Search Results (345)

Sometimes, mandatory rules for eradicating pathogens specifically target crops that hold intrinsic economic value, cultural heritage, and are a lucrative tourist attraction as well as an appealing part of the landscape due to their historical presence in the region. An example of this is the introduction of Xylella fastidiosa subsp. pauca (Xfp), mainly vectored by Philaenus spumarius to olive groves in Apulia. Twelve years after the first official report on its presence and numerous studies, this review aims to reconsider some of the quarantine measures in place to prevent the spread of Xfp. Surveys carried out within the demarcated areas have shown a low incidence of Xfp over the years ranging from 0.06% to 0.70%. Furthermore, the bacterium is now present throughout the region, from the south to the north, potentially suggesting that the bacterium may be endemic in the region. Epidemiological models have indicated low or negligible infectivity for asymptomatic trees. Rigorous vector control, achieved through the mechanical removal of eggs and juvenile forms, coupled with the contemporary reduction in the Xfp load within the olive crown using bactericidal compounds, could effectively reduce the spread of Xfp in both infected and demarcated areas. These actions could also serve as preventive measures in current free areas. Once the prevalence of both vectors and Xfp is low, only olive trees in demarcated areas that test positive for the bacterium should be uprooted. Trees within a 50 m radius of an Xfp-positive olive tree should not be removed if they test negative for Xfp upon detection. Full article

Background: Pancreatic hamartoma (PH) is an exceptionally rare, benign, mass-forming lesion accounting for less than 1% of all pancreatic tumors. Its rarity and non-neoplastic nature contribute to significant diagnostic challenges, often leading to misclassification as malignant disease. This study presents a case of PH and a systematic review of all reported cases, with emphasis on histopathological and imaging characteristics. Methods: A comprehensive electronic search of PubMed, Scopus, and Web of Science was conducted up to 1 April 2025, to identify eligible case reports and series. Results: We describe a 37-year-old woman with a cystic lesion of the pancreatic tail, ultimately confirmed histologically as a cystic pancreatic hamartoma following distal pancreatectomy with splenectomy, with an uneventful postoperative course. Of 687 screened studies, 51 met the inclusion criteria, comprising 77 cases (68 adults, 9 pediatric). PHs occurred most frequently in males (52.9%), with a mean age of 59.5 ± 12.9 years, and were often asymptomatic (57.4%). The pancreatic head was the most common site (52.9%). On MRI, PHs typically exhibited low T1-weighted and high T2-weighted signal intensity, with no FDG uptake (82%) and moderate or no restriction on DWI, distinguishing them from neuroendocrine tumors (NETs). Histologically, most lesions were solid (64.7%) or solid–cystic (35.3%), with low spindle cell cellularity and absent Langerhans islets. Conclusions: Low T1WI signal and moderate DWI signal are the key features distinguishing PHs from NETs. Incorporating these findings with EUS-FNA and immunohistochemistry can support a provisional diagnosis and help avoid unnecessary radical surgery. Full article

Usutu virus (USUV) is an emerging arbovirus recently associated with outbreaks in Western Europe. Although USUV is typically associated with asymptomatic or nonspecific febrile disease, the occurrence of severe neuroinvasive forms of disease has raised concern. There is currently no antiviral treatment available for USUV infection; therefore, we sought to investigate the protective effects of the nucleoside analogue 7DMA against USUV. Adding to 7DMA’s activity against USUV in vitro reported by us and others, we found that 7DMA inhibits USUV replication at multiple stages in mammalian cell lines Vero CCL81 and SH-SY5Y. In vivo testing of 7DMA using the susceptible IFNAR^-/- mouse model indicated that 7DMA treatment significantly reduced USUV viremia and viral load in tissues and prolonged mice survival. The characterization of the protective effects of 7DMA indicated that treatment also altered immunological aspects of disease development, further increasing the expression of mediators such as CXCL10, IL-15, and IFN-γ, and increasing neutrophil recruitment to target organs. We did not observe significant tissue damage or pathology in USUV-infected mouse brains, suggesting that systemic infection and disease are the major components leading to mortality in this model. We conclude that 7DMA exerts protective effects against USUV infection in the IFNAR^-/- model. Full article

Background and Clinical Significance: FLNC encodes filamin C, a muscle-scaffolding protein crucial for cardiac integrity. Pathogenic FLNC variants cause diverse cardiomyopathies (hypertrophic, dilated, restrictive, and arrhythmogenic) and myofibrillar myopathies, but their role in congenital cardiac malformations is unclear. Notably, FLNC has not been implicated in structural defects such as Tetralogy of Fallot (TOF) to date. Case Presentation: Two fetuses from the same family were prenatally diagnosed with TOF via ultrasound. The trio whole-exome sequencing of the second fetus and her parents identified a novel heterozygous truncating FLNC variant (NM_001458.5:c.1453C>T, p.Q485*). Sanger sequencing confirmed the same variant in the earlier TOF fetus. The mother carried the variant but was asymptomatic. In vitro mutagenesis in rat cardiomyocytes showed that the mutant FLNC construct produced markedly reduced FLNC proteins compared to the wild type and did not form abnormal cytoplasmic aggregates. Conclusions: We report on a novel FLNC truncating variant associated with fetal TOF, extending the spectrum of FLNC-related cardiac anomalies. The variable outcomes among variant carriers—from fetal TOF to adult cardiomyopathy or no clinical manifestations—underscore the complex genotype–phenotype correlations of filaminopathy. This case highlights the importance of comprehensive genetic evaluation in families with diverse cardiac phenotypes and suggests that additional genetic factors likely influence phenotypic expression. Full article

Backgroud/Objectives: Canine Visceral Leishmaniasis (CVL), caused by Leishmania infantum, is a significant public health concern due to dogs serving as reservoirs for human infection. An accurate and rapid diagnostic method to distinguish symptomatic and asymptomatic CVL from healthy and vaccinated animals is essential for controlling canine and human disease. Developing innovative antibody detection techniques and exploring new antigens are essential for enhancing CVL testing efficiency. Our study focuses on a multiplex flow cytometry technique to detect Leishmania-specific antibodies in canine serum. This involved conjugating small peptides with carrier proteins or peptide tags, sequences designed to facilitate bead coupling. Methods: A peptide from the L. infantum A2 protein was coupled to beads in three forms: unconjugated, conjugated with BSA, and conjugated with a C-terminal β-alanine–lysine (x4)–cysteine TAG. This TAG was previously designed to enhance peptide solubility, improve binding efficiency, and provide functional groups for covalent attachment to the beads, ensuring stable immobilization in the multiplex assay. Results: Our results suggest that the multiplex approach shows promise as a rapid serological test for CVL, particularly with TAG-conjugated peptides, which optimize bead coupling. However, peptide/BSA conjugation revealed anti-BSA antibodies in samples from healthy and CVL dogs. Conclusions: In conclusion, our findings highlight the potential of multiplex methodologies to enhance CVL diagnostics and caution against using BSA as a bead coupling agent in serological tests for canine samples due to its impact on test specificity and sensitivity. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system, increasingly recognized as a disease continuum that begins years before the first neurological event. Genetic susceptibility, environmental exposures, and silent neuroinflammation contribute to early disease activity. Recent studies have highlighted a preclinical phase that includes both a biological stage, characterized by elevated biomarkers such as serum neurofilament light chain up to 10 years before onset, and a prodromal phase, marked by subtle but measurable symptoms. Population-based cohorts consistently show increased healthcare use, higher prevalence of psychiatric and cognitive disturbances, fatigue, pain, and gastrointestinal disorders years before diagnosis, which may represent prodromal symptoms. Radiologically isolated syndrome (RIS), defined by incidental demyelinating lesions in asymptomatic individuals, represents the visible form of this phase and provides a unique opportunity to study the transition to clinical disease. Approximately half of RIS patients develop MS within a decade, with predictors including younger age, male sex, CSF oligoclonal bands, and spinal cord involvement. Recent randomized controlled trials demonstrated that early use of disease-modifying therapies in RIS significantly reduces conversion risk. Defining the preclinical and prodromal phases of MS offers a major opportunity to refine risk stratification, enable earlier intervention, and ultimately prevent or delay the onset of clinically definite MS. Full article

Background and Clinical Significance: Intermediate-high-risk pulmonary embolism is characterized by right-ventricular dysfunction and positive cardiac biomarkers in the absence of hemodynamic instability. Current guidelines recommend anticoagulation with vigilant monitoring, and reserve systemic fibrinolysis for patients who deteriorate hemodynamically. However, some patients may experience physiologic decompensation manifested by refractory hypoxemia rather than hypotension, despite preserved systemic perfusion and normal lung parenchyma. In such cases, oxygenation failure reflects the severity of perfusion impairment and incipient right-ventricular-circulatory collapse. Whether this scenario justifies systemic fibrinolysis remains uncertain. Case Presentation: We present a 75-year-old man, five days after arthroscopic meniscus repair, presenting with acute dyspnea, tachycardia, and severe respiratory failure despite normal chest radiography. Laboratory findings revealed elevated troponin-I and brain natriuretic peptide, and echocardiography demonstrated marked right-ventricular dilation. Computed tomographic pulmonary angiography confirmed extensive bilateral central emboli with preserved lung parenchyma. Despite high-flow nasal oxygen at 100% fraction of inspired oxygen, respiratory failure worsened, necessitating intubation under lung-protective settings. With catheter-directed therapy unavailable and transfer unsafe, a multidisciplinary team administered staged systemic fibrinolysis with alteplase, pausing heparin during infusion. No bleeding or surgical complications occurred. Oxygenation and right-ventricular indices improved promptly. The patient was extubated on day 2, discharged from intensive care unit on day 7, and remained asymptomatic with normal echocardiography at 3 months. Conclusions: Refractory hypoxemia in intermediate-high-risk, normotensive pulmonary embolism, particularly when parenchymal disease and ventilator confounding are excluded, may represent an early form of circulatory decompensation warranting rescue reperfusion. In the absence of catheter-directed options and with acceptable bleeding risk, staged full-dose systemic fibrinolysis can be life-saving and physiologically justified. This case supports expanding the concept of “clinical deterioration” in intermediate-risk pulmonary embolism to include isolated, unexplained respiratory failure, highlighting the need for future trials to refine individualized reperfusion thresholds. Full article

Arteriovenous malformations (AVMs) are fast-flow vascular malformations formed by direct artery-to-vein shunts without an intervening capillary bed, which increases the risk of hemorrhage and organ-specific damage. A synthesis of recent advances shows that AVMs arise from interplay between germline susceptibility (ENG, ACVRL1, SMAD4, RASA1, EPHB4), somatic mosaicism (KRAS, MAP2K1, PIK3CA), perturbed signaling (TGF-β/BMP, Notch, VEGF, PI3K/AKT, RAS/MAPK), hemodynamic stress, and inflammation. Multimodal imaging—digital subtraction angiography (DSA), MRI/MRA with perfusion and susceptibility sequences, CTA, Doppler ultrasound, and 3D rotational angiography—underpins diagnosis and risk stratification, while arterial spin labeling and 4D flow techniques refine hemodynamic assessment. Management is individualized and multidisciplinary, combining endovascular embolization, microsurgical resection, and stereotactic radiosurgery (SRS); a non-surgical approach and monitoring remain reasonable for some asymptomatic AVMs. Device and technique innovations (detachable-tip microcatheters, pressure-cooker approaches, and newer liquid embolics such as PHIL and Squid) have broadened candidacy, and precision-medicine strategies, including pathway-targeted pharmacotherapy, are emerging for syndromic and somatic-mutation–driven AVMs. Animal models and computational/radiomics tools increasingly guide hypothesis generation and treatment selection. We outline practical updates and future priorities: integrated genomic-imaging risk scores, genotype-informed medical therapy, rational hybrid sequencing, and long-term outcome standards focused on hemorrhage prevention and quality of life. Full article

Limb-Girdle Muscular Dystrophies (LGMDs) are genetically heterogeneous disorders primarily affecting proximal limb muscles. The most common form, LGMDR1, results from biallelic CAPN3 mutations encoding calpain-3, a muscle-specific protease. Recently, growing evidence implicates heterozygous CAPN3 variants in autosomal dominant disease (LGMDD4), with pathogenic mechanisms still incompletely understood. In a retrospective multicenter Italian study of patients harboring monoallelic CAPN3 variants (ClinicalTrials.gov NCT05956132), the p.Asp753Asn substitution was the most frequent change, detected in eight unrelated individuals. These patients, aged 6–80 years, exhibited a spectrum of presentations ranging from asymptomatic hyperCKemia and exertional myalgia to mild proximal weakness. Muscle biopsies showed mild, nonspecific myopathic changes, while calpain-3 expression was variably reduced. Structural modeling suggested that Asp753 may stabilize the Ca²⁺-bound conformation, with substitution potentially disrupting inter-domain interactions. Literature review identified 31 additional reports worldwide, confirming recurrence while highlighting marked phenotypic heterogeneity and limited clinical annotation. The aggregated evidence supports a pathogenic role for p.Asp753Asn, though the precise mechanism, potentially involving a dominant-negative effect, remains to be validated. These findings emphasize diagnostic challenges posed by single CAPN3 variants and underscore the need for integrated clinical, segregation, and functional studies to clarify pathogenic mechanisms, refine counseling, and guide patient-specific rehabilitation and therapeutic strategies. Full article

Statin exposure has been associated with a broad spectrum of muscle toxicity, ranging from asymptomatic creatine kinase (CK) elevation to immune-mediated necrotizing myopathy (IMNM) with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. The mechanisms underlying these adverse effects are not fully understood, and genetic predisposition may play a role. This observational study evaluated the association of HLA-DRB1*11 and SLCO1B1 rs4149056 variants with statin-induced muscle toxicity. A total of 62 statin-exposed patients treated at a single tertiary center were included and classified as follows: IMNM with anti-HMGCR antibodies (n = 11), non-immune myotoxicity (n = 20), and statin-exposed controls without myopathy (n = 31). The mean age was 66 ± 7.5 years, and 62% were women. The frequency of the HLA-DRB1*11 allele was significantly higher in patients with anti-HMGCR IMNM compared to those with non-immune myotoxicity (81.0% vs. 25.0%; OR = 13.5, 95% CI 1.73–15.3; p < 0.01) and controls (81.0% vs. 17.2%; OR = 21.6, 95% CI 2.87–23.7; p < 0.01). No significant difference was found between the non-immune myotoxicity and control groups. Likewise, the SLCO1B1 rs4149056 variant showed no association with either IMNM or non-immune muscle toxicity. These findings confirm a strong association between the HLA-DRB1*11 allele and anti-HMGCR IMNM. This genetic marker may help to better distinguish immune-mediated from non-immune forms of statin-related myopathy. Full article

Epichloë is a genus of endophytic fungi that forms systemic, vertically transmitted, and asymptomatic mutualistic associations with grasses in the subfamily Pooideae. These symbioses are non-pathogenic and are of considerable importance in agronomic and livestock systems due to their roles in enhancing host fitness under biotic and abiotic stress. Several studies have reported associations between Epichloë endophytes and species of the genus Bromus, a taxonomically complex group characterized by varying ploidy levels and frequent hybridization. Among its sections, Bromopsis includes the highest number of species naturally colonized by Epichloë fungi, while sections Bromus and Ceratochloa show lower infection rates. In South America, endophytes such as E. pampeana, E. tembladerae, E. typhina, and morphotypes of Neotyphodium spp. have been documented in species including B. auleticus, B. brachyanthera, and B. setifolius, where they appear to contribute to stress resilience. Although most findings originate from Argentina, significant knowledge gaps remain regarding the diversity and distribution of these endophytes in native Bromus species across the continent. This review synthesizes the current understanding of Epichloë–Bromus interactions, emphasizing their ecological and agronomic relevance, particularly in South America. Key factors influencing the establishment of these symbioses are examined, and future research directions are proposed to advance the study of these associations. Full article

Autosomal recessive (AR) disorders represent a significant public health challenge, as asymptomatic carriers are often unaware of their reproductive risks. This study provides the first comprehensive assessment of AR gene variant frequencies and their molecular landscape in a fertile Western Romanian population. Genetic results from 604 unrelated, unaffected Caucasian individuals of reproductive age, tested at a single genetic center between 2020 and 2024, were retrospectively analyzed. Next-generation sequencing (NGS) with a multi-gene panel targeting 300 AR-associated genes was used for molecular profiling. Variants were identified in 156 genes, with 75% of individuals carrying at least one AR variant (mean 1.77 variants/person). A subgroup with >3 pathogenic variants comprised 7.5%, posing a notable risk for future offspring. The most frequent variants were detected in HFE (1:5), CFTR (1:9), BTD (1:16), GJB2 (1:17), and CYP21A2 (1:19). Four variants (HFE, c.187C>G; BTD, c.1330G>C; CFTR, c.1210-34TG[11]T[5]; GALT, c.-119_-116del) were particularly prevalent, each exceeding 3% frequency. Considerable allelic heterogeneity was observed for distrinctive variants in CFTR (14), PAH (12), USH2A (12), and ATP7B (9). Several variants were linked to severe disorders, with CFTR, GALT, ATP7B, and SMN1 identified as “red zone” genes associated with high morbidity and mortality. Low-frequency variants formed a “long tail” (83.9%), reflecting marked population heterogeneity and potential hidden disease risks. The study reveals high allelic diversity and a strong prevalence of AR variants in Western Romania. Variant-based gene classification supports population-level screening, highlighting the public health value of a national program to identify carriers and prevent severe inherited disorders. Full article

Introduction: In hemoglobinopathies, the amount of globin synthesis in hemoglobin (Hb) or its structure is altered. Clinical features are related to the rate and kind of structural aberrations. The heterozygous form of the Lepore syndrome resembles minor thalassemia both clinically and hematologically. On electrophoresis, abnormal Hb Lepore fractions are found at a rate of 5–15%, with a mildly higher percentage of HbF and lower HbA. In general, Hb Lepore heterozygotes are asymptomatic. Case presentation: A 32-year-old male was admitted to our hospital with complaints of pain and swelling in multiple large joints and high-grade fever for 11 days. His past history was unremarkable; one of his sisters had the β-thalassemia trait. On physical examination, he was moderately anemic, with mild hepatomegaly and normal spleen; both knees and ankles were tender and swollen. Laboratory showed mild microcytic hypochromic anemia with variables similar to the thalassemia trait and signs of inflammation with very high CRP, serum ferritin, and leukocytosis. Blood sugars were increased. Hb electrophoresis showed an abnormal pattern with mild elevation in HbS, normal Hb F, mild reduction in HbA, and high HbA2, compatible with heterozygosity for the Hb Lepore beta chain variant. He was initially diagnosed with diabetes (treated with insulin) and sepsis from unknown origin, but fever and joint pains did not respond to NSAIDs or antibiotics. He had very good response on high-dose methylprednisolone. Undifferentiated arthritis was diagnosed in the patient with Hb Lepore, and he was treated with oral prednisolone and sulfasalazine (SSZ). At follow up, the patient was doing well. He refused further investigations and did not allow testing on his family members. In summary: Hb Lepore is a rare hemoglobinopathy linked to thalassemia, which may manifest with musculoskeletal problems. Our patient with the Hb Lepore trait presented with undifferentiated polyarthritis and fever, but in our case, a causal relationship remains unclear. This is one of the first adult cases of Hb Lepore in Bangladesh and the first with arthritis of unknown origin. The prevalence of Hb Lepore in Bangladesh is unknown. Full article

Ovarian cancer (OC) is an aggressive and lethal gynecologic cancer due to its asymptomatic nature resulting in a late diagnosis. OC encompasses distinct histological subtypes, with serous OC representing the most common and aggressive form. However, within the same histological OC subtype, additional heterogeneity has been found in terms of genetic mutations and metabolic profiles probably contributing to treatment response. In cancer, metabolic reprogramming strongly involves mitochondria. Mitochondrial function can be regulated by the cAMP pathway, and its deregulation has been reported in various cancers including OC. Here we analyzed two serous OC cell lines, OC316 and OV56, and eleven human OC tissues. OC316 cell lines showed elevated cAMP level with respect to OV56. The high cAMP levels were associated with activation of thecAMP/PKA/CREB/PGC-1α axis resulting in increased mitochondrial biogenesis, respiratory chain activity, modulation of mitochondrial dynamics and apoptosis resistance. Accordingly, principal component analysis (PCA) of the twenty-three biochemical parameters, in eleven human OC tissues, classified OC into two groups showing different cAMP levels associated with distinct mitochondrial profiles. This analysis highlights a cAMP-dependent stratification revealing two mitochondrial subpopulations within serous OC. These findings indicate that the molecular heterogeneity of OC poses a challenge for understanding disease mechanisms and developing effective targeted therapies. Full article

Background and objectives: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with autosomal dominant forms most often linked to MAPT, GRN, and C9orf72. We aimed to evaluate the prevalence of pathogenic variants in these genes in a hospital-based cohort of FTD patients assessed at a tertiary referral center in southeastern Serbia. Methods: We studied 58 consecutive patients with FTD spectrum syndromes evaluated at a tertiary referral center. All underwent standardized neurological, neuropsychological, and imaging assessments, and family history was recorded. Genetic testing included validated assays for C9orf72 repeat expansions and next-generation sequencing of MAPT and GRN. Results: Women comprised 53.45% of the cohort. The mean age was 67.88 years, with mean onset at 61.70 years. Behavioral variant FTD predominated (75.87%), while language forms were less frequent. Positive family history was present in 16 patients (27.59%). Pathogenic variants were identified in three individuals (5.17%): two unrelated carriers of the intronic MAPT mutation c.1920+16C>T and one patient with a C9orf72 expansion. No GRN variants were detected. Mutation frequency was 18.75% in familial cases, while none were found among sporadic patients (p = 0.018). Four of nine relatives were asymptomatic MAPT mutation carriers. Conclusions: This first genetic study of FTD in southeastern Serbia revealed a lower mutation frequency than in Northern and Western Europe, but similar to cohorts from Southeastern Europe. The detection of MAPT c.1920+16C>T in two unrelated families extends the geographic range of this splice-site variant and underscores the importance of systematic genetic testing and larger collaborative studies in the Balkans. Full article