Gastric Foveolar Hyperplastic Polyps in 2 Children With Short Bowel Syndrome on Long-Term Teduglutide.

The natural history of short bowel syndrome involves intestinal adaptation wherein the remnant small intestine undergoes histologic and anatomic changes aimed at increasing absorption. Teduglutide-a glucagon-like peptide 2 analog approved for pediatric use in 2019-stimulates this process by causing proliferation of intestinal epithelial cells resulting in increased villous height and crypt depth. Food and Drug Administration approval for pediatric patients followed safety and efficacy studies in children that were limited to 24-week duration. Pediatric-specific postmarketing studies evaluating long-term safety and efficacy are underway. Formation of colorectal polyps has been repeatedly observed in studies of adult patients on long-term teduglutide, including in individuals without endoscopic evidence of polyps before treatment initiation. Recent studies, however, suggest increased risk of small bowel hyperplastic and dysplastic polyp formation with long-term glucagon-like peptide 2 analog use. We report 2 cases of small bowel foveolar hyperplastic polyps found during surveillance endoscopies after 1 year of treatment with teduglutide.

Patient-derived enteroids provide a platform for the development of therapeutic approaches in microvillus inclusion disease.

Microvillus inclusion disease (MVID), caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid/base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na+/H+ exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking antidiarrheal drug crofelemer dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. γ-Secretase inhibition with DAPT recovered apical brush border structure and functional Na+/H+ exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum/glucocorticoid-regulated kinase 2 (SGK2) and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID.

Therapy Development for Microvillus Inclusion Disease using Patient-derived Enteroids.

Microvillus Inclusion Disease (MVID), caused by loss-of-function mutations in the motor protein Myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid-base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex Immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na + /H + exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking anti-diarrheal drug, Crofelemer, dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. Inhibition of Notch signaling with the γ-secretase inhibitor, DAPT, recovered apical brush border structure and functional Na + /H + exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum- and glucocorticoid-induced protein kinase 2 (SGK2), and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID. Conflict-of-interest statement: The authors have declared that no conflict of interest exists.

Factors Associated With Chronic Intestinal Inflammation Resembling Inflammatory Bowel Disease in Pediatric Intestinal Failure: A Matched Case-Control Study.

BACKGROUND AND AIMS: There is a subset of intestinal failure patients with associated chronic intestinal inflammation resembling inflammatory bowel disease. This study aimed to evaluate factors associated with chronic intestinal inflammation in pediatric intestinal failure. METHODS: This was a single-center retrospective case-control study of children <18 years old with intestinal failure. Cases were defined by abnormal amounts of chronic intestinal inflammation on biopsies. Children with diversion colitis, eosinophilic colitis, or isolated anastomotic ulceration were excluded. Cases were matched 1:2 to intestinal failure controls based on sex, etiology of intestinal failure, and duration of intestinal failure. Multivariable conditional logistic regression was used to compare clinical factors between cases and controls, accounting for clustering within matched sets. A subgroup analysis was performed assessing factors associated with escalation of anti-inflammatory therapy. RESULTS: Thirty cases were identified and matched to 60 controls. On univariate analysis, longer parenteral nutrition (PN) duration (1677 vs 834 days, P = 0.03), current PN use (33.3% vs 20.0%, P = 0.037), and culture-proven bacterial overgrowth (53.3% vs 31.7%, P = 0.05) were associated with chronic intestinal inflammation. On multivariable analysis, no variable reached statistical significance. On subgroup analysis, duration of intestinal failure, location of inflammation, and worst degree of inflammation on histology were associated with escalation of therapy. CONCLUSIONS: PN dependence and intestinal dysbiosis are associated with chronic intestinal inflammation in children with intestinal failure. Severity of inflammation is associated with escalation of therapy. Further analysis is needed to assess these associations and the efficacy of treatments in this population.

Puberty and growth in patients with pediatric intestinal failure.

BACKGROUND: Pediatric intestinal failure (PIF) affects nutrition, metabolism, and endocrine development, but its downstream impact on puberty is unknown. METHODS: A retrospective review was performed of patients age >8 years with PIF managed at an intestinal rehabilitation program. Outcomes of interest were peak height velocity (PHV), age at PHV, and age at pubertal onset (Tanner stage 2). Outcomes were stratified by sex and compared to established norms. RESULTS: Of 110 patients with PIF, 54.5% were male. Compared to the CDC 50th percentile, PHV in PIF patients was similar for females (8.09±2.36 vs. 7.37 cm/yr;p = 0.23) but significantly higher for males (9.27±2.56 vs. 7.91 cm/yr;p = 0.038). Age at PHV in PIF patients was significantly younger for both males (12.31±2.14 vs. 13.38 years;p = 0.049) and females (10.70±1.06 vs. 11.71 years;p = 0.001). PIF patients reached pubertal onset earlier than published norms; this was significant for males (12.41±1.80 vs. 13.44 years;p = 0.014), but not for females (10.45±1.81 vs. -11.15 years;p = 0.13). The mean height-for-age Z-score was -1.2, with 20% of patients having a Z-score less than -2. CONCLUSIONS: Pubertal onset and growth are neither delayed nor diminished in patients with PIF. The high incidence of short stature, however, highlights the importance of optimizing prepubertal linear growth to attain full height potential. TYPE OF STUDY: Prognosis study (Retrospective cohort study).

Novel variants in the stem cell niche factor WNT2B define the disease phenotype as a congenital enteropathy with ocular dysgenesis.

WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein's putative involvement in multiple developmental and stem cell maintenance pathways.

Is Serum Methylmalonic Acid a Reliable Biomarker of Vitamin B12 Status in Children with Short Bowel Syndrome: A Case Series.

We describe 3 patients with short bowel syndrome who had persistently elevated serum methylmalonic acid (MMA) levels while being treated for vitamin B12 deficiency. Following treatment for presumed small bowel bacterial overgrowth, MMA levels normalized. Among patients with short bowel syndrome, MMA levels may have limited specificity for vitamin B12 deficiency.

Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications.

In the last 30 years, since the discovery that vanadium is a cofactor found in certain enzymes of tunicates and possibly in mammals, different vanadium-based drugs have been developed targeting to treat different pathologies. So far, the in vitro studies of the insulin mimetic, antitumor and antiparasitic activity of certain compounds of vanadium have resulted in a great boom of its inorganic and bioinorganic chemistry. Chemical speciation studies of vanadium with amino acids under controlled conditions or, even in blood plasma, are essential for the understanding of the biotransformation of e.g. vanadium antidiabetic complexes at the physiological level, providing clues of their mechanism of action. The present article carries out a bibliographical research emphaticizing the chemical speciation of the vanadium with different amino acids and reviewing also some other important aspects such as its chemistry and therapeutical applications of several vanadium complexes.

Timing of the initiation of parenteral nutrition in critically ill children.

PURPOSE OF REVIEW: To review the current literature evaluating clinical outcomes of early and delayed parenteral nutrition initiation among critically ill children. RECENT FINDINGS: Nutritional management remains an important aspect of care among the critically ill, with enteral nutrition generally preferred. However, inability to advance enteral feeds to caloric goals and contraindications to enteral nutrition often leads to reliance on parenteral nutrition. The timing of parenteral nutrition initiation is varied among critically ill children, and derives from an assessment of nutritional status, energy requirements, and physiologic differences between adults and children, including higher nutrient needs and lower body reserves. A recent randomized control study among critically ill children suggests improved clinical outcomes with avoiding initiation of parenteral nutrition on day 1 of admission to the pediatric ICU. SUMMARY: Although there is no consensus on the optimal timing of parenteral nutrition initiation among critically ill children, recent literature does not support the immediate initiation of parenteral nutrition on pediatric ICU admission. A common theme in the reviewed literature highlights the importance of accurate assessment of nutritional status and energy expenditure in deciding when to initiate parenteral nutrition. As with all medical interventions, the initiation of parenteral nutrition should be considered in light of the known benefits of judiciously provided nutritional support with the known risks of artificial, parenteral feeding.

Socially induced brain development in a facultatively eusocial sweat bee Megalopta genalis (Halictidae).

Changes in the relative size of brain regions are often dependent on experience and environmental stimulation, which includes an animal's social environment. Some studies suggest that social interactions are cognitively demanding, and have examined predictions that the evolution of sociality led to the evolution of larger brains. Previous studies have compared species with different social organizations or different groups within obligately social species. Here, we report the first intraspecific study to examine how social experience shapes brain volume using a species with facultatively eusocial or solitary behaviour, the sweat bee Megalopta genalis. Serial histological sections were used to reconstruct and measure the volume of brain areas of bees behaving as social reproductives, social workers, solitary reproductives or 1-day-old bees that are undifferentiated with respect to the social phenotype. Social reproductives showed increased development of the mushroom body (an area of the insect brain associated with sensory integration and learning) relative to social workers and solitary reproductives. The gross neuroanatomy of young bees is developmentally similar to the advanced eusocial species previously studied, despite vast differences in colony size and social organization. Our results suggest that the transition from solitary to social behaviour is associated with modified brain development, and that maintaining dominance, rather than sociality per se, leads to increased mushroom body development, even in the smallest social groups possible (i.e. groups with two bees). Such results suggest that capabilities to navigate the complexities of social life may be a factor shaping brain evolution in some social insects, as for some vertebrates.

Growth hormone-releasing hormone: cerebral cortical sleep-related EEG actions and expression.

Growth hormone-releasing hormone (GHRH), its receptor (GHRHR), and other members of the somatotropic axis are involved in non-rapid eye movement sleep (NREMS) regulation. Previously, studies established the involvement of hypothalamic GHRHergic mechanisms in NREMS regulation, but cerebral cortical GHRH mechanisms in sleep regulation remained uninvestigated. Here, we show that unilateral application of low doses of GHRH to the surface of the rat somatosensory cortex ipsilaterally decreased EEG delta wave power, while higher doses enhanced delta power. These actions of GHRH on EEG delta wave power occurred during NREMS but not during rapid eye movement sleep. Further, the cortical forms of GHRH and GHRHR were identical to those found in the hypothalamus and pituitary, respectively. Cortical GHRHR mRNA and protein levels did not vary across the day-night cycle, whereas cortical GHRH mRNA increased with sleep deprivation. These results suggest that cortical GHRH and GHRHR have a role in the regulation of localized EEG delta power that is state dependent, as well as in their more classic hypothalamic role in NREMS regulation.