CXCR4 and CXCL12 signaling regulates the development of extrinsic innervation to the colorectum.

The gastrointestinal tract is innervated by an intrinsic neuronal network, known as the enteric nervous system (ENS), and by extrinsic axons arising from peripheral ganglia. The nerve of Remak (NoR) is an avian-specific sacral neural crest-derived ganglionated structure that extends from the cloaca to the proximal midgut and, similar to the pelvic plexus, provides extrinsic innervation to the distal intestine. The molecular mechanisms controlling extrinsic nerve fiber growth into the gut is unknown. In vertebrates, CXCR4, a cell-surface receptor for the CXCL12 chemokine, regulates migration of neural crest cells and axon pathfinding. We have employed chimeric tissue recombinations and organ culture assays to study the role of CXCR4 and CXCL12 molecules in the development of colorectal innervation. CXCR4 is specifically expressed in nerve fibers arising from the NoR and pelvic plexus, while CXCL12 is localized to the hindgut mesenchyme and enteric ganglia. Overexpression of CXCL12 results in significantly enhanced axonal projections to the gut from the NoR, while CXCR4 inhibition disrupts nerve fiber extension, supporting a previously unreported role for CXCR4 and CXCL12 signaling in extrinsic innervation of the colorectum.

A distinct transcriptome characterizes neural crest-derived cells at the migratory wavefront during enteric nervous system development.

Enteric nervous system development relies on intestinal colonization by enteric neural crest-derived cells (ENCDCs). This is driven by a population of highly migratory and proliferative ENCDCs at the wavefront, but the molecular characteristics of these cells are unknown. ENCDCs from the wavefront and the trailing region were isolated and subjected to RNA-seq. Wavefront-ENCDCs were transcriptionally distinct from trailing ENCDCs, and temporal modelling confirmed their relative immaturity. This population of ENCDCs exhibited altered expression of ECM and cytoskeletal genes, consistent with a migratory phenotype. Unlike trailing ENCDCs, the wavefront lacked expression of genes related to neuronal or glial maturation. As wavefront ENCDC genes were associated with migration and developmental immaturity, the genes that remain expressed in later progenitor populations may be particularly pertinent to understanding the maintenance of ENCDC progenitor characteristics. Dusp6 expression was specifically upregulated at the wavefront. Inhibiting DUSP6 activity prevented wavefront colonization of the hindgut, and inhibited the migratory ability of post-colonized ENCDCs from midgut and postnatal neurospheres. These effects were reversed by simultaneous inhibition of ERK signaling, indicating that DUSP6-mediated ERK inhibition is required for ENCDC migration in mouse and chick.

Transforming the Future of Surgeon-Scientists.

OBJECTIVE: To create a blueprint for surgical department leaders, academic institutions, and funding agencies to optimally support surgeon-scientists. BACKGROUND: Scientific contributions by surgeons have been transformative across many medical disciplines. Surgeon-scientists provide a distinct approach and mindset toward key scientific questions. However, lack of institutional support, pressure for increased clinical productivity, and growing administrative burden are major challenges for the surgeon-scientist, as is the time-consuming nature of surgical training and practice. METHODS: An American Surgical Association Research Sustainability Task Force was created to outline a blueprint for sustainable science in surgery. Leaders from top NIH-sponsored departments of surgery engaged in video and in-person meetings between January and April 2023. A strength, weakness, opportunities, threats analysis was performed, and workgroups focused on the roles of surgeons, the department and institutions, and funding agencies. RESULTS: Taskforce recommendations: (1) SURGEONS: Growth mindset : identifying research focus, long-term planning, patience/tenacity, team science, collaborations with disparate experts; Skill set : align skills and research, fill critical skill gaps, develop team leadership skills; DEPARTMENT OF SURGERY (DOS): (2) MENTORSHIP: Chair : mentor-mentee matching/regular meetings/accountability, review of junior faculty progress, mentorship training requirement, recognition of mentorship (eg, relative value unit equivalent, awards; Mentor: dedicated time, relevant scientific expertise, extramural funding, experience and/or trained as mentor, trusted advisor; Mentee : enthusiastic/eager, proactive, open to feedback, clear about goals; (3) FINANCIAL SUSTAINABILITY: diversification of research portfolio, identification of matching funding sources, departmental resource awards (eg, T-/P-grants), leveraging of institutional resources, negotiation of formalized/formulaic funds flow investment from academic medical center toward science, philanthropy; (4) STRUCTURAL/STRATEGIC SUPPORT: Structural: grants administrative support, biostats/bioinformatics support, clinical trial and research support, regulatory support, shared departmental laboratory space/equipment; Strategic: hiring diverse surgeon-scientist/scientists faculty across DOS, strategic faculty retention/ recruitment, philanthropy, career development support, progress tracking, grant writing support, DOS-wide research meetings, regular DOS strategic research planning; (5) COMMUNITY AND CULTURE: Community: right mix of faculty, connection surgeon with broad scientific community; Culture: building research infrastructure, financial support for research, projecting importance of research (awards, grand rounds, shoutouts); (6) THE ROLE OF INSTITUTIONS: Foundation: research space co-location, flexible start-up packages, courses/mock study section, awards, diverse institutional mentorship teams; Nurture: institutional infrastructure, funding (eg, endowed chairs), promotion friendly toward surgeon-scientists, surgeon-scientists in institutional leadership positions; Expectations: RVU target relief, salary gap funding, competitive starting salaries, longitudinal salary strategy; (7) THE ROLE OF FUNDING AGENCIES: change surgeon research training paradigm, offer alternate awards to K-awards, increasing salary cap to reflect market reality, time extension for surgeon early-stage investigator status, surgeon representation on study section, focused award strategies for professional societies/foundations. CONCLUSIONS: Authentic recommitment from surgeon leaders with intentional and ambitious actions from institutions, corporations, funders, and society is essential in order to reap the essential benefits of surgeon-scientists toward advancements of science.

Avian ceca are indispensable for hindgut enteric nervous system development.

The enteric nervous system (ENS), which is derived from enteric neural crest cells (ENCCs), represents the neuronal innervation of the intestine. Compromised ENCC migration can lead to Hirschsprung disease, which is characterized by an aganglionic distal bowel. During the craniocaudal migration of ENCCs along the gut, we find that their proliferation is greatest as the ENCC wavefront passes through the ceca, a pair of pouches at the midgut-hindgut junction in avian intestine. Removal of the ceca leads to hindgut aganglionosis, suggesting that they are required for ENS development. Comparative transcriptome profiling of the cecal buds compared with the interceca region shows that the non-canonical Wnt signaling pathway is preferentially expressed within the ceca. Specifically, WNT11 is highly expressed, as confirmed by RNA in situ hybridization, leading us to hypothesize that cecal expression of WNT11 is important for ENCC colonization of the hindgut. Organ cultures using embryonic day 6 avian intestine show that WNT11 inhibits enteric neuronal differentiation. These results reveal an essential role for the ceca during hindgut ENS formation and highlight an important function for non-canonical Wnt signaling in regulating ENCC differentiation.

RET overactivation leads to concurrent Hirschsprung disease and intestinal ganglioneuromas.

Appropriately balanced RET signaling is of crucial importance during embryonic neural crest cell migration, proliferation and differentiation. RET deficiency, for example, leads to intestinal aganglionosis (Hirschsprung disease), whereas overactive RET can lead to multiple endocrine neoplasia (MEN) syndromes. Some RET mutations are associated with both intestinal aganglionosis and MEN-associated tumors. This seemingly paradoxical occurrence has led to speculation of a 'Janus mutation' in RET that causes overactivation or impairment of RET activity depending on the cellular context. Using an intestinal catenary culture system to test the effects of GDNF-mediated RET activation, we demonstrate the concurrent development of distal colonic aganglionosis and intestinal ganglioneuromas. Interestingly, the tumors induced by GDNF stimulation contain enteric neuronal progenitors capable of reconstituting an enteric nervous system when transplanted into a normal developmental environment. These results suggest that a Janus mutation may not be required to explain co-existing Hirschsprung disease and MEN-associated tumors, but rather that RET overstimulation alone is enough to cause both phenotypes. The results also suggest that reprogramming tumor cells toward non-pathological fates may represent a possible therapeutic avenue for MEN-associated neoplasms.

Bone Marrow Stem Cells Derived from Nerves Have Neurogenic Properties and Potential Utility for Regenerative Therapy.

Neurons and glia of the peripheral nervous system are derived from progenitor cell populations, originating from embryonic neural crest. The neural crest and vasculature are intimately associated during embryonic development and in the mature central nervous system, in which they form a neurovascular unit comprised of neurons, glia, pericytes, and vascular endothelial cells that play important roles in health and disease. Our group and others have previously reported that postnatal populations of stem cells originating from glia or Schwann cells possess neural stem cell qualities, including rapid proliferation and differentiation into mature glia and neurons. Bone marrow receives sensory and sympathetic innervation from the peripheral nervous system and is known to contain myelinating and unmyelinating Schwann cells. Herein, we describe a population of neural crest-derived Schwann cells residing in a neurovascular niche of bone marrow in association with nerve fibers. These Schwann cells can be isolated and expanded. They demonstrate plasticity in vitro, generating neural stem cells that exhibit neurogenic potential and form neural networks within the enteric nervous system in vivo following transplantation to the intestine. These cells represent a novel source of autologous neural stem cells for the treatment of neurointestinal disorders.

Essential Role of BMP4 Signaling in the Avian Ceca in Colorectal Enteric Nervous System Development.

The enteric nervous system (ENS) is principally derived from vagal neural crest cells that migrate caudally along the entire length of the gastrointestinal tract, giving rise to neurons and glial cells in two ganglionated plexuses. Incomplete migration of enteric neural crest-derived cells (ENCDC) leads to Hirschsprung disease, a congenital disorder characterized by the absence of enteric ganglia along variable lengths of the colorectum. Our previous work strongly supported the essential role of the avian ceca, present at the junction of the midgut and hindgut, in hindgut ENS development, since ablation of the cecal buds led to incomplete ENCDC colonization of the hindgut. In situ hybridization shows bone morphogenetic protein-4 (BMP4) is highly expressed in the cecal mesenchyme, leading us to hypothesize that cecal BMP4 is required for hindgut ENS development. To test this, we modulated BMP4 activity using embryonic intestinal organ culture techniques and retroviral infection. We show that overexpression or inhibition of BMP4 in the ceca disrupts hindgut ENS development, with GDNF playing an important regulatory role. Our results suggest that these two important signaling pathways are required for normal ENCDC migration and enteric ganglion formation in the developing hindgut ENS.

Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells.

Interplay between embryonic enteric neural stem cells (ENSCs) and enteric mesenchymal cells (EMCs) in the embryonic gut is essential for normal development of the enteric nervous system. Disruption of these interactions underlies the pathogenesis of intestinal aganglionosis in Hirschsprung disease (HSCR). ENSC therapy has been proposed as a possible treatment for HSCR, but whether the survival and development of postnatal-derived ENSCs similarly rely on signals from the mesenchymal environment is unknown and has important implications for developing protocols to expand ENSCs for cell transplantation therapy. Enteric neural crest-derived cells (ENCDCs) and EMCs were cultured from the small intestine of Wnt1-Rosa26-tdTomato mice. EMCs promoted the expansion of ENCDCs 9.5-fold by inducing ENSC properties, including expression of Nes, Sox10, Sox2, and Ngfr. EMCs enhanced the neurosphere-forming ability of ENCDCs, and this persisted after withdrawal of the EMCs. These effects were mediated by paracrine factors and several ligands known to support neural stem cells were identified in EMCs. Using the optimized expansion procedures, neurospheres were generated from small intestine of the Ednrb-/- mouse model of HSCR. These ENSCs had similar proliferative and migratory capacity to Ednrb+/+ ENSCs, albeit neurospheres contained fewer neurons. ENSCs derived from Ednrb-/- mice generated functional neurons with similar calcium responses to Ednrb+/+ ENSCs and survived after transplantation into the aganglionic colon of Ednrb-/- recipients. EMCs act as supporting cells to ENSCs postnatally via an array of synergistically acting paracrine signaling factors. These properties can be leveraged to expand autologous ENSCs from patients with HSCR mutations for therapeutic application.

Pearls and Pitfalls for Surgical Investigators in Basic and Translational Research.

Surgeon-scientists are uniquely positioned to contribute to our understanding of the fundamental biology of surgical disease and to bring a unique perspective that leads to innovation in the diagnosis and treatment of many conditions. However, it is broadly recognized that due to the changing landscape of surgery and science, the surgeon-scientists of today face multiple challenges in this pursuit. Today, surgeon-scientists face an increased pressure from their department and hospital to generate clinical revenue, decreased availability of grant funding, greater administrative burden, rising complexity of fundamental research, increased medical school debt, and a growing desire for work-life balance. Given that survival of surgeon-scientists is critical for the progress of not only surgery but medical innovation at large, many surgical societies, notably the Association for Academic Surgery (AAS) and the Society of University Surgeons (SUS) have focused on the issues faced by surgeon-scientists. In this regard, the Basic and Translational Research Committee of the AAS and the Research Committee of the SUS organized a hot topic session at the 2021 Academic Surgical Congress in which experts discussed and addressed many issues concerning the surgeon-scientist pathway. This manuscript provides an overview of the issues discussed at this session.

Intestinal Pathology in Patients With Pathogenic ACTG2-Variant Visceral Myopathy: 16 Patients From 12 Families and Review of the Literature.

BACKGROUND: Dominant gamma-smooth muscle actin gene (ACTG2) variants cause clinically diverse forms of visceral myopathy. Many patients undergo intestinal resection or biopsy before identification of their genetic defect. The pathology of ACTG2-variant visceral myopathy has not been evaluated systematically. METHODS: Glass slides, ultrastructural images, molecular genetic reports, and clinical records from 16 patients with pathogenic (15) or likely pathogenic (1) ACTG2 variants were reviewed and compared with surgical specimens from controls (no evidence of a primary myopathy or pseudo-obstruction due to Hirschsprung disease) and published descriptions. RESULTS: The variable clinical manifestations in our cohort matched those in the literature. Only non-specific light and electron microscopic findings observed in non-myopathic controls were encountered in 13 of 16 patients. The remaining 3 patients harbored hyalinized cytoplasmic inclusions in smooth muscle cells and 1 of them had polyglucosan bodies in the muscularis propria. CONCLUSIONS: Apart from hyalinized inclusions, which were only observed in 3/16 patients, intestinal pathology in the majority of patients with ACTG2 variants is not indicative of an underlying visceral myopathy. Molecular testing should be considered even when no diagnostic intestinal pathology is identified.

A pilot study characterizing longitudinal changes in fecal microbiota of patients with Hirschsprung-associated enterocolitis.

PURPOSE: Hirschsprung disease is a neurointestinal disease that occurs due to failure of enteric neural crest-derived cells to complete their rostrocaudal migration along the gut mesenchyme, resulting in aganglionosis along variable lengths of the distal bowel. Despite the effective surgery that removes the aganglionic segment, children with Hirschsprung disease remain at high risk for developing a potentially life-threatening enterocolitis (Hirschsprung-associated enterocolitis). Although the etiology of this enterocolitis remains poorly understood, several recent studies in both mouse models and in human subjects suggest potential involvement of gastrointestinal microbiota in the underlying pathogenesis of Hirschsprung-associated enterocolitis. METHODS: We present the first study to exploit the Illumina MiSeq next-generation sequencing platform within a longitudinal framework focused on microbiomes of Hirschsprung-associated enterocolitis in five patients. We analyzed bacterial communities from fecal samples collected at different timepoints starting from active enterocolitis and progressing into remission. RESULTS: We observed compositional differences between patients largely attributable to variability in age at the time of sample collection. Remission samples across patients exhibited compositional similarity, including enrichment of Blautia, while active enterocolitis samples showed substantial variability in composition. CONCLUSIONS: Overall, our findings provide continued support for the role of GI microbiota in the pathogenesis of Hirschsprung-associated enterocolitis.

Association of Surgeon Representation on NIH Study Sections With Receipt of Funding by Surgeon-scientists.

OBJECTIVE: Our goal was to evaluate the relationship between surgeon representation on NIH study sections and success in grant funding. SUMMARY OF BACKGROUND DATA: NIH funding for surgeon-scientists is declining. Prior work has called for increased surgeon participation in the grant review process as a strategy to increase receipt of funding by surgeon-scientists. METHODS: A retrospective review of surgeon (primary department: General, Urology, Orthopedic, Ophthalmology, Otolaryngology, Neurosurgery) representation on NIH study sections and receipt of funding was performed using NIH Research Portfolio Online Reporting Tools Expenditures and Results (RePORTER) and 2019 Blue Ridge Institute for Medical Research data. NIH chartered study section panels and ad hoc reviewers for each 2019 review date were also obtained. RESULTS: In 2019, 9239 individuals reviewed in at least 1 of the 168 study sections [190 (2.1%) surgeons, 64 (0.7%) standing members, 126 (1.4%) ad-hoc]. Most surgeons on study sections were male (65%) professors (63%). Surgeons most commonly served on bioengineering, technology, and surgical sciences (29.6% surgeons), diseases and pathophysiology of the visual system (28.3%), and surgery, anesthesiology and trauma (21%). In 2019, 773 surgeons received 1235 NIH grants (>$580 M) out of a total of 55,012 awards (2.2%). Funded surgeons were predominantly male (79%), White (68%), non-Hispanic (97%), full professors (50%), and 43% had additional advanced degrees (MPH/PhD/MBA). surgery, anesthesiology and trauma, diseases and pathophysiology of the visual system, and bioengineering, technology, and surgical sciences were the most common study sections that reviewed funded grants to surgeon-scientists. Ninety-two surgeons both received grant funding and served on study section. Study sections with higher surgeon representation were more likely to fund surgeon-scientists (P < 0.001). CONCLUSIONS: Surgeon representation on NIH study sections is strongly associated with receipt of funding by surgeon-scientists. Increasing NIH study section representation by surgeons may help to preserve the surgeon-scientist phenotype.

Collagen 18 and agrin are secreted by neural crest cells to remodel their microenvironment and regulate their migration during enteric nervous system development.

The enteric nervous system (ENS) arises from neural crest cells that migrate, proliferate, and differentiate into enteric neurons and glia within the intestinal wall. Many extracellular matrix (ECM) components are present in the embryonic gut, but their role in regulating ENS development is largely unknown. Here, we identify heparan sulfate proteoglycan proteins, including collagen XVIII (Col18) and agrin, as important regulators of enteric neural crest-derived cell (ENCDC) development. In developing avian hindgut, Col18 is expressed at the ENCDC wavefront, while agrin expression occurs later. Both proteins are normally present around enteric ganglia, but are absent in aganglionic gut. Using chick-mouse intestinal chimeras and enteric neurospheres, we show that vagal- and sacral-derived ENCDCs from both species secrete Col18 and agrin. Whereas glia express Col18 and agrin, enteric neurons only express the latter. Functional studies demonstrate that Col18 is permissive whereas agrin is strongly inhibitory to ENCDC migration, consistent with the timing of their expression during ENS development. We conclude that ENCDCs govern their own migration by actively remodeling their microenvironment through secretion of ECM proteins.

Open innovation facilitates department-wide engagement in quality improvement: experience from the Massachusetts General Hospital.

BACKGROUND: Quality improvement (QI) initiatives commonly originate 'top-down' from senior leadership, as staff engagement is often sporadic. We describe our experience with a technology-enabled open innovation contest to encourage participation from multiple stakeholders in a Department of Surgery (DoS) to solicit ideas for QI. We aimed to stimulate engagement and to assist DoS leadership in prioritizing QI initiatives. METHODS: Observational study of a process improvement. The process had five phases: anonymous online submission of ideas by frontline staff; anonymous online crowd-voting to rank ideas on a scale whether the DoS should implement each idea (1 = No, 3 = Maybe, 5 = Yes); ideas with scores ≥ 95th percentile were invited to submit implementation plans; plans were reviewed by a multi-disciplinary panel to select a winning idea; an award ceremony celebrated the completion of the contest. RESULTS: 152 ideas were submitted from 95 staff (n = 850, 11.2%). All Divisions (n = 12) and all staff roles (n = 12) submitted ideas. The greatest number of ideas were submitted by faculty (27.6%), patient service coordinators (18.4%), and residents (17.8%). The most common QI category was access to care (20%). 195 staff (22.9%) cast 3559 votes. The mean score was 3.5 ± 0.5. 10 Ideas were objectively invited to submit implementation plans. One idea was awarded a grand prize of funding, project management, and leadership buy-in. CONCLUSION: A web-enabled open innovation contest was successful in engaging faculty, residents, and other critical role groups in QI. It also enabled the leadership to re-affirm a positive culture of inclusivity, maintain an open-door policy, and also democratically vet and prioritize solutions for quality improvement.

Enteric nervous system development: A crest cell's journey from neural tube to colon.

The enteric nervous system (ENS) is comprised of a network of neurons and glial cells that are responsible for coordinating many aspects of gastrointestinal (GI) function. These cells arise from the neural crest, migrate to the gut, and then continue their journey to colonize the entire length of the GI tract. Our understanding of the molecular and cellular events that regulate these processes has advanced significantly over the past several decades, in large part facilitated by the use of rodents, avians, and zebrafish as model systems to dissect the signals and pathways involved. These studies have highlighted the highly dynamic nature of ENS development and the importance of carefully balancing migration, proliferation, and differentiation of enteric neural crest-derived cells (ENCCs). Proliferation, in particular, is critically important as it drives cell density and speed of migration, both of which are important for ensuring complete colonization of the gut. However, proliferation must be tempered by differentiation among cells that have reached their final destination and are ready to send axonal extensions, connect to effector cells, and begin to produce neurotransmitters or other signals. Abnormalities in the normal processes guiding ENCC development can lead to failure of ENS formation, as occurs in Hirschsprung disease, in which the distal intestine remains aganglionic. This review summarizes our current understanding of the factors involved in early development of the ENS and discusses areas in need of further investigation.

A Roadmap for Aspiring Surgeon-Scientists in Today's Healthcare Environment.

OBJECTIVE: Surgeon-scientists are an essential component of the field of academic surgery, contributing to the fundamental understanding of disease and the discovery of innovative therapies. Despite this recognized value, the current landscape of academic medicine presents significant barriers to establishing and maintaining a successful career as a surgeon performing basic/translational research. Our objective is to define these barriers to academic success for surgeons, and to provide a consensus strategy for optimizing the chances of success. SUMMARY BACKGROUND DATA: There is a significant decline in the proportion of academic surgeons who are pursuing basic science/translational research, which represents a potential threat to the very identify of the translational surgeon-scientist. METHODS: Based on published literature and expert opinion, the Basic Science Committee of the Society of University of Surgeons prepared this roadmap to encourage and guide the next generation of surgeon-scientists as they embark on their academic careers. RESULTS: This roadmap highlights key elements to consider in choosing an initial job and the importance of identifying a team of committed mentors. Expectations and guidelines for the first several years in practice are offered. CONCLUSIONS: With guidance and mentorship, aspiring surgeonscientists can overcome the challenges inherent in choosing this career path and sustain the important legacy of those before them.

Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix.

The enteric nervous system (ENS) develops from neural crest cells that migrate along the intestine, differentiate into neurons and glia, and pattern into two plexuses within the gut wall. Inductive interactions between epithelium and mesenchyme regulate gut development, but the influence of these interactions on ENS development is unknown. Epithelial-mesenchymal recombinations were constructed using avian hindgut mesenchyme and non-intestinal epithelium from the bursa of Fabricius. These recombinations led to abnormally large and ectopically positioned ganglia. We hypothesized that sonic hedgehog (Shh), a secreted intestinal epithelial protein not expressed in the bursa, mediates this effect. Inhibition of Shh signaling, by addition of cyclopamine or a function-blocking antibody, resulted in large, ectopic ganglia adjacent to the epithelium. Shh overexpression, achieved in ovo using Shh-encoding retrovirus and in organ culture using recombinant protein, led to intestinal aganglionosis. Shh strongly induced the expression of versican and collagen type IX, whereas cyclopamine reduced expression of these chondroitin sulfate proteoglycans that are known to be inhibitory to neural crest cell migration. Shh also inhibited enteric neural crest-derived cell (ENCC) proliferation, promoted neuronal differentiation, and reduced expression of Gdnf, a key regulator of ENS formation. Ptc1 and Ptc2 were not expressed by ENCCs, and migration of isolated ENCCs was not inhibited by Shh protein. These results suggest that epithelial-derived Shh acts indirectly on the developing ENS by regulating the composition of the intestinal microenvironment.

The Pediatric Surgeon-Scientist: Succeeding in Today's Academic Environment.

BACKGROUND: Pediatric surgeons have long been advocates of basic science research. However, new challenges facing the scientific community have threatened the success of academic surgeons pursuing basic science careers. The purpose of this study was to compare academic pediatric surgeons' perceptions of their ability to effectively conduct basic science research to those of other surgical subspecialties. METHODS: An online survey was distributed to all members of the Association for Academic Surgery and Society of University Surgeons. A total of 1033 members (41%) responded, and 137 (13.3%) were pediatric surgeons. Comparisons were made between the five most-represented surgical subspecialties. Data are presented as reporting percentage and P values by Student's t-test. RESULTS: Among the specialists studied, pediatric surgeons are those most likely to believe that surgeons can succeed as basic scientists in today's research environment. Pediatric surgery reported the highest rates of National Institutes of Health funding of all surgical specialties and the lowest rates of perceived external pressures related to clinical demands, hospital administrative duties, and work-life balance concerns than their surgical peers. CONCLUSIONS: Pediatric surgeons have a more optimistic perspective on the state of basic science research in surgery while exhibiting an enhanced ability to overcome the challenges that surgeon-scientists currently face. Our findings suggest that pediatric surgery may provide a model for succeeding in basic science in today's challenging surgical research environment.

Intraganglionic macrophages: a new population of cells in the enteric ganglia.

The enteric nervous system shares embryological, morphological, neurochemical, and functional features with the central nervous system. In addition to neurons and glia, the CNS includes a third component, microglia, which are functionally and immunophenotypically similar to macrophages, but a similar cell type has not previously been identified in enteric ganglia. In this study we identify a population of macrophages in the enteric ganglia, intermingling with the neurons and glia. These intraganglionic macrophages (IMs) are highly ramified and express the hematopoietic marker CD45, major histocompatibility complex (MHC) class II antigen, and chB6, a marker specific for B cells and microglia in avians. These IMs do not express antigens typically associated with T cells or dendritic cells. The CD45+ /ChB6+ /MHCII+ signature supports a hematopoietic origin and this was confirmed using intestinal chimeras in GFP-transgenic chick embryos. The presence of green fluorescent protein positive (GFP+) /CD45+ cells in the intestinal graft ENS confirms that IMs residing within enteric ganglia have a hematopoietic origin. IMs are also found in the ganglia of CSF1RGFP chicken and CX3CR1GFP mice. Based on the expression pattern and location of IMs in avians and rodents, we conclude that they represent a novel non-neural crest-derived microglia-like cell population within the enteric ganglia.

Surgical Management of Idiopathic Constipation in Pediatric Patients.

Constipation is a common childhood problem, but an anatomic or physiologic cause is identified in fewer than 5% of children. By definition, idiopathic constipation is a diagnosis of exclusion. Careful clinical evaluation and thoughtful use of imaging and other testing can help exclude specific causes of constipation and guide therapy. Medical management with laxatives is effective for the majority of constipated children. For those patients unresponsive to medications, however, several surgical options can be employed, including anal procedures, antegrade colonic enemas, colorectal resection, and intestinal diversion. Judicious use of these procedures in properly selected patients and based on appropriate preoperative testing can lead to excellent outcomes. This review summarizes the surgical options available for managing refractory constipation in children and provides guidance on how to choose the best procedure for a given patient.