Search Results (18,880)

Chronic limb-threatening ischemia (CLTI) in patients with no conventional targets for revascularization presents a formidable challenge in limb salvage. Deep venous arterialization (DVA) is an emerging endovascular approach that redirects arterial blood flow into the venous system to perfuse the ischemic foot. Despite early promising results, appropriate wound management of the ischemic foot following a DVA procedure has been described in the literature, albeit infrequently and with limited standardization. Here, we present a case of an 85-year-old male with multiple comorbidities, including peripheral artery disease and a prior right above-knee amputation (AKA), who underwent a successful left-sided DVA following an open transmetatarsal amputation (TMA) for infection. A staged wound care approach with guillotine amputation, delayed revision and skin grafting ultimately preserved his only remaining limb and allowed for ambulation. This case underscores the potential of DVA as a limb-saving option in complex “no-option” patients when paired with multidisciplinary care and tailored wound management. Full article

Traditional Mediterranean grapevine landraces represent irreplaceable reservoirs of adaptive diversity, yet many regional germplasm pools remain poorly characterized, limiting conservation strategies and climate-resilient breeding. This study presents the first comparative genetic assessment of 154 local Vitis accessions from three historically interconnected but genomically underrepresented Mediterranean regions: Greece, Morocco, and Slovenia. Using 12 highly polymorphic nuclear SSR markers, we detected substantial genetic diversity (168 alleles; mean heterozygosity He = 0.881) with distinct regional signatures. Moroccan accessions exhibited the highest allelic richness and 11 private alleles, reflecting diverse agroecological adaptation. Slovenian germplasm formed a cohesive, genetically stable cluster with high effective allele numbers. Greek accessions exhibited the highest observed heterozygosity and 14 private alleles, consistent with the Aegean’s role as a major diversification hotspot. Despite >90% of variance occurring within individuals, AMOVA and pairwise FST (0.050–0.061) revealed low to moderate but significant geographic differentiation. Multivariate analyses (PCA, UPGMA) and Bayesian clustering (sNMF, K = 3) consistently resolved three regional genetic groups with varying admixture levels, consistent with a mosaic domestication model, as previously proposed for the Mediterranean basin, shaped by recurrent introductions, wild introgression, and region-specific selection. Our results show that peripheral Mediterranean germplasm harbors meaningful, regionally distinctive, substantial, non-redundant diversity not fully represented in surveys focused on climate adaptation, disease resistance breeding, and long-term genetic resource conservation. These findings challenge simplistic diffusion models and emphasize the strategic importance of geographically comprehensive sampling in grapevine conservation programs. Full article

Oocyte formation occurs successfully within a meticulously controlled follicular environment characterized by well-documented endocrine, metabolic, and paracrine signals. Yet, the immunological landscape of the follicle and its role in influencing oocyte competency has received less attention in research. Growing research indicates that the ovarian follicle functions as an immunological-active niche necessitating a precise equilibrium between controlled inflammation and targeted immune tolerance. The programmed cell death-1 (PD-1) receptor and its ligand PD-L1 constitute a crucial immune checkpoint pathway, essential for sustaining peripheral immunological tolerance and averting excessive immune activation. Despite their comprehensive research in cancer biology and maternal–fetal interactions, their possible function in the follicular microenvironment remains mostly unexamined. We propose that PD-1/PD-L1 signaling may facilitate the formation of a localized immune-tolerant milieu inside the follicle to safeguard the developing oocyte from inflammatory injury and immune-mediated stress. The disturbance of this suggested equilibrium may lead to a pro-inflammatory follicular environment, compromised granulosa cell function, and modified oocyte maturation, hence affecting fertilization and embryonic developmental potential. In clinical contexts with immunological dysregulation, such as endometriosis, polycystic ovarian syndrome, and unexplained IVF failure, such processes may be especially significant. The purpose of this narrative review is to assimilate the current comprehension of immune regulation in the follicle with the established biology of PD-1/PD-L1 and to investigate a potential correlation between immune checkpoint signaling, oocyte competence, and assisted reproductive outcomes. Considering the follicle as an immune-regulated microenvironment offers a new paradigm for comprehending infertility and identifying novel indicators or therapeutic targets. Full article

Bronchial atresia (BA) is a rare congenital anomaly that develops as a consequence of an intrauterine bronchial artery insult. Distal to the atresia, a mucocele can form with consecutive hyperinflation of the peripheral lung parenchyma. We describe an asymptomatic patient with a well-demarcated segmental emphysematous area within the right lower lobe revealed by computed tomography (CT). Here, the right lateral basal segmental bronchus (B9) is proximally interrupted while the distal, mucus-filled bronchus forms a bronchocele. The down-stream segmental parenchyma is hyperinflated. 3D reconstruction of the tracheobronchial tree reveals a normal architecture of the tracheobronchial tree except for the characteristic discontinuation of the right ninth bronchus. Asymptomatic patients with BA do not require treatment, however, follow-up CT is recommended to assess stability of the segmental hyperinflation. Full article

Pancreatic ductal adenocarcinoma (PDAC) is increasingly recognized as a systemic malignancy, characterized by profound alterations in tumor–host interactions. Small extracellular vesicles (sEVs) in peripheral blood may reflect these alterations and represent a promising minimally invasive source of biomarker information. In this proof-of-principle study, plasma-derived sEVs from patients with PDAC, healthy controls, and a comparative cohort with neuroendocrine lung cancer (NLC) were isolated by differential ultracentrifugation and characterized by western blotting and nanoparticle tracking analysis. Surface marker profiling was performed using the MACSPlex EV Kit IO, followed by univariate, multivariate, and machine-learning-based analyses. PDAC samples exhibited a distinct sEV immunophenotype with coordinated enrichment of angiogenesis-related markers (including CD105 and CD146), immune-regulatory markers (including CD25 and CD40), the coagulation-related marker CD142 and the invasion-associated marker MCSP. Principal component analysis, hierarchical clustering, and Random Forest classification showed exploratory separation of PDAC patients from healthy controls and NLC, supporting the presence of disease-specific vesicle surface marker patterns. In a very small subset of paired samples, descriptive longitudinal analyses illustrated measurable intra-individual changes during chemotherapy. Plasma sEV immunophenotyping is a technically feasible approach for capturing systemic disease-associated alterations in PDAC and provides a foundation for future biomarker-oriented validation studies. Full article

Background/Objectives: Coronary artery disease (CAD) is a leading cause of cardiovascular morbidity and mortality worldwide. Type 2 diabetes mellitus (T2DM) further increases CAD risk through metabolic disturbances and endothelial dysfunction. Adropin, S100A1, and SERCA2b are important regulators of endothelial function, energy metabolism, and calcium homeostasis. This study aimed to investigate the gene and protein expression levels of these biomarkers in CAD patients with and without T2DM. Methods: Gene and protein expression levels of adropin (ENHO), S100A1, and SERCA2b were evaluated in peripheral blood samples obtained from healthy controls (n = 50), CAD patients (n = 46), and CAD patients with T2DM (CAD+T2DM) (n = 40). Gene expression was determined using real-time PCR, while protein levels were measured with ELISA. Additionally, in silico bioinformatics analyses, such as protein–protein interaction networks and pathway enrichment analyses, were performed to explore potential molecular relationships among these biomarkers. Results: Adropin and ENHO gene expression levels were significantly lower in CAD patients and inversely related to the SYNTAX score. S100A1 levels were also reduced, and SERCA2b gene expression was significantly decreased, especially in the CAD+T2DM group. Bioinformatics analyses revealed that these molecules participate in interconnected pathways related to calcium signaling, cardiac muscle contraction, and metabolic regulation. Conclusions: These findings demonstrate links between altered levels of adropin, S100A1, and SERCA2b and CAD with or without T2DM. However, these observations are preliminary and need validation in larger prospective studies and mechanistic research before drawing definitive conclusions about their clinical utility, disease progression, or prognostic value. Full article

Background: Selecting the most efficient and specific adeno-associated virus (AAV) capsids for gene delivery to the nervous system via minimally invasive routes is critical to gene therapy advancement. While AAV9, rAAV2-retro, AAV-PHP.eB, and AAV-MacpnS1 have demonstrated significant central nervous system (CNS) transduction ability after systemic delivery, their tropism, efficiency, and safety profiles in a developmentally relevant model have yet to be systematically compared. This study comparatively evaluated four capsids after intravenous administration in neonatal C57BL/6 mice. Methods: Transgene expression was quantitatively assessed across multiple CNS regions, as well as in the heart and liver. Associated biochemical indicators of hepatic stress were also evaluated. Results: The resulting transduction profiles were distinct and capsid-specific. Both AAV9 and AAV-MacpnS1 induced widespread CNS transduction and robust peripheral organ expression. However, AAV-MacpnS1-neuronal tropism in the thalamus was superior, and it was also associated with the most prominent biochemical indicators of hepatic stress. In contrast, rAAV2-retro was remarkably specific to the medulla and spinal motor neurons, demonstrating a valuable safety profile. AAV-PHP.eB achieved broad cellular transduction in the spinal cord, but it was the least specific towards cholinergic motor neurons. Furthermore, transduction in DRG neurons using AAV9 and AAV-MacpnS1 was efficient, but that using rAAV2-retro or AAV-PHP.eB was not. Conclusions: These findings provide an “atlas-like” comparative framework that clearly outlines the strengths and limitations of each vector. They also offer valuable guidance on selecting the most suitable AAV capsid for fundamental neuroscience applications and for developing targeted gene therapies, particularly for neurodevelopmental and motor neuron disorders, where intravenous administration in the early stages of life is a promising strategy. Full article

Climate change is increasingly reshaping species habitat suitability worldwide. Primula L., the largest genus in Primulaceae, comprises 404 species in China (including 296 endemic species) and is characterized by high endemism and numerous rare and endangered taxa. However, global warming has intensified habitat fragmentation and loss, while its distribution patterns and key environmental drivers remain insufficiently understood. We compiled 7647 occurrence records of 404 wild Primula species in China and integrated 60 environmental variables (climatic, topographic, and soil factors). Using the MaxEnt model combined with ArcGIS spatial analysis, we assessed current and future habitat suitability, identified dominant environmental drivers, and quantified conservation gaps under multiple climate scenarios. Species richness is highly concentrated in Sichuan (186 species), Yunnan (177 species), and Xizang (165 species), with the Hengduan Mountains and eastern Himalayas representing the core distribution area and showing clear peripheral differentiation. The optimized MaxEnt model performed well (AUC = 0.858), identifying temperature seasonality (bio4, 39.8%) and elevation (27.1%) as the main limiting factors. The total suitable habitat area is 268.52 × 10⁴ km², with high-suitability areas mainly distributed in the Hengduan Mountains, southeastern Qinghai–Xizang Plateau, and the Central Mountain Range of Taiwan. Under three shared socioeconomic pathway (SSP) scenarios (SSP126, SSP245, and SSP585), suitable habitat shows a persistent decline, most pronounced under SSP585 in the 2090s (−20.73%), accompanied by a 25.86% reduction in low-suitability areas. Localized expansion of high-suitability habitats suggests that the Hengduan Mountains and southeastern Qinghai–Xizang Plateau may act as potential climatic refugia. Habitat loss consistently exceeds habitat gain, while the distribution centroid shifts westward and northwestward, with migration distances increasing under higher-emission scenarios. Conservation gap analysis indicates that 90.01% of high-suitability habitats lie outside the current protected area network, revealing a strong mismatch between biodiversity hotspots and conservation coverage. These findings highlight the urgent need to expand protected areas and establish micro-reserves in key gap regions (southwestern Sichuan, northwestern Yunnan, southeastern Xizang, and southern Gansu), and to integrate climate-driven migration corridors into conservation planning to support long-term alpine plant persistence under climate change. Full article

Essential blepharospasm (BEB) is a focal dystonia characterized by abnormal brainstem excitability and impaired inhibitory control within trigeminal–facial circuits. Botulinum toxin type A (BoNT-A) is the established first-line treatment, primarily acting at the neuromuscular junction. However, whether BoNT-A also modulates central brainstem circuits in BEB patients remains unclear, and dedicated neurophysiological studies have yielded conflicting results. To investigate whether BoNT-A modulates brainstem interneuronal excitability in BEB using the blink reflex recovery cycle and to correlate clinical outcomes with neurophysiological results. Thirteen patients with BEB underwent neurophysiological and clinical evaluation before (T0) and one month after (T1) BoNT-A treatment. The blink reflex recovery cycle was assessed at interstimulus intervals (ISIs) of 200, 300, 500, and 1000 ms. Clinical severity was assessed using the BSPSS, JRS, and BDS scales. The R2 amplitude ratio showed a statistically significant decrease after treatment across all ISIs (all p ≤ 0.001), indicating reduced brainstem interneuronal excitability. All clinical scales demonstrated statistically significant improvement after treatment (BSPSS, JRS, BDS; all p < 0.001). This pilot study provides preliminary evidence that BoNT-A treatment may reduce brainstem interneuronal excitability in BEB patients, as evidenced by a substantial and consistent decrease in R2 amplitude ratios of the blink reflex recovery cycle. These findings are consistent with a central modulatory effect of BoNT-A beyond its established peripheral action. Larger controlled studies are warranted to confirm these results. Full article

(1) Background: Although the rhesus macaque (Macaca mulatta) is widely maintained in captive populations for translational research, reliable molecular tools for monitoring their physiological status remain limited—a gap that directly affects population management and health monitoring. In particular, no validated panel of housekeeping genes (HKGs) is currently available for expression analysis at the mRNA level in peripheral blood of the species. (2) Methods: Peripheral blood samples from healthy male rhesus macaques aged 4–7 years were used. The expression stability of candidate HKGs was evaluated using RefFinder based on cycle threshold (Ct) values obtained from real-time PCR. (3) Results: A panel of 29 candidate HKGs was compiled. After multistage bioinformatic and experimental selection, 22 genes were excluded. Expression stability analysis of the remaining seven genes (AHSA1, B4GALT3, CYB5R1, HPCAL1, PSMD6, SSR2, and VPS72) identified B4GALT3 and PSMD6 as the most stable. (4) Conclusions: This study presents the experimentally validated set of HKGs for expression studies in Macaca mulatta. Based on the results of expression stability analysis, the B4GALT3 and PSMD6 genes can be recommended as reference genes for studying changes in gene expression in peripheral blood. Full article

Background: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in older adults. An important challenge is the recognition of its early asymptomatic stages and the monitoring of its progression, which requires reliable biomarkers. Growing evidence indicates that AMD-related biochemical changes are reflected in the proteome of tear fluid (TF). Although TF is a non-invasive and easily collectable diagnostic material, its proteomic analysis is complex and costly and therefore has limited clinical value. Methods: In this pilot single-center retrospective cross-sectional study, we developed a new method for dry AMD screening based on analysis of nano-differential scanning fluorimetry (nanoDSF) tear protein denaturation profiles (TDPs) within 15 min. The TDPs were recorded in representative groups of dry AMD patients (37% early, 48% intermediate, 15% geographic atrophy), and in control groups, including patients with refractive abnormalities (basic control), other retinal degenerative diseases (diabetic retinopathy, peripheral retinal dystrophy), or TF-affecting conditions (dry eye syndrome). High-dimensional TDP data were processed using unsupervised machine learning followed by k-means cluster analysis. Results: The presented pipeline distinguished AMD from the basic control with 74% accuracy and a sensitivity of 0.81 without relying on prior labels. The specificity of AMD detection was confirmed by its effective differentiation from diabetic retinopathy (72%; 0.74), peripheral retinal dystrophy (79%; 0.76) and dry eye disease (76%; 0.81). Classifying the AMD group from the entire population of other patients yielded an accuracy of 71% and a sensitivity of 85%, with a false-negative rate of only 15%. Conclusions: This study is a proof of concept for the nanoDSF-based approach, which can be considered a fast, cost-effective, and convenient tool for population screening for dry AMD, suitable for use in preventive medicine and public health. Full article

Bipolar vessel sealing systems are widely used in surgery, yet their effectiveness varies depending on the histological composition of the target vessel. In particular, the influence of elastin on seal stability is not well understood. Porcine carotid arteries, which show a pronounced proximal–distal elastin gradient, provide an ideal model for systematic analysis. In this study, fresh porcine carotid arteries were divided into three segments based on vessel diameter (<5 mm, 5–7 mm, >7 mm). Histological EvG staining was used to quantify elastin and collagen content. All vessels (n = 8 per group) were sealed using a bipolar marSeal^® 5 plus device, followed by burst pressure testing and peel force measurements. Elastin content increased significantly from peripheral to central segments (9% → 25% → 42%; p < 0.001), while collagen content remained constant (22 ± 2%). In parallel, seal stability decreased markedly: burst pressures dropped from 723 mmHg to 240 mmHg and to 31.5 mmHg (p < 0.001). Peel forces showed the same trend (1.75 ± 0.07 N → 0.65 ± 0.03 N → 0.26 ± 0.11 N; p < 0.001). Wall thickness showed no proportional relationship to seal quality. Interestingly, the sealing performance of bipolar systems seems to be greatly influenced by the histological structure of the vessel wall. A high elastin content—rising from 9% to 42% along the carotid artery—was associated with a reduction in burst pressure and peel strength. These findings highlight the need to consider tissue composition when selecting sealing methods and support the development of adaptive energy delivery technologies. Full article

Background: Pain is a prominent and disabling manifestation of inflammatory bowel disease (IBD), including abdominal, pelvic, musculoskeletal, axial, and neuropathic pain phenotypes. Patients referred to pain clinics represent a selected subgroup with clinically meaningful, persistent, refractory, or diagnostically complex pain. Objective: To characterize pain phenotypes, treatment patterns, interventional pain-care exposure, and utilization burden among patients with IBD evaluated in tertiary pain-clinic settings and to explore differences between Crohn’s disease and ulcerative colitis patients. Methods: We performed a retrospective electronic medical-record cohort study of patients with documented IBD who were evaluated in pain-clinic settings between 24 October 2010 and 14 May 2026. Repeated clinical entries were aggregated into unique visit dates and patient-level variables. IBD diagnosis, pain phenotypes, treatment documentation, interventional procedures, and pain-clinic utilization were summarized descriptively using counts, percentages, means, medians, interquartile ranges, and ranges as appropriate. Crohn’s disease and ulcerative colitis subgroups were compared using univariable odds ratios with 95% confidence intervals and two-sided p-values. Because repeated clinical entries could belong to the same patient, the primary analytic unit was the patient rather than the individual note. Results: The source dataset included 19,615 clinical entries representing 7053 unique pain-clinic visits among 596 unique patients with IBD. The cohort included 314 patients with Crohn’s disease (52.7%), 247 with ulcerative colitis (41.4%), and 35 with IBD-unclassified (5.9%). The mean number of pain-clinic visits per patient was 11.8, with a median of four visits (interquartile range, 1–11). The dominant patient-level pain phenotypes were limb or peripheral joint pain (395/596, 66.3%), back or axial spine pain (358/596, 60.1%), and abdominal or pelvic pain (246/596, 41.3%). Overall, 437 patients (73.3%) had documentation of at least one interventional pain procedure. Compared with ulcerative colitis, Crohn’s disease was associated with higher documentation of abdominal or pelvic pain (148/314, 47.1% vs. 82/247, 33.2%; odds ratio, 1.79; 95% confidence interval, 1.27–2.53; p = 0.001) and fibromyalgia-like or widespread pain (83/314, 26.4% vs. 39/247, 15.8%; odds ratio, 1.92; 95% confidence interval, 1.25–2.93; p = 0.0027). In contrast, radiofrequency procedures (59/314, 18.8% vs. 78/247, 31.6%; odds ratio, 0.50; 95% confidence interval, 0.34–0.74; p = 0.0005) and facet or medial branch procedures (79/314, 25.2% vs. 87/247, 35.2%; odds ratio, 0.62; 95% confidence interval, 0.43–0.89; p = 0.012) were less frequently documented in Crohn’s disease than in ulcerative colitis. Conclusions: Among patients with IBD referred to tertiary pain-clinic evaluation, pain was heterogeneous and predominantly musculoskeletal, axial, neuropathic, and procedurally targetable rather than exclusively visceral. These findings support structured, mechanism-based pain assessment integrated with gastroenterology, rheumatology, and pain-medicine care. Full article

The rapidly urbanizing peripheries of the Global South face significant demographic pressures, leading to governance deficits that often neglect the long-term structural safety of new buildings. While regulatory frameworks predominantly emphasize initial construction quality, they frequently overlook the critical “post-occupancy” phase, during which distinct structural risks accumulate. This study introduces a reproducible, open-data risk identification framework designed to trace theoretical “windows of vulnerability” in Çekmeköy, a peripheral district of Istanbul. By triangulating temporal, spatial, and demographic municipal administrative records from 2018 to 2024, we illustrated how low-cost data can serve as proxies for prioritizing structural risk assessments. The findings demonstrate that a 103% population increase between 2008 and 2023, coupled with a 21% reduction in the average household size, has generated urgent housing demand that outpaces supply. We hypothesize that these conditions create high-probability zones for “informality creep,” where demographic pressures induce informal practices, such as unauthorized structural modifications within ostensibly formal high-rise settings. The primary contribution is a transferable algorithmic tool, the Weighted Post-Occupancy Vulnerability Index (POVI). Rather than serving as a deterministic building-level diagnostic, this framework operates much like an epidemiological screening process; it acts as a macroscopic prioritization heuristic that allows resource-constrained municipalities to proactively direct their inspection efforts. By mathematically quantifying the conditions under which post-occupancy risks develop, this framework provides an essential resource for enhancing urban resilience during reactive urbanism planning. Full article

Systemic hypoxia influences the state of the intestinal epithelial barrier and the microbiome; however, the role of the initial tolerance of the organism to oxygen deficiency in the development of these changes remains poorly studied. The aim of the study was to evaluate the colon histophysiological features and the gut microbiome in rats that were tolerant and susceptible to hypoxia under intermittent hypoxic exposure of varying severity. In male Wistar rats, tolerance to oxygen deficiency was determined according to the Hif1a, Epas1, and Hif3a expression levels in peripheral blood leukocytes, after which they were subjected to intermittent hypoxic exposure at an “altitude” of 5000 m or 7000 m for 1 h daily for 21 days. Subsequently, the state of the intestinal epithelial barrier was assessed using histological, histochemical, and immunohistochemical methods, and the microbiota composition was analyzed by PCR. Under normoxic conditions, in comparison with rats that are tolerant to hypoxia, susceptible animals demonstrated a greater volume fraction of goblet cells and a low abundance of Parabacteroides spp. Intermittent hypoxic exposure induced multidirectional changes depending on the initial tolerance and the severity of the regimen. In tolerant-to-hypoxia animals, an increase in the goblet cells volume fraction was detected after the exposure at the 5000 m “altitude”, while at an “altitude” of 7000 m, a decrease in the number of cells in the lamina propria of the mucosa and Clostridium perfringens gr. abundance, as well as a reduction in the Firmicutes/Bacteroidetes ratio, was observed. In susceptible-to-hypoxia animals, a higher abundance of Clostridium perfringens gr. in comparison with tolerant rats was revealed after the exposure at an “altitude” of 7000 m, with no structural changes in the intestinal wall. Thus, intermittent hypoxic exposure led to a rearrangement of the gut microbiome and the morphofunctional characteristics of the intestinal barrier, and the severity of these changes depended on the initial tolerance of the organism to oxygen deficiency and the severity of the hypoxic regime, which should be taken into account when conducting biomedical research. Full article