Anti-Neuronal IgG4 Autoimmune Diseases and IgG4-Related Diseases May Not Be Part of the Same Spectrum: A Comparative Study

BackgroundIgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features.MethodsWe collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD.ResultsA significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, p = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD.ConclusionOur observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.

Performance Evaluation of the KRYPTOR Compact PLUS Analyzer-Based B.R.A.H.M.S. CgA Ⅱ KRYPTOR Assay for Chromogranin A Measurement

Numerous immunoassays have been developed to measure the levels of chromogranin A (CgA), a useful biomarker for diagnosing and monitoring generally heterogeneous neuroendocrine tumors (NETs). Here, we evaluated the imprecision and linearity of three such assays: KRYPTOR (ThermoFisher Scientific), NEOLISA (EuroDiagnostica), and CgA-RIA (CisBio), using 123 samples for each assay. The correlation coefficients between the assays were 0.932 (CgA-RIA versus NEOLISA), 0.956 (KRYPTOR versus CgA-RIA), and 0.873 (NEOLISA versus KRYPTOR). KRYPTOR showed good precision, with percent coefficients of variation less than 5% for low and high concentration quality controls. Linearity was maintained over a wide concentration range. Comparison of CgA levels from three disease entities (NETs, non-NET pancreatic tumors, and prostate cancer) and healthy controls showed that patients with NETs had significantly higher CgA levels (n = 57, mean: 1.82 ± 0.43 log ng/mL) than healthy individuals (n = 20, mean: 1.51 ± 0.23 log ng/mL; p = 0.018). No other significant differences between groups were observed. All three immunoassays showed strong correlations in measured CgA levels. Because KRYPTOR operation uses a fully automated random-access system and requires shorter incubation times and smaller sample volumes, the KRYPTOR assay may improve laboratory workflow while maintaining satisfactory analytical performance.

Comparison of Necrotizing Enterocolitis in Pre-mature Infants vs. Term-Born Infants With Congenital Heart Disease

Purpose: Necrotizing enterocolitis (NEC) is a serious illness that occurs among premature infants and term-born infants with congenital heart disease (CHD). Prior studies have suggested these two groups may experience different disease entities. We sought to evaluate if there are differences in disease characteristics between these two populations.Materials and Methods: A retrospective chart review of infants treated for Bells stage 2-3 NEC from 2011 to 2020 was performed. Demographic information, CHD diagnoses and clinical data were recorded. Prior to data analysis, patients were divided into two groups: term-born patients with CHD (TC) and premature patients without CHD (PT).Results: 99 patients were analyzed−23 TC patients and 76 PT patients. Platelet counts (222.7 ± 176.1 vs. 310.2 ± 174.5 cells/uL, P = 0.03) and C-reactive protein (CRP) levels (53.6 ± 81.7 vs. 117.6 ± 90.4 mg/L, P < 0.001) were significantly higher among the PT group. In addition, PT patients were more likely to develop pneumatosis (30.4 vs. 68.4%, P = 0.002) than TC patients. NEC-specific mortality was similar between both groups of patients.Conclusions: When compared to TC patients, PT patients had higher CRP levels, higher platelet counts and more commonly developed pneumatosis. These factors may point toward a difference in disease pathophysiology regarding NEC development in premature patients vs. term-born patients with CHD.

The Important Role of Endothelium and Extracellular Vesicles in the Cellular Mechanism of Aortic Aneurysm Formation

Homeostasis is a fundamental property of biological systems consisting of the ability to maintain a dynamic balance of the environment of biochemical processes. The action of endogenous and exogenous factors can lead to internal balance disorder, which results in the activation of the immune system and the development of inflammatory response. Inflammation determines the disturbances in the structure of the vessel wall, connected with the change in their diameter. These disorders consist of accumulation in the space between the endothelium and the muscle cells of low-density lipoproteins (LDL), resulting in the formation of fatty streaks narrowing the lumen and restricting the blood flow in the area behind the structure. The effect of inflammation may also be pathological dilatation of the vessel wall associated with the development of aneurysms. Described disease entities strongly correlate with the increased migration of immune cells. Recent scientific research indicates the secretion of specific vesicular structures during migration activated by the inflammation. The review focuses on the link between endothelial dysfunction and the inflammatory response and the impact of these processes on the development of disease entities potentially related to the secretion of extracellular vesicles (EVs).

Three-Dimensional Super-Resolved Imaging of Paraffin-Embedded Kidney Samples

Background: Diseases of the glomeruli, the renal filtration units, are a leading cause of progressive kidney disease. Assessment of the ultrastructure of podocytes at the glomerular filtration barrier is essential for diagnosing diverse disease entities, providing insight into the disease pathogenesis as well as monitoring treatment responses. Methods: We here apply previously published sample preparation methods together with STED and confocal microscopy for resolving nanoscale podocyte substructure. The protocols are modified and optimized in order to be applied to samples which have been formalin fixed and paraffin-embedded (FFPE). Results: We successfully modify our protocols to allow for deep three-dimensional STED and confocal imaging of FFPE kidney tissue with similar staining and image quality as compared to our previous approaches. We further show that quantitative analysis can be applied to extract morphometrics of healthy and diseased samples from both mice and humans. Conclusions: The results from this study could increase the feasibility to implement optical kidney imaging protocols in clinical routines, as FFPE is the gold standard method for storage of patient samples.

Concept of Vidradhi WSR to abscess: an ayurvedic review

Ayurveda, a characteristic arrangement of medication, started in India over 3,000 years prior. The term Ayurveda is taken from the Sanskrit words ayur (life) and veda (science or information). In this manner, Ayurveda means information on life. In the wake of Collecting the information from various samhitas, ayurvedic texts and current books. Acharya sushruta- the father of Indian surgery has logically characterized in a foundational way an abundance of clinical material and the standards of the board for vidradhi, which are legitimate even today. "Sheegra vidhahivat'' meaning of vidradhi itself recommends the destructiveness of the disease. Vidradhi word is advanced from vidra, i.e, a painfull condition like pricking, stabbing or cutting sensation in the skin. The infection Vidradhi (abscess) is a typical infirmity disturbing mankind and debilitate the victim for his standard work. It presents as a limited expanding with torment, red discoloration,local rise of temperature, delicacy and confined capacity of impacted part. it is normal in India with second most noteworthy frequency because of helpless disinfection, stuffing and deficient sustenance. Around the world, roughly 40-50 million individuals are contaminated every year with amoebic abscesses. The current exploration article is intended for relative investigation of Vidradhi and Abscess as far as Samprapti (Pathophysiology), Lakshanas (Clinical elements) and Chikitsa (Treatment) affirms that Vidradhi and Abscess can be comparable disease entities.

Past, present and imaginary: Pathography in all its forms

Diagnosis is a profoundly social phenomenon which, while putatively identifying disease entities, also provides insights into how societies understand and explain health, illness and deviance. In this paper, we explore how diagnosis becomes part of popular culture through its use in many non-clinical settings. From historical diagnosis of long-deceased public personalities to media diagnoses of prominent politicians and even diagnostic analysis of fictitious characters, the diagnosis does meaningful social work, explaining diversity and legitimising deviance in the popular imagination. We discuss a range of diagnostic approaches from paleopathography to fictopathography, which all take place outside of the clinic. Through pathography, diagnosis creeps into widespread and everyday domains it has not occupied previously, performing medicalisation through popularisation. We describe how these pathographies capture, not the disorders of historical or fictitious figures, rather, the anxieties of a contemporary society, eager to explain deviance in ways that helps to make sense of the world, past, present and imaginary.

Primary Gastrointestinal T-Cell Lymphoma and Indolent Lymphoproliferative Disorders: Practical Diagnostic and Treatment Approaches

Primary gastrointestinal (GI) T-cell neoplasms are extremely rare heterogeneous disease entities with distinct clinicopathologic features. Given the different prognoses of various disease subtypes, clinicians and pathologists must be aware of the key characteristics of these neoplasms, despite their rarity. The two most common aggressive primary GI T-cell lymphomas are enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. In addition, extranodal natural killer (NK)/T-cell lymphoma of the nasal type and anaplastic large cell lymphoma may also occur in the GI tract or involve it secondarily. In the revised 4th World Health Organization classification, indolent T-cell lymphoproliferative disorder of the GI tract has been incorporated as a provisional entity. In this review, we summarize up-to-date clinicopathological features of these disease entities, including the molecular characteristics of primary GI T-cell lymphomas and indolent lymphoproliferative disorders. We focus on the latest treatment approaches, which have not been summarized in existing reviews. Further, we provide a comprehensive review of available literature to address the following questions: How can pathologists discriminate subtypes with different clinical prognoses? How can primary GI neoplasms be distinguished from secondary involvement? How can these neoplasms be distinguished from non-specific inflammatory changes at an early stage?

NcRNAs in Vascular and Valvular Intercellular Communication

Non-coding RNAs have been shown to be important biomarkers and mediators of many different disease entities, including cardiovascular (CV) diseases like atherosclerosis, aneurysms, and valvulopathies. Growing evidence suggests a central role of ncRNAs as regulators of different pathological pathways involved in endothelial dysfunction, cardiovascular inflammation, cell differentiation, and calcification. This review will discuss the role of protein-bound and extracellular vesicular-bound ncRNAs as biomarkers of vascular and valvular diseases, their role as intercellular communicators, and regulators of disease pathways and also highlights possible treatment strategies.

Artificial Intelligence-Assisted Mapping of Proliferation Centers in Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Identifies Patterns That Reliably Distinguish Accelerated Phase and Large Cell Transformation

Background Chronic lymphocytic leukemia (CLL) involving tissues is characterized by sheets of small lymphocytes and vague nodules of larger cells, known as proliferation centers (PCs). CLL can undergo progression to accelerated CLL (aCLL) or further progress to diffuse large B-cell lymphoma, also known as Richter transformation (RT). Distinguishing CLL with many PCs from aCLL or RT can be challenging, particularly in small needle-biopsy specimens. In this study, we sought to design an artificial intelligence (AI)-based tool to automate and enhance the delineation of PCs and provide an objective approach to CLL/SLL acceleration/transformation. Material & Methods We manually annotated 25, 28 and 21 regions of interest (ROIs) encompassing small round PCs and confluent/ expanded PCs of 10 CLL, 12 aCLL, and 8 RT digitized hematoxylin & eosin stained slides, respectively (Figure A1). We analyzed the ROIs with both length and width larger than 2,000 pixels and set the tile length and stride as 1,000 and 100 pixels, respectively (Figure A1), and were able to extract sufficient tiles from each ROI (Figure A2). To recreate PCs, after performing nuclear segmentation via convolutional neural network and quality control, we quantified the nuclear size/intensity of cells occupying each tile (Figure A3). Nuclear size varied from 8 to 108 square micrometers, and nuclear mean intensity varied from 0 to 255. We normalized both the values of nuclear size and mean intensity to 0.0 and 1.0, by subtracting the minimum value and dividing it by the value range length. Nuclear size and mean intensity were represented as S(celli) and Imean(celli), respectively. We estimated the heat value of one tile integrating nuclear and mean intensity using the equationin Figure A2. Results We generated heatmaps based on the heat values per tile inside each ROI from the 3 disease entities (CLL, aCLL and RT), as illustrated in Figures B1-4. Areas with high heat values (in the yellow spectrum) correspond to tiles harboring cells with increased nuclear size and mean intensity (PCs in CLL cases and expanded/ confluent PCs in aCLL and RT cases). In contrast, areas with low heat values (in the blue spectrum) correspond to tiles with decreased nuclear size and mean intensity (small neoplastic lymphocytes surrounding PCs) (Figure B4).We then generated a heat value histogram per tile for each ROI (Figure B5).Based on these results, the two optimal thresholds isolated to obtain the highest separation value among the three disease entities based on the optimal F-score were: 0.228, below which the case was most likely to be CLL, and 0.288, above which the case was most likely to be RT. Cases with heat values ranging between 0.228 and 0.288 were most likely aCLL cases. We then plotted the mean heat value frequencies of the 3 entities: There was a significant difference in the ranges of mean heat value frequencies for CLL, aCLL, and RT, which were 0.168 to 0.233, 0.212 to 0.307, and 0.261 to 0.353, respectively (Figure C). The accuracy and area under the curve diagnostic predictive values using data from nuclear size alone were 0.658 (+/-0.115) and 0.771 (+/-0.096), respectively; and using mean nuclear intensity, 0.679 (+/-0.094) and 0.841 (+/-0.052), respectively; with a noticeable increase using heat value frequencies (integrating the nuclear size and mean nuclear intensity) reaching 0.813 (+/-0.0630) and 0.885 (+/-0.109), respectively. Conclusion We describe a novel AI-based heatmap technique to objectively assess the extent of PCs in CLL, based on the integrative analysis of cell nuclear size and mean nuclear intensity. We suggest that an ROI mean heat value less than 0.228 is predictive of CLL, and more than 0.288 is predictive of RT. aCLL cases demonstrate a mean heat value ranging from 0.228 to 0.288. Using the mean heat value of all cases, we were able to reliably separate the three entities in question with robust diagnostic predictive values. Figure 1 Figure 1. Disclosures Khoury: Stemline Therapeutics: Research Funding; Kiromic: Research Funding; Angle: Research Funding.