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Journal of Bacteriology Sep 2023is a Gram-positive, spore-forming anaerobe that causes clinical diseases ranging from diarrhea and pseudomembranous colitis to toxic megacolon and death. infection...
is a Gram-positive, spore-forming anaerobe that causes clinical diseases ranging from diarrhea and pseudomembranous colitis to toxic megacolon and death. infection (CDI) is associated with antibiotic usage, which disrupts the indigenous gut microbiota and causes the loss of microbial-derived secondary bile acids that normally provide protection against colonization. Previous work has shown that the secondary bile acid lithocholate (LCA) and its epimer isolithocholate (iLCA) have potent inhibitory activity against clinically relevant strains. To further characterize the mechanisms by which LCA and its epimers iLCA and isoallolithocholate (iaLCA) inhibit we tested their minimum inhibitory concentration against R20291 and a commensal gut microbiota panel. We also performed a series of experiments to determine the mechanism of action by which LCA and its epimers inhibit through bacterial killing and effects on toxin expression and activity. Additionally, we tested the cytotoxicity of these bile acids through Caco-2 cell apoptosis and viability assays to gauge their effects on the host. Here, we show that the epimers iLCA and iaLCA strongly inhibit growth while sparing most commensal Gram-negative gut microbes. We also show that iLCA and iaLCA have bactericidal activity against and these epimers cause significant bacterial membrane damage at subinhibitory concentrations. Finally, we observe that iLCA and iaLCA decrease the expression of the large cytotoxin , while LCA significantly reduces toxin activity. Although iLCA and iaLCA are both epimers of LCA, they have distinct mechanisms for inhibiting . LCA epimers, iLCA and iaLCA, represent promising compounds that target with minimal effects on members of the gut microbiota that are important for colonization resistance. IMPORTANCE In the search for a novel therapeutic that targets , bile acids have become a viable solution. Epimers of bile acids are particularly attractive as they may provide protection against while leaving the indigenous gut microbiota largely unaltered. This study shows that LCA epimers isolithocholate (iLCA) and LCA epimers isoallolithocholate (iaLCA) specifically are potent inhibitors of affecting key virulence factors including growth, toxin expression, and activity. As we move toward the use of bile acids as therapeutics, further work will be required to determine how best to deliver these bile acids to a target site within the host intestinal tract.
Topics: Humans; Virulence; Gastrointestinal Microbiome; Clostridioides difficile; Caco-2 Cells; Bile Acids and Salts; Lithocholic Acid
PubMed: 37695856
DOI: 10.1128/jb.00180-23 -
Quality of Life Research : An... Dec 2023Chronic diseases are notorious in the way that they interfere with many aspects of a child's development, and this holds true for children with Hirschsprung disease...
PURPOSE
Chronic diseases are notorious in the way that they interfere with many aspects of a child's development, and this holds true for children with Hirschsprung disease (HD). The present research aims to (1) determine whether the health-related quality of life (HRQoL) of HD children differs from healthy paediatric populations; and (2) explore the relationship between HD children's HRQoL and psychosocial outcomes of parents.
METHODS
Using a cross-sectional survey study design, children's HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL), while parental psychosocial outcomes were measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression short-forms, Family Management Measure (FaMM), and Parent Experience of Child Illness. Surveys were administered over telephone to parents of 48 Australian children treated for HD (87.5% male, median age 4.5 years) during the period May to November 2021.
RESULTS
While postoperative HRQoL of HD children was comparable to that of healthy age-matched controls, psychosocial quality of life of HD children was significantly poorer (mean difference = 3.40, CI [0.05, 6.76]). All parental outcome measures were significantly correlated with the PedsQL (r = - 0.77-0.67, p < 0.05) in expected directions, with FaMM subscales (except parent mutuality) demonstrating the most variation (R = 0.41-0.59). Of note, 31.3% of parents reported moderate to severe symptoms of anxiety on the PROMIS.
CONCLUSION
Despite overall positive results for children, parents reported elevated symptoms of anxiety. This study highlights the importance of long-term follow-up care for HD patients and their families.
Topics: Child; Humans; Male; Child, Preschool; Female; Quality of Life; Hirschsprung Disease; Cross-Sectional Studies; Australia; Surveys and Questionnaires; Parents; Melanoma, Cutaneous Malignant
PubMed: 37474849
DOI: 10.1007/s11136-023-03482-2 -
ANZ Journal of Surgery Sep 2023
Topics: Humans; Robotic Surgical Procedures; Hirschsprung Disease; Rectum; Rectal Diseases
PubMed: 37095589
DOI: 10.1111/ans.18371 -
Biochimica Et Biophysica Acta.... Mar 2024Hirschsprung disease (HSCR) is a complex genetic disorder characterized by the absence of enteric nervous system (ENS) in the distal region of the intestine. Down...
Hirschsprung disease (HSCR) is a complex genetic disorder characterized by the absence of enteric nervous system (ENS) in the distal region of the intestine. Down Syndrome (DS) patients have a >50-fold higher risk of developing HSCR than the general population, suggesting that overexpression of human chromosome 21 (Hsa21) genes contribute to HSCR etiology. However, identification of responsible genes remains challenging. Here, we describe a genetic screening of potential candidate genes located on Hsa21, using the zebrafish. Candidate genes were located in the DS-HSCR susceptibility region, expressed in the human intestine, were known potential biomarkers for DS prenatal diagnosis, and were present in the zebrafish genome. With this approach, four genes were selected: RCAN1, ITSN1, ATP5PO and SUMO3. However, only overexpression of ATP5PO, coding for a component of the mitochondrial ATPase, led to significant reduction of ENS cells. Paradoxically, in vitro studies showed that overexpression of ATP5PO led to a reduction of ATP5PO protein levels. Impaired neuronal differentiation and reduced mitochondrial ATP production, were also detected in vitro, after overexpression of ATP5PO in a neuroblastoma cell line. Finally, epistasis was observed between ATP5PO and ret, the most important HSCR gene. Taken together, our results identify ATP5PO as the gene responsible for the increased risk of HSCR in DS patients in particular if RET variants are also present, and show that a balanced expression of ATP5PO is required for normal ENS development.
Topics: Animals; Humans; Hirschsprung Disease; Down Syndrome; Zebrafish; Enteric Nervous System; Biomarkers
PubMed: 38128843
DOI: 10.1016/j.bbadis.2023.166991 -
European Journal of Neurology Jan 2024Advances in multidisciplinary care are extending overall survival in Duchenne muscular dystrophy (DMD) patients. Our research objective was to delineate the clinical...
BACKGROUND AND PURPOSE
Advances in multidisciplinary care are extending overall survival in Duchenne muscular dystrophy (DMD) patients. Our research objective was to delineate the clinical characteristics of this particular cohort and identify novel challenges associated with the disease.
METHODS
Nineteen individuals aged 25-48 years (median 34 years) with a confirmed diagnosis of out-of-frame DMD gene mutation were selected.
RESULTS
All patients were mechanically ventilated (5/19 via tracheostomy), with different patterns of cardiomyopathy. Swallowing and nutritional issues were frequent (median body mass index 18.95), with six cases requiring artificial enteral feeding (median age at start 29 years), as well as bone density alterations (11/19, 58%). Only 2/19 had been on long-term prednisone therapy. Issues requiring at-home/hospital assistance were respiratory infections (15/19, 79%), gastroenterological symptoms (9/19, 47%, including toxic megacolon and rectal perforation after repeated enemas), metabolic acidosis (2/19, 11%) and recurrent ischaemic strokes (1/19, 5%). From a social perspective, augmented-alternative communication devices were necessary for 7/19 (37%), with most of the patients being assisted at home and 2/19 institutionalized. Eight/19 (42%) patients experienced psychiatric symptoms (median age at presentation 16 years) and 9/19 (47%) chronic pain (median age at onset 23 years), in both cases treated with psychoactive/analgesic drugs without major adverse events. The patients' subjective perception of physical health resulted in unfavourable scores, whilst the subjective assessment of mental health unexpectedly showed more positive values compared to other chronic neurological conditions.
CONCLUSIONS
The analysis of adults living with DMD reveals several new health-related issues, such as the management of emergencies and safety of pharmacological treatments for psychiatric symptoms, chronic pain management, as well as an increasing caregivers burden.
Topics: Adult; Humans; Young Adult; Muscular Dystrophy, Duchenne; Prednisone; Cardiomyopathies; Patients; Deglutition
PubMed: 37724986
DOI: 10.1111/ene.16060 -
Journal of Inflammation Research 2023Paraneoplastic syndromes often cause endocrine, neurological, cutaneous, and hematologic pathologies, and cases with digestive symptoms as prominent cases are rare.
BACKGROUND
Paraneoplastic syndromes often cause endocrine, neurological, cutaneous, and hematologic pathologies, and cases with digestive symptoms as prominent cases are rare.
CASE DESCRIPTION
A 1-year-old child admitted to the emergency department with severe abdominal distension was later diagnosed with sacrococcygeal yolk cystoma with ulcerative colitis. After symptomatic management, surgical removal of the tumor, and JEB chemotherapy, the symptoms of ulcerative colitis disappeared completely. After 7 years of follow-up, the child grew and developed well, and there was no recurrence of tumor and ulcerative colitis.
CONCLUSION
Yolk sac tumor with ulcerative colitis is a rare paraneoplastic syndrome with complex clinical manifestations.
PubMed: 37576158
DOI: 10.2147/JIR.S418733 -
PeerJ 2023The discovery of low-coverage (i.e. uncovered) regions containing clinically significant variants, especially when they are related to the patient's clinical phenotype,...
The discovery of low-coverage (i.e. uncovered) regions containing clinically significant variants, especially when they are related to the patient's clinical phenotype, is critical for whole-exome sequencing (WES) based clinical diagnosis. Therefore, it is essential to develop tools to identify the existence of clinically important variants in low-coverage regions. Here, we introduce a desktop application, namely DEVOUR (DEleterious Variants On Uncovered Regions), that analyzes read alignments for WES experiments, identifies genomic regions with no or low-coverage (read depth < 5) and then annotates known variants in the low-coverage regions using clinical variant annotation databases. As a proof of concept, DEVOUR was used to analyze a total of 28 samples from a publicly available Hirschsprung disease-related WES project (NCBI Bioproject: https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJEB19327), revealing the potential existence of 98 disease-associated variants in low-coverage regions. DEVOUR is available from https://github.com/projectDevour/DEVOUR under the MIT license.
Topics: Humans; Exome Sequencing; Databases, Factual; Existentialism; Genomics; Hirschsprung Disease
PubMed: 37727687
DOI: 10.7717/peerj.16026 -
The American Journal of Tropical... Jan 2024The aims of this study were to estimate the prevalence of gastrointestinal manifestations among individuals with positive serology for Chagas disease (ChD) and to... (Meta-Analysis)
Meta-Analysis
The aims of this study were to estimate the prevalence of gastrointestinal manifestations among individuals with positive serology for Chagas disease (ChD) and to describe the clinical gastrointestinal manifestations of the disease. A systematic review with meta-analysis was conducted based on the criteria and recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The PubMed, Scopus, Virtual Health Library, Web of Science, and Embase databases were used to search for evidence. Two reviewers independently selected eligible articles and extracted data. RStudio® software was used for the meta-analysis. For subgroup analysis, the studies were divided according to the origin of the individuals included: 1) individuals from health units were included in the health care service prevalence analysis, and 2) individuals from the general population were included in the population prevalence analysis. A total of 2,570 articles were identified, but after removal of duplicates and application of inclusion criteria, 24 articles were included and 21 were part of the meta-analysis. Most of the studies were conducted in Brazil. Radiological diagnosis was the most frequent method used to identify the gastrointestinal clinical form. The combined effect of meta-analysis studies showed a prevalence of gastrointestinal manifestations in individuals with ChD of 12% (95% CI, 8.0-17.0%). In subgroup analysis, the prevalence for studies involving health care services was 16% (95% CI, 11.0-23.0%), while the prevalence for population-based studies was 9% (95% CI, 5.0-15.0%). Megaesophagus and megacolon were the main forms of ChD presentation in the gastrointestinal form. The prevalence of gastrointestinal manifestations of ChD was 12%. Knowing the prevalence of ChD in its gastrointestinal form is an important step in planning health actions for these patients.
Topics: Humans; Gastrointestinal Tract; Chagas Disease; Brazil
PubMed: 38052078
DOI: 10.4269/ajtmh.23-0323 -
Alternative Therapies in Health and... Nov 2023To analyze the effect of laparoscopic Soave combined with Deloyers turnover on the efficacy and prognosis of children with congenital Hirschsprung's disease, and to...
OBJECTIVE
To analyze the effect of laparoscopic Soave combined with Deloyers turnover on the efficacy and prognosis of children with congenital Hirschsprung's disease, and to explore an effective and safe operation, so as to provide a reference for clinical development of treatment plan and promote the faster recovery of children.
METHODS
A total of 80 children with Hirschsprung's disease admitted to our hospital from July 2021 to June 2022 were selected and included in the traditional group and minimally invasive group according to different surgical procedures, with 40 cases in each group. The traditional group was treated with open Soave, and the minimally invasive group was treated with laparoscopic Soave combined with Deloyers reversal. Compared two groups in terms of operation indicators (operation time, intraoperative blood loss, fasting time, intestinal function recovery time, and hospital stay), the stress response (serum cortisol, heart sodium, plasma epinephrine, and norepinephrine), intestinal flora (Bifidobacterium, Lactobacillus, Escherichia coli, and Enterococcus faecalis), anal function, recent complications (urinary retention, hematochezia, anus week dermatitis, incision infection, and abdominal bleeding), long-term complications (constipation, anastomotic stenosis, enterocolitis, and dirty feces).
RESULTS
The operation time, intraoperative blood loss, fasting time, intestinal function recovery time, and hospital stay in the minimally invasive group were significantly shorter than those in the traditional group (P < .05). The levels of serum cortisol, atrial natriuretic peptide, plasma epinephrine, and norepinephrine in the minimally invasive group were lower than those in the traditional group (P < .05). The levels of Bifidobacterium and Enterococcus faecalis in the minimally invasive group were higher than those in the traditional group (P < .05). The excellent and good rate of anal function in the minimally invasive group was higher than that in the traditional group (P < .05). The incidence of short-term and long-term complications in the minimally invasive group was lower than that in the traditional group (P < .05).
CONCLUSION
Joint Deloyers flip Soave under laparoscopic surgery for children with congenital Hirschsprung disease has a better curative effect, with shorter operation time, less blood loss compared to traditional open surgery.
Topics: Humans; Child; Infant; Hirschsprung Disease; Blood Loss, Surgical; Hydrocortisone; Postoperative Complications; Prognosis; Laparoscopy; Epinephrine; Norepinephrine; Treatment Outcome; Retrospective Studies
PubMed: 37678856
DOI: No ID Found -
Journal of Proteome Research Jul 2023Hirschsprung's disease (HSCR) is a congenital digestive tract malformation characterized by the absence of intramural ganglion cells in the myenteric and submucosal...
Hirschsprung's disease (HSCR) is a congenital digestive tract malformation characterized by the absence of intramural ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract. Although the improvement of surgical methods has allowed great progress in the treatment of HSCR, its incidence and postoperative prognosis are still not ideal. The pathogenesis of HSCR remains unclear to date. In this study, metabolomic profiling of HSCR serum samples was performed by an integrated analysis of gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) as well as multivariate statistical analyses. Based on the random forest algorithm and receiver operator characteristic analysis, 21 biomarkers related to HSCR were optimized. Several amino acid metabolism pathways were identified as important disordered pathways of HSCR, among which tryptophan metabolism was crucial. To our knowledge, this is the first serum metabolomics study focusing on HSCR, and it provides a new perspective for explaining the mechanism of HSCR.
Topics: Humans; Hirschsprung Disease; Gas Chromatography-Mass Spectrometry; Chromatography, Liquid; Tandem Mass Spectrometry; Metabolomics
PubMed: 37235583
DOI: 10.1021/acs.jproteome.3c00008