Publications

Abstract

• Bowman P, Sulen Å, Barbetti F, Beltrand J, Svalastoga P, Codner E, Tessmann EH, Juliusson PB, Skrivarhaug T, Pearson ER, Flanagan SE, Babiker T, Thomas NJ, Shepherd MH, Ellard S, Klimes I, Szopa M, Polak M, Iafusco D, Hattersley AT, Njølstad PR; Neonatal Diabetes International Collaborative Group.  Effectiveness and Safety of Long-Term Treatment with Sulfonylureas in Patients with Neonatal Diabetes due to KCNJ11 mutations: An International Cohort Study.  Lancet Diabetes Endocrinol. 2018 Aug;6(8):637-646. doi: 10.1016/S2213-8587(18)30106-2. Epub 2018 Jun 4. Erratum in: Lancet Diabetes Endocrinol. 2018 Sep;6(9):e17. PMID:29880308 (2018)
• Tsay E., Cerrone D, Assavapisitkul E., Keough A., Hathout E. Reduction of Insulin Requirements on a Gluten-Free Diet for Type 1 Diabetes Mellitus. Poster presented at: 10th International Meeting of Pediatric Endocorinology, Washington, D.C. September 2017 (09/2017)
• (PEER REVIEWED) Reduction of InsulinTsay, E., Cerrone, D., Assavapisitkul, E., Keough, A., Hathout, E.. (September, 14, 2017). Requirements on a Gluten-Free Diet for Type 1 Diabetes Mellitus: A Case Report Poster presented at: 10th International Meeting of Pediatric Endocrinology; Washington D.C., DC, USA. (06/2017 - 09/2017)
• Hoang PTH, Tsay E, Mace J, Hathout E. Congenital Adrenocortical Tumor in an Asymptomatic Neonate with Positive Newborn Screen for Congenital Adrenal Hyperplasia.  International Journal of Integrative Pediatrics and Environmental Medicine,2017, 000-000 1 (2017)
• Sakata N, Chan N K, Chrisler J, Obenaus A, & Hathout E. (2010). Bone Marrow Cell Co-Transplantation with Islets Improves Their Vascularization and Function. American Journal of Transplantation, 10, 232-232. (04/2010)
• Hathout E, Fitts J, Johnston J, & Chinnock R. (2009). Post-Transplant Diabetes in Pediatric Heart Transplant Recipients Treated with Sirolimus. Journal of Heart and Lung Transplantation, 28(2), S296-S297. (02/2009)
• Sakata N, Obenaus A, Hayes P, Chan N, Mace J, Chinnock R, & Hathout E. (2009). Assessment of Liver Ischemia Early after Islet Transplantation Using Magnetic Resonance Imaging. American Journal of Transplantation, 9, 467-468. (2009)
• (PEER REVIEWED) Eba Hathout, Rong Wang, John Mace, Richard Chinnock, Andre Obenaus.. "In Vivo Dynamic Contrast Enhanced Magnetic Resonance Imaging Outlines the Chronology of Vascularization in Transplanted Islets.." Diabetes 56(S1). (2007): A523-. (06/2007)
• (PEER REVIEWED) Hathout et al. "Detection and Prevention of Hypoxia in Pancreatic Islets.." Pediatric Research x. (2007): x-. (05/2007)
• (PEER REVIEWED) Gang Miao, Rong Wang, Andy Obenaus, John Zhang, John Mace, Richard Chinnock, Eba Hathout.. "In Vivo Imaging of Neovascularization in Islet Transplantation.." AJT 7(S2). (2007): 513-. (05/2007)
• (PEER REVIEWED) Pal R Njolstad, MD PhD, Dianne Abuelo, MD, Halvor Baevre, MD, Torben Hansen, MD PhD, Eba Hathout, MD et al. "Long-term effect of sulfonylura in permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2." Diabetes 54. (2005): A293-. (06/2005)
• (PEER REVIEWED) Hathout E, Johnston J, Fitts J, Kuhn M, Razzouk A, Bailey L and Chinnock R. "Coronary Artery Disease in Pediatric Heart Transplant Recipients(1) ." American Journal of Transplantation 5. (2005): 408-. (01/2005)
• (PEER REVIEWED) Miao G, Mace J, Kirby M, Peverini R, Hopper A, Chinnock R, Shapiro J and Hathout EH. . "Beneficial Effect of NGF in Islet Transplantation.." International Pancreas and Islet Transplant Association . (2005): -. (01/2005)
• (PEER REVIEWED) Hathout E, Beeson L, Ischander M, Touma M, Rao R, and Mace J. . "Air Pollution and Autoimmune Endocrine Disease. A Relation With Type 1 Diabetes and Thyroiditis in Children? ." Pediatric Academic Society 57. (2005): 436-. (01/2005)
• (PEER REVIEWED) Hathout E, Touma M, Beeson L, Webber S, Janner D, Racine M, Chinnock R and Mace J. . "Epstein-Barr Viral Infection and Childhood Diabetes.." Pediatric Academic Society 57. (2005): 435-. (01/2005)
• (PEER REVIEWED) Eba Hathout, MD, Sally Sartin, BAH, Marlin Touma, MD, Larry Beeson, DrPH and John Mace, MD. "Effect of Family Structure on Glycemic Control in Children with Diabetes.." Pediatric Academic Society . (2005): 440-. (01/2005)
• (PEER REVIEWED) Miao G, Mace J, Kirby M, Peverini R, Hopper A, Chinnock R, Shapiro J and Hathout EH. "Beneficial Effect of Nerve Growth Factor in Islet Transplantation.." Diabetes Late Breaking. (2005): 101-. (01/2005)
• (PEER REVIEWED) Eba Hathout, MD, Marlin Touma, MD, Long Tran, MA, Jeannine Sharkey, CNP, Michael Racine, MD and John Mace, MD. . "Type 2 Diabetes in Children. A Ten-Year Experience." Diabetes 54. (2005): A668-. (01/2005)
• (PEER REVIEWED) Eba Hathout, MD, Marlin Touma, MD, Long Tran, MD, Jeannine Sharkey, CNP, Michael Racine, MD and John Mace, MD.. "Effects of Oral and Insulin Therapy on Type 2 Diabetes in Children and Adolescents. ." Diabetes 54. (2005): A668-. (01/2005)
• (PEER REVIEWED) Eba Hathout, Gang Miao, John Mace, Ricardo Peverini, John Zhang, Lawrence Sowers, Richard Chinnock.. "Detection and Prevention of Hypoxia in Pancreatic Islets.." . (): -. (Present)

Scholarly Journals--Published

• Saito Y, Chan N K, & Hathout E. (2012). Partial hepatectomy improves the outcome of intraportal islet transplantation by promoting revascularization. Islets, 4(2), 138-144. Revascularization of grafts is one of the important key factors for the success of islet transplantation. After partial hepatectomy, many growth factors such as hepatocyte growth factor and vascular endothelial growth factor are increased in the remnant liver. These growth factors have properties that promote angiogenesis. This might be an optimal environment for revascularization of islets transplanted intraportally. To verify this hypothesis, syngeneic islets (330 per recipient) were transplanted into the right hepatic lobes of streptozotocin-induced diabetic Balb/c mice with (hepatectomy group) or without (control group) left liver resection. Blood glucose was monitored for 28 d after transplantation. Glucose tolerance test was performed on post-operative day (POD) 30, and histological assessments were performed on POD 7 and 30 respectively. Analysis revealed that 36.7% of the control and 90.0% of the hepatectomy mice attained normoglycemia during the observation period (*p = 0.0142). Glucose tolerance was improved in the hepatectomy group (Area under the curve of intraperitoneal glucose tolerance tests on POD 30, Control; 47,700 +/- 5,890 minmg/dl, Hepatectomy; 26,000 +/- 2,060 minmg/dl: **p = 0.00314). Revascularization of grafted islets was more pronounced in the hepatectomy group (Vessel number per islet area on POD 7, Control; 3.20 +/- 0.463 x 10(-4)/mu m(2), Hepatectomy; 7.08 +/- 0.513 x 10(-4)/mu m(2): **p < 0.01). In the present study, partial hepatectomy (30%) improved the outcome of intraportal islet transplantation. Revascularization of islets transplanted into the liver may have been promoted by the induction of liver regeneration. (03/2012) (link)
• Saito Y, Chan N K, Sakata N, & Hathout E. (2012). Nerve growth factor is associated with islet graft failure following intraportal transplantation. Islets, 4(1), . Nerve growth factor (NGF) has recently been recognized as an angiogenic factor with an important regulatory role in pancreatic beta-cell function. We previously showed that treatment of pancreatic islets with NGF improved their quality and viability. Revascularization and survival of islets transplanted under the kidney capsule were improved by NGF. However, the usefulness of NGF in intraportal islet transplantation was not previously tested. To resolve this problem, we transplanted syngeneic islets (360 islet equivalents per recipient) cultured with or without NGF into the portal vein of streptozotocin-induced diabetic BALB/c mice. Analysis revealed that 44.4% (4/9) of control and 12.5% (1/8) of NGF-treated mice attained normoglycemia (<= 200 mg/dL) (p = 0.195). NGF-treated islets led to worse graft function (area under the curve of intraperitoneal glucose tolerance tests (IPGTT) on post-operative day (POD) 30, control; 35,800 +/- 3,960 min*mg/dl, NGF-treated; 47,900 +/- 3,220 min*mg/dl: *p = 0.0348). NGF treatment of islets was also associated with increased graft failure [the percentage of TdT-mediated dUTP-biotin nick-end labeling (TUNEL)-positive and necrotic transplanted islets on POD 5, control; 23.8% (5/21), NGF-treated; 52.9% (9/17): p = 0.0650] following intraportal islet transplantation. Nonviable (TUNEL-positive and necrotic) islets in both groups expressed vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1 alpha). On the other hand, viable (TUNEL-negative and not necrotic) islets in both groups did not express VEGF and HIF-1 alpha. In the present study, pre-transplant NGF treatment was associated with impaired survival and angiogenesis of intraportal islet grafts. The effect of NGF on islet transplantation may significantly vary according to the transplant site. (01/2012) (link)
• Saito Y, Chan NK, Sakata N, Hathout E. Nerve Growth Factor is Associated with Islet Graft Failure Following Intraportal Transplantation. Islets. 2012; 4(1). [Epub ahead of print] PMID: 22192949 (2012)
• Saito Y, Chan NK, Sakata N, Hathout E. Partial Hepatectomy Improves the Outcome of Intraportal Islet Transplantation by Promoting Revascularization. Islets. 2012; 4(2):138-44. PMID: 22622159 (2012)
• Saito Y, Chan NK, Sakata N, Hathout E. Nerve Growth Factor is Associated with Islet Graft Failure Following Intraportal Transplantation. Islets. 2012:4(1). [Epub ahead of print] PMID: 22192949 (2012)
• Shahawy S, Chan N K, Ellard S, Young E, Shahawy H, . . . Hathout E. (2011). A pathway to insulin independence in newborns and infants with diabetes. Journal of Perinatology, 31(8), 567-570. Permanent neonatal diabetes was previously assumed to require insulin injection or infusion for life. Recently, permanent neonatal diabetes resulting from mutations in the two protein subunits of the adenosine triphosphate-sensitive potassium channel (Kir6.2 and SUR1) has proven to be successfully treatable with high doses of sulfonylureas rather than insulin. Many patients with these mutations first develop hyperglycemia in the nursery or intensive care unit. The awareness of the neonatolgist of this entity can have dramatic effects on the long-term care and quality of life of these patients and their families. In this study, we present the experience of our center, highlighting aspects relevant to neonatal diagnosis and treatment. Journal of Perinatology (2011) 31, 567-570; doi:10.1038/jp.2011.4 (08/2011) (link)
• Lango Allen H, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R, the International Pancreatic Agenesis Consortium, Ferrer J, Hattersley AT, Ellard S. GATA6 Haploinsufficiency Causes Pancreatic Agenesis in Humans. Nat Genet. 2011; 44(1):20-2. PMID: 22158542 (2011)
• Shahawy S, Chan NK, Ellard S, Young E, Shahawy H, Mace J, Peverini R, Chinnock R, Njolstad PR, Hattersley A, Hathout E. A Pathway to Insulin-Independence in Newborns and Infants with Diabetes. J Perinatol. 2011; 31(8):567-70. PMID: 21796147 (2011)
• Sakata N, Chan N K, Ostrowski R P, Chrisler J, Hayes P, . . . Hathout E. (2010). Hyperbaric oxygen therapy improves early posttransplant islet function. Pediatric Diabetes, 11(7), 471-478. Objective: This study investigates the therapeutic potential of hyperbaric oxygen therapy (HBO) in reducing hypoxia and improving engraftment of intraportal islet transplants by promoting angiogenesis. Methods: Diabetic BALB/c mice were transplanted with 500 syngeneic islets intraportally and received six consecutive twice-daily HBO treatments (n = 9; 100% oxygen for 1 h at 2.5 atmospheres absolute) after transplantation. Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) was used to assess new vessel formation at postoperative days (POD) 3, 7, and 14. Liver tissue was recovered at the same time points for correlative histology, including: hematoxylin and eosin, hypoxia-inducible factor (HIF1 alpha), Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL), vascular endothelial growth factor (VEGF), and von Willebrand Factor immunohistochemistry. Results: HBO therapy significantly reduced HIF-1 alpha, TUNEL and VEGF expression in islets at POD 7. In the non-HBO transplants, liver enhancement on DCE MRI peaked at POD 7 consistent with less mature vasculature but this enhancement was suppressed at POD 7 in the HBO-treated group. The number of new peri-islet vessels at POD 7 was not significantly different between HBO and control groups. Conclusion: These results are consistent with a hyperbaric oxygen-mediated decrease in hypoxia that appeared to enhance vessel maturation in the critical days following intraportal islet transplantation. (11/2010) (link)
• Sakata N, Obenaus A, Chan N K, Hayes P, Chrisler J, & Hathout E. (2010). Correlation between angiogenesis and islet graft function in diabetic mice: magnetic resonance imaging assessment. Journal of Hepato-Biliary-Pancreatic Sciences, 17(5), 692-700. Background/purpose Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to evaluate neovascularization after intravenous injection of gadolinium, where contrast leaks out of new vessels and remains within the tissues. We examined the relationship between DCE-MRI and metabolic parameters such as blood glucose, serum insulin and glucose tolerance test (GTT) after intraportal islet transplantation. Methods Streptozotocin-induced diabetic BALB/c mice (n = 15) received syngeneic intraportal islet transplantation (500 islet equivalent). Blood glucose, serum insulin and GTT were evaluated till postoperative day (POD) 14. Liver DCE-MRI was performed at POD 3, 7 and 14. Correlations between DCE-MRI and metabolic parameters were examined using regression analysis. Results Eight mice achieved normoglycemia after intraportal transplantation. At POD 3 a significant but moderate correlation between DCE-MRI and blood glucose was found. No DCE-MRI or metabolic parameters correlated at POD 7. However, at POD 14 strong or moderate correlations between DCE-MRIs were found: negative correlations with blood glucose (R(2) = 0.86) and GTT (R(2) = 0.48) but a positive correlation with serum insulin (R(2) = 0.32). Conclusion We report that DCE-MRI can reflect the metabolic and functional condition of the transplanted islets. (09/2010) (link)
• Sakata N, Chan N K, Chrisler J, Obenaus A, & Hathout E. (2010). Bone Marrow Cell Cotransplantation With Islets Improves Their Vascularization and Function. Transplantation, 89(6), 686-693. Background. To test the angiogenesis-promoting effects of bone marrow cells when cotransplanted with islets. Methods. Streptozotocin-induced diabetic BALB/c mice were transplanted syngeneically under the kidney capsule: (1) 200 islets, (2) 1 to 5 x 10(6) bone marrow cells, or (3) 200 islets and 1 to 5 x 10(6) bone marrow cells. All mice were evaluated for blood glucose, serum insulin, and glucose tolerance up to postoperative day (POD) 28, and a subset was monitored for 3 months after transplantation. Histologic assessment was performed at PODs 3, 7, 14, 28, and 84 for the detection of von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), insulin, cluster of differentiation-34, and pancreatic duodenal homeobox-1 (PDX-1) protein. Results. Blood glucose was the lowest and serum insulin was the highest in the islet + bone marrow group at POD 7. Blood glucose was significantly lower in the islet + bone marrow group relative to the islet only group after 63 days of transplantation (P < 0.05). Significantly more new periislet vessels were detected in the islet + bone marrow group compared with the islet group (P < 0.05). Vascular endothelial growth factor staining was more prominent in bone marrow than in islets (P < 0.05). Pancreatic duodenal homeobox-1-positive areas were identified in bone marrow cells with an increase in staining over time. However, there were no normoglycemic mice and no insulin-positive cells in the bone marrow alone group. Conclusions. Cotransplantation of bone marrow cells with islets is associated with enhanced islet graft vascularization and function. (03/2010) (link)
• Sakata N, Chan N K, Chrisler J, Obenaus A, & Hathout E. (2010). Bone marrow cells produce nerve growth factor and promote angiogenesis around transplanted islets. World Journal of Gastroenterology, 16(10), 1215-1220. AIM: To clarify the mechanism by which bone marrow cells promote angiogenesis around transplanted islets. METHODS: Streptozotocin induced diabetic BALB/c mice were transplanted syngeneically under the kidney capsule with the following: (1) 200 islets (islet group: n = 12), (2) 1-5 x 10(6) bone marrow cells (bone marrow group: n = 11), (3) 200 islets and 1-5 x 10(6) bone marrow cells (islet + bone marrow group: n = 13), or (4) no cells (sham group: n = 5). All mice were evaluated for blood glucose, serum insulin, serum nerve growth factor (NGF) and glucose tolerance (GTT) up to postoperative day (POD) 14. Histological assessment for insulin, von Willebrand factor (vWF) and NGF was performed at POD 3, 7 and 14. RESULTS: Blood glucose level was lowest and serum insulin was highest in the islet + bone marrow group. Serum NGF increased in islet, bone marrow, and islet + bone marrow groups after transplantation, and there was a significant difference (P = 0.0496, ANOVA) between the bone marrow and sham groups. The number of vessels within the graft area was significantly increased in both the bone marrow and islet + bone marrow groups at POD 14 as compared to the islet alone group (21.2 +/- 3.6 in bone marrow, P = 0.01, vs islet group, 22.6 +/- 1.9 in islet + bone marrow, P = 0.0003, vs islet group, 5.3 +/- 1.6 in islet-alone transplants). NGF was more strongly expressed in bone marrow cells compared with islets. CONCLUSION: Bone marrow cells produce NGF and promote angiogenesis. Islet co-transplantation with bone marrow is associated with improvement of islet graft function. (C) 2010 Baishideng. All rights reserved. (03/2010) (link)
• Sakata N, Chan NK, Chrisler J, Obenaus A, Hathout E.  Bone Marrow Cell Co-Transplantation with Islets Improves their Vascularization and Function. Transplantation. 2010; 89(6):686-93. PMID: 20101199 (2010)
• Sakata N, Chan NK, Chrisler J, Obenaus A, Hathout E. Bone Marrow Cells Produce Nerve Growth Factor and Promote Angiogenesis around Transplanted Islets. World J Gastroenterol. 2010; 16(10):1215-20. PMID: 20222164 (2010)
• Sakata N, Obenaus A, Chan NK, Hayes P, Chrisler J, Hathout E. Correlation between Angiogenesis and Islet Graft Function in Diabetic Mice: Magnetic Resonance Imaging Assessment. J Hepatobiliary Pancreat Sci. 2010; 17(5):692-700. [Epub 2010 Mar 18] PMID: 20703848 (2010)
• Sakata N, Chan NK, Ostrowski RP, Chrisler J, Hayes P, Kim S, Obenaus A, Zhang JH, Hathout E. Hyperbaric Oxygen Therapy Improves Early Posttransplant Islet Function. Pediatr Diabetes. 2010; 11(7):471-8. PMID: 20144181 (2010)
• Chan N K, Obenaus A, Tan A, Sakata N, Mace J, . . . Hathout E. (2009). Monitoring neovascularization of intraportal islet grafts by dynamic contrast enhanced magnetic resonance imaging. Islets, 1(3), 249-255. Fifteen thousand youths are diagnosed yearly with type 1 diabetes mellitus. Pancreatic islet transplantation has been shown clinically to provide short-term (similar to 1 year) insulin independence. However, challenges associated with early vascularization of transplanted islet grafts and long-term islet survival remain. We utilized dynamic contrast enhanced magnetic resonance imaging (DCE MRI) to monitor neovascularization of islets transplanted into the right lobe of the liver in a syngeneic mouse model. The left lobe received no islets and served as a control. DCE data were analyzed for temporal dynamics of contrast (gadolinium) extravasation and the results were fit to a Tofts two-compartment exchange model. We observed maximal right lobe enhancement at seven days post-transplantation. Histological examination up to 28 days was used to confirm imaging results. DCE-derived enhancement strongly correlated with immunohistochemical measures of neovascularization. To our knowledge these results are the first to demonstrate, using a FDA approved contrast agent, that DCE MRI can effectively and non-invasively monitor the progression of angiogenesis in intraportal islet grafts. (11/2009) (link)
• Hathout E, Chan N K, Tan A, Sakata N, Mace J, . . . Obenaus A. (2009). In vivo imaging demonstrates a time-line for new vessel formation in islet transplantation. Pediatric Transplantation, 13(7), 892-897. Vascularization of transplanted islets must be maintained to provide long-term graft function. In vivo assessment of new vessel formation in islet grafts has been poorly documented. The purpose of this study was to investigate whether neovascularization was detectable in vivo in a Feridex-labeled murine syngeneic subcapsular islet mass using DCE MRI over 180 days. Subcapsular transplants could be visualized at post-transplant days three, seven, 14, and 28 using T2-weighted MRI and at post-transplant day 180 by immunohistochemistry. Injection of the contrast agent gadolinium (Gd)-DTPA for DCE at three, seven, and 14 days showed increased signal in the transplant area consistent with new vessel formation. Areas under contrast enhancement curves suggested peak angiogenesis at 14 days. At 180 days, there was no observable change in signal intensity after contrast injection suggesting established vascularization or islet mass reduction. Immunohistochemistry confirmed MRI and DCE findings. These data suggest that islet angiogenesis occurs early after transplantation and is likely established after one month of transplantation. This study provides an in vivo time-line of neovascularization in subcapsular islet grafts. We anticipate that contrast extravasation captured by MRI may provide useful monitoring of graft angiogenesis if reproduced in a clinically relevant intraportal model. (11/2009) (link)
• Hathout E, Alonso E, Anand R, Martz K, Imseis E, . . . Split Study Grp. (2009). Post-transplant diabetes mellitus in pediatric liver transplantation. Pediatric Transplantation, 13(5), 599-605. To determine the characteristics of pediatric liver transplant recipients who develop GI and/or PTDM, data on children undergoing their first liver transplant from the SPLIT database were analyzed (n = 1611). Recipient and donor characteristics that were evaluated included age at transplant, gender, race, primary disease, hospitalization status at transplant, BMI, recipient and donor CMV status, donor type, donor age, and primary immunosuppression. GI/PTDM was found in 214 individuals (13%) of whom 166 (78%) were diagnosed within 30 days of transplantation (early GI/PTDM). Multivariate analyses suggests that age > 5 yr at transplant, hospitalization at transplant, a primary diagnosis other than BA, early steroid use, and tacrolimus use are associated with increased incidence of early GI. Routine monitoring for the development of GI and post-transplant diabetes is indicated in the short- and long-term care of children after liver transplantation. (08/2009) (link)
• Sakata N, Obenaus A, Chan N, Mace J, Chinnock R, & Hathout E. (2009). Factors affecting islet graft embolization in the liver of diabetic mice. Islets, 1(1), 26-33. Background: Embolic occlusion of the portal vein due to islet transplantation is one of the major reasons for reduced survival of transplanted islets. In this study, we examined the location of islets as well as the correlation between islet and portal vein size after intraportal islet transplantation and evaluated liver and islet pathology. Results: The liver was divided into peripheral and central sites. Islet and liver apoptosis/necrosis were significantly higher at peripheral sites. In regions without liver apoptosis or necrosis, portal vein diameter was significantly larger and embolic ratios were significantly lower. Methods: BALB/c mice were intraportally transplanted with 800 islets and the liver was examined at postoperative day (POD) 0 (n = 7), POD 2 (n = 4) and POD 28 (n = 3). Liver specimens were stained for hematoxylin and eosin (necrosis), insulin and TUNEL (apoptosis). We evaluated distance from liver surface to islets, islet and portal vein diameter, embolic ratio (islet diameter/portal vein diameter), apoptosis/necrosis of islets and apoptosis/necrosis of the liver tissue surrounding the islet. Conclusion: Transplanted islets and liver tissue exhibited more injury at peripheral sites, in part, due to smaller diameters of portal venules that result in more frequent emboli following islet transplantation. (07/2009) (link)
• Sakata N, Hayes P, Tan A, Chan N K, Mace J, . . . Hathout E. (2009). MRI Assessment of Ischemic Liver After Intraportal Islet Transplantation. Transplantation, 87(6), 825-830. Background. There is a recent focus on embolization of the portal vein by transplanted islets as a major cause of early graft loss. The resultant ischemia causes necrosis or apoptosis of cells within the liver. Thus, noninvasive assessment of the liver receiving the islet transplant is important to evaluate the status islet grafts. Methods. This study used noninvasive magnetic resonance imaging (MRI) for assessment of the posttransplant ischemic liver. Syngeneic islets in streprozotocin-induced diabetic mice were used: MRI and morphological liver assessments were performed at 0, 2, and 28 days after transplantation. Histologic assessment of insulin, hypoxia induced factor 1-alpha, and apoptosis were undertaken at similar time points. Results. Ischemic/necrotic regions in the liver were detected by MRI at 2 days but not at 28 days after transplantation and were confirmed histologically. Liver injury was quantified from high intensity areas on T2-weighted images. Insulin release peaked 2 days after transplantation. Conclusion. Onset and reversal of liver ischemia due to intraportal islet transplantation are detectable using T2-weighted MRI. These changes coincide with periods of maximum insulin release likely due to partial islet destruction. We propose that MRI, as a noninvasive monitor of graft-related ischemia, may be useful in assessment of liver and islet engraftment after intraportal islet transplantation in a clinical setting. (03/2009) (link)
• Sakata N, Tan A, Chan N, Obenaus A, Mace J, . . . Hathout E. (2009). Efficacy Comparison Between Intraportal and Subcapsular Islet Transplants in a Murine Diabetic Model. Transplantation Proceedings, 41(1), 346-349. Background. It is important to determine the efficacy of intraportal (IP) islet transplantation in comparison with other transplant sites. In this study, we sought to determine the optimal number of islets to achieve normoglycemia following transplantation into the liver versus the kidney using a mouse model. Methods. Streptozotocin-induced diabetic mice (Balb/C) were transplanted with syngeneic islets via the IP versus renal subcapsular (SC) routes. The transplanted islet numbers were 0 to 800 (n = 3-5). We assessed the correlation between parameters and islet numbers, comparing IP versus SC groups. The parameters were: (1) percentage of normoglycemia; (2) postoperative days to normoglycemia; (3) mean blood glucose levels at various points from pretransplantation to the end of the study (postoperative day 28); (4) mean serum insulin; and (5) area under the curve of blood glucose levels after glucose injection. Results. Two hundred islets yielded normoglycemia in renal subcapsular grafts, while 800 islets were the minimum required for normoglycemia with IP transplantation. The transplant efficacy in SC transplantation was 2 to 5 times greater than that of IP transplantation. The days to normoglycemia were significantly different between IP versus renal SC islets (13.25 +/- 4.38 days vs 4.50 +/- 0.81 days; P = .007). Conclusion. The efficacy of islet transplantation in murine diabetic models was significantly greater under the kidney capsule. Clinical islet transplantation could benefit from trials of alter-native transplant sites. (01/2009) (link)
• Hathout E, Alonso E, Anand R, Martz K, Imseis E, Johnston J, Lopez J, Chinnock R, McDiarmid S, on behalf of the SPLIT study group. Post-Transplant Diabetes Mellitus in Pediatric Liver Transplantation. Pediatr Transplant. 2009; 13(5):599-605. [Epub 2007 Dec 30] PMID: 18179639 (2009)
• Sakata N, Tan A, Chan NK, Obenaus O, Mace J, Peverini R, Sowers L, Chinnock R, Hathout E. Efficacy Comparison between Intraportal and Subcapsular Islet Transplants in a Murine Diabetic Model. Transplant Proc. 2009; 41(1):346-9. PMID: 19249553 (2009)
• Hathout E, Chan NK, Tan A, Sakata N, Mace J, Pearce W, Peverini R, Chinnock R, Sowers L, Obenaus A. In vivo Imaging Demonstrates a Time-Line for New Vessel Formation in Islet Transplantation. Pediatr Transplant. 2009; 13(7):892-7. [Epub 2008 Oct 31] PMID: 19017287 (2009)
• Sakata N, Hayes P, Tan A, Chan N, Mace J, Peverini R, Sowers L, Pearce W, Chinnock R, Obenaus A, Hathout E. MRI Assessment of Ischemic Liver after Intraportal Islet Transplantation. Transplantation. 2009; 87(6):825-30. PMID: 19300184 (2009)
• Sakata N, Obenaus A, Chan N, Mace J, Chinnock R, Hathout E. Factors Affecting Islet Graft Embolization in the Liver of Diabetic Mice. Islets. 2009; 1(1):26-33. PMID: 21087846 (2009)
• Chan NK, Obenaus A, Tan A, Sakata N, Mace J, Peverini R, Chinnock R, Sowers L, Hathout E. Monitoring Neovascularization of Intraportal Islet Grafts by Dynamic Contrast Enhanced Magnetic Resonance Imaging. Islets. 2009; 1(3):249-55. PMID: 21099279 (2009)
• Hathout E, Sowers L, Wang R, Tan A, Mace J, Peverini R, Chinnock R, Obenaus A.  In vivo Magnetic Resonance Imaging of Vascularization in Islet Transplantation. Transpl Int. 2007; 20(12):1059-65. [Epub 2007 Sep 10] PMID: 17850231 (2007)
• Miao G, Ostrowski RP, Mace J, Hough J, Hopper A, Peverini, R, Chinnock R, Zhang J, Hathout E. Dynamic Production of Hypoxia-Inducible Factor-1alpha in Early Transplanted Islets. Am J Transplant. 2006; 6(11):2636-43. PMID: 17049056 (11/2006)
• Hathout E, Mace J, Bell G, Njolstaad P. Treatment of Hyperglycemia in a 7 year old Child with Neonatal Diabetes. Diabetes Care. 2006; 29(6):1458. PMID: 16732049 (06/2006)
• Hathout EH, Beeson WL, Ischander M, Rao R, Mace JW. Air Pollution and Type 1 Diabetes in Children. Pediatr Diabetes. 2006; 7(2):81-7. PMID: 16629713 (04/2006)
• Hathout E, Beeson WL, Kuhn M, Johnston J, Fitts J, Razzouk A, Bailey L, Chinnock RE. Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients. Transpl Int. 2006; 19(3):184-9. PMID: 16441766 (03/2006)
• Miao G, Mace J, Kirby M, Hopper A, Peverini R, Chinnock R, Shapiro J, Hathout EH. In Vitro and In Vivo Improvement of Islet Survival Following Treatment with Nerve Growth Factor. Transplantation. 2006; 81(4):519-24. PMID: 16495797 (02/2006)
• Miao G, Mace J, Kirby M, Hopper A, Peverini R, Chinnock R, Shapiro J, Hathout EH. Beneficial Effects of NGF in Islet Transplantation. Transplant Proc. 2005; 37(8):3490-2. PMID: 16298638 (09/2005)
• Hathout EH, Patel N, Southern C, Hill J, Anderson J, Sharkey J, Hadley-Scofield M, Tran L, Leptien A, Lopatin M, Wang B, Mace J, Eastman R. Home Use of the Glucowatch G2 Biographer in Children with Diabetes. Pediatrics. 2005; 115(3):662-6. PMID: 15741369 (01/2005)
• Sagen JV, Raeder H, Hathout E et al..  Permanent Neonatal Diabetes due to Mutations in KCNJ11 encoding Kir6.2.  Diabetes. 2004; 53: 2713-2718. (10/2004)
• Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, et al.. Permanent Neonatal Diabetes due to Mutations in KCNJ11 encoding Kir6.2.  Diabetes.  2004; 53: 2713-2718. (01/2004)
• Sagen JV, Raeder H, Hathout EH, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Glyon AL, Hattersley AT, Molven A, Sovik O, Njolstad PR. Permanent Neonatal Diabetes due to Mutations in KCNJ11 encoding Kir6.2: Patient Characteristics and Initial Response to Sulfonylurea Therapy. Diabetes. 2004; 53(10):2713-8. PMID: 15448106 (01/2004)
• Hathout EH and Chinnock RE. Growth after Heart Transplantation. Pediatr Transplant. 2004; 8(2):97-100. PMID: 15049786 (Invited Editorial) (2004)
• Reutrakul S, Hathout EH, Janner D, Hara M, Donfack J, Bass J, Refetoff S. Familial Juvenile Autoimmune Hypothyroidism, Pituitary Enlargement, Obesity, and Insulin Resistance. Thyroid. 2004; 14(4):311-9. PMID: 15142366 (2004)
• Hathout EH, Lakey J, Shapiro J. Islet Transplantation: An Option for Childhood Diabetes? Arch Dis Child. 2003; 88(7):591-4. PMID: 12818905 (2003)
• Hathout EH, Hartwick N, Fagoaga OR, Colacino AR, Sharkey J, Racine M, Nelsen-Cannarella S, Mace JW. Clinical, Autoimmune, and HLA Characteristics of Children Diagnosed with Type 1 Diabetes before Five Years of Age. Pediatrics. 2003; 111(4 Pt 1):860-3. PMID: 12671124 (2003)
• Hathout EH, McClintock T, Sharkey J, Kytsenko D, Hartwick N, Hadley-Scofield M, Torgeson S, Mace JW, 2003. Glycemic, Auxologic and Seasonal Aspects of Continuous Subcutaneous Insulin Infusion Therapy in Children and Young Adults with Type 1 Diabetes. Diabetes Technol Ther. 2003; 5(2):175-81. PMID: 12871607 (2003)
• Hathout EH, Chinnock RE, Johnston J, Fitts J, Razzouk A, Mace JW, Bailey L. Pediatric Post-transplant Diabetes: Data from a Large Cohort of Pediatric Heart Transplant Recipients. Am J Transplant. 2003; 3(8):994-8. PMID: 12859535 (2003)
• Hathout, EH, Fujishige L, Geach J, Ischandar M, Maruo S, Mace JW. Effect of Therapy with Insulin Glargine (Lantus) on Glycemic Control in Toddlers, Children, and Adolescents with Diabetes. Diabetes Technol Ther. 2003; 5(5):801-6. PMID: 14633345 (2003)
• Eastman RC, Chase HP, Buckingham B, Hathout EH, Tamada J, Ginsberg B. How Should We Interpret “Real Life” Conditions. Pediatr Diabetes. 2003; 4(1):59. PMID: 14655525 (2003)
• Hathout EH, Beeson WL, Nahab F,Rabadi A,Thomas W,Mace JW. Role of Exposure to Air Pollutants in the Development of Type 1 Diabetes before and after Five Years of Age. Pediatr Diabetes. 2002; 3(4):184-8. PMID: 15016145 (2002)
• Eastman RC,Chase P,Buckingham B,Hathout EH,Fuller-Byk L,Leptien A, Van Wyhe MM, Davis TL, Fermi SJ, Pechler H, Sahyun G, Lopatin M, Wang BY, Wei C, Bartkowiak M, Ginsberg BH, Tamada JA, Pitzer KR. Use of the GlucoWatchâ Biographer in Children and Adolescents with Diabetes. Pediatr Diabetes. 2002; 3(3):127-34. PMID: 15016152 (2002)
• Hathout EH, Thomas W, El-Shahawy M, Nahab F, Mace JW. Diabetic Autoimmune Markers in Children and Adolescents with Type 2 Diabetes. Pediatrics. 2001; 107(6):E102. PMID: 11389300 (2001)
• Hathout EH, Mace JW. Suprasellar Dysplasia: A Pediatric Perspective. Clini Pediatr. 2000; 39(1):45-9. PMID: 10660819 (2000)
• Hathout EH, Sharkey J, Racine M, Thomas W, Nahab F, El-Shahawy M, Mace JW. Diabetic Autoimmunity in Infants and Preschoolers with Type 1 Diabetes. Pediatr Diabetes. 2000; 1(3):131-4. PMID: 15016223 (2000)
• Hathout EH, Cockburn BN, Mace JW, Sharkey J, Chen-Daniel J, Bell GI. A Case of Hepatocyte Nuclear Factor-1alpha Diabetes/MODY3 Masquerading as Type 1 Diabetes in a Mexican-American Adolescent and Responsive to a Low Dose of Sulfonylurea. Diabetes Care. 1999; 22(5):867-8. PMID: 10332709 (1999)
• Hathout EH, Baylink DJ, Mohan S. Normal Growth Despite GH, IGF-I, and IGF-II Deficiency. Growth Horm IGF Res. 1999; 9(4):272-7. PMID: 10512693 (1999)
• Hathout EH, Sharkey J, Racine M, Ahn D, Mace JW and Saad MF.  Changes in Plasma Leptin During the Treatment of Diabetic Ketoacidosis. J Clin Endocrinol Metab. 1999; 84(12):4545-8. PMID: 10599716 (1999)
• Hathout EH, Sharkey J, Racine M, Ahn D, Mace JW, Saad MF. Changes in Plasma Leptin During the Treatment of Diabetic Ketoacidosis. J Clin Endocrinol Metab. 1999; 84(12):4545-8. PMID: 10599716 (1999)
• Hathout EH, Elmendorf E, Bartley J. Hemifacial Microsomia and Abnormal Chromosome 22. Am J Med Genet. 1998; 76(1):71-3. PMID: 9508069 (1998)
• Hathout EH, Thompson K, Baum M, Dumars K. Association of Terminal Chromosome 1 Deletion with Sertoli Cell-Only Syndrome. Am J Med Genet. 1998; 80(4):396-8. PMID: 9856570 (1998)
• Hathout EH, Kumagai AK, Sangkharat A, Geffner ME, Mullen Y. Absence of GLUT2 Protein in Near Term Fetal Rat Pancreatic Islets. Pancreas. 1997; 14:(3)318-21. PMID: 9094168 (1997)