Search Results (567)

Chronic pain is a pervasive and debilitating condition that affects millions of individuals worldwide. Unlike acute pain, which serves a protective physiological role, chronic pain persists beyond routine tissue healing and often arises without a discernible peripheral cause. Accumulating evidence indicates that chronic pain is not merely a symptom but a disorder of the central nervous system, underpinned by interacting molecular, neurochemical, and network-level alterations. Molecular neuroimaging using PET and MR spectroscopy has revealed dysregulated excitatory–inhibitory balance (glutamate/GABA), altered monoaminergic and opioidergic signaling, and neuroimmune activation (e.g., TSPO-indexed glial activation) in key pain-related regions such as the insula, anterior cingulate cortex, thalamus, and prefrontal cortex. Converging multimodal imaging—including functional MRI, diffusion MRI, and EEG/MEG—demonstrates aberrant activity and connectivity across the default mode, salience, and sensorimotor networks, alongside structural remodeling in cortical and subcortical circuits. Parallel advances in neuromodulation, including transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), deep brain stimulation (DBS), and emerging biomarker-guided closed-loop approaches, provide tools to perturb these maladaptive circuits and to test mechanistic hypotheses in vivo. This review integrates neuroimaging findings with molecular and systems-level mechanistic insights into chronic pain and its modulation, highlighting how imaging markers can link biochemical signatures to neural dynamics and guide precision pain management and individualized therapeutic strategies. Full article

Background/Objectives: Isotretinoin remains an essential therapy for severe acne, yet its safety profile continues to raise concerns. This study analyzed adverse event reporting patterns for isotretinoin versus topical retinoids using EudraVigilance data. Methods: Aggregated ADR data for isotretinoin and four topical retinoids (tretinoin, adapalene, tazarotene, trifarotene) were retrieved from the EMA ADRreports portal (April 2025). Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals at the MedDRA system organ class (SOC) level. Significant demographic differences (age and sex; both p < 0.001) justified stratified ROR analyses for SOCs showing positive signals. Results: Among 35,030 isotretinoin and 3795 topical retinoid reports, isotretinoin showed strong over-reporting in six SOCs: psychiatric disorders (ROR 11.96; 95% CI 10.11–14.14), gastrointestinal disorders (3.88; 3.50–4.31), musculoskeletal and connective tissue disorders (2.89; 2.50–3.35), surgical and medical procedures, social circumstances, and ear and labyrinth disorders. Fourteen SOCs demonstrated significant under-reporting, including neoplasms, immune system disorders, cardiac disorders, and blood/lymphatic disorders. Stratified analyses confirmed the robustness of the positive signals. Psychiatric disorders exhibited the highest disproportionality in males (22.10; 16.11–30.31) and adolescents aged 12–17 (25.85; 13.32–50.19). Gastrointestinal and musculoskeletal signals remained significant across all age and sex strata. Conclusions: Isotretinoin presents a distinct safety profile characterized by consistently elevated reporting of psychiatric, gastrointestinal, and musculoskeletal adverse events, independent of age and sex. These results refine the comparative safety landscape of systemic versus topical retinoids and support focused pharmacovigilance monitoring. Full article

Background: Coffin–Siris syndrome 12 (CSS12) is a recently described neurodevelopmental disorder caused by heterozygous pathogenic variants in BICRA, a gene encoding a core subunit of the non-canonical BAF (ncBAF) chromatin-remodeling complex. The condition is characterized by developmental delay, hypotonia, hypertrichosis, and joint laxity. However, long-term data remain limited, and systemic manifestations are incompletely defined. Case Description: We report a 22-year-old male with a de novo BICRA frameshift variant, c.2479_2480delinsA (p.Ala827Thrfs*15), previously included in the original cohort reported by Barish et al. Longitudinal follow-up revealed an expanded phenotype extending beyond neurodevelopmental features. Early findings included global developmental delay, growth hormone deficiency, short stature, and joint hypermobility. In adolescence and adulthood, he developed severe intestinal dysmotility requiring total colectomy, recurrent spontaneous pneumothoraces from bilateral apical bullous disease, and portal-vein thrombosis, representing visceral and vascular complications not previously emphasized in BICRA-related disorders. The identified BICRA variant truncates the coiled-coil domain critical for BRD9/BRD4 interaction, consistent with a loss-of-function mechanism. The patient’s systemic features suggest that BICRA haploinsufficiency affects not only neurodevelopmental pathways but also smooth-muscle and connective-tissue integrity. Conclusions: This case expands the phenotypic spectrum of BICRA-related CSS12, demonstrating that visceral and vascular involvement can occur alongside neurodevelopmental and connective-tissue features. Recognition of these broader manifestations underscores the need for lifelong multidisciplinary surveillance and contributes to understanding the diverse biological roles of the ncBAF complex in human development. Full article

Background: The three Synuclein family members (α-, β-, and γ-synuclein) are presynaptic proteins that regulate synaptic vesicle trafficking and thereby influence neurotransmitter release. Synucleins belong to a class of intrinsically disordered proteins and are prone to aggregation into pathological deposits, which may impair their physiological synaptic functions. Knockout (KO) mouse lines, commonly used to model synuclein depletion in the nervous system, reveal a range of phenotypes with different motor and behavioral deficits. However, given the high sequence homology and functional interplay among the three synucleins, the specific contribution of each family member to these phenotypes remains poorly understood. Objective: In this study, we conducted a comparative phenotypic analysis of γ-synuclein KO, α- and β-synuclein KO, and αβγ-synuclein KO mice. Methods: Mice were subjected to a battery of behavioral tests assessing motor activity and coordination, anxiety-like behavior, and spatial learning and memory. Synaptic vesicle proteins were analyzed in brain tissues using Western blotting. Results: We observed that knocking out γ-synuclein but not α- and β-synucleins reduces mouse lifespan and leads to sustained reduction in muscle strength implicating that γ-synuclein is essential for longevity and motor system function. Another consequence of γ-synuclein deficiency is altered anxiety-like behavior manifested as a diminished aversive response, while exploratory behavior and memory remain intact. The triple KO mice mirror γ-synuclein KO mice in some behavioral changes, including shortened lifespan, reduced muscle strength, and decreased anxiety-like behavior. However, the triple KO mice additionally exhibit hyperactivity, which is not present in the other groups. No changes in synaptic vesicle marker levels were detected, indicating that the observed motor and behavioral abnormalities are not attributable to impaired synaptic connectivity. Conclusions: Taken together, these findings demonstrate nonredundant functions of individual synuclein family members and highlight a distinct role of γ-synuclein in regulating motor performance and behavioral responses. Full article

(1) Background: Wound healing is a highly coordinated process encompassing hemostasis, inflammation, angiogenesis, keratinocyte migration, collagen deposition, and extracellular matrix remodeling. Successful repair also requires adequate nutrient and oxygen delivery through a well-developed vascular supply. Disruption of these processes can occur through aberrations in diverse biological pathways, including extracellular matrix organization, cellular adhesions, angiogenesis, and immune regulation. (2) Methods: We reviewed mechanisms of impaired tissue repair in monogenic disorders by focusing on three categories—connective tissue, hematological/immunological, and aging-related disorders—to illustrate how single-gene defects disrupt inflammation, cellular proliferation, and matrix remodeling. Additionally, we reviewed various polygenic disorders—chronic kidney disease, diabetes mellitus, hypertension, and obesity—to contrast complex multifactorial pathologies with single-gene defects. (3) Results: This review establishes that genetic impediments, despite their distinct etiologies, monogenic and polygenic disorders share critical downstream failures in the wound healing cascade. While monogenic diseases illustrate direct causal links between specific protein deficits and repair failure, polygenic diseases demonstrate how multifactorial stressors overwhelm the body’s regenerative capacity. (4) Conclusions: This review synthesizes current evidence on both monogenic diseases and polygenic contributions to impaired wound healing. These findings highlight that genetic susceptibility is a decisive factor in the ability to restore tissue homeostasis. This underscores the profound impact of genetic background on the efficacy of hemostasis, inflammation, and remodeling. Full article

Background: Brachial artery aneurysms are a rare entity occurring sporadically at all ages. Common causes are trauma, infection, connective tissue disorders, genetic syndromes, immunosuppression, and a history of arteriovenous vascular access. Pseudoaneurysms are mainly of traumatic or iatrogenic origin. Idiopathic true brachial artery aneurysms are even scarcer, attributed to inherited susceptibility for aneurysm formation or to atherosclerosis. Due to the rarity of these aneurysms, we report our experience along with a current literature review. Methods: A retrospective search was conducted in the Vascular Surgery Department database of a tertiary referral center for vascular surgery, covering procedures from January 1991 to October 2025. Patients were included if they had undergone idiopathic true brachial artery aneurysm repair. Clinical records, operative details, imaging studies, and follow-up data were reviewed. We additionally provide a literature review regarding clinical presentation, signs, pathophysiology, diagnosis, and treatment of these aneurysms. Results: Amongst all procedures performed for aneurysmal repair, in the searched period, we identified three patients who met these criteria. All three underwent successful elective operations. Individual characteristics of the retrieved cases are reported. Conclusions: The open repair of true idiopathic brachial artery aneurysms is a technically simple approach that leads to satisfactory outcomes. Endovascular therapy is technically unfavorable in this type of aneurysm. Full article

The adenosine 3′,5′-cyclic monophosphate–protein kinase A (cAMP-PKA) signaling pathway is highly utilized in human physiology. It is a crucial component of development and is vital to cellular function in nearly all tissues. Indeed, genetic mutations to cAMP-PKA machinery are found in many pathologies, including multiple cancers, cardiac myxoma, neurodevelopmental disorders, and hypercortisolism. Cyclic AMP and PKA were first identified as vital components in cortisol synthesis over 50 years ago, yet the cellular mechanisms connecting PKA to cortisol production are still not well understood. This article will review evidence for PKA’s roles in adrenal gland zona fasciculata steroidogenesis and consider recent studies of the stress hormone disease adrenal Cushing’s syndrome to synthesize a current model for cAMP-PKA actions in cortisol production. Full article

Background: Bicuspid aortic valve (BAV) is the most common congenital heart defect, and its complications (namely, dilatation of the thoracic ascending aorta) raise concerns regarding the proper timing of aortic surgery. The study aim is to unravel the genetic basis of BAV and its complications through a high-throughput sequencing (HTS) approach and segregation analysis if family members were available. Methods: Fifty-two Italian BAV patients were analyzed by HTS using the Illumina MiSeq platform. Targeted sequencing of 97 genes known to be or plausibly associated with connective tissue disorders or aorthopathy was performed. Thirty-five first-degree relatives of N = 10 probands underwent mutational screening for variants identified in the index cases. Results: HTS identified 194 rare (MAF < 0.01) variants in 63 genes. Regarding previously reported genes, five NOTCH1 variants in four BAV patients, four FBN1 variants in two patients and one GATA5 variant in one patient were identified. Interestingly, among further loci, the possible contribution of PDIA2, LRP1 and CAPN2 was suggested by (a) the increased prevalence of rare genetic variants, independently from their ACMG classification in the whole BAV cohort, and (b) segregation analyses of variants identified in family members. Moreover, the present data also suggest the possible contribution of rare variants to BAV complications, specifically MYLK in aortic dilatation, CAPN2 in BAV calcification and VHL and AGGF1 in valve stenosis. Conclusions: Our results underline clinical and genetic diagnosis complexity in traits considered monogenic, such as BAV, but characterized by variability in disease phenotypic expression (incomplete penetrance), as well as the contribution of different major and modifier genes to the development of complications. Full article

With the accelerating trend of global population aging, oral and gut diseases are imposing a rising socioeconomic burden, both of which have well-known connections to microbial dysbiosis. As the gateway to the human body, the oral cavity exhibits close interactions with the gastrointestinal tract, which includes translocation of bacteria and bacterial extracellular vesicles (BEVs), as well as intermucosal immunity and neural signaling. These oral–gut crosstalk pathways play vital roles in the pathogenesis and progression of oral diseases, such as periodontitis, and gut diseases, such as inflammatory bowel disease (IBD). Focusing on periodontitis and IBD as representative conditions, this review summarizes current understanding of the oral–gut crosstalk and underlying mechanisms. Among diverse interactions, we emphasize BEVs as effective trans-barrier mediators and their therapeutic potentials during oral–gut crosstalk. Beneficial BEVs, notably those from Akkermansia muciniphila (Akk), exert various probiotic roles, including modulating microbial homeostasis, promoting tissue repair and alleviating inflammation, thereby shedding light on the prevention and treatment of oral and gut diseases, even systemic disorders. Full article

Background: Marfan syndrome is an autosomal dominant connective tissue disorder that affects multiple organ systems, with cardiovascular complications posing a major risk. With advancements in medical care and the increasing lifespan of patients with Marfan syndrome, the spectrum of medical issues has evolved. This case report highlights the complex anaesthetic management of a patient with Marfan syndrome during elective ventral hernia repair. Case presentation: A 37-year-old male with Marfan syndrome was admitted for elective open ventral hernia repair. Challenges included severe arterial hypertension, prior aortic valve replacement, scoliosis, and an anticipated difficult airway, as the patient presented with restricted mouth opening due to craniofacial abnormalities consistent with difficult laryngoscopy. Preoperative assessments included routine tests, echocardiography and chest X-ray. The anaesthetic management focused on specific patient positioning with head-up tilt, maintenance of haemodynamic stability with the insertion of an arterial line before the induction of anaesthesia and neuromuscular block (NMB) monitoring, followed by titrated doses of all medications. Lung ventilation strategies were specifically adjusted to address the patient’s underlying comorbidities. The patient was extubated and transferred to the recovery unit. The intraoperative and immediate postoperative periods were relatively uneventful. Dyspnea due to external pressure on the abdominal wall caused by a specific binder was treated with the release of pressure. Later postoperative recovery was complicated by hydrothorax and pneumonia, both treated successfully. Conclusions: This case emphasises the importance of multidisciplinary approaches and vigilant monitoring in the management of a patient with Marfan syndrome perioperatively, even for seemingly low-risk operations. Appropriate anaesthetic management helped to avoid major perioperative complications. Full article

Connective tissue disease-associated interstitial lung disease (CTD-ILD) comprises a heterogeneous group of immune-mediated pulmonary disorders with significant morbidity and mortality. The pathogenesis involves complex interactions of autoimmunity, chronic inflammation, and fibrosis. B cells play a central role in these processes through antigen presentation, autoantibody production, cytokine secretion, and the formation of ectopic lymphoid tissue within the lung parenchyma. Rituximab (RTX)—a chimeric anti-CD20 monoclonal antibody—depletes B cells and has emerged as a promising therapeutic agent for CTD-ILD. This review comprehensively presents the immunopathogenic mechanisms underlying CTD-ILD, elaborating on the multifaceted mode of action of RTX and summarizing the evolving clinical evidence. Full article

Background/Objectives: Lipedema is a chronic, progressive adipo-fascial disorder characterized by connective tissue dysfunction, fibrosis, microangiopathy, and adipose tissue proliferation. Although lipedema has traditionally been described as a regionally confined disorder, emerging evidence suggests that it may reflect a broader stromal and connective tissue dysfunction. It is therefore plausible that anatomical regions not historically associated with lipedema may also exhibit alterations consistent with this dysfunctional stromal pattern. From this perspective, breast tissue—rich in fibro-glandular and stromal components—represents a compelling model in which to investigate whether such features are present. The breast, with its complex fibro-glandular and stromal architecture, represents a physiologically plausible site of involvement; however, its structural features in lipedema have never been systematically examined. The primary aim of this study was therefore to determine whether breast tissue—rich in fibro-glandular and stromal components—shows recurrent imaging or histopathological features suggestive of lipedema-related involvement. A secondary aim was to compare the frequency of these findings with patterns typically reported in healthy screening populations. Methods: This retrospective cross-sectional study analyzed 62 women (mean age: 44 ± 8 years), obtained between September and November 2025, with a clinical diagnosis of lipedema who voluntarily provided breast imaging reports (ultrasound, mammography, or magnetic resonance imaging, MRI). Results: The findings revealed a remarkably high prevalence of fibro-glandular parenchyma (45%), multiple diffuse cysts (42%), microcalcifications (21%), and fibroadenomas (43.5%), with frequencies substantially exceeding those documented in healthy screening populations. Additional features included significant breast asymmetry or tuberous morphology (6%), reactive or sclero-lipomatous lymph nodes (19%), and recurrent stromal hyperplasia on biopsy. Histological evaluations (n = 9) consistently showed fibroproliferative alterations, including stromal hypercellularity, adenosis, fibroepithelial lesions, apocrine metaplasia, and pseudoangiomatous stromal hyperplasia, suggesting a shared extracellular matrix-related dysplastic phenotype between lipedema-affected breast tissue and peripheral adipose tissue. Conclusions: These findings support the hypothesis that lipedema may express a characteristic breast phenotype driven by stromal and extracellular matrix dysregulation. If confirmed in larger controlled studies, these recurrent alterations could contribute to improved diagnostic frameworks and raise awareness of lipedema as a systemic connective tissue disorder with underrecognized breast manifestations. Full article

Meester–Loeys syndrome (MLS) is an X-linked connective tissue disorder caused by pathogenic BGN variants. We describe a family carrying a novel missense variant. The index male, initially diagnosed with Ehlers–Danlos syndrome, had joint hypermobility, multiple visceral artery aneurysms, and recurrent musculoskeletal problems. A brother of the proband had an aortic root aneurysm. Female carriers had no or only minor manifestations. Studies of the aortic wall were consistent with a dysregulation of the TGF-β/SMAD pathway and assays with reporter vectors revealed reduced canonical Wnt and TGF-β activity in cell lines expressing mutant biglycan. However, patients’ dermal fibroblasts did not show consistent differences in the nuclear abundance of β-catenin or p-SMAD2/3 compared to cells from controls. This 3-generation family expands the genetic and phenotypic spectrum of MLS and underscores the importance of considering BGN testing in hypermobility syndromes to enable early surveillance and targeted management. Full article

Collagen VI-related myopathies (COL6-RM) encompass a spectrum of disorders characterized by muscle weakness, joint contractures, and connective tissue abnormalities resulting from mutations in the collagen VI genes. While muscle pathology has been extensively studied, tendon dysfunction has emerged as a critical yet underexplored contributor to disease severity, particularly in the development of joint contractures. Tendons from patients and animal models show disrupted collagen fibrillogenesis, altered extracellular matrix (ECM) composition, and impaired cellular mechanotransduction. Various defects in ECM remodeling pathways further exacerbate tendon pathology. Importantly, current clinical management remains limited to orthopedic interventions with modest outcomes, and targeted pharmacological strategies or gene-editing therapies are not yet available for clinical application. Therefore, understanding the basic pathogenic mechanisms underlying tendon dysfunction is essential for identifying novel therapeutic targets. This review provides a comprehensive synthesis of current understanding and recent advances concerning the role of mutated collagen VI in cellular and molecular mechanisms underlying tendon dysfunction. Emphasis is placed on the role of mutated collagen VI in the modulation of key signaling pathways related to mechanotransduction and primary cilium function in COL6-RM. By discussing these multifaceted contributions to disease pathogenesis, this review outlines future research directions in the field and highlights potential pathways for targeted therapeutic interventions. Full article

Background: Lipedema is a progressive disorder of subcutaneous connective tissue, predominantly affecting women, and characterized by an increase in subcutaneous adipose tissue, particularly in the lower body. This study aims to explore the gut microbiota (GM) profile in lipedema patients to characterize the associated GM and compare it with the control group. Methods: A prospective randomized case–control pilot study was conducted from September 2023 to May 2024, involving 55 Caucasian women, aged 20–60. The participants were divided into two groups: 35 with lipedema (LIPPY) and 20 controls (CTRL). Body composition was assessed using Dual X-ray Absorbimetry (DXA), and GM analysis was performed through 16S rRNA gene sequencing. Results: LIPPY subjects showed increased Intramuscular Adipose Tissue (IMAT) and reduced Lean Mass (LM)/Fat Mass (FM) ratios. While alpha and beta diversity metrics did not differ significantly between groups, differential abundance analysis identified a significant reduction in Eggerthellaceae (Log Fold Change (LFC) = −0.19, p = 0.04) and enrichment of Propionibacteriaceae (LFC = +0.18, p = 0.009) and Acidaminococcaceae (LFC = +0.32, p = 0.013) in the LIPPY group. Genus-level analysis showed a significant reduction in Blautia and Ruminiclostridium (LFC = −0.32 and −0.02; p = 0.02 and 0.04) and enrichment of Anaerostipes, Propionibacterium, and Phascolarctobacterium (LFC = +0.07, +0.17, and +0.34; p = 0.02, 0.005, 0.005, respectively). In correlation analyses, within LIPPY, Eggerthellaceae correlated negatively with Body Mass Index (BMI) (ρ = −0.61, p < 0.05) and positively with Appenicular (Appen) LM/Weight and AppenLM/BMI (ρ = +0.43 and +0.41, p < 0.05), while Anaerostipes correlated positively with these lean mass indices (ρ = +0.40, p < 0.05). In CTRL, only Anaerostipes showed a significant negative correlation with BMI (ρ = −0.64, p < 0.05). Conclusions: This study provides the first evidence of a distinct GM profile in LIPPY, with notable links to adverse body composition markers such as IMAT. Trial Registration: Trial registered on 24 June 2013 with ClinicalTrial.gov (NCT01890070). Full article