Search Results (1,500)

Chronic pain is a significant and complex health condition characterized by persistent or recurrent pain lasting more than three months. Exercise-based rehabilitation is an effective non-pharmacological intervention, yet its underlying mechanisms have not been fully elucidated. This review systematically maps the molecular pathways of exercise-induced analgesia onto the pathophysiological cascades of chronic pain, aiming to fill a key gap in the current literature. It explores the molecular and cellular mechanisms underpinning the pathophysiology of chronic pain, indicating that the persistence of chronic pain stems from peripheral sensitization driven by inflammatory mediators and central sensitization involving glial cell activation and N-methyl-D-aspartate (NMDA) receptor-mediated neuroplasticity. Exercise can interrupt these pathological cascades through multi-system adaptations, including activation of the endogenous opioid and serotonergic systems activation and anti-inflammation. However, a significant gap remains in translating this mechanistic understanding of chronic pain into optimized, personalized exercise prescriptions, requiring future research into different exercise modalities, sex-specific responses, and the impact of comorbidities. Full article

Chronic pain is a dynamic, brain-wide condition that eludes effective management by conventional, static treatment approaches. Transcutaneous Electrical Nerve Stimulation (TENS), traditionally perceived as a simple and generic modality, is on the verge of a significant transformation. Guided by advances in brain-state decoding and adaptive algorithms, TENS can evolve into a precision neuromodulation system tailored to individual needs. By integrating multimodal neuroimaging—including the spatial resolution of functional magnetic resonance imaging (fMRI), the temporal sensitivity of an Electroencephalogram (EEG), and the ecological validity of functional near-infrared spectroscopy (fNIRS)—with real-time machine learning, we envision a paradigm shift from fixed stimulation protocols to personalized, closed-loop modulation. This comprehensive review outlines a translational framework to reengineer TENS from an open-loop device into a responsive, intelligent therapeutic platform. We examine the underlying neurophysiological mechanisms, artificial intelligence (AI)-driven infrastructures, and ethical considerations essential for implementing this vision in clinical practice—not only for chronic pain management but also for broader neuroadaptive healthcare applications. Full article

Background/Objectives: Patients with erythropoietic protoporphyria (EPP) have a decreased activity of the ferrochelatase enzyme which converts protoporphyrin IX (PpIX) into heme, causing PpIX to accumulate in erythrocytes. The ensuing release of PpIX to the skin when exposed to visible light causes a phototoxic reaction with severe pain, erythema, and edema. Erythrocyte PpIX levels in adult EPP patients are rather stable and largely unaffected by pharmaceutical treatments. It is important to be aware of drugs causing an increase in PpIX as this may increase the risk of liver toxicity. Method: The patient had blood samples taken regularly for analyses of PpIX, znPpIX, ALT, ALP, iron, leucocytes, C-reactive protein, and hemoglobin before, during, and after treatment with teriflunomide. Additionally, we tested if teriflunomide increased PpIX in vitro. Results: A female EPP patient was treated for 7 years with teriflunomide for multiple sclerosis attacks. During treatment, her natural PpIX level increased from about 30 µmol/L to about 200 µmol/L, without significant simultaneous changes in hemoglobin, iron levels, alanine transaminase (ALT), or alkaline phosphatase (ALP). The patient experienced no increase in photosensitivity. In vitro addition of teriflunomide did not affect PpIX levels. Discussion: In patients with lead intoxication, the release of PpIX from erythrocytes is very slow. The increase in PpIX during treatment with teriflunomide compared to periods with no medication could be caused by a similar slow PpIX release from the erythrocytes. This theory is supported by the patient’s unchanged light sensitivity and stable levels of hemoglobin, iron, and liver enzymes. Full article

Introduction: Chronic primary low back pain (CPLBP) is a prevalent condition in primary care and a leading cause of disability and absenteeism worldwide. Multidimensional approaches may be necessary to achieve physical and mental health benefits in individuals with CPLBP. Objective: The BACKFIT randomized controlled trial aims to evaluate the effectiveness of a multidimensional intervention—combining supervised exercise and mindfulness—on pain, physical fitness, mental health, and functional outcomes in individuals with CPLBP. Hypothesis: Both the supervised exercise program focused on motor control and trunk muscle strength (IG1) and the multidimensional intervention combining supervised exercise with mindfulness training (IG2) are expected to produce significant health improvements in individuals with CPLBP. It is further hypothesized that IG2 will yield greater improvements compared to IG1, both immediately post-intervention and at the two-month follow-up. Design: Randomized controlled trial. Setting: Virgen de las Nieves University Hospital, Granada (Spain). Participants: 105 individuals. Inclusion criteria: Previously diagnosed with CPLBP, aged ≥18 and ≤65 years, able to read and understand the informed consent, and able to walk, move, and communicate without external assistance. Exclusion criteria: serious lumbar structural disorders, acute or terminal illness, physical injury, mental illness, and medical prescriptions that prevent participation in the study. Intervention: Individuals will be randomly assigned to a supervised physical exercise group (2 days per week, 45 min per session), a multidimensional intervention group (same as supervised physical exercise group, and mindfulness 1 day per week, 2.5 h per session) or an active control group (usual care, 2 days per week, 45 min per session). The intervention will last 8 weeks. Main Outcome Measures: Primary outcome: pain threshold, perceived acute pain, and disability due to pain. Secondary measures: body composition, muscular fitness, gait parameters, device-measured physical activity and sedentary behavior, self-reported sedentary behavior, quality of life, pain catastrophizing, mental health, sleep duration and quality, and central sensitization. The groups will undergo pre-intervention, post-intervention, and a 2-month follow-up after a detraining period. Statistical Analysis: Both per-protocol and intention-to-treat approaches (≥70% attendance) will be used. Program effects will be assessed via one-way ANCOVA for between-group changes in primary and secondary outcomes. Conclusions: Given the complex nature of CPLBP, multidimensional approaches are recommended. If effective, this intervention may provide low-cost alternatives for health professionals. Full article

Background: Functional Neurological Disorder (FND) encompasses a spectrum of symptoms—including motor, cognitive, and seizure-like manifestations—that are not fully explained by structural neurological disease. Accumulating evidence suggests that comorbid psychiatric and somatic conditions significantly influence the clinical course, diagnostic complexity, and treatment response in FND. Objective: This study systematically explores psychiatric and medical comorbidities across major FND subtypes—Functional Cognitive Disorder (FCD), Functional Movement Disorder (FMD), and Psychogenic Non-Epileptic Seizures (PNES)—with an emphasis on subtype-specific patterns and shared vulnerabilities. Methods: We conducted a narrative review of the published literature, guided by systematic principles for transparency, covering both foundational and contemporary sources to examine comorbid conditions in patients with FCD, FMD, PNES, PPPD and general (mixed) FND populations. Relevant studies were identified through structured research and included based on methodological rigor and detailed reporting of comorbidities (PRISMA). Extracted data were organized by subtype and comorbidity type (psychiatric or medical/somatic). Results: Across all FND subtypes, high rates of psychiatric comorbidities were observed, particularly depression, anxiety, PTSD, and dissociative symptoms. FCD was predominantly associated with internalizing symptoms, affective misattribution, and heightened cognitive self-monitoring. FMD demonstrated strong links with trauma, emotional dysregulation, and personality vulnerabilities. PNES was characterized by the highest burden of psychiatric illness, with complex trauma histories and dissociation frequently reported. Somatic comorbidities—such as fibromyalgia, chronic pain, irritable bowel syndrome, and fatigue—were also prevalent across all subtypes, reflecting overlapping mechanisms involving interoception, central sensitization, and functional symptom migration. Conclusions: Comorbid psychiatric and medical conditions are integral to understanding the presentation and management of FND. Subtype-specific patterns underscore the need for individualized diagnostic and therapeutic approaches, while the shared biopsychosocial mechanisms suggest benefits of integrated care models across the FND spectrum. Full article

Background/Objectives: Evidence suggests a J-shaped association between alcohol consumption and depression, but it remains unclear whether this reflects a true causal effect, reverse causation, or methodological bias. This uncertainty is particularly relevant in older adults, who are at increased risk for both depression and alcohol-related harms. This study aimed to examine the association between varying levels of alcohol consumption and depression risk in community-dwelling older adults. Methods: We analyzed 16,563 community-dwelling older adults (mean age 75.1 ± 4.6 years) from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Alcohol intake, reported at baseline and follow-up, was categorized as abstinent, occasional, moderate, or above-guideline. Both intention-to-treat (classified by baseline alcohol consumption, regardless of later changes) and per-protocol (using annual time-updated alcohol consumption ) analyses were performed. To address confounding, informative censoring, and selection bias, we applied marginal structural models with inverse probability weighting. Results: In per-protocol analyses, abstainers (OR 1.17), occasional drinkers (OR 1.11), and above-guideline drinkers (OR 1.15) were significantly associated with a higher risk of depression compared with moderate drinkers, consistent with a J-shaped association. Sensitivity analyses excluding former drinkers and those with baseline depressive symptoms showed similar results. The association remained robust after adjusting for social isolation, social support, social interactions, physical activity, pain, sleep duration, sleep difficulties, and sleep medication use (n = 14,892; Australian sub-sample), and did not differ by sex. Conclusions: Moderate alcohol consumption was associated with the lowest depression risk, confirming a J-shaped relationship after comprehensive confounder adjustment. Full article

Retained products of conception (RPOC) represent a significant cause of morbidity in the post-abortive and postpartum periods, potentially leading to abnormal uterine bleeding, pelvic pain, infections, and intrauterine adhesions. Accurate diagnosis is crucial to avoid unnecessary surgical interventions and to preserve future fertility. Transvaginal ultrasound constitutes the primary imaging modality for identifying RPOC, but the lack of standardized diagnostic criteria complicates clinical decision-making. This narrative review explores the current literature on sonographic findings associated with RPOC, focusing on the diagnostic value of endometrial thickness (ET), the presence of intrauterine echogenic masses, and the use of Color Doppler imaging. Although an ET ≥15 mm is frequently used to suspect RPOC, the variability in cut-off thresholds and limited specificity reduce its diagnostic reliability. The detection of an echogenic intrauterine mass appears to be the most sensitive and specific sonographic feature. Color Doppler assessment, particularly the presence of enhanced myometrial vascularity (EMV) and classification systems like the Gutenberg score, offers further insight by stratifying hemorrhagic risk and guiding therapeutic choices. However, vascular parameters such as peak systolic velocity (PSV) and resistive index (RI) demonstrate a substantial overlap between benign and pathological conditions, limiting their stand-alone utility. The review also addresses the differential diagnosis of RPOC, including blood clots, arteriovenous malformations, placental polyps, gestational trophoblastic disease, and endometrial osseous metaplasia. The role of three-dimensional ultrasound remains limited in clinical practice, offering no significant advantage over two-dimensional imaging. Finally, the timing of follow-up ultrasound after medical treatment with misoprostol is critical: delayed assessment reduces overtreatment by allowing time for spontaneous resolution. In conclusion, despite advances in ultrasound technology, the diagnosis of RPOC remains challenging due to heterogeneity in imaging findings and inter-observer variability. A multimodal approach integrating grayscale and Doppler ultrasound with clinical evaluation is essential for optimal management. Full article

Paracetamol (PAR) is a common antipyretic and analgesic extensively used to treat cold and flu symptoms. It has been proven to be effective in headaches and relieving fever and pain. It is usually found as an over-the-counter drug, which has been associated with an increase in cases of poisoning due to overdose. Therefore, the development of new analytical tools for the detection of PAR at low concentrations in different samples is necessary. In this work, a Molecularly Imprinted Polymer (MIP)-based electrochemical sensor was designed for the selective and sensitive determination of PAR using a glassy carbon electrode (GCE) modified with a polymeric film obtained through the electropolymerization of o-aminophenol. A complete characterization based on electrochemical techniques, such as electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV), and scanning electron microscopy (SEM) was used to examine all steps involved in the construction of the MIP-based electrochemical sensor. In addition, all parameters affecting the MIP were optimized. As a result, the MIP-based electrochemical sensor showed a very low limit of detection (LOD) of 10 nM, with an analytical sensitivity of (3.4 ± 0.1) A M⁻¹. In addition, construction of the MIP-based electrochemical sensor showed highly reproducibility, expressed in terms of a variation coefficient lower than 4%. The MIP-based electrochemical sensor was successfully used in an assay for the determination of PAR in pharmaceutical products. The performance of the MIP-based electrochemical sensor was compared to High Performance Liquid Chromatography (HPLC) for the determination of PAR in pharmaceutical samples, showing excellent agreement between the two methodologies. A very important aspect of the developed sensor was its reusability for at least twenty times. The MIP-based electrochemical sensor is a reliable analytical tool for the determination of PAR. Full article

Background/Objectives: Mechanical, physiological, and biochemical changes contribute to post-traumatic osteoarthritis (PTOA). Specific mouse models that are highly reproducible, less invasive, and easy to use are lacking. This limitation hinders the progress of PTOA-related studies on therapeutic applications. The goal of the study was to establish a methodologically innovative, efficient, and less technically challenging surgical model for PTOA. Methods: We developed a modified medial meniscectomy (MMM) model demonstrating high reproducibility and applicability. The MMM model features distinct differences in the execution of transection of the medial meniscus on the lateral side and includes a smaller incision, which enhances reproducibility and is beneficial for studying pain, structure, and function. Results: One month after the MMM surgery, the mice showed increased sensitivity to pain and decreased biomechanical abilities, such as shorter running times and distances. This was further supported by higher Osteoarthritis Research Society International (OARSI) histology scores, a standardized system for determining the severity and extent of OA in cartilage. Additionally, transcriptomic analysis showed an elevated enrichment of immune activity and bone tissue formation gene sets in the knee joint. Conclusions: Overall, functional studies and transcriptomic analyses suggested that the MMM model can be utilized for future biomechanistic and therapeutic applications and could serve as a new resource for studying PTOA. Full article

Background and Clinical Significance: Zoledronic acid (ZA) is a widely used bisphosphonate for the prevention of skeletal-related events in patients with metastatic bone disease. While it is generally well tolerated, rare immune-mediated complications may be underrecognized. To date, myocarditis has not been reported in association with ZA. Case Presentation: A 35-year-old woman with metastatic pheochromocytoma developed acute, non-exertional chest pain approximately 36 h after receiving her first intravenous ZA infusion. Laboratory testing revealed elevated high-sensitivity troponin T, peaking at 1182 ng/L. Cardiac magnetic resonance imaging (CMR) demonstrated myocardial edema and subepicardial late gadolinium enhancement, consistent with acute myocarditis per the 2018 revised Lake Louise criteria. An extensive diagnostic workup excluded infectious, autoimmune, and ischemic causes. Symptoms and troponin levels improved following ZA discontinuation and supportive care. In the absence of alternative etiologies, and given the close temporal association with ZA administration, the diagnosis of presumed ZA-associated myocarditis was supported by clinical presentation, biochemical markers, and CMR findings, recognizing that histopathological confirmation is rarely pursued in clinically stable patients. Conclusions: To our knowledge, this is the first reported case of presumed zoledronic acid–associated myocarditis confirmed by cardiac MRI. This report highlights the diagnostic utility of CMR in suspected drug-related cardiac inflammation and the importance of considering myocarditis in patients presenting with unexplained chest pain following ZA infusion, particularly when other causes have been excluded. Full article

Background/Aim: Third molar impaction with the consequent root resorption of second molars often creates complexities in treatment planning and execution. In the past, the root canal treatment (RCT) of second molars was required in these cases to avoid pulp necrosis and infection. The aim of this paper is to report a surgical/retrograde approach for the maintenance of pulp vitality, proposed as retrograde vital pulp treatment (rVPT), in cases of asymptomatic or reversibly affected teeth with root resorptions caused by impacted adjacent teeth. Methods: A case report on the rVPT of two upper second molars with root resorption due to third molar impaction is presented. The chief complaint of the patient was a slight pain during bite involving the upper second molars. Heat and cold sensitivity tests were performed, suggesting a healthy pulp status. A cone beam computed tomography (CBCT) scan was performed to aid the diagnosis and treatment planning, showing bilateral upper third molar impaction and both distal roots of the upper second molars affected by external root resorption (ERR). In both cases, the third molar was surgically extracted, the surface of the root with ERR was smoothened and rVPT was carried out by performing a 3 mm retrograde preparation of the root canal and its retrograde sealing using a hydraulic calcium silicate-based cement (hCSCs). Results: Heat and cold sensitivity tests were performed 1 month, 3 months, 6 months and 1 year after the treatment. The patient reported no pain, and the pulp sensitivity was maintained in all follow-up periods. A CBCT scan was performed 24 months after the treatment, reporting a complete perirradicular endogenous bone apposition. Conclusions: Based on the successful clinical and radiographic outcomes observed in the present case after two years of follow-up, rVPT is proposed for the maintenance of pulp vitality in cases of asymptomatic or reversibly affected teeth with ERR caused by impacted adjacent teeth. Full article

Although opioids are effective in treating pain, they cause serious side effects. The use of regional anesthesia, although effective in the perioperative period, may not be suitable if mobility and lack of numbness is desired. Hence, there is a clear need for novel pain therapies. Low-voltage activated (T-type) calcium channels (Ca_V3.2 isoform) could be a promising therapeutic target for the development of novel pain therapies. Indeed, our published findings suggest that novel neuroactive steroid (NAS) analogs that modulate the activity of Ca_V3.2 channels have unique anti-nociceptive properties. However, the concern with current NASs appears to be their hypnotic/sedative properties, thus potentially hindering the future development of NASs for novel pain therapies. Hence, we developed a new line of NASs that are effective blockers of neuronal Ca_V3.2 channels in pain pathways while having more favorable pharmacodynamic properties, i.e., lack of sedative/hypnotic side effects. We present two promising novel analogs of NASs—B372 ((3β,5α,17β)-3-Hydroxyandrostan-17-carbonitrile) and YX23 ((3β,5α,17β)-3-Methoxyestran-17-ol). Using an in vitro approach, we show that B372 and YX23 are effective in blocking Ca_V3.2 channels. Using an in vivo approach, we show that they are effective anti-nociceptives in wild-type but not Ca_V3.2 knock-out mice. Importantly, we show that they lack sedative/hypnotic effects. Full article

Exercise-induced muscle damage (EIMD) is the most common health risk in physical exercise. However, instant and non-invasive methods for EIMD prediction have not been reported. Urine is a promising tool for EIMD prediction. However, urinary metabolite variations after EIMD occurrence have not been revealed, and potential biomarkers have not been identified. In this study, eighteen young students without regular exercise habits were recruited to perform high-intensity rowing exercise. EIMD occurrence was determined using blood biochemical analyses and pain assessment. The changes in urinary metabolites were revealed by quasi-targeted metabolomics. Results demonstrated that high-intensity rowing exercise induced EIMD and obviously changed urinary metabolites, including 23 upregulated metabolites and 26 downregulated metabolites. These differential metabolites were related to energy metabolism, exercise performance, and antioxidant metabolism. Among these metabolites, potential urinary biomarkers were identified with high sensitivity and specificity. Full article

Background: The aim of this study was to evaluate the diagnostic potential of salivary C-reactive protein (CRP) as a non-invasive biomarker for acute appendicitis in children and to compare its levels with those found in blood. Methods: Salivary and serum CRP levels were measured in patients with histologically confirmed acute appendicitis (n = 46) and a control group with non-specific abdominal pain (n = 43). Diagnostic performance was evaluated using receiver-operating characteristic analysis, while the agreement between salivary and serum CRP levels was evaluated using Spearman’s correlation and the Bland–Altman method. Results: Salivary CRP levels were significantly elevated in children with acute appendicitis than in controls (median 35.7 vs. 1.1 mg/L, p < 0.001), closely mirroring serum CRP trends (median 44.3 mg/L vs. 1.1 mg/L, p < 0.001). Moreover, they demonstrated excellent discriminatory power (Area Under the Curve; AUC = 0.97; 91.3% sensitivity, 95.4% specificity at the optimal cut-off of 6.95 mg/L), comparable to that of serum CRP (AUC = 0.98; 89.1% sensitivity and 95.4% specificity at 10.3 mg/L cut-off). Levels of CRP in serum and saliva were strongly correlated (Spearman’s ρ = 0.963, p < 0.001) and overall showed good agreement on Bland–Altman. Although larger discrepancies (>10 mg/L) occurred in 29% of cases, there was no consistent bias favoring either the salivary or serum CRP measurements. Conclusions: Salivary CRP is a promising non-invasive biomarker for diagnosing acute appendicitis in children, demonstrating diagnostic performance closely comparable to that of serum CRP and acceptable agreement between the two measures. This method may reduce the need for invasive blood sampling and streamline early evaluation in pediatric emergency settings. Full article

Background/Objectives: This study evaluates the effectiveness of a toothpaste containing Java Tea and Little Ironweed in alleviating tooth sensitivity compared to a conventional potassium nitrate toothpaste. Methods: A total of 90 healthy patients aged 18–70 with up to two teeth exhibiting gingival recession were recruited into this study. All selected teeth had a visual analog scale (VAS) score ≥ 4 in response to tactile or air blast stimuli. Excluded teeth included those requiring restoration or participants undergoing treatments affecting sensitivity or taking pain medication/anti-sensitivity agents. Participants were randomly divided into three groups and instructed to brush twice daily with different toothpastes. The S1 group was prescribed toothpaste containing Java Tea and Little Ironweed extract, the S2 group was prescribed toothpaste containing Java Tea and Little Ironweed extract with 0.7% potassium nitrate, and the S3 group was prescribed toothpaste containing potassium nitrate. VAS scores were recorded at baseline, 2 weeks, and 4 weeks. Data were then compared and statistically analyzed between the groups. Results: For the tactile test, the final number of included teeth was 47 in the S1 group, 46 in the S2 group, and 22 in the S3 group. For the air blast test, the number of teeth included was 38 in the S1 group, 30 in the S2 group, and 27 in the S3 group. At baseline, mean VAS scores were comparable across groups for both tactile (S1: 6.89 ± 0.98; S2: 6.65 ± 1.52; S3: 6.82 ± 1.99) and air blast tests (S1: 7.39 ± 1.15; S2: 7.53 ± 1.31; S3: 6.89 ± 2.12). All groups showed significant reductions in VAS scores from baseline at both 2 and 4 weeks. A Kruskal–Wallis test indicated significant between-group differences in VAS scores at 2 and 4 weeks (p = 0.001). Post hoc analysis (Dunn’s test with Bonferroni correction) at 2 weeks revealed that the S1 group had significantly higher VAS scores than those of S2 (tactile p = 0.001, air blast p = 0.001) and S3 (tactile p = 0.002, air blast p = 0.018). By 4 weeks, the S2 group demonstrated superior efficacy, with significantly lower VAS scores compared to those of S1 (tactile p < 0.001, air blast p = 0.030) and S3 (tactile p = 0.035, air blast p = 0.001). Conclusions: All tested toothpastes effectively reduced dentin hypersensitivity over the study period. Potassium nitrate toothpaste provided more rapid initial relief, when compared to the herbal formulation alone; however, both achieved similar outcomes by 4 weeks. The herbal toothpaste supplemented with potassium nitrate demonstrated superior efficacy and may offer a promising natural alternative for managing dentin hypersensitivity. Full article