Spontaneous intestinal perforation (SIP) will soon become the most common form of surgical bowel disease in the extremely low birth weight (ELBW) infant.

Recent data have revealed declines in the prevalence rates of NEC over the last decade in premature infants. In contrast, SIP has either remained steady or risen during the same epoch. These trends are consistent with our knowledge of the clinical arena.

Changing the paradigm of defining, detecting, and diagnosing NEC: Perspectives on Bell's stages and biomarkers for NEC.

Better means to diagnose and define necrotizing enterocolitis are needed to guide clinical practice and research. Adequacy of Bell's staging system for clinical practice and clarity of cases used in NEC clinical datasets has been a topic of controversy for some time. This article provides reasons why a better global definition for NEC is needed and offers a simple alternative bedside definition for preterm NEC called the "Two out of Three" rule.

A critical question for NEC researchers: Can we create a consensus definition of NEC that facilitates research progress?

In the last decades the reported incidence of preterm necrotizing enterocolitis (NEC) has been declining in large part due to implementing comprehensive NEC prevention initiatives, including breast milk feeding, standardized feeding protocols, transfusion guidelines, and antibiotic stewardship and improving the rigor with which non-NEC cases are excluded from NEC data. However, after more than 60 years of NEC research in animal models, the promise of a "magic bullet" to prevent NEC has yet to materialize. There are also serious issues involving clinical NEC research.

Necrotizing enterocolitis is one disease with many origins and potential means of prevention.

Background: The field of necrotizing enterocolitis (NEC) research has been in existence for over 60 years. During the first five decades little progress in NEC prevention and no definitive progress in treatment was achieved. One of the major determinants of this ineffectiveness may have been a global propensity to lump NEC into a single disease entity rather than a spectrum of diseases with a common outcome.

Necrotizing enterocolitis in term infants.

This article is an overview of NEC in term neonates and also summarizes data from 52 cases within Intermountain Healthcare during the last 11 years. In all 52, NEC occurred among neonates already admitted to a neonatal intensive care unit for some other reason; thus, NEC invariably developed as a complication of treatment, not as a primary diagnosis. The authors speculate that the incidence of term NEC can be reduced by identifying neonatal intensive care unit patients at risk for NEC and applying appropriate-volume human milk feeding programs for these patients.

Ileal Immunoglobulin Binding by the Neonatal Fc Receptor: A Previously Unrecognized Mechanism of Protection in the Neonatal Rat Model of Necrotizing Enterocolitis?

Background: Mucosal apoptosis is the initiating event in models of necrotizing enterocolitis (NEC) within rodents. It is possible there are species-specific differences that make apoptosis a more prominent feature of NEC in rodents than in humans.

Hypothesis: A lower threshold for mucosal apoptosis in the rodent distal intestine might have evolutionary advantages (via enhanced opsonization with the neonatal Fc receptor [FcRn]), since many short-gestation mammals are comparatively premature (histomorphologically) but are protected from NEC by breast milk.

Understanding clinical literature relevant to spontaneous intestinal perforations.

Spontaneous intestinal perforation (SIP) has emerged as a disease of extremely low-birth-weight (ELBW) infants over the last two decades. Several risk factors have been associated with this disease including early postnatal steroids (EPS; use within the first week of life), early use of indomethacin (EUI; use within the first 3 postnatal days), and the synergistic combination of the two. These two risk factors are thought to play a causal role in the etiology of SIP through their effects on ileal trophism and motility.

Understanding intestinal vulnerability to perforation in the extremely low birth weight infant.

Spontaneous intestinal perforation (SIP) occurs commonly in extremely low birth weight (ELBW) infants. Our understanding of its etiologies has improved dramatically over the last decade. Included in this comprehension is an ongoing reconciliation of the iatrogenic risk factors, the microbiology, and the histopathology.

An analysis of IGFBP evolution.

Objectives: To perform a synonymous, non-synonymous codon mutational analysis of the IGFBP gene family and identify mechanisms by which the IGFBP subfamilies diverged.

Methods: We identified 78 intact nucleotide sequences from 6 IGFBP subfamilies and 12 different species and used them for phylogenetic and synonymous, non-synonymous codon mutational analysis. Deletion and insertion comparisons were performed across subfamilies to determine if this might play a unique role in subfamily genesis.

A role for plasmin in platelet aggregation: differential regulation of IGF release from IGF-IGFBP complexes?

Objectives: To determine if plasmin differentially augments platelet aggregation through variable efficiencies of IGF-IGFBP complex cleavage.

Methods: We utilized ADP-triggered platelet aggregation assays to test the effects of IGF-I versus IGF-II in complex with IGFBP-2 or IGFBP-3 upon the efficiency of plasmin (a known IGFBP protease) as a pro-aggregatory stimulus. In vitro proteolysis assays were performed as controls.

A neonatal mouse model of intestinal perforation: investigating the harmful synergism between glucocorticoids and indomethacin.

Background: Early postnatal steroids and indomethacin in combination have been shown to increase the risk of spontaneous intestinal perforation (SIP) in infants with extremely low birth weight (ELBW), but the mechanism behind this synergistic effect is unknown.

Materials And Methods: Based on literature in a variety of models suggesting that glucocorticoids and nonsteroidal antiinflammatory agents diminish complementary isoforms of nitric oxide synthase (NOS), we hypothesized that perturbations in NO metabolism contribute to SIP.

Results: Our results using newborn wild-type (WT) and endothelial NOS-knockout (eNOS KO) mice treated with dexamethasone and/or indomethacin indicate that indomethacin treatment diminishes ileal eNOS abundance; dexamethasone treatment diminishes ileal inducible NOS and neuronal NOS (nNOS); 100% of dexamethasone-treated eNOS KO mice die after 3 days; eNOS KO mice treated for 2 days with dexamethasone develop acute pyloric stenosis in association with reduced expression of pyloric nNOS; and isolated ileum from eNOS KO mice treated for 2 days with dexamethasone exhibit a significant decrease in spontaneous peristalsis, decreased circumference, and decreased capacitance for forced volume before ileal perforation compared with ileum from untreated controls.

A 14-kDa cathepsin L-derived carboxyl IGFBP-2 fragment is sequestered by cultured rat ileal crypt cells.

IGF-II gut drives mucosal growth during gestation. IGF binding protein-2 (IGFBP-2) has a high affinity for IGF-II and tightly regulates IGF-II availability during fetal and early neonatal growth. We have previously demonstrated that glucocorticoids alter IGF homeostasis in the neonatal ileum, but the mechanism(s) by which this occurs is poorly understood.

A methodology for distinguishing divergent cell fates within a common progenitor population: adenoma- and neuroendocrine-like cells are confounders of rat ileal epithelial cell (IEC-18) culture.

Background: IEC-18 cells are a non-transformed, immortal cell line derived from juvenile rat ileal crypt cells. They may have experimental advantages over tumor-derived gastrointestinal lineages, including preservation of phenotype, normal endocrine responses and retention of differentiation potential. However, their proclivity for spontaneous differentiation/transformation may be stereotypical and could represent a more profound experimental confounder than previously realized.

A randomized-controlled trial of prophylactic hydrocortisone supplementation for the prevention of hypotension in extremely low birth weight infants.

Objective: Extremely low birth weight (ELBW) infants are at risk for hypotension. Abnormal adrenal function may play a role in the pathogenesis of hypotension, and therefore, the administration of hydrocortisone (HC) may be an effective treatment for hypotension in some infants. However, the efficacy of prophylactic HC to prevent the use of vasopressors for a defined hypotensive state has not been studied.

Bladder wall necrosis in an extremely low-birth-weight infant: a thought-provoking complication of necrotizing enterocolitis.

An 879-g baby boy had catastrophic necrotizing enterocolitis (NEC) at 29 days of life and underwent surgical laparotomy with a subsequent ileostomy and peritoneal drain placement. The infant was subsequently stable until 42 days of life when a spontaneous perforation of the bladder apex was diagnosed by a suprapubic cystogram. Laparotomy on day of life 46 found a loop of dead bowel herniating into a necrotic hole of the bladder dome.

Insulin-like growth factor-I governs submucosal growth and thickness in the newborn mouse ileum.

Spontaneous intestinal perforations in extremely premature infants are associated with glucocorticoid-induced thinning of the ileal bowel wall. We have previously demonstrated that insulin-like growth factor-1 (IGF-1) is abundant within the submucosa of the newborn mouse ileum but is diminished by glucocorticoid exposure, concomitant with bowel wall thinning. These findings prompted us to hypothesize that IGF-I governs submucosal growth during neonatal gut development and that diminished IGF-I abundance results in submucosal thinning.

Igf-I accelerates ileal epithelial cell migration in culture and newborn mice and may be a mediator of steroid-induced maturation.

We have previously hypothesized that IGF-I is a mediator of dexamethasone (DEX) effect in the newborn mouse ileum-a model designed to mimic the precocious mucosal maturation associated with spontaneous ileal perforations in extremely premature neonates. We have further investigated this hypothesis using in vivo and in vitro models of accelerated epithelial migration (a transient property, temporally associated with mucosal maturation). These experiments include a steroid-treatment model comparing IGF-I immunolocalization with bromo-deoxyuridine (BrdU)-pulse-labeling, as a means of assessing epithelial cell migration, within the ileum of newborn mice that received either daily intraperitoneal injections of DEX (1 microg/gm) or vehicle.