Publications by authors named "Kathleen M Campbell"

25 Publications

  • Page 1 of 1

Natural Course of Pediatric Portal Hypertension.

Hepatol Commun 2020 Sep 16;4(9):1346-1352. Epub 2020 Jul 16.

Division of Pediatric General and Thoracic Surgery Cincinnati Children's Hospital Medical Center Cincinnati OH.

The etiology of portal hypertension (pHTN) in children differs from that of adults and may require different management strategies. We set out to review the etiology, management, and natural history of pHTN at a pediatric liver center. From 2008 to 2018, 151 children and adolescents with pHTN were identified at a free-standing children's hospital. Patients were stratified by etiology of pHTN (intrahepatic disease [IH], defined as cholestatic disease and fibrotic or hepatocellular disease; extrahepatic disease [EH], defined as hepatic vein obstruction and prehepatic pHTN). Patients with EH were more likely to undergo an esophagoduodenscopy for a suspected gastrointestinal bleed (77% vs. 41%;  < 0.01). Surgical interventions differed based on etiology ( < 0.01), with IH more likely resulting in a transplant only (65%) and EH more likely to result in a shunt only (43%); 30% of patients with IH and 47% of patients with EH did not undergo an intervention for pHTN. Kaplan-Meier analysis revealed a significant increase in mortality in the group that received no intervention compared to shunt, transplant, or both and lower mortality in patients with prehepatic pHTN compared to other etiologies ( < 0.01 each). Multivariate analysis revealed increased odds of mortality in patients with refractory ascites (odds ratio [OR], 4.34; 95% confidence interval [CI], 1.00, 18.88;  = 0.05) and growth failure (OR, 13.49; 95% CI, 3.07, 58.99;  < 0.01). In this single institution study, patients with prehepatic pHTN had better survival and those who received no intervention had higher mortality than those who received an intervention. Early referral to specialized centers with experience managing these complex disease processes may allow for improved risk stratification and early intervention to improve outcomes.
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http://dx.doi.org/10.1002/hep4.1560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471417PMC
September 2020

Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes.

Dig Dis Sci 2020 04 23;65(4):1239-1251. Epub 2019 Sep 23.

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, MLC 2023, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.

Background: Congenital portosystemic shunt (CPSS) is a rare malformation in which splanchnic venous flow bypasses the liver. CPSS is associated with other congenital anomalies and syndromes and can be associated with life-threatening complications. CPSS and their management remain underreported in the literature. Here, we review the clinical characteristics, management, and outcomes of a cohort of children and young adults with CPSS from two pediatric centers.

Methods: Cases of CPSS from Cincinnati Children's Hospital Medical Center and C.S. Mott Children's Hospital were reviewed to define CPSS anatomy, associated anomalies, complications, interventions, and outcomes. The imaging features and histopathology of liver lesions were characterized in detail.

Results: A total of 11 cases were identified. Median age was 10 years (range 0-26); 8 (73%) cases were female. Associated anomalies included six patients with heterotaxy (55%), five patients with congenital heart disease (45%), three patients with Turner syndrome (27%), and two patients with omphalocele, exstrophy, imperforate anus, spinal defects (OEIS) complex (18%). Eight (73%) cases had hyperammonemia ± encephalopathy. A 4-month-old presented with hepatopulmonary syndrome, and 12-year-old presented with pulmonary hypertension. Eight patients (73%) had liver lesions including five with premalignant adenomas and three with well-differentiated hepatocellular carcinoma (HCC). Four children underwent successful CPSS occlusion/ligation. Three children underwent liver transplant (2) or resection (1) for HCC without recurrence at extended follow-up.

Conclusions: CPSS is associated with multiple anomalies (heterotaxy, congenital heart disease) and syndromes (Turner syndrome). CPSS liver lesions should be very carefully evaluated due to risk of premalignant adenomas and HCC. Serious complications of CPSS can occur at a young age but can be managed endovascularly or with open surgery.
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http://dx.doi.org/10.1007/s10620-019-05834-wDOI Listing
April 2020

Prospective Assessment of Ultrasound Shear Wave Elastography for Discriminating Biliary Atresia from other Causes of Neonatal Cholestasis.

J Pediatr 2019 09 26;212:60-65.e3. Epub 2019 Jun 26.

Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH.

Objective: To prospectively assess the diagnostic performance of ultrasound shear wave elastography (SWE) and hepatobiliary laboratory biomarkers for discriminating biliary atresia from other causes of neonatal cholestasis.

Study Design: Forty-one patients <3 months of age with neonatal cholestasis (direct bilirubin >2 mg/dL) and possible biliary atresia were prospectively enrolled. Both 2-dimensional (2D) and point ultrasound SWE were performed prior to knowing the final diagnosis. Median 2D (8) and point (10) shear wave speed measurements were calculated for each subject and used for analyses. The Mann-Whitney U test was used to compare shear wave speed and laboratory measurements between patients with and without biliary atresia. Receiver operating characteristic curve analyses and multivariable logistic regression were used to evaluate diagnostic performance.

Results: Thirteen subjects (31.7%) were diagnosed with biliary atresia, and 28 subjects (68.3%) were diagnosed with other causes of neonatal cholestasis. Median age at the time of ultrasound SWE was 37 days. Median 2D (2.08 vs 1.49 m/s, P = .0001) and point (1.95 vs 1.21 m/s, P = .0014) ultrasound SWE measurements were significantly different between subjects with and without biliary atresia. Using a cut-off value of >1.84 m/s, 2D ultrasound SWE had a sensitivity = 92.3%, specificity = 78.6%, and area under the receiver operating characteristic curve (AuROC) of 0.89 (P < .0001). Using a cut-off value of >320 (U/L), gamma-glutamyl transferase (GGT) had a sensitivity = 100.0%, specificity = 77.8%, and AuROC of 0.85 (P < .0001). Multivariable logistic regression demonstrated an AuROC of 0.93 (P < .0001), with 2 significant covariates (2D ultrasound SWE [OR = 23.06, P = .01]; GGT [OR = 1.003, P = .036]).

Conclusions: Ultrasound SWE and GGT can help discriminate biliary atresia from other causes of neonatal cholestasis.
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http://dx.doi.org/10.1016/j.jpeds.2019.05.048DOI Listing
September 2019

Extracorporeal Membrane Oxygenation in a Patient with Biliary Atresia: Case and Review of Extracorporeal Life Support Organization Data.

ASAIO J 2018 Nov/Dec;64(6):e191-e195

From the Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Biliary atresia is a newborn cholangiopathy that may lead to portopulmonary hypertension and cirrhosis-induced cardiomyopathy while awaiting liver transplantation. Extracorporeal life support and hepatic toxin filtration are life-saving interventions that provide cardiopulmonary support and hepatic dialysis to allow resolution of a child's illness. We utilized a combination of these extreme measures to bridge an infant with biliary atresia to transplantation. We reviewed cases of extracorporeal life support utilization in transplantation recipients in the Extracorporeal Life Support Organization database and determined that ours was the only use of pretransplant extracorporeal life support in biliary atresia.
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http://dx.doi.org/10.1097/MAT.0000000000000749DOI Listing
September 2019

Emerging advancements in liver regeneration and organogenesis as tools for liver replacement.

Curr Opin Organ Transplant 2016 Dec;21(6):581-587

aDivision of Gastroenterology, Hepatology and Nutrition bDivision of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Purpose Of Review: Although the liver possesses a unique, innate ability to regenerate through mass compensation, transplantation remains the only therapy when damage outpaces regeneration, or liver metabolic capacity is irreversibly impacted. Recent insight from developmental biology has greatly influenced the advancement of alternative options to transplantation in these settings.

Recent Findings: Factors known to direct liver cell specification, expansion, and differentiation have been used to generate hepatocyte-like cells from stem and somatic cells for developing cell therapies. Additionally, interactions between hepatic epithelial and nonepithelial cells key to establishing hepatic architecture have been used in tissue engineering approaches to advance self-organizing hepatic organoids and bioartificial liver devices. Simultaneously, recent clinically applicable advances in human hepatocyte transplantation and promotion of innate hepatic regeneration have been limited.

Summary: Although mature hepatocytes have the potential to bridge to, or replace whole organ transplantation, limits in the ability to obtain healthy cells, stabilize in-vitro expansion, cryopreserve, and alleviate rejection, still exist. Alternative sources for generating hepatocytes hold promise for cell therapy and tissue engineering. These may allow generation of autologous or universal donor cells that eliminate the need for immunosuppression; however, limits exist regarding hepatocyte maturity and efficacy at liver repopulation, as well as applicability to human chronic liver disease.
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http://dx.doi.org/10.1097/MOT.0000000000000365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439303PMC
December 2016

Neurologic outcome of urea cycle disorder liver transplant recipients may be predicted by pretransplant neurological imaging.

Pediatr Transplant 2015 Aug 12;19(5):527-30. Epub 2015 May 12.

Pediatric Liver Care Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Unlabelled: Liver transplantation treats the hepatic affectation of UCDs; however, irreversible neurologic damage pretransplant is difficult to assess providing transplant teams with ethical dilemmas for liver transplantation. The purpose of our study was to determine whether pretransplant neuroimaging can predict developmental outcomes post-liver-transplant in children with UCDs.

Methods: Patients undergoing liver transplantation for UCDs at Cincinnati Children's Hospital Medical Center between 2002 and 2012 were identified. Neurologic assessments prior to and after transplantation were categorized into mild, moderate, or severe disability. Neuroimaging data were categorized into mild, moderate, or severe by a single pediatric neuroradiologist.

Results: Fifteen patients were identified of whom eight had neuroimaging prior to transplantation. Of the eight patients that had neuroimaging, four were categorized as severe, one moderate, and three no-to-mild delay. All four patients whose imaging was severe were found to have moderate-to-severe neurologic delay. Of the three patients with no-to-mild changes on neuroimaging two of three were found to have no-to-mild delay on developmental assessments after transplantation.

Conclusion: Neuroimaging may be a helpful tool in determining developmental prognosis and outcomes post-liver-transplantation for UCDs. Further studies maybe needed to validate our preliminary findings.
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http://dx.doi.org/10.1111/petr.12520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485533PMC
August 2015

Magnetic resonance elastography of the liver in patients status-post fontan procedure: feasibility and preliminary results.

Congenit Heart Dis 2014 Jan-Feb;9(1):7-14. Epub 2013 Oct 17.

Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Objective: The purpose of this study was to evaluate the feasibility of performing magnetic resonance elastography (MRE) as a screening tool for elevated liver stiffness in patients' status-post Fontan procedure.

Background: With greater numbers of Fontan patients surviving far into adulthood, a factor increasingly affecting long-term prognosis is the presence of hepatic congestion and fibrosis. If detected early, steps can be taken to potentially slow or halt the progression of fibrosis. MRE is a relatively new, noninvasive imaging technique, which can quantitatively measure liver stiffness and provide an estimate of the extent of fibrosis.

Methods: A retrospective study was conducted using MRE to evaluate liver stiffness in patients with a history of Fontan procedure. An MRE was performed in the same session as a clinical cardiac MRI. The liver was interrogated at four slice locations, and a mean liver stiffness value was calculated for each patient using postprocessing software. The medical records were reviewed for demographic and clinical characteristics.

Results: During the time frame of this investigation, 17 MRE exams were performed on 16 patients. All patients had elevated liver stiffness values as defined by MRE standards. The median of the individual mean liver stiffness values was 5.1 kPa (range: 3.4-8.2 kPa). This range of liver stiffness elevation would suggest the presence of mild to severe fibrosis in a patient with standard cardiovascular anatomy. We found a significant trend toward higher liver stiffness values with greater duration of Fontan circulation (rs = 0.55, P = .02).

Conclusion: Our preliminary findings suggest that MRE is a feasible method for evaluating the liver in Fontan patients who are undergoing surveillance cardiac MRI. Further investigation with histologic correlation is needed to determine the contributions of hepatic congestion and fibrosis to the liver stiffness in this population.
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http://dx.doi.org/10.1111/chd.12144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584140PMC
September 2014

Management and long-term consequences of portal vein thrombosis after liver transplantation in children.

Liver Transpl 2013 Mar;19(3):315-21

Pediatric Gastroenterology, Primary Children's Medical Center, University of Utah, Salt Lake City, UT, USA.

Portal vein thrombosis (PVT) occurs in ≤12% of pediatric recipients of liver transplantation (LT). Known complications of PVT include portal hypertension, allograft loss, and mortality. The management of PVT is varied. A single-center, case-control study of pediatric LT recipients with portal vein (PV) changes after LT was performed. Cases were categorized as early PVT (if PVT was detected within 30 days of transplantation) or late PVT (if PVT was detected more than 30 days after transplantation or if early PVT persisted beyond 30 days). Two non-PVT control patients were matched on the basis of the recipient weight, transplant indication, and allograft type to each patient with PVT. Thirty-two of the 415 LT recipients (7.7%) received 37 allografts and developed PVT. In comparison with control patients, a higher proportion of patients with PVT had PVT present before LT (13.3% versus 0%, P = 0.01). Patients with early PVT usually returned to the operating room, and 9 of 15 patients (60%) had PV flow restored. Patients with late PVT had lower white blood cell (4.9 [1000/μL] versus 6.8 [1000/μL], P < 0.01) and platelet counts (140 [1000/μL] versus 259 [1000/μL], P < 0.01), an elevated international normalized ratio (1.2 versus 1.0, P < 0.001), and more gastrointestinal bleeding (25% versus 8.3%, P = 0.03) compared to controls. Patients with PVT were also less frequently at the expected grade level (52% versus 88%, P < 0.001). The patient survival rates were 84%, 78%, and 78% and 91%, 84%, and 79% for cases and controls at 1, 5, and 10 years, respectively. The allograft survival rates were 90%, 80%, and 80% for cases and 94%, 89%, and 87% for controls at 1, 5, and 10 years, respectively. In conclusion, patients with early and late PVT had preserved allograft function, and there was no impact on mortality. Patients diagnosed with early PVT often underwent operative interventions with successful restoration of flow. Patients diagnosed with late PVT experienced variceal bleeding, and some required portosystemic shunting procedures. Academic delays were also more common. In late PVT, the clinical presentation dictates care because the optimal management algorithm has not yet been determined. Multi-institutional studies are needed to confirm these findings and improve patient outcomes.
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http://dx.doi.org/10.1002/lt.23583DOI Listing
March 2013

Characteristics of successful recruitment in prospective pediatric pharmacogenetic studies.

Clin Ther 2011 Dec 2;33(12):2072-81. Epub 2011 Dec 2.

Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Background: There is a need to explore feasible means of accruing an appropriate study cohort to help fill the knowledge gap between pharmacogenetic contributions to drug response and clinical application in the pediatric population.

Objectives: The aim of this study was to identify factors affecting recruitment of eligible subjects in pharmacogenetic studies at a large Midwestern pediatric academic medical center. The objectives were to evaluate recruitment success of ongoing trials and ascertain contributors to differential recruitment rates. We hypothesized that studies with good recruitment of eligible subjects would share characteristics not present in studies with lower than anticipated recruitment. The goal was to better understand barriers to good recruitment in pharmacogenetic studies to help inform future trial and infrastructure design.

Methods: Investigators designed a survey with proposed elements of success, which was then completed by lead and/or site investigators of all pharmacogenetics studies at the institution. Results were evaluated using an investigator-developed likelihood of success scoring system.

Results: Two studies recruited >95% of the approached eligible patients; 4 studies were consistent with investigator-anticipated recruitment (>50%), and 1 study did not meet expected recruitment. A study's total score on the investigator-devised scoring tool correlated well with the proportion of approached patients recruited (Pearson's correlation, r = 0.82; P < 0.001). Multiple factors impacted successful recruitment into these pharmacogenetic studies. Features of studies with successful recruitment included standardized clinical care, an ongoing team-patient relationship, severe and/or life-threatening outcome measures, study coordinator with experience in clinical research, a study medication with few or no alternative treatment options, and active involvement of the research team in clinical care.

Conclusions: A scoring system for study characteristics may be useful to calculate the risk of failure for successful recruitment, allow discrimination among characteristics contributing to the risk, and permit study design alterations to improve likelihood of successful recruitment in pediatric pharmacogenetic studies.
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http://dx.doi.org/10.1016/j.clinthera.2011.10.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319746PMC
December 2011

Renal function in the long term after pediatric liver transplantation: is there a need for protocol kidney biopsies?

Curr Opin Organ Transplant 2010 Oct;15(5):608-13

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

Purpose Of Review: With improving survival rates following solid organ transplantation, assessment of its success has broadened with a focus on long-term outcomes, including nongraft-related medical outcomes and family and patient perceptions of quality of life. Posttransplant renal dysfunction contributes to long-term morbidity and mortality following pediatric liver transplantation. In this review, we provide an overview of our understanding and approach to managing posttransplant renal dysfunction and highlight the existing gaps in knowledge in this area.

Recent Findings: The literature regarding renal dysfunction following liver transplant primarily focuses on the experience in the adult population. Studies on children are limited by small numbers and varying definitions of outcomes. Thus, lessons in the current literature must be closely examined before they can be extrapolated and applied to children.

Summary: The current literature validates that posttransplant renal dysfunction is a frequent and important outcome for adults and children. Although the characteristics of children at high risk are less clear, calcineurin inhibitor minimization is considered a viable strategy for preserving renal function. The risk-benefit ratio of kidney biopsy in children and the possibility of renal preservation via immunosuppression withdrawal are intriguing concepts that remain to be defined.
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http://dx.doi.org/10.1097/MOT.0b013e32833da439DOI Listing
October 2010

Nonimmune complications after transplantation.

Pediatr Clin North Am 2010 Apr;57(2):505-21, table of contents

Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.

As posttransplant longevity has increased, nonimmune complications related to the transplant and posttransplant course have emerged as important factors in defining long-term outcomes. The incidence of, and risk factors for these complications may vary by transplanted organ based on immunosuppressive protocols and preexisting risk factors. This article discusses the relevant nonimmune complications associated with posttransplant care, with a focus on risk factors and management strategies.
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http://dx.doi.org/10.1016/j.pcl.2010.01.008DOI Listing
April 2010

Ductal plate malformation-like arrays in early explants after a Kasai procedure are independent of splenic malformation complex (heterotaxy).

Pediatr Dev Pathol 2009 Sep-Oct;12(5):355-60

Division of Pathology and Laboratory Medicine, Children's Hospital Research Foundation; Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

Biliary atresia has at least 2 proposed forms, the common perinatal and the less common embryonic subtype with earlier onset and/or extrahepatic developmental anomalies. Histologic evidence of ductal plate malformation (DPM)-like change in liver has been proposed both as a marker for the embryonic type and as a predictor of poor outcome after Kasai portoenterostomy. We investigated the prevalence of DPM-like change in liver explants in usual biliary atresia (BA) and in BA with splenic malformation syndrome (BASM). Liver sections from 8 patients with BA and 6 with BASM, all of whom had a Kasai procedure followed by explant before age 2 years, were analyzed using hematoxylin and eosin, trichrome, CK7, and AE1/AE3 stains. Each block was scored for inflammation and fibrosis. We estimated the number of portal areas per block and counted the number of definite and possible examples of DPM-like change, defined as a circumferential duct complex arranged around a fibrovascular core. We assessed whether the frequency per portal area was related to low and high scores for either inflammation or fibrosis. Definite and possible examples of DPM-like arrays were present in about 10% of portal areas in both patient groups, but these were unevenly distributed. There was no statistical difference between BA and BASM in terms of the number of examples per portal area. No correlation existed between degree of fibrosis and the intensity of portal inflammation and the number of DPM-like arrays. Ductal plate malformation-like arrays do not distinguish perinatal BA from BA associated with heterotaxy in liver explants after a failed Kasai procedure.
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http://dx.doi.org/10.2350/09-01-0598-OA.1DOI Listing
December 2009

Logistic regression.

Methods Mol Biol 2007 ;404:273-301

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

The Medical Subject Headings (MeSH) thesaurus used by the National Library of Medicine defines logistic regression models as "statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable." Logistic regression models are used to study effects of predictor variables on categorical outcomes and normally the outcome is binary, such as presence or absence of disease (e.g., non-Hodgkin's lymphoma), in which case the model is called a binary logistic model. When there are multiple predictors (e.g., risk factors and treatments) the model is referred to as a multiple or multivariable logistic regression model and is one of the most frequently used statistical model in medical journals. In this chapter, we examine both simple and multiple binary logistic regression models and present related issues, including interaction, categorical predictor variables, continuous predictor variables, and goodness of fit.
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http://dx.doi.org/10.1007/978-1-59745-530-5_14DOI Listing
May 2008

PEGylated bioactive molecules in biodegradable polymer microparticles.

Expert Opin Biol Ther 2007 Sep;7(9):1427-36

PR Pharmaceuticals, Inc., Fort Collins, Colorado 80524, USA.

Injectable peptide and oligonucleotide biotherapeutics offer great promise for treatment of serious chronic diseases but almost always need further formulation work to increase stability and circulation lifetimes. Covalent attachment of poly(ethylene glycol) (PEG) will increase circulation lifetimes up to a week or so and decrease degradation in favorable cases. Encapsulation in biodegradable polymer microparticles has been highly successful, mostly for peptides to provide sustained release up to several months after injection. Although products are on the market using these technologies, PEGylation and microparticle encapsulation each have drawbacks that prevent more widespread use. When they are combined, the limitations of one technology may be resolved by the other. Work in several laboratories on encapsulation of PEGylated bioactive molecules has revealed a synergy. Activity reduction and restricted circulation lifetimes for PEGylated bioactive agents is addressed by microencapsulation and using a lower PEG molecular weight. Chemical degradation, excessive burst release and limited drug content are typical problems for microparticles that are ameliorated by using PEGylated actives. The case for synergy between PEGylation and microencapsulation is illustrated in this review by work with several proteins and peptides including insulin, and the oligonucleotide therapeutic, pegaptanib.
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http://dx.doi.org/10.1517/14712598.7.9.1427DOI Listing
September 2007

High prevalence of alpha-1-antitrypsin heterozygosity in children with chronic liver disease.

J Pediatr Gastroenterol Nutr 2007 Jan;44(1):99-103

Pediatric Liver Care Center, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Objective: Alpha-1-antitrypsin (A1AT) deficiency is the most common genetic cause of liver disease in children; however, the role of polymorphic heterogeneity in the A1AT gene as a modifier of other forms of pediatric liver disease is not clear. We hypothesized that non-M A1AT allele variants are more common in children with chronic liver disease than in the general population.

Methods: A retrospective, single-center study was performed in which A1AT phenotypes were obtained by reviewing charts of children with chronic liver disease. Chi-square analysis was used to compare allele frequencies in the population of children with liver disease with published epidemiologic data and to compare allele frequencies among disease subgroups.

Results: The frequency of A1AT Z and other alleles was increased in children with chronic liver disease (n = 241) when compared with the published reference database (P < 0.001). This increase remained significant when the population was divided into disease subsets: biliary atresia (n = 67) and other liver disease (n = 174) (P < 0.001 for both). Among children with biliary atresia referred for liver transplant evaluation, the presence of a non-M allele was associated with a lower mean age at transplant listing than the MM phenotype (235 vs 779 days, P = 0.036) and more frequent loss of native liver by 24 months of age (90% vs 65%, P = 0.04).

Conclusions: A1AT non-M alleles are more frequent in children with chronic liver disease than in the general population. We speculate that these non-M alleles may act as genetic modifiers in pediatric liver disease in general and modulate disease progression in children with biliary atresia in particular.
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http://dx.doi.org/10.1097/01.mpg.0000243434.54958.21DOI Listing
January 2007

Outcomes after liver transplantation: keep the end in mind.

J Pediatr Gastroenterol Nutr 2006 Jul;43 Suppl 1:S41-8

Division of Gastroenterology, Hepatology and Nutrition, Pediatric Liver Care Center, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati College of Medicine, OH 45229, USA.

Since the advent of transplantation as a life-saving procedure for patients with end-stage liver disease, more than 15,000 children and adolescents have received liver transplants. With the improvements in long-term posttransplant survival offered by advances in medical and surgical therapy, the concept of transplantation outcome has expanded beyond simple patient and graft survival rates. The quality of the life years restored, the long-term complications of transplant immunosuppression, and the overall cost of care have been increasingly recognized as important components of liver transplantation outcome. This review focuses on the efforts of a single pediatric transplant center to examine the incidence of, and risk factors for, common posttransplantation complications, to characterize posttransplantation health-related quality of life, to describe the cost of posttransplant care, and to implement novel programs to improve health care delivery. Together, these projects set the future course for research and care improvement initiatives in this population and encourage us to "keep the end in mind" when considering pediatric liver transplantation.
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http://dx.doi.org/10.1097/01.mpg.0000226389.64236.dcDOI Listing
July 2006

High prevalence of renal dysfunction in long-term survivors after pediatric liver transplantation.

J Pediatr 2006 Apr;148(4):475-80

Pediatric Liver Care Center, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, OH 45229, USA.

Objective: To determine the prevalence and identify variables associated with renal dysfunction in long-term survivors of pediatric liver transplantation.

Study Design: Data from 117 patients who survived>or=3 years after liver transplantation were analyzed. Demographic and clinical information was obtained from chart review and from a clinical care database. The dependent variable was renal function as determined by measured glomerular filtration rate (mGFR). Univariate and multivariate analyses were performed to identify independent variables associated with renal dysfunction (mGFR<70 mL/min per 1.73 m2).

Results: The average time since liver transplant was 7.6+/-3.4 years (range, 3 to 14.6 years). When the last available mGFR for all patients was analyzed, renal dysfunction was present in 32%. In the univariate analysis, mGFR at 1 year after transplant, cyclosporine immunosuppression, and time since transplant were significant; the second two were strongly collinear. Using multiple logistic regression modeling excluding time since transplant, cyclosporine and mGFR at 1 year after transplant were strongly associated with renal dysfunction.

Conclusions: Renal dysfunction is a common complication in children who survive liver transplantation. Our observations are of critical importance because children may live long enough to move from a stage of renal insufficiency characterized by asymptomatic decreased GFR to symptomatic end-stage renal disease.
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http://dx.doi.org/10.1016/j.jpeds.2005.11.013DOI Listing
April 2006

PEGylated insulin in PLGA microparticles. In vivo and in vitro analysis.

J Control Release 2005 Jun;104(3):447-60

PR Pharmaceuticals, Inc., Ft. Collins, CO 80524, USA.

A novel controlled release formulation has been developed with PEGylated human insulin encapsulated in PLGA microspheres that produces multi-day release in vivo. The insulin is specifically PEGylated at the amino terminus of the B chain with a relatively low molecular weight PEG (5000 Da). Insulin with this modification retains full biological activity, but has a limited serum half-life, making encapsulation necessary for sustained release beyond a few hours. PEGylated insulin can be co-dissolved with PLGA in methylene chloride and microspheres made by a single o/w emulsion process. Insulin conformation and biological activity are preserved after PEGylation and PLGA encapsulation. The monolithic microspheres have inherently low burst release, an important safety feature for an extended release injectable insulin product. In PBS at 37 degrees C, formulations with a drug content of approximately 14% show very low (< 1%) initial release of insulin over one day and near zero order drug release after a lag of 3-4 days. In animal studies, PEG-insulin microspheres administered subcutaneously as a single injection produced < 1% release of insulin in the first day but then lowered the serum glucose levels of diabetic rats to values < 200 mg/dL for approximately 9 days. When doses were given at 7-day intervals, steady state drug levels were achieved after only 2 doses. PEG-insulin PLGA microparticles show promise as a once-weekly dosed, sustained release basal insulin formulation.
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http://dx.doi.org/10.1016/j.jconrel.2005.02.020DOI Listing
June 2005

Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia.

J Clin Invest 2004 Aug;114(3):322-9

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Ohio 45229-3039, USA.

The etiology and pathogenesis of bile duct obstruction in children with biliary atresia are largely unknown. We have previously reported that, despite phenotypic heterogeneity, genomic signatures of livers from patients display a proinflammatory phenotype. Here, we address the hypothesis that production of IFN-gamma is a key pathogenic mechanism of disease using a mouse model of rotavirus-induced biliary atresia. We found that rotavirus infection of neonatal mice has a unique tropism to bile duct cells, and it triggers a hepatobiliary inflammation by IFN-gamma-producing CD4(+) and CD8(+) lymphocytes. The inflammation is tissue specific, resulting in progressive jaundice, growth failure, and greater than 90% mortality due to obstruction of extrahepatic bile ducts. In this model, the genetic loss of IFN-gamma did not alter the onset of jaundice, but it remarkably suppressed the tissue-specific targeting of T lymphocytes and completely prevented the inflammatory and fibrosing obstruction of extrahepatic bile ducts. As a consequence, jaundice resolved, and long-term survival improved to greater than 80%. Notably, administration of recombinant IFN-gamma led to recurrence of bile duct obstruction following rotavirus infection of IFN-gamma-deficient mice. Thus, IFN-gamma-driven obstruction of bile ducts is a key pathogenic mechanism of disease and may constitute a therapeutic target to block disease progression in patients with biliary atresia.
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http://dx.doi.org/10.1172/JCI21153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC484981PMC
August 2004

Transcriptional reprogramming in murine liver defines the physiologic consequences of biliary obstruction.

J Hepatol 2004 Jan;40(1):14-23

Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.

Background/aims: While the metabolic and histological responses to cholestasis are recognized, the consequences of impaired biliary flow on liver gene expression are largely undefined. We hypothesized that biliary obstruction results in transcriptional reprogramming that dictates the physiologic response.

Methods: We determined global gene expression in murine livers 1-21 days following bile duct ligation. Total hepatic cRNA from experimental and sham mice was hybridized to Affymetrix gene chips. Gene expression data was analyzed by GeneSpring software and validated by Northern analysis.

Results: We found 92 genes over-expressed > or =2-fold at one or more time points following bile duct ligation. Functional classification of these genes revealed the activation of three main biological processes in a sequential and time-restricted fashion. At day 1, genes involved in sterol metabolism were uniquely over-expressed, including HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. This was followed by an increased expression of growth-promoting genes at day 7, the time point coinciding with peak cholangiocyte proliferation. In later phases (days 14-21), the liver over-expressed genes encoding structural proteins and proteases.

Conclusions: Transcriptional reprogramming in the liver following biliary obstruction favors the activation of genes regulating metabolism, cell proliferation, and matrix remodeling in a time-restricted and sequential fashion.
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http://dx.doi.org/10.1016/j.jhep.2003.09.025DOI Listing
January 2004

Teamwork. Getting there & staying there.

AWHONN Lifelines 2003 Jun-Jul;7(3):201-3

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http://dx.doi.org/10.1177/1091592303255728DOI Listing
August 2003

Structurally distinct modes of recognition of the KIX domain of CBP by Jun and CREB.

Biochemistry 2002 Nov;41(47):13956-64

Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523-1870, USA.

Gene expression is coordinated in part by interactions between transcriptional activators and other transcription factors such as coactivators. The KIX domain of the coactivator and histone acetyltransferase CREB binding protein (CBP) binds numerous mammalian and viral transcriptional activators such as BRCA1, CREB, c-Jun, c-Myb, p53, papillomavirus E2, and HTLV-1 Tax. Formation of the CREB-CBP complex depends on phosphorylation of the KID region of CREB and involves induced folding of KID upon binding a hydrophobic groove of the KIX domain of CBP. Here we investigate the formation of the complex formed by human KIX and the N-terminal activation domain of human c-Jun. The c-Jun activation domain and KID do not share significant sequence similarity. Circular dichroism spectroscopy shows that the Jun N-terminal activation domain is intrinsically disordered in isolation and that KIX binding is independent of Jun phosphorylation. In contrast to the mode of binding exhibited by CREB, NMR chemical shift mapping indicates that the c-Jun activation domain binds to a distinctly different surface of KIX than used by CREB. Moreover, NMR and sedimentation equilibrium studies show that the activation domains of c-Jun and CREB can simultaneously bind the KIX domain of CBP. The results illustrate a new mode of binding and combinatorial recruitment via the KIX domain of CBP by multiple transcriptional activators.
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http://dx.doi.org/10.1021/bi026222mDOI Listing
November 2002

Round window application of D-methionine provides complete cisplatin otoprotection.

Otolaryngol Head Neck Surg 2002 Jun;126(6):683-9

Division of Otolaryngology, Southern Illinois University, Springfield, USA.

Objective: Cisplatin is a widely used, very effective chemotherapeutic agent that can cause severe ototoxicity. In this study, D-methionine was tested as an otoprotectant via round window membrane (RWM) application in the chinchilla.

Methods: A minute amount of cisplatin alone, or D-methionine followed by cisplatin, was applied topically directly to the intact RWM of anesthetized adult chinchillas. Auditory brainstem responses were measured before and 1 week after topical round window application. Animals were killed, and the cochleas were examined.

Results: The ears pretreated with D-methionine were completely protected from hearing loss and hair cell loss in the organ of Corti compared with controls. The ears receiving cisplatin without D-methionine protection sustained nearly complete hearing loss with threshold shifts of >60 dB, with extensive outer hair cell loss throughout the organ of Corti but particularly in the basal turn.

Conclusion: These results demonstrate that topical D-methionine provides excellent otoprotection against cisplatin-induced ototoxicity both electrophysiologically and structurally.
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http://dx.doi.org/10.1067/mhn.2002.125299DOI Listing
June 2002

Complementation of buried lysine and surface polar residues in a designed heterodimeric coiled coil.

Biochemistry 2002 Jun;41(22):7169-75

Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523-1870, USA.

The coiled coil is an attractive target for protein design. The helices of coiled coils are characterized by a heptad repeat of residues denoted a to g. Residues at positions a and d form the interhelical interface and are usually hydrophobic. An established strategy to confer structural uniqueness to two-stranded coiled coils is the use of buried polar Asn residues at position a, which imparts dimerization and conformational specificity at the expense of stability. Here we show that polar interactions involving buried position-a Lys residues that can interact favorably only with surface e' or g' Glu residues also impart structural uniqueness to a designed heterodimeric coiled coil with the nativelike properties of sigmoidal thermal and urea-induced unfolding transitions, slow hydrogen exchange and lack of ANS binding. The position-a Lys residues do not, however, confer a single preference for helix orientation, likely reflecting the ability of Lys at position a to from favorable interactions with g' or e' Glu residues in the parallel and antiparallel orientations, respectively. The Lys-Glu polar interaction is less destabilizing than the Asn-Asn a-->a' interaction, presumably reflecting a higher desolvation penalty associated with the completely buried polar position-a groups. Our results extend the range of approaches for two-stranded coiled-coil design and illustrate the role of complementing polar groups associated with buried and surface positions of proteins in protein folding and design.
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http://dx.doi.org/10.1021/bi025559lDOI Listing
June 2002

Contribution of buried lysine residues to the oligomerization specificity and stability of the fos coiled coil.

Biochemistry 2002 Apr;41(15):4866-71

Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523-1870, USA.

Coiled coils comprise two or more helices characterized by a heptad repeat of amino acids denoted a through g. The buried a and d positions are usually occupied by hydrophobic residues. Fos dimerizes via a coiled coil (leucine zipper) with Jun family members to form the transcription factor AP-1. Fos homodimers are relatively unstable due to unfavorable interhelical electrostatic interactions within the Fos two-stranded coiled coil. The Fos coiled coil contains two polar position a Lys residues (Lys 16 and Lys 30 of Fos-p1, a peptide corresponding to the coiled-coil domain of v-Fos). Lys 16 and Lys 30 of Fos-p1 were replaced individually and together with the unnatural amino acid norleucine (2-aminohexanoic acid), which corresponds to a deletion of the Lys epsilon-amino group. The midpoint of thermal denaturation (T(m)) of Fos-p1 (10 microM) is 30 degrees C at pH 7. The Lys 16 --> Nle variant forms predominantly homodimers that are relatively unstable (T(m) = 46 degrees C). The Lys 30 --> Nle variant forms a stable homotetramer (T(m) = 60 degrees C). The Lys 16/Lys 30 --> Nle variant forms a very stable homotetramer (T(m) = 80 degrees C). The results show that (i) the effects of buried position a Lys residues on coiled-coil oligomerization are context dependent and (ii) electrostatic destabilization of the Fos homodimer can be mitigated by an oligomerization switch moderated by a single buried Lys residue.
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http://dx.doi.org/10.1021/bi0159276DOI Listing
April 2002