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Design, synthesis and in vitro and in vivo evaluation of an 18F-labeled sphingosine 1-phosphate receptor 1 (S1P1) PET tracer. - Journal of medicinal chemistry
Sphingosine 1-phosphate receptor 1 (S1P1) plays a pivotal role in inflammatory response and has been identified as a therapeutic target for various diseases. Fifteen new compounds were synthesized and their in vitro binding affinities were measured. Four compounds had high affinity and selectivity for S1P1 (IC50 < 10 nM, > 100-fold for S1P1 over S1P2 and S1P3). The most potent ligand, [18F]28c (IC50 = 2.63 nM for S1P1) was radiolabeled and evaluated in a mouse model of LPS-induced acute liver injury to demonstrate its in vivo S1P1-binidng specificity. The results from biodistribution, autoradiography, and microPET imaging showed higher accumulation of [18F]28c in the injured liver in response to the increased expression of S1P1 that was confirmed by immunohistochemistry. These data suggest that [18F]28c is a S1P1-specific radiotracer which has high potential for imaging S1P1 in vivo.
PET Imaging Study of S1PR1 Expression in a Rat Model of Multiple Sclerosis. - Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging
Upregulation of sphingosine-1-phosphate receptor 1 (S1PR1) expression in multiple sclerosis (MS) lesions is associated with neuroinflammatory response. This study investigated the correlation between neuroinflammation and S1PR1 expression in the spinal cord of an experimental autoimmune encephalomyelitis (EAE) rat model of MS, using the S1PR1 positron emission tomography (PET) radiotracer [(11)C]TZ3321.MicroPET imaging studies of [(11)C]TZ3321 were performed to measure uptake of [(11)C]TZ3321 in the spinal cord of EAE rats. Immunohistochemical staining was performed to confirm the overexpression of S1PR1 and other inflammatory biomarkers.MicroPET imaging demonstrated a 20-30Â % increase in [(11)C]TZ3321 uptake in the lumbar spinal cord of EAE rats versus sham controls at 35-60Â min post injection. The increased uptake of [(11)C]TZ3321 was correlated with the overexpression of S1PR1 in the lumbar spinal cord of EAE rats that was confirmed by immunohistochemical staining. Upregulated S1PR1 expression was associated with glial cell activation and immune cell infiltration.MicroPET imaging modality with a specific radioligand [(11)C]TZ3321 is able to assess the expression of S1PR1 in EAE rat lumbar spinal cord. This may provide a new approach to the assessment of neuroinflammatory response in MS and other inflammatory diseases.
A promising carbon-11-labeled sphingosine-1-phosphate receptor 1-specific PET tracer for imaging vascular injury. - Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology
Sphingosine-1-phosphate receptor 1 (S1PR1) is highly expressed in vascular smooth muscle cells from intimal lesions. PET imaging using S1PR1 as a biomarker would increase our understanding of its role in vascular pathologies including in-stent restenosis.The S1PR1 compound TZ3321 was synthesized for in vitro characterization and labeled with Carbon-11 for in vivo studies. The biodistribution of [(11)C]TZ3321 was evaluated in normal mice; microPET and immunohistochemistry (IHC) studies were performed using a murine femoral artery wire-injury model of restenosis.The high potency of TZ3321 for S1PR1 (IC 50Â =Â 2.13Â Â±Â 1.63Â nM), and high selectivity (>1000Â nM) for S1PR1 over S1PR2 and S1PR3 were confirmed. Biodistribution data revealed prolonged retention of [(11)C]TZ3321 in S1PR1-enriched tissues. MicroPET imaging of [(11)C]TZ3321 showed higher uptake in the wire-injured arteries of ApoE(-/-) mice than in injured arteries of wild-type mice (SUV 0.40Â Â±Â 0.06 vs 0.28Â Â±Â 0.04, nÂ =Â 6, PÂ <Â .001); FDG-PET showed no difference (SUV 0.98Â Â±Â 0.04 vs 0.94Â Â±Â 0.01, nÂ =Â 6, PÂ >Â .05). Post-PET autoradiography showed >4-fold higher [(11)C]TZ3321 retention in the injured artery of ApoE(-/-) mice than in wild-type mice. Subsequent IHC staining confirmed higher expression of S1PR1 in the neointima of the injured artery of ApoE(-/-) mice than in wild-type mice.This preliminary study supports the potential use of PET for quantification of the S1PR1 expression as a biomarker of neointimal hyperplasia.
In Pursuit of Meaningful Use of Learning Goals in Residency: A Qualitative Study of Pediatric Residents. - Academic medicine : journal of the Association of American Medical Colleges
Medical education aims to equip physicians for lifelong learning, an objective supported by the conceptual framework of self-regulated learning (SRL). Learning goals have been used to develop SRL skills in learners across the medical education continuum. This study's purpose was to elicit residents' perspectives on learning goal use and to develop explanations suggesting how aspects of the learning environment may facilitate or hinder the meaningful use of learning goals in residency.Resident focus groups and program director interviews were conducted in 2012-2013, audio-recorded, and transcribed. Programs were selected to maximize diversity of size, geographic location, type of program, and current use of learning goals. Data were analyzed using the constant comparative method associated with grounded theory. Further analysis compared themes frequently occurring together to strengthen the understanding of relationships between the themes. Through iterative discussions, investigators built a grounded theory.Ninety-five third-year residents and 12 program directors at 12 pediatric residency programs participated. The analysis identified 21 subthemes grouped into 5 themes: program support, faculty roles, goal characteristics and purposes, resident attributes, and accountability and goal follow-through. Review of relationships between the themes revealed a pyramid of support with program support as the foundation that facilitates the layers above it, leading to goal follow-through.Program support facilitates each step of the SRL process that leads to meaningful use of learning goals in residency. A strong foundation of program support should include attention to aspects of the implicit curriculum as well as the explicit curriculum.
A potent and selective C-11 labeled PET tracer for imaging sphingosine-1-phosphate receptor 2 in the CNS demonstrates sexually dimorphic expression. - Organic & biomolecular chemistry
Sphingosine-1-phosphate receptor 2 (S1PR2) plays an essential role in regulating blood-brain barrier (BBB) function during demyelinating central nervous system (CNS) disease. Increased expression of S1PR2 occurs in disease-susceptible CNS regions of female versus male SJL mice and in female multiple sclerosis (MS) patients. Here we reported a novel sensitive and noninvasive method to quantitatively assess S1PR2 expression using a C-11 labeled positron emission tomography (PET) radioligand [(11)C]5a for in vivo imaging of S1PR2. Compound 5a exhibited promising binding potency with IC50 value of 9.52 Â± 0.70 nM for S1PR2 and high selectivity over S1PR1 and S1PR3 (both IC50 > 1000 nM). [(11)C]5a was synthesized in âˆ¼40 min with radiochemistry yield of 20 Â± 5% (decayed to the end of bombardment (EOB), n > 10), specific activity of 222-370 GBq Î¼mol(-1) (decayed to EOB). The biodistribution study in female SJL mice showed the cerebellar uptake of radioactivity at 30 min of post-injection of [(11)C]5a was increased by Cyclosporin A (CsA) pretreatment (from 0.84 Â± 0.04 ID% per g to 2.21 Â± 0.21 ID% per g, n = 4, p < 0.01). MicroPET data revealed that naive female SJL mice exhibited higher cerebellar uptake compared with males following CsA pretreatment (standardized uptake values (SUV) 0.58 Â± 0.16 vs. 0.48 Â± 0.12 at 30 min of post-injection, n = 4, p < 0.05), which was consistent with the autoradiographic results. This data suggested that [(11)C]5a had the capability in assessing the sexual dimorphism of S1PR2 expression in the cerebellum of the SJL mice. The development of radioligands for S1PR2 to identify a clinical suitable S1PR2 PET radiotracer, may greatly contribute to investigating sex differences in S1PR2 expression that contribute to MS subtype and disease progression and it will be very useful for detecting MS in early state and differentiating MS with other patients with neuroinflammatory diseases, and monitoring the efficacy of treating diseases using S1PR2 antagonism.
A practical process for the preparation of [(32)P]S1P and binding assay for S1P receptor ligands. - Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine
Sphingosine-1-phosphate receptors (S1PRs) are important regulators of vascular permeability, inflammation, angiogenesis and vascular maturation. Identifying a specific S1PR PET radioligand is imperative, but it is hindered by the complexity and variability of current for binding affinity measurement procedures. Herein, we report a streamlined protocol for radiosynthesis of [(32)P]S1P with good radiochemical yield (36-50%) and high radiochemical purity (>99%). We also report a reproducible procedure for determining the binding affinity for compounds targeting S1PRs in vitro.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
Measuring pediatric resident competencies in adolescent medicine. - The Journal of adolescent health : official publication of the Society for Adolescent Medicine
To compare third-year pediatric resident competence on an adolescent medicine with competence in treating younger children.The participants were third-year residents (2010 [nÂ = 24] and 2011 [nÂ = 23]) at University of Colorado School of Medicine. Resident competence was measured in the domains of professionalism, communication, and history-taking skills in a multicase Objective Structured Clinical Examination.Percent correct scores in professionalism, history-taking, and communication skills on the adolescent case ranked in the bottom half of cases in both years. T-tests comparing mean score difference between the adolescent case and pediatric cases combined were statistically significant for professionalism (79.57 Â± 4.15 vs. 89.51 Â± 14.14, pÂ = .01) and history taking (66.27 Â± 11.02 vs. 75.10 Â± 18.40, pÂ = .05).Resident's history taking addressed immediate issues but not public health issues with adolescents. The professionalism findings suggest that residents engage in less patient-centered care when caring for adolescents, even while their communication skills remain on par.Copyright Â© 2014 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.
Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. - Pediatrics
We previously reported decreased transfusions and donor exposures in preterm infants randomized to Darbepoetin (Darbe) or erythropoietin (Epo) compared with placebo. As these erythropoiesis-stimulating agents (ESAs) have shown promise as neuroprotective agents, we hypothesized improved neurodevelopmental outcomes at 18 to 22 months among infants randomized to receive ESAs.We performed a randomized, masked, multicenter study comparing Darbe (10 Î¼g/kg, 1Ã—/week subcutaneously), Epo (400 U/kg, 3Ã—/week subcutaneously), and placebo (sham dosing 3Ã—/week) given through 35 weeks' postconceptual age, with transfusions administered according to a standardized protocol. Surviving infants were evaluated at 18 to 22 months' corrected age using the Bayley Scales of Infant Development III. The primary outcome was composite cognitive score. Assessments of object permanence, anthropometrics, cerebral palsy, vision, and hearing were performed.Of the original 102 infants (946 Â± 196 g, 27.7 Â± 1.8 weeks' gestation), 80 (29 Epo, 27 Darbe, 24 placebo) returned for follow-up. The 3 groups were comparable for age at testing, birth weight, and gestational age. After adjustment for gender, analysis of covariance revealed significantly higher cognitive scores among Darbe (96.2 Â± 7.3; mean Â± SD) and Epo recipients (97.9 Â± 14.3) compared with placebo recipients (88.7 Â± 13.5; P = .01 vs ESA recipients) as was object permanence (P = .05). No ESA recipients had cerebral palsy, compared with 5 in the placebo group (P < .001). No differences among groups were found in visual or hearing impairment.Infants randomized to receive ESAs had better cognitive outcomes, compared with placebo recipients, at 18 to 22 months. Darbe and Epo may prove beneficial in improving long-term cognitive outcomes of preterm infants.Copyright Â© 2014 by the American Academy of Pediatrics.
Copper- and palladium-catalyzed amidation reactions for the synthesis of substituted imidazo[4,5-c]pyridines. - The Journal of organic chemistry
Imidazo[4,5-c]pyridines were synthesized in three steps utilizing a palladium-catalyzed amidation/cyclization strategy. N-Aryl substrates were synthesized using copper-catalyzed amidation of 3-amino-N-Boc-4-chloropyridine. Complementary protocols for the selective chlorination of imidazo[4,5-c]pyridines at the C2 and C7 positions were also developed.
A longitudinal career-focused block for third-year pediatrics residents. - Journal of graduate medical education
The traditional 1-month training blocks in pediatrics may fail to provide sufficient exposure to develop the knowledge, skills, and attitudes residents need for practice and may not be conducive to mentoring relationships with faculty and continuity with patients.We created a 4-month career-focused experience (CFE) for third-year residents. The CFE included block time and longitudinal experiences in different content areas related to residents' choice of urban and rural primary care, hospitalist medicine, or subspecialty care (prefellowship). Content was informed by graduate surveys, focus groups with primary care pediatricians and hospitalists, and interviews with fellowship directors. Outcomes were assessed via before and after surveys of residents' attitudes and skills, assessment of skills with an objective structured clinical examination (OSCE), and interviews with residents and mentors.Twenty-three of 49 third-year residents took part in the first 2Â years of CFE. Two residents dropped out, leaving 21 who completed the 4-month experience (9 in primary care, 2 in hospitalist medicine, and 10 in a subspecialty). Residents reported improvement in their clinical skills, increased satisfaction with faculty mentoring and evaluation, and the ability to focus on what was important to their careers. OSCE performance did not differ between residents who completed the CFE and those who did not. Administrative burden was high.Four-month career-focused training for pediatrics residents is feasible and may be effective in meeting part of the new requirement for 6Â months of career-focused training during pediatrics residency.
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13123 E 16Th Ave Aurora, CO 80045
12605 E 16Th Ave
13123 E 16Th Ave