Features Of Disease Research Articles

Prevalence and clinical features of gastroesophageal reflux disease in residents of the Makhachkala-Caspian agglomeration

Prevalence and clinical features of gastroesophageal reflux disease in residents of the Makhachkala-Caspian agglomeration

RXRα/MR signaling promotes diabetic kidney disease by facilitating renal tubular epithelial cells senescence and metabolic reprogramming

Cell senescence and metabolic reprogramming are significant features of diabetic kidney disease (DKD). However, the underlying mechanisms between cell senescence and metabolic reprogramming are poorly defined. Here, we report that retinoid X receptor α (RXRα), a key nuclear receptor transcription factor, regulates cell senescence and metabolic reprogramming in DKD. Through high-throughput sequencing, bioinformatic analysis and experimental validation, we confirmed the critical role of RXRα in promoting senescence and metabolic disturbances in renal tubular epithelial cells (RTECs) induced by lipid overload. In vivo, in situ injection of AAV9-shRxra into the kidney reduced proteinuria, RTECs senescence and insulin resistance in DKD mice. In vitro, knockdown of RXRα markedly improved G2/M phase arrest and suppressed the expression of senescence-associated secretory phenotypes (SASPs). Protein-protein interaction (PPI) analysis and unbiased bioinformatics were employed to identify the direct interactions between RXRα and the mineralocorticoid receptor (MR), which were subsequently validated through coimmunoprecipitation. Gene network analysis revealed the collaborative regulatory role of RXRα and MR in RTECs senescence. In an accelerated aging mouse model, an MR antagonist inhibited RXRα/MR signaling, improved RTECs senescence, and reduce interstitial fibrosis and lipid deposition in the kidneys. These findings indicate that inhibition of RXRα/MR signaling could alleviate cell senescence during metabolic disorders. Thus, our study revealed that RXRα/MR signaling serves as a critical regulatory factor mediating the crosstalk between cell senescence and metabolic reprogramming, shedding light on a novel mechanism for targeting cell senescence and metabolic dysregulation in DKD.

Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling.

This study addresses the contribution of mutant p53 to the process of cancer cell dissemination in physiologically relevant three-dimensional environments - a key characteristic of metastatic disease. Several mutant p53 proteins display pro-oncogenic activity with respect to cancer cell invasion in 3D environments via mevalonate pathway-dependent Rho/ROCK signaling axis.

A Gender Perspective on Coloproctological Diseases: A Narrative Review on Female Disorders.

Coloproctological diseases, including both benign and malignant conditions, are among the most common diagnoses in clinical practice. Several disorders affect both men and women, while others are unique to women, or women are at a greater risk of developing them. This is due to anatomical, biological, and social conditions and also due to females' exclusive capabilities of reproduction and pregnancy. In this context, the same proctological disease could differ between men and women, who can experience different perceptions of health and sickness. There is a raised awareness about the impact of different diseases in women and a growing need for a personalized approach to women's health. In this review, we aim to summarize the specific features of the main coloproctological diseases, specifically in the female population. This includes common complaints during pregnancy, conditions linked to vaginal delivery, functional consequences after colorectal resections, and conditions presenting a gender disposition.

Unexpected Presentations of Histiocytic Disorders as Mass Lesions in the Central Nervous System and Spine

Abstract Introduction/Objective A number of neoplastic and non-neoplastic hematolymphoid lesions can involve the CNS and spine. The majority are lymphomas, but some are rare lesions that mimic primary neoplasms clinically, radiologically, and even pathologically. Here, we present our experience of such cases. Methods/Case Report Pathology archives were searched, and five cases representing different challenges were identified to review clinical, radiological, and pathologic features. Case 1. 31-year-old female presented with vision changes and hearing loss and numerous supratentorial extra-axial masses, suspicious for meningiomatosis. Extensive lymphoplasmacytic infiltrate was seen at Intraoperative consult (IOC). Final diagnosis was Rosai-Dorfman disease with features of IgG4 related disease. Case 2. 31-year-old female with Chronic myeloid leukemia (CML), which progressed to AML presented with a right frontal brain mass. IOC displayed atypical hematolymphoid infiltrate. Final diagnosis was myeloid sarcoma. Case 3. 29-year-old male presented with a T10 vertebral lesion. IOC showed hypercellular tissue with atypia and was deferred. Subsequently, histiocytic sarcoma was diagnosed. Case 4. 22-year- old male presented with a T3-T4 intradural, extramedullary mass radiologically thought to be a meningioma. No IOC was requested. Final diagnosis was juvenile xanthogranuloma. Case 5. 36-year-old male presented with a C7-T1 dura-based mass. IOC revealed granulomatous inflammation, eventually resulting in a diagnosis of non-necrotizing granulomatous inflammation, suggesting sarcoidosis. Results (if a Case Study enter NA) NA Conclusion These cases highlight the importance of incorporating all clinical and radiological findings into pathologic evaluation, while being alert for mimickers and pitfalls. Both practicing general surgical pathologists and neuropathologists should remain alert to such unexpected and unusual cases especially at the time of IOC and initiate appropriate work-up with expedited diagnostic protocols such as intraoperative cultures, flow cytometry, and cytogenetics, as the differential diagnosis is broad with inflammatory, infectious, and neoplastic possibilities, presenting a variety of challenges.

Proteome Aggregation in Cells Derived from Amyotrophic Lateral Sclerosis Patients for Personalized Drug Evaluation.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP. The results provide valuable insight into the different characterization of sporadic and genetic ALS patients' immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients' cells.

Proposed Immunopathogenetic Mechanisms Underlying Lyme Arthritis

Abstract Lyme disease is commonly associated with musculoskeletal features, inflammatory and noninflammatory. The precise pathogenesis of the clinical features of this infection are complex and often multiple. A better understanding of how Borrelia burgdorferi causes these musculoskeletal manifestations is necessary in order to determine the proper treatment and eschew that which is unlikely to work, often associated with toxicities. The following review seeks to summarize the various immunopathogenic mechanisms that may cause these features of Lyme disease and suggests a series of approaches based on the most likely underlying mechanism(s).

Exposure to Gold Induces Autoantibodies against Nuclear Antigens in A.TL Mice.

To demonstrate causation or/and assess pathogenic mechanisms of environment-induced autoimmunity, various animal models that mimic the characteristics of the human autoimmune diseases need to be developed. Experimental studies in mice reveal the genetic factors that contribute to autoimmune diseases. Here, the immune response of two mouse strains congenic for non-H-2 genes, A.TL (H-2tl) and A.SW (H-2s), was evaluated after 15 weeks' exposure to gold aurothiomalate (AuTM). AuTM-treated A.TL mice showed anti-nuclear antibodies (ANA) with homogenous and/or fine speckled staining patterns and serum autoantibodies to ds-DNA, chromatin, histones, and ribonucleoproteins (RNP). Female A.TL mice showed a stronger immune response than males, as well as an increase of B cells in their spleen after 15 weeks of gold exposure. A.SW exposed for AuTM showed the induction of anti-nucleolar antibodies (ANoA) with a clumpy staining pattern, as well as an increase in splenic B and T cells. The serum autoantibodies levels in A.SW mice were limited compared to those of A.TL mice. Overall, A.TL presents a stronger immune response after gold exposure than A.SW. The immune response developed in A.TL presents similarities with the clinical manifestations in human autoimmune diseases. Thus, gold-exposed A.TL could constitute a potential experimental mouse model for the study of autoimmunity.

Relation of CMV and brain atrophy to trajectories of immunosenescence in diverse populations.

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach. Most results are consistent across the three populations, but some cell populations display evidence of heterogeneity, such as a PD-L1 + CD56 + NK cell subset. The study estimated "Immunological Age" (IA) during physiologic aging. While we found no relation of IA to Multiple Sclerosis, IA is associated with entorhinal cortex atrophy, a presymptomatic feature of Alzheimer's disease, linking neurodegeneration and peripheral immunity. ISC trajectories were also inferred, highlighting age, CMV status, and genetic ancestry as key influences. Our assessment offers reference ISC trajectories for personalization of assessments of immune function over the life course in diverse populations.

A multi-class fundus disease classification system based on an adaptive scale discriminator and hybrid loss

Fundus images are crucial in the observation and detection of ophthalmic diseases. However, detecting multiple ophthalmic diseases from fundus images using deep learning techniques is a complex and challenging task One challenge is the complexity of fundus disease structures, which leads to low detection accuracy. Another challenge is the class imbalance problem common in multi-label image classification, which increases the difficulty of algorithm training and evaluation. To address these issues, this study leverages deep learning to propose an ophthalmic disease classification system. We first employ ResNet50 as the backbone network to extract image features, and then use our designed multi-dimensional attention module and adaptive scale discriminator to enhance the network's ability to detect disease features. During training, we innovatively propose a hybrid loss function method to improve the detection capability on imbalanced data. Finally, we conducted experiments on the ODRI-5K dataset with the proposed classification system. In the test set, our method achieved an AUC of 98.53 and an F1-score of 89.73. This result fully demonstrates the excellent disease classification capability of our method. In summary, the multi-label fundus image disease classification system we proposed exhibits outstanding recognition capability, providing an effective solution for the diagnosis of multi-label fundus image diseases.

Temporal distribution characteristics of hand, foot and mouth disease in Beijing, 2008-2023

Objective: To analyze the temporal distribution characteristics of hand, foot and mouth disease (HFMD) in Beijing and provide reference evidence in HFMD prevention and control. Methods: The monthly incidence data of HFMD in Beijing from 2008 to 2023 were collected from Notifiable Disease Management Information System of the Chinese Information System of Disease Control and Prevention, and the epidemiological characteristics of HFMD were analyzed by the methods of time series seasonal decomposition graph, concentration degree, and circular distribution.The WPS office software 2019 was used to clean the data, Python software 3.12 was used to analyze and make statistical charts. Results: The monthly incidence fluctuation of HFMD in Beijing from 2008 to 2015 was higher than that from 2016 to 2022. From 2016 to 2022, the fluctuation range of monthly incidence showed a gradually decreasing trend.From 2008 to 2015, the concentration (M) was 0.58, indicating a relatively strong seasonality; the mean angle (α) calculated by the circular distribution method was 174.95°, and the mean angle standard deviation (s) was 60.43°. The annual incidence peak occurred on June 27, and the incidence peak period was from April 27 to August 27. From 2016 to 2019 and 2023, the M was 0.57, indicating a relatively strong seasonality. The α was 228.05°, and s was 61.44°. The annual incidence peak occurred on August 20, and the incidence peak period was from June 18 to October 21. From 2020 to 2022, the M was 0.42, indicating a seasonality, the α was 238.27° and s was 76.35°. The annual incidence peak occurred on July 15, and the incidence peak period was from June 14 to November 14. The α of 2008-2015, 2016-2019 and 2023, and 2020-2022 were tested by the Watson-Williams method and the difference was statistically significant (F=33 443.09, P<0.001). In 2023, the M was 0.77, indicating a strong seasonality. The incidence peak occurred on September 16, and the incidence peak period was from August 5 to October 28. Conclusions: The seasonality of HFMD in Beijing was obvious from 2008 to 2023, and the incidence peak day and peak period overall had rearward shifts. It is necessary to strengthen the comprehensive analysis of the distribution characteristics at different dimensions and the comprehensive prevention and control in key areas, places, and populations during the peak incidence period.

Late-onset renal TMA and tubular injury in cobalamin C disease: a report of three cases and literature review

BackgroundMutation of MMACHC gene causes cobalamin C disease (cblC), an inherited metabolic disorder, which presents as combined methylmalonic aciduria (MMA-uria) and hyperhomocysteinaemia in clinical. Renal complications may also be present in patients with this inborn deficiency. The most common histological change is thrombotic microangiopathy (TMA). However, to our acknowledge, renal tubular injury in the late-onset presentation of cblC is rarely been reported. This study provides a detailed description of the characteristics of kidney disease in cblC deficiency, aiming to improve the early recognition of this treatable disease for clinical nephrologists.Case presentationHere we described three teenage patients who presented with hematuria, proteinuria, and hypertension in clinical presentation. They were diagnosed with renal involvement due to cblC deficiency after laboratory tests revealing elevated serum and urine homocysteine, renal biopsy showing TMA and tubular injury, along with genetic testing showing heterogeneous compound mutations in MMACHC. Hydroxocobalamin, betaine, and L-carnitine were administered to these patients. All of them got improved, with decreased homocysteine, controlled blood pressure, and kidney outcomes recovered.ConclusionsThe clinical diagnosis of cblC disease associated with kidney injury should be considered in patients with unclear TMA accompanied by a high concentration of serum homocysteine, even in teenagers or adults. Early diagnosis and timely intervention are vital to improving the prognosis of cobalamin C disease.Clinical Trial NumberNot applicable.

Mannose coated selenium nanoparticles normalize intestinal homeostasis in mice and mitigate colitis by inhibiting NF-κB activation and enhancing glutathione peroxidase expression

Impaired intestinal homeostasis is a major pathological feature of inflammatory bowel diseases (IBD). Mannose and selenium (Se) both demonstrate potential anti-inflammatory and anti-oxidative properties. However, most lectin receptors bind free monosaccharide ligands with relatively low affinity and most Se species induce side effects beyond a very narrow range of dosage. This has contributed to a poorly explored therapies for IBD that combine mannose and Se to target intestinal epithelial cells (IECs) for normalization gut homeostasis. Herein, a facile and safe strategy for ulcerative colitis (UC) treatment was developed using optimized, mannose-functionalized Se nanoparticles (M-SeNPs) encapsulated within a colon-targeted hydrogel delivery system containing alginate (SA) and chitosan (CS). This biocompatible nanosystem was efficiently taken up by IECs and led to increased expression of Se-dependent glutathione peroxidases (GPXs), thereby modulating IECs’ immune response. Using a mouse model of DSS-induced colitis, (CS/SA)-embedding M-SeNPs (C/S-MSe) were found to mitigate oxidative stress and inflammation through the inhibition of the NF-kB pathway in the colon. This stabilized mucosal homeostasis of IECs and ameliorated colitis-related symptoms, thereby providing a potential new approach for treatment of IBD.

Biologic Correlates of Radiologic Features of Systemic Sclerosis Interstitial Lung Disease

Background and objectivesThe extent and pattern of radiological features (e.g., fibrosis, ground glass) can influence treatment approaches for systemic sclerosis-related interstitial lung disease (SSc-ILD). However, the pathobiology underlying these radiologic features is poorly understood and warrants further investigation.MethodsSixty-eight proteins were measured in bronchoalveolar lavage (BAL) fluid from 103 SSc-ILD participants in Scleroderma Lung Study I. Quantitative image analysis calculated the extent of fibrosis (QLF) and ground glass opacity (QGG) from concurrent high-resolution computerized tomography (HRCT) scans. The relationship between BAL proteins and quantitative HRCT scores was assessed by univariate and multivariate analyses.ResultsQLF scores correlated weakly with the extent of QGG, suggesting two distinct processes. In a univariate analysis, 25 proteins from several biologic pathways correlated with QLF scores, including pro-fibrotic factors, tissue remodeling proteins, proteins involved in monocyte/macrophage migration and activation, and proteins linked to inflammation and immune regulation. In contrast, QGG scores correlated with only 6 proteins of which four were unique and related to granulocyte activation, mobilization of bone marrow mesenchymal stem cells, and activation of T cells, B cells, macrophages and eosinophils. In the multivariate models, IL-4, CCL7, receptor activator of NF-κB, and tumor necrosis factor alpha were independently associated with QLF, whereas, IFN-γ was independently associated with QGG.InterpretationQLF and QGG represent distinct radiologic features of SSc-ILD, a conclusion reinforced by the presence of different biologic pathways present within BAL fluid that associate with each. The identified proteins and related biologic pathways may represent important therapeutic targets.

IMMUNE AND MOLECULAR CORRELATES OF RESPONSE TO IMMUNOTHERAPY REVEALED BY BRAIN-METASTATIC MELANOMA MODELS.

Despite the promising results of immune checkpoint blockade (ICB) therapy, outcomes for patients with brain metastasis (BrM) remain poor. Identifying resistance mechanisms has been hindered by limited access to patient samples and relevant preclinical models. Here, we developed two mouse melanoma BrM models that recapitulate the disparate responses to ICB seen in patients. We demonstrate that these models capture the cellular and molecular complexity of human disease and reveal key factors shaping the tumor microenvironment and influencing ICB response. BR1-responsive tumor cells express inflammatory programs that polarize microglia into reactive states, eliciting robust T cell recruitment. In contrast, BR3-resistant melanoma cells are enriched in neurological programs and exploit tolerance mechanisms to maintain microglia homeostasis and limit T cell infiltration. In humans, BR1 and BR3 expression signatures correlate positively or negatively with T cell infiltration and BrM patient outcomes, respectively. Our study provides clinically relevant models and uncovers mechanistic insights into BrM ICB responses, offering potential biomarkers and therapeutic targets to improve therapy efficacy.

S100A2 activation promotes interstitial fibrosis in kidneys by FoxO1-mediated epithelial-mesenchymal transition

BackgroundRenal interstitial fibrosis (RIF) is a common feature of chronic kidney diseases (CKD), with epithelial-mesenchymal transition (EMT) being one of its important mechanisms. S100A2 is a protein associated with cell proliferation and differentiation, but its specific functions and molecular mechanisms in RIF remain to be determined.MethodsS100A2 levels were evaluated in three mouse models, including unilateral ureteral obstruction (UUO), ischemia-reperfusion injury (IRI), and aristolochic acid nephropathy (AAN), as well as in TGF-β1- treated HK-2 cells and in kidney tissue samples. Furthermore, the role of S100A2 and its interaction with FoxO1 was investigated using RT-qPCR, immunoblotting, immunofluorescence staining, co-immunoprecipitation (Co-IP), transcriptome sequencing, and gain- or loss-of-function approaches in vitro.ResultsElevated expression levels of S100A2 were observed in three mouse models and TGF-β1-treated HK2 cells, as well as in kidney tissue samples. Following siRNA silencing of S100A2, exposure to TGF-β1 in cultured HK-2 cells suppressed EMT process and extracellular matrix (ECM) accumulation. Conversely, Overexpression of S100A2 induced EMT and ECM deposition. Notably, we identified that S100A2-mediated EMT depends on FoxO1. Immunofluorescence staining indicated that S100A2 and FoxO1 colocalized in the nucleus and cytoplasm, and their interaction was verified in Co-IP assay. S100A2 knockdown decreased TGF-β1-induced phosphorylation of FoxO1 and increased its protein expression, whereas S100A2 overexpression hampered FoxO1 activation. Furthermore, pharmacological blockade of FoxO1 rescued the induction of TGF-β1 on EMT and ECM deposition in S100A2 siRNA-treated cells.ConclusionS100A2 activation exacerbates interstitial fibrosis in kidneys by facilitating FoxO1-mediated EMT.Graphical abstractA schematic diagram of the underlying mechanisms by which S100A2 regulates EMT and renal fibrosis. Following injury, the cytoplasmic expression of S100A2 in renal tubular epithelial cells is markedly elevated. This increase promotes the phosphorylation of FoxO1, preventing its translocation into the nucleus and enhances EMT and extracellular matrix ECM deposition, thereby exacerbating renal interstitial fibrosis.

Elevated Circulating Levels of Gut Microbe-Derived Trimethylamine N-Oxide Are Associated with Systemic Sclerosis.

Background/Objectives: Alterations in fecal microbial communities in patients with systemic sclerosis (SSc) are common, but the clinical significance of this observation is poorly understood. Gut microbial production of trimethylamine (TMA), and its conversion by the host to trimethylamine N-oxide (TMAO), has clinical and mechanistic links to cardiovascular and renal diseases. Direct provision of TMAO has been shown to promote fibrosis and vascular injury, hallmarks of SSc. We sought to determine levels of TMAO and related metabolites in SSc patients and investigate associations between the metabolite levels with disease features. Methods: This is an observational case:control study. Adults with SSc (n = 200) and non-SSc controls (n = 400) were matched for age, sex, indices of renal function, diabetes mellitus, and cardiovascular disease. Serum TMAO, choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine were measured using stable isotope dilution liquid chromatography tandem mass spectrometry. Results: Median TMAO concentration was higher (p = 0.020) in SSc patients (3.31 [interquartile range 2.18, 5.23] µM) relative to controls (2.85 [IQR 1.88, 4.54] µM). TMAO was highest among obese and male SSc participants compared to all other groups. Following adjustment for sex, BMI, age, race, and eGFR in a quantile regression model, elevated TMAO levels remained associated with SSc at each quantile of TMAO. Conclusions: Patients with SSc have increased circulating levels of TMAO independent of comorbidities including age, sex, renal function, diabetes mellitus, and cardiovascular disease. As a potentially modifiable factor, further studies examining the link between TMAO and SSc disease severity and course are warranted.

Automated mental health screening in pediatric lupus: associations with disease features and treatment.

Patients with childhood-onset systemic lupus erythematosus (c-SLE) have higher rates of depression than their peers, which has been associated with worse medical outcomes. Therefore, it is imperative that their mental health be addressed. We utilized quality improvement (QI) methodology to automate mental health screening for patients with lupus within a pediatric rheumatology clinic. The retrospective cohort study aims to evaluate the association between mental health screening outcomes and demographics, medications, and disease activity measures in patients with childhood lupus. The mental health QI team at a quaternary pediatric rheumatology center implemented an automated process for mental health screening in patients with c-SLE. Patients seen between 2017 and June 2023 with a diagnosis of c-SLE were identified using International Classification of Disease -Clinical Modification (ICD-CM) codes. Disease activity was assessed with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K). Medications were identified on outpatient and inpatient orders for conventional synthetic and biologic disease-modifying anti-rheumatic drugs, hydroxychloroquine, corticosteroids, and aspirin. Mental health screening was accomplished with the Patient Health Questionnaire (PHQ). Descriptive statistics, univariate and multivariate linear regression were used. Between January 2017 and June 2023, 117 patients with c-SLE (41% with lupus nephritis) completed 534 total screenings. Each patient completed PHQ screenings, a median of 5 [interquartile range 2, 6] times. Screening increased when the screening process was automated. Those who were Black, female, or prescribed leflunomide, mycophenolate, and corticosteroids had higher PHQ scores. Mental health support is essential for patients with chronic rheumatologic diseases such as SLE. Sustainable processes for quickly identifying depression are needed for optimal care of patients with SLE. Our process of automated, streamlined mental health screening successfully increased the screening of patients with SLE at every visit and led to timely interventions for positive PHQ scores. Higher PHQ scores were correlated with patients on leflunomide, mycophenolate, and corticosteroids. Future research should identify modifiable risk factors for high PHQ scores that the medical team can target.

Clinical correlates and pathology of non-diabetic renal disease in diabetes mellitus

Objectives: Early identification and differentiation of patients with non-diabetic renal disease (NDRD) from diabetic nephropathy (DN) or those with NDRD superimposed on DN improves the prognosis and reduces associated morbidity. The objectives of the study were to compare the clinical profile, nature of renal involvement, and etiopathogenesis (renal biopsy) of patients with isolated NDRD and NDRD superimposed on DN. Materials and Methods: It is a descriptive study in patients with T2D and renal involvement suggestive of non-diabetic etiology further evaluated with renal biopsy and grouped as NDRD alone or NDRD with DN. Results: Of the total 50, 66% were male, the mean age was 55.57 ± 12.28 years, and all were proteinuric. Overall, isolated NDRD and NDRD superimposed on DN were observed in 64% and 36% of patients, respectively. Diabetic retinopathy was absent in 82% of cases. The most common finding in isolated NDRD was membranous nephropathy, followed by immunoglobulin A (IgA) nephropathy and rapid progression of glomerular nephritis (RPGN). At the same time, in the NDRD and DN group, maximum patients displayed IgA nephropathy followed by acute tubular necrosis and RPGN. The incidence of atypical features of renal disease was almost twice as high in the isolated NDRD group than in the group with both NDRD + DN. Conclusion: NDRDs are highly prevalent, and DN may superimpose these. Recognizing NDRD solely on the basis of clinical indicators is challenging. Therefore, histopathological analysis seems essential to accurately diagnose NDRD in diabetic patients to reduce the probability of missed NDRD diagnosis and initiate prompt treatment.

α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson's disease.

Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson's disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. aSYN PFFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.