Publications by authors named "Mark A Lovell"

104 Publications

Outcomes of Severe Seronegative Hepatitis-associated Aplastic Anemia: A Pediatric Case Series.

J Pediatr Gastroenterol Nutr 2021 Feb;72(2):194-201

Section of Gastroenterology, Hepatology and Nutrition, and the Digestive Health Institute, Children's Hospital Colorado, University of Colorado Denver School of Medicine.

Objectives: Hepatitis-associated aplastic anemia (HAAA) is a potentially life-threatening diagnosis without clear treatment guidelines. The goal of the study was to characterize the presentation, evaluation, histopathology, and outcomes of therapy in children with HAAA to guide future research and to develop standardized care guidelines for this rare disease.

Methods: Retrospective chart review of 4 patients with HAAA who presented to Children's Hospital Colorado between 2016 and 2019 was conducted. Patient presentation, evaluation, bone marrow and liver pathology, interventions, and clinical course were collected. Immunohistochemistry of liver biopsies was performed.

Results: We treated 4 patients with HAAA without liver failure. All had evidence of systemic hyperinflammation and CD8+ T cell predominant liver tissue infiltration. One had a genetic mutation predisposing him to immune-mediated disease, but all other genetic testing was negative. In 3 of the 4 patients, hepatitis was poorly responsive to standard therapy with steroids, azathioprine, or tacrolimus; however, sustained biochemical remission of hepatitis was induced after more aggressive immunosuppressive therapies including Anti-Thymocyte Globulin (ATG) at standard immunosuppressive therapy (IST) dosing for severe Aplastic Anemia (sAA). Two patients underwent hematopoietic stem cell transplant (HSCT); 1 as first line therapy and 1 for refractory sAA.

Conclusions: We found that ATG-based IST induced remission of hepatitis in patients with steroid-refractory HAAA. This is also an appropriate initial treatment for severe Aplastic Anemia, though may not prevent the need for HSCT. We propose that equine ATG based IST at standard dosing regimen for sAA is a therapy that in select cases can be considered early on in the treatment course and could lead to a sustained remission of both hepatitis and sAA. This should be considered in collaboration with a pediatric hematologist.
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http://dx.doi.org/10.1097/MPG.0000000000002940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856235PMC
February 2021

Pediatric sublingual dermoid and epidermoid cysts: A 20-year institutional review.

Int J Pediatr Otorhinolaryngol 2020 Nov 4;138:110265. Epub 2020 Aug 4.

Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine, Aurora, CO, USA; Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, USA. Electronic address:

Introduction: Pediatric cystic sublingual masses often present a diagnostic dilemma for practitioners. Though uncommon, dermoid or epidermoid cysts can present in the sublingual space at any age and are often misdiagnosed as an inflammatory pseudocyst (ranula) or lymphatic malformation. Imaging may not always identify the underlying etiology, requiring physicians to maintain a high index of suspicion for these relatively rare oral cysts.

Objectives: To describe the presentation and treatment of sublingual dermoid and epidermoid cysts presenting to a tertiary children's hospital over 20 years.

Methods: A retrospective review of all pathology specimens identified as dermoid or epidermoid cysts within the sublingual space from 1999 to 2019. Patient charts were then reviewed for relevant clinical, imaging, and operative data.

Results: Twelve pediatric patients were identified (8 female, 4 male) with a mean age of 7.2 years (SD 5.6). Eighty six percent (6/7) of dermoid cysts were found in female patients, while 60% (3/5) of epidermoid cysts were in male patients. Multiple dermoid and epidermoid cysts were each found in one patient (8%). Two epidermoid cysts presented in the neonatal period. Preoperative diagnosis included nondiagnostic "cystic mass" (33%), ranula (25%), lymphatic malformation (LM) (17%), and dermoid/epidermoid cyst (17%). Two thirds of patients (8/12) underwent imaging, with all receiving either MRI or CT. Although MRI was the most likely to suggest the possibility of a dermoid/epidermoid cyst (2/4), ranula was the most common primary radiographic diagnosis (5/8). One patient underwent sclerotherapy for presumed LM one year prior to surgical excision of the cyst. Eleven patients (92%) underwent intraoral excision, one (8.3%) underwent a combined intraoral/extraoral approach.

Conclusions: To our knowledge, this review represents the largest case series of pediatric sublingual dermoid and epidermoid cysts to date. This series contained higher levels of epidermoid cysts and female patients than previously reported in the literature. Identifying more dermoid cysts in females and epidermoid cysts in males is also a new finding. MRI was superior to CT and US regarding the presence of a dermoid/epidermoid cyst. Frequently misdiagnosed, it is important to consider these relatively rare pathologies when treating children presenting with sublingual masses in order to avoid delayed and/or inappropriate treatment.
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http://dx.doi.org/10.1016/j.ijporl.2020.110265DOI Listing
November 2020

Markers of Hypoxia Correlate with Histologic and Endoscopic Severity of Colitis in Inflammatory Bowel Disease.

Hypoxia (Auckl) 2020 10;8:1-12. Epub 2020 Feb 10.

Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA.

Background: Inflammation results in significant shifts in tissue metabolism. Recent studies indicate that inflammation and hypoxia occur concomitantly. We examined whether circulating and tissue markers of hypoxia could serve as surrogate indicators of disease severity in adult and pediatric patients with inflammatory bowel disease (IBD).

Methods: Serum and colonic biopsies were obtained from pediatric subjects with active IBD colitis and adult subjects with active and inactive ulcerative colitis, along with healthy non-colitis controls of all ages. Disease activity was evaluated by endoscopy and histopathology. Levels of serum hypoxia markers (macrophage inflammatory protein-3α [MIP-3α], vascular endothelial growth factor [VEGF], and erythropoietin [EPO]) were measured.

Results: Children with active IBD colitis had higher levels of serum MIP-3α and VEGF compared to non-colitis controls (p<0.01 and p<0.05, respectively). In adult subjects with endoscopically active ulcerative colitis, serum MIP-3α and EPO were significantly elevated compared to non-colitis controls (both p<0.01). In parallel, analysis of colon tissue MIP-3α mRNA and protein in pediatric subjects revealed increased expression in those with IBD colitis compared to controls (p<0.05 and p<0.01 for mRNA and protein, respectively). Serum MIP-3α and VEGF significantly increased with histology grade.

Conclusion: Peripheral blood hypoxia markers may be useful indicators of disease activity for pediatric and adult IBD patients.
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http://dx.doi.org/10.2147/HP.S219049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026141PMC
February 2020

Head and neck pleomorphic myxoid liposarcoma in a child with Li-Fraumeni syndrome.

Int J Pediatr Otorhinolaryngol 2019 Aug 18;123:191-194. Epub 2019 May 18.

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, USA. Electronic address:

Introduction: Pleomorphic myxoid liposarcoma is a rare and aggressive cancer seen in the pediatric population that has been previously associated with hereditable cancer disorders like Li Fraumeni syndrome. We present a case report and review of the relevant literature.

Case Presentation: Pleomorphic myxoid liposarcoma presenting as a second primary tumor in a child with a strong family history for cancer led to diagnosis of Li-Fraumeni syndrome, which is associated with TP53 tumor suppressor gene inactivation.

Management And Outcome: The tumor was fully excised, but postoperative radiation was deferred to limit future radiation-induced tumorgenesis.

Discussion: Pleomorphic myxoid liposarcoma is rare but aggressive, and should prompt caregivers to test for potential hereditable cancer disorders. Li-Fraumeni syndrome is associated with early onset neoplasia and development of recurrent primary tumors. Its presence affects treatment decisions and methods of surveillance. Chemoradiation should be used judiciously in this population.
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http://dx.doi.org/10.1016/j.ijporl.2019.05.016DOI Listing
August 2019

Esophagitis Dissecans Superficialis Diagnosed by Unsedated Transnasal Esophagoscopy.

J Pediatr Gastroenterol Nutr 2019 08;69(2):e54

Digestive Health Institute, Section of Pediatric Gastroenterology, Hepatology and Nutrition.

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http://dx.doi.org/10.1097/MPG.0000000000002173DOI Listing
August 2019

Head and neck presentation of Gardner Syndrome: A pediatric case series.

Int J Pediatr Otorhinolaryngol 2018 07 25;110:31-33. Epub 2018 Apr 25.

Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijporl.2018.04.018DOI Listing
July 2018

Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood.

Am J Hum Genet 2018 04 22;102(4):557-573. Epub 2018 Mar 22.

Department of Neuropediatrics, Christian-Albrechts-University of Kiel, Kiel 24105, Germany; Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address:

Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.
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http://dx.doi.org/10.1016/j.ajhg.2018.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985287PMC
April 2018

Tracheal paraganglioma presenting as stridor in a pediatric patient, case report and literature review.

Int J Pediatr Otorhinolaryngol 2018 Apr 7;107:145-149. Epub 2018 Feb 7.

Department of Pediatric Otolaryngology, Children's Hospital Colorado & University of Colorado School of Medicine, Aurora, CO, United States. Electronic address:

Objective: To review tracheal paragangliomas and describe the clinical presentation, radiologic findings, operative management, and histologic findings of a pediatric patient who presented with stridor refractory to traditional asthma therapy.

Methods: Chart review of an 8-year-old male who presented to a tertiary care pediatric hospital and literature review of tracheal paragangliomas.

Results: We present the case of an 8-year-old male who presented with new-onset of wheezing and dyspnea on exertion. He was given a new diagnosis of asthma and treated with bronchodilators that failed to improve his symptoms, which progressed over 3 months until he presented urgently with biphasic stridor. Bedside flexible laryngoscopy failed to reveal an etiology. Computed tomography (CT) imaging demonstrated 17 × 12 × 16 mm exophytic mass arising from the posterior membranous trachea with extension of the mass to the border of the thyroid gland and separate from the esophagus. Magnetic resonance imaging (MRI) angiography confirmed vascular supply from the right thyrocervical trunk and inferior thyroid artery. Rigid microlaryngoscopy revealed a friable vascular polypoid mass 2 cm distal to the vocal folds with 75% obstruction of the airway from which a small biopsy was taken. Pathology confirmed paraganglioma with neuroendocrine cells arranged in "zellballen" architecture and strong immunopositivity for chromogranin and synaptophysin in the neuroendocrine cells and S100 immunopositivity in the sustentacular cells. The patient underwent complete open resection of the tumor including three tracheal rings with primary anastomosis. Final pathology confirmed paraganglioma and negative margins. Genetic screening revealed a succinate dehydrogenase complex subunit C (SDHC) germline mutation, confirming hereditary paraganglioma/pheochromocytoma syndrome. He remains well at 3 month follow up without dyspnea or stridor.

Conclusion: Tracheal paragangliomas are exceptionally rare, with 12 reported cases. This is the only pediatric case reported. In pediatric patients with persistent airway complaints, subglottic and tracheal masses and obstruction should be considered. Due to the vascularity and endotracheal component of tracheal paragangliomas, a detailed surgical plan should consider embolization, endotracheal laser photocoagulation and electrocautery, and open surgical resection. Additionally, pediatric patients benefit from a multidisciplinary approach including radiology, endocrinology, and genetic counseling.
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http://dx.doi.org/10.1016/j.ijporl.2018.02.010DOI Listing
April 2018

A novel method for the rapid detection of post-translationally modified visinin-like protein 1 in rat models of brain injury.

Brain Inj 2018 28;32(3):363-380. Epub 2017 Dec 28.

f Sanders-Brown Center on Aging & Department of Chemistry , University of Kentucky , Lexington , KY , USA.

Background: Although elevated serum levels of visinin-like protein 1 (VILIP-1), a neuron-specific calcium sensor protein, are associated with ischaemic stroke, only a single study has evaluated VILIP-1 as a biomarker of traumatic brain injury (TBI). The current proof-of-concept study was designed to determine whether serum VILIP-1 levels increase post-injury in a well-characterized rat unilateral cortical contusion model.

Methods: Lateral flow devices (LFDs) rapidly (< 20 min) detected trace serum levels (pg/mL) of VILIP-1 in a small input sample volume (10 µL). Temporal profiles of serum levels at baseline and post-injury were measured in male Sprague Dawley rats subjected to very mild-, mild unilateral-cortical contusion, or naïve surgery and in male Sprague Dawley rats following a diffuse TBI or sham surgery.

Results: Mean serum levels were significantly elevated by 0.5 h post-injury and remained so throughout the temporal profile compared with baseline in very mild and mild unilateral contusions but not in naïve surgeries. Serum levels were also elevated in a small cohort of animals subjected to a diffuse TBI injury.

Conclusions: Overall, the current study demonstrates that the novel LFD is a reliable and rapid point-of-care diagnostic for the detection and quantification of serum levels of UB-VILIP-1 in a clinically relevant time frame.
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http://dx.doi.org/10.1080/02699052.2017.1418907DOI Listing
March 2019

Diagnostic utility of core needle biopsy versus open wedge biopsy for pediatric intraabdominal solid tumors: Results of a prospective clinical study.

J Pediatr Surg 2017 Dec 4;52(12):2042-2046. Epub 2017 Sep 4.

University of Colorado School of Medicine, Department of Surgery; Children's Hospital Colorado, Division of Pediatric Surgery.

Purpose: The best method for diagnosing pediatric nonnephroblastoma solid intraabdominal tumors is unknown. We hypothesized that core needle biopsy (CNB) is noninferior to open wedge biopsy (OWB) for pathologic diagnosis.

Methods: We prospectively enrolled children aged 1day to 17years with radiographic evidence of nonnephroblastoma solid intraabdominal tumors scheduled for OWB from 5/2013 to 12/2015 at a single institution. Four 16-gauge CNBs were obtained, followed by OWB. Two pathologists independently reviewed all specimens to determine adequacy for diagnosis.

Results: Fourteen patients enrolled, 57% male, with an average age of 4years (range 7days to 16years). Both pathologists agreed OWB was completely sufficient for diagnosis in 13 patients (93%), compared to 4 patients for CNB (29%: Burkitt lymphoma, adrenocortical tumor, inflammatory myofibroblastic tumor, p=0.001, δ=-0.64±0.27, 95% CI). In 6 patients (43%), CNB was incompletely diagnostic according to at least one pathologist (neuroblastoma, hepatoblastoma). In 4 patients (29%), both pathologists determined that CNB was nondiagnostic (ganglioneuroblastoma, teratoma, hepatoblastoma, and recurrent neuroblastoma).

Conclusions: In a prospective clinical study, CNB is inferior to OWB for the pathologic diagnosis of pediatric nonnephroblastoma solid intraabdominal tumors. These data suggest that OWB should generally be performed in these patients.

Level Of Evidence: Study of Diagnostic Test, Level I.
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http://dx.doi.org/10.1016/j.jpedsurg.2017.08.032DOI Listing
December 2017

Single-Base Resolution Mapping of 5-Hydroxymethylcytosine Modifications in Hippocampus of Alzheimer's Disease Subjects.

J Mol Neurosci 2017 Oct 2;63(2):185-197. Epub 2017 Sep 2.

Department of Chemistry, University of Kentucky, Lexington, KY, USA.

Epigenetic modifications to cytosine have been shown to regulate transcription in cancer, embryonic development, and recently neurodegeneration. While cytosine methylation studies are now common in neurodegenerative research, hydroxymethylation studies are rare, particularly genome-wide mapping studies. As an initial study to analyze 5-hydroxymethylcytosine (5-hmC) in the Alzheimer's disease (AD) genome, reduced representation hydroxymethylation profiling (RRHP) was used to analyze more than 2 million sites of possible modification in hippocampal DNA of sporadic AD and normal control subjects. Genes with differentially hydroxymethylated regions were filtered based on previously published microarray data for altered gene expression in hippocampal DNA of AD subjects. Our data show significant pathways for altered levels of 5-hmC in the hippocampus of AD subjects compared to age-matched normal controls involved in signaling, energy metabolism, cell function, gene expression, protein degradation, and cell structure and stabilization. Overall, our data suggest a possible role for the dysregulation of epigenetic modifications to cytosine in late stage AD.
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http://dx.doi.org/10.1007/s12031-017-0969-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909840PMC
October 2017

Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice.

J Neurosci 2017 06 30;37(25):6132-6148. Epub 2017 May 30.

Sanders-Brown Center on Aging,

Hyperexcitable neuronal networks are mechanistically linked to the pathologic and clinical features of Alzheimer's disease (AD). Astrocytes are a primary defense against hyperexcitability, but their functional phenotype during AD is poorly understood. Here, we found that activated astrocytes in the 5xFAD mouse model were strongly associated with proteolysis of the protein phosphatase calcineurin (CN) and the elevated expression of the CN-dependent transcription factor nuclear factor of activated T cells 4 (NFAT4). Intrahippocampal injections of adeno-associated virus vectors containing the astrocyte-specific promoter Gfa2 and the NFAT inhibitory peptide VIVIT reduced signs of glutamate-mediated hyperexcitability in 5xFAD mice, measured with microelectrode arrays and brain slices, using whole-cell voltage clamp. VIVIT treatment in 5xFAD mice led to increased expression of the astrocytic glutamate transporter GLT-1 and to attenuated changes in dendrite morphology, synaptic strength, and NMDAR-dependent responses. The results reveal astrocytic CN/NFAT4 as a key pathologic mechanism for driving glutamate dysregulation and neuronal hyperactivity during AD. Neuronal hyperexcitability and excitotoxicity are increasingly recognized as important mechanisms for neurodegeneration and dementia associated with Alzheimer's disease (AD). Astrocytes are profoundly activated during AD and may lose their capacity to regulate excitotoxic glutamate levels. Here, we show that a highly active calcineurin (CN) phosphatase fragment and its substrate transcription factor, nuclear factor of activated T cells (NFAT4), appear in astrocytes in direct proportion to the extent of astrocyte activation. The blockade of astrocytic CN/NFAT signaling in a common mouse model of AD, using adeno-associated virus vectors normalized glutamate signaling dynamics, increased astrocytic glutamate transporter levels and alleviated multiple signs of neuronal hyperexcitability. The results suggest that astrocyte activation drives hyperexcitability during AD through a mechanism involving aberrant CN/NFAT signaling and impaired glutamate transport.
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http://dx.doi.org/10.1523/JNEUROSCI.0877-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481945PMC
June 2017

Pediatric Intraocular Immature Teratoma Associated With Sacrococcygeal Teratoma.

Pediatr Dev Pathol 2017 Jun 25;20(3):240-244. Epub 2017 Jan 25.

1 University of Colorado, Denver, CO, USA.

Intraocular teratomas are rare neoplasms with only three previously reported cases. We present the fourth case of intraocular teratoma and the second associated with sacrococcygeal teratoma. While the nature of the association between intraocular teratomas and sacrococcygeal teratomas is unclear, it suggests a need for careful ophthalmologic follow-up of infants with congenital sacrococcygeal teratomas.
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http://dx.doi.org/10.1177/1093526616686233DOI Listing
June 2017

Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly.

Hum Mol Genet 2017 02;26(4):702-716

Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.

An infant presented with fatal infantile lactic acidosis and cardiomyopathy, and was found to have profoundly decreased activity of respiratory chain complex I in muscle, heart and liver. Exome sequencing revealed compound heterozygous mutations in NDUFB10, which encodes an accessory subunit located within the PD part of complex I. One mutation resulted in a premature stop codon and absent protein, while the second mutation replaced the highly conserved cysteine 107 with a serine residue. Protein expression of NDUFB10 was decreased in muscle and heart, and less so in the liver and fibroblasts, resulting in the perturbed assembly of the holoenzyme at the 830 kDa stage. NDUFB10 was identified together with three other complex I subunits as a substrate of the intermembrane space oxidoreductase CHCHD4 (also known as Mia40). We found that during its mitochondrial import and maturation NDUFB10 transiently interacts with CHCHD4 and acquires disulfide bonds. The mutation of cysteine residue 107 in NDUFB10 impaired oxidation and efficient mitochondrial accumulation of the protein and resulted in degradation of non-imported precursors. Our findings indicate that mutations in NDUFB10 are a novel cause of complex I deficiency associated with a late stage assembly defect and emphasize the role of intermembrane space proteins for the efficient assembly of complex I.
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http://dx.doi.org/10.1093/hmg/ddw431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251674PMC
February 2017

Distinct GATA1 Point Mutations in Monozygotic Twins With Down Syndrome and Transient Abnormal Myelopoiesis From a Triplet Pregnancy: A Case Report and Review of Literature.

Am J Clin Pathol 2016 Dec 27;146(6):753-759. Epub 2016 Dec 27.

From the Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora

Objectives: Down syndrome (DS)-associated transient abnormal myelopoiesis (TAM) or acute megakaryoblastic leukemia (AMKL) in monozygotic twins is exceedingly rare and has not been well characterized.

Methods: We describe a unique case of monozygotic twins with simultaneous TAM from a triplet pregnancy at 34 weeks' gestation. Previously reported cases of TAM and DS-AMKL in monozygotic twins have been reviewed to compare with our cases. The current concept of a sequential multistep process in leukemogenesis and disease evolution of TAM into DS-AMKL through the collaboration among trisomy 21, GATA1, and other gene mutations is also reviewed.

Results: Distinct GATA1 mutations are identified in our neonate twins with TAM from a triplet pregnancy, whereas precisely identical GATA1 mutations have been detected in all three monozygotic DS twins reported in the literature.

Conclusions: Identical GATA1 mutations in cases of monozygotic twins are likely derived from twin-twin transmission. Distinct GATA1 mutations identified in our neonate twins with TAM provide unequivocal evidence of independent intra-utero GATA1 mutations, a completely different mechanism of development of TAM in monozygotic twins from previously reported cases. Interaction of trisomy 21 and GATA1 mutation produces TAM, but additional gene mutations are required for TAM to transform into DS-AMKL.
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http://dx.doi.org/10.1093/ajcp/aqw190DOI Listing
December 2016

Multiregional analysis of global 5-methylcytosine and 5-hydroxymethylcytosine throughout the progression of Alzheimer's disease.

J Neurochem 2017 02;140(3):383-394

Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA.

Epigenetic modifications to cytosine are known to alter transcriptional states and deregulate gene expression in cancer, embryonic development, and most recently in neurodegeneration. To test the hypothesis that global levels of cytosine modification are altered throughout the progression of Alzheimer's disease, 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) were quantified using gas chromatography/mass spectrometry (GC/MS) and stable labeled internal standards of cytosine, 5-mC, and 5-hmC. Cytosine modifications were quantified in DNA extracted from tissue specimens of four brain regions (cerebellum, inferior parietal lobe, superior and middle temporal gyrus, and hippocampus/parahippocampal gyrus) of cognitively normal control (NC) subjects and subjects with mild cognitive impairment (MCI), preclinical Alzheimer's disease (PCAD), late onset Alzheimer's disease, frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB). Repeated measures analyses of the data show significant alterations in 5-mC and 5-hmC in early stages of Alzheimer's disease (PCAD and MCI), as well as FTLD and DLB subjects, across multiple regions of the brain. These data suggest alterations in epigenetic regulation of genes may play an early role in the progression of AD as well as other types of neurodegeneration.
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http://dx.doi.org/10.1111/jnc.13912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5250541PMC
February 2017

Key Histopathologic Features of Liver Biopsies That Distinguish Biliary Atresia From Other Causes of Infantile Cholestasis and Their Correlation With Outcome: A Multicenter Study.

Am J Surg Pathol 2016 12;40(12):1601-1615

*Department of Pathology and Laboratory Medicine, the Children's Hospital of Philadelphia, Philadelphia, PA ¶¶Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA Departments of †Surgery §§§Biostatistics, University of Michigan, Ann Arbor, MI ‡Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD §Division of Pediatric Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH ¶Department of Pathology, Indiana University School of Medicine, Indianapolis, IN #Department of Pathology, Texas Children's Hospital, Houston, TX **Department of Pathology, Seattle Children's Hospital, Seattle, WA ††Department of Pathology, University of California San Francisco, San Francisco, CA ***Department of Pathology, Children's Hospital Los Angeles, Los Angeles, CA ‡‡Department of Pathology, Children's Hospital Colorado, Aurora, CO §§Department of Pathology, Kravis Children's Hospital, Mount Sinai Health System, New York, NY ∥∥Department of Pathology, Ann & Robert H. Lurie Children's Hospital, Chicago, IL ##Department of Pathology, Children's Healthcare of Atlanta, Atlanta, GA †††Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO ‡‡‡Quest Diagnostics, Health Informatics, Madison, NJ ∥Division of Pathology, The Hospital of Sick Children, Toronto, ON, Canada.

The liver biopsy guides diagnostic investigation and therapy in infants with undiagnosed cholestasis. Histologic features in the liver may also have prognostic value in the patient with biliary atresia (BA). We assessed the relative value of histologic features in 227 liver needle biopsies in discriminating between BA and other cholestatic disorders in infants enrolled in a prospective Childhood Liver Disease Research Network (ChiLDReN) cohort study by correlating histology with clinical findings in infants with and without BA. In addition, we reviewed 316 liver biopsies from clinically proven BA cases and correlated histologic features with total serum bilirubin 6 months after hepatoportoenterostomy (the Kasai procedure, HPE) and transplant-free survival up to 6 years. Review pathologists were blinded to clinical information except age. Semiquantitative scoring of 26 discrete histologic features was based on consensus. Bile plugs in portal bile ducts/ductules, moderate to marked ductular reaction, and portal stromal edema had the largest odds ratio for predicting BA versus non-BA by logistic regression analysis. The diagnostic accuracy of the needle biopsy was estimated to be 90.1% (95% confidence interval [CI]: 85.2%, 94.9%), whereas sensitivity and specificity for a diagnosis of BA are 88.4% (95% CI: 81.4, 93.5) and 92.7% (95% CI: 84.8, 97.3), respectively. No histologic features were associated with an elevated serum bilirubin 6 months after HPE, although it (an elevated serum bilirubin) was associated with an older age at HPE. Higher stages of fibrosis, a ductal plate configuration, moderate to marked bile duct injury, an older age at HPE, and an elevated international normalized ratio were independently associated with a higher risk of transplantation.
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http://dx.doi.org/10.1097/PAS.0000000000000755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123664PMC
December 2016

A Novel Small Molecule Modulator of Amyloid Pathology.

J Alzheimers Dis 2016 05;53(1):273-87

Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.

Because traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer's disease.
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http://dx.doi.org/10.3233/JAD-151160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025774PMC
May 2016

Cavernous Hemangiomas of the Pediatric Calvaria.

Pediatr Neurosurg 2015 22;50(6):321-4. Epub 2015 Oct 22.

This series reports 2 pediatric cases of calvarial cavernous hemangioma (cavernoma, cavernous malformation) treated surgically at Children's Hospital Colorado between 2008 and 2010. Both cases presented as painless bony masses which enlarged over time. Both patients underwent surgical resection without complication and have remained recurrence free since surgery. Because so few cases have been reported among pediatric populations, little is known regarding the epidemiology and prognosis of calvarial cavernous hemangiomas in children. These cases represent interesting additions to the small body of literature on these rare tumors.
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http://dx.doi.org/10.1159/000439281DOI Listing
September 2016

A Novel Plasma Based Biomarker of Alzheimer's Disease.

J Alzheimers Dis 2015 ;47(3):761-71

Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA.

Specific biomarkers in a readily accessible biological fluid, such as blood, could aid in the identification, characterization, validation, and routine monitoring of Alzheimer's disease (AD) progression. In the current study, levels of the previously described novel cerebrospinal fluid aberrant protein complex composed of prostaglandin-D-synthase (PDS) and transthyretin (TTR) were quantified in plasma by a custom two-probe sandwich ELISA and compared to amyloid-β (Aβ)(1-42) as a standard plasma biomarker of AD. Plasma was analyzed from 140 probable AD subjects, 135 subjects with mild cognitive impairment (MCI), 74 normal control subjects (NC) prior to MCI transition, 23 diseased control (DC) subjects with either frontotemporal dementia or dementia with Lewy bodies, and 182 normal control (NC) subjects who did not progress to MCI or dementia. Levels of Aβ(1-42) were significantly elevated in NC subjects prior to MCI conversion but significantly reduced in probable AD subjects compared to NC subjects. Similarly, levels of the PDS-TTR complex were significantly reduced in both MCI and probable AD subjects compared to NC subjects. Furthermore, levels of Aβ(1-42) and the PDS-TTR complex were not significantly different in DC subjects compared to NC subjects. MMSE scores were weakly but significantly correlated with plasma levels of the PDS-TTR complex and Aβ(1-42). Trail B scores were weakly but significantly correlated with plasma levels of Aβ(1-42). Comparison of receiver operating curves shows the PDS-TTR complex is comparable to Aβ(1-42) in both MCI and probable AD subjects.
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http://dx.doi.org/10.3233/JAD-150183DOI Listing
July 2016

Calcium Channel Blockers, Progression to Dementia, and Effects on Amyloid Beta Peptide Production.

Oxid Med Cell Longev 2015 28;2015:787805. Epub 2015 Jun 28.

Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA ; Sanders-Brown Center on Aging and Alzheimer's Disease Center, University of Kentucky, Lexington, KY 40536, USA.

Previous epidemiologic studies suggest that antihypertensive drugs may be protective against cognitive decline. To determine if subjects enrolled in the University of Kentucky longitudinal aging study who used antihypertensive drugs showed diminished progression to dementia, we used a 3-parameter logistic regression model to compare the rate of progression to dementia for subjects who used any of the five common categories of antihypertensive drugs to those with similar demographic characteristics but who did not use antihypertensives. Regression modeling showed that subjects who used calcium channel blockers (CCBs) but not the other classes of antihypertensives showed a significant decrease in the rate of progression to dementia. Significantly, use of CCBs ameliorated the negative effects of the presence of APOE-4 alleles on cognitive decline. To determine if CCBs could minimize amyloid beta peptide (Aβ(1-42)) production, H4 neuroglioma cultures transfected to overexpress APP were treated with various CCBs and Aβ(1-42) levels and levels of proteins involved in Aβ production were quantified. Results show that treatment with nifedipine led to a significant decrease in levels of Aβ(1-42), with no significant decrease in cell viability. Collectively, these data suggest that use of CCBs significantly diminishes the rate of progression to dementia and may minimize formation of Aβ(1-42).
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http://dx.doi.org/10.1155/2015/787805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499419PMC
April 2016

Biomarkers of lipid peroxidation in Alzheimer disease (AD): an update.

Arch Toxicol 2015 Jul 18;89(7):1035-44. Epub 2015 Apr 18.

Sanders Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY, 40536-0230, USA.

Increasing evidence suggests that free radical-mediated oxidation of biological substrates is a key feature of Alzheimer's disease (AD) pathogenesis. While it has long been established that biomarkers of lipid peroxidation (LPO) are elevated in AD brain as well as ventricular CSF postmortem, more recent studies have demonstrated increased LPO biomarkers in postmortem brain from subjects with mild cognitive impairment, the earliest clinically detectable phase of dementia and preclinical AD, the earliest detectable pathological phase. Furthermore, multiple LPO biomarkers are elevated in readily accessible biological fluids throughout disease progression. Collectively, these studies demonstrate that LPO is an early feature during disease progression and may be considered a key pathway for targeted therapeutics as well as an enhancer of diagnostic accuracy for early detection of subjects during the prodromal phase.
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http://dx.doi.org/10.1007/s00204-015-1517-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466146PMC
July 2015

Mitochondrial energy failure in HSD10 disease is due to defective mtDNA transcript processing.

Mitochondrion 2015 Mar 6;21:1-10. Epub 2015 Jan 6.

Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA. Electronic address:

Muscle, heart and liver were analyzed in a male subject who succumbed to HSD10 disease. Respiratory chain enzyme analysis and BN-PAGE showed reduced activities and assembly of complexes I, III, IV, and V. The mRNAs of all RNase P subunits were preserved in heart and overexpressed in muscle, but MRPP2 protein was severely decreased. RNase P upregulation correlated with increased expression of mitochondrial biogenesis factors and preserved mitochondrial enzymes in muscle, but not in heart where this compensatory mechanism was incomplete. We demonstrate elevated amounts of unprocessed pre-tRNAs and mRNA transcripts encoding mitochondrial subunits indicating deficient RNase P activity. This study provides evidence of abnormal mitochondrial RNA processing causing mitochondrial energy failure in HSD10 disease.
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http://dx.doi.org/10.1016/j.mito.2014.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355277PMC
March 2015

Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas.

Am J Med Genet A 2015 Feb 26;167A(2):421-7. Epub 2014 Nov 26.

Department of Pediatrics, Children's Hospital Colorado, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.

We report on a young girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas. These features are similar to those reported in individuals with variant forms of orofaciodigital syndrome known as congenital heart defects, hamartomas of the tongue and polysyndactly (CHDHTP: OMIM 217085) [Örstavik et al., 1992] and orocardiodigital syndrome [Digilio et al., 1996]. Whole exome sequencing revealed that she is a compound heterozygote for a frame shift mutation and a likely pathogenic sequence variant in WDPCP, a gene that regulates planar cell polarity and ciliogenesis. Results of genotyping in her parents and unaffected siblings were consistent with autosomal recessive inheritance of the mutation and the WDPCP variant. These results suggest that disruption of planar cell polarity and ciliogenesis may result in this unusual form of orofaciodigital syndrome.
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http://dx.doi.org/10.1002/ajmg.a.36852DOI Listing
February 2015

Parapharyngeal and skull base yolk sac tumor: a case report with lessons in diagnosis and management.

Int J Pediatr Otorhinolaryngol 2014 Nov 28;78(11):2003-6. Epub 2014 Aug 28.

Department of Otolaryngology-Head and Neck Surgery, University of Colorado, Aurora, CO, United States.

Yolk sac tumors are rare in the head and neck. A previously healthy 2-year-old female presented with a large parapharyngeal mass. Pathology was pathognomonic for yolk sac tumor, with glandular differentiation and focal mucin production, which has not been reported in a yolk sac tumor. She was treated aggressively with chemotherapy followed by endoscopic exploration with planned resection, but no viable tumor was encountered. Yolk sac tumors can be difficult to diagnose in the head and neck, but complete clinical response can be achieved. New endoscopic approaches to skull base tumors are applicable to the pediatric population with some technical modifications.
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http://dx.doi.org/10.1016/j.ijporl.2014.08.027DOI Listing
November 2014

Cervical bronchogenic cysts: case report and review of the literature.

Am J Otolaryngol 2014 Sep-Oct;35(5):655-7. Epub 2014 Jul 10.

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA; Department of Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, USA.

Pediatric cervical masses can present a diagnostic dilemma given their broad differential diagnosis. We present a 3-year-old girl with a midline anterior neck mass found to have histopathologic findings consistent with a bronchogenic cyst. Although rare, bronchogenic cysts should be considered in the differential diagnosis in both lateral and anterior pediatric cervical masses as their pathophysiology and embryogenesis differ considerably from more common cervical masses. Imaging is an important aspect in the pre-operative work-up, although diagnosis is only made after histopathologic analysis. Complete surgical excision is the definitive treatment.
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http://dx.doi.org/10.1016/j.amjoto.2014.06.015DOI Listing
May 2015

Nasal congestion and a rapidly enlarging mass at the nasofacial junction.

JAMA Otolaryngol Head Neck Surg 2013 Sep;139(9):953-4

Baylor College of Medicine, Houston, Texas.

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http://dx.doi.org/10.1001/jamaoto.2013.4050DOI Listing
September 2013

Nucleic acid oxidation: an early feature of Alzheimer's disease.

J Neurochem 2014 Jan 21;128(2):294-304. Epub 2013 Oct 21.

Sanders-Brown Center on Aging and Alzheimer's Disease Center, University of Kentucky, Lexington, Kentucky, USA.

Studies of oxidative damage during the progression of Alzheimer's disease (AD) suggest its central role in disease pathogenesis. To investigate levels of nucleic acid oxidation in both early and late stages of AD, levels of multiple base adducts were quantified in nuclear and mitochondrial DNA from the superior and middle temporal gyri (SMTG), inferior parietal lobule (IPL), and cerebellum (CER) of age-matched normal control subjects, subjects with mild cognitive impairment, preclinical AD, late-stage AD, and non-AD neurological disorders (diseased control; DC) using gas chromatography/mass spectrometry. Median levels of multiple DNA adducts in nuclear and mitochondrial DNA were significantly (p ≤ 0.05) elevated in the SMTG, IPL, and CER in multiple stages of AD and in DC subjects. Elevated levels of fapyguanine and fapyadenine in mitochondrial DNA suggest a hypoxic environment early in the progression of AD and in DC subjects. Overall, these data suggest that oxidative damage is an early event not only in the pathogenesis of AD but is also present in neurodegenerative diseases in general. Levels of oxidized nucleic acids in nDNA and mtDNA were found to be significantly elevated in mild cognitive impairment (MCI), preclinical Alzheimer's disease (PCAD), late-stage AD (LAD), and a pooled diseased control group (DC) of frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) subjects compared to normal control (NC) subjects. Nucleic acid oxidation peaked early in disease progression and remained elevated. The study suggests nucleic acid oxidation is a general event in neurodegeneration.
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http://dx.doi.org/10.1111/jnc.12444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947319PMC
January 2014

4-Hydroxyhexenal (HHE) impairs glutamate transport in astrocyte cultures.

J Alzheimers Dis 2012 ;32(1):139-46

Department of Chemistry, University of Kentucky, Lexington, KY, USA.

Multiple studies show elevations of α,β-unsaturated aldehydic by-products of lipid peroxidation including 4-hydroxynonenal and acrolein in vulnerable brain regions of subjects throughout the progression of Alzheimer's disease (AD). More recently 4-hydroxyhexenal (HHE), a diffusible α,β-unsaturated aldehyde resulting from peroxidation of ω-3 polyunsaturated fatty acids, was shown to be elevated in the hippocampus/parahippocampal gyrus (HPG) of subjects with preclinical AD (PCAD) and in late stage AD (LAD). HHE treatment of primary rat cortical neuron cultures led to a time- and concentration-dependent decrease in survival and glucose uptake. To determine if HHE also impairs glutamate uptake, primary rat astrocyte cultures were exposed to HHE for 4 hours and glutamate transport measured. Results show subtoxic (2.5 μM) HHE concentrations significantly (p < 0.05) impair glutamate uptake in primary astrocytes. Immunoprecipitation of excitatory amino acid transporter-2 (EAAT-2), the primary glutamate transporter in brain, from normal control, mild cognitive impairment (MCI), PCAD, and LAD HPG followed by quantification of HHE immunolabeling showed a significant increase in HHE positive EAAT-2 in MCI and LAD HPG. Together these data suggest HHE can significantly impair glutamate uptake and may play a role in the pathogenesis of AD.
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http://dx.doi.org/10.3233/JAD-2012-120409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646088PMC
February 2013

Clinicopathological characteristics of extramedullary acute megakaryoblastic leukemia (AMKL): report of a case with initial mastoid presentation and review of literature to compare extramedullary AMKL and non-AMKL cases.

Pediatr Dev Pathol 2012 Sep-Oct;15(5):385-92. Epub 2012 Jun 5.

Department of Pediatric Otolaryngology, Children's Hospital Colorado, Aurora, CO, USA.

Extramedullary acute megakaryoblastic leukemia (AMKL) is a rare neoplasm with a varied clinical presentation. AMKL with initial mastoid presentation has never been reported. The extreme rarity of mastoid AMKL, together with the tendency of extramedullary AMKL to mimic other small blue cell tumors, can create a diagnostic challenge. We report a case of AMKL that initially presented as a mastoid lesion and provide a comprehensive review and analysis that compares the characteristics of extramedullary AMKL and nonmegakaryoblastic acute myeloid leukemia (AML) in reported pediatric cases over the past 30 years. We found that patients with extramedullary AMKL were not only younger than patients without megakaryocytic differentiation but were also limited to those ≤ 2 years of age. In addition, girls predominated in both AMKL and AML MLL(+) groups compared with other types of AML (P  =  0.0366 and P  =  0.0082). Furthermore, we found that extramedullary AMKL was more likely to involve bone than AML MLL(+) (P < 0.0001) or other types of AML (P  =  0.0002). These findings suggest that extramedullary AMKL should be considered in the differential diagnosis of SBCT in children, especially in patients with mastoid or other bony lesions, those ≤ 2 years of age, and female patients.
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http://dx.doi.org/10.2350/11-12-1124-CR.1DOI Listing
April 2013