Search Results (108)

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. While hepatic manifestations are frequent, psychiatric symptoms occur in up to 30% of patients and may precede neurological signs. This study was the first to assess the relationship between oxidative stress, selected genetic polymorphisms, and psychiatric symptoms in WD. A total of 464 patients under the care of the Institute of Psychiatry and Neurology in Warsaw were studied. Genotyping for GPX1 (rs1050450), SOD2 (rs4880), and CAT (rs1001179) was performed, along with biochemical analyses of copper metabolism, oxidative DNA, lipid and protein damage, and systemic antioxidant capacity. Among the most important observations are the following: the homozygous GPX1 rs1050450 TT and SOD2 rs4880 CC genotypes were associated with the lowest prevalence of psychiatric symptoms. The CAT rs1001179 TT genotype was linked to a delayed onset of psychiatric symptoms by 6.0–8.5 years. Patients with or without psychiatric symptoms did not differ significantly in saliva 8-OHdG, total antioxidant capacity, serum glutathione (GSH), catalase, and MnSOD; however, patients reporting psychiatric symptoms had significantly higher prostaglandin F2α 8-epimer (8-iso-PGF2α) concentrations and tended to have lower serum glutathione peroxidase (Gpx) concentrations compared to those without such symptoms. Our data firstly provide consistent evidence that oxidative stress balance associated with copper overload in the CNS may be associated with CNS damage and the development of psychiatric symptoms of WD. In particular, our findings of increased oxidative lipid damage together with decreased Gpx activity indirectly suggest that damage to neuronal membrane lipids, which may be potentially related to abnormalities in GSH metabolism, may have an etiological role in CNS damage and related symptoms. Full article

Acute heart failure (AHF) is a clinical syndrome characterized by the sudden onset or rapid worsening of heart failure signs and symptoms, frequently triggered by myocardial ischemia, pressure overload, or cardiotoxic injury. A central component of its pathophysiology is the activation of intracellular signal transduction cascades that translate extracellular stress into cellular responses. Among these, the mitogen-activated protein kinase (MAPK) pathways have received considerable attention due to their roles in mediating inflammation, apoptosis, hypertrophy, and adverse cardiac remodeling. The canonical MAPK cascades—including extracellular signal-regulated kinases (ERK1/2), p38 MAPK, and c-Jun N-terminal kinases (JNK)—are activated by upstream stimuli such as angiotensin II (Ang II), aldosterone, endothelin-1 (ET-1), and sustained catecholamine release. Additionally, emerging evidence highlights the role of receptor-mediated signaling, cellular stress, and myeloid cell-driven coagulation events in linking MAPK activation to fibrotic remodeling following myocardial infarction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade plays a central role in regulating cardiomyocyte survival, hypertrophy, energy metabolism, and inflammation. Activation of the PI3K/Akt pathway has been shown to confer cardioprotective effects by enhancing anti-apoptotic and pro-survival signaling; however, aberrant or sustained activation may contribute to maladaptive remodeling and progressive cardiac dysfunction. In the context of AHF, understanding the dual role of this pathway is crucial, as it functions both as a marker of compensatory adaptation and as a potential therapeutic target. Recent reviews and preclinical studies have linked PI3K/Akt activation with reduced myocardial apoptosis and attenuation of pro-inflammatory cascades that exacerbate heart failure. Among the multiple signaling pathways involved, glycogen synthase kinase-3β (GSK-3β) has emerged as a key regulator of apoptosis, inflammation, metabolic homeostasis, and cardiac remodeling. Recent studies underscore its dual function as both a negative regulator of pathological hypertrophy and a modulator of cell survival, making it a compelling therapeutic candidate in acute cardiac settings. While earlier investigations focused primarily on chronic heart failure and long-term remodeling, growing evidence now supports a critical role for GSK-3β dysregulation in acute myocardial stress and injury. This comprehensive review discusses recent advances in our understanding of the MAPK signaling pathway, the PI3K/Akt cascade, and GSK-3β activity in AHF, with a particular emphasis on mechanistic insights, preclinical models, and emerging therapeutic targets. Full article

Introduction: In the literature, depression is a medical condition that is well known and has been studied for decades, yet in clinical practice it often happens that depressive symptoms are confused with structured disorders or complexes. This incorrect interpretation can lead the psychiatrist to choose to make a psychopharmacological prescription, relegating psychotherapy to mere support or in any case reducing its importance, risking making the patient’s symptoms chronic and overloading the healthcare system. Materials and Methods: The literature up to December 2024 was reviewed and 40 articles were included in the review. A pilot study was conducted to verify the effectiveness and validation of the proposed theoretical model. Results: We propose the use of the “Perrotta Depressive Symptoms Assessment” (PDSYA) for the differential diagnosis in disorders with the manifestation of depressive symptoms, to facilitate the correct diagnosis and to reduce interpretative errors, both at a nosographic and therapeutic level. Conclusions: In the pilot study, in the content validity analysis, all items obtained a CVR score greater than the cut-off value, with a minimum score of 0.811. Therefore, all items of the scale were considered essential; also, regarding the relevance of the items in exploring the constructs investigated, optimal values of I-CVI (>0.93) and scale (S-CVI > 0.98) were obtained. Therefore, all items were rated as relevant. The validation study of the model is underway with a representative sample. Full article

Obesity and low back pain (LBP) are major contributors to global disability and healthcare burden in both adults and children. Although a growing body of research supports a bidirectional relationship between these conditions, the underlying mechanisms remain poorly integrated in the current literature. While mechanical overload has traditionally been viewed as the principal link, emerging evidence points to additional roles for metabolic dysregulation, chronic low-grade inflammation, and adipokine activity in the development and persistence of LBP. This review addresses the need for a comprehensive synthesis of how obesity affects spinal structures, including the intervertebral discs, paraspinal muscles, facet joints, and epidural fat, through both biomechanical and systemic biological pathways. We specifically highlight key mechanisms such as oxidative stress, adipokine signalling, and neuroinflammation that may accelerate spinal degeneration and promote chronic pain. In doing so, we aim to bridge gaps between anatomical, biochemical, and clinical perspectives. Additionally, we assess current clinical evidence on weight loss as a potential strategy for alleviating LBP symptoms. By consolidating diverse lines of evidence, this review provides a clearer framework for understanding obesity-related spinal pathology and outlines priorities for future research and targeted interventions. Full article

Background/Objectives: Cycling has become a popular recreational sport, but it can lead to injuries and overload syndromes. The goal of this study is to evaluate the effectiveness of a training-accompanied myofascial self-massage intervention on two primary outcomes: injury occurrence and perceived training intensity. Methods: To achieve this goal, we conducted a randomized controlled trial (RCT) with 35 cyclists. A difference-in-differences (DiD) regression analysis was employed to analyze the effects of the intervention. Results: The DiD analysis revealed, on the one hand, no statistically significant effect of the intervention on the overall injury score. On the other hand, the intervention group showed a significantly smaller increase in perceived training intensity compared to the control group, supporting the hypothesis that myofascial self-massage decreases the perception of training intensity. In one of our strongest models, which estimated the impact of the intervention from baseline to the second post-test, we observed an adjusted R-squared value of 0.89 and an interaction term coefficient of 1.35 at a significance level of p < 0.01. This indicates that, on average, the increase in perceived training intensity was 1.35 points higher (on a scale of 0 to 10) in the control group than in the intervention group. Conclusions: This study found no evidence to support the effectiveness of a training-accompanied myofascial self-massage in reducing injury levels, but it demonstrated that the intervention may reduce perceived training intensity. Future studies with larger sample sizes and more objective injury tracking methods are needed to further explore these findings and their long-term implications for injury prevention in cycling. Full article

Background/Objectives: To review the problem of diagnostic delay in soft tissue sarcomas with the aim of identifying its causes and consequences, understanding how to clinically suspect and refer them, and evaluating the main limitations of the referral guidelines already in use. Methods: A systematic review of the available literature was performed, focusing on the theoretical framework, the elements and time intervals to be considered, causes and consequences, “red flag” symptoms/signs, the main referral guidelines in use, their results, and the methods used to avoid excessive referrals. Results: Diagnostic delay in soft tissue sarcomas is a frequent event that is poorly characterized and has important consequences, including prognostic, medico-legal and psycho-social effects. The common denominator is the lack of knowledge and awareness. Several referral guidelines have been described, and most of them are based on clinical data. Their results have been disappointing. Thus, it is necessary to implement new methods to improve their results and avoid the overload of pre-referral imaging systems, sarcoma diagnostic triage meetings, and telemedicine systems. Conclusions: Sarcoma units and health system leaders need to study this issue to determine the extent of the problem and its causes. Without this information, it is almost impossible to properly address the problem and take corrective actions. Early referral of suspected soft tissue sarcoma lesions, although desirable, is a complex issue due to the non-specificity of the symptoms. Existing clinical referral guidelines need to be modified to improve detection and conversion rates. Full article

Background: Heart failure (HF), chronic kidney disease (CKD), and atrial fibrillation (AF) frequently coexist, forming a high-risk triad that amplifies morbidity and mortality through shared pathophysiological mechanisms such as neurohormonal activation, fluid overload, and inflammation. Current risk stratification tools, including CHA₂DS₂-VASc and HAS-BLED, inadequately capture the complexity of these multimorbid patients. This study aims to explore the influence of comorbidities, hypertension severity, anticoagulation strategy, and risk scores on hospitalization outcomes in patients with coexisting HF, CKD, and AF. Materials and Methods: A retrospective case study was conducted on 174 hospitalized patients with HF, CKD, and AF. Clinical data included hypertension grade, HF phenotype (HFpEF vs. HFrEF), NYHA classification, renal function (KDIGO stage), stroke and bleeding risk scores (CHA₂DS₂-VASc: congestive heart failure, hypertension, age ≥ 75, diabetes, and stroke/TIA; HAS-BLED: hypertension, abnormal renal/liver function, stroke, bleeding, labile INR, elderly, and drugs/alcohol), comorbidities (neurological, psychiatric, COPD, and diabetes), anticoagulation type (DOACs vs. VKAs), and length of hospital stay. Statistical analysis included Spearman correlation, independent t-tests, and multivariate regression to evaluate associations between variables and clinical outcomes. Results: Most patients were elderly (mean age 75 ± 12), with advanced CKD (stage 3b) and systolic HF (77% HFrEF). Mean CHA₂DS₂-VASc was 5.67, HAS-BLED was 4.40, and ATRIA was 4.74, indicating high stroke and bleeding risk. Anticoagulation was predominantly via DOACs (69.5%). Hypertension severity did not significantly correlate with NYHA class (ρ = −0.14, p = 0.068). Neurological, psychiatric, and metabolic comorbidities showed no significant associations with HF severity. COPD and diabetes correlated inversely with CHA₂DS₂-VASc scores (ρ = −0.83, p = 0.014). No significant differences were observed in hospital stay between HF phenotypes or prior stroke history. In-hospital mortality was low (2.3%). Conclusions: Traditional risk scores do not fully capture the complexity of multimorbid patients. Metabolic comorbidities showed an inverse correlation with stroke risk scores, and no significant correlation was observed between hypertension severity and HF symptom burden. Hypertension and common comorbidities did not correlate with HF symptom burden, and metabolic diseases may paradoxically associate with lower stroke risk scores. These findings highlight the need for improved multimodal risk assessment strategies that consider the heterogeneity of multimorbid populations. Personalized, integrated approaches are essential to optimize anticoagulation, reduce hospitalization, and improve prognosis. Full article

Background/Objectives: Thalassemia, a hereditary blood disorder, leads to reduced hemoglobin levels, impairing oxygen transport and negatively impacting patient health. Recent research suggests a possible association between thalassemia and gastrointestinal (GI) symptoms, such as abdominal pain, diarrhea, and GI bleeding, potentially due to immune compromise and iron overload. This systematic review aims to explore the prevalence and underlying factors of GI pathologies in thalassemia patients, excluding treatment-related effects and iron overload. Methods: A comprehensive search following the PRISMA guidelines was conducted to identify the prevalence and causes of GI disorders in thalassemia patients. Studies assessing non-treatment-related GI symptoms and their links to thalassemia were analyzed. After screening 1902 studies, 13 were included to investigate gastrointestinal manifestations in thalassemia patients. Results: Evidence indicates potential associations between thalassemia and GI disorders, including malabsorption, inflammatory bowel disease, Heliobacter pylori (H. pylori) infection, and celiac disease. Findings highlight immune compromise and iron dysregulation as possible contributing factors. Conclusions: This review highlights the importance of further research into the GI manifestations of thalassemia to enable early detection and improve patient health outcomes and quality of life. Addressing this gap may provide insights into better clinical management strategies for thalassemia patients. Full article

Wilson’s disease (WD) is an inherited disorder characterized by abnormal copper metabolism with complex pathological features. Currently, the mechanism of copper overload-induced hepatic injury is unclear. Green tea is a natural chelator, and its main ingredients, green tea polyphenol (GTP) and L-theanine (L-TA) are good at binding to heavy metals like iron and copper. There have been no reports on green tea extracts (GTE) for the treatment of Wilson’s disease. This study investigated the hepatoprotective effect of GTE on WD model mice. Initially, we examined the impact of green tea extract on copper metabolism, excretion, and hepatoprotective effects in WD model toxic milk mice. Then, Ultra performance liquid chromatography (UPLC-DAD) was established to analyze GTP and L-TA in green tea extract. Further screening of eight active components and copper complex active components in green tea extract was carried out by ion analyzer. Finally, we verified the pharmacodynamic effects of these active ingredients at the animal level. The results showed that GTE improves liver function and attenuates liver injury in TX mice by promoting tissue copper excretion and inhibiting oxidative stress, which provides a theoretical basis for green tea’s potential to improve the clinical symptoms of WD. Full article

Neurodegeneration with brain iron accumulation (NBIA) involves a group of rare neurogenetic disorders often linked with iron overload in the basal nuclei of the brain presenting with spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration. Among NBIA subtypes, beta-propeller-protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45 (WD repeat domain 45). Previously, we demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism, and cell bioenergetics. In addition, antioxidant supplementation partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected. In this work, we explored the possibility of expressing the normal WDR45 allele present in the inactive chromosome X (Xi) of BPAN cells through treatment with epigenetic modulators. The aim of this study was to demonstrate whether biotin, an epigenetic nutrient, was able to restore the expression levels of WDR45 by a mechanism involving Xi reactivation and, consequently, correct BPAN defects. Our study demonstrated that biotin supplementation increases histone biotinylation and allows for the transcription of the WDR45 allele in Xi. Consequently, all physiopathological alterations in BPAN cells were notably corrected. The reactivation of Xi by epigenetic modulators can be a promising approach for the treatment of BPAN and other X-linked diseases. Full article

Background: The utilization of digital technologies in the field of dentistry is becoming increasingly prevalent. Such technologies facilitate more precise and efficient dental treatment while also enhancing the overall quality of care. The advent of digitalization has brought with it a plethora of advantages, yet it has also given rise to a number of potential challenges. These have the potential to give rise to a variety of negative consequences, including an increase in stress perception. Objectives: This study identifies the digital demands and resources as well as the prevalence of digital stress perception among German dentists. Furthermore, the study examines the relationship between digital stress perception and work- and health-related outcomes, and it identifies potential preventive measures. Methods: The quantitative cross-sectional study involved a total of 325 German dentists. Data collection took place between January and April 2024. The questionnaire was validated using several established scales, including the Technostress Scale and the Copenhagen Psychosocial Questionnaire (COPSOQ). Multiple correlation and regression analyses were conducted to ascertain the reliability and validity of the data collected. Results: The study results demonstrated that the participating dentists exhibited a moderate level of digital stress (M = 3.73 (SD = 0.71). Regarding the individual technostress creators, the highest mean was observed for the constructs of techno-overload (M = 3.91; SD = 0.76), techno-complexity (M = 3.63; SD = 0.71), and techno-uncertainty (M = 2.01; SD = 0.75). The participants reported an average level of exhaustion symptoms (M = 3.21; SD = 0.91) and job satisfaction (M = 4.52; SD = 0.78). The association between technostress and emotional exhaustion (as a burnout symptom) showed a significant positive correlation (r = 0.38; CI: 0.07, 0.52; p < 0.05). A significant negative correlation was observed between the variables of technostress and job satisfaction, with a correlation coefficient of r = −0.33 (CI: −0.25, 0.07; p < 0.05). Conclusions: This study presents preliminary findings on the digital stress experience in dentistry and relevant associations. In the context of ongoing digitalization, there is a need for support and preventive measures to reduce technology-related stress. An optimized design of digital applications and the working environment are of crucial importance to improve the health of dentists and the quality of patient care. Full article

Doxorubicin (DOX) has been widely used as a cytotoxic chemotherapeutic. However, DOX has a number of side effects, such as myelotoxicity or gonadotoxicity, the most dangerous of which is cardiotoxicity. Cardiotoxicity can manifest as cardiac arrhythmias, myocarditis, and pericarditis; life-threatening late cardiotoxicity can result in heart failure months or years after the completion of chemotherapy. The development of late cardiomyopathy is not yet fully understood. The most important question is how DOX reprograms the cardiomyocyte, after which DOX is excreted from the body, initially without symptoms. However, clinically overt cardiomyopathy develops over the following months and years. Since the 1980s, DOX-induced disorders in cardiomyocytes have been thought to be related to oxidative stress and dependent on the Fe/reactive oxygen species (ROS) mechanism. That line of evidence was supported by dexrazoxane (DEX) protection, the only Food and Drug Administration (FDA)-approved drug for preventing DOX-induced cardiomyopathy, which complexes iron. Thus, the hypothesis related to Fe/ROS provides a plausible explanation for the induction of the development of late cardiomyopathy via DOX. However, in subsequent studies, DEX was used to identify another important mechanism in DOX-induced cardiomyopathy that is related to topoisomerase 2β (Top2β). Does the Top2β hypothesis explain the mechanisms of the development of DOX-dependent late heart failure? Several of these mechanisms have been identified to date, proving the involvement of Top2β in the regulation of the redox balance, including oxidative stress. Thus, the development of late cardiomyopathy can be explained based on mechanisms related to Top2β. In this review, we highlight free radical theory, iron imbalance, calcium overload, and finally, a theory based on Top2β. Full article

Background/Objectives: Early identification of complications in chronic and infectious diseases can reduce clinical deterioration, lead to early therapeutic interventions and lower morbidity and mortality rates. Here, we aimed to assess the feasibility of a novel clinical decision support system (CDSS) based on the automatic generation of alerts through remote patient monitoring and to identify the patient profile associated with the likelihood of severe medical alerts. Methods: A prospective, multicenter, open-label, randomized controlled trial was conducted. Patients with COVID-19 in home isolation were randomly assigned in a 1:1 ratio to receive either conventional primary care telephone follow-up plus access to a mobile app for self-reporting of symptoms (control group) or conventional primary care telephone follow-up plus access to the mobile app for self-reporting of symptoms and wearable devices for real-time telemonitoring of vital signs (case group). Results: A total of 342 patients were randomized, of whom 247 were included in the per-protocol analysis (103 cases and 144 controls). The case group received a more exhaustive follow-up, with a higher number of alerts (61,827 vs. 1825; p < 0.05) but without overloading healthcare professionals thanks to automatic alert management through artificial intelligence. Baseline factors independently associated with the likelihood of a severe alert were having asthma (OR: 1.74, 95% CI: 1.22–2.48, p = 0.002) and taking corticosteroids (OR: 2.28, 95% CI: 1.24–4.2, p = 0.008). Conclusions: The CDSS could be successfully implemented and enabled real-time telemonitoring of patients’ clinical status, providing valuable information to physicians and public health agencies. Full article

Background: This study evaluated the effectiveness of radio electric asymmetric conveyer (REAC) neurobiological optimization treatments on muscle strength (MS) in individuals with post-polio syndrome (PPS), a condition causing new muscle weakness in polio survivors. Traditional treatments focus on symptom management, whereas REAC technology uses radio electric symmetric conveyed fields to modulate neurotransmission and cellular function. Methods: This open-label study involved 17 PPS patients who maintained their existing medications. The participants underwent four REAC treatment protocols: neuro-postural optimization (NPO), neuro-psycho-physical optimization (NPPO), neuro-psycho-physical optimization—cervical brachial (NPPO-CB), and neuromuscular optimization (NMO). MS was assessed using manual muscular tests (MMT) before and after each protocol. Results: A statistical analysis via repeated measures ANOVA showed significant MS improvements, particularly in the proximal muscles of the left lower limb (LLL), distal muscles of both lower limbs (LLs), and distal muscles of the left upper limb. The LLL, the most severely affected limb at this study’s start, exhibited the greatest improvement. Conclusions: These results suggest REAC treatments could enhance MS in PPS patients, potentially reorganizing motor patterns and reducing functional overload on less affected limbs. Full article

Background: Pyruvate kinase (PK) deficiency is an inherited red blood cell (RBC) enzyme disorder that results in non-immune chronic hemolytic anemia. Characteristic symptoms of PK deficiency include anemia, fatigue, splenomegaly, jaundice, gallstones, thrombosis, and transfusional iron overload. Previously, treatments aimed at symptomatic management with RBC transfusions, phototherapy, folic acid supplementation, splenectomy, and iron chelation therapy when iron overload was documented. Mitapivat, a recently approved medication for treatment of PK-deficiency hemolytic anemia, is an oral allosteric activator of wild-type and mutant RBC PK enzymes. In this paper, we describe three cases of PK-deficiency anemia treated with mitapivat and describe modern management of this rare hemolytic disorder. Methods: A retrospective healthcare database analysis was conducted to extract relevant information. Both quantitative and qualitative methods were integrated to provide a more comprehensive understanding of the cases. Results: Two patients responded well to treatment with mitapivat, noted by an increase in hemoglobin levels, improvements in hemolytic markers, less frequent or no RBC transfusion requirements, and improvements in fatigue. One patient carrying two non-missense mutations of the PKLR gene did not respond to treatment with mitapivat. As variations in patient-specific factors (including genotype) can lead to different clinical manifestations and responses to treatment, we recommend considering both the phenotype (clinical symptoms and signs) and the genotype of the PKLR gene when making therapeutic decisions about starting a patient on mitapivat. Conclusions: While mitapivat addresses the previously unmet needs of most patients with PK deficiency as the first and only disease-modifying medication to receive approval for this condition, not all patients with PK deficiency are amenable to treatment with mitapivat. Full article