Search Results (572)

Clozapine, a second-generation antipsychotic known for its effectiveness in treating resistant schizophrenia, is often linked with serious hematological side effects, particularly neutropenia and agranulocytosis. This review investigates the underlying pathophysiological mechanisms of clozapine-induced neutropenia (CIN) and agranulocytosis (CIA), outlines associated risk factors, and evaluates current clinical management strategies. Clozapine’s pharmacological profile, marked by its antagonism of dopamine D4 and serotonin receptors, contributes to both its therapeutic advantages and hematological toxicity. Epidemiological data show a prevalence of CIN and CIA at approximately 3.8% and 0.9%, respectively, with onset typically occurring within the first six months of treatment. Key risk factors include older age, Asian and African American ethnicity, female sex, and certain genetic predispositions. The development of CIN and CIA may involve bone marrow suppression and autoimmune mechanisms, although the exact processes remain partially understood. Clinical presentation often includes nonspecific symptoms such as fever and signs of infection, necessitating regular hematological monitoring in accordance with established guidelines. Management strategies include dosage adjustments, cessation of clozapine, and the administration of granulocyte colony-stimulating factors (G-CSF). Advances in pharmacogenomics show promise for predicting susceptibility to CIN and CIA, potentially improving patient safety. This review emphasizes the importance of vigilant monitoring and personalized treatment approaches to reduce the risks associated with clozapine therapy. Full article

Antibody-mediated autoimmune diseases are common, can involve any organ system, and pose a large burden for patients and healthcare systems. Most antibody-mediated diseases are mediated by IgG antibodies. Selective targeting of pathogenic antibodies is an attractive treatment option which has already proven to be effective in antibody-positive generalized myasthenia gravis, maternal-fetal alloimmune cytopenias, and immune thrombocytopenic purpura. Warm autoimmune hemolytic anemia (wAIHA) is an autoimmune disorder mediated by pathogenic antibodies mainly of the IgG class with no approved therapy. Current treatment includes non-specific immunosuppression with corticosteroids, rituximab, and other immunosuppressive agents. With most therapies, time to response can be delayed and transfusions may be needed. Neonatal Fc receptor (FcRN) therapies provide rapid and sustained reduction of pathogenic IgG levels providing potential for fast, effective therapy in antibody-mediated autoimmune diseases including warm autoimmune hemolytic anemia. This review focuses on the emerging role of FcRn inhibition in autoimmune hematologic diseases, and their therapeutic potential in wAIHA. Full article

Background/Objective: Early-onset neonatal sepsis (EOS), defined as infection occurring within the first 72 h after birth, remains a major contributor to neonatal morbidity and mortality worldwide. Although advances in perinatal care have improved overall outcomes, the diagnosis of EOS continues to be challenging. Clinical presentations are often nonspecific, laboratory confirmation is often delayed, and immune responses vary considerably among neonates. Expanding our understanding of the molecular mechanisms underlying EOS is essential in enhancing early detection, refining risk stratification, and guiding therapeutic strategies. This systematic review aims to synthesize the available information on the molecular pathways involved in EOS, focusing on pathogen-induced inflammation, systemic immune responses, sterile inflammatory processes, interactions between infectious and non-infectious pathways, as well as emerging molecular diagnostic approaches. Methods: A comprehensive review of original research articles and reviews published between January 2015 and January 2025 was conducted; studies were included based on their focus on human neonates and their analysis of molecular or immunological mechanisms relevant to EOS pathogenesis, immune dysregulation, or novel diagnostic strategies. Results: Pathogen-driven inflammation typically involves the activation of Toll-like receptors (TLRs), the recruitment of neutrophils, and the release of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, particularly in response to vertical transmission of organisms like Escherichia coli and Streptococcus agalactiae. Systemic inflammatory responses are marked by cytokine dysregulation, contributing to multi-organ dysfunction. Sterile inflammation, often initiated by hypoxia–reperfusion injury or intrauterine stress, amplifies susceptibility to sepsis. Interactions between immune, metabolic, and endothelial pathways further exacerbate tissue injury. Recent advances, including transcriptomic profiling, microRNA-based biomarkers, and immune checkpoint studies, offer promising strategies for earlier diagnosis and individualized therapeutic options. Conclusions: EOS arises from a complex interplay of infectious and sterile inflammatory mechanisms. A deeper molecular understanding holds promise for advancing correct diagnostics and targeted therapies, aiming to improve neonatal outcomes. Full article

Background: Adhesive capsulitis (AC) causes a global limitation of both active and passive range of motion (ROM) in the shoulder, with or without pain, and no specific radiographic findings. Its course is self-limiting and progresses through three or four stages. The diagnosis is primarily clinical, since imaging tests are nonspecific. Treatment options include physical therapy (PT), intra-articular corticosteroid injections, suprascapular nerve block (SSNB), and hydrodilatation (HD). The latter is useful for expanding and reducing inflammation of the joint capsule through the insufflation of saline solution, anesthetics, and corticosteroids. Objectives: To compare whether patients with AC, stratified by phase 1 and 2, who receive high-volume HD as treatment achieve better outcomes in terms of shoulder pain and function compared to patients who receive low-volume HD. To compare whether there are differences in PT times and to determine mean axillary recess (AR) values. Methods: A randomized, parallel-block, triple-blind clinical trial will be conducted in 64 patients with AC in phases 1 and 2, aged 30 to 70 years, with limited active and passive ROM in two planes, and shoulder pain lasting more than 3 months. HD will be administered with volumes of 20 mL or 40 mL, followed by a conventional rehabilitation program. Outcomes will be reviewed at the 1st, 3rd, and 6th months of HD. Variables collected will include Shoulder Pain and Disability Index (SPADI), Visual Analog Scale (VAS), Range of motion (ROM), Lattinen index (LI), AR size, and time to completion of PT. Results: HD has been gaining clinical relevance in interventional rehabilitation as a treatment for AC, although its medium- and long-term efficacy remains a matter of debate. The variability in the volumes used for capsular expansion, with studies ranging from 18 mL to 47 mL, is compounded by the fact that most of these studies do not differentiate between AC stages. This could influence treatment effectiveness. Furthermore, diagnosis remains a challenge since valid and specific diagnostic parameters are lacking. Conclusions: Understanding the differences between HD techniques, considering the influence of certain factors such as the volume used or the stages of AC, as well as improving diagnosis and the coordination of scientific work. This could facilitate the development of protocols for the use of HD in AC. Full article

Background/Objectives: Pulmonary embolism (PE) remains a major cause of morbidity and mortality. Despite advances in care, its nonspecific symptoms pose diagnostic and therapeutic challenges. Emerging evidence suggests sex-based differences in PE presentation, management, and outcomes, yet real-world data from European settings remain scarce. This study aimed to investigate sex differences in clinical presentation, diagnostic workup, therapeutic interventions, and outcomes among hospitalized PE patients. Methods: We conducted a retrospective cohort study including all adult patients (≥18 years) admitted with a main diagnosis of acute PE at the Cantonal Hospital Baselland between January 2018 and December 2020. Data were extracted from electronic medical records and included demographics, comorbidities, symptoms, diagnostics, treatments, and outcomes. Sex-based comparisons were performed using univariate analyses. Results: Among 197 patients, 54% were women. Compared to men, women were more often admitted by ambulance (42% n = 45 vs. 24% n = 22, p = 0.009), had more frequent tachycardia (38% n = 41 vs. 23% n = 21, p = 0.024), and received lysis therapy more often (10% n = 11 vs. 2% n = 2, p = 0.023). DVT was more frequently diagnosed in women when sonography was performed (82% n = 49 vs. 64% n = 34, p = 0.035). Men had higher rates of B symptoms, smoking, and family history of PE. Women had longer hospital stays and were more frequently discharged to rehabilitation facilities. No sex differences were found in in-hospital mortality, 6-month rehospitalization, or adherence to diagnostic guidelines. Conclusions: This study reveals sex-based differences in PE presentation and management, suggesting potential disparities in care pathways. Further research is needed to promote equitable, personalized treatment strategies. Full article

Background/Objectives: Primary malignant lung tumors in children are rare and diagnostically challenging. This study presents a single-center experience in the diagnosis and treatment of these tumors, emphasizing the role of histopathological and genetic profiling in informing individualized therapeutic strategies. Methods: We retrospectively reviewed records of seven pediatric patients (ages 2–18) treated from 2015 to 2025. Diagnostics included laboratory tests, chest CT, bronchoscopy, and histopathological/immunohistochemical analysis. Treatment primarily involved surgical resection, complemented by chemo-, radio-, or targeted therapies when indicated. Results: Inflammatory myofibroblastic tumor (IMT) represented the most commonly diagnosed entity (3/7 cases). The tumors presented with nonspecific symptoms, most frequently dry cough. Tumor type distribution was age-dependent, with aggressive forms such as pleuropulmonary blastoma predominantly affecting younger children, whereas IMT and carcinoid tumors were more common in older patients. Surgical resection remained the mainstay of treatment in the majority of cases. Bronchoscopy served as a valuable adjunct in the initial management of tumors exhibiting intraluminal growth, allowing for direct visualization, tissue sampling, and partial debulking to alleviate airway obstruction. In patients with an initially unresectable IMT harboring specific gene fusion rearrangement (e.g., TFG::ROS1), neoadjuvant targeted therapy with crizotinib enabled adequate tumor shrinkage to allow for subsequent surgical resection. Two patients in the study cohort died as a result of disease progression. Conclusions: A multidisciplinary diagnostic approach—integrating radiologic, bronchoscopic, histopathological, and genetic evaluations—ensures high diagnostic accuracy. While conventional treatments remain curative in many cases, targeted therapies directed at specific molecular alterations may offer essential therapeutic options for selected patients. Full article

Alcohol dependency is a complex and chronic condition that negatively impacts multiple organ systems, including the skin. A key pathological factor in this process is oxidative stress, leading to progressive cellular damage, chronic inflammation, and accelerated cutaneous aging. Alcohol metabolism generates reactive oxygen species (ROS), which overwhelm endogenous antioxidant defenses and contribute to a range of skin alterations, including nonspecific changes such as xerosis, erythema, and wrinkle formation, as well as inflammatory and neoplastic skin disorders. Additionally, alcohol-induced alterations of the skin microbiome may further exacerbate skin barrier dysfunction and inflammatory responses. This review explores the biochemical mechanisms and skin microbiome alterations linking alcohol-induced oxidative stress to skin damage and disease. Furthermore, it evaluates the therapeutic potential of antioxidant-based interventions, both natural and synthetic. Antioxidants may offer protective and regenerative effects by scavenging free radicals, modulating inflammatory responses, and enhancing skin barrier function. The paper aims to provide a comprehensive overview of the molecular and microbial interplay between alcohol, oxidative stress, and skin health, while identifying future directions for targeted antioxidant therapy in individuals with alcohol dependency. Full article

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, progressive form of pre-capillary pulmonary hypertension characterized by persistent, organized thromboemboli in the pulmonary vasculature, leading to vascular remodeling, elevated pulmonary artery pressures, right heart failure, and significant morbidity and mortality if untreated. Despite advances, CTEPH remains underdiagnosed due to nonspecific symptoms and overlapping features with other forms of pulmonary hypertension. Basic Methodology: This review synthesizes data from large international registries, epidemiologic studies, translational research, and multicenter clinical trials. Key methodologies include analysis of registry data to assess incidence and risk factors, histopathological examination of lung specimens, and molecular studies investigating endothelial dysfunction and inflammatory pathways. Diagnostic modalities and treatment outcomes are evaluated through observational studies and randomized controlled trials. Recent Advances and Affected Population: Research has elucidated that CTEPH arises from incomplete resolution of pulmonary emboli, with subsequent fibrotic transformation mediated by dysregulated TGF-β/TGFBI signaling, endothelial dysfunction, and chronic inflammation. Affected populations are typically older adults, often with prior venous thromboembolism, splenectomy, or prothrombotic conditions, though up to 25% have no history of acute PE. The disease burden is substantial, with delayed diagnosis contributing to worse outcomes and higher societal costs. Microvascular arteriopathy and PAH-like lesions in non-occluded vessels further complicate the clinical picture. Conclusions: CTEPH is now recognized as a treatable disease, with multimodal therapies—surgical endarterectomy, balloon pulmonary angioplasty, and targeted pharmacotherapy—significantly improving survival and quality of life. Ongoing research into molecular mechanisms and biomarker-driven diagnostics promises earlier identification and more personalized management. Multidisciplinary care and continued translational investigation are essential to further reduce mortality and optimize outcomes for this complex patient population. Full article

Introduction: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the clonal expansion of myeloid progenitors. While it primarily affects the bone marrow, extramedullary relapse occurs in 3–5% of cases, and it is linked to poor prognosis. Central nervous system (CNS) involvement presents diagnostic challenges due to nonspecific symptoms. CNS manifestations include leptomeningeal dissemination, nerve infiltration, parenchymal lesions, and myeloid sarcoma, occurring at any disease stage and frequently asymptomatic. Methods: A 62-year-old man with a recent history of AML in remission presented with diplopia and aching paresthesias in the left periorbital region spreading to the left frontal area. The diagnostic workup included neurological and hematological evaluation, lumbar puncture, brain CT, brain magnetic resonance imaging (MRI) with contrast, and dermatological evaluation with skin biopsy due to the appearance of nodular skin lesions on the abdomen and thorax. Results: Neurological evaluation showed hypoesthesia in the left mandibular region, consistent with left trigeminal nerve involvement, extending to the periorbital and frontal areas, and impaired adduction of the left eye with divergent strabismus in the primary position due to left oculomotor nerve palsy. Brain MRI showed an equivocal thickening of the left oculomotor nerve without enhancement. Cerebrospinal fluid (CSF) analysis initially showed elevated protein (47 mg/dL) with negative cytology; a repeat lumbar puncture one week later detected leukemic cells. Skin biopsy revealed cutaneous AML localization. A diagnosis of AML relapse with CNS and cutaneous localization was made. Salvage therapy with FLAG-IDA-VEN (fludarabine, cytarabine, idarubicin, venetoclax) and intrathecal methotrexate, cytarabine, and dexamethasone was started. Subsequent lumbar punctures were negative for leukemic cells. Due to high-risk status and extramedullary disease, the patient underwent allogeneic hematopoietic stem cell transplantation. Post-transplant aplasia was complicated by septic shock; the patient succumbed to an invasive fungal infection. Conclusions: This case illustrates the diagnostic complexity and poor prognosis of extramedullary AML relapse involving the CNS. Early recognition of neurological signs, including cranial nerve dysfunction, is crucial for timely diagnosis and management. Although initial investigations were negative, further analyses—including repeated CSF examinations and skin biopsy—led to the identification of leukemic involvement. Although neuroleukemiosis cannot be confirmed without nerve biopsy, the combination of clinical presentation, neuroimaging, and CSF data strongly supports the diagnosis of extramedullary relapse of AML. Multidisciplinary evaluation remains essential for detecting extramedullary relapse. Despite treatment achieving CSF clearance, the prognosis remains unfavorable, underscoring the need for vigilant clinical suspicion in hematologic patients presenting with neurological symptoms. Full article

Background: Multiple Chemical Sensitivity (MCS) is a complex, disabling condition marked by non-specific symptoms in response to low-level chemical exposures. It often leads to substantial impairments in quality of life, psychological health, and daily functioning. Although non-pharmacological approaches—such as lifestyle and psychological interventions—are widely used, their clinical effectiveness remains unclear. Objective: We aim to evaluate the effectiveness of lifestyle-based approaches in improving clinical and psychosocial outcomes in adults with Multiple Chemical Sensitivity. Methods: A systematic review was conducted in accordance with PRISMA guidelines (PROSPERO: CRD420251013537). Literature searches were carried out in MEDLINE (PubMed), CINAHL, Google Scholar, and ResearchGate between March and April 2025. Eligible studies included adults (≥18 years) with a confirmed diagnosis of MCS and reported outcomes such as perceived stress, anxiety, depressive symptoms, or quality of life. Methodological quality and risk of bias were independently assessed using the PEDro scale, NIH Quality Assessment Tool, CEBMa checklist, and Cochrane RoB 2.0. Results: Twelve studies (N = 378) met the inclusion criteria. Cognitive and behavioral therapies demonstrated the most consistent evidence of efficacy, with reductions in symptom severity, maladaptive cognitive patterns, and functional limitations. Mindfulness-based stress reduction showed favorable outcomes, while other mindfulness-based interventions yielded mixed results. Exposure-based therapies contributed to increased chemical tolerance and reduced avoidance behavior. Electromagnetic and biomedical approaches demonstrated preliminary but limited effectiveness. Aromatherapy was well tolerated and perceived as relaxing, though its clinical impact was modest. Conclusions: Cognitive and behavioral therapies appear to be most effective among lifestyle-based interventions for MCS/IEI. However, study heterogeneity limits the generalizability of findings, underscoring the need for more rigorous research. Full article

Background/Objectives: A randomized controlled trial (RCT) was designed to test the emerging role of respiratory mechanics as part of physiotherapy in patients with non-specific chronic neck pain (NSCNP). Methods: Ninety patients with NSCNP and symptom duration >3 months were randomly allocated to three intervention groups of equal size, receiving either cervical spine (according to the Mulligan Concept) and diaphragm manual therapy plus breathing reeducation exercises (experimental group—EG1), cervical spine manual therapy plus sham diaphragmatic manual techniques (EG2), or conventional physiotherapy (control group—CG). The treatment period lasted one month (10 sessions) for all groups. The effect on the cervical spine range of motion (CS-ROM) and on the craniovertebral angle (CVA) was examined. Outcomes were collected before treatment (0/12), after treatment (1/12), and three months after the end of treatment (4/12). The main analysis comprised a two-way mixed ANOVA with a repeated measures factor (time) and a between-groups factor (group). Post hoc tests assessed the source of significant interactions detected. The significance level was set at p = 0.05. Results: No significant between-group baseline differences were identified. Increases in CS-ROM and in CVA were registered mainly post-treatment, with improvements maintained at follow-up for CS-ROM. EG1 significantly improved over CG in all movement directions except for flexion and over EG2 for extension only, at 1/12 and 4/12. All groups improved by the same amount for CVA. Conclusions: EG1, which included diaphragm manual therapy and breathing re-education exercises, registered the largest overall improvement over CG (except for flexion and CVA), and for extension over EG2. The interaction between respiratory mechanics and neck mobility may provide new therapeutic and assessment insights of patients with NSCNP. Full article

Brain cancer is a heterogeneous collection of malignant neoplasms, such as glioblastoma multiforme (GBM), astrocytomas and medulloblastomas, with high morbidity and mortality. Its treatment is complicated by the tumor’s site, infiltrative growth mode and selective permeability of the blood–brain barrier (BBB). During tumor formation, the BBB dynamically remodels into the blood–brain tumor barrier (BBTB), disrupting homeostasis and preventing drug delivery. Furthermore, the TME (Tumor Micro Environment) supports drug resistance, immune evasion and treatment failure. This review points out the ways in which nanomedicine overcomes these obstacles with custom-designed delivery systems, sophisticated diagnostics and personalized therapies. Traditional treatments fail through a lack of BBB penetration, non-specific cytotoxicity and swift tumor adaptation. Nanomedicine provides greater drug solubility, protection against enzymatic degradation, target drug delivery and control over the release. Nanotheranostics’ confluence of therapeutic and diagnostic modalities allows for dynamic adjustment and real-time monitoring. Nanotechnology has paved the way for the initiation of a new era in precision neuro-oncology. Transcending the limitations of conventional therapy protocols, nanomedicine promises to deliver better outcomes by way of enhanced targeting, BBB penetration and real-time monitoring. Multidisciplinary collaboration, regulatory advancements and patient-centered therapy protocols customized to the individual patient’s tumor biology will be necessary to facilitate translation success in the future. Full article

Background: Enterovirus A71 (EV-A71) is considered as the primary causative agent of hand, foot, and mouth disease (HFMD) in young children, leading to severe neurological complications and contributing to substantial mortalities in recent HFMD outbreaks across Asia. Despite this, there is currently no effective antiviral treatment available for EV-A71. RNA interference (RNAi) is a powerful mechanism of post-transcriptional gene regulation that utilizes small interfering RNA (siRNA) to target and degrade specific RNA sequences. Objectives: The aim of this study was to design various siRNAs targeting EV-A71 genomic regions and evaluate the RNAi efficacy against a novel, previously genetically uncharacterized EV-A71 strain. Methods: A novel EV-A71 strain was first sequenced to design target-specific siRNAs. The viral titers, viral protein expression, cytopathic effects, and cell viability of EV-A71-infected HeLa cells were examined to evaluate the specific viral inhibition by the siRNAs. Results: A substantial reduction in viral titers and viral protein synthesis was observed in EV-A71-infected HeLa cells treated with specific siRNAs targeting the VP4, VP3, 2B, and 3A genes. siRNAs delayed cytopathic effects and increased cell viability of EV-A71-infected HeLa cells. Nonspecific interferon induction caused by siRNAs was not observed in this study. In contrast, replication of coxsackievirus B3, another important member of the Enterovirus genus, remained unaffected. Conclusions: Overall, the findings demonstrate that RNAi targeting genomic regions of EV-A71 VP4, VP3, 2B, or 3A could become a potential strategy for controlling EV-A71 infection, and this promising result can be integrated into future anti-EV-A71 therapy developments. Full article

The neutrophil-to-lymphocyte ratio (NLR) is a simple, inexpensive and easily accessible inflammatory biomarker that reflects the balance between innate and adaptive immunity. In recent years, NLR has emerged as a potential prognostic and disease severity marker for different diseases, including idiopathic pulmonary fibrosis (IPF), a progressive and fatal interstitial lung disease with a highly variable course and poor prognosis. Several studies have highlighted that NLR can be associated with several clinical outcomes such as lung function decline, increased risk of hospitalization, acute exacerbation of IPF, and mortality over time. It might also correlate with overall survival in the course of antifibrotic therapy and validated prognostic score as a gender–age–physiology score. Despite these findings, the clinical use of NLR remains limited due to its non-specific nature, the lack of standardized cut-off values, and high variability related to demographic factors, comorbidities and medications. Hence, NLR may display the underlying immune dysregulation in IPF and could be exploited as a non-invasive tool for risk stratification and disease monitoring. Further studies are needed to confirm and validate its use in IPF and to establish reliable cut-off values in clinical applications. Full article

Background/Objectives: Manual therapy techniques, including mobilization and manipulation, are commonly used for chronic low back pain (CLBP), with clinical guidelines recommending their use. This study aimed to compare the immediate hypoalgesic effects of mobilization and manipulation in patients with non-specific CLBP, evaluating their impact on pain sensitivity and range of motion. Methods: A cross-over randomized controlled trial was conducted with 27 participants with non-specific CLBP. Participants received either mobilization or manipulation on two different intervention days. Outcome measures included pressure pain thresholds (PPTs) assessed with a digital algometer, pain intensity using a numeric rating scale, and lumbar range of motion (ROM) measured with a digital inclinometer. Results: The results indicated no statistically significant differences between mobilization and manipulation for any outcome measures (all p > 0.05). However, significant within-intervention improvements were observed, including pain reduction, increased PPTs, and enhanced ROM of the lower back. Conclusions: Our findings suggest that both mobilization and manipulation provide similar immediate benefits for patients with CLBP. The choice between these techniques should be based on therapists’ clinical reasoning and individualized risk stratification, considering the potential benefits and risks of each approach for a specific patient. Full article