What Is New in Pediatric Bone Health.

BACKGROUND: This review paper aims to report on the last 5 years of relevant research on pediatric bone health in regard to nutrition and obesity, ethnic disparities, common orthopaedic conditions, trauma, spine, and sports medicine. METHODS: A search of the PubMed database was completed using the following terms: bone health, Vitamin D, pediatric, adolescent, sports medicine, fractures, spine, scoliosis, race, ethnicity, obesity, Slipped Capital Femoral Epiphysis, Osteogenesis Imperfecta, Duchenne's Muscular Dystrophy, neuromuscular, and cancer. Resultant papers were reviewed by study authors and determined to be of quality and relevance for description in this review. Papers from January 1, 2015 to August 31, 2020 were included. RESULTS: A total of 85 papers were selected for review. General results include 7 key findings. (1) Obesity inhibits pediatric bone health with leptin playing a major role in the process. (2) Socioeconomic and demographic disparities have shown to have a direct influence on bone health. (3) Vitamin D deficiency has been linked to an increased fracture risk and severity in children. (4) Formal vitamin D monitoring can aid with patient compliance with treatment. (5) Patients with chronic medical conditions are impacted by low vitamin D and need ongoing monitoring of their bone health to decrease their fracture risk. (6) Vitamin D deficiency in pediatrics has been correlated to low back pain, spondylolysis, and adolescent idiopathic scoliosis. Osteopenic patients with AIS have an increased risk of curve progression requiring surgery. Before spine fusion, preoperative screening for vitamin D deficiency may reduce complications of fractures, insufficient tissue repair, loosening hardware, and postoperative back pain. (7) Increasing youth sports participation has resulted in increased bone health related injuries. However, improved understanding of Relative Energy Deficiency in Sport effects on bone health has recently occurred. CONCLUSIONS: Increasing awareness of bone health issues in children will improve their recognition and treatment. Further research is needed on diagnosis, treatment, outcomes, and most importantly prevention of pediatric bone health diseases.

Severity of Asynchronous Slipped Capital Femoral Epiphyses in Skeletally Immature Versus More Skeletally Mature Patients.

BACKGROUND: Routine prophylactic screw fixation for skeletally immature patients with slipped capital femoral epiphysis (SCFE) continues to be debated. The purpose of this study was to assess the slip severity of a second SCFE in skeletally immature versus more mature patients and determine necessity of contralateral hip prophylactic screw fixation. METHODS: All patients treated for SCFE at 3 pediatric hospitals over a 10-year time period (January 1, 2002 to December 31, 2011) were evaluated. Patients were included if they had a unilateral SCFE and a contralateral asynchronous SCFE, and were divided into immature (Oxford triradiate score 1) versus more mature (Oxford triradiate score 2 and 3) groups. Data evaluation included age, time between slips, body mass index, Southwick angles of first then second SCFEs, and follow-up duration. RESULTS: There were a total of 45 patients: 16 patients in the skeletally immature and 29 patients in the more mature group. Average age at first SCFE in immature patients was 10.9 years and in more mature patients 12.1 years (P=0.70). Age at second SCFE in immature patients was 11.5 years and in more mature patients 13.0 years (P=0.023). Average time between SCFEs was 6.6 months for immature and 11.4 months for more mature patients (P=0.093). Southwick angles for immature patient first and second SCFEs were 25 and 12.9 degrees, respectively, and for more mature patient first and second SCFEs were 31 and 21 degrees, respectively. Southwick angles were higher at first and second slips in the more mature group, significant only at the second slip (P=0.032). SCFE severity at initial event was predictive of severity of second SCFE regardless of maturity (P=0.043). Regression analysis of slip severity against multiple patient factors demonstrated triradiate score was not a factor assessing subsequent SCFE magnitude (P=0.099). CONCLUSIONS: There was no significant difference between first and second SCFEs regardless of skeletal maturity but severity of initial SCFE did correlate with severity of the second SCFE. Deciding not to prophylactically pin an unaffected hip does not lead to worse deformity if a second SCFE occurs in skeletally immature or more mature patients, unless the initial event is severe. Prophylactic pin fixation in skeletally immature patients should occur as a shared decision between patient, guardians, and treating surgeon. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Vitamin D Deficiency in Children Undergoing Vertical Expandable Prosthetic Titanium Rib Treatment.

BACKGROUND: Vitamin D deficiency is prevalent in the pediatric population and multiple risk factors have been identified. Low vitamin D levels can result in poor bone mineralization and have been associated with a significantly higher risk of forearm fracture in children. Vitamin D deficiency has also been associated with pediatric critical illness. The purpose of this study was to determine whether children undergoing vertical expandable prosthetic titanium rib (VEPTR) treatment have low vitamin D levels. METHODS: Patients undergoing VEPTR treatment at a single institution were prospectively enrolled (VEPTR). All patients either had a diagnosis of thoracic insufficiency syndrome (TIS), or were at risk of developing TIS secondary to progressive scoliosis or chest wall deformity. Exclusion criteria were patients with rickets and patients receiving vitamin D supplementation at the time of VEPTR insertion. A group of healthy children who presented with fractures during the winter season were used as controls (FX). Vitamin D status and risk factors for vitamin D deficiency were evaluated. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25-OH-D) <20 ng/mL and vitamin D insufficiency as serum 25-OH-D between 20 and 29 ng/mL. RESULTS: Twenty-eight VEPTR and 25 FX patients were compared. The average age was 8.6 years in the VEPTR group and 9.1 years in the FX group. Twenty VEPTR patients (71%) and 19 FX patients (76%) demonstrated low vitamin D levels. The average 25-OH-D level was 27.3 ng/mL in the VEPTR group and 25.4 ng/mL in the FX group. Patient characteristics and vitamin D levels were similar between the groups. No association was found between vitamin D status and sex, race, obesity, or multivitamin use. CONCLUSIONS: Low vitamin D levels are common in children undergoing VEPTR treatment. In our series, the prevalence of vitamin D deficiency in this patient population was similar to reported rates in the general pediatric population. Vitamin D status should be routinely monitored in children undergoing VEPTR treatment and supplementation should be initiated if necessary.

The use of arthrography in pediatric orthopaedic surgery.

Surgery near pediatric joints can be challenging because it is difficult to visualize vital articular structures. Assessment of underlying pathology is also challenging because the joint structures have not yet ossified. Arthrography is a useful tool that is quick and minimally invasive and allows adequate visualization of joint anatomy during surgery, which aids intraoperative decision making. In pediatric patients, arthrography is most useful for visualization of the elbow, knee, and hip joints. This tool can help the surgeon to refine the diagnosis and management of pediatric fractures and aids in surgical assessment during joint and limb reconstruction. Arthrography adds minimal time to surgery and carries a low risk of complications; it should be part of the armamentarium of any surgeon who treats pediatric orthopaedic patients.

Perioperative pain control in pediatric patients undergoing orthopaedic surgery.

Management of perioperative pain is critical in the pediatric patient undergoing orthopaedic surgery. A variety of modalities can be used to manage pain and optimize recovery and patient satisfaction, including nonopioid and opioid analgesia; local anesthetic injection; and regional analgesia such as intrathecal morphine, epidural therapy, and peripheral nerve blocks. Acute pain management can be tailored based on the needs of the patient, the surgical site, and the anticipated level of postoperative pain. A preoperative discussion of the plan for perioperative pain control with the patient, his or her parents, and the anesthesiologist can help manage expectations and maximize patient satisfaction.

Reliability of digital radiographs for pediatric lower extremity alignment.

BACKGROUND: Digital radiography is the standard method for sharing and storing radiographs. The purpose of this study was to evaluate the interobserver and intraobserver reliability of computer-based and manual measurement methods in determining lower extremity alignment on digital images of pediatric patients. METHODS: Thirty-two digital standing long leg radiographs of pediatric patients were evaluated with 9 varus, 11 valgus, and 12 neutral alignment films. Six evaluators measured the digital images with a standard computer-based measurement method twice and a manual paper print out method twice. Measurements included the lateral distal femoral angle (LDFA), the medial proximal tibia angle (MPTA), the joint line congruency angle, and the mechanical axis deviation (MAD). Interobserver and intraobserver reliability for computer-based and manual methods were calculated using intraclass correlation coefficients. RESULTS: The interobserver reliability for all angular measurements was found to be fair to good for both measurement methods. The MAD had excellent intraobserver and interobserver reliability. LDFA and MPTA interobserver reliabilities were better by the manual method than the computer-based method. Intraobserver reliability was higher in the computer-based LDFA than manual methods, whereas the MPTA measurements were more reliable by manual methods. CONCLUSIONS: Computer-based and manual methods for determining lower extremity alignment from digital radiographs are not dissimilar and both provide fair to good reliability. The MAD was a highly reliable measurement. Overall, measurement of the digital images was not as reliable by either method as measurement of traditional full-length teloroentgenograms. The observer should be familiar with the measurement program to minimize errors. Digital images can be measured reliably and then used for treatment decisions, however, time and care should be taken with measurements. LEVEL OF EVIDENCE: Diagnostic level II.

A comparison of hip dislocation rates and hip containment procedures after selective dorsal rhizotomy versus intrathecal baclofen pump insertion in nonambulatory cerebral palsy patients.

BACKGROUND: Spasticity is the major etiology for hip dislocation in nonambulatory cerebral palsy patients. Selective dorsal rhizotomy (SDR) was used to control lower extremity spasticity, but is now done infrequently in nonambulatory cerebral palsy. Current surgical treatment is usually intrathecal baclofen pump (ITBP) placement. A major theoretical difference between SDR and ITBP is the effect on the iliopsoas through the L1 nerve root. This study compares the rate of hip dislocation and the need for further hip surgeries in SDR and ITBP patients. METHODS: All nonambulatory cerebral palsy patients who had either an SDR or ITBP and had minimum follow-up of 2 years were retrospectively reviewed for demographic data and timing, total number, and type of hip procedures (soft tissue vs. bony), and occurrence of hip dislocation. χ (2)test was used to assess for statistical significance. RESULTS: Sixty-nine patients who underwent SDR (40 males) and 50 patients who underwent ITBP (27 males) were included in the study. Average age at spasticity intervention was 6 years 11 months for SDR and 9 years 8 months for ITBP. In the SDR group, 25% of hips underwent reconstruction versus 32% of hips in the ITBP group. There were a total of 19 hip procedures in the SDR group and 20 in the ITBP group (P = 0.15). Seventeen soft-tissue procedures were performed in both SDR and ITBP groups (P = 0.265). Six bony procedures (0 salvage) were performed in the SDR group and 10 in the ITBP group (4 salvage; P = 0.075). At final follow-up the hip dislocation rate was 10.6% in the SDR group and 7.4% in the ITBP group. CONCLUSIONS: There was no significant difference in the rate of secondary hip reconstructive surgery or dislocation between nonambulatory cerebral palsy patients who underwent SDR versus ITBP. Reconstruction was required for 25% to 32% of hips despite spasticity intervention with either procedure. This suggests that the L1 nerve root alone does not play a major role in the progression of hip dislocation. LEVEL OF EVIDENCE: Level 3--therapeutic study.

Oral tetrahydrobiopterin improves the beneficial effect of adenoviral-mediated eNOS gene transfer after induction of hindlimb ischemia.

We tested the hypothesis that oral supplementation with the endothelial nitric oxide synthase (eNOS) cofactor tetrahydrobiopterin (BH(4)) improved the therapeutic efficacy of eNOS gene transfer in the ischemic rat hindlimb. BH(4) or vehicle were begun 1 week before induction of hindlimb ischemia, whereas recombinant adenovirus containing bovine eNOS cDNA (AdeNOS) or vehicle [phosphate-buffered saline (PBS)] was infused intra-arterially into the ischemic hindlimb 10 days after induction of ischemia. Rats receiving co-treatment with dietary BH(4) and eNOS gene transfer (the [eNOS, +BH(4)] group) had greater eNOS expression, phospho-eNOS expression (Ser(1177)), Ca(2+)-dependent NOS activity, and nitrite + nitrate concentrations in the ischemic gastrocnemius than did rats receiving AdeNOS alone. The [eNOS, +BH(4)] group demonstrated less nitrotyrosine and a higher ratio of reduced:oxidized glutathione (GSH:GSSG) in the ischemic gastrocnemius muscle than did rats receiving AdeNOS alone. The [eNOS, +BH(4)] group had greater flow recovery and a higher capillary:myocyte ratio in the ischemic hindlimb than did rats receiving AdeNOS alone. Finally, the [eNOS,+BH(4)] group had less necrosis of hindlimb muscles than rats given AdeNOS alone. We conclude that adjunctive dietary therapy with BH(4) increases the beneficial effects of eNOS gene transfer within the ischemic gastrocnemius muscle, as evidenced by increased nitric oxide (NO) production, diminished oxidative stress, enhanced flow recovery, and reduced necrosis.

Oxidized low-density lipoprotein induces apoptosis in endothelial progenitor cells by inactivating the phosphoinositide 3-kinase/Akt pathway.

We tested the hypothesis that oxidized low-density lipoprotein (oxLDL)-induced inactivation of Akt within endothelial progenitor cells (EPCs) is mediated at the level of phosphoinositide 3-kinase (PI3K), specifically by nitrosylation of the p85 subunit of PI3K, and that this action is critical in provoking oxLDL-induced EPC apoptosis. Hypercholesterolemic ApoE null mice had a significant reduction of the phosphorylated Akt (p-Akt)/Akt ratio in EPCs, as well as a greater percentage of apoptosis in these cells than EPCs isolated from wild-type (WT) C57Bl/6 mice. EPCs were isolated from WT spleen and exposed to oxLDL in vitro. oxLDL increased O2⁻ and H2O2 in these cells and induced a dose- and time-dependent reduction in the p-Akt/Akt ratio and increase in EPC apoptosis. These effects were significantly reduced by the antioxidants superoxide dismutase, L-NAME, epicatechin and FeTPPs. oxLDL also induced nitrosylation of the p85 subunit of PI3K and subsequent dissociation of the p85 and p110 subunits, an effect significantly reduced by all the antioxidant agents tested. EPC transfection with a constitutively active Akt isoform (Ad-myrAkt) significantly reduced oxLDL-induced apoptosis of WT EPCs. The present findings indicate that oxLDL disrupts the PI3K/Akt signaling pathway at the level of p85 in EPCs. This dysfunction can be reversed by ex vivo antioxidant therapy.

Endothelial nitric oxide synthase affects both early and late collateral arterial adaptation and blood flow recovery after induction of hind limb ischemia in mice.

OBJECTIVE: The goals of this study were to determine if endothelial nitric oxide synthase (eNOS) affects both early and late collateral arterial adaptation and blood flow recovery after severe limb ischemia in a mouse model and to determine if eNOS-derived NO is necessary for recruitment of chemokine (C-X-C motif) receptor 4 (CXCR4)(+) vascular endothelial growth factor receptor-1 (VEGFR1)(+) hemangiocytes to the site of ischemia. METHODS: Two studies were completed. In the first, hind limb ischemia was induced by unilateral femoral artery excision in three groups: C57Bl6 (wild-type), eNOS(-/-), and C57Bl/6 mice treated with N(G)-nitro-L-arginine methyl ester (L-NAME) from 1 day before excision through day 3 after excision (early L-NAME group). These groups were studied on day 3 after induction of ischemia. In the second study, hind limb ischemia was induced in C57Bl/6 mice (wild-type) and C57Bl/6 mice treated with L-NAME from days 3 through 28 after induction of ischemia. These groups were studied day 28 after ischemia induction. Dependent variables included hind limb perfusion, collateral artery diameter, and the number and location of hemangiocytes within the ischemic hind limb. RESULTS: In the first study, toe gangrene developed in the eNOS(-/-) and early L-NAME treatment groups by day 2. These groups demonstrated less blood flow recovery and smaller collateral artery diameter than the wild-type group. Hemangiocytes were present within the adventitia of collateral arteries in the wild-type group but were only sparsely present, in a random pattern, in the eNOS(-/-) and early L-NAME treatment groups. In the second study, the late L-NAME group showed less blood flow recovery and smaller collateral artery diameter on day 28 of ischemia than the wild-type group. Hemangiocytes were present in a pericapillary distribution in the wild-type group, but were present only sparsely in the late L-NAME treatment group. CONCLUSION: Early (day 3) and late (day 28) adaptive responses to hind limb ischemia both require eNOS-derived NO. NO is necessary for normal hemangiocyte recruitment to the ischemic tissue.

Regenerative medicine in the treatment of peripheral arterial disease.

The last decade has witnessed a dramatic increase in the mechanistic understanding of angiogenesis and arteriogenesis, the two processes by which the body responds to obstruction of large conduit arteries. This knowledge has been translated into novel therapeutic approaches to the treatment of peripheral arterial disease, a condition characterized by progressive narrowing of lower extremity arteries and heretofore solely amenable to surgical revascularization. Clinical trials of molecular, genetic, and cell-based treatments for peripheral artery obstruction have generally provided encouraging results.

Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: roles of endothelial nitric oxide synthase and endothelial progenitor cells.

OBJECTIVE: We sought to directly compare the effects of type 1 and type 2 diabetes on postischemic neovascularization and evaluate the mechanisms underlying differences between these groups. We tested the hypothesis that type 2 diabetic mice have a greater reduction in endothelial nitric oxide synthase (eNOS) expression, a greater increase in oxidative stress, and reduced arteriogenesis and angiogenesis, resulting in less complete blood flow recovery than type 1 diabetic mice after induction of hind limb ischemia. METHODS: Hind limb ischemia was generated by femoral artery excision in streptozotocin-treated mice (model of type 1 diabetes), in Lepr(db/db) mice (model of type 2 diabetes), and in control (C57BL/6) mice. Dependent variables included eNOS expression and markers of arteriogenesis, angiogenesis, and oxidative stress. RESULTS: Postischemia recovery of hind limb perfusion was significantly less in type 2 than in type 1 diabetic mice; however, neither group demonstrated a significant increase in collateral artery diameter or collateral artery angioscore in the ischemic hind limb. The capillary/myofiber ratio in the gastrocnemius muscle decreased in response to ischemia in control or type 1 diabetic mice but remained the same in type 2 diabetic mice. Gastrocnemius muscle eNOS expression was lower in type 1 and 2 diabetic mice than in control mice. This expression decreased after induction of ischemia in type 2 but not in type 1 diabetic mice. The percentage of endothelial progenitor cells (EPC) in the peripheral blood failed to increase in either diabetic group after induction of ischemia, whereas this variable significantly increased in the control group in response to ischemia. EPC eNOS expression decreased after induction of ischemia in type 1 but not in type 2 diabetic mice. EPC nitrotyrosine accumulation increased after induction of ischemia in type 2 but not in type 1 diabetic mice. EPC migration in response to vascular endothelial growth factor was reduced in type 1 and type 2 diabetic mice vs control mice. EPC incorporation into tubular structures was less effective in type 2 diabetic mice. Extensive fatty infiltration was present in ischemic muscle of type 2 but not in type 1 diabetic mice. CONCLUSION: Type 2 diabetic mice displayed a significantly less effective response to hind limb ischemia than type 1 diabetic mice.

The Role of Obesity in Pediatric Orthopedics.

Pediatric obesity has become a worldwide epidemic and leads to notable effects on the developing skeleton that can have lifelong implications. Obesity in the pediatric population alters bone metabolism, increasing the risk for fracture. It can alter the presentation of common pediatric orthopaedic conditions such as scoliosis. Obesity also leads to changes in the patterns and severity of pediatric fractures as well as alters conservative fracture treatment due to increased displacement risk. Obese pediatric trauma patients place a high burden on the nationwide hospital system in a variety of ways including the increased risk of perioperative complications. Obesity is modifiable, and addressing the issue can improve the orthopaedic and overall health of children.

Measurement of Intraoperative Blood Loss in Pediatric Orthopaedic Patients: Evaluation of a New Method.

INTRODUCTION: Our goal was to validate a new method of intraoperative blood loss measurement in pediatric patients who undergo orthopaedic surgery. METHODS: We prospectively collected surgical sponges from 55 patients who underwent pediatric posterior spinal fusion, single-event multilevel surgery, or hip reconstruction for measurement of intraoperative blood loss. We enrolled patients if expected estimated blood loss (EBL) was >200 mL. The methods used for blood loss assessment included the Triton sponge scanning system, visual method, gravimetric method, and measured assay (reference) method. RESULTS: The Triton system calculation of cumulative EBL per patient against the reference method yielded a strong positive linear correlation (R2 = 0.88). A weaker correlation was noted between the gravimetric method and reference EBL (R2 = 0.49). The Triton system had a low bias and narrow limits of agreement relative to the reference method (49 mL; 95% CI, 30 to 68). The gravimetric method had a higher bias and wider limits of agreement (101 mL; 95% CI, 67 to 135). The comparison of visual total EBL against the reference method yielded a notable discrepancy. DISCUSSION: Estimated blood loss measured using the Triton system correlated better with the reference method than with the gravimetric method. The visual estimation method was found to be inaccurate. Intraoperative use of the Triton system is convenient and precise for monitoring intraoperative blood loss.

Endothelial nitric oxide synthase in human intestine resected for necrotizing enterocolitis.

OBJECTIVE: To determine the expression and function of endothelial nitric oxide synthase (eNOS) in submucosal arterioles harvested from human intestine resected for necrotizing enterocolitis (NEC) or congenital bowel disease. STUDY DESIGN: eNOS expression was determined by using immunohistochemistry. The arteriolar diameter was measured in vitro at pressures of 10 to 40 mm Hg and also in response to the eNOS agonist acetylcholine (ACh), the exogenous nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine, and the smooth muscle relaxant papaverine. Arteriolar release of NO in response to ACh was determined with a Sievers NOAnalyzer. Hemodynamics were also determined at flow rates of 50 and 100 microL/min. RESULTS: eNOS was present in microvessels from both groups, but NEC arterioles failed to demonstrate physiological evidence of eNOS function: they constricted in response to pressure, failed to dilate or generate NO in response to ACh, and failed to dilate in response to flow. However, they dilated in response to exogenous NO and papaverine, indicating functional vascular smooth muscle and vasodilator reserve. CONCLUSION: eNOS-derived NO, a vasodilator in the newborn intestine, did not contribute to vasoregulation in arterioles harvested from intestine resected for NEC. These vessels were constricted; lack of eNOS-derived NO may contribute to this vasoconstriction.

Ischemia and necrotizing enterocolitis: where, when, and how.

While it is accepted that ischemia contributes to the pathogenesis of necrotizing enterocolitis (NEC), three important questions regarding this role subsist. First, where within the intestinal circulation does the vascular pathophysiology occur? It is most likely that this event begins within the intramural microcirculation, particularly the small arteries that pierce the gut wall and the submucosal arteriolar plexus insofar as these represent the principal sites of resistance regulation in the gut. Mucosal damage might also disrupt the integrity or function of downstream villous arterioles leading to damage thereto; thereafter, noxious stimuli might ascend into the submucosal vessels via downstream venules and lymphatics. Second, when during the course of pathogenesis does ischemia occur? Ischemia is unlikely to the sole initiating factor of NEC; instead, it is more likely that ischemia is triggered by other events, such as inflammation at the mucosal surface. In this context, it is likely that ischemia plays a secondary, albeit critical role in disease extension. Third, how does the ischemia occur? Regulation of vascular resistance within newborn intestine is principally determined by a balance between the endothelial production of the vasoconstrictor peptide endothelin-1 (ET-1) and endothelial production of the vasodilator free radical nitric oxide (NO). Under normal conditions, the balance heavily favors NO-induced vasodilation, leading to a low resting resistance and high rate of flow. However, factors that disrupt endothelial cell function, eg, ischemia-reperfusion, sustained low-flow perfusion, or proinflammatory mediators, alter the ET-1:NO balance in favor of constriction. The unique ET-1-NO interaction thereafter might facilitate rapid extension of this constriction, generating a viscous cascade wherein ischemia rapidly extends into larger portions of the intestine.

Dysplasia epiphysealis hemimelica (Trevor disease) of the ankle.

An 11-year-old boy presented with a 2-year history of left ankle pain and abnormal gait, worsened with sports activities such as football and wrestling.

Newborn intestinal circulation. Physiology and pathophysiology.

The physiologic characteristics of the newborn intestinal circulation are unique when compared with the adult condition. Most important, intestinal vascular resistance across newborn intestine is exceptionally low and this transient reduction is mediated by an increased constitutive and stimulated production of NO. The low vascular resistance characteristic of newborn intestine alters the capacity of this vasculature to respond to systemic circulatory perturbations, such as hypotension and arterial hypoxemia. The essential role of endothelial production of NO in maintaining newborn intestinal hemodynamics might be important in the pathogenesis of NEC, because endothelial dysfunction would limit, or possibly eliminate, NO production, leading to substantial intestinal ischemia.