Clinical Manifestations Of Disease Research Articles

Routine Coronary Angiography and Functional Cardiac Tests before Resection of Abdominal Aortic Aneurysm in Patients without Symptoms of Myocardial Infarction

INTRODUCTION: Cardiac complications are leaders in the structure of mortality of patients after resection of abdominal aortic aneurysms (AAA). In recent years more data have been obtained on the possibility of performing invasive coronary angiography (CAG) as a method of preoperative assessment of the condition of the coronary arteries. AIM: To assess the tactics of routine CAG and preventive revascularization of the myocardium in comparison with non-invasive functional tests in patients without clinical manifestations of coronary heart disease (CHD) from positions of the hospital outcomes of AAA resections. MATERIALS AND METHODS: A retrospective study included 205 patients without clinical and instrumental signs of CHD who underwent AAA resection at National Medical Research Center of Surgery named after A. Vishnevsky in 2001–2021. Patients of the first group (n = 55) underwent CAG before AAA resection and, if significant stenosis of coronary arteries was detected, revascularization of the myocardium was performed. In patients of the second group (n = 71), only functional cardiac tests were conducted before the operation. Patients of the third group were operated on without additional evaluation of cardiac status. RESULTS: In 30.9% of patients of the first group, significant coronary lesions were detected, in 29.5% of them with the involvement of the left main coronary artery. This required 10 percutaneous coronary interventions and 5 coronary artery bypass surgeries, which made 27.0% of patients in this group. No cases of myocardial infarction were recorded in this group. In the second and third groups, one case of myocardial infarction in each group was recorded (p = 0.688). There was no significant difference in the postoperative mortality in all the groups (1.8%; 4.2%; 2.5%, respectively; p = 0.704). To this end, maximally invasive diagnostic tactics increased the average waiting time for AAA resection: 52.2 ± 6.0 days in groups without coronary angiography and myocardial revascularization versus 99.2 ± 13.0 days in the first group. CONCLUSION: In a cohort of patients without anamnestic and clinical manifestations of coronary artery disease, the tactics of routine coronary angiography followed by prophylactic myocardial revascularization did not improve the short-term results of AAA resection, while the waiting period for intervention on the abdominal aorta increased. Preoperative tactics with functional cardiac tests also did not affect the treatment results.

Diagnosis of Anxiety in COPD Patients: Usefulness of the HADS Test in Primary Care and Pulmonology Services

Anxiety disorders, characterized by excessive fear and anxiety, are increasingly recognized as significant comorbidities in chronic diseases such as chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the prevalence of anxiety in COPD patients referred from primary care centers to pulmonology services and to identify predictive factors for anxiety. This was a multicentric, observational, and prospective study in which 293 COPD patients were recruited, and they underwent comprehensive respiratory and smoking histories, spirometry, and anxiety assessments using the Hospital Anxiety and Depression Scale (HADS). The results showed a diagnosis of suspected anxiety in 85 patients (29.0%): 17 possible and 68 with a strong suspicion. The study found significant associations between anxiety and factors such as gender (women had a risk that was 3.5 times higher than men), weight, and body mass index (BMI). Disease severity, smoking status, and clinical manifestations did not significantly influence anxiety prevalence. These findings underscore the need for systematic psychological evaluations in COPD management and support the use of simple diagnostic tools like the HADS to facilitate referrals to mental health services. Addressing anxiety in COPD patients could potentially improve their quality of life and disease outcomes. This study highlights the importance of a multidisciplinary approach involving family medicine, pulmonology, and psychiatry to optimize COPD patient care and suggests that future research should focus on the impact of anxiety treatment on COPD progression. These insights call for integrating psychological assessments into routine clinical practice for comprehensive COPD management. The registration number is 10.14201/gredos.148549.

Serological immune biomarker for disease severity in dengue-infectedpediatric hospitalized patients.

Clinical manifestation of dengue disease ranges from asymptomatic, febrile fever without warning sign (DOS) to serious outcome dengue with warning sign (DWS) and severe disease (SD) leading to shock syndrome and death. The role of antibody response in natural dengue infection is complex and not completely understood. Here, we aimed to assess serological marker for disease severity. Antibody response of dengue-confirmed pediatric patients with acute secondary infection were evaluated against infecting virus, immature virus, and recombinant envelop protein. Immature virus antibody titers were significantly higher in DWS as compared to DOS (p = 0.0006). However, antibody titers against recombinant envelop protein were higher in DOS as compared to DWS, and antibody avidity was significantly higher against infecting virus in DOS. Serum samples of DOS patients displayed higher in vitro neutralization potential in plaque assay as compared to DWS, whereas DWS serum samples showed higher antibody-dependent enhancement in the in vitro enhancement assays. Thus, antibodies targeting immature virus can predict disease severity and could be used in early forecast of disease outcome using anenzyme-linked immunoassay assaysystem which is less laborious and cheaper than plaque assay system for correlates of protection and could help optimize medical care and resources.

Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies.

4-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R-tauopathies are progressive-supranuclear-palsy (PSP) and corticobasal-degeneration (CBD) characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aβ-negative patients with clinically diagnosed PSP variants (n=26) or Corticobasal Syndrome (CBS; n=25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol, to determine an early 0.5-2.5 min post-tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post-tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early-window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlasses. We determined tau epicenters as subcortical regions with highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicenters to cortical ROIs using a resting-state fMRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether i) higher subcortical tau-PET was associated with reduced cortical perfusion and ii) whether cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicenters. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicenters aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicenter showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

Cluster analysis of clinical, angiographic, and laboratory parameters in patients with ST-segment elevation myocardial infarction

IntroductionST-segment elevation myocardial infarction (STEMI) represents the most harmful clinical manifestation of coronary artery disease. Risk assessment plays a beneficial role in determining both the treatment approach and the appropriate time for discharge. Hierarchical agglomerative clustering (HAC), a machine learning algorithm, is an innovative approach employed for the categorization of patients with comparable clinical and laboratory features. The aim of the present study was to investigate the role of HAC in categorizing STEMI patients and to compare the results of these patients.MethodsA total of 3205 patients who were diagnosed with STEMI at the university hospital emergency clinic between 2015 and 2023 were included in the study. The patients were divided into 2 different phenotypic disease clusters using the HAC method, and their outcomes were compared.ResultsIn the present study, a total of 3205 STEMI patients were included; 2731 patients were in cluster 1, and 474 patients were in cluster 2. Mortality was observed in 147 (5.4%) patients in cluster 1 and 108 (23%) patients in cluster 2 (chi-square P value < 0.01). Survival analysis revealed that patients in cluster 2 had a significantly greater risk of death than patients in cluster 1 did (log-rank P < 0.001). After adjustment for age and sex in the Cox proportional hazards model, cluster 2 exhibited a notably greater risk of death than did cluster 1 (HR = 3.51, 95% CI = 2.71–4.54; P < 0.001).ConclusionOur study showed that the HAC method may be a potential tool for predicting one-month mortality in STEMI patients.

Deep learning-based quantification of osteonecrosis using magnetic resonance images in Gaucher disease

Gaucher disease is one of the most common lysosomal storage disorders. Osteonecrosis is a principal clinical manifestation of Gaucher disease and often leads to joint collapse and fractures. T1-weighted (T1w) modality in MRI is widely used to monitor bone involvement in Gaucher disease and to diagnose osteonecrosis. However, objective and quantitative methods for characterizing osteonecrosis are still limited. In this work, we present a deep learning-based quantification approach for the segmentation of osteonecrosis and the extraction of characteristic parameters. We first constructed two independent U-net models to segment the osteonecrosis and bone marrow unaffected by osteonecrosis (UBM) in spine and femur respectively, based on T1w images from patients in the UK national Gaucherite study database. We manually delineated parcellation maps including osteonecrosis and UBM from 364 T1w images (176 for spine, 188 for femur) as the training datasets, and the trained models were subsequently applied to all the 917 T1w images in the database. To quantify the segmentation, we calculated morphological parameters including the volume of osteonecrosis, the volume of UBM, and the fraction of total marrow occupied by osteonecrosis. Then, we examined the correlation between calculated features and the bone marrow burden score for marrow infiltration of the corresponding image, and no strong correlation was found. In addition, we analyzed the influence of splenectomy and the interval between the age at first symptom and the age of onset of treatment on the quantitative measurements of osteonecrosis. The results are consistent with previous studies, showing that prior splenectomy is closely associated with the fractional volume of osteonecrosis, and there is a positive relationship between the duration of untreated disease and the quantifications of osteonecrosis. We propose this technique as an efficient and reliable tool for assessing the extent of osteonecrosis in MR images of patients and improving prediction of clinically important adverse events.

Molecular detection of ovine gammaherpesvirus 2 in free ranging wild boars (Sus scrofa) from Southern Brazil.

Ovine gammaherpesvirus 2 (OvGHV2) is a member of Macavirus genus, subfamily Gammaherpesvirinae, family Herpesviridae, and causes sheep associated-malignant catarrhal fever (SA-MCF) in a wide range of ungulates. However, no descriptions of SA-MCF and/or infections due to OvGHV2 were identified in the wild boar (Sus scrofa). This study investigated the occurrence of OvGHV2 in the lungs (n = 44) of asymptomatic, free ranging wild boars captured in several regions of Paraná State, Southern Brazil. A PCR assay targeting the OvGHV2 tegument protein gene amplified OvGHV2 DNA in 4.55% (2/44) of the pulmonary tissues evaluated. Sequence analysis confirmed that the OvGHV2 strains herein identified have 98.4% deducedamino acid (aa) sequence identity with the prototype strain of OvGHV2 and 96.4-100% aa identity with similar strains of OvGHV2 detected in several animal species from diverse countries. These findings confirmed that these two wild boars were infected by OvGHV2, represent the first description of this infection in these animals, and add to the number of pathogens identified in this animal species. Furthermore, these findings contrast earlier descriptions of OvGHV2 in swine since in all previous reports the infected pigs demonstrated clinical manifestations of disease. Consequently, these wild boars from Southern Brazil were subclinically infected or suffered asymptomatic infections by OvGHV2.

Caesalpinia sappan Reduce Fever with An Anti-inflammatory and Antioxidant Mechanism: A Review

&lt;p&gt;&lt;em&gt;&lt;span lang="EN-US"&gt;Caesalpinia sappan L&lt;/span&gt;&lt;/em&gt;&lt;span lang="EN-US"&gt; (Sappan wood) is an herbal plant that has long been trusted by the public as an herbal medicine for tuberculosis, diarrhea, dysentery, skin infections, anemia, and other diseases by utilizing the decoction of &lt;em&gt;C.sappan&lt;/em&gt;. Sappan wood is an herbal plant widely used as a raw material for traditional medicinal products. Sappan wood has been reported to have substantial pharmacological effects in analgesic, antioxidant, antibacterial, anti-inflammatory, and anti-viral. Fever is a clinical manifestation of certain conditions or diseases characterized by increased body temperature above the normal range (36.5–37.5 °C). Many studies declare that antioxidant and anti-inflammatory activity in &lt;em&gt;C.sappan&lt;/em&gt; reduces oxidative stress and pro-inflammatory cytokines. This literature review shows that the antioxidant and anti-inflammatory properties of &lt;em&gt;C.sappan&lt;/em&gt; are linked to fever as a sign of illness. Literature review using the last ten years' Scopus, ScienceDirect, and Pubmed databases. There are as many as 20 journals regarding sappan wood's antioxidant and anti-inflammatory effects. Sappan wood has been shown to have an antioxidant effect by lowering reactive oxygen species levels via SOD, GPx, or CAT markers. It inhibits inflammation cytokines such as IL-1, IL-6, TNF-&lt;/span&gt;&lt;span lang="EN-US"&gt;𝝰&lt;/span&gt;&lt;span lang="EN-US"&gt;, and INF produced during fever. Sappan wood also has an anti-inflammatory effect by inhibiting PGE2 production when someone has a fever. The findings of our review state that &lt;em&gt;C.sappan&lt;/em&gt; can be used to treat fever for both of these reasons. The use of &lt;em&gt;C.sappan&lt;/em&gt; as a component in producing traditional health beverages has potential.&lt;/span&gt;&lt;/p&gt;

HIV/AIDS and its marker diseases-manifestations

An objective confirmation of the seriousness of the human community’s understanding of the global significance of such a «relatively young» infection as HIV/AIDS is the extensive discussions — the discussion of this seemingly purely medical problem at several meetings of the UN General Assembly, as well as the creation of a specialized UNAIDS program (of the United Nations AIDS Program) which this year published a final report entitled «In danger». It assessed the current situation with this infectious disease as an absolute threat to the entire modern human society. Objective — to conduct an analysis of professional publications of recent years regarding the modern clinical and epidemiological features of the clinical course of HIV-infection/AIDS and to determine organizational measures to ensure at least partial well-being of the public health of the population of Ukraine in wartime conditions and the conduct of active hostilities. It is important to emphasize to primary care physicians not only the significant variety of clinical manifestations of various forms of this acutely contagious viral pathology, but also the real possibility of visually diagnosing it — suspecting it at a daily outpatient polyclinic appointment, based on the clinical manifestations of numerous marker diseases already present on the skin and mucous membranes. Materials and methods. Official documents and scientific publications related to public health policy, approaches to overcoming the HIV/AIDS epidemic, dynamics of morbidity and specific manifestations and clinical course of certain marker dermatological manifestations of this viral pathology in Ukraine were analyzed. Results and discusion. The content of the analyzed professional publications indisputably shows that the problem of HIV/AIDS has gone far beyond the scope of the purely medical field and has acquired the status of national significance. A modern approach to improving the state of public health requires constant coordination of the efforts of different people, who at the same time have a wide range of professional skills in many different disciplines, as well as the ability to collaborate fruitfully with others in joint multiprofessional teams to achieve the common goal of overcoming this viral epidemic. Conclusions. The analysis of scientific publications of recent years on the problem of HIV/AIDS indicates an urgent need to consider this disease in the state public health system as a socially significant infectious disease of the whole organism, in which early visual identification on the skin of clinical manifestations of a number of marker dermatoses allows prompt suspicion, and then and to quickly confirm both the fact of HIV infection and to start a course of ART. This requires an interdisciplinary approach and systematic methodological cooperation of primary care physicians, dermatovenerologists, infectious disease specialists, and pathologists in the aspect of timely (early) diagnosis and complex therapy of this viral infectious pathology.

The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.

Impact of the host immune response on the development of equine herpesvirus myeloencephalopathy in horses.

Herpesviruses establish a well-adapted balance with their host's immune system. Despite this co-evolutionary balance, infections can lead to severe disease including neurological disorders in their natural host. In horses, equine herpesvirus 1 (EHV-1) causes respiratory disease, abortions, neonatal foal death and myeloencephalopathy (EHM) in ~10 % of acute infections worldwide. Many aspects of EHM pathogenesis and protection from EHM are still poorly understood. However, it has been shown that the incidence of EHM increases to >70 % in female horses >20 years of age. In this study we used old mares as an experimental equine EHV-1 model of EHM to identify host-specific factors contributing to EHM. Following experimental infection with the neuropathogenic strain EHV-1 Ab4, old mares and yearling horses were studied for 21 days post-infection. Nasal viral shedding and cell-associated viremia were assessed by quantitative PCR. Cytokine/chemokine responses were evaluated in nasal secretions and cerebrospinal fluid (CSF) by Luminex assay and in whole blood by quantitative real-time PCR. EHV-1-specific IgG sub-isotype responses were measured by ELISA. All young horses developed respiratory disease and a bi-phasic fever post-infection, but only 1/9 horses exhibited ataxia. In contrast, respiratory disease was absent in old mares, but all old mares developed EHM that resulted in euthanasia in 6/9 old mares. Old mares also presented significantly decreased nasal viral shedding but higher viremia coinciding with a single fever peak at the onset of viremia. According to clinical disease manifestation, horses were sorted into an EHM group (nine old horses and one young horse) and a non-EHM group (eight young horses) for assessment of host immune responses. Non-EHM horses showed an early upregulation of IFN-α (nasal secretions), IRF7/IRF9, IL-1β, CXCL10 and TBET (blood) in addition to an IFN-γ upregulation during viremia (blood). In contrast, IFN-α levels in nasal secretions of EHM horses were low and peak levels of IRF7, IRF9, CXCL10 and TGF-β (blood) coincided with viremia. Moreover, EHM horses showed significantly higher IL-10 levels in nasal secretions, peripheral blood mononuclear cells and CSF and higher serum IgG3/5 antibody titres compared to non-EHM horses. These results suggest that protection from EHM depends on timely induction of type 1 IFN and upregulation cytokines and chemokines that are representative of cellular immunity. In contrast, induction of regulatory or TH-2 type immunity appeared to correlate with an increased risk for EHM. It is likely that future vaccine development for protection from EHM must target shifting this 'at-risk' immunophenotype.

Exploring molecular mechanisms, therapeutic strategies, and clinical manifestations of Huntington's disease.

Huntington's disease (HD) is a paradigm of a genetic neurodegenerative disorder characterized by the expansion of CAG repeats in the HTT gene. This extensive review investigates the molecular complexities of HD by highlighting the pathogenic mechanisms initiated by the mutant huntingtin protein. Adverse outcomes of HD include mitochondrial dysfunction, compromised protein clearance, and disruption of intracellular signaling, consequently contributing to the gradual deterioration of neurons. Numerous therapeutic strategies, particularly precision medicine, are currently used for HD management. Antisense oligonucleotides, such as Tominersen, play a leading role in targeting and modulating the expression of mutant huntingtin. Despite the promise of these therapies, challenges persist, particularly in improving delivery systems and the necessity for long-term safety assessments. Considering the future landscape, the review delineates promising directions for HD research and treatment. Innovations such as Clustered regularly interspaced short palindromic repeats associated system therapies (CRISPR)-based genome editing and emerging neuroprotective approaches present unprecedented opportunities for intervention. Collaborative interdisciplinary endeavors and a more insightful understanding of HD pathogenesis are on the verge of reshaping the therapeutic landscape. As we navigate the intricate landscape of HD, this review serves as a guide for unraveling the intricacies of this disease and progressing toward transformative treatments.

Understanding Hepatic Porphyrias: Symptoms, Treatments, and Unmet Needs.

Hepatic porphyrias are a group of metabolic disorders that are characterized by overproduction and accumulation of porphyrin precursors in the liver. These porphyrins cause neurologic symptoms as well as cutaneous photosensitivity, and in some cases patients can experience life-threatening acute neurovisceral attacks. This review describes the acute hepatic porphyrias in detail, including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, as well as the hepatic porphyrias with cutaneous manifestations such as porphyria cutanea tarda and hepatoerythropoietic porphyria. Each section will cover disease prevalence, clinical manifestations, and current therapies, including strategies to manage symptoms. Finally, we review new and emerging treatment modalities, including gene therapy through use of adeno-associated vectors and chaperone therapies such as lipid nanoparticle and small interfering RNA-based therapeutics.

Preclinical evaluation of combined therapy with amiodarone and low-dose benznidazole in a mouse model of chronic Trypanosoma cruzi infection

Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC.

2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson's Disease.

Aggregative α-synuclein and incurring oxidative stress are pivotal cascading events, leading to dopaminergic (DAergic) neuronal loss and contributing to clinical manifestations of Parkinson's disease (PD). Our previous study demonstrated that 2-butoxytetrahydrofuran (2-BTHF), isolated from Holothuria scabra (H. scabra), could inhibit amyloid-β aggregation and its ensuing toxicity, which leads to Alzheimer's disease. In the present study, we found that 2-BTHF also attenuated the aggregative and oxidative activities of α-synuclein and lessened its toxicity in a transgenic Caenorhabditis elegans (C. elegans) PD model. Such worms treated with 100 μM of 2-BTHF showed substantial reductions in α-synuclein accumulation and DAergic neurodegeneration. Mechanistically, 2-BTHF, at this concentration, significantly decreased aggregation of monomeric α-synuclein and restored locomotion and dopamine-dependent behaviors. Molecular docking exhibited potential bindings of 2-BTHF to HSF-1 and DAF-16 transcription factors. Additionally, 2-BTHF significantly increased the mRNA transcripts of genes encoding proteins involved in proteostasis, including the molecular chaperones hsp-16.2 and hsp-16.49, the ubiquitination/SUMOylation-related ubc-9 gene, and the autophagy-related genes atg-7 and lgg-1. Transcriptomic profiling revealed an additional mechanism of 2-BTHF in α-synuclein-expressing worms, which showed upregulation of PPAR signaling cascades that mediated fatty acid metabolism. 2-BTHF significantly restored lipid deposition, upregulated the fat-7 gene, and enhanced gcs-1-mediated glutathione synthesis in the C. elegans PD model. Taken together, this study demonstrated that 2-BTHF could abrogate aggregative and oxidative properties of α-synuclein and attenuate its toxicity, thus providing a possible therapeutic application for the treatment of α-synuclein-induced PD.

Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is a muco-cutaneous autoimmune disease characterized and caused by autoantibodies targeting type VII collagen (COL7). The treatment of EBA is notoriously difficult, with a median time to remission of 9 months. In preclinical EBA models, we previously discovered that depletion of regulatory T cells (Treg) enhances autoantibody-induced, neutrophil-mediated inflammation and blistering. Increased EBA severity in Treg-depleted mice was accompanied by an increased cutaneous expression of interferon gamma (IFN-γ). The functional relevance of IFN-γ in EBA pathogenesis had been unknown. Given that emapalumab, an anti-IFN-γ antibody, is approved for primary hemophagocytic lymphohistiocytosis patients, we sought to assess the therapeutic potential of IFN-γ inhibition in EBA. Specifically, we evaluated if IFN-γ inhibition has modulatory effects on skin inflammation in a pre-clinical EBA model, based on the transfer of COL7 antibodies into mice. Compared to isotype control antibody, anti-IFN-γ treatment significantly reduced clinical disease manifestation in experimental EBA. Clinical improvement was associated with a reduced dermal infiltrate, especially Ly6G+ neutrophils. On the molecular level, we noted few changes. Apart from reduced CXCL1 serum concentrations, which has been demonstrated to promote skin inflammation in EBA, the expression of cytokines was unaltered in the serum and skin following IFN-γ blockade. This validates IFN-γ as a potential therapeutic target in EBA, and possibly other diseases with a similar pathogenesis, such as bullous pemphigoid and mucous membrane pemphigoid.

Observational and cross-sectional study on clinical profile of nontuberculous mycobacterial (NTM) disease in patients at tertiary care hospital of central India

Background Nontuberculous Mycobacterial (NTM) diseases present unique clinical challenges and are increasingly recognised as significant contributors to respiratory and extrapulmonary morbidity. This study protocol outlines an observational and cross-sectional investigation aiming to comprehensively understand the clinical profile of NTM disease, including its prevalence, risk factors, and clinical features, in patients at a tertiary care hospital in central India. Methods Over two years, from July 2022 to June 2024, a convenience sample size will be recruited from TB suspects meeting inclusion criteria. Comprehensive data collection will be conducted, including demographic information, clinical history, radiological findings, microbiological test results, and risk factor assessments. Statistical methods will be applied to the collected data, including descriptive statistics, comparative analysis, risk factor assessments, and multivariate analyses. Expected Results The study aims to provide valuable insights into the prevalence and clinical manifestations of NTM disease, shedding light on the risk factors contributing to its occurrence. The statistical analyses will identify key factors associated with NTM disease and characterise its clinical and radiological features.

A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece.

Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.

African ancestry-derived APOL1 risk genotypes show proximal epigenetic associations

Apolipoprotein L1 (APOL1) coding variants, termed G1 and G2, are established genetic risk factors for a growing spectrum of diseases, including kidney disease, in individuals of African ancestry. Evidence suggests that the risk variants, which show a recessive mode of inheritance, lead to toxic gain-of-function changes of the APOL1 protein. Disease occurrence and presentation vary, likely due to modifiers or second hits. To understand the role of the epigenetic landscape in relation to APOL1 risk variants, we performed methylation quantitative trait locus (meQTL) analysis to identify differentially methylated CpGs influenced by APOL1 risk variants in 611 African American individuals. We identified five CpGs that were significantly associated with APOL1 risk alleles in discovery and replication studies, and one CpG-APOL1 association was independent of other genomic variants. Our study highlights proximal DNA methylation alterations that may help explain the variable disease risk and clinical manifestation of APOL1 variants.

Abstract PO5-19-12: Innovative Trial Design: ARTIDIS Nanomechanical Generated Measurements for Early Breast Lesions (ANGEL) - Multicentre Study

Abstract Background: The diagnosis of breast cancer based on histopathology of core needle biopsies and the delineation into breast cancer subtypes to drive clinical treatment decisions can be time consuming and cause patient (and clinician) anxiety. Alternative, near patient, approaches to conventional diagnostic pathways would be desirable to drive diagnostic and therapeutic planning. This study harnesses the novel concept of evaluating diagnostic cores for nanomechanical features at the time of core biopsy. Clinical manifestations of disease are often accompanied by biomechanical alterations at sub-/cellular, extracellular, tissue and organ level. Mechanical properties of cancer cells and their microenvironment play a critical role in cancer invasion, progression, and immune cell infiltration. Ultrastructural (sub-) cellular alterations (nanoscale level), including the remodulation and alteration of cellular cytoskeleton dynamics, contribute to altered mechanical state of cancer cells, and lead to increased deformability and motility of soft cancer cells to overcome stromal barrier, and spread into the adjacent tissues and distant sites in the body. This results in a direct mechanistic correlation between nanomechanical properties and clinical outcome in cancer tissues. The ARTIDIS Nanomechanical Generated measurements for Early Lesions (ANGEL) Study will prospectively evaluate the efficacy of the ARTIDIS system as an aid to diagnosis, as well as subtyping breast cancer and predicting clinical outcomes based on tissue nanomechanics, particularly in the context of neoadjuvant therapy (NAT). Methods: The study seeks to validate the predictive power of the nanomechanical signature, a unique tissue biomarker reflecting the tissue phenotype, by comparing it to standard histological assessment. A projected cohort of 2,705 patients will be enrolled, from diverse ethnic and socioeconomic backgrounds, with benign or malignant breast conditions undergoing diagnostic core biopsy. A single core biopsy (gauge agnostic) is placed in a cassette and subjected to thousands of mechanical measurements at the “nano” scale over a period of 1-3 hours. The ARTIDIS technology builds upon the Atomic Force Microscopy platform to non-disruptively detect up to 17 different nanomechanical parameters in soft tissues with a subcellular resolution. The same core biopsy can then undergo fixation and conventional histopathological analyses for comparison with the final pathology. The primary aim is to confirm the potential of the ARTIDIS system in diagnosis (benign vs malignant) and secondarily address whether the nanomechanical signature can differentiate subtypes of breast cancer, associate with clinical outcome, and guide treatment decisions. Particularly, we will investigate ARTIDIS potential as a predictor of treatment response for patients receiving NAT. Results: The multicenter ANGEL study is a prospective investigation that builds upon previous clinical data from the NANO study at the University Hospital Basel (Switzerland) and is designed to demonstrate the power of using a nanomechanical signature to evaluate breast biopsies within a routine clinical setting in a multicenter setting. The data will be used to develop ARTIDIS as an aid to diagnosis, as well as NEO Match test applications to predict and guide response to NAT. Conclusion: This study presents the first of its kind as a direct prospective, multi-center based clinical translation of the Physics of Cancer findings into clinical settings. This innovative trial design allows the prospective development of ARTIDIS as an aid to diagnosis and NAT outcome prediction and therapy guidance applications. Citation Format: Karla Sepulveda, Ashley Roark, Sagar Dhamne, Chandandeep Nagi, Ivan Marin, Iqbal Tabish, Susanne G. Hilsenbeck Hilsenbeck, Sara Nizzero, Mariam Gachechiladze, Tobias A Appenzeller, Marko Loparic, Marija Plodinec, Alastair Thompson. Innovative Trial Design: ARTIDIS Nanomechanical Generated Measurements for Early Breast Lesions (ANGEL) - Multicentre Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-12.