Manifestations Of Disease Research Articles

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.

Sex-specific developmental gene expression atlas unveils dimorphic gene networks in C. elegans

Sex-specific traits and behaviors emerge during development by the acquisition of unique properties in the nervous system of each sex. However, the genetic events responsible for introducing these sex-specific features remain poorly understood. In this study, we create a comprehensive gene expression atlas of pure populations of hermaphrodites and males of the nematode Caenorhabditis elegans across development. We discover numerous differentially expressed genes, including neuronal gene families like transcription factors, neuropeptides, and G protein-coupled receptors. We identify INS-39, an insulin-like peptide, as a prominent male-biased gene expressed specifically in ciliated sensory neurons. We show that INS-39 serves as an early-stage male marker, facilitating the effective isolation of males in high-throughput experiments. Through complex and sex-specific regulation, ins-39 plays pleiotropic sexually dimorphic roles in various behaviors, while also playing a shared, dimorphic role in early life stress. This study offers a comparative sexual and developmental gene expression database for C. elegans. Furthermore, it highlights conserved genes that may underlie the sexually dimorphic manifestation of different human diseases.

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.

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.

ERCP (endoscopic retrograde cholangiopancreatography) and EUS (endoscopic ultrasonography) in diagnosis of choledocholithiasis – battle or cooperation?

Introduction: Diagnosis of choledocholithiasis, a common manifestation of gallstone disease, is mainly based on advanced endoscopic techniques such as ERCP and EUS. Since the 1970s, ERCP has been a key method in the diagnosis and treatment of choledocholithiasis, allowing direct visualization and therapeutic interventions. However, technological developments have brought the emergence of EUS as a complementary tool, providing high-resolution imaging of the bile ducts. Understanding the diagnostic accuracy, therapeutic options and complications of both modalities is key to optimizing the care of patients with bile duct stones. Aim of the study: The aim of our study is to review and compare various diagnostic methods of bile duct stones, as well as to assess their effectiveness, accuracy, and potential complications. Materials and methods: We searched electronic sources, aspecially in the PubMed and Google Scholar databases, using keywords such as ,,endoscopic ultrasonography”, ,,endoscopic retrograde cholangiopancreatography” and ,,choledocholithiasis”. Conclusions: With the use of modern technologies, such as endoscopic ultrasonography (EUS) and retrograde choleangiopancreatography (ERCP), it has become possible to diagnose bile duct stones more accurately and introduce more effective and less invasive therapies. The development of the availability of diagnostic tests, especially those that do not require invasive procedures, has helped reduce the risk of complications. EUS may be the preferred tool of choice for patients with gallstones, as it is associated with a lower risk of complications compared to ERCP alone. Decisions regarding the use of specific diagnostic and therapeutic modalities should be made on a case-by-case basis, taking into account medical and economic considerations.

Current Developments in the Prevention and Improvement of Intestinal Disorders: A Mini-Review.

Recently, the number of patients who manifest intestinal disorders has increased. Particularly, Irritable Bowel Syndrome (IBS) patients and Inflammatory Bowel Disease (IBD) patients, which include Ulcerative Colitis (UC) and Crohn's Disease (CD), are on the rise, especially in the young generation. Behcet's disease (an autoimmune disease) and bowel obstruction are also common intestinal disorders. Furthermore, colorectal cancer, including colon and rectum cancer and small intestinal cancer, are the typical disorders in the intestine. Other disorders in the digestive tract are infectious diseases like Helicobacter pylori infection. Even though symptomatic treatments have been increasing for the treatment of intestinal disorders, the ways of improving and preventing these diseases are still controversial. The progress of medicine and treatment is rapid. However, recent approaches to the prevention and improvement of these intestinal disorders are suppressing dysbiosis and preventing chronic inflammation. This mini-review discusses the hypothesis of whether the improvement of the diet is a preferable choice for the prevention of these intestinal disorders. Dietary interventions are beneficial for the prevention and improvement of intestinal disorders since the first approach to intestinal disorders is dietary intervention. The Mediterranean diet, the diet from the 5-a-day campaign, and the Japanese diet are well-known healthy dietary strategies. A healthy diet regimen is not only beneficial for the prevention of intestinal disorders but also a useful strategy to reduce stress and ameliorate mental illness. In addition, the intake of phytochemicals is good for keeping healthy gut microbiota and preventing intestinal disorders. Furthermore, vitamin D3 intake with these phytochemicals works as an adjuvant to improve gut microbiota and upregulate immune responses. As a result, the decreasing production of TNF-α ameliorates chronic inflammation and intestinal disorders at an early stage. In recent years, prevention of the non-disease condition "ME-BYO" has been a popular approach for healthy and long living in Japan. This idea prevents the manifestation of diseases before the onset and is also applicable to intestinal disorders. This mini-review discusses ways of preventing and ameliorating intestinal disorders.

Alzheimer’s disease and oral manifestations: a bi-directional Mendelian randomization study

BackgroundEpidemiological studies have provided evidence suggesting an association between Alzheimer’s disease (AD) and various oral manifestations. However, conflicting conclusions have been drawn, and whether a causal association truly exists remains unclear.MethodsIn order to investigate the potential causal association between AD and prevalent oral diseases, we conducted a bi-directional two-sample Mendelian randomization analysis based on summary statistics from genome-wide association studies of AD (N = 63,926), as well as mouth ulcer (N = 461,103), oral cavity cancer (N = 4,151), and periodontal disease (N = 527,652).ResultsWe identified that one standard increase in the risk of AD was causally associated with a reduced risk of oral cavity cancer (OR = 0.76, 95% CI: 0.63–0.92, p = 3.73 × 10−3). In the opposite direction, oral conditions were not causally associated with risk of AD.ConclusionThe present findings contributed to a better understanding of the correlation between AD and oral conditions, specifically oral cavity cancer. These results also identified new avenues for exploring the underlying mechanisms of oral cavity cancer.

Pathophysiology of cerebral small vessel disease: a journey through recent discoveries.

Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related small vessel pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, small deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% of ischemic strokes and the vast majority of spontaneous intracerebral hemorrhage and is also the most important vascular contributor to dementia. Despite its high prevalence and potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview of the recent advances in this field. We summarize recent data highlighting the remarkable continuum between monogenic and multifactorial cSVDs involving NOTCH3, HTRA1, and COL4A1/A2 genes. Taking a vessel-centric view, we discuss possible cause-and-effect relationships between risk factors, structural and functional vessel changes, and disease manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction is rightly considered a central feature of cSVD, the contributions of smooth muscle cells, pericytes, and other perivascular cells warrant continued investigation.

The role of social inequalities in the epidemiology of urological cancers: can this inform cancer screening?

Health inequalities are systematic and potentially remediable differences in health across populations. Understanding the origins of these discrepancies, the healthcare consequences and the manifestations of related diseases can help improve the outcomes of underserved communities. Here I discuss how social factors may be used to help identify particular at-risk populations with regards to urological malignancies, and how these can be potentially used as biomarkers that inform cancer screening targets.

Sonographic evaluation of peripheral nerve involvement in leprosy with electrophysiologic correlation: a cross-sectional study in sub-Himalayan region

BackgroundLeprosy is an age-old chronic infectious disease with the majority of annual new case detections from South-East Asia. The disease manifestations coupled with the stigma attached to it often creates grave socioeconomic problems. Leprosy is curable and if detected and treated in the early stages can prevent disability. Ultrasonography provides information regarding location and degree of the nerve damage, nerve morphologic alterations, echo texture, fascicular pattern and vascularity. The aim of this study was to study the ultrasonographic features of neuropathy in leprosy with electrophysiologic correlation.ResultsA total of 34 histopathological proven cases of leprosy were included in this study, which was conducted for 1 year. High-resolution ultrasound (HRUS) of a total of 204 peripheral nerves in these 34 patients, including bilateral ulnar, median and common peroneal nerves, was performed. Cross-sectional areas, nerve diameters, nerve morphology and vascularity were noted and correlated with electrophysiologic study of these nerves. The results showed that all the patients having reduced motor or sensory function [decreased compound muscle action potential (CMAP), decreased compound nerve action potential (SNAP) and increased latency] in ulnar and common peroneal nerves were thickened on HRUS (100% in ulnar and common peroneal nerves) while 92% right median and 89% left median nerves with reduced motor or sensory function showed thickening on HRUS. Also, 5.8% ulnar nerves and 11.7% common peroneal nerves showed thickening on HRUS; however, sensory or motor conduction of these nerves was unaffected on nerve conduction study (NCS). So, a positive correlation was observed for nerve involvement as detected by ultrasonographic findings of nerve hypertrophy and the electrophysiologic study. The most common finding was focal or diffuse nerve thickening. Ulnar nerve was the most commonly thickened nerve in leprosy patients with the most common location of nerve thickening at medial epicondyle.ConclusionsUltrasound and electrophysiologic study of peripheral nerves in leprosy are complimentary to each other in diagnosing leprotic neuropathy.

The problem of excessive hair loss as a signal for the diagnosis of coeliac disease – A family case

Celiac disease is an autoimmune disorder in which the small intestine is damaged after ingesting gluten. Baldness often co-occurs with various systemic diseases including autoimmune diseases. In addition, alopecia can result from nutritional deficiencies. In the case of celiac disease, we are mainly talking about deficiencies of iron, fat-soluble vitamins (A,D,E,K), vitamin B12 and folic acid. Telogenetic alopecia (TE) is diffuse and reversible alopecia, and the causes of this condition can be nutritional deficiencies and impaired absorption. Celiac disease has been linked to alopecia areata (AA). We describe the case of a mother and daughter with a history of hair loss, which represented the only incipient (mother’s case) and subsequent (daughter’s case) extraintestinal manifestation of celiac disease.

Oral health and multimorbidity: Is diet the chicken or the egg?

Oral health is a critical component of overall health and well-being, not just the absence of disease. The objective of this review paper is to describe relationships among diet, nutrition, oral, and systemic diseases that contribute to multi-morbidity. Diet and nutrient-related risk factors for oral diseases include high intakes of free sugars, low intakes of fruits and vegetables, and nutrient poor diets which are similar to diet and nutrient-related risk factors for systemic diseases. Oral diseases are chronic diseases. Once the disease process is initiated, it persists throughout the lifespan. Pain and tissue loss from oral disease leads to oral dysfunction which contributes to impaired biting, chewing, oral motility, and swallowing. Oral dysfunction makes it difficult to eat nutrient dense whole grains, fruits, and vegetables associated with a healthy diet. Early childhood caries (ECC) associated with frequent intake of free sugars is one of the first manifestations of oral disease. The presence of ECC is our 'canary in the coal mine' for diet-related chronic diseases. The dietary sugars causing ECC are not complementary to an Eatwell Guide compliant diet, but rather consistent with a diet high in energy dense, nutrient poor foods - typically ultra-processed in nature. This diet generally deteriorates throughout childhood, adolescence, and adulthood increasing the risk of diet-related chronic diseases. Recognition of ECC is an opportunity to intervene and disrupt the pathway to multi-morbidities. Disruption of this pathway will reduce risk of multi-morbidities and enable individuals to fully engage in society throughout the lifespan.

Post Covid Auto Immune Mediated Encephalopathy by Caspr2 Auto Antibody: The Report of Neurological Division o f “Carlo Poma Civil” Hospital of Mantua

Post Covid Auto Immune Mediated Encephalopathy by Caspr2 Auto Antibody: The Report of Neurological Division o f “Carlo Poma Civil” Hospital of Mantua

Arteriovenous metabolomics in pigs reveals CFTR regulation ofmetabolism inmultiple organs.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that exhibits diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects are uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disrupted lung uptake of fatty acids yet enhanced uptake of arachidonic acid, a precursor of pro-inflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multi-organ metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue.

Mortality among extrapulmonary tuberculosis patients in the HIV endemic setting: lessons from a tertiary level hospital in Mbeya, Tanzania

Extrapulmonary tuberculosis (EPTB) has received less attention than pulmonary tuberculosis due to its non-contagious nature. EPTB can affect any organ and is more prevalent in people living with HIV. Low- and middle-income countries are now facing the double burden of non-communicable diseases (NCDs) and HIV, complicating the management of patients with symptoms that could be compatible with both EPTB and NCDs. Little is known about the risk of death of patients presenting with symptoms compatible with EPTB. We included patients with a clinical suspicion of EPTB from a tertiary level hospital in Mbeya, Tanzania, to assess their risk of dying. A total of 113 (61%) patients were classified as having EPTB, and 72 (39%) as having non-TB, with corresponding mortality rates of 40% and 41%. Associated factors for mortality in the TB groups was hospitalization and male sex. Risk factors for hospitalization was having disease manifestation at any site other than lymph nodes, and comorbidities. Our results imply that NCDs serve as significant comorbidities amplifying the mortality risk in EPTB. To strive towards universal health coverage, focus should be on building robust health systems that can tackle both infectious diseases, such as EPTB, and NCDs.

Noninvasive diagnosis of laryngopharyngeal reflux as an extraesophageal manifestation of gastroesophageal reflux disease: A literature review

Noninvasive diagnosis of laryngopharyngeal reflux as an extraesophageal manifestation of gastroesophageal reflux disease: A literature review

Tomato Leaf Disease Detection System

Tomato is a widely cultivated crop with significant economic importance in the agro based industry. However, tomato plants are susceptible to various diseases that can severely impact yield and quality. Early and accurate detection of these diseases is crucial for effective disease management and ensuring optimal production. In this study, we propose a novel approach that a convolutional Neural Network (CNN) for the automated detection of tomato leaf diseases. First, Convolutions is employed to reduce the dimensionality of the input data, extracting the most relevant features for disease detection. The CNN leverages its ability to learn complex patterns and features from the data, enabling accurate classification of various tomato leaf diseases. To evaluate the effectiveness of our approach, we conducted experiments using a diverse dataset of tomato leaf images with different disease manifestations. Key Words: Agriculture, Tomato diseases, Leaf disease detection, Deep learning, neural network, Disease Diagnosis.

Role of Ayurvedic Herbs in the Management of Celiac Disease

Celiac disease or gluten-sensitive enteropathy is an autoimmune hypersensitivity disorder affecting the small intestine. It occurs due to an inappropriate immune reaction to gluten, which results in inflammation and damage to the small intestine. One of the most prevalent illnesses, celiac disease, is brought on by both environmental (gluten) and genetic causes of human leukocyte antigen (HLA) and non-HLA genes. The prevalence of celiac disease has been estimated to approximate 0.5%-1% in different parts of the world. Due to improved physician awareness and expertise, as well as the widespread use of extremely sensitive and precise diagnostic tests for celiac disease, the prevalence of celiac disease has considerably grown in the past 30 years. While older children have either limited or unusual symptoms, only a small percentage of celiac patients have the classic signs of the condition like chronic or intermittent diarrhea, failure to thrive, weight loss, delayed puberty, short stature, nausea, vomiting, chronic abdominal pain, abdominal distension, chronic constipation. Early detection of celiac disease is crucial to preventing long-term consequences. According to Ayurveda, some symptoms of celiac disease found in Grahani Dosha. Grahani is described as an Agni Adhisthana by most of Acharya. Mandagini is the root cause of Ama Dosha, and it is a crucial factor for the manifestation of most diseases. The treatment approach of celiac disease in Ayurveda medicinal science involves the intake of various preparations of some specific medicinal plants like Kutaja (Holarrhena antidysenterica) Pippali, (Piper longum Linn.), Chitraka, (Plumbago zeylanica) Guduchi, (Tinospora cordifolia) Ashwagandha, (Withania somnifera), Haridra (Curcuma longa Linn.), etc which have Agni Deepana and Ama Pachana properties. These illness-specific medicinal herbs help normalize digestive fire and evict "Ama" toxins from the body channels, which pacify the vitiated Agni and maintain homeostasis among vitiated Doshas.

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.

Parvovirus B19 infection: characteristics of population immunity in the world

Parvovirus B19 infection (PVI) is one of the relatively new problems in infectology, data on the study of its prevalence in our country began to appear only at the beginning of the twenty-first century. The article presents the results of an analysis of studies from available literature sources highlighting the prevalence of PVI markers at the population level among different social groups of the population at the present stage. The clinical manifestations of PVI are diverse, which requires differential diagnosis, both with exanthemic infectious diseases and with non-infectious pathology. Due to the peculiarity of PVI pathogenesis, it is relevant for various socially significant populations, primarily patients with exanthemic manifestations of various diseases, persons from among blood donors, pregnant women and women planning pregnancy. Furthermore, unlike most countries, our country does not have a system for PVI detecting and reporting in the system of state sanitary and epidemiological supervision, which makes it difficult to conduct research on this topic.