Stages Of Disease Progression Research Articles

Abnormal saccade profiles in hereditary spinocerebellar degeneration reveal cerebellar contribution to visually guided saccades

ObjectiveTo study how the pathophysiology underlying hereditary spinocerebellar degeneration (spinocerebellar ataxia; SCA) with pure cerebellar manifestation evolves with disease progression using saccade recordings. MethodsWe recorded visually- (VGS) and memory-guided saccade (MGS) task performance in a homogeneous population of 20 genetically proven SCA patients (12 SCA6 and eight SCA31 patients) and 19 normal controls. ResultsFor VGS but not MGS, saccade latency and amplitude were increased and more variable than those in normal subjects, which correlated with cerebellar symptom severity assessed using the International Cooperative Ataxia Rating Scale (ICARS). Parameters with significant correlations with cerebellar symptoms showed an aggravation after disease stage progression (ICARS > 50). The saccade velocity profile exhibited shortened acceleration and prolonged deceleration, which also correlated with disease progression. The main sequence relationship between saccade amplitude and peak velocity as well as saccade inhibitory control were preserved. ConclusionsThe cerebellum may be involved in initiating VGS, which was aggravated acutely during disease stage progression. Dysfunction associated with disease progression occurs mainly in the cerebellum and brainstem interaction but may also eventually involve cortical saccade processing. SignificanceSaccade recording can reveal cerebellar pathophysiology underlying SCA with disease progression.

Association of Predisposing Factors of Diabetes with six Stages of Disease Progression in Ayurveda (Shatkriyakala): A Cross-Sectional Pilot Study

Introduction: Diabetes has emerged as a global health crisis. It not only causes morbidity and mortality figures but deteriorates quality of life, national productivity and economic burden too. Besides this, no major advancement has been made for early diagnosis and prevention of diabetes. Clinical Staging of morbidity has been depicted in classical texts of Ayurveda modelled on pathogenesis.) This type of classification can serve as the basis of levelled and precise preventive interventions. Thus, identification of cases pertaining to each stage of pathogenesis based on validated parameters is a prerequisite. This research is a preliminary work on validation of clinical staging. This Ayurveda system of staging method can serve as a holistic model of prevention as it includes variable responsible host factors, etiology, risk factor stratification and grading of pathological state. Aim: The present study aimed to explore the six stage pathogonomic model SKK (Shat kriyakala and its relevance in tracking pathogenesis at preclinical stages. Materials and methods: A cross-sectional trial was conducted in forty- two subjects. Study participants were subjected to a questionnaire (Q2) to assess clinical features in latent and clinical stages of Prameha (~ Diabetes Mellitus) and biomarkers (CRP and Serum cortisol).Result: The mean score of SKK questionnaire was found maximum with the corresponding stages designed on the basis of predisposing factors and laboratory parameters.Conclusion: It can be inferred from the study that SKK may act as a tool to check pathogenesis at an early stage. The model may act as a potential paradigm for preventing diabetes risk as well as preventive care from a public health perspective.

AYURVEDIC INSIGHTS: UNDERSTANDING THE PATHOGENESIS AND NATURAL MANAGEMENT OF HYPERTENSION

Hypertension, or high blood pressure, is a prevalent health concern worldwide. As medical advancements con-tinue, alternative systems of medicine like Ayurveda offer valuable insights into understanding and managing this condition. This article provides an in-depth exploration of the intersection between hypertension and Ayur-veda, emphasizing the holistic approach of this ancient healing system. The article begins by elucidating the pathogenesis of hypertension according to Ayurveda's Shat Kriya Kala, which encompasses six stages of disease progression. It delves into how doshic imbalances, particularly Pitta and Vata, accumulate and disrupt the cardi-ovascular system, leading to increased blood pressure. Furthermore, the article offers a comprehensive treatment protocol derived from Ayurvedic principles. Lifestyle modifications, such as regular exercise, balanced routines, stress management, and adequate sleep, play a crucial role in managing hypertension. Dietary recommendations focus on reducing salt intake, incorporating fresh fruits and vegetables, and including healthy fats. Herbal reme-dies like Ashwagandha, Arjuna, and Brahmi, known for their beneficial effects on blood pressure regulation, are discussed. Stress management techniques, including yoga asanas, pranayama, and meditation, are highlighted as effective tools for managing hypertension. Additionally, the article emphasizes the importance of personalized treatment and the role of qualified Ayurvedic practitioners in guiding individuals toward tailored interventions. It also suggests considering therapies like Panchakarma to detoxify the body and restore doshic equilibrium. By embracing Ayurveda's holistic approach, individuals can gain a deeper understanding of hypertension and ex-plore natural methods to restore balance and promote optimal blood pressure levels. Integrating the wisdom of Ayurveda with modern medical knowledge offers a comprehensive and personalized approach to hypertension management, contributing to overall well-being and vitality.

An application of soliton solutions of a differential equation in the progression of aortic dissection

Aortic dissection is a serious pathology involving the vessel wall of the aorta with significant societal impact. To understand aortic dissection, we explain the role of the dynamic pathology in the absence or presence of structural and/or functional abnormalities. We frame a differential equation to evaluate the impact of mean blood pressure on the aortic wall and prove the existence and uniqueness of its solution for homeostatic recoil and relaxation for infinitesimal aortic tissue. We model and analyze a generalized (3 + 1)‐dimensional nonlinear partial differential equation for aortic wave dynamics. We use the Lie group of transformations on this nonlinear evolution equation to obtain invariant solutions, traveling wave solutions including solitons. We find that abnormalities in the dynamic pathology of aortic dissection act as triggers for the progression of disease in the early stage through the formation of soliton‐like pulses and their interaction. We address the role of unstable wavefields in waveform dynamics when waves are unidirectional. Moreover, the notion of dynamic pathology within the domain of vascular geometry may explain the evolution of aneurysms in cerebral arteries and cardiomyopathies even in the absence of anatomical and physiological abnormalities.

The direct influence of retinal degeneration on electrical stimulation efficacy: Significant implications for retinal prostheses.

Photoreceptor loss and inner retinal network remodeling severely impacts the ability of retinal prosthetic devices to create artificial vision. We developed a computational model of a degenerating retina based on rodent data and tested its response to retinal electrical stimulation. This model includes detailed network connectivity and diverse neural intrinsic properties, capable of exploring how the degenerated retina influences the performance of electrical stimulation during the degeneration process. Our model suggests the possibility of quantitatively modulating retinal ON and OFF pathways between phase II and III of retinal degeneration without requiring any differences between ON and OFF RGC intrinsic cellular properties. The model also provided insights about how remodeling events influence stage-dependent differential electrical responses of ON and OFF pathways.Clinical Relevance-This data-driven model can guide future development of retinal prostheses and stimulation strategies that may benefit patients at different stages of retinal disease progression, particularly in the early and mid-stages, thus increasing their global acceptance.

Accurate Prediction of Alzheimer's Disease Progression Trajectory via a Novel Encoder-Decoder LSTM Architecture.

With an increase in life expectancy, there has been an increase in the aged population globally, and around 10% of this population suffers from Alzheimer's disease. Alzheimer's hugely impacts the quality of life and well-being of older adults and their caregivers. Thus, it is an emerging challenge to improve the early diagnosis and prognosis of the disease. Detecting hidden patterns in complex multidimensional datasets using recent advancements in machine learning provides a tremendous opportunity to meet this crucial need. In this study, using multimodal features and an individual's clinical status on one or more time points, we aimed to predict the individual's cognitive test scores, changes in Magnetic Resonance Imaging features, and the individual's diagnostic status for the next three years. We presented a novel Encoder-Decoder Long Short-Term Memory deep-learning model architecture for implementing our prediction. We applied it to data from the Alzheimer's Disease Neuroimaging Initiative, comprising longitudinal data of 1737 participants and 12,741 instances. The proposed model was found to be competent, with a validation accuracy of 0.941, a multi-class area under the curve of 0.960, and a test accuracy of 0.88 in identifying the various stages of Alzheimer's disease progression in patients with an initially cognitively normal or mild cognitive impairment which is a significant improvement over previous methods.Clinical relevance- The proposed approach can help improve diagnostic understanding of Alzheimer's Disease progression and assist in the early detection of various stages of Alzheimer's Disease based on clinical heterogeneity.

MiR-124 as a Liquid Biopsy Prognostic Biomarker in Small Extracellular Vesicles from NSCLC Patients.

Despite advances in non-small cell lung cancer (NSCLC) research, this is still the most common cancer type that has been diagnosed up to date. microRNAs have emerged as useful clinical biomarkers in both tissue and liquid biopsy. However, there are no reliable predictive biomarkers for clinical use. We evaluated the preclinical use of seven candidate miRNAs previously identified by our group. We collected a total of 120 prospective samples from 88 NSCLC patients. miRNA levels were analyzed via qRT-PCR from tissue and blood samples. miR-124 gene target prediction was performed using RNA sequencing data from our group and interrogating data from 2952 NSCLC patients from two public databases. We found higher levels of all seven miRNAs in tissue compared to plasma samples, except for miR-124. Our findings indicate that levels of miR-124, both free-circulating and within exosomes, are increased throughout the progression of the disease, suggesting its potential as a marker of disease progression in both advanced and early stages. Our bioinformatics approach identified KPNA4 and SPOCK1 as potential miR-124 targets in NSCLC. miR-124 levels can be used to identify early-stage NSCLC patients at higher risk of relapse.

Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical and radiological recovery with oral folinic acid therapy and review of the literature

BackgroundNeurodegeneration due to cerebral folate transport deficiency is a rare autosomal recessive disorder caused by biallelic pathogenic variants in FOLR1. Onset typically occurs in late infancy and is characterized by psychomotor regression, epilepsy, and a hypomyelinating leukodystrophy on magnetic resonance imaging. If left untreated, progressive neurodegeneration occurs. However, early treatment with folinic acid has been shown to stabilize or reverse neurological features. Approximately thirty patients have been described worldwide. Here, we report the first two cases with genetically proven cerebral folate transport deficiency from South-Eastern Europe, describe the effect of oral folinic acid therapy on clinical and neuroradiological features and review the literature.ResultsTwo siblings presented in childhood with clinical and radiological findings consistent with a hypomyelinating leukodystrophy. Exome sequencing revealed a novel homozygous pathogenic variant in FOLR1 (c.465_466delinsTG; p.W156G), confirming the diagnosis of neurodegeneration due to cerebral folate transport deficiency. Folinic acid treatment was promptly initiated in both patients. The younger sibling was treated early in disease course at 2 years of age, and demonstrated complete recovery in clinical and MRI features. The older sibling, who was 8 years of age at the time of diagnosis and treatment, demonstrated partial but substantial improvements.ConclusionWe present the first account in the literature that early treatment initiation with oral folinic acid alone can result in complete neurological recovery of both clinical and radiological abnormalities in neurodegeneration due to cerebral folate deficiency. Moreover, through the report of these patients along with review of the literature, we provide information about the natural history of the disease with comparison of treatment effects at different stages of disease progression. This report also reinforces the importance of universal access to genetic testing to ensure prompt diagnoses for treatable disorders.

Estimated health economic impact of conducting urine albumin-to-creatinine ratio testing alongside estimated glomerular filtration rate testing in the early stages of chronic kidney disease in patients with type 2 diabetes

AimTo estimate the health economic impact of undertaking urine albumin-to-creatinine ratio (UACR) testing versus no UACR testing in early stages of chronic kidney disease (CKD) progression in patients with type 2 diabetes (T2D).MethodsAn economic model, taking a UK healthcare system perspective, estimated the impact of UACR testing on additional costs, clinical benefits measured as prevented dialyses and cardiovascular-related deaths, life years gained (LYg), LYg before kidney failure, and incremental cost-effectiveness ratio (ICER). Sixteen of the 18 Kidney Disease: Improving Global Outcomes (KDIGO) heatmap categories were considered separately, and grouped in health states according to CKD risk. Results were derived for current standard-of-care and emerging CKD therapies.ResultsThe cohort that adhered to both UACR and estimated glomerular filtration rate (eGFR) testing guidelines in early stages of CKD (n = 1000) was associated with approximately 500 LYg before kidney failure onset; costing approximately £2.5 M. ICERs across the KDIGO heatmap categories were approximately £5,000.LimitationsThis model used data from a comprehensive meta-analysis that was initiated more than 10 years ago (2009). While this was the most comprehensive source identified, recent changes in the treatment landscape, patient population and social determinants of CKD will not be captured. Furthermore, a narrow approach was taken, aligning included costs with UK NHS reference materials. This means that some direct and indirect drivers of costs in late-stage disease have been excluded.ConclusionsUACR testing in the early stages of CKD is cost effective in T2D patients. Emerging therapies with the potential to slow CKD progression, mean that optimal monitoring through UACR/eGFR testing will become increasingly important for accurate identification and timely treatment initiation, particularly for the highest-risk A3 category.

Amisulpride Decreases Tau Protein Hyperphosphorylation in the Brain of OXYS Rats.

In this study, OXYS rats of three ages (1, 3, and 6 months), a proven model of Alzheimer's disease (AD), at various stages of disease progression were used to thoroughly study the effects of amisulpride on behavior and tau protein phosphorylation. With the growing number of patients with AD, the problem of finding a cure is very acute. Neurodegeneration in AD has various causes, one of which is hyperphosphorylation of tau protein. This study aimed to investigate whether amisulpride would affect pathological tau phosphorylation in AD. We assessed the influence of chronic administration of amisulpride (3 weeks, 3 mg/kg per day, intraperitoneally)-a 5-HT7 receptor inverse agonist-on behavior and tau hyperphosphorylation in OXYS rats (at ages of 1, 3, and 6 months). Chronic administration of amisulpride dramatically decreased tau phosphorylation in the frontal cortex and hippocampus of 3-month-old OXYS rats. Additionally, in 1- and 3-month-old rats' hippocampi, amisulpride diminished the mRNA level of the Cdk5 gene encoding one of the main tau kinases involved in the 5-HT7 receptor-induced effect on tau phosphorylation. Thus, We found that chronic administration of amisulpride could reduce pathological tau hyperphosphorylation while reducing anxiety. We propose amisulpride to have therapeutic potential against AD and that it can be the most effective in the early stages of the disease.

Deriving Convergent and Divergent Metabolomic Correlates of Pulmonary Arterial Hypertension.

High-dimensional metabolomics analyses may identify convergent and divergent markers, potentially representing aligned or orthogonal disease pathways that underly conditions such as pulmonary arterial hypertension (PAH). Using a comprehensive PAH metabolomics dataset, we applied six different conventional and statistical learning techniques to identify analytes associated with key outcomes and compared the results. We found that certain conventional techniques, such as Bonferroni/FDR correction, prioritized metabolites that tended to be highly intercorrelated. Statistical learning techniques generally agreed with conventional techniques on the top-ranked metabolites, but were also more inclusive of different metabolite groups. In particular, conventional methods prioritized sterol and oxylipin metabolites in relation to idiopathic versus non-idiopathic PAH, whereas statistical learning methods tended to prioritize eicosanoid, bile acid, fatty acid, and fatty acyl ester metabolites. Our findings demonstrate how conventional and statistical learning techniques can offer both concordant or discordant results. In the case of a rare yet morbid condition, such as PAH, convergent metabolites may reflect common pathways to shared disease outcomes whereas divergent metabolites could signal either distinct etiologic mechanisms, different sub-phenotypes, or varying stages of disease progression. Notwithstanding the need to investigate the mechanisms underlying the observed results, our main findings suggest that a multi-method approach to statistical analyses of high-dimensional human metabolomics datasets could effectively broaden the scientific yield from a given study design.

Role of vascular endothelial growth factor B in nonalcoholic fatty liver disease and its potential value.

Nonalcoholic fatty liver disease (NAFLD) refers to fatty liver disease caused by liver injury factors other than alcohol. The disease is characterized by diffuse fat infiltration, including simple steatosis (no inflammatory fat deposition), nonalcoholic fatty hepatitis, liver fibrosis, and so on, which may cause liver cirrhosis, liver failure, and even liver cancer in the later stage of disease progression. At present, the pathogenesis of NAFLD is still being studied. The "two-hit" theory, represented by lipid metabolism disorder and inflammatory reactions, is gradually enriched by the "multiple-hit" theory, which includes multiple factors, such as insulin resistance and adipocyte dysfunction. In recent years, vascular endothelial growth factor B (VEGFB) has been reported to have the potential to regulate lipid metabolism and is expected to become a novel target for ameliorating metabolic diseases, such as obesity and type 2 diabetes. This review summarizes the regulatory role of VEGFB in the onset and development of NAFLD and illustrates its underlying molecular mechanism. In conclusion, the signaling pathway mediated by VEGFB in the liver may provide an innovative approach to the diagnosis and treatment of NAFLD.

Complex interactions of cellular players in chronic Graft-versus-Host Disease.

Chronic Graft-versus-Host Disease is a life-threatening inflammatory condition that affects many patients after allogeneic hematopoietic stem cell transplantation. Although we have made substantial progress in understanding disease pathogenesis and the role of specific immune cell subsets, treatment options are still limited. To date, we lack a global understanding of the interplay between the different cellular players involved, in the affected tissues and at different stages of disease development and progression. In this review we summarize our current knowledge on pathogenic and protective mechanisms elicited by the major involved immune subsets, being T cells, B cells, NK cells and antigen presenting cells, as well as the microbiome, with a special focus on intercellular communication of these cell types via extracellular vesicles as up-and-coming fields in chronic Graft-versus-Host Disease research. Lastly, we discuss the importance of understanding systemic and local aberrant cell communication during disease for defining better biomarkers and therapeutic targets, eventually enabling the design of personalized treatment schemes.

Cathepsin-K inhibition enhances anti-cancerous activity within oral squamous cell carcinoma cells: Uncloaking the potency of new K21 formulation

BackgroundThe ability of cancer cells to be invasive and metastasize depend on several factors, of which the action of protease activity takes center stage in disease progression. Purpose/objectiveTo analyze function of new K21 molecule in the invasive process of oral squamous cell carcinoma (OSCC) cell line. Materials & methodsThe Fusobacterium (ATCC 23726) streaks were made, and pellets were resuspended in Cal27 (ATCC CRL-2095) OSCC cell line spheroid cell microplate. Cells were seeded and Lysotracker staining performed for CathepsinK red channel. Cell and morphology were evaluated using Transmission Electron microscopy. Thiobarbituric acid assay was performed. OSCC was analyzed for Mic60. Raman spectra were collected from the cancer cell line. L929 dermal fibroblast cells were used for Scratch Assay. ELISA muti arrays were used for cytokines and matrix molecules. Internalization ability of fibroblast cells were also analyzed. Structure of K21 as a surfactant molecule with best docked poses were presented. ResultsDecrease in lysosomal staining was observed after 15 and 30 min of 0.1% treatment. Tumor clusters were associated with cell membrane destruction in K21 primed cells. There was functional silencing of Mic60 via K21, especially with 1% concentration with reduced cell migration and invasiveness. Raman intensity differences were seen at 700 cm−1, 1200 cm−1 and 1600 cm−1 regions. EVs were detected within presence of fibroblast cells amongst K21 groups. Wound area and wound closure showed the progress of wound healing. ConclusionOver expression of CatK can be reduced by a newly developed targeted K21 based drug delivery system leading to reduced migration and adhesion of oral squamous cell carcinoma cells. The K21 drug formulation can have great potential for cancer therapies due to targeting and cytotoxicity effects.

DISEASE MANAGEMENT THROUGH SHADKRIYAKALA: AN AYURVEDIC APPROACH

The term Kriya Kala refers to the diagnosis of the stage of disease progression. Shadkriyakala has six stages: Sanchaya, Prakopa, Prasara, Sthansamshraya, Vyaktavastha and Bhedawastha. Shad means 6 (number six), Kriya means action, and Kala means time or period Hence Shadkriyakala means "Appropriate time Periods to take action/treatment". The term Kriyakala, also known as Chikitsa Avasara Kala, means the stage of the necessity of treatment.1 The diagnosis in Ayurveda is not always based on the name of the disease but on nature or phenomenon. This phenomenon is described in the Samprapti terms of each patient's disease, covering the components of Dosha, Dushya, and Adhishtana. The main factors in the pathogenesis of the disease are Dosha and Dushya. Shad Kriyakala refers to the developmental stage of the disease process where the physician can intervene with the most accurate treatment and medicine to halt the progression of the disease process. By understanding the process of Shad Kriyakala, the pathological process can be stopped, and further complications avoided. Shad Kriyakala helps to stop the process of disease at a very early stage. The need for research for the validation of Shad kriyakala will benefit humanity in the long term

Predicting cognitive decline using neuropsychiatric symptoms in prodromal Lewy body disease

AbstractBackgroundNeuropsychiatric symptoms (NPS) in Lewy body diseases, including dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) dementia, occur frequently and at an early stage in disease progression. Such symptoms are significantly associated with quality of life, caregiver burden and functional limitations. Limited evidence exists, however, outlining the relationship between NPS and cognitive decline.MethodsData from 217 participants were derived from three cohort studies. Patients diagnosed with either MCI with Lewy bodies (MCI‐LB, n = 67), PD‐MCI (n = 56) or Alzheimer’s disease (MCI‐AD, n = 39) and a group of healthy older adults (n = 55) completed comprehensive neuropsychological and neuropsychiatric assessment and were followed up longitudinally for a median of three years. NPS identified at baseline by the Neuropsychiatric Inventory (NPI) were included as predictors in linear regressions and linear mixed effects models to assess the relationship between NPS and performance on a range of cognitive tests both at baseline and longitudinally.ResultsAt baseline, NPS were most prevalent and severe among the MCI‐LB group (49% with NPI score >4 in at least one symptom) and least prevalent in controls (7% with NPI score >4). Total NPI score was not related to baseline cognitive function in any domain in any group. Greater baseline total NPI score was associated with steeper rates of decline among PD‐MCI patients on a measure of processing speed (p = .01). Among healthy adults, only sleep disturbance was associated with steeper rates of decline on global cognition (p = .005). None of the patient groups showed any association between individual NPS and decline on a measure of global cognitive function.ConclusionsThe lack of a significant relationship found between NPS and either global cognitive function or decline in global cognition seen among MCI patients suggests that at this prodromal stage of disease, NPS appear to be of limited clinical impact and indicates that the mechanisms of cognitive and neuropsychiatric symptoms may differ in early Lewy body disease. Future work will investigate these mechanisms using multimodal imaging data from this cohort.

Establishment of repeated liver biopsy technique in experimental mice

Biopsy is a commonly used method for determining pathological diagnoses by directly using human tissues and cells. Biopsies are widely used to determine disease progression and treatment efficacy. Although organs and tissues are usually obtained by sacrifice during animal experiments, it is theoretically possible to use the same biopsy techniques in humans. In the present study, we examined the feasibility of performing four repeated liver biopsies in a spontaneous metabolic syndrome mouse model. Even though a small number of mice died accidently, most mice were able to undergo four liver biopsies without significant adverse events. We also performed three liver biopsies in mouse liver tumor carcinogen models at 4, 8, and 12 weeks of age. In addition to the sample collected at 16 weeks of age during sacrifice, we successfully collected four liver samples from the same mice at different stages of disease progression. The application of this liver biopsy technique might make it possible for direct evaluation of pathological conditions in the same individual over time, thereby reducing the number of experimental animals.

Mechanism of angiotensin-converting enzyme inhibitors in the treatment of dilated cardiomyopathy based on a protein interaction network and molecular docking.

Dilated cardiomyopathy (DCM) is a severe manifestation or intermediate stage of cardiovascular disease progression with a significantly poor prognosis. Based on a protein interaction network and molecular docking, the present study determined the genes and mechanism of action of angiotensin-converting enzyme inhibitors (ACEIs) in the treatment of DCM, providing a direction for future studies on ACEI drugs for DCM. This is a retrospective study. DCM samples and healthy controls were downloaded from the GSE42955 dataset, and the targets of the potential active ingredients were obtained from PubChem. Hub genes in ACEIs were analyzed by constructing network models and a protein-protein interaction (PPI) network using the STRING database and Cytoscape software. Molecular docking was performed using Autodock vina software. Twelve DCM samples and five control samples were finally included. A total of 62 intersected genes were obtained by intersecting the differentially expressed genes with six ACEI target genes. PPI analysis identified 15 intersecting hub genes from these 62 genes. Enrichment analysis showed that the hub genes were associated with T helper type 17 (Th17) cell differentiation as well as the nuclear factor kappa-B (NF-kappa B), interleukin 17 (IL-17), mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) (PI3K-Akt), and Toll-like receptor signaling pathways. Molecular docking indicated that the compound Benazepril to produce favorable interactions with TNF proteins with a relatively higher score (-8.3). This study primarily revealed that the preventive and curative effects of ACEI treatment on DCM could be realized through multiple targets and pathways, and its mechanism of action is related to genes such as TNF, vascular endothelial growth factor A (VEGFA), interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2), Cyclin D1 (CCND1), and AKT serine/threonine kinase 1 (AKT1), with immune- and inflammation-related signaling pathways involvement.

Physiological biomarkers of silent brain damage leading to cognitive impairment and Dementia – direct and accessible clinical evidence

AbstractBackgroundCognitive assessment is the best clinical tool to detect cognitive impairments, yet it is evident only at late stages of disease progression. In contrast, silent brain network changes occur at early stages of the disease and it is estimated that a large proportion of dementias may be prevented or at‐least delayed if detected during early pathophysiology stages. Neuroimaging studies have shown that silent brain network findings, including white matter hyperintensities, lacunar infarctions and temporal atrophy are evident before objective cognitive impairment is detected and even more in ‘at risk’ population with risk factors for dementia. We aimed to evaluate direct physiological biomarkers that provide accessible clinical evidence of silent brain network damage that precede clinical cognitive findings and provide early clinical biomarkers that can facilitate early interventions.MethodBrain network performance was evaluated in 168 subjects ‘at risk’ for developing dementia (Table 1). Direct electrophysiological imaging (“Delphi”) was used to measure magnetically induced brain network electrophysiological response. MRI scans included T1, T2, FLAIR, Diffusion Weighted Imaging (DWI) and (SWI). They were analysed according to Fazekas scale for white matter Hyperintensities (WMH), lacunar Infarctions and medial temporal lobe atrophy (MTA). Objective cognitive evaluations were performed by a neuropsychologist interview and a computerized cognitive battery (NeurotraxTM).ResultDirect electrophysiological imaging (“Delphi”) was able to distinguish between severities of different MRI detected silent brain network damage findings. Magnetically induced direct electrophysiological response wave form adherence (WFA) significantly decreased with increase in WMH (Fig.1A; p<0.0001) and increase in MTA levels (Fig.1B; p<0.0001). Furthermore, WFA significantly decreased in subjects with lacunar infarctions (Fig.1C; p<0.0001).ConclusionSilent brain network deficits preceding dementia and cognitive decline are widely under detected due to lack of accessible tools. Data presented in this study demonstrates “Delphi” technology’s ability to detect silent brain network damage findings and severity levels that are identified in MRI scans. “Delphi” is a clinically accessible, direct, and objective technology that can facilitate early detection, prevention, delayed progression and management of mild cognitive impairment and dementia.

Systematic Microbiome Dysbiosis Is Associated with IgA Nephropathy.

IgA nephropathy (IgAN) is reportedly associated with microbial dysbiosis. However, the microbiome dysregulation of IgAN patients across multiple niches remains unclear. To gain a systematic understanding of microbial dysbiosis, we conducted large-scale 16S rRNA gene sequencing in IgAN patients and healthy volunteers across 1,732 oral, pharynx, gut, and urine samples. We observed a niche-specific increase of several opportunistic pathogens, including Bergeyella and Capnocytophaga in the oral and pharynx, whereas some beneficial commensals decreased in IgAN patients. Similar alterations were also observed in the early versus advanced stage of chronic kidney disease (CKD) progression. Moreover, Bergeyella, Capnocytophaga, and Comamonas in the oral and pharynx were positively associated with creatinine and urea, indicating renal lesions. Random forest classifiers were developed by using the microbial abundance to predict IgAN, achieving an optimal accuracy of 0.879 in the discovery phase and 0.780 in the validation phase. IMPORTANCE This study provides microbial profiles of IgAN across multiple niches and underlines the potential of these biomarkers as promising, noninvasive tools with which to differentiate IgAN patients for clinical applications.