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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 -
Cureus Aug 2023infection (CDI) is a prevalent source of hospital-acquired diarrhea. The most common presentation of CDI is colitis. In cases of fulminant colitis/toxic megacolon, a...
infection (CDI) is a prevalent source of hospital-acquired diarrhea. The most common presentation of CDI is colitis. In cases of fulminant colitis/toxic megacolon, a colectomy and end ileostomy are part of the treatment plan. There is evidence to suggest that it may be beneficial to surgically treat severe complex CDI by constructing a loop ileostomy for fecal stream diversion followed by colonic lavage, also referred to as the Pittsburgh protocol, which has demonstrated decreased death rates in this patient population. In our case study, we present a rare case of a 60-year-old female patient diagnosed with fulminant small bowel CDI requiring resection of the necrotic small bowel. This was followed by creating an ileostomy and the Pittsburgh protocol, leading to a complete recovery. With an increasing incidence of CDI, it is important to be aware of the small bowel infection and its treatment.
PubMed: 37711949
DOI: 10.7759/cureus.43460 -
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 -
Cureus Aug 2023Lynch syndrome is a hereditary colorectal cancer caused by mutations in DNA mismatch repair genes. Immune checkpoint therapies have shown promise in treating Lynch...
Lynch syndrome is a hereditary colorectal cancer caused by mutations in DNA mismatch repair genes. Immune checkpoint therapies have shown promise in treating Lynch syndrome-associated cancers but can lead to immune-related adverse events, such as colitis. In this report, we present a severe case of immune-mediated colitis (IMC) induced by checkpoint inhibitors in a young patient with Lynch syndrome. This 20-year-old male with Lynch syndrome and a history of glioblastoma underwent dual checkpoint therapy, after initial treatment with systemic steroids. Despite this, his condition worsened, resulting in complications, such as toxic megacolon and small bowel obstruction. He was subjected to various treatments, including infliximab and vedolizumab, but ultimately required total abdominal colectomy with J-pouch creation. This case highlights the challenges of managing severe IMC in patients with Lynch syndrome. The patient's suboptimal response to standard treatments and the development of complications emphasizes the need for a better understanding and alternative therapeutic options for IMC. This case also calls into question whether a subset of patients with IMC should be "treated to target," even though the current standard of care for IMC is guided by symptom response, and if so, further research is necessary to identify potential therapeutic targets. Further research is also required to understand the mechanisms of IMC and develop effective treatment strategies tailored to patients with Lynch syndrome and immune-related adverse events.
PubMed: 37692727
DOI: 10.7759/cureus.43246 -
PloS One 2023Although most patients with Hirschsprung disease (HSCR) improve after pull-through, some patients still have persistent obstructive symptoms. Most previous studies...
BACKGROUND
Although most patients with Hirschsprung disease (HSCR) improve after pull-through, some patients still have persistent obstructive symptoms. Most previous studies reported persistent obstructive symptoms after pull-through in HSCR patients from developed countries. Our study determined the prognostic factors of persistent obstructive symptoms in patients with HSCR following pull-through from a particular developing country.
METHODS
A cross-sectional study was conducted using medical records of patients with HSCR at our institution from January 2017 to January 2022.
RESULTS
We ascertained 114 patients with HSCR: 79 males and 35 females. Most of them (90.4%) showed a short aganglionosis and underwent transanal endorectal pull-through (55.3%). Twenty-two percent of patients showed persistent obstructive symptoms following pull-through. Operative technique and age at definitive surgery were significantly associated with the persistent obstructive symptoms after pull-through (p = 0.011 and 0.019, respectively), while sex, aganglionic segment length, presence of global developmental delay, and Down syndrome were not (p = 0.873, 0.525, 0.647, and 0.301, respectively). Multivariate analysis revealed that age at pull-through was a significant independent factor for persistent obstructive symptoms after pull-through, with an odds ratio of 3.41 (95% CI = 1.18-9.91; p = 0.02).
CONCLUSIONS
Our study shows a moderate frequency of persistent obstructive symptoms after pull-through in our institution. In addition, patients who underwent pull-throughs at a younger age might have persistent obstructive symptoms following a definitive surgery. Our study provides new data on persistent obstructive symptoms after pull-through from a particular population that might be beneficial for pediatric surgeons' consideration before performing definitive surgery on patients with HSCR.
Topics: Female; Male; Child; Humans; Hirschsprung Disease; Cross-Sectional Studies; Prognosis; Down Syndrome; Health Facilities
PubMed: 37682877
DOI: 10.1371/journal.pone.0290430 -
Mathematical Biosciences and... Jun 2023Possible complications, such as intestinal obstruction and inflammation of the intestinal tract, can have a detrimental effect on the prognosis after surgery for...
Possible complications, such as intestinal obstruction and inflammation of the intestinal tract, can have a detrimental effect on the prognosis after surgery for Hirschsprung disease. The aim of this study was to investigate the potential targets and mechanisms of action of echinacoside to improve the prognosis of Hirschsprung disease. Genes related to the disease were obtained through analysis of the GSE96854 dataset and four databases: OMIM, DisGeNET, Genecard and NCBI. The targets of echinacoside were obtained from three databases: PharmMapper, Drugbank and TargetNet. The intersection of disease genes and drug targets was validated by molecular docking. The valid docked targets were further explored for their expression by using immunohistochemistry. In this study, enrichment analysis was used to explore the mechanistic pathways involved in the genes. Finally, we identified CA1, CA2, CA9, CA12, DNMT1, RIMS2, RPGRIP1L and ZEB2 as the core targets. Except for ZEB2, which is predominantly expressed in brain tissue, the remaining seven genes show tissue specificity and high expression in the gastrointestinal tract. RIMS2 possesses a high mutation phenomenon in pan-cancer, while a validated ceRNA network of eight genes was constructed. The core genes are involved in several signaling pathways, including the one-carbon metabolic process, carbonate dehydratase activity and others. This study may help us to further understand the pharmacological mechanisms of echinacoside and provide new guidance and ideas to guide the treatment of Hirschsprung disease.
Topics: Humans; Hirschsprung Disease; Powders; Molecular Docking Simulation; Glycosides
PubMed: 37679133
DOI: 10.3934/mbe.2023636 -
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 -
International Journal of Surgery Case... Sep 2023Entamoeba histolytica is an anaerobic protozoan. It infects humans causing Amoebiasis. Most infections are asymptomatic; however, clinical manifestations include...
INTRODUCTION AND IMPORTANCE
Entamoeba histolytica is an anaerobic protozoan. It infects humans causing Amoebiasis. Most infections are asymptomatic; however, clinical manifestations include intestinal or extraintestinal. In rare instances, patients can present with Ameboma: a mass of granulation tissue consisting of a core of inflammation with peripheral fibrosis related to chronic amoebic infection usually found in the cecum/ascending colon.
PRESENTATION OF CASE
A 50-year-old patient presented with signs and symptoms of bowel obstruction. He had raised inflammatory markers and was HIV positive on treatment and virally suppressed. At laparotomy a hepatic flexure stricture with desmoid reaction, and wall thickening with induration at the mesenteric border of mid-transverse colon was found, with disseminated nodular disease. Histology confirmed entamoeba histolytica infection.
DISCUSSION
The parasite exists in two forms: a cyst stage and a trophozoite stage: the form causing invasive disease. The presentation of intestinal amoebiasis ranges from an asymptomatic carrier state, colitis, to abscess formation and bowel perforation The management principles: to eliminate the invading trophozoites and eradicate the organism's intestinal carriage and manage complications such as obstruction, fulminant colitis, or toxic megacolon with surgery.
CONCLUSION
This case identifies a rare cause of bowel obstruction in a patient without a travel history. Even with the lack of significant risk factors other than HIV, clinicians should be aware of the infective causes of colonic mass/stricture outside of malignant causes. Entamoeba histolytica is an infection of impoverished communities in developing countries, it should remain high on our differential for tumour-like granulation tissue in the colon.
PubMed: 37657387
DOI: 10.1016/j.ijscr.2023.108768 -
Biology Aug 2023(), responsible for 15-25% of gastrointestinal infections, causes health problems mainly due to the toxic activity of toxins A and B (Tcds). These are responsible for... (Review)
Review
(), responsible for 15-25% of gastrointestinal infections, causes health problems mainly due to the toxic activity of toxins A and B (Tcds). These are responsible for its clinical manifestations, including diarrhea, pseudomembranous colitis, toxic megacolon and death, with a mortality of 5-30% in primary infection, that increase following relapses. Studies on Tcd-induced cell death have highlighted a key role of caspases, calpains, and cathepsins, with involvement of mitochondria and reactive oxygen species (ROS) in a complex signaling pathway network. The complex response in the execution of various types of cell death (apoptosis, necrosis, pyroptosis and pyknosis) depends on the amount of Tcd, cell types, and Tcd receptors involved, and could have as initial/precocious event the alterations in calcium homeostasis. The entities, peculiarities and cell types involved in these alterations will decide the signaling pathways activated and cell death type. Calcium homeostasis alterations can be caused by calcium influx through calcium channel activation, transient intracellular calcium oscillations, and leakage of calcium from intracellular stores. These increases in cytoplasmic calcium have important effects on all calcium-regulated molecules, which may play a direct role in several cell death types and/or activate other cell death effectors, such as caspases, calpains, ROS and proapoptotic Bcl-2 family members. Furthermore, some support for the possible role of the calcium homeostasis alteration in Tcd-induced cell death originates from the similarity with cytotoxic effects that cause pore-forming toxins, based mainly on calcium influx through plasma membrane pores.
PubMed: 37627001
DOI: 10.3390/biology12081117 -
Proceedings of the National Academy of... Aug 2023The receptor tyrosine kinase RET plays a critical role in the fate specification of enteric neural crest-derived cells (ENCDCs) during enteric nervous system (ENS)...
The receptor tyrosine kinase RET plays a critical role in the fate specification of enteric neural crest-derived cells (ENCDCs) during enteric nervous system (ENS) development. loss of function (LoF) is associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. Although the major phenotypic consequences and the underlying transcriptional changes from LoF in the developing ENS have been described, cell type- and state-specific effects are unknown. We performed single-cell RNA sequencing on an enriched population of ENCDCs from the developing GI tract of null heterozygous and homozygous mice at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: 1) -expressing ENCDCs are a heterogeneous population comprising ENS progenitors as well as glial- and neuronal-committed cells; 2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under LoF, leaving behind a mostly excitatory motor neuron developmental program; 3) expression patterns of HSCR-associated and gene regulatory network genes are impacted by LoF; and 4) deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which contributes to multiple distinct cellular phenotypes during development of the ENS, including the specification of inhibitory neuron subtypes, cell cycle dynamics of ENS progenitors, and the developmental timing of neuronal and glial commitment.
Topics: Animals; Mice; Cell Differentiation; Cell Proliferation; Enteric Nervous System; Hirschsprung Disease; Neural Crest; Proto-Oncogene Proteins c-ret
PubMed: 37585461
DOI: 10.1073/pnas.2211986120