Search Results (9,762)

Sprouty-related proteins with enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain (SPREDs) are negative regulators of the Ras/MAPK signaling pathway and are known to modulate developmental and endocrine processes. While the roles of SPRED1 and SPRED2 are increasingly understood, the physiological relevance of SPRED3 remains elusive. To elucidate its function, we generated SPRED3 knockout (KO) mice and performed phenotypic, molecular, and hormonal analyses. SPRED3-deficient mice exhibited growth retardation and a non-Mendelian genotype distribution. X-Gal staining revealed Spred3 promoter activity in the thyroid, adrenal gland, pituitary, cerebral cortex, and kidney. Hormonal profiling identified elevated thyroid-stimulating hormone (TSH) and reduced thyroxine (T₄) levels, indicating primary hypothyroidism. Thyroidal extracellular signal-regulated kinase (ERK) signaling was mildly reduced in SPRED3 KO mice, and immunoblotting revealed altered expression of autophagy regulators, including reduced sequestosome 1 (p62), increased autophagy-related gene 5 (ATG5), as well as an elevated microtubule-associated protein 1 light chain 3 (LC3) II/I ratio and a decreased pBeclin/Beclin ratio in SPRED3 KO mice. Our findings indicate that SPRED3 is involved in thyroidal homeostasis and plays a regulatory role in autophagy processes within the thyroid gland. Full article

Moyamoya disease (MMD) is primarily associated with genetic variants in RNF213. RNF213 p.R4810K (c.14429G>A, p.Arg4810Lys) is a founder variant predominantly found in East Asian populations and is strongly associated with MMD, a rare cerebrovascular condition characterized by progressive stenosis of intracranial arteries and the development of abnormal collateral networks. Recent evidence suggests that RNF213 variants are also enriched in non-moyamoya intracranial arteriopathies, such as large-artery atherosclerotic stroke and intracranial arterial stenosis/occlusion (ICASO), particularly in east Asian individuals with early-onset or cryptogenic stroke. This expanded phenotypic spectrum, termed RNF213-related vasculopathy (RRV), represents a distinct pathogenic entity that may involve unique pathogenic processes separate from traditional atherosclerosis. In this review, we synthesize current genetic, clinical, radiological, and experimental findings that delineate the unique features of RRV. Patients with RRV typically exhibit a lower burden of traditional vascular risk factors, negative vascular remodeling in the absence of atheromatous plaques, and an increased propensity for disease progression. RNF213 variants may compromise vascular resilience by impairing adaptive responses to hemodynamic stress. Furthermore, emerging cellular and animal model data indicate that RNF213 influences angiogenesis, lipid metabolism, and stress responses, offering mechanistic insights into its role in maintaining vascular integrity. Recognizing RRV as a distinct clinical entity has important implications for diagnosis, risk stratification, and the development of genome-informed therapeutic strategies. Full article

Background. Studies of comorbid (syntropic) and inversely comorbid (rarely occurring together, i.e., dystropic) diseases have focused on the search for molecular causes of this phenomenon. Materials. We investigated DNA methylation levels in regulatory regions of 23 apoptosis-associated genes as candidate loci associated with the “cancer–neurodegeneration” dystropy in patients with Huntington’s disease (HD) and patients with non–small cell lung cancer (LC). Results. Statistically significant differences in methylation levels between the HD and LC groups were found for 41 CpG sites in 16 genes. The results show that five genes (SETDB1, TWIST1, HDAC1, SP1, and GRIA2) are probably involved in the phenomenon of inverse comorbidity of these diseases. For these genes, the methylation levels of the studied CpG sites were altered in opposite directions in the two groups of patients, compared to the control group. Conclusions. For the SP1 gene, the above hypothesis is supported by our analysis of open-access data on gene expression in patients with the aforementioned diagnoses and fits a probable mechanism of the “HD–LC” dystropy. Full article

Sexually transmitted infections (STIs) are a significant global health concern, affecting millions of people worldwide, particularly sexually active adolescents and young adults. These infections, caused by various pathogens, including bacteria, viruses, parasites, and fungi, can have profound implications for women’s reproductive health and fertility. This review explores the role of vaginal and uterine infections in women’s infertility, focusing on the most common pathogens and their impact on reproductive outcomes. Bacterial infections, such as those caused by intracellular bacteria (Mycoplasma, Ureaplasma, and Chlamydia), Neisseria gonorrhoeae, and bacterial vaginosis, are among the most prevalent causes of infertility in women. Studies have shown that these infections can lead to pelvic inflammatory disease, tubal occlusion, and endometrial damage, all of which can impair fertility. Mycobacterium tuberculosis, in particular, is a significant cause of genital tuberculosis and infertility in high-incidence countries. Viral infections, such as Human papillomavirus (HPV) and Herpes simplex virus (HSV), can also affect women’s fertility. While the exact role of HPV in female infertility remains unclear, studies suggest that it may increase the risk of endometrial implantation issues and miscarriage. HSV may be associated with unexplained infertility. Parasitic infections, such as trichomoniasis and schistosomiasis, can directly impact the female reproductive system, leading to infertility, ectopic pregnancy, and other complications. Fungal infections, such as candidiasis, are common but rarely have serious outcomes related to fertility. The vaginal microbiome plays a crucial role in maintaining reproductive health, and alterations in the microbial balance can increase susceptibility to STIs and infertility. Probiotics have been proposed as a potential therapeutic strategy to restore the vaginal ecosystem and improve fertility outcomes, although further research is needed to establish their efficacy. In conclusion, vaginal and uterine infections contribute significantly to women’s infertility, with various pathogens affecting the reproductive system through different mechanisms. Early diagnosis, appropriate treatment, and preventive measures are essential to mitigate the impact of these infections on women’s reproductive health and fertility. Full article

Background/Objectives: Glycogen storage disease type II, also known as Pompe disease (PD), is a rare autosomal recessive genetic disorder triggered by a deficiency in lysosomal acid α-glucosidase (GAA). Recently, we discovered two deleterious missense variants of the GAA gene, c.1799G>A (p.Arg600His) (a pathogenic mutation) and c.55G>A (p.Val19Met), in a domestic short-haired cat with PD. This study aimed to design genotyping assays for these two variants and ascertain their allele frequencies in Japanese cat populations. Methods: We developed fluorescent probe-based real-time polymerase chain reaction assays to genotype the c.1799G>A and c.55G>A variants. A total of 738 cats, comprising 99 purebred cats from 20 breeds and 540 mixed-breed cats, were screened using these assays. Results: Genotyping assays clearly differentiated all known genotypes of the two variants. None of the 738 cats tested carried the c.1799G>A variant. However, we identified cats with c.55G/A and c.55A/A genotypes in the purebred (A allele frequency: 0.081) and mixed-breed cats (0.473). A significant difference (p < 0.001) was observed in the A allele frequency between the two groups. Conclusions: The c.1799G>A mutation appears rare in cat populations, suggesting it may be confined to specific pedigree Japanese mixed-breed cats. The c.55G>A variant was detected in purebred and mixed-breed cats, suggesting that it may not be directly linked to feline PD. However, additional studies are required to elucidate the precise relationship between this variant and cardiac function. Genotyping assays will serve as valuable tools for diagnosing and genotyping feline PD. Full article

Conventional melanoma is exceedingly rare in the pediatric population, particularly among prepubescent children, and its diagnosis and management necessitate a multidisciplinary approach. The objective of this present report is to delineate the diagnostic pathway and therapeutic management of a 4-year-old girl with conventional melanoma, with particular focus on the molecular context. A pigmented lesion located on the auricle was surgically excised, and subsequent histopathological and immunohistochemical analyses confirmed the diagnosis of malignant melanoma (pT3b). Radiologic investigations revealed no evidence of metastatic disease, and comprehensive genetic testing utilizing next-generation sequencing (NGS) identified no pathogenic variants in the germline genes examined, nor in the BRAF, NRAS, KRAS, and TP53 genes within the excised lesion. The patient remains in good general health. This case report adds to the limited body of literature on melanoma in pediatric patients and underscores the importance of thorough diagnostic evaluation in this age group. Full article

Background: Endometriosis is a chronic inflammatory condition affecting 10–15% of women of reproductive age. Genome-wide association studies (GWASs) have accounted for only a fraction of its high heritability, indicating the need for alternative approaches to identify rare genetic variants contributing to its etiology. To this end, we performed whole-exome sequencing (WES) in a multi-affected family. Methods: A multigenerational family was studied, comprising three sisters, their mother, grandmother, and a daughter, all diagnosed with endometriosis. WES was conducted on the three sisters and their mother. We used the enGenome-Evai and Varelect software to perform our analysis, which mainly focused on rare, missense, frameshift, and stop variants. Results: Bioinformatic analysis identified 36 co-segregating rare variants. Six missense variants in genes associated with cancer growth were prioritized. The top candidates were c.3319G>A (p.Gly1107Arg) in the LAMB4 gene and c.1414G>A (p.Gly472Arg) in the EGFL6 gene. Variants in NAV3, ADAMTS18, SLIT1, and MLH1 may also contribute to disease onset through a synergistic and additive model. Conclusions: We identified novel candidate genes for endometriosis in a multigenerational affected family, supporting a polygenic model of the disease. Our study is an exploratory family-based WES study, and replication and functional studies are warranted to confirm these preliminary findings. Full article

Background: In high-risk and frail patients with multivessel coronary artery disease (MV CAD), guidelines indicated complete revascularization with or without the use of cardiopulmonary bypass (CPB) bears a high morbidity and mortality risk. In cases where catheter interventions were deemed unsuitable and conventional coronary artery bypass grafting (CABG) posed an unacceptable perioperative risk, patients were scheduled for minimally invasive direct coronary artery bypass (MIDCAB) grafting or minimally invasive multivessel coronary artery bypass grafting (MICS-CABG). We called this approach “palliative revascularization.” This study assesses the safety and impact of palliative revascularization on clinical outcomes and overall survival. Methods: A consecutive series of 57 patients undergoing MIDCAB or MICS-CABG as a palliative surgery between 2008 and 2018 was included. The decision for palliative surgery was met in heart team after carefully assessing each case. The patients underwent single or double-vessel revascularization using the left internal thoracic artery and rarely radial artery/saphenous vein segments, both endoscopically harvested. Inpatient data could be completed for all 57 patients. The mean follow-up interval was 4.2 ± 3.7 years, with a follow-up rate of 91.2%. Results: Mean patient age was 79.7 ± 7.4 years. Overall, 46 patients (80.7%) were male, 26 (45.6%) had a history of atrial fibrillation and 25 (43.9%) of chronic kidney disease. In total, 13 patients exhibited a moderate EuroSCORE II, while 27 were classified as high risk, with a EuroSCORE II exceeding 5%. Additionally, 40 patients (70.2%) presented with three-vessel disease, 17 (29.8%) suffered an acute myocardial infarction within three weeks prior to surgery and 50.9% presented an impaired ejection fraction. There were 48 MIDCAB and nine MICS CABG with no conversions either to sternotomy or to CPB. Eight cases were planned as hybrid procedures and only 15 patients (26.3%) were completely revascularized. During the first 30 days, four patients (7%) died. A myocardial infarction occurred in only one case, no patient necessitated immediate reoperation. The one-, three- and five-year survival rates were 83%, 67% and 61%, respectively. Conclusions: MIDCAB and MICS CABG can be successfully conducted as less invasive palliative surgery in high-risk multimorbid patients with MV CAD. The early and mid-term results were better than predicted. A higher rate of hybrid procedures could improve long-term outcome in selected cases. Full article

Background/Objectives: Mumps remains a relevant vaccine-preventable disease globally, especially in settings where immunization coverage fluctuates or vaccine-induced immunity wanes. This study aimed to assess long-term trends in mumps incidence, vaccination coverage, clinical outcomes, and demographic characteristics in the Autonomous Province of Vojvodina (AP Vojvodina), Serbia, over a 47-year period. Methods: We conducted a retrospective observational study using surveillance data from the Institute of Public Health of Vojvodina. Analyses included annual mumps incidence rates (1978–2024), coverage with mumps-containing vaccines (MuCVs; 1986–2024), monthly case counts, and individual-level case data for the 1997–2024 period. Variables analyzed included age, month of notification, gender, vaccination status, presence of clinical complications, and the method used for case confirmation. Results: Following the introduction of MuCV in 1986, the mumps incidence markedly declined, with limited resurgences in 2000, 2009, and 2012. Between 1997 and 2024, a total of 1358 cases were reported, with 62.7% occurring in males. Over time, the age distribution shifted, with adolescents and young adults being increasingly affected during the later (2011–2024) observed period. In 2012, the highest age-specific incidence was observed among individuals aged 10–19 and 20–39 years (49.1 and 45.5 per 100,000, respectively). Vaccination coverage for both MuCV doses was suboptimal in several years. The proportion of unvaccinated cases decreased over time, while the proportion with unknown vaccination status increased. Mumps-related complications—such as orchitis, pancreatitis, and meningitis—were rare and predominantly affected unvaccinated individuals: 84.2% of orchitis, 40.0% of pancreatitis, and all meningitis cases. Only two pancreatitis cases (40.0%) were reported after one MMR dose, while fully vaccinated individuals (two doses) had one orchitis case (5.3%) and no other complications. Laboratory confirmation was applied more consistently from 2009 onward, with 49.6% of cases confirmed that year (58 out of 117), and, in several years after 2020, only laboratory-confirmed cases were reported, indicating improved diagnostic capacity. Conclusions: Despite substantial progress in controlling mumps, gaps in vaccine coverage, waning immunity, and incomplete vaccination records continue to pose a risk for mumps transmission. Strengthening routine immunization, ensuring high two-dose MuCV coverage, improving vaccination record keeping, and enhancing laboratory-based case confirmation are critical. Consideration should be given to booster doses in high-risk populations and to conducting a seroepidemiological study to estimate the susceptible population for mumps in AP Vojvodina. Full article

Scrofuloderma, a cutaneous manifestation of tuberculosis, is a rare but clinically significant form of mycobacterial infection. It typically results from the local spread of Mycobacterium tuberculosis from an infected lymph node or bone area to the overlying skin. This disease is mainly characterized by chronic granulomatous inflammation, leading to skin ulcers and abscesses. Due to its nonspecific clinical presentation, scrofuloderma can mimic various dermatological conditions, making its diagnosis particularly challenging. This case report presents the clinical course of a patient who was positive for the Human Immunodeficiency Virus (HIV) with a diagnosis of scrofuloderma, managed at a tertiary healthcare center, with follow-up before and after treatment. A literature review was also made, highlighting the importance of maintaining a high index of clinical suspicion and utilizing appropriate diagnostic methods to ensure timely diagnosis. Full article

Background: Thyroid eye disease (TED) is a rare autoimmune orbital disorder predominantly associated with Graves’ disease. It is characterized by orbital inflammation, tissue remodeling, and potential visual morbidity. Conventional therapies, particularly systemic glucocorticoids, offer only partial symptomatic relief, failing to reverse chronic structural changes such as proptosis and diplopia, and are associated with substantial adverse effects. This review aims to synthesize recent developments in understandings of TED pathogenesis and to critically evaluate emerging therapeutic strategies. Methods: A systematic literature review was conducted using MEDLINE, Embase, and international clinical trial registries focusing on pivotal clinical trials and investigational therapies targeting core molecular pathways involved in TED. Results: Current evidence suggests that TED pathogenesis is primarily driven by the autoimmune activation of orbital fibroblasts (OFs) through thyrotropin receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R) signaling. Teprotumumab, a monoclonal IGF-1R inhibitor and the first therapy approved by the U.S. Food and Drug Administration for TED, has demonstrated substantial clinical benefit, including improvements in proptosis, diplopia, and quality of life. However, concerns remain regarding relapse rates and treatment-associated adverse events, particularly hearing impairment. Investigational therapies, including next-generation IGF-1R inhibitors, small-molecule antagonists, TSH-R inhibitors, neonatal Fc receptor (FcRn) blockers, cytokine-targeting agents, and gene-based interventions, are under development. These novel approaches aim to address both inflammatory and fibrotic components of TED. Conclusions: Teprotumumab has changed TED management but sustained control and toxicity reduction remain challenges. Future therapies should focus on targeted, mechanism-based, personalized approaches to improve long-term outcomes and patient quality of life. Full article

Objectives: Lermoyez syndrome (LS) is a rare variant of endolymphatic hydrops with a unique clinical presentation characterized by reversible sensorineural hearing loss preceding vertigo. This review aims to synthesize available literature on LS to clarify its clinical characteristics, diagnostic approach, management strategies, and outcomes, and to highlight the distinguishing features from Menière’s disease (MD). Methods: A systematic literature review according to PRISMA guidelines was conducted from 1919 to 2025. The extracted data included demographics, symptom profiles, audiovestibular testing, imaging findings, treatment approaches, and patient outcomes. Results: A total of 23 studies were identified, reporting 53 individual cases of LS. Patients ranged from 27 to 85 years of age, with a mean age of 50.34 years and a male predominance (64.1%). The hallmark of LS across cases was a reproducible clinical pattern of unilateral low-frequency hearing loss followed by vertigo and subsequent auditory recovery. Audiometry typically confirmed reversible sensorineural hearing loss, while vestibular tests and imaging were often unremarkable, primarily used to exclude alternative diagnoses. Treatment approaches varied and were often based on MD protocols, including dietary modifications, vasodilators, diuretics, and vestibular suppressants. Prognosis was generally favorable, with most patients experiencing both hearing recovery and symptom resolution. Conclusions: LS remains a clinically distinct but underrecognized inner ear disorder. Its defining feature—the paradoxical improvement in hearing after vertigo—distinguishes it from Menière’s disease and should prompt clinicians to consider LS in differential diagnosis. Due to the rarity of LS and the lack of standardized guidelines, diagnosis and treatment rely on careful clinical assessment and individualized management strategies. Full article

Background: Coronavirus disease 2019 (COVID-19) has led to the expansion of the spectrum of invasive fungal infections beyond traditional immunocompromised populations. Although COVID-19-associated pulmonary aspergillosis is increasingly being recognised, COVID-19-associated mucormycosis remains rare, particularly in non-endemic regions. Concurrent COVID-19-associated invasive tracheobronchial aspergillosis and pulmonary mucormycosis with histopathological confirmation is exceedingly uncommon and poses significant diagnostic and therapeutic challenges. Case presentation: We report the case of a 57-year-old female with myelodysplastic syndrome who underwent haploidentical allogeneic haematopoietic stem cell transplantation. During post-transplant recovery, she developed COVID-19 pneumonia, complicated by respiratory deterioration and radiological findings, including a reverse halo sign. Bronchoscopy revealed multiple whitish plaques in the right main bronchus. Despite negative serum and bronchoalveolar lavage fluid galactomannan assay results, cytopathological examination revealed septate hyphae and Aspergillus fumigatus was subsequently identified. Given the patient’s risk factors and clinical features, liposomal amphotericin B therapy was initiated. Subsequent surgical resection and histopathological analysis confirmed the presence of Rhizopus microsporus. Following antifungal therapy and surgical intervention, the patient recovered and was discharged in stable condition. Conclusions: This case highlights the critical need for heightened clinical suspicion of combined invasive fungal infections in severely immunocompromised patients with COVID-19, even in non-endemic regions for mucormycosis. Early tissue-based diagnostic interventions and prompt initiation of optimal antifungal therapy are essential for obtaining ideal outcomes when co-infection is suspected. Full article

Background: Fixed-dose combinations have advanced in many therapeutic areas, including otorhinolaryngology, where hearing disorders are increasingly prevalent. Objectives: The present study focuses on developing and evaluating a new capsule combining nicergoline (NIC), piracetam (PIR), and hawthorn extract (HE) for the management of sensorineural hearing loss. Methods: The first phase methodology comprised preformulation studies (DSC, FTIR, and PXRD) to assess compatibility among active substances and excipients. Subsequently, four formulations were prepared and tested for flowability, dissolution behavior in acidic and neutral media, and stability under oxidative, thermal, and photolytic stress. Quantification of the active substances and flavonoids was performed using validated spectrophotometric and HPLC-UV methods. Results: Among the tested variants, the F1 formulation (4.5 mg NIC, 200 mg PIR, 50 mg HE, 2.5 mg magnesium stearate, 2.5 mg sodium starch glycolate, and 240.5 mg monohydrate lactose per capsule) displayed optimal technological properties, superior dissolution in acidic media, and was further selected for evaluation. The antioxidant activity of the formulation was confirmed through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, Trolox Equivalent Antioxidant Capacity (TEAC), and iron chelation tests, and was primarily attributed to the flavonoid content of the HE. Acute toxicity tests in mice and rats indicated a high safety margin (LD₅₀ > 2500 mg/kg), while ototoxicity assessments showed no adverse effects on auditory function. Conclusions: The developed formulation displayed good stability, safety, and therapeutic potential, while the applied workflow could represent a model for the development of future fixed-dose combinations. Full article

Acromegaly is caused by an excessive secretion of growth hormone and the secondary elevation of IGF-1 levels, leading to progressive changes in multiple body systems, including the craniofacial region and oral cavity. Dental manifestations such as mandibular overgrowth, macroglossia, malocclusion, periodontal disease, and prosthetic difficulties represent not only a clinical component of the disease but also a significant therapeutic and diagnostic challenge. The aim of this review is to present the current state of knowledge on the relationship between acromegaly and oral health and to analyze the role of interdisciplinary collaboration between endocrinologists and dentists in patient care. For this narrative review, a literature search was conducted in the PubMed, Scopus, and Web of Science databases covering the period from 2000 to 2025. Sixty-two peer-reviewed publications meeting the methodological and thematic criteria were included in the analysis, including original studies, meta-analyses, systematic reviews, and case reports. The results indicate significant correlations between disease activity and the severity of periodontal and microbiological changes, while effective endocrine treatment only results in the partial regression of morphological changes. Particular attention was given to the role of the dentist in recognizing the early symptoms of the disease, planning prosthetic and surgical treatment, and monitoring therapy-related complications. Interdisciplinary collaboration models, including integrated clinics and co-managed care, were also described as optimal systemic solutions for improving treatment quality. The conclusion drawn from the analysis are as follows: there is a need for the permanent integration of dentistry into the standard of interdisciplinary care for patients with acromegaly, in both diagnostic and therapeutic dimensions. Increasing awareness among dentists and developing integrated collaboration models may reduce the time to diagnosis, improve patients’ quality of life, and enable the more effective management of craniofacial complications in the course of this rare disease. Full article