Publications by authors named "AiXuan Holterman"

10 Publications

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Granulocyte-colony stimulating factor GCSF mobilizes hematopoietic stem cells in Kasai patients with biliary atresia in a phase 1 study and improves short term outcome.

J Pediatr Surg 2021 Apr 9. Epub 2021 Apr 9.

Vietnam National Children Hospital, Hanoi, Vietnam.

Aims: In RCT of adults with decompensated cirrhosis, GCSF mobilizes hematopoietic stem cells HSC and improves short-term outcome. An FDA-IND for sequential Kasai-GCSF treatment in biliary atresia BA was approved. This phase 1 study examines GCSF safety in Kasai subjects. Preliminary short-term outcome was evaluated.

Methods: GCSF (Neupogen) at 5 or 10 μg/kg (n = 3/group) was given in 3 daily doses starting on day 3 of Kasai surgery (NCT03395028). Serum CD34+ HSC cell counts, and 1-month of GCSF-related adverse events were monitored. The 6-months Phase 1 clinical outcome was compared against 10 subsequent post Phase 1 Kasai patients who did not receive GCSF.

Results: With GCSF, WBC and platelet count transiently increased, LFT and serum creatinine remained stable. Reversible splenic enlargement (by 8.5-20%) occurred in 5/6 subjects. HSC count increased 12-fold and 17.5-fold for the 5 μg/kg and10 ug/kg dose respectively; with respective median total bilirubin levels for GCSF vs no-GCSF groups of 55 vs 91 μM at 1 month, p = 0.05; 15 vs 37 μM at 3 months, p = 0.24); and the 6-months cholangitis frequency of 40% vs 90%, p = 0.077.

Conclusions: GCSF safely mobilizes HSC in Kasai infants and may improve short-term biliary drainage and cholangitis. Phase 2 efficacy outcome of GCSF adjunct therapy for sequential Kasai and GCSF is pending.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.03.038DOI Listing
April 2021

Biliary atresia liver histopathological determinants of early post-Kasai outcome.

J Pediatr Surg 2021 Mar 26. Epub 2021 Mar 26.

University of Illinois College of Medicine, Chicago, IL, Untied States. Electronic address:

Background: A retrospective chart review of liver histologies in Kasai biliary atresia BA patients operated 1/2017- 7/2019 at our institution was conducted to identify histologic prognostic factors for biliary outcome.

Methods: Patients with wedge liver biopsies and portal plate biopsies (n = 85) were categorized into unfavorable and favorable outcome, based on a 3-month serum total bilirubin level of <34 μM or mortality. Hepatocellular histologies, presence of ductal plate malformation (DPM) and of large bile duct of ≥ 150 μm diameter size at the portal plate were evaluated.

Results: Total Bilirubin levels> 34 μM correlates with worse 1-year survival. Age at surgery, histologic fibrosis or inflammation does not predict outcome. Potential adverse predictors are severe hepatocellular swelling, severe cholestasis, presence of DPM (n = 24), and portal plate bile duct size < 150 µm (n = 28). In multivariate analyses adjusting for age at Kasai and postop cholangitis, bile duct size and severe hepatocellular swelling remain independent histologic prognosticators (OR 3.25, p = 0.039 and OR 3.26, p = 0.006 respectively), but not DPM.

Conclusion: Advanced histologic findings of portal plate bile duct size of <150 µm and severe hepatocellular damage predict poor post-Kasai jaundice clearance and short-term survival outcome, irrespective of Kasai timing.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.03.039DOI Listing
March 2021

The Heterogeneity of Global Pediatric Surgery: Defining Needs and Opportunities Around the World.

World J Surg 2019 06;43(6):1404-1415

Division of Pediatric Surgery, University of California, Los Angeles, Los Angeles, USA.

Background: The global burden of pediatric surgical conditions continues to remain inadequately addressed, particularly in low- and middle-income countries. Among the many factors contributing to this gap are a lack of access to care secondary to resource shortages and inequitable distribution, underfinancing of healthcare systems, poor quality of care, and contextual challenges such as natural disasters and conflict. The relative contribution of these and other factors varies widely by region and even with countries of a region.

Methods: This review seeks to discuss the heterogeneity of global pediatric surgery and offer recommendations for addressing the barriers to high-quality pediatric surgical care throughout the world.

Results: There is significant heterogeneity in pediatric surgical challenges, both between regions and among countries in the same region, although data are limited. This heterogeneity can reflect differences in demographics, epidemiology, geography, income level, health spending, historical health policies, and cultural practices, among others.

Conclusion: Country-level research and stakeholder engagement are needed to better understand the heterogeneity of local needs and drive policy changes that contribute to sustainable reforms. Key to these efforts will be improved financing, access to and quality of pediatric surgical care.
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http://dx.doi.org/10.1007/s00268-018-04884-xDOI Listing
June 2019

Guide to research in academic global surgery: A statement of the Society of University Surgeons Global Academic Surgery Committee.

Surgery 2018 02 6;163(2):463-466. Epub 2017 Dec 6.

Program in Global Surgery and Social Change, Harvard Medical School, Boston, MA.

Global surgery is an emerging academic discipline that is developing in tandem with numerous policy and advocacy initiatives. In this regard, academic global surgery will be crucial for measuring the progress toward improving surgical care worldwide. However, as a nascent academic discipline, there must be rigorous standards for the quality of work that emerges from this field. In this white paper, which reflects the opinion of the Global Academic Surgery Committee of the Society for University Surgeons, we discuss the importance of research in global surgery, the methodologies that can be used in such research, and the challenges and benefits associated with carrying out this research. In each of these topics, we draw on existing examples from the literature to demonstrate our points. We conclude with a call for continued, high-quality research that will strengthen the discipline's academic standing and help us move toward improved access to and quality of surgical care worldwide.
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http://dx.doi.org/10.1016/j.surg.2017.10.013DOI Listing
February 2018

Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6.

PLoS One 2016 9;11(12):e0167085. Epub 2016 Dec 9.

Department of Surgery/Pediatric Surgery, U of Illinois College of Medicine, Peoria, IL, United States of America.

Background And Aims: Growth hormone (GH) not only supports hepatic metabolism but also protects against hepatocyte cell death. Hnf6 (or Oc1) belonging to the Onecut family of hepatocyte transcription factors known to regulate differentiated hepatic function, is a GH-responsive gene. We evaluate if GH mediates Hnf6 activity to attenuate hepatic apoptotic injury.

Methods: We used an animal model of hepatic apoptosis by bile duct ligation (BDL) with Hnf6 -/- (KO) mice in which hepatic Hnf6 was conditionally inactivated. GH was administered to adult wild type WT and KO mice for the 7 days of BDL to enhance Hnf6 expression. In vitro, primary hepatocytes derived from KO and WT liver were treated with LPS and hepatocyte apoptosis was assessed with and without GH treatment.

Results: In WT mice, GH treatment enhanced Hnf6 expression during BDL, inhibited Caspase -3, -8 and -9 responses and diminished hepatic apoptotic and fibrotic injury. GH-mediated upregulation of Hnf6 expression and parallel suppression of apoptosis and fibrosis in WT BDL liver were abrogated in KO mice. LPS activated apoptosis and suppressed Hnf6 expression in primary hepatocytes. GH/LPS co-treatment enhanced Hnf6 expression with corresponding attenuation of apoptosis in WT-derived hepatocytes, but not in KO hepatocytes. ChiP-on-ChiP and electromobility shift assays of KO and WT liver nuclear extracts identified Ciap1 (or Birc2) as an Hnf6-bound target gene. Ciap1 expression patterns closely follow Hnf6 expression in the liver and in hepatocytes.

Conclusion: GH broad protective actions on hepatocytes during liver injury are effected through Hnf6, with Hnf6 transcriptional activation of Ciap1 as an underlying molecular mediator.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167085PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147851PMC
July 2017

General endotracheal vs. non-endotracheal regional anesthesia for elective inguinal hernia surgery in very preterm neonates: A single institution experience.

J Pediatr Surg 2017 Jan 27;52(1):56-59. Epub 2016 Oct 27.

Children's Hospital of Illinois, University of Illinois College of Medicine at Peoria. Electronic address:

Background: Very pre-term infants (VP) at <32 weeks post menstrual age PMA have a high incidence of bronchopulmonary dysplasia BPD. BPD places them at risk for pulmonary-related perioperative complications from general endotracheal anesthesia GE during elective inguinal hernia repair.

Methods: A retrospective cohort study was done to compare pulmonary-related perioperative risks between VP patients undergoing non-emergent inguinal hernia repair prior to NICU discharge under GE (n=58) vs regional anesthesia RA (n=37).

Results: Median PMA (RA 26 vs GE 27 weeks), operative weight (RA 2.2 vs GE 2.27 kg), % with BPD, medical and surgical comorbidities, number of concurrent procedures are similar between groups, except for sac laparoscopy (0% RA vs 36% GE). Procedural anesthesia time was 40 minutes for RA vs 69 minutes for GE, (p < 0.001). GE (17%) vs RA (0%) remained intubated post op (p<0.001). Oral feeding was fully tolerated in RA (97%) vs GE (72%, p=0.002) by 48h after surgery. The statistical differences hold after regression analysis controlling for sac laparoscopy and procedure time. No difference in intraoperative or postoperative hernia complications is found.

Conclusion: RA is safe. RA is associated with early resumption of full feed, avoidance of prolonged mechanical intubation. We recommend a randomized controlled trial comparing the safety and efficacy of GE vs RA in VP infants undergoing elective NICU inguinal hernia repair.

Level Of Evidence: II Retrospective study.
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http://dx.doi.org/10.1016/j.jpedsurg.2016.10.019DOI Listing
January 2017

Surgical treatment of nonalcoholic fatty liver disease in severely obese patients.

Hepat Med 2014 29;6:103-12. Epub 2014 Oct 29.

University of Illinois College of Medicine at Peoria, Children's Hospital of Illinois, Department of Surgery/Pediatric Surgery, Peoria, IL, USA.

Obesity is a multi-organ system disease with underlying metabolic abnormalities and chronic systemic inflammation. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of obesity metabolic dysfunction and its associated cardiovascular- and liver-related morbidities and mortality. Our current understanding of NAFLD pathogenesis, disease characteristics, the role of insulin resistance, chronic inflammation, gut-liver and gut-brain crosstalk and the effectiveness of pharmacotherapy is still evolving. Bariatric surgery significantly improves metabolic and NAFLD histology in severely obese patients, although its positive effects on fibrosis are not universal. Bariatric surgery benefits NAFLD through its metabolic effect on insulin resistance, inflammation, and insulinotropic and anorexinogenic gastrointestinal hormones. Further studies are needed to understand the natural course of NAFLD in severely obese patients and the role of weight loss surgery as a primary treatment for NAFLD.
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http://dx.doi.org/10.2147/HMER.S64819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218902PMC
November 2014

Nonalcoholic fatty liver disease and bariatric surgery in adolescents.

Semin Pediatr Surg 2014 Feb 31;23(1):49-57. Epub 2013 Oct 31.

Department of Surgery, University of Illinois College of Medicine, Peoria, Illinois; Pediatric Surgery, Children's Hospital of Illinois, University of Illinois College of Medicine, Peoria, Illinois.

Obesity is a multi-organ system disease with underlying insulin resistance and systemic chronic inflammation. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the underlying metabolic dysfunction. This review provides a highlight of the current understanding of NAFLD pathogenesis and disease characteristics, with updates on the challenges of NAFLD management in obese and severely obese (SO) patients and recommendations for the pediatric surgeons' role in the care of SO adolescents.
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http://dx.doi.org/10.1053/j.sempedsurg.2013.10.016DOI Listing
February 2014

Multifunctional roles of urokinase plasminogen activator (uPA) in cancer stemness and chemoresistance of pancreatic cancer.

Mol Biol Cell 2013 Sep 17;24(17):2620-32. Epub 2013 Jul 17.

Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.

Pancreatic ductal adenocarcinoma (PDAC) is almost always lethal. One of the underlying reasons for this lethality is believed to be the presence of cancer stem cells (CSC), which impart chemoresistance and promote recurrence, but the mechanisms responsible are unclear. Recently the poor prognosis of PDAC has been correlated with increased expression of urokinase plasminogen activator (uPA). In the present study we examine the role of uPA in the generation of PDAC CSC. We observe a subset of cells identifiable as a side population (SP) when sorted by flow cytometry of MIA PaCa-2 and PANC-1 pancreatic cancer cells that possess the properties of CSC. A large fraction of these SP cells are CD44 and CD24 positive, are gemcitabine resistant, possess sphere-forming ability, and exhibit increased tumorigenicity, known characteristics of cancer stemness. Increased tumorigenicity and gemcitabine resistance decrease after suppression of uPA. We observe that uPA interacts directly with transcription factors LIM homeobox-2 (Lhx2), homeobox transcription factor A5 (HOXA5), and Hey to possibly promote cancer stemness. uPA regulates Lhx2 expression by suppressing expression of miR-124 and p53 expression by repressing its promoter by inactivating HOXA5. These results demonstrate that regulation of gene transcription by uPA contributes to cancer stemness and clinical lethality.
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http://dx.doi.org/10.1091/mbc.E12-04-0306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756915PMC
September 2013