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International Journal of Molecular... Nov 2023In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic... (Review)
Review
In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome.
Topics: Humans; Esophageal and Gastric Varices; Hepatorenal Syndrome; Reactive Oxygen Species; Endotoxemia; Gastrointestinal Hemorrhage; Liver Cirrhosis; Hypertension, Portal; Oxidative Stress; Inflammation; Cardiomyopathies; Cardiovascular Abnormalities; Endotoxins
PubMed: 38069125
DOI: 10.3390/ijms242316805 -
Cancers Oct 2023Beckwith-Wiedemann syndrome (BWS) is a genetic imprinting disorder that most commonly presents as overgrowth, macroglossia, abdominal wall defects, lateralized...
Beckwith-Wiedemann syndrome (BWS) is a genetic imprinting disorder that most commonly presents as overgrowth, macroglossia, abdominal wall defects, lateralized overgrowth, and embryonal tumors [...].
PubMed: 37894306
DOI: 10.3390/cancers15204939 -
Frontiers in Genetics 2024Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and... (Review)
Review
Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and or organs. Depending on the underlying physiological pathway affected by pathogenic genetic alterations, overgrowth syndromes are associated with a broad spectrum of neoplasia predisposition, (cardio) vascular and neurodevelopmental anomalies, and dysmorphisms. Pathologic overgrowth may be of prenatal or postnatal onset. It either results from an increased number of cells (intrinsic cellular hyperplasia), hypertrophy of the normal number of cells, an increase in interstitial spaces, or from a combination of all of these. The underlying molecular causes comprise a growing number of genetic alterations affecting skeletal growth and Growth-relevant signaling cascades as major effectors, and they can affect the whole body or parts of it (mosaicism). Furthermore, epigenetic modifications play a critical role in the manifestation of some overgrowth diseases. The diagnosis of overgrowth syndromes as the prerequisite of a personalized clinical management can be challenging, due to their clinical and molecular heterogeneity. Physicians should consider molecular genetic testing as a first diagnostic step in overgrowth syndromes. In particular, the urgent need for a precise diagnosis in tumor predisposition syndromes has to be taken into account as the basis for an early monitoring and therapy. With the (future) implementation of next-generation sequencing approaches and further technologies, clinical diagnoses can not only be verified, but they also confirm the clinical and molecular spectrum of overgrowth disorders, including unexpected findings and identification of atypical cases. However, the limitations of the applied assays have to be considered, for each of the disorders of interest, the spectrum of possible types of genomic variants has to be considered as they might require different methodological strategies. Additionally, the integration of artificial intelligence (AI) in diagnostic workflows significantly contribute to the phenotype-driven selection and interpretation of molecular and physiological data.
PubMed: 38894719
DOI: 10.3389/fgene.2024.1382371 -
Orphanet Journal of Rare Diseases Sep 2023Somatic mutations of cancer driver genes are found to be responsible for vascular malformations with clinical manifestations ranging from cutaneous birthmarks to...
BACKGROUND
Somatic mutations of cancer driver genes are found to be responsible for vascular malformations with clinical manifestations ranging from cutaneous birthmarks to life-threatening systemic anomalies. Till now, only a limited number of cases and mutations were reported in Chinese population. The purpose of this study was to describe the somatic mutation spectrum of a cohort of Chinese pediatrics with vascular malformations.
METHODS
Pediatrics diagnosed with various vascular malformations were collected between May 2019 and October 2020 from Beijing Children's Hospital. Genomic DNA of skin lesion of each patient was extracted and sequenced by whole-exome sequencing to identify pathogenic somatic mutations. Mutations with variant allele frequency less than 5% were validated by ultra-deep sequencing.
RESULTS
A total of 67 pediatrics (33 males, 34 females, age range: 0.1-14.8 years) were analyzed. Exome sequencing identified somatic mutations of corresponding genes in 53 patients, yielding a molecular diagnosis rate of 79.1%. Among 29 PIK3CA mutations, 17 were well-known hotspot p.E542K, p.E545K and p.H1047R/L. Non-hotspot mutations were prevalent in patients with PIK3CA-related overgrowth spectrum, accounting for 50.0% (11/22) of detected mutations. The hotspot GNAQ p.R183Q and TEK p.L914F mutations were responsible for the majority of port-wine stain/Sturge-Weber syndrome and venous malformation, respectively. In addition, we identified a novel AKT1 p.Q79K mutation in Proteus syndrome and MAP3K3 p.E387D mutation in verrucous venous malformation.
CONCLUSIONS
The somatic mutation spectrum of vascular malformations in Chinese population is similar to that reported in other populations, but non-hotspot PIK3CA mutations may also be prevalent. Molecular diagnosis may help the clinical diagnosis, treatment and management of these pediatric patients with vascular malformations.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Class I Phosphatidylinositol 3-Kinases; East Asian People; Hemangioma; Mutation; Vascular Malformations
PubMed: 37658401
DOI: 10.1186/s13023-023-02860-w -
Current Research in Immunology 2023The studies on the composition of the human microbiomes in healthy individuals, its variability in the course of inflammation, infection, antibiotic therapy, diets and... (Review)
Review
The studies on the composition of the human microbiomes in healthy individuals, its variability in the course of inflammation, infection, antibiotic therapy, diets and different pathological conditions have revealed their intra and inter-kingdom relationships. The lung microbiome comprises of major species members of the phylum Bacteroidetes, Firmicutes, Actinobacteria, Fusobacteria and Proteobacteria, which are distributed in ecological niches along nasal cavity, nasopharynx, oropharynx, trachea and in the lungs. Commensal and pathogenic species are maintained in equilibrium as they have strong relationships. Bacterial overgrowth after dysbiosis and/or imbalanced of CD4 helper T cells, CD8 cytotoxic T cells and regulatory T cells (Treg) populations can promote lung inflammatory reactions and distress, and consequently acute and chronic respiratory diseases. This review is aimed to summarize the latest advances in resident lung microbiome and its participation in most common pulmonary infections and pneumonia, community-acquired pneumonia (CAP), ventilator-associated pneumonia (VAP), immunodeficiency associated pneumonia, SARS-CoV-2-associated pneumonia, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). We briefly describe physiological and immunological mechanisms that selectively create advantages or disadvantages for relative growth of pathogenic bacterial species in the respiratory tract. At the end, we propose some directions and analytical methods that may facilitate the identification of key genera and species of resident and transient microbes involved in the respiratory diseases' initiation and progression.
PubMed: 37456520
DOI: 10.1016/j.crimmu.2023.100065 -
Journal of Psychopathology and Clinical... Aug 2023Sotos syndrome (Sotos) and Tatton-Brown-Rahman Syndrome (TBRS) are two of the most common overgrowth disorders associated with intellectual disability. Individuals with...
Sotos syndrome (Sotos) and Tatton-Brown-Rahman Syndrome (TBRS) are two of the most common overgrowth disorders associated with intellectual disability. Individuals with these syndromes tend to have similar cognitive profiles and high likelihood of autism symptomatology. However, whether and how sensory processing is affected is currently unknown. Parents/caregivers of 36 children with Sotos and 20 children with TBRS completed the Child Sensory Profile-2 (CSP-2) and the Sensory Behavior Questionnaire (SBQ) along with other standardized questionnaires assessing autistic traits (Social Responsiveness Scale, Second Edition, SRS-2), attention deficit hyperactivity disorder (ADHD) traits (Conners 3), anxiety (Spence Children's Anxiety Scale, Parent Version, SCAS-P), and adaptive behavior (Vineland Adaptive Behavior Scales Third Edition). Sensory processing differences were clearly evident in both syndromes, though there was significant variation in both cohorts. SBQ data indicated that both the and of sensory behavior were more severe when compared to neurotypicals, with levels of sensory behavior impact and frequency being similar to autistic children. CSP-2 data indicated 77% of children with Sotos and 85% children with TBRS displayed clear differences in sensory Registration (missing sensory input). Clear differences relating to Body Position (proprioceptive response to joint and muscle position; 79% Sotos; 90% TBRS) and Touch (somatosensory response to touch on skin; 56% Sotos; 60% TBRS) were also particularly prevalent. Correlation analyses demonstrated that in both syndromes sensory processing differences tend to be associated with difficulties relating to autistic traits, anxiety, and some domains of ADHD. In Sotos, sensory processing differences were also associated with lower adaptive behavior skills. This first detailed assessment of sensory processing, alongside other clinical features, in relatively large cohorts of children with Sotos and TBRS, demonstrates that sensory processing differences have a profound impact on everyday life. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Topics: Child; Humans; Intellectual Disability; Sotos Syndrome; Abnormalities, Multiple; Touch; Musculoskeletal Abnormalities; Touch Perception
PubMed: 37289542
DOI: 10.1037/abn0000837 -
Histology and Histopathology Jul 2024Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent... (Review)
Review
Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in or . Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to mutations. mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.
Topics: Humans; Congenital Hyperinsulinism; Phenotype; Mutation; Pancreatic Neoplasms; Hyperinsulinism; Insulinoma; Hypoglycemia; Genotype; Genetic Association Studies
PubMed: 38305063
DOI: 10.14670/HH-18-709 -
Clinical and Experimental Pediatrics Sep 2023Small intestinal bacterial overgrowth (SIBO) is defined as the presence of an excessive number of bacteria within the small bowel. Pediatric SIBO is a heterogeneous...
Small intestinal bacterial overgrowth (SIBO) is defined as the presence of an excessive number of bacteria within the small bowel. Pediatric SIBO is a heterogeneous disorder that manifests as various symptoms ranging from mild gastrointestinal symptoms to malabsorption or malnutrition. The carbohydrate breath test is a commonly used, safe, and noninvasive diagnostic test; however, a standardized methodology is lacking. Multiple factors, such as neuromuscular disorders, systemic diseases, chronic drug use, or altered intestinal anatomy that disturb intestinal motility or induce an abnormality in the body's defense systems against intestinal bacteria, predispose children to SIBO. The high prevalence and similar symptoms of SIBO in functional gastrointestinal disorders, including irritable bowel syndrome, suggest an association between them. The principles of treatment include managing predisposing conditions, nutritional support, symptom control, and antibacterial treatment. Rifaximin is the most commonly used drug. To date, studies of antibiotic treatment in pediatric populations with irritable bowel syndrome or SIBO are lacking and have shown mixed results. Here we review the prevalence, diagnostic tests, and treatment results in pediatric populations.
PubMed: 37599259
DOI: 10.3345/cep.2022.00969 -
JCI Insight Jan 2024Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27...
Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity. RNA-Seq comparing osteoblasts differentiated from Ezh2R684C/+, and Ezh2+/+ BM-mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs.
Topics: Animals; Mice; Osteogenesis; Fibroblasts; Polycomb Repressive Complex 2; Disease Models, Animal; Histone Demethylases
PubMed: 38015625
DOI: 10.1172/jci.insight.173392 -
Expert Review of Gastroenterology &... 2023The irritable bowel syndrome (IBS) is the best-recognized disorder of gut brain interactions (DGBI). However, it is controversial if the Rome IV criteria iteration for... (Review)
Review
INTRODUCTION
The irritable bowel syndrome (IBS) is the best-recognized disorder of gut brain interactions (DGBI). However, it is controversial if the Rome IV criteria iteration for IBS diagnosis is fit for purpose.
AREAS COVERED
This review critically evaluates Rome IV criteria for diagnosis of IBS and addresses clinical considerations in IBS treatment and management, including dietary factors, biomarkers, disease mimics, symptom severity, and subtypes. The role of diet in IBS is critically reviewed along with the influence of the microbiota, including small intestinal bacterial overgrowth.
EXPERT OPINION
Emerging data suggest the Rome IV criteria are more suitable for identifying severe IBS and least useful for sub-diagnostic patients who are still likely to benefit from IBS treatment. Despite convincing evidence that IBS symptoms are diet-driven and often postprandial, a relationship to eating is not a Rome IV diagnostic criterion. Few IBS biomarkers have been identified, suggesting the syndrome is too heterogeneous to be measured by a single marker, and combined biomarker, clinical, dietary, and microbial profiling may be needed for objective characterization. With many organic diseases mimicking and overlapping with IBS, it's important clinicians are knowledgable about this to mitigate the risk of missing comorbid organic intestinal disease and to optimally treat IBS symptoms.
Topics: Humans; Irritable Bowel Syndrome; Diet; Biomarkers
PubMed: 37317843
DOI: 10.1080/17474124.2023.2223975