Extended total colonic aganglionosis and total intestinal aganglionosis: Challenging enemies.

AIM: Extended total colonic aganglionosis (ETCA) represents uncommon forms of Hirschsprung disease (HD), with aganglionosis extending into the proximal small bowel. ETCA management is challenging and associated with poor outcomes and high mortality. This study compares management and outcomes of ETCA to more common HD forms. METHODS: A retrospective cohort of HD patients (2012-2023) from two institutions. Three HD forms were compared: short-segment HD (SSHD, n = 19), long-segment HD or total colonic aganglionosis (LS/TCA, n = 9) and ETCA (n = 7). RESULTS: Normally innervated segments in ETCA patients ranged 0-70 cm. Median times to first surgery were; ETCA = 3 days versus TCA = 21 days (p = 0.017) and SSHD = 95 days (p < 0.001), respectively. Median number of surgeries were; ETCA = 4, versus TCA = 2 (p = 0.17) and SSHD = 1 (p = 0.002), respectively. All the patients underwent a definitive pull-through procedure, except four ETCA patients with a permanent jejunostomy and residual aganglionic segment of 57-130 cm. ETCA patients had 92% lower odds of enterocolitis (14%) compared to TCA patients (67%, p = 0.054), and comparable odds to SSHD patients (16%, p = 0.92). ETCA mortality was 14%. CONCLUSION: Extended total colonic aganglionosis patients require earlier and multiple interventions. Leaving an aganglionic segment may be advantageous, without increasing risk for enterocolitis. Tailored surgical treatment and rehabilitation programmes may prevent mortality and need for transplantation.

Mmp2 Deficiency Leads to Defective Parturition and High Dystocia Rates in Mice.

Parturition is the final and essential step for mammalian reproduction. While the uterus is quiescent during pregnancy, fundamental changes arise in the myometrial contractility, inducing fetal expulsion. Extracellular matrix (ECM) remodeling is fundamental for these events. The gelatinases subgroup of matrix metalloproteinases (MMPs), MMP2 and MMP9, participate in uterine ECM remodeling throughout pregnancy and parturition. However, their loss-of-function effect is unknown. Here, we determined the result of eliminating Mmp2 and/or Mmp9 on parturition in vivo, using single- and double-knockout (dKO) mice. The dystocia rates were measured in each genotype, and uterine tissue was collected from nulliparous synchronized females at the ages of 2, 4, 9 and 12 months. Very high percentages of dystocia (40-55%) were found in the Mmp2-/- and dKO females, contrary to the Mmp9-/- and wild-type females. The histological analysis of the uterus and cervix revealed that Mmp2-/- tissues undergo marked structural alterations, including highly enlarged myometrial, endometrial and luminal cavity. Increased collagen deposition was also demonstrated, suggesting a mechanism of extensive fibrosis in the Mmp2-/- myometrium, which may result in dystocia. Overall, this study describes a new role for MMP2 in myometrium remodeling during mammalian parturition process, highlighting a novel cause for dystocia due to a loss in MMP2 activity in the uterine tissue.

Age as an Exclusion Criterion for Nonoperative Management in Simple Acute Appendicitis in Children.

OBJECTIVE: Nonoperative management (NOM) for simple acute appendicitis (SAA) is an acceptable mode of treatment in healthy children. Previous studies of NOM routinely excluded young children (< 5 years); however, the effect of age on NOM failure has not been directly assessed. Efficiency of NOM in young adults is questionable. Therefore, adolescents may also be at greater risk of NOM failure. Our aim was to investigate the effect of age on NOM failure. METHODS: This is a retrospective analysis of children with SAA who received NOM between January 1, 2019, and June 30, 2021, at our institution. NOM failure was defined by subsequent appendectomy. Age was assessed as a continuous variable, and we also compared different age subgroups. RESULTS: In this study, 151 children were included (60% male), mean age 11.2 ± 3.2 years (range: 5-17). Overall, 66 children (44%) failed NOM, 90% of them within the first year (median 7 weeks). Ten percent of the cohort were younger than 6 years of age and 33% of them failed NOM (p = 0.39). Per 1 year increase in age, the odds of NOM failure increased by 12% (p = 0.027). Children over 14 years of age had 2.46 times higher odds to fail NOM (p = 0.03). These higher odds remained after adjusting for appendiceal diameter and appendicolith. Linear regression showed a decrease by a factor of 12 at the time of NOM failure with every 1-year increase in age (ß = -12, p = 0.09). CONCLUSION: The risk of NOM failure in children increases with age; therefore, age should be considered when deciding on the optimal management of SAA, especially in adolescents. Effectiveness of NOM in children younger than 6 years is noninferior to older children and therefore should not be excluded.

The Use of Post-Natal Skeleton Development as Sensitive Preclinical Model to Test the Quality of Alternative Protein Sources in the Diet.

Dietary protein is necessary throughout all life stages. Adequate intake of protein during juvenile years is essential to enable appropriate synthesis of bone matrix and achieve the full peak bone mass (PBM). Due to socio-demographic changes, accompanied by environmental damage and ethical problems, a transition to the consumption of different and alternative protein sources in the human diet must occur. This transition requires the precise evaluation of protein quality. Here, we utilize a preclinical model of young rats during their post-natal developmental period to define the nutritive quality of a number of alternative protein sources (soy, spirulina, chickpea, and fly larvae) by their health impact on growth performance and skeletal development. We indicate that when restricted (10% of calories) not one of the tested alternative protein sources have succeeded in causing optimal growth, as compared to the referenced source, casein; yet fly larvae protein followed by chickpea flour were found to be superior to the rest. Growth-plate histology and µ-CT analyses demonstrated a number of changes in growth patterns and bone morphometric parameters. Bone mechanical testing, by three-point bending analyses, was sensitive in demonstrating the effect of the reduction in the amount of the dietary protein. Moreover, the rats' weight and length, as well as their eating patterns, were found to reflect the proteins' quality better than their amino acid composition. Hence, our study emphasizes the importance of evaluating protein as a whole food source, and suggests a new approach for this purpose.

Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder.

Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic- and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.