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The Surgical Clinics of North America Jun 2024Inflammatory bowel disease (IBD) patients are at risk for undergoing emergency surgery for fulminant disease, toxic megacolon, bowel perforation, intestinal obstruction,... (Review)
Review
Inflammatory bowel disease (IBD) patients are at risk for undergoing emergency surgery for fulminant disease, toxic megacolon, bowel perforation, intestinal obstruction, or uncontrolled gastrointestinal hemorrhage. Unfortunately, medical advancements have failed to significantly decrease rates of emergency surgery for IBD. It is therefore important for all acute care and colorectal surgeons to understand the unique considerations owed to this often-challenging patient population.
Topics: Humans; Inflammatory Bowel Diseases; Emergencies; Intestinal Obstruction; Intestinal Perforation; Digestive System Surgical Procedures; Gastrointestinal Hemorrhage
PubMed: 38677830
DOI: 10.1016/j.suc.2023.11.012 -
Annals of Neurology Nov 2023GM2 gangliosidosis is usually fatal by 5 years of age in its 2 major subtypes, Tay-Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no...
OBJECTIVE
GM2 gangliosidosis is usually fatal by 5 years of age in its 2 major subtypes, Tay-Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no effective treatment today, and children succumb to the disease after a protracted neurodegenerative course and semi-vegetative state. This study seeks to further develop adeno-associated virus (AAV) gene therapy for human translation.
METHODS
Cats with Sandhoff disease were treated by intracranial injection of vectors expressing feline β-N-acetylhexosaminidase, the enzyme deficient in GM2 gangliosidosis.
RESULTS
Hexosaminidase activity throughout the brain and spinal cord was above normal after treatment, with highest activities at the injection sites (thalamus and deep cerebellar nuclei). Ganglioside storage was reduced throughout the brain and spinal cord, with near complete clearance in many regions. While untreated cats with Sandhoff disease lived for 4.4 ± 0.6 months, AAV-treated cats lived to 19.1 ± 8.6 months, and 3 of 9 cats lived >21 months. Correction of the central nervous system was so effective that significant increases in lifespan led to the emergence of otherwise subclinical peripheral disease, including megacolon, enlarged stomach and urinary bladder, soft tissue spinal cord compression, and patellar luxation. Throughout the gastrointestinal tract, neurons of the myenteric and submucosal plexuses developed profound pathology, demonstrating that the enteric nervous system was inadequately treated.
INTERPRETATION
The vector formulation in the current study effectively treats neuropathology in feline Sandhoff disease, but whole-body targeting will be an important consideration in next-generation approaches. ANN NEUROL 2023;94:969-986.
Topics: Child; Animals; Cats; Humans; Sandhoff Disease; Multiple Organ Failure; Genetic Vectors; Central Nervous System; Gangliosidoses, GM2; Genetic Therapy
PubMed: 37526361
DOI: 10.1002/ana.26756 -
Cureus Oct 2023Hirschsprung disease in newborns can be a potentially life-threatening condition, with risks for complications such as Hirschsprung-associated enterocolitis. Accessing...
OBJECTIVE
Hirschsprung disease in newborns can be a potentially life-threatening condition, with risks for complications such as Hirschsprung-associated enterocolitis. Accessing health information in a readable format for complex diseases demonstrates an important outlet for families to address concerns. While it is important to seek out information from trusted providers, many individuals seek out ways to educate themselves further by using common search engines and turning to the internet. This article will evaluate the readability of relevant articles on Hirschsprung disease and information accessibility to the average health literacy individual.
METHODS
A readability analysis of the first 20 Google search results from the keywords "Hirschsprung disease" and "aganglionic megacolon" was performed. Results were documented and averaged using standardized scoring systems. Scoring systems included an Automated Readability Index, Coleman Liau index, SMOG index, Gunning Fog score, Flesch Kinkaid grade level, Flesch Kinkaid reading ease, and average readability across all scoring systems. The number of sentences, number of words, number of complex words, percent of complex words, average words per sentence, and average syllables per word were included as a sample of criteria within scoring systems.
RESULTS
The average readability score for the first 20 search results of keywords "Hirschsprung disease" and "aganglionic megacolon" was 9.4, indicating a reading level just above the ninth grade. Readability ease was scored separately due to its unique scoring system on a scale of 0-100. Flesch Kincaid Readability ease score was averaged and resulted in a score of 46.4, which is considered "college level" or "difficult."
CONCLUSIONS
The average health consumer will turn to Google to find information about their own health, as well as the health of their loved ones. Hirschsprung disease in newborns presents a complex disease process and can be potentially life-threatening. Current resources available to the average health consumer averaged at a grade level of 9.4 relative to search results from keywords "Hirschsprung disease" and "aganglionic megacolon." Depending on the target audience for online information, more work needs to be done to improve readability for the average health information consumer.
PubMed: 37954798
DOI: 10.7759/cureus.46806 -
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 -
Toxins May 2024, a Gram-positive anaerobic bacterium, is the leading cause of hospital-acquired antibiotic-associated diarrhea worldwide. The severity of infection (CDI) varies,... (Review)
Review
, a Gram-positive anaerobic bacterium, is the leading cause of hospital-acquired antibiotic-associated diarrhea worldwide. The severity of infection (CDI) varies, ranging from mild diarrhea to life-threatening conditions such as pseudomembranous colitis and toxic megacolon. Central to the pathogenesis of the infection are toxins produced by , with toxin A (TcdA) and toxin B (TcdB) as the main virulence factors. Additionally, some strains produce a third toxin known as transferase (CDT). Toxins damage the colonic epithelium, initiating a cascade of cellular events that lead to inflammation, fluid secretion, and further tissue damage within the colon. Mechanistically, the toxins bind to cell surface receptors, internalize, and then inactivate GTPase proteins, disrupting the organization of the cytoskeleton and affecting various Rho-dependent cellular processes. This results in a loss of epithelial barrier functions and the induction of cell death. The third toxin, CDT, however, functions as a binary actin-ADP-ribosylating toxin, causing actin depolymerization and inducing the formation of microtubule-based protrusions. In this review, we summarize our current understanding of the interaction between toxins and host cells, elucidating the functional consequences of their actions. Furthermore, we will outline how this knowledge forms the basis for developing innovative, toxin-based strategies for treating and preventing CDI.
Topics: Clostridioides difficile; Bacterial Toxins; Host Microbial Interactions; Clostridium Infections; Gene Order; Inflammation; Humans; Animals
PubMed: 38922136
DOI: 10.3390/toxins16060241 -
Journal of Pediatric Surgery Aug 2023Hirschsprung-associated enterocolitis (HAEC) is the most common cause of morbidity and mortality amongst patients with Hirschsprung disease (HD); rectal Botulinum toxin... (Review)
Review
BACKGROUND
Hirschsprung-associated enterocolitis (HAEC) is the most common cause of morbidity and mortality amongst patients with Hirschsprung disease (HD); rectal Botulinum toxin (Botox) has been reported a possible prevention strategy. We aimed to evaluate our institution's historic cohort of HD patients, first to determine our incidence of HAEC and second to begin assessing the effect of Botox on HAEC incidence.
METHODS
Patients with HD seen at our institution between 2005 and 2019 were reviewed. Incidence of HD and frequencies of HAEC and Botox injections were tallied. Associations between initial Botox treatment or transition zone and HAEC incidence were evaluated.
RESULTS
We reviewed 221 patients; 200 were included for analysis. One hundred thirteen (56.5%) patients underwent primary pull-through at a median age of 24 days (IQR 91). Eighty-seven (43.5%) patients with initial ostomy had their intestinal continuity reestablished at a median of 318 days (IQR 595). Ninety-four (49.5%) experienced at least one episode of HAEC and 62 (66%) experienced multiple episodes of HAEC. Nineteen (9.6%) patients had total colonic HD and had an increased total incidence of HAEC compared to patients without total colonic HD (89% vs 44%, p < 0.001). Six (2.9%) patients received Botox injections at the time of pull-through or ostomy takedown; one experienced an episode of HAEC (versus 50.7% of the patients who were confirmed to have not received Botox injections at their surgery, p = 0.102).
CONCLUSION
Further prospective study on Botox's effect on Hirschsprung-associated enterocolitis is required and is the next step in our investigation.
LEVEL OF EVIDENCE
Level III.
Topics: Humans; Infant; Retrospective Studies; Prospective Studies; Botulinum Toxins, Type A; Hirschsprung Disease; Enterocolitis; Rectum; Postoperative Complications
PubMed: 37221126
DOI: 10.1016/j.jpedsurg.2023.04.008 -
World Journal of Gastroenterology Sep 2023Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious... (Review)
Review
Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung's disease (HD), meconium ileus due to Cystic Fibrosis, The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis, such as anorectal manometry or rectal suction biopsy. What if there was another etiology of perinatal constipation, that is far lesser known? Cow's milk protein allergy (CMPA) is often diagnosed in infants within the first few weeks of life, however, there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero, therefore allowing symptoms to show as early as day one of life. The presentation is more atypical, with perinatal constipation rather than with bloody stools, diarrhea, and vomiting. The diagnosis and management would be avoidance of cow's milk protein within the diet, with results and symptom improvement in patients immediately. Therefore, we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients. This entails first ruling out CMPA with safe, noninvasive techniques with diet modification, and if unsuccessful, then moving forward with further diagnostic modalities.
Topics: Animals; Cattle; Female; Infant; Pregnancy; Humans; Milk Hypersensitivity; Constipation; Biopsy; Diarrhea; Hirschsprung Disease
PubMed: 37731998
DOI: 10.3748/wjg.v29.i33.4920 -
Tropical Medicine and Infectious Disease Nov 2023infection (CDI) is a leading nosocomial infection, posing a substantial public health challenge within the United States and globally. CDI typically occurs in... (Review)
Review
infection (CDI) is a leading nosocomial infection, posing a substantial public health challenge within the United States and globally. CDI typically occurs in hospitalized elderly patients who have been administered antibiotics; however, there has been a rise in the occurrence of CDI in the community among young adults who have not been exposed to antibiotics. releases toxins, which damage large intestinal epithelium, leading to toxic megacolon, sepsis, and even death. Unfortunately, existing antibiotic therapies do not always prevent these consequences, with up to one-third of treated patients experiencing a recurrence of the infection. Host factors play a crucial role in the pathogenesis of CDI, and accumulating evidence shows that modulation of host immune responses may potentially alter the disease outcome. In this review, we provide an overview of our current knowledge regarding the role of innate and adaptive immune responses on CDI outcomes. Moreover, we present a summary of non-antibiotic microbiome-based therapies that can effectively influence host immune responses, along with immunization strategies that are intended to tackle both the treatment and prevention of CDI.
PubMed: 38133438
DOI: 10.3390/tropicalmed8120506 -
European Journal of Human Genetics :... Jun 2024Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is...
Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis.
Topics: Humans; DNA Methylation; Intellectual Disability; Zinc Finger E-box Binding Homeobox 2; Microcephaly; Hirschsprung Disease; Homeodomain Proteins; Repressor Proteins; Female; Male; Facies; Child; Child, Preschool; Adolescent; CpG Islands
PubMed: 38351292
DOI: 10.1038/s41431-024-01548-4 -
Pediatric Surgery International Nov 2023Children with Hirschsprung's disease (HD) and anorectal malformations (ARM) may benefit from a bowel management program (BMP) to treat constipation and fecal...
PURPOSE
Children with Hirschsprung's disease (HD) and anorectal malformations (ARM) may benefit from a bowel management program (BMP) to treat constipation and fecal incontinence. This study describes a pilot BMP in Uganda.
METHODS
Patients treated for HD or ARM were recruited for the BMP. Local staff underwent training and progressively took over decision-making. The rates of patient involuntary bowel movements (IBMs) and provider confidence were evaluated pre- and post-BMP with questionnaires. The results were compared with Fischer's exact test.
RESULTS
Ten staff-2 surgeons, 6 nurses and 2 physiotherapists-and 12 patients participated. Patient median age was 4.5 years (IQR 3-6.6) and ten were male. Ten reported at least daily IBMs prior to the BMP. All patients underwent a clean-out. The parents were then taught to perform daily enemas or irrigations. Specific regimens were determined by patient history and imaging and titrated throughout the BMP. There were differences in the rates of both daytime and nighttime IBMs before and after the BMP (p = 0.0001 and 0.002, respectively). All staff reported increased confidence.
CONCLUSIONS
We describe the first BMP in Uganda. BMPs can successfully treat constipation and fecal incontinence in low-income countries, although there are challenges with resources and follow-up.
Topics: Child; Humans; Male; Child, Preschool; Female; Fecal Incontinence; Uganda; Constipation; Defecation; Hirschsprung Disease; Anorectal Malformations; Hospitals
PubMed: 37962686
DOI: 10.1007/s00383-023-05574-z