patients with syncope were randomized to receive Midodrine, sucrose placebo, or their combination over three weeks. All participants underwent 24 h Holter ECG with heart rate variability (HRV) analysis and ambulatory blood pressure monitoring before and after therapy. Structural analysis of Midodrine tablets, sucrose, and Midodrine placebo was performed using Raman spectroscopy and X-ray diffraction (XRD). Results: Patients receiving the Midodrine–placebo combination showed a significant reduction in HRV markers of parasympathetic activity (RMSSD, pNN50, HF) and an increase in sympathetic dominance (LF/HF ratio) compared to the other groups. Only this group showed a statistically significant rise in average systolic and diastolic blood pressure. Raman and XRD analyses revealed structural alterations in the sucrose-based placebo compared to its original form, indicating subtle changes in crystalline structure. Conclusions: In this exploratory study, the combination of Midodrine and placebo was associated with autonomic imbalance and modest increases in blood pressure, which may indicate a potential effect in patients with hypotensive syncope phenotypes. These preliminary findings should be interpreted with caution, and the structural modifications observed in the placebo formulation are presented as hypotheses requiring further investigation rather than established mechanisms. Full article