Search Results (588)

Background/Objectives: Transmission electron microscopy (TEM) is an essential tool for diagnosing renal diseases. It produces high-resolution visualization of glomerular and mesangial ultrastructural features. However, manual interpretation of TEM images is labor-intensive and prone to interobserver variability. In this study, we introduced and evaluated deep learning architectures based on YOLOv8-OBB for automated detection of six ultrastructural features in kidney biopsy TEM images: glomerular basement membrane, mesangial folds, mesangial deposits, normal podocytes, podocytopathy, and subepithelial deposits. Methods: Building on our previous work, we propose a modified YOLOv8-OBB architecture that incorporates three major refinements: a grayscale input channel, a high-resolution P2 feature pyramid with refinement blocks (FPRbl), and a four-branch oriented detection head designed to detect small-to-large structures at multiple image scales (feature-map strides of 4, 8, 16, and 32 pixels). We compared two pretrained variants: our previous YOLOv8-OBB model developed with a grayscale input channel (GSch) and four additional feature-extraction layers (4FExL) (Pretrained + GSch + 4FExL) and the newly developed (Pretrained + FPRbl). Results: Quantitative assessment showed that our previously developed model (Pretrained + GSch + 4FExL) achieved an F1-score of 0.93 and mAP@0.5 of 0.953, while the (Pretrained + FPRbl) model developed in this study achieved an F1-score of 0.92 and mAP@0.5 of 0.941, demonstrating strong and clinically meaningful performance for both approaches. Qualitative assessment based on expert visual inspection of predicted bounding boxes revealed complementary strengths: (Pretrained + GSch + 4FExL) exhibited higher recall for subtle or infrequent findings, whereas (Pretrained + FPRbl) produced cleaner bounding boxes with higher-confidence predictions. Conclusions: This study presents how targeted architectural refinements in YOLOv8-OBB can enhance the detection of small, low-contrast, and variably oriented ultrastructural features in renal TEM images. Evaluating these refinements and translating them into a web-based platform (Renal-AI) showed the clinical applicability of deep learning-based tools for improving diagnostic efficiency and reducing interpretive variability in kidney pathology. Full article

Aging-associated facial hyperpigmentation is driven not only by enhanced melanogenesis but also by dermal senescence and deterioration of the dermal–epidermal junction. The purpose of this study was to evaluate whether monopolar radiofrequency (MRF) monotherapy can improve aging-related facial hyperpigmentation by simultaneously suppressing melanogenic signaling and restoring senescence-associated dermal alterations. We assumed that deep dermal heating induced by MRF would modulate fibroblast senescence and basement membrane integrity, thereby indirectly regulating melanocyte activity. In a retrospective review of 26 Asian women, MRF treatment significantly decreased multiple pigmentation parameters, including melanin level, hyperconcentration, and Hemi Melasma Area and Severity Index (hemi-MASI) scores, while concurrently reducing wrinkles, pores, and enhanced overall skin texture without inducing inflammation. Complementary ex vivo experiments using ultraviolet B (UVB)-irradiated human skin demonstrated that MRF markedly reduced pro-melanogenic markers (α-MSH, MC1R, MITF, TYR, TRP1/2), restored collagen type IV expression at the basement membrane, decreased senescence-associated genes (p16, p21), and upregulated protective heat shock proteins (HSP70/47). Together, these findings suggest that MRF improves aging-associated hyperpigmentation by both suppressing melanogenesis and rejuvenating the senescent dermal microenvironment. MRF may serve as an effective non-invasive treatment option for pigmentation disorders in aging skin. Full article

Fabry disease (FD) is an X-linked lysosomal disorder caused by GLA mutations, typically associated with glycosphingolipid accumulation and a wide phenotypic spectrum. The p.R112H variant is generally linked to a non-classic predominantly renal phenotype with mild biochemical abnormalities and slow progression. We report the case of a young woman carrying the R112H mutation who exhibited early-onset kidney involvement and unusually rapid progression to end-stage renal disease. Clinical history, serial evaluations, and kidney biopsy findings initially supported a diagnosis of Fabry nephropathy; however, re-evaluation of the native kidney biopsy revealed marked remodeling and multilamellation of the glomerular basement membrane, suggesting Alport-like lesions. Subsequent genetic testing confirmed a heterozygous pathogenic COL4A4 variant (G912R), indicating coexistence of Fabry disease and autosomal dominant Alport syndrome. This dual genetic condition likely accounted for the accelerated decline in kidney function, in contrast with the typically mild phenotype associated with R112H. Our literature review indicates that coexistence of these two inherited nephropathies has not previously been confirmed either histologically or genetically. This case underscores the importance of integrating genetic and ultrastructural assessment in patients with atypical or rapidly progressive renal disease Full article

Τargeted genetic sequencing in a 6-year-old with steroid-resistant nephrotic syndrome and biopsy findings of focal segmental glomerulosclerosis (FSGS) revealed a novel COL4A3 pathogenic variant (p.Arg341His). Combined with electron microscopy findings of glomerular basement membrane abnormality, this led to a diagnosis of type IV collagen-related nephropathy. This case underscores the benefit of early genetic testing in presumed FSGS for prognosis and avoiding unnecessary immunosuppression in pediatric nephrotic syndrome. Full article

Background/Objectives: Recurrent corneal erosion syndrome (RCES) is a chronic, recurrent, and painful disorder characterized by repeated episodes of sudden ocular pain due to abnormalities in the corneal epithelium or basement membrane (BM). The aim of this study was to investigate the triggering factors in patients with recurrent corneal erosion syndrome. Methods: Medical charts of patients diagnosed with recurrent corneal erosion syndrome among those who visited the outpatient department of Kangnam Sacred Heart Hospital between 2013 and 2017 were investigated. The trigger factors and the patient’s ocular symptoms were surveyed, and the severity of symptoms was investigated using a questionnaire. Anterior segment photos and anterior segment optical coherence tomography (AS-OCT) scans were performed. Results: The study included a total of 40 patients, with an average age of 46.18 (±13.81) years. Of these, 17 were men and 23 were women. Twelve patients (30%) had a history of trauma. Twelve (30%) drank alcohol the day before the onset of the disease, thirteen (32.5%) had severe fatigue, eight (20%) smoked and two (5%) exercised heavily. The severity of symptoms is related to age and fatigue. AS-OCT was performed in 18 patients; 94.4% had corneal anterior stromal hyperreflectivity, 61.1% had epithelial edema, 50.0% had irregular epithelial break-up, 44.4% had intraepithelial inclusion cysts, 33.3% had intraepithelial BM, and 11.1% had undetectable epithelial BM. Blurred vision and decreased visual acuity are associated with the absence of epithelial BM. Other AS-OCT findings showed no statistically significant difference from the visual symptoms. Conclusions: The most common triggering factors were fatigue and alcohol drinking. The AS-OCT findings may reflect the pathogenesis and progression of RCES. Full article

The premetastatic niche (PMN) represents a specialized microenvironment established in distant organs before the arrival of metastatic cells. This concept has fundamentally altered our understanding of cancer progression, shifting it from a random event-driven process to an orchestrated one. This review examines the critical role of extracellular proteases in PMN formation, focusing on matrix metalloproteinases (MMPs), serine proteases, and cysteine cathepsins that collectively orchestrate extracellular matrix remodeling, immune modulation, and vascular permeability changes essential for metastatic colonization. Key findings demonstrate that MMP9 and MMP2 facilitate basement membrane degradation and the recruitment of bone marrow-derived cells. At the same time, tissue inhibitor of metalloproteinase-1 (TIMP-1) promotes organ-specific hepatic PMN recruitment through neutrophil recruitment mechanisms. The plasminogen–plasmin system emerges as a master regulator through its broad-spectrum proteolytic activity and ability to activate downstream proteases, with S100A10-mediated plasmin generation providing mechanistic pathways for remote PMN conditioning. Neutrophil elastase and cathepsin G contribute to the degradation of anti-angiogenic proteins, thereby creating pro-metastatic microenvironments. These protease-mediated mechanisms represent the earliest interventional window in metastatic progression, offering therapeutic potential to prevent niche formation rather than treat established metastases. However, significant methodological challenges remain, including the need for organ-specific biomarkers, improved in vivo methods for measuring protease activity, and a better understanding of temporal PMN dynamics across different target organs. Full article

The biliary tree is a fundamental structural and functional component of the liver, lined with cholangiocytes which control bile flow and regulate bile homeostasis. In addition to their physiological roles, cholangiocytes are involved in pathological processes known as cholangiopathies. These biliary disorders significantly impair liver function, and their effects are often irreversible, making liver transplantation the only curative option. This substantial clinical burden highlights the need for innovative bioengineered strategies to study disease mechanisms and to restore or replace biliary tissue. In this framework, biliary organoids offer a robust platform to model liver diseases in vitro with physiological accuracy. Compared with traditional 2D or explant-based systems, organoids provide higher physiological relevance, patient specificity, and scalability, although challenges remain in standardization and clinical translation. Organoids are traditionally cultured within basement membrane extract (BME) matrices, which are commercially available under various names. While BME-based matrices support organoid growth and function, their undefined composition, variability, and animal origin limit reproducibility and clinical translation. These drawbacks have driven the development of alternative matrices based on engineered hydrogels. Hydrogels, whether of natural or synthetic origin, provide chemically defined and tunable environments that allow independent modulation of their biochemical and biophysical properties. Acting at the interface between materials science and biology, they enable the creation of microenvironments with precisely controlled cues. In this review, we summarize advances in biliary organoid bioengineering and discuss how hydrogel-based systems are shaping next-generation platforms for organoid growth, differentiation, and disease modeling toward more translationally relevant biliary models. Full article

Perlecan, a major heparan sulfate proteoglycan in the vascular basement membrane, plays an essential role in maintaining endothelial barrier integrity, regulating fibroblast growth factor-2 signaling, and exerting anticoagulant activity. Although alterations in perlecan expression are implicated in the initiation and progression of atherosclerosis, the upstream regulatory mechanisms remain unclear. In this study, we investigated the effects of extracellular ATP on perlecan expression in vascular endothelial cells. ATP, but not ADP or adenosine, suppressed perlecan expression at both mRNA and protein levels in a time- and concentration-dependent manner. This suppression was recovered by knockdown of P2Y2 receptor (P2Y2R), but not by P2X4 receptor, P2X7 receptor, or P2Y1 receptor knockdown, indicating the selective involvement of P2Y2R. Mechanistically, ATP reduced Akt phosphorylation mediated by P2Y2R, and inhibition of Akt by inhibitors decreased perlecan expression, whereas inhibitors of phosphoinositide 3-kinase, mammalian target of rapamycin complex 1, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases did not exhibit this recovery effect. These results suggest that ATP downregulates perlecan synthesis via the P2Y2R-mediated inhibition of Akt signaling. Given that ATP is markedly elevated under pathological conditions, such as inflammation and platelet activation, suppression of perlecan synthesis is an important mechanism by which ATP promotes vascular disease progression. Full article

Kidney diseases in patients with SLE include glomerulonephritis (GN), tubulointerstitial nephritis (TIN) and vasculitis alone or in combination. Immune complex (IC) deposition with complement activation in renal glomeruli causes lupus GN. However, IC deposition can also occur in the tubular basement membrane, renal interstitium, peritubular capillaries and arteries/arterioles to elicit inflammatory responses. TIN is usually associated with more severe GN with inflammation induced by IC. Immunopathologically, the aberrant presentation of T cell subpopulations, T_h1, T_h2, T_h9, T_h17, Treg and follicular T helper cells (T_fh), is closely implicated in TIN in SLE. In addition, M₁/M₂ macrophages and more specific dendritic cells (DCs) contribute to the inflammatory reactions of SLE-TIN. TIN may also present alone (isolated TIN) in apparently normal glomeruli or class I GN. It is intriguing that lupus nephritis constitutes two different pathological predilections, i.e., GN and tubulointerstitial inflammation. Alternatively, these two types may represent a continuous spectrum of inflammatory renal damages. In the present review, we will discuss in detail the pathology/immunopathogenesis, likely specific biomarkers/predictors and novel therapeutic designs for SLE-tubulointerstitial inflammation. In addition, we also raise several plausible investigation methods in SLE-tubulointerstitial inflammation that may help further elucidate this setting of perplexing renal diseases with rheumatic characteristics. Full article

Background/Objectives: The guinea pig is a unique experimental model because of the evolutionary loss of the GULO gene, which encodes an enzyme involved in vitamin C synthesis. Since vitamin C plays an essential role in collagen biochemistry, numerous studies have investigated the effects of pre- and postnatal vitamin C deficiency. However, only a few studies, including ours, have indicated a possible link between vitamin C deprivation and potential weakening of the basement membrane, which may lead to significant alterations in brain structure. Methods: The experiment included guinea pig foetuses completely deprived from the 10th (E2 group) and the 20th (E1 group) to the 50th day of intrauterine life. Tissue samples from the cerebrum and cerebellum were taken for biochemical, molecular, and immunohistochemical analyses. Results: In the E2 group alone, we found marked gross changes: cerebral bleeding, porencephaly, and a lissencephalic cerebellar surface. Microscopic examination revealed diffuse bleeding in the cerebrum along with a loss of neurons in the area of the defect, specifically in the E2 group. The complete maturation of ectopic neurons characterised dysplastic changes in the cerebellum. Hydroxyproline analysis of both the cerebrum and cerebellum showed no significant differences among the E1, E2, and control groups. However, decreased expression of COL1, COL4A1, and SLC23A1 was observed solely in the cerebellar tissue of the E1 group. Conclusions: The morphological, biochemical, and molecular results represent preliminary associations with vitamin C deficiency, but require further validation. Full article

The adaptor molecule DNAX-activating protein of 12 kDa (DAP12) is broadly expressed in innate immune cells, but its role in autoimmunity remains unclear due to its dual regulatory functions. We investigated the contribution of the DAP12 pathway to bullous pemphigoid (BP), the most common autoimmune blistering disease, using a mouse model induced by transfer of anti-type XVII collagen (Col17) IgG. Repeated anti-Col17 IgG injections over 12 days produced comparable disease activity in DAP12-deficient and wildtype mice (n = 17/group), indicating that disease induction occurs independently of DAP12 signaling. Flow cytometry and immunofluorescence analysis of lesional skin further revealed a strong upregulation of the DAP12-associated triggering receptors expressed on myeloid cells (TREM) 1 in wildtype BP lesions, whereas TREM2⁺ cell frequencies in anti-Col17 IgG-treated wildtype and DAP12 knock-out animals were significantly lower than in healthy controls. Additional flow cytometry analysis demonstrated altered inflammatory infiltrates with notably reduced frequencies of Siglec-f⁺ eosinophils in DAP12-deficient vs. wildtype lesional skin. In addition, pharmacological inhibition of PI3Kδ, a downstream kinase of the DAP12/TREM pathway, did not affect disease progression in anti-Col17 IgG-induced BP. Collectively, these findings indicate that while DAP12 signaling modulates local immune cell composition, the DAP12/TREM1/2-axis does not influence overall disease activity in experimental BP. Full article

Mutable collagenous tissue (MCT) is a type of connective tissue that is characterized by its capacity to undergo rapid, nervously mediated changes in mechanical properties. In terms of both the magnitude of these changes and the timescale within which they occur (less than one second to a few minutes), this tissue appears to be unique to the phylum Echinodermata and, as it is ubiquitous in all five extant echinoderm classes, it represents one of the four major defining features of the phylum, together with pentaradial symmetry, endoskeletal stereom (calcite meshwork), and the water vascular system. MCT has been the subject of intensive scientific investigation for over 50 years. The primary aim of this contribution is to provide a comprehensive and definitive survey of the current state of knowledge of this remarkable tissue. After outlining the history of the scientific investigation of MCT, we review current information on its anatomical distribution, organization at the histological, ultrastructural and molecular levels, and physiology—focusing on its mechanical behavior and the regulation of this behavior; its significance for echinoderm biology, including pathology; and biomedical and other applications that exploit MCT-derived components or biological principles. We conclude by drawing attention to more serious deficiencies in the current knowledge base and suggesting how these should be rectified. Full article

Background: Lichen planus (LP) is a common inflammatory disease affecting skin, mucous membranes, hairs, and nails, with an unpredictable course involving remissions and relapses. LP is a Type-I-Inflammation disease involving IFN-γ and IL-17 as key inflammatory mediators. Materials and Methods: We searched PubMed/MEDLINE and Google Scholar search engines for studies on the esophageal manifestation of lichen planus over an unlimited time frame. Articles were searched with combinations of Medical Subject Heading (MeSH) terms. Given the limited number of publications, no exclusion criteria were applied. Results: Esophageal lichen planus (ELP) is an underreported manifestation of LP that primarily affects middle-aged women. Its prevalence among LP patients remains to be defined. Though potentially clinically silent, ELP can significantly impact patient wellbeing and serve as a precursor to esophageal squamous cell carcinoma. While dysphagia is the primary symptom, the condition may also remain subclinical. The endoscopic hallmarks of ELP are mucosal denudation and tearing, trachealization, and hyperkeratosis. Chronic disease progression may lead to scarring esophageal stenosis. Histologically, ELP shows mucosal detachment, T-lymphocytic infiltrations, epithelial cell apoptosis (Civatte bodies), dyskeratosis, and hyperkeratosis. Fibrinogen deposits along the basement membrane zone distinguish ELP from various immunological esophageal diseases. There is currently no standardized therapy available. Topical steroids lead to symptomatic and histologic improvements in two-thirds of patients. Severe or refractory cases require immunosuppressive therapy, whereas JAK-inhibitors represent a promising emerging option. Endoscopic dilation helps symptomatic stenosis. Considering ELP’s precancerous potential, timely diagnosis and treatment are crucial in preventing complications, such as stenosis or invasive esophageal squamous cell carcinoma. Conclusions: ELP is an underdiagnosed and underreported manifestation of LP. While it may remain clinically silent, it can nevertheless significantly affect patients’ wellbeing and life expectancy. This narrative review aims to initiate multidisciplinary cooperation among gastroenterologists, dermatologists, oral health professionals, and histopathologists to support clinical diagnosis and management. Full article

Background and Clinical Significance: Wolf–Hirschhorn syndrome (WHS, OMIM #194190) is caused by deletion of the distal short arm of chromosome 4. It is characterized by intrauterine growth restriction (IUGR), developmental delay, epilepsy, distinctive facial features, and urinary tract anomalies, particularly renal hypoplasia. However, the histological profile of renal involvement in WHS is rarely documented. Case presentation: We report a case of fetal WHS with renal hypoplasia and histological evidence of oligomeganephronia (OMN). At 21 weeks’ gestation, a prenatal ultrasound revealed oligo/anhydramnios and IUGR. Genetic testing (karyotype and CGH-array) confirmed a de novo 17.92 Mb terminal deletion from 4p16.3 to 4p15.31. The pregnancy was legally terminated at 23 weeks. The autopsy showed characteristic WHS dysmorphisms, growth restriction, and markedly small kidneys. Histology revealed OMN with a thinned renal cortex with reduced glomeruli, mainly hypoplastic, some of which were hypertrophic, and dilated proximal tubules. Scattered medullary tubules were present within the tubulointerstitial compartment, alongside thickened tubular basement membranes highlighted by Collagen IV staining. Conclusions: This case suggests that OMN may be a histological hallmark of renal hypoplasia in WHS, especially in larger 4p deletions. Recognizing this pattern may help with prenatal prognosis and clinical management. Further studies are needed to confirm this association. Full article

The cause of nephrotic–nephritic syndrome and elevated blood pressure values was investigated by renal biopsy in a 72-year-old Caucasian male with B-cell chronic lymphocytic leukemia (B-CLL) and a low level of IgG/lambda paraprotein. Double-contoured glomerular capillaries, glomerular thrombi, interstitial B-CLL infiltrates, and normal-looking arteries and arterioles were observed histologically. The glomerular capillaries displayed nonspecific entrapment of IgM and C3 and pseudolinear C4d positivity immunohistochemically. With electron microscopy, diffusely effaced foot processes, widened and duplicated glomerular basement membrane (BM), mesangial cell interposition, and thickened, non-fenestrated, and serrated endothelial cells located on subendothelial BM layer(s) were seen. The peritubular capillaries lacked any significant BM multilayering. Chronic glomerular thrombotic microangiopathy (TMA) was diagnosed; the C4d positivity result indicated structural remodeling of glomerular capillary walls. Laboratory features of microangiopathic hemolytic anemia were absent. The functional complement assay found selective classical pathway activation and the consumption of early complement components. The components of the alternative pathway were not consumed. A disease-causing variant in the coding region of the complement C2 gene was screened, with negative results. The kidney function gradually deteriorated to stage 4 chronic kidney disease over a period of six months. Second-line treatment with ibrutinib markedly decreased the leukemic symptoms, stopped the production of paraprotein, and eliminated the nephrotic syndrome; the kidney function improved. The decreased activity of the classical pathway remained unchanged. The culprit of glomerular anomalies seemed to be the paraprotein, which acted as a nephrotoxic mediator and triggered glomerular TMA. A hypothetical pathophysiologic explanation of TMA is presented. The paraneoplastic classical pathway activation of complement did not play any role in the development of glomerular TMA. Full article