87 results on '"El-Gohary Y"'
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2. Heterosis and combining ability for yield and yield components in bread wheat under different nitrogen rates
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EL-Gohary, Y., primary and el Rashidy, Zainab, additional
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- 2021
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3. In-situ emergency pediatric surgery in the intensive care unit
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Ghallab, A., El-Gohary, Y., Redmond, M., and Corbally, M.
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- 2013
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4. Path-Coefficient Analysis and Correlation Studies on Grain Yield and its Components of some Bread Wheat Genotypes under Three Irrigation Treatments
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Abd El-Dayem, S., primary, EL-Gohary, Y., additional, and Ibrahim, Hoda, additional
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- 2021
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5. Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4
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ROSSIGNOL, J. F., KABIL, S. M., EL-GOHARY, Y., ELFERT, A., and KEEFFE, E. B.
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- 2008
6. Nitazoxanide in the treatment of viral gastroenteritis: a randomized double-blind placebo-controlled clinical trial
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ROSSIGNOL, J.-F. and EL-GOHARY, Y. M.
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- 2006
7. ECONOMIC EVALUATION FOR THE EFFECT OF IRRIGATION RATES ON SOME BREAD WHEAT GENOTYPES
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Ibrahem, Sahar, primary, Eid, Wafaa, additional, and El-Gohary, Y., additional
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- 2019
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8. ECONOMIC EVALUATION FOR THE OPTIMUM SEEDING RATE FOR SOME BREAD WHEAT GENOTYPES
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Mahmoud, Enas, primary, Mahmoud, Rania, additional, and El- Gohary, Y., additional
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- 2019
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9. Colonoscopic management of ileocolic anastomotic torsion
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El-Gohary, Y., primary, Abbas, S. K., additional, Yelika, S. B., additional, Smithy, W., additional, and Bergamaschi, R., additional
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- 2017
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10. Study of Humoral Immunity in Cerebrospinal Fluid of Patients Infected with Schistosomiasis
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El-Sawy, M., Abaza, H., Hammouda, N., El-Gohary, Y., El-Fatatry, M., Karcher, D., editor, Lowenthal, A., editor, and Strosberg, A. D., editor
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- 1979
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11. Regulation of β Cell Proliferation by Targeting SMAD2
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Gaffar, I., primary, Xiao, X., additional, El-Gohary, Y., additional, Wiersch, J., additional, Prasadan, K., additional, Guo, P., additional, Shiota, C., additional, and Gittes, G., additional
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- 2014
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12. Pancreatic Duct Glands: Are They the Missing Pancreas Specific Stem Cells
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El-Gohary, Y., primary, Xiao, X., additional, Guo, P., additional, Wiersch, J., additional, Prasadan, K., additional, Shiota, C., additional, and Gittes, G., additional
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- 2013
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13. Three-Dimensional Analysis of the Islet Vasculature
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El-Gohary, Y., primary, Sims-Lucas, S., additional, Lath, N., additional, Tulachan, S., additional, Guo, P., additional, Xiao, X., additional, Welsh, C., additional, Paredes, J., additional, Wiersch, J., additional, Prasadan, K., additional, Shiota, C., additional, and Gittes, G.K., additional
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- 2012
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14. In-situ emergency pediatric surgery in the intensive care unit
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Ghallab, A., primary, El-Gohary, Y., additional, Redmond, M., additional, and Corbally, M., additional
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- 2012
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15. Pancreatic Ducts and Alpha Cells Contribute to New Beta Cells Under Normal Physiological Conditions and During Pancreatic Regeneration
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El-Gohary, Y., primary, Tulachan, S., additional, Prasadan, K., additional, Shiota, C., additional, Guo, P., additional, and Gittes, G., additional
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- 2012
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16. Pancreatic Ducts Contributes To Islet Cell Regeneration In Adult Mice
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El-Gohary, Y., primary, Tulachan, S., additional, and Gittes, G.K., additional
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- 2011
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17. A 9-Year Single Center Experience with Circumumbilical Ramstedt's Pyloromyotomy
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El-Gohary, Y., primary, Yeap, B., additional, Hempel, G., additional, and Gillick, J., additional
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- 2010
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18. 68 RANDOMIZED CONTROLLED TRIAL OF NITAZOXANIDE-PEGINTERFERON-RIBAVIRIN, NITAZOXANIDE-PEGINTERFERON AND PEGINTERFERON-RIBAVIRIN IN THE TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS C GENOTYPE 4
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Rossignol, J.F., primary, Elfert, A., additional, El-Gohary, Y., additional, and Keeffe, E.B., additional
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- 2008
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19. 831 RANDOMIZED DOUBLE BLIND PLACEBO-CONTROLLED TRIAL OF NITAZOXANIDE IN THE TREATMENT OF PATIENTS WITH CHRONIC HEPATITIS C GENOTYPE 4
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Rossignol, J.F., primary, Kabil, S.M., additional, El-Gohary, Y., additional, and Keeffe, E.B., additional
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- 2008
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20. Gorlin syndrome presenting with a unilateral ovarian fibroma in a 22-year-old woman: a case report
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Finch Terence, Pushpanathan Chitra, Brown Krista, and El-Gohary Yasser
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Medicine - Abstract
Abstract Introduction Nevoid basal cell carcinoma syndrome, or Gorlin syndrome, is an inherited disorder characterized by malignancies of the skin and other organs, skeletal abnormalities, and congenital malformations. The syndrome follows an autosomal dominant inheritance pattern with a gene mutation localized to 9q22.3. Case presentation We present the case of a 22-year-old Caucasian woman with a unilateral ovarian fibroma, falx cerebri calcification and odontogenic keratocysts, but without any skin manifestations. The diagnosis of nevoid basal cell carcinoma syndrome was made after a right salpingo-oophorectomy for a calcified ovarian fibroma with cystic degeneration. Pathologic examination of the 10 cm right ovarian mass revealed a well-circumscribed spindle cell lesion. Immunohistochemical staining of the lesion demonstrated positivity for vimentin and smooth muscle actin. Conclusion It is important to recognize that nevoid basal cell carcinoma syndrome may present in the absence of skin lesions. Additionally, ovarian fibromas are typically bilateral in nevoid basal cell carcinoma syndrome, but can uncommonly be unilateral, which may alter clinical management. Ovarian fibromas are managed with surgical excision with an attempt at ovarian functional preservation.
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- 2012
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21. Long-gap esophageal atresia: gastric transposition or esophageal lengthening with delayed primary anastomosis? A systematic review.
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Nasher O, Hall NJ, Mehta R, El-Gohary Y, and Knight M
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- Humans, Infant, Newborn, Tracheoesophageal Fistula surgery, Stomach surgery, Treatment Outcome, Esophageal Atresia surgery, Anastomosis, Surgical methods, Esophagus surgery
- Abstract
Purpose: This study aims to evaluate different surgical approaches to long-gap esophageal atresia (LGEA) with or without tracheoesophageal fistula (TEF) is unclear., Methods: A systematic literature review was done comparing gastric transposition versus esophageal lengthening with delayed primary anastomosis in infants with LGEA+/-TEF. The primary outcome was time to full oral feeds. Secondary outcomes were time to full enteric feeds, need for further surgery, growth, mortality, and postoperative adverse events., Results: No comparative studies were found. However, the literature was re-interrogated for non-comparative studies. Four hundred thirty-eight articles were identified and screened, and 18 met the inclusion criteria. All were case series. Forty-three infants underwent gastric transposition, and 106 had esophageal lengthening with delayed primary anastomosis. One study on gastric transposition reported time to full oral feeds, and one study in each group reported growth. Time to full enteric feeds was reported in one study in each group. 30% of infants had further surgery following gastric transposition, including hiatus hernia repair (5/43, 12%) and esophageal dilation (7/43, 16%). Following esophageal lengthening, 62/106 (58%) had anti-reflux surgery, 58/106 (55%) esophageal dilatation and 11/106 (10%) esophageal stricture resection. Anastomotic complications occurred in 13/43 (30%), gastrointestinal in 16/43 (37%), respiratory in 17/43 (40%), and nerve injury in 2/43 (5%) of the gastric transposition group. In the esophageal lengthening group, anastomotic complications occurred in 68/106 (64%), gastrointestinal in 62/106 (58%), respiratory in 6/106 (6%), and none sustained nerve injury. Each group had one death due to a cause not directly related to the surgical procedure., Conclusions: This systematic review highlights the morbidity associated with both surgical procedures and the variety in reporting outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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22. The Risk and Prognosis of COVID-19 Infection in Cancer Patients: A Systematic Review and Meta-Analysis.
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ElGohary GM, Hashmi S, Styczynski J, Kharfan-Dabaja MA, Alblooshi RM, de la Cámara R, Mohmed S, Alshaibani A, Cesaro S, Abd El-Aziz N, Almaghrabi R, Gergis U, Majhail NS, El-Gohary Y, Chemaly RF, Aljurf M, and El Fakih R
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- Humans, SARS-CoV-2, Respiration, Artificial, Intensive Care Units, Prognosis, COVID-19 complications, Neoplasms complications
- Abstract
Numerous studies have been published regarding outcomes of cancer patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causing the coronavirus disease 2019 (COVID-19) infection. However, most of these are single-center studies with a limited number of patients. To better assess the outcomes of this new infection in this subgroup of susceptible patients, we performed a systematic review and meta-analysis to evaluate the impact of COVID-19 infection on cancer patients. We performed a literature search using PubMed, Web of Science, and Scopus for studies that reported the risk of infection and complications of COVID-19 in cancer patients and retrieved 22 studies (1018 cancer patients). The analysis showed that the frequency of cancer among patients with confirmed COVID-19 was 2.1% (95% confidence interval [CI]: 1.3-3) in the overall cohort. These patients had a mortality of 21.1% (95% CI: 14.7-27.6), severe/critical disease rate of 45.4% (95% CI: 37.4-53.3), intensive care unit (ICU) admission rate of 14.5% (95% CI: 8.5-20.4), and mechanical ventilation rate of 11.7% (95% CI: 5.5-18). The double-arm analysis showed that cancer patients had a higher risk of mortality (odds ratio [OR]=3.23, 95% CI: 1.71-6.13), severe/critical disease (OR=3.91, 95% CI: 2.70-5.67), ICU admission (OR=3.10, 95% CI: 1.85-5.17), and mechanical ventilation (OR=4.86, 95% CI: 1.27-18.65) than non-cancer patients. Furthermore, cancer patients had significantly lower platelet levels and higher D-dimer levels, C-reactive protein levels, and prothrombin time. In conclusion, these results indicate that cancer patients are at a higher risk of COVID-19 infection-related complications. Therefore, cancer patients need diligent preventive care measures and aggressive surveillance for earlier detection of COVID-19 infection.
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- 2022
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23. One-year impact of a bowel management program in treating fecal incontinence in patients with anorectal malformations.
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Wood RJ, Vilanova-Sanchez A, El-Gohary Y, Ahmad H, Halleran DR, Reck-Burneo CA, Rentea R, Sebastiao Y, Nash O, Booth K, Trimble C, Zahora P, Baxter C, Driesbach S, Halaweish I, Gasior AC, and Levitt MA
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- Child, Child, Preschool, Constipation etiology, Constipation therapy, Humans, Quality of Life, Rectum, Retrospective Studies, Anorectal Malformations, Fecal Incontinence etiology, Fecal Incontinence therapy
- Abstract
Background: Many patients with anorectal malformations (ARM) need a bowel management program (BMP) to manage lifelong problems of fecal incontinence or severe constipation. We aimed to evaluate the sustainability of the results in such a program., Methods: A single-institution retrospective review was performed in children with ARM who attended our BMP (2015-2019). Standardized definitions and validated tools were used to assess fecal continence (Baylor Continence Scale), constipation (Cleveland Constipation Scoring System), urinary symptoms (Vancouver Symptoms Score), and the Pediatric Quality of Life (PedsQL) and health-related quality of life (HRQOL) at the start of BMP and 1-year after completion of the program., Results: 222 patients with ARM at a median age of 6.7 (IQR, 4.9-10.1) years were identified. All (100%) soiled at intake with 149 (67.1%) patients being treated with rectal or antegrade enemas and 73 (32.9%) with oral laxatives. At 1 year 150 (70.4%) were clean, 72.7% were on enemas and 27.3% were on laxatives (p = 0.08). 109 out of 148 (73.6%) patients were clean on enemas. A further 41 out of 66 (62.1%) patients were continent on laxatives with voluntary bowel movements and clean. In the group that was clean, there was improvement in Baylor Continence Scale (25 vs. 13.0, p < 0.000000002), Vancouver (11 vs. 6, p = 0.0110) scores, and clinically relevant improvement in the total PedsQL HRQL (78-85) and the PedsQL HRQL physical function (86-92) and psychosocial domain (77-82). There was no improvement in Cleveland (10 vs. 9, p = 0.31) score., Conclusion: An intensive BMP offers significant benefits in the treatment of fecal incontinence in ARM. It appears to also improve urinary incontinence and urinary voiding as well as the patient's quality of life. These changes are sustainable over at least one year., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)
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- 2021
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24. The use of computed tomography versus clinical acumen in diagnosing appendicitis in children: A two-institution international study.
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El-Gohary Y, Molina M, Chang J, Dodd A, Miller E, Harrell C, Wang F, Zhang H, Davidoff AM, Fernandez-Pineda I, Murphy AJ, and Huang EY
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- Appendectomy, Child, Hospitals, Pediatric, Humans, Retrospective Studies, Tomography, X-Ray Computed, Ultrasonography, Appendicitis diagnostic imaging
- Abstract
Background: Appendicitis in children can be diagnosed utilizing clinical and laboratory findings, with the assistance of ultrasound (US) and/or computed tomography (CT). However, repeated exposure to ionizing radiation increases the lifetime risk of cancer. We compared the work-up of suspected appendicitis between a children's hospital in the United States (USA) and one in Spain to identify differences in imaging use and associated outcomes., Methods: A two-institution retrospective review was performed for surgical consultations of suspected appendicitis from 2015-2017. We compared imaging use, the utilization of overnight observation, and diagnostic accuracy rates between the two centers., Results: A total of 1,952 children were evaluated. Among the 1,288 in the USA center, 754(58.5%) underwent CT during their evaluation. The most common imaging modality was US only (39.9%), then CT only (39.3%), CT+US (19.3%), and no imaging (i.e. only clinical acumen) (1.6%). In Spain, only 19 (2.9%) of 664 children underwent CT compared to the USA (p < 0.0001). Only clinical acumen was the most common modality employed (48.6%), followed by US only (48.5%), US+CT (2.4%), and CT only (0.5%). In the USA, 16.8% were observed overnight, 2.3% of whom received no imaging. In Spain, 33.4% were observed overnight, 32.4% of whom had no imaging (p < 0.0001). The accuracy rates for diagnosing appendicitis in the USA and Spain centers were 94.7% and 95.1%, respectively., Conclusion: Use of clinical acumen and/or US have similar clinical outcomes and similar accuracy rates compared to heavy reliance on CT imaging for diagnosing appendicitis, with associated decrease in radiation exposure. The disparate diagnostic approach of the two centers may reflect that physical examination is a dying art in North America., Level of Evidence: III., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2021
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25. Primary Spinal Melanoma: Case Report and Systematic Review.
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Haberfellner E, Elbaroody M, Alkhamees AF, Alaosta A, Eaton S, Quint E, Shahab S, O'Connor A, Im J, Khan A, El-Gohary Y, Lotfy M, Sawan M, Shamisa A, and Soliman MAR
- Abstract
Introduction: Primary malignant melanoma of the spinal cord (PSM) is a rare condition with limited evidence regarding its diagnosis (clinical and radiographic), management, and prognosis. Our aim was to report an extremely rare two cases of primary malignant melanoma of the spine one of them is sacral melanoma which represents the second reported case in the literature and to conduct a systematic review of the relevant literature., Methods: The diagnosis and management of these cases were retrospectively reviewed. Using the PRISMA guideline, we conducted a systematic review of the literature to analyze different management strategies and the prognosis of such pathology., Results: All two patients were operated on, and received gross total removal of their tumors, with extended follow up for tumor recurrences. One of the cases involved a sacral tumor, which was resected without adjuvant therapy. The other one was seen by oncology and received post-operative chemo- and radio- therapy. In addition to the aforementioned cases, we present a comprehensive review of the literature on PSM from 1950 to the present, demonstrating that PSM is a very rare tumor, with a limited counted number of cases reported worldwide., Conclusion: In conclusion, we report an exceedingly rare two cases of primary malignant melanoma of the spine. Early surgical intervention is key to the management of these rare and aggressive tumors. GTR should be attempted if possible., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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26. Case report of a skip segment Hirschsprung's disease: A real phenomenon.
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El-Gohary Y, Skerritt C, Prasad V, Halaweish I, and Wood RJ
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Introduction and Importance: Hirschsprung's disease is a congenital anomaly that results from an incomplete craniocaudal migration and maturation of intestinal ganglion progenitor cells leading to distal intestinal aganglionosis. Skip segment Hirschsprung's disease is an extremely rare phenomenon. We report a case involving only the small bowel with confirmed colonic ganglionosis., Case Presentation: A case report of a 14-month-old with a skipped segment involving the distal 50 cm of the small bowel associated with colonic ganglionosis is presented. A current review of the literature is discussed., Clinical Discussion: Our patient had persistent obstructive symptoms despite undergoing a technically good, ganglionic pull-through operation at an outside institution. A laparoscopic-assisted pull-through might have documented a small bowel wall diameter discrepancy., Conclusion: Although rare, skip segment Hirschsprung's disease is a real phenomenon that paediatric surgeons should be aware of and could involve small and large bowels., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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27. Splenic function is not maintained long-term after partial splenectomy in children with sickle cell disease.
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El-Gohary Y, Khan S, Hodgman E, Wynn L, Kimble A, Abdelhafeez A, Talbot L, Wang W, Davidoff AM, and Murphy AJ
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- Adolescent, Child, Humans, Retrospective Studies, Spleen surgery, Splenectomy, Anemia, Sickle Cell surgery, Spherocytosis, Hereditary surgery
- Abstract
Background: Partial splenectomy (PS) may allow preservation of splenic function in cases where splenectomy is indicated for hematologic diseases; however, the long-term outcomes are uncertain. We investigated the long-term outcomes of PS in patients with sickle cell disease (SCD)., Methods: A single-institution retrospective chart review was performed for children with SCD who underwent PS from 1997 to 2017. For comparison, we reviewed outcomes for patients who underwent PS for hereditary spherocytosis (HS). The primary endpoint was viability of the splenic remnant as inferred by the presence of remnant perfusion on ultrasound and/or liver spleen scan., Results: Nine patients with SCD and 26 patients with HS underwent PS at a median age of 11 (IQR, 9-14) and 7.5 (IQR, 6-13) years, respectively. All underwent laparoscopic PS with three (7.9%) conversions to open. Two SCD patients were lost to long-term follow-up. The remaining seven SCD patients had initial postoperative splenic remnant perfusion demonstrated by ultrasonography. By 42 months postoperatively, however, none had a functioning splenic remnant. The median time to loss of splenic remnant was 12.6 (IQR 9.2-28.5) months. In contrast, all HS patients demonstrated robust splenic remnant blood flow with a median follow-up of 46 (IQR 37-82) months., Conclusion: No patient with SCD who underwent PS had viable splenic tissue for more than 42 months, likely due to continued autoinfarction typical of patients with this disease. Therefore, we believe that PS to preserve splenic function is not indicated in patients with SCD., Level of Evidence: III., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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28. Single-site retroperitoneoscopy in pediatric metastatic lymphadenopathy.
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El-Gohary Y, Mansfield S, Talbot L, Murphy AJ, Davidoff AM, and Abdelhafeez A
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- Adolescent, Humans, Lymph Node Excision, Male, Neoplasm Staging, Neoplasms, Germ Cell and Embryonal, Neuroblastoma, Retroperitoneal Space, Retrospective Studies, Testicular Neoplasms pathology, Laparoscopy, Lymphadenopathy surgery, Testicular Neoplasms surgery
- Abstract
Background: Retroperitoneoscopic surgery (RS) is increasingly used for the diagnosis, staging, and treatment of solid tumors, but rarely in pediatric surgical oncology for retroperitoneal lymph node dissection (RPLND). Herein, we use single-site RS for RPLND in children and compare the perioperative outcomes with those for the transperitoneal laparoscopic approach (TPLA)., Methods: A single institution retrospective chart review was performed for patients undergoing single-site RS and TPLA (January 2018 till June 2019). We compared patient demographics, diagnoses, operative times, complications, postoperative analgesia, and length of hospital stay between both groups., Results: Eight patients (median age of 16.5 years) undergoing single-site RS for RPLND and five patients (median age 17 years) undergoing TPLA RPLND were compared. Groups were comparable in age, median operative duration (232 vs 234 min, p = 0.77), and complications (1 vs 1, p = 0.72). Median postoperative hospital stay and total morphine equivalent doses used postoperatively were significantly lower in the RS group, (0.5 vs 2 days, [p = 0.03] and 0.1 vs 0.4 mg/kg [p = 0.01], respectively). Eight patients underwent ipsilateral modified template RPLND for paratesticular RMS (six single-site RS and two TPLA) and lymph node metastases were found in 50% of these patients. The rest were resections of metastatic lesions for germ cell tumor and neuroblastoma (two single-site RS and three TPLA)., Conclusions: Single-site RS is a safe and feasible technique in carefully selected pediatric surgical oncology patients. RS provides an excellent view of the retroperitoneum, requires less postoperative analgesia, and is associated with faster recovery., Level of Evidence Rating: IV., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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29. Management of pancreatic pseudocysts in pediatric oncology patients.
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El-Gohary Y, Mansfield S, Staszak J, Abdelhafeez A, Talbot L, Pui CH, Gold R, Murphy AJ, and Davidoff AM
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- Child, Drainage, Humans, Pancreas surgery, Retrospective Studies, Pancreatic Pseudocyst surgery
- Abstract
Background: Management of children with pancreatic pseudocysts has historically been adopted from the adult experience where pancreatic pseudocysts greater than 6 cm are unlikely to resolve without intervention. We reviewed the clinical course of pediatric oncology patients with pancreatic pseudocysts., Methods: A retrospective review of patients treated over a 15-year period was performed. Variables evaluated included cancer type, medications administered, clinical and imaging characteristics of the pancreatic pseudocysts, treatment and outcome., Results: A total of 132 patients with a median age of 13 (IQR, 9-17) years were identified with pancreatitis. Thirty-one (23.5%) patients developed a pancreatic pseudocyst, of which 84% were associated with PEG-asparaginase treatment. The median pseudocyst size was 7.6 (IQR, 4.4-9.9) cm with 59% being greater than 6 cm. Twenty-two (71%) patients with a pancreatic pseudocyst underwent successful conservative management, while only 9 (29%) required procedural intervention including six percutaneous drainage, one of whom recurred and required surgical cyst-enteric drainage. Two other patients had primary surgical cyst-enteric drainage and one patient underwent endoscopic retrograde cholangiopancreatography with stenting. The indication for intervention was worsening pain rather than pseudocyst imaging characteristics, size or serum amylase/lipase., Conclusion: Most medication-induced pancreatic pseudocysts in children being treated for cancer, regardless of pseudocyst size, can be managed non-operatively or with transgastric percutaneous drainage. The need for intervention can be safely dictated by patient symptoms., Level of Evidence: III., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2020
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30. A Quality Improvement Intervention to Decrease Postoperative Opioid Prescriptions in Pediatric Oncology Patients.
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Mansfield SA, El Gohary Y, Kimble A, Wynn L, Hall EA, Anghelescu DL, Davidoff AM, and Murphy AJ
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- Adolescent, Adult, Analgesics, Opioid adverse effects, Child, Child, Preschool, Female, Humans, Male, Retrospective Studies, Analgesics, Opioid administration & dosage, Neoplasms surgery, Pain Management, Pain, Postoperative drug therapy, Quality Improvement
- Abstract
Purpose: This quality improvement initiative aimed to minimize opioid prescribing after oncologic pediatric surgery., Methods: Retrospective surgical data collected at a pediatric cancer hospital from July 2016 to June 2018 included hospitalization details, oral morphine equivalents prescribed, unplanned visits/calls because of pain, and parental/patient satisfaction with pain control. The quality improvement initiative promoted opioid prescription at discharge on the basis of prior inpatient requirements and education regarding nonopioid analgesia. Upon commencing this project in July 2018, we collected data prospectively., Results: The retrospective and the prospective cohorts included 271 and 99 patients, respectively. Mean (SD) oral morphine equivalents (mg/kg) prescribed upon discharge was significantly reduced in the prospective (0.75±1.34) versus retrospective cohorts (5.48±6.94, P<0.001). The unplanned visits/calls regarding pain were 23 (retrospective, 8.5%) and 2 (prospective, 2.0%). In total, 44 patients (44.4%) received an opioid prescription at discharge in the prospective cohort, significantly fewer than retrospective cohort (251, 92.6%, P<0.001), and used a mean of 34.3 of 159.8 (21.5%) doses dispensed. Length of stay was comparable (P=0.88) between cohorts. Prospective satisfaction rate was 96.2%, leaving 3 patients (3.8%) not satisfied with their pain control regimen., Conclusions: Dramatic reduction of opioid prescriptions after oncologic surgery can be achieved without detriment to patient satisfaction or readmissions., Level of Evidence: Level V.
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- 2020
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31. Acute Chest Syndrome After Splenectomy in Children With Sickle Cell Disease.
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El-Gohary Y, Fleming A, Zhang H, Estepp JH, Hankins JS, Wang W, Davidoff AM, and Murphy AJ
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- Acute Chest Syndrome diagnosis, Acute Chest Syndrome etiology, Analgesics, Opioid therapeutic use, Anemia, Sickle Cell complications, Chest Pain diagnosis, Chest Pain etiology, Child, Child, Preschool, Elective Surgical Procedures adverse effects, Elective Surgical Procedures methods, Female, Humans, Infant, Laparoscopy adverse effects, Laparoscopy methods, Length of Stay statistics & numerical data, Male, Pain Management methods, Pain Management statistics & numerical data, Pain Measurement, Pain, Postoperative diagnosis, Pain, Postoperative etiology, Retrospective Studies, Risk Factors, Splenectomy methods, Acute Chest Syndrome epidemiology, Anemia, Sickle Cell surgery, Chest Pain epidemiology, Pain, Postoperative epidemiology, Splenectomy adverse effects
- Abstract
Background: Individuals with sickle cell disease (SCD) are at high risk of developing life-threatening complications, particularly acute chest syndrome (ACS) postoperatively. The perioperative factors associated with the development of ACS in children with SCD after splenectomy have not been clearly identified., Materials and Methods: We retrospectively reviewed medical records of all children who underwent splenectomy at our institution between 1997 and 2017 with the goal of identifying perioperative factors associated with postoperative ACS. Categorical and noncategorical variables were compared using Fisher's exact test and Student's two-tailed t-test, respectively., Results: Sixty-five patients with SCD underwent splenectomy at a median of 4.0 (interquartile range [IQR] 2.0-8.0) years of age. A laparoscopic approach was used for 64 (98.5%) patients. Fifty-six (86.2%) underwent laparoscopic total splenectomy, and eight (12.3%) underwent laparoscopic partial splenectomy, of which two were converted to open. One had an open partial splenectomy (1.5%). Of the 65 patients, 10 (15.4%) developed ACS with a mean time to diagnosis of 49.0 ± 34.5 h. Children who developed ACS had a higher postoperative median pain score of 6.8 (IQR 5.1-9.1) versus 2.7 (IQR 1.6-4.2), P < 0.001, higher median pain score area under the curve 111.5 (IQR 76.9-169.1) versus 47.3 (IQR 30.5-78.3), P = 0.01, and received more total morphine equivalents (median 1.4 [IQR 0.4-2.7] versus 0.5 [IQR 0.3-0.9] mg/kg, respectively; P = 0.003), compared with children who did not develop ACS., Conclusions: Significant postoperative pain may be an early sign of ACS that could be worsened by opioid use, supporting the investigation of nonopioid pain control options in this patient population., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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32. Pyloric stenosis: an enigma more than a century after the first successful treatment.
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El-Gohary Y, Abdelhafeez A, Paton E, Gosain A, and Murphy AJ
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- Atropine therapeutic use, History, 19th Century, History, 20th Century, Humans, Intraoperative Complications, Laparoscopy, Parasympatholytics therapeutic use, Postoperative Care, Postoperative Complications, Preoperative Care, Pyloric Stenosis, Hypertrophic etiology, Pyloromyotomy methods, Pyloric Stenosis, Hypertrophic diagnosis, Pyloric Stenosis, Hypertrophic therapy
- Abstract
Despite hypertrophic pyloric stenosis (HPS) being one of the most frequently treated pediatric surgical conditions, its etiology remains incompletely understood. We review the diagnosis and treatment of this condition with an emphasis on the evolution of surgical techniques that led to laparoscopic pyloromyotomy, the most frequently performed technique for HPS today. In addition, we review key developments in the understanding of HPS etiology and treatment, including the postulated etiology of work-induced hypertrophy of the pylorus, its association with prokinetic macrolide antibiotics, and the emerging role of atropine sulfate as a medical treatment for HPS or a rescue treatment for incomplete myotomy.
- Published
- 2018
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33. Treatment of striae distensae with needling therapy versus microdermabrasion with sonophoresis.
- Author
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Nassar A, Ghomey S, El Gohary Y, and El-Desoky F
- Subjects
- Adult, Collagen, Female, Humans, Middle Aged, Patient Satisfaction, Striae Distensae pathology, Striae Distensae radiotherapy, Dermabrasion methods, Needles, Striae Distensae therapy, Ultrasonic Therapy methods, Ultrasonic Waves
- Abstract
Unlabelled: Striae distensae (SD) is a challenging cosmetic problem for which various treatment modalities have been applied. Our aim was to evaluate the efficacy and tolerability of needling therapy versus microdermabrasion with sonophoresis in the treatment of SD., Materials and Methods: Forty female patients with SD (mean duration 2.98 ± 2.66) were enrolled in this study. Patients were assigned to two groups, Group 1 treated with needling therapy and Group 2 treated by microdermabrasion with sonophoresis. In Group 1, three sessions of needling therapy were performed for each patient with 4-week interval between the sessions, while in Group 2, ten sessions of combined microdermabrasion and sonophoresis were performed for each patient. Skin biopsies were taken from the most atrophic site stained with hematoxylin and eosin stain and Masson trichrome stains to study the histopathological changes and efficacy of treatment, respectively., Results: There was a significant clinical improvement in SD in Group 1 compared with Group 2. Amount of collagen, number of fibroblasts, and epidermal thickness increased in the dermis at the end of treatment sessions (90% in Group 1 compared to 50% in Group 2)., Conclusion: Needling therapy is an easy, safe, and economic method and considered as a suitable modality in management of striae.
- Published
- 2016
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34. Intraislet Pancreatic Ducts Can Give Rise to Insulin-Positive Cells.
- Author
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El-Gohary Y, Wiersch J, Tulachan S, Xiao X, Guo P, Rymer C, Fischbach S, Prasadan K, Shiota C, Gaffar I, Song Z, Galambos C, Esni F, and Gittes GK
- Subjects
- Adolescent, Age Factors, Animals, Cadaver, Child, Preschool, Female, Humans, Infant, Insulin-Secreting Cells physiology, Islets of Langerhans growth & development, Islets of Langerhans physiology, Luminescent Proteins genetics, Luminescent Proteins metabolism, Male, Mice, Mutant Strains, Mice, Transgenic, Mutant Proteins genetics, Mutant Proteins metabolism, Pancreatectomy, Pancreatic Ducts growth & development, Pancreatic Ducts physiology, Protein Serine-Threonine Kinases genetics, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta genetics, Regeneration, Red Fluorescent Protein, Cell Transdifferentiation, Insulin biosynthesis, Insulin-Secreting Cells cytology, Islets of Langerhans cytology, Pancreatic Ducts cytology, Protein Serine-Threonine Kinases metabolism, Receptors, Transforming Growth Factor beta metabolism
- Abstract
A key question in diabetes research is whether new β-cells can be derived from endogenous, nonendocrine cells. The potential for pancreatic ductal cells to convert into β-cells is a highly debated issue. To date, it remains unclear what anatomical process would result in duct-derived cells coming to exist within preexisting islets. We used a whole-mount technique to directly visualize the pancreatic ductal network in young wild-type mice, young humans, and wild-type and transgenic mice after partial pancreatectomy. Pancreatic ductal networks, originating from the main ductal tree, were found to reside deep within islets in young mice and humans but not in mature mice or humans. These networks were also not present in normal adult mice after partial pancreatectomy, but TGF-β receptor mutant mice demonstrated formation of these intraislet duct structures after partial pancreatectomy. Genetic and viral lineage tracings were used to determine whether endocrine cells were derived from pancreatic ducts. Lineage tracing confirmed that pancreatic ductal cells can typically convert into new β-cells in normal young developing mice as well as in adult TGF-β signaling mutant mice after partial pancreatectomy. Here the direct visual evidence of ducts growing into islets, along with lineage tracing, not only represents strong evidence for duct cells giving rise to β-cells in the postnatal pancreas but also importantly implicates TGF-β signaling in this process.
- Published
- 2016
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35. Pancreatic cell tracing, lineage tagging and targeted genetic manipulations in multiple cell types using pancreatic ductal infusion of adeno-associated viral vectors and/or cell-tagging dyes.
- Author
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Xiao X, Guo P, Prasadan K, Shiota C, Peirish L, Fischbach S, Song Z, Gaffar I, Wiersch J, El-Gohary Y, Husain SZ, and Gittes GK
- Subjects
- Animals, Cell Lineage, Dimethylamines administration & dosage, Female, Genetic Techniques, Laparotomy, Male, Mice, Inbred C57BL, Mice, Transgenic, Pancreatic Ducts physiology, Promoter Regions, Genetic, RNA, Small Interfering, Transduction, Genetic, Transgenes, Coloring Agents administration & dosage, Dependovirus genetics, Genetic Vectors, Pancreas cytology, Pancreatic Ducts surgery
- Abstract
Genetic manipulations, with or without lineage tracing for specific pancreatic cell types, are very powerful tools for studying diabetes, pancreatitis and pancreatic cancer. Nevertheless, the use of Cre/loxP systems to conditionally activate or inactivate the expression of genes in a cell type- and/or temporal-specific manner is not applicable to cell tracing and/or gene manipulations in more than one lineage at a time. Here we report a technique that allows efficient delivery of dyes for cell tagging into the mouse pancreas through the duct system, and that also delivers viruses carrying transgenes or siRNA under a specific promoter. When this technique is applied in genetically modified mice, it enables the investigator to perform either double lineage tracing or cell lineage tracing combined with gene manipulation in a second lineage. The technique requires <40 min.
- Published
- 2014
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36. Barrier function of the coelomic epithelium in the developing pancreas.
- Author
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Guo P, Preuett B, Krishna P, Xiao X, Shiota C, Wiersch J, Gaffar I, Tulachan S, El-Gohary Y, Song Z, and Gittes G
- Subjects
- Activin Receptors metabolism, Animals, Epithelium embryology, Mesoderm embryology, Mice, Organ Culture Techniques, Signal Transduction physiology, Organogenesis physiology, Pancreas embryology
- Abstract
Tight spatial regulation of extracellular morphogen signaling within the close confines of a developing embryo is critical for proper organogenesis. Given the complexity of extracellular signaling in developing organs, together with the proximity of adjacent organs that use disparate signaling pathways, we postulated that a physical barrier to signaling may exist between organs in the embryo. Here we describe a previously unrecognized role for the embryonic coelomic epithelium in providing a physical barrier to contain morphogenic signaling in the developing mouse pancreas. This layer of cells appears to function both to contain key factors required for pancreatic epithelial differentiation, and to prevent fusion of adjacent organs during critical developmental windows. During early foregut development, this barrier appears to play a role in preventing splenic anlage-derived activin signaling from inducing intestinalization of the pancreas-specified epithelium., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
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37. Pancreatic duct cells as a source of VEGF in mice.
- Author
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Xiao X, Prasadan K, Guo P, El-Gohary Y, Fischbach S, Wiersch J, Gaffar I, Shiota C, and Gittes GK
- Subjects
- Animals, Epithelial Cells cytology, Gene Knockdown Techniques, Human Umbilical Vein Endothelial Cells, Humans, Islets of Langerhans cytology, Islets of Langerhans Transplantation, Mice, Neovascularization, Physiologic, RNA, Small Interfering metabolism, SOX9 Transcription Factor genetics, Vascular Endothelial Growth Factor A genetics, Insulin-Secreting Cells metabolism, Pancreatic Ducts metabolism, Vascular Endothelial Growth Factor A metabolism
- Abstract
Aims/hypothesis: Vascular endothelial growth factor (VEGF) is essential for proper pancreatic development, islet vascularisation and insulin secretion. In the adult pancreas, VEGF is thought to be predominantly secreted by beta cells. Although human duct cells have previously been shown to secrete VEGF at angiogenic levels in culture, an analysis of the kinetics of VEGF synthesis and secretion, as well as elucidation of an in vivo role for this ductal VEGF in affecting islet function and physiology, has been lacking., Methods: We analysed purified duct cells independently prepared by flow cytometry, surgical isolation or laser-capture microdissection. We infected duct cells in vivo with Vegf (also known as Vegfa) short hairpin RNA (shRNA) in an intrapancreatic ductal infusion system and examined the effect of VEGF knockdown in duct cells in vitro and in vivo., Results: Pancreatic duct cells express high levels of Vegf mRNA. Compared with beta cells, duct cells had a much higher ratio of secreted to intracellular VEGF. As a bioassay, formation of tubular structures by human umbilical vein endothelial cells was essentially undetectable when cultured alone and was substantially increased when co-cultured with pancreatic duct cells but significantly reduced when co-cultured with duct cells pretreated with Vegf shRNA. Compared with islets transplanted alone, improved vascularisation and function was detected in the islets co-transplanted with duct cells but not in islets co-transplanted with duct cells pretreated with Vegf shRNA., Conclusions/interpretation: Human islet preparations for transplantation typically contain some contaminating duct cells and our findings suggest that the presence of duct cells in the islet preparation may improve transplantation outcomes.
- Published
- 2014
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38. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7.
- Author
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Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, Song Z, El-Gohary Y, Prasadan K, Shiota C, and Gittes GK
- Subjects
- Animals, Cell Movement, Cell Nucleus metabolism, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Disease Models, Animal, ErbB Receptors metabolism, Inflammation metabolism, Inflammation pathology, Ligation, Mice, Mice, Inbred C57BL, Models, Biological, Signal Transduction, Transforming Growth Factor beta metabolism, Insulin-Secreting Cells metabolism, Insulin-Secreting Cells pathology, Macrophages metabolism, Smad7 Protein metabolism, Up-Regulation
- Abstract
Determination of signaling pathways that regulate beta-cell replication is critical for beta-cell therapy. Here, we show that blocking pancreatic macrophage infiltration after pancreatic duct ligation (PDL) completely inhibits beta-cell proliferation. The TGFβ superfamily signaling inhibitor SMAD7 was significantly up-regulated in beta cells after PDL. Beta cells failed to proliferate in response to PDL in beta-cell-specific SMAD7 mutant mice. Forced expression of SMAD7 in beta cells by itself was sufficient to promote beta-cell proliferation in vivo. M2, rather than M1 macrophages, seem to be the inducers of SMAD7-mediated beta-cell proliferation. M2 macrophages not only release TGFβ1 to directly induce up-regulation of SMAD7 in beta cells but also release EGF to activate EGF receptor signaling that inhibits TGFβ1-activated SMAD2 nuclear translocation, resulting in TGFβ signaling inhibition. SMAD7 promotes beta-cell proliferation by increasing CyclinD1 and CyclinD2, and by inducing nuclear exclusion of p27. Our study thus reveals a molecular pathway to potentially increase beta-cell mass through enhanced SMAD7 activity induced by extracellular stimuli.
- Published
- 2014
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39. A smad signaling network regulates islet cell proliferation.
- Author
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El-Gohary Y, Tulachan S, Wiersch J, Guo P, Welsh C, Prasadan K, Paredes J, Shiota C, Xiao X, Wada Y, Diaz M, and Gittes G
- Subjects
- Animals, Cell Proliferation, Insulin-Secreting Cells cytology, Mice, Mice, Transgenic, Phosphorylation, Receptors, Transforming Growth Factor beta metabolism, Smad Proteins genetics, Transforming Growth Factor beta metabolism, Cell Dedifferentiation physiology, Insulin-Secreting Cells metabolism, Signal Transduction physiology, Smad Proteins metabolism
- Abstract
Pancreatic β-cell loss and dysfunction are critical components of all types of diabetes. Human and rodent β-cells are able to proliferate, and this proliferation is an important defense against the evolution and progression of diabetes. Transforming growth factor-β (TGF-β) signaling has been shown to affect β-cell development, proliferation, and function, but β-cell proliferation is thought to be the only source of new β-cells in the adult. Recently, β-cell dedifferentiation has been shown to be an important contributory mechanism to β-cell failure. In this study, we tie together these two pathways by showing that a network of intracellular TGF-β regulators, smads 7, 2, and 3, control β-cell proliferation after β-cell loss, and specifically, smad7 is necessary for that β-cell proliferation. Importantly, this smad7-mediated proliferation appears to entail passing through a transient, nonpathologic dedifferentiation of β-cells to a pancreatic polypeptide-fold hormone-positive state. TGF-β receptor II appears to be a receptor important for controlling the status of the smad network in β-cells. These studies should help our understanding of properly regulated β-cell replication.
- Published
- 2014
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40. Specific transduction and labeling of pancreatic ducts by targeted recombinant viral infusion into mouse pancreatic ducts.
- Author
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Guo P, Xiao X, El-Gohary Y, Criscimanna A, Prasadan K, Rymer C, Shiota C, Wiersch J, Gaffar I, Esni F, and Gittes GK
- Subjects
- Animals, Cell Lineage, Genetic Vectors, Green Fluorescent Proteins genetics, HEK293 Cells, Humans, Infusion Pumps, Mice, Pancreas cytology, Pancreas metabolism, Pancreatic Ducts cytology, Promoter Regions, Genetic, Recombinant Proteins genetics, Regeneration, SOX9 Transcription Factor genetics, Transduction, Genetic instrumentation, Dependovirus genetics, Pancreatic Ducts metabolism, Transduction, Genetic methods
- Abstract
Specific labeling of pancreatic ducts has proven to be quite difficult. Such labeling has been highly sought after because of the power it would confer to studies of pancreatic ductal carcinogenesis, as well as studies of the source of new insulin-producing β-cells. Cre-loxp recombination could, in theory, lineage-tag pancreatic ducts, but results have been conflicting, mainly due to low labeling efficiencies. Here, we achieved a high pancreatic duct labeling efficiency using a recombinant adeno-associated virus (rAAV) with a duct-specific sox9 promoter infused into the mouse common biliary/pancreatic duct. We saw rapid, diffuse duct-specific labeling, with 50 and 89% labeling in the pancreatic tail and head region, respectively. This highly specific labeling of ducts should greatly enhance our ability to study the role of pancreatic ducts in numerous aspects of pancreatic growth, development and function.
- Published
- 2013
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41. α-Cells are dispensable in postnatal morphogenesis and maturation of mouse pancreatic islets.
- Author
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Shiota C, Prasadan K, Guo P, El-Gohary Y, Wiersch J, Xiao X, Esni F, and Gittes GK
- Subjects
- Ablation Techniques, Animals, Animals, Newborn, Biomarkers metabolism, Exons, Female, Glucagon chemistry, Glucagon genetics, Glucose Transporter Type 2 metabolism, Hypertrophy, Hypoglycemia etiology, Insulin-Secreting Cells cytology, Insulin-Secreting Cells metabolism, Islets of Langerhans cytology, Islets of Langerhans surgery, Luminescent Proteins chemistry, Luminescent Proteins metabolism, Male, Mice, Mice, Transgenic, Pancreas pathology, Peptide Fragments chemistry, Peptide Fragments genetics, Peptide Fragments metabolism, Promoter Regions, Genetic, Recombinant Fusion Proteins metabolism, Urocortins metabolism, Glucagon metabolism, Glucagon-Secreting Cells physiology, Islets of Langerhans growth & development
- Abstract
Glucagon-producing α-cells are the second-most abundant cell type in the islet. Whereas α-cells make up less than 20% of the cells in a mature mouse islet, they occupy a much larger proportion of the pancreatic endocrine cell population during the early postnatal period, the time when morphological and functional maturation occurs to form adult islets. To determine whether α-cells have a role in postnatal islet development, a diphtheria toxin-mediated α-cell ablation mouse model was established. Rapid and persistent depletion of α-cells was achieved by daily injection of the toxin for 2 wk starting at postnatal day 1 (P1). Total pancreatic glucagon content in the α-cell-ablated mice was undetectable at P14 and still less than 0.3% of that of the control mice at 4 mo of age. Histological analyses revealed that formation of spherical islets occurred normally, and the islet size distribution was not changed despite the near-total lack of α-cells. Furthermore, there were no differences in expression of β-cell maturation marker proteins, including urocortin 3 and glucose transporter 2, in the α-cell-ablated islets at P14. Mice lacking α-cells grew normally and appeared healthy. Both glucose and insulin tolerance tests demonstrated that the α-cell-ablated mice had normal glucose homeostasis. These results indicate that α-cells do not play a critical role in postnatal islet morphogenesis or functional maturation of β-cells.
- Published
- 2013
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- View/download PDF
42. Neurogenin3 activation is not sufficient to direct duct-to-beta cell transdifferentiation in the adult pancreas.
- Author
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Xiao X, Guo P, Shiota C, Prasadan K, El-Gohary Y, Wiersch J, Gaffar I, and Gittes GK
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Fluoresceins pharmacology, Fluorescent Dyes pharmacology, Insulin-Secreting Cells cytology, Mice, Mice, Transgenic, Nerve Tissue Proteins genetics, Pancreatic Ducts cytology, Succinimides pharmacology, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Transdifferentiation physiology, Insulin-Secreting Cells metabolism, Nerve Tissue Proteins metabolism, Pancreatic Ducts metabolism
- Abstract
It remains controversial whether adult pancreatic ducts harbor facultative beta cell progenitors. Because neurogenin3 (Ngn3) is a key determinant of pancreatic endocrine cell neogenesis during embryogenesis, many studies have also relied upon Ngn3 expression as evidence of beta cell neogenesis in adults. Recently, however, Ngn3 as a marker of adult beta cell neogenesis has been called into question by reports of Ngn3 expression in fully-developed beta cells. Nevertheless, direct evidence as to whether Ngn3 activation in adult pancreatic duct cells may lead to duct-to-beta cell transdifferentiation is lacking. Here we studied two models of Ngn3 activation in adult pancreatic duct cells (low-dose alloxan treatment and pancreatic duct ligation) and lineage-traced Ngn3-activated duct cells by labeling them through intraductal infusion with a cell-tagging dye, CFDA-SE No dye-labeled beta cells were found during the follow-up in either model, suggesting that activation of Ngn3 in duct cells is not sufficient to direct their transdifferentiation into beta cells. Therefore, Ngn3 activation in duct cells is not a signature for adult beta cell neogenesis.
- Published
- 2013
- Full Text
- View/download PDF
43. Smad signaling pathways regulate pancreatic endocrine development.
- Author
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El-Gohary Y, Tulachan S, Guo P, Welsh C, Wiersch J, Prasadan K, Paredes J, Shiota C, Xiao X, Wada Y, Diaz M, and Gittes G
- Subjects
- Animals, Blotting, Western, Cell Proliferation, Epithelium metabolism, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Immunohistochemistry, Islets of Langerhans cytology, Islets of Langerhans embryology, Mice, Mice, Knockout, Mice, Transgenic, Microscopy, Fluorescence, Phosphorylation, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction genetics, Smad2 Protein genetics, Smad3 Protein genetics, Smad7 Protein genetics, Time Factors, Transforming Growth Factor beta metabolism, Islets of Langerhans metabolism, Smad2 Protein metabolism, Smad3 Protein metabolism, Smad7 Protein metabolism
- Abstract
Expansion of the pancreatic endocrine cell population occurs during both embryonic development and during post-natal pancreatic growth and regeneration. Mechanisms of the expansion of endocrine cells during embryonic development are not completely understood, and no clear mechanistic link has been established between growth of the embryonic endocrine pancreas and the islet cell replication that occurs in an adult animal. We found that transforming growth factor-beta (TGF-β) superfamily signaling, which has been implicated in many developmental processes, plays a key role in regulating pancreatic endocrine maturation and development. Specifically, the intracellular mediators of TGF-β signaling, smad2 and smad3, along with their inhibitor smad7, appear to mediate this process. Smad2, smad3 and smad7 were all broadly expressed throughout the early embryonic pancreatic epithelium. However, during later stages of development, smad2 and smad3 became strongly localized to the nuclei of the endocrine positive cells, whereas the inhibitory smad7 became absent in the endocrine component. Genetic inactivation of smad2 and smad3 led to a significant expansion of the embryonic endocrine compartment, whereas genetic inactivation of smad7 led to a significant decrease in the endocrine compartment. In vitro antisense studies further corroborated these results and supported the possibility that interplay between the inhibitory smad7 and the intracellular mediators smad2/3 is a control point for pancreatic endocrine development. These results should provide a better understanding of the key control mechanisms for β-cell development., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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44. No evidence for β cell neogenesis in murine adult pancreas.
- Author
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Xiao X, Chen Z, Shiota C, Prasadan K, Guo P, El-Gohary Y, Paredes J, Welsh C, Wiersch J, and Gittes GK
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Proliferation, Cell Separation, Female, Flow Cytometry, Green Fluorescent Proteins metabolism, Immunohistochemistry, Inflammation, Insulin genetics, Insulin metabolism, Mice, Mice, Transgenic, Microscopy, Fluorescence, Nerve Tissue Proteins metabolism, RNA metabolism, Time Factors, Insulin-Secreting Cells cytology, Pancreas cytology, Pancreas metabolism
- Abstract
Whether facultative β cell progenitors exist in the adult pancreas is a major unsolved question. To date, lineage-tracing studies have provided conflicting results. To track β cell neogenesis in vivo, we generated transgenic mice that transiently coexpress mTomato and GFP in a time-sensitive, nonconditional Cre-mediated manner, so that insulin-producing cells express GFP under control of the insulin promoter, while all other cells express mTomato (INSCremTmG mice). Newly differentiated β cells were detected by flow cytometry and fluorescence microscopy, taking advantage of their transient coexpression of GFP and mTomato fluorescent proteins. We found that β cell neogenesis predominantly occurs during embryogenesis, decreases dramatically shortly after birth, and is completely absent in adults across various models of β cell loss, β cell growth and regeneration, and inflammation. Moreover, we demonstrated upregulation of neurogenin 3 (NGN3) in both proliferating ducts and preexisting β cells in the ligated pancreatic tail after pancreatic ductal ligation. These results are consistent with some recent reports, but argue against the widely held belief that NGN3 marks cells undergoing endocrine neogenesis in the pancreas. Our data suggest that β cell neogenesis in the adult pancreas occurs rarely, if ever, under either normal or pathological conditions.
- Published
- 2013
- Full Text
- View/download PDF
45. TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation.
- Author
-
Xiao X, Wiersch J, El-Gohary Y, Guo P, Prasadan K, Paredes J, Welsh C, Shiota C, and Gittes GK
- Subjects
- Animals, Cell Proliferation, Glucose pharmacology, Insulin pharmacology, Insulin-Secreting Cells cytology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pancreatectomy methods, RNA-Directed DNA Polymerase, Receptors, Transforming Growth Factor beta genetics, Signal Transduction, Transforming Growth Factor beta genetics, Insulin-Secreting Cells metabolism, Receptors, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta metabolism
- Abstract
Protection and restoration of a functional β-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional β-cell mass is of immense clinical relevance. Transforming growth factor β (TGFβ) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult β-cell homeostasis is not well defined. Here, we ablated TGFβ receptor I and II genes in mice undergoing two surgical β-cell replication models (partial pancreatectomy or partial duct ligation), representing two triggers for β-cell proliferation, increased β-cell workload and local inflammation, respectively. Our data suggest that TGFβ receptor signaling is necessary for baseline β-cell proliferation. By either provision of excess glucose or treatment with exogenous insulin, we further demonstrated that inflammation and increased β-cell workload are both stimulants for β-cell proliferation but are TGFβ receptor signaling dependent and independent, respectively. Collectively, by using a pancreas-specific TGFβ receptor-deleted mouse model, we have identified two distinct pathways that regulate adult β-cell proliferation. Our study thus provides important information for understanding β-cell proliferation during normal growth and in pancreatic diseases.
- Published
- 2013
- Full Text
- View/download PDF
46. Hypoglycemia reduces vascular endothelial growth factor A production by pancreatic beta cells as a regulator of beta cell mass.
- Author
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Xiao X, Guo P, Chen Z, El-Gohary Y, Wiersch J, Gaffar I, Prasadan K, Shiota C, and Gittes GK
- Subjects
- Animals, Apoptosis, Arabidopsis Proteins genetics, Arabidopsis Proteins metabolism, Cell Proliferation, Cells, Cultured, Gene Expression, Insulin-Secreting Cells physiology, Intramolecular Transferases genetics, Intramolecular Transferases metabolism, Mice, Pancreas blood supply, Pancreas pathology, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A physiology, Hypoglycemia metabolism, Insulin-Secreting Cells metabolism, Vascular Endothelial Growth Factor A biosynthesis
- Abstract
VEGF-A expression in beta cells is critical for pancreatic development, formation of islet-specific vasculature, and Insulin secretion. However, two key questions remain. First, is VEGF-A release from beta cells coupled to VEGF-A production in beta cells? Second, how is the VEGF-A response by beta cells affected by metabolic signals? Here, we show that VEGF-A secretion, but not gene transcription, in either cultured islets or purified pancreatic beta cells, was significantly reduced early on during low glucose conditions. In vivo, a sustained hypoglycemia in mice was induced with Insulin pellets, resulting in a significant reduction in beta cell mass. This loss of beta cell mass could be significantly rescued with continuous delivery of exogenous VEGF-A, which had no effect on beta cell mass in normoglycemic mice. In addition, an increase in apoptotic endothelial cells during hypoglycemia preceded an increase in apoptotic beta cells. Both endothelial and beta cell apoptosis were prevented by exogenous VEGF-A, suggesting a possible causative relationship between reduced VEGF-A and the loss of islet vasculature and beta cells. Furthermore, in none of these experimental groups did beta cell proliferation and islet vessel density change, suggesting a tightly regulated balance between these two cellular compartments. The average islet size decreased in hypoglycemia, which was also prevented by exogenous VEGF-A. Taken together, our data suggest that VEGF-A release in beta cells is independent of VEGF-A synthesis. Beta cell mass can be regulated through modulated release of VEGF-A from beta cells based on physiological need.
- Published
- 2013
- Full Text
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47. A simplified purification method for AAV variant by polyethylene glycol aqueous two-phase partitioning.
- Author
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Guo P, Xiao X, El-Gohary Y, Paredes J, Prasadan K, Shiota C, Wiersch J, Welsh C, and Gittes GK
- Subjects
- Ammonium Sulfate chemistry, Cell Line, Cesium chemistry, Chlorides chemistry, Dependovirus genetics, Humans, Dependovirus isolation & purification, Polyethylene Glycols chemistry
- Abstract
Adeno-Associated Virus (AAV) has been widely used for in vivo study and preclinical therapy due to its ability to mediate long-term transgene expression, its lack of pathogenicity and low immunogenicity. It has been found that AAV has more than ten serotypes, which each transfect certain types of cells in the viral infected organ. Current methods for purification of different AAV serotypes utilize CsCl or Iodixanol ultrahigh speed density gradient centrifugation, which is expensive and time consuming. We recently developed a simplified method, PEG/(NH(4))(2)SO(4) aqueous two phase partitioning, for purification of AAV serotype 2 and 8. The method does not require ultrahigh speed gradient centrifugation or chromatography. Here we further explore the simplified method for purification of other serotypes of AAV, serotype 6 and 9. This simplified method not only can be used to purify serotype 2 and 8, but also serotype 6 and 9, indicating that a variety of AAV serotypes can be purified by this method.
- Published
- 2013
- Full Text
- View/download PDF
48. Three-dimensional analysis of the islet vasculature.
- Author
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El-Gohary Y, Sims-Lucas S, Lath N, Tulachan S, Guo P, Xiao X, Welsh C, Paredes J, Wiersch J, Prasadan K, Shiota C, and Gittes GK
- Subjects
- Animals, Female, Mice, Mice, Inbred NOD, Microscopy, Confocal methods, Imaging, Three-Dimensional methods, Islets of Langerhans blood supply, Islets of Langerhans cytology
- Abstract
The pancreatic islets of Langerhans are highly vascularized structures scattered throughout the pancreas that contain a capillary network 5-10 times denser than that of the exocrine pancreas. A simple method for three-dimensional (3D) analysis of this intricate intraislet vasculature has been difficult because of the intrinsic opacity of the pancreas. We developed a whole-mount imaging technique that allows relatively easy visualization of the islet vasculature. In combination with confocal microscopy and the use of 3D imaging software, we were able to readily reconstruct the 3D architecture of an islet, allowing delineation of the islet volume, length of the intraislet vessels, and the number of vessel branch-points. This technique allows for straightforward 3D image analysis that may help toward understanding islet function., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2012
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- View/download PDF
49. Rapid and simplified purification of recombinant adeno-associated virus.
- Author
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Guo P, El-Gohary Y, Prasadan K, Shiota C, Xiao X, Wiersch J, Paredes J, Tulachan S, and Gittes GK
- Subjects
- Ammonium Sulfate chemistry, Animals, Buffers, Carbonates chemistry, Chemical Precipitation, Dependovirus genetics, Genetic Vectors, Green Fluorescent Proteins biosynthesis, Green Fluorescent Proteins genetics, HEK293 Cells, Humans, Liquid-Liquid Extraction, Liver metabolism, Liver virology, Mice, Organisms, Genetically Modified, Polyethylene Glycols chemistry, Saline Solution, Hypertonic chemistry, Transduction, Genetic, Dependovirus isolation & purification
- Abstract
Preclinical gene therapy studies both in vitro and in vivo require high purity preparations of adeno-associated virus (AAV). Current methods for purification of AAV entail the use of centrifugation over either a CsCl or iodixanol gradient, or the use of chromatography. These methods can be cumbersome and expensive, necessitating ultrahigh speed gradient centrifugation or, for chromatography the use of other expensive equipment. In addition, these methods are time consuming, and the viral yield is not high. Currently no commercial purification kits are available for other than AAV serotype 2. A simplified method was used for the purification of AAV, with a viral yield that is able to be used effectively in adult and embryo mice. The method does not require ultrahigh speed gradient centrifugation nor chromatography. Instead, polyethylene glycol (PEG)/aqueous two-phase partitioning is used to remove soluble proteins from the PEG8000 precipitated virus-protein mixture. The procedure obtained rapidly up to 95% recovery of high quality purified AAV. The entire purification process, including HEK293 cell transfection, can be completed readily within one week, with purity seemingly higher than that obtained after one round of CsCl gradient purification., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
50. Whole-mount imaging demonstrates hypervascularity of the pancreatic ducts and other pancreatic structures.
- Author
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El-Gohary Y, Tulachan S, Branca M, Sims-Lucas S, Guo P, Prasadan K, Shiota C, and Gittes GK
- Subjects
- Animals, Capillaries physiology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Pancreas physiology, Pancreatic Ducts cytology, Pancreatic Ducts physiology, Capillaries anatomy & histology, Imaging, Three-Dimensional methods, Microcirculation physiology, Organ Culture Techniques methods, Pancreas anatomy & histology, Pancreas blood supply, Pancreatic Ducts blood supply
- Abstract
Confocal microscopy in combination with commercial software is frequently used to generate three-dimensional images of tissue architecture. Here we report a novel, whole-mount imaging protocol technique that allows detailed three-dimensional imaging of adult pancreatic structures. This technique provides an improved appreciation of the anatomical detail of pancreatic structures and of the relationship between the pancreatic ducts and islets. In addition, imaging of the pancreatic ducts revealed a previously unappreciated high degree of hypervascularity., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2012
- Full Text
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