IntroductionIntestinal dysmotility following human necrotizing enterocolitis suggests that the enteric nervous system is injured during the disease. We examined human intestinal specimens to characterize the enteric nervous system injury that occurs in necrotizing enterocolitis, and then used an animal model of experimental necrotizing enterocolitis to determine whether transplantation of neural stem cells can protect the enteric nervous system from injury.MethodsHuman intestinal specimens resected from patients with necrotizing enterocolitis (n = 18), from control patients with bowel atresia (n = 8), and from necrotizing enterocolitis and control patients undergoing stoma closure several months later (n = 14 and n = 6 respectively) were subjected to histologic examination, immunohistochemistry, and real-time reverse-transcription polymerase chain reaction to examine the myenteric plexus structure and neurotransmitter expression. In addition, experimental necrotizing enterocolitis was induced in newborn rat pups and neurotransplantation was performed by administration of fluorescently labeled neural stem cells, with subsequent visualization of transplanted cells and determination of intestinal integrity and intestinal motility.ResultsThere was significant enteric nervous system damage with increased enteric nervous system apoptosis, and decreased neuronal nitric oxide synthase expression in myenteric ganglia from human intestine resected for necrotizing enterocolitis compared with control intestine. Structural and functional abnormalities persisted months later at the time of stoma closure. Similar abnormalities were identified in rat pups exposed to experimental necrotizing enterocolitis. Pups receiving neural stem cell transplantation had improved enteric nervous system and intestinal integrity, differentiation of transplanted neural stem cells into functional neurons, significantly improved intestinal transit, and significantly decreased mortality compared with control pups.ConclusionsSignificant injury to the enteric nervous system occurs in both human and experimental necrotizing enterocolitis. Neural stem cell transplantation may represent a novel future therapy for patients with necrotizing enterocolitis.
Background We have previously demonstrated that heparin-binding EGF-like growth factor (HB-EGF) administration protects the intestines from ischemia/reperfusion (I/R) injury in vivo. We have also shown that HB-EGF promotes mesenchymal stem cell (MSC) proliferation and migration in vitro. The goals of the current study were to examine the effects of HB-EGF and both bone marrow (BM)- and amniotic fluid (AF)-derived MSC on intestinal I/R injury in vivo. Materials and Methods MSC were isolated from pan-EGFP mice, expanded, and purified. Pluripotency was confirmed by induced differentiation. Mice were subjected to terminal ileum I/R and received either: 1) no therapy; 2) HB-EGF; 3) BM-MSC; 4) HB-EGF + BM-MSC; 5) AF-MSC; or 6) HB-EGF +AF-MSC. MSC engraftment, histologic injury, and intestinal permeability were quantified. Results There was increased MSC engraftment into injured compared to uninjured intestine for all experimental groups, with significantly increased engraftment for AF-MSC + HB-EGF compared to AF-MSC alone. Administration of HB-EGF and MSC improved intestinal histology and intestinal permeability after I/R injury. The greatest improvement was with combined administration of HB-EGF + AF-MSC. Conclusions Both HB-EGF alone and MSC alone can protect the intestines from I/R injury, with synergistic efficacy occurring when HB-EGF and AF-MSC are administered together.
A 7 year old male with a history of congenital neutropenia and growth hormone deficiency presented with abdominal pain, fevers, and diarrhea. Imaging and endoscopy revealed significant inflammation of the ascending colon with stenosis at the level of the hepatic flexure. A right hemicolectomy was performed, and pathologic findings were consistent with diffuse intestinal ganglioneuromatosis. Due to recurrent mass effect at the intestinal anastomotic site detected radiologically, a second intestinal resection was performed 7 months later. Genetic testing was negative for mutations in the RET protooncogene, NF1 and PTEN tumor suppressor genes. We report a case of diffuse intestinal ganglioneuromatosis in a child with congenital neutropenia.
The Purkinje cell degeneration (PCD) mutant mouse is characterized by a degeneration of cerebellar Purkinje cells and progressive ataxia. To identify the molecular mechanisms that lead to the death of Purkinje neurons in PCD mice, we used Affymetrix microarray technology to compare cerebellar gene expression profiles in pcd3J mutant mice 14 days of age (prior to Purkinje cell loss) to unaffected littermates. Microarray analysis, Ingenuity Pathway Analysis (IPA) and Expression Analysis Systematic Explorer (EASE) software were used to identify biological and molecular pathways implicated in the progression of Purkinje cell degeneration. IPA analysis indicated that mutant pcd3J mice showed dysregulation of specific processes that may lead to Purkinje cell death, including several molecules known to control neuronal apoptosis such as Bad, CDK5 and PTEN. These findings demonstrate the usefulness of these powerful microarray analysis tools and have important implications for understanding the mechanisms of selective neuronal death and for developing therapeutic strategies to treat neurodegenerative disorders.
Background We have previously demonstrated that heparin-binding EGF-like growth factor (HB-EGF) and mesenchymal stem cell (MSC) administration protect the intestines from ischemia/reperfusion (I/R) injury in vivo, with amniotic fluid-derived MSC (AF-MSC) being more efficacious than bone marrow-derived MSC (BM-MSC). The goal of the current study was to determine whether the protective effects of HB-EGF were from direct effects on MSC or via alternative mechanisms. Methods Murine MSC were transfected with an HB-EGF plasmid or control plasmid by electroporation. Mice were subjected to segmental intestinal I/R injury and received either BM-MSC or AF-MSC either with or without exogenous HB-EGF, or BM-MSC or AF-MSC that endogenously over-expressed HB-EGF. MSC engraftment, intestinal histologic injury, and intestinal permeability were quantified. Results There was increased MSC engraftment into injured compared to uninjured intestine. HB-EGF increased AF-MSC engraftment into injured intestine. Administration of HB-EGF and MSC improved intestinal histology and intestinal permeability after I/R injury, with AF-MSC being most efficacious. The effect of HB-EGF on MSC was similar when the growth factor was administered exogenously, or when it was overexpressed endogenously. Conclusions The effect of HB-EGF on AF-MSC was similar with both exogenous administration or endogenous overexpression of the growth factor, implying that HB-EGF has a direct effect on AF-MSC. This information may assist in guiding potential future AF-MSC-based therapies for patients at risk of intestinal ischemic injuries.
Purpose Radiation therapy (RT) often induces enteritis by inhibiting proliferation and inducing apoptosis. Heparin-binding EGF-like growth factor (HB-EGF) has been shown to protect the intestine in several animal injury models. The objective of this study was to examine whether HB-EGF affects RT-induced intestinal injury. Methods HB-EGF or PBS was administered intraperitoneally to mice daily for 3 days, followed by total body irradiation (TBI). Three days after TBI, intestinal segments were harvested, and BrdU immunohistochemistry was performed to identify proliferating crypts (n=25). Four days after TBI, intestinal segments were harvested and assessed for histologic injury (n=34), and FITC-dextran was administered via gavage with serum FITC-dextran levels quantified to determine gut barrier function (n=18). Results Compared to non-HB-EGF-treated irradiated mice, administration of HB-EGF to irradiated mice led to a significantly increased percentage of proliferative crypts (72.6% vs. 50.5%, p=0.001), a significantly decreased percent of histologic sections with severe histologic injury (13.7% vs. 20.3%, p=0.005), and significantly reduced intestinal permeability (18.8 µg/mL vs. 22.6 µg/mL, p=0.02). Conclusions These results suggest that administration of HB-EGF protects the intestines from injury after exposure to radiation therapy. Administration of HB-EGF may represent a novel therapy for the prevention of radiation enteritis in the future.
Objective To survey the Society for Vascular Surgery (SVS) membership with regard to practice trends related to work effort, employment status, practice ownership, endovascular cases, and anticipated changes in practice in the near future. Methods A survey questionnaire was developed to gather information about member demographics and practice, hours worked, full-time (FT) or part-time status, employment status, practice ownership, competition for referrals, proportion of endovascular vs open procedures, and anticipated changes in practice in the next 3 years. We used SurveyMonkey and distributed the survey to all active vascular surgeon (VS) members of the SVS. Results The response rate was 207 of 2230 (10.7%). Two thirds were in private practice, and 21% were in solo practice. Twenty-four percent were employed by hospitals/health systems. Those VS under the age of 50 years were more likely to exclusively practice vascular surgery compared with VS over the age of 50 years (P = .0003). Sixty-eight of the physicians (32.7%) were between 50 and 59 years old, 186 (90.3%) were men, 192 (92.8%) worked FT (>36 hours of patient care per week), and almost two thirds worked >60 hours per week. Those in physician-owned practices worked >40 hours of patient care per week more often than did FT employed VS (P = .012). Younger VS (age <50 years) more frequently reported >50% of their workload being endovascular compared with older VS (age ≥50 years; P < .001). Eighty percent of FT VS planned to continue their current practice over the next 3 years. Of the 43.6% indicating loss of referrals, 82% pointed to cardiologists as the competition. Conclusions The current workforce is predominately male and works FT; one-third is between the ages of 50 and 59 years. Younger VS (age <50 years) are more likely to exclusively practice VS and have a higher caseload of endovascular procedures. Those in physician-owned practices are more likely to put in >40 hours of patient care per week than are FT employed VS. Longitudinal surveys of SVS members are imperative to help tailor educational, training, and practice management offerings, guide governmental activities, advocate for issues important to members, improve branding initiatives, and sponsor workforce analyses.
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