Publications by authors named "Laura Chalmers"

22 Publications

  • Page 1 of 1

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

J Clin Endocrinol Metab 2020 05;105(5)

Clinical Research Branch, National Institute of Environmental Health Sciences, Durham, North Carolina.

Context: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.

Objective: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.

Methods: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.

Results: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient.

Conclusions: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.
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http://dx.doi.org/10.1210/clinem/dgaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108682PMC
May 2020

Values-based interprofessional education: how interprofessional education and values- based practice interrelate and are vehicles for the benefit of patients and health and social care professionals.

J Interprof Care 2020 Jul-Aug;34(4):569-571. Epub 2020 Feb 3.

Faculty of Health and Life Sciences, Oxford Brookes University , Oxford, UK.

The 2016 All Together Better Health VIII Oxford conference brought together interprofessional education (IPE) and values-based practice (VBP) communities. As there is a paucity of research and publications in the area, following the event a working party consisting of representatives from both communities continued to meet and has developed a joint community of practice. This report describes the work achieved by the group so far and is intended for those involved in the planning and implementation of IPE and collaborative working. The authors consider that incorporating principles of VBP within a framework of IPE can provide a different perspective and understanding of the complexities involved in delivering realistic, student centered learning for collaborative practice, relevant in the 21st century workplace. In particular the authors suggest that using the principles of values and VBP in this way can inform the transition between IPE and collaborative practice facilitating effective person centered collaborative care. This process will require not only the incorporation of these principles within IPE sessions, but also incorporation within the training and support of new and established teachers involved in IPE.
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http://dx.doi.org/10.1080/13561820.2020.1713065DOI Listing
February 2020

Technology for Augmenting Type 1 Diabetes Mellitus Management.

J Pediatr Pharmacol Ther 2019 Mar-Apr;24(2):99-106

Type 1 diabetes mellitus has witnessed significant progress in its management over the past several decades. This review highlights technologic advancements in type 1 diabetes management. Continuous glucose monitoring systems are now available at various functionality and cost levels, addressing diverse patient needs, including a recently US Food and Drug Administration (FDA)-approved implantable continuous glucose monitoring system (CGMS). Another dimension to these state-of-the-art technologies is CGMS and insulin pump integration. These integrations have allowed for CGMS-based adjustments to basal insulin delivery rates and suspension of insulin delivery when a low blood glucose event is predicted. This review also includes a brief discussion of upcoming technologies such as patch-based CGMS and insulin-glucagon dual-hormonal delivery.
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http://dx.doi.org/10.5863/1551-6776-24.2.99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478356PMC
April 2019

Evolving Pharmacotherapeutic Strategies for Type 1 Diabetes Mellitus.

J Pediatr Pharmacol Ther 2018 Sep-Oct;23(5):351-361

Despite pharmacotherapeutic advancements in the management of type 1 diabetes mellitus during the past several decades, patients struggle to achieve glycemic goals. Additionally, hypoglycemia, especially in extremes of age, decreases quality of life. The lack of optimal glycemic control and risk for hypoglycemia are multifactorial. Nevertheless, endeavors aiming to develop pharmacotherapeutic options with enhanced pharmacokinetic, pharmacodynamic, and clinical profiles continue. This review article discusses recent ventures in 3 categories of insulin, non-insulin, and glucagon products.
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http://dx.doi.org/10.5863/1551-6776-23.5.351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213629PMC
November 2018

Neonatal Diabetes: Case Report of a 9-Week-Old Presenting Diabetic Ketoacidosis Due to an Activating Gene Mutation.

J Investig Med High Impact Case Rep 2017 Jan-Mar;5(1):2324709617698718. Epub 2017 Mar 24.

The Children's Hospital at Saint Francis, Tulsa, OK, USA.

Neonatal diabetes mellitus, a rare condition occurring in approximately 1 in 500 000 live births, is defined as insulin-requiring hyperglycemia presenting in the first months of life. Neonatal diabetes can be transient or permanent, with studies characterizing the condition as a monogenic disorder. We describe a case of a 9-week-old infant with neonatal diabetes who presented in diabetic ketoacidosis due to a mutation affecting the gene that encodes the SUR1 subunit of the potassium ATP channel. This genetic diagnosis has therapeutic implications regarding the initiation of sulfonylurea administration as 85% of patients with neonatal diabetes due to gene mutations can be successfully treated with oral sulfonylurea treatment.
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http://dx.doi.org/10.1177/2324709617698718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433553PMC
March 2017

Epidermal stem cells: an update on their potential in regenerative medicine.

Expert Opin Biol Ther 2013 Jun 21;13(6):901-10. Epub 2013 Mar 21.

Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Trauma Center of Postgraduate Medical School, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853 , P. R. China.

Introduction: Adult epidermal stem cells are crucial for skin tissue regeneration during homeostasis and disease. Recent updates relating to the function, cellular role and properties of these cells have been published. Notably, a recent study showed that keratinocytes may possess a transcriptional profile that is more amenable to reprogramming and this may open new avenues for exploring novel strategies to create patient-specific cell therapies.

Areas Covered: In this paper, an overview of recent research pertaining to epidermal stem cells' properties and location, and their capacity for differentiation and transdifferentiation, as well as potential for tumorigenesis are presented.

Expert Opinion: More efforts should be made to develop effective approaches to induce lineage conversion between different cell types and tailor the treatment to specific patient, while minimizing cancer risk.
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http://dx.doi.org/10.1517/14712598.2013.776036DOI Listing
June 2013

A Molecular Link Between Interleukin 22 and Intestinal Mucosal Wound Healing.

Adv Wound Care (New Rochelle) 2012 Dec;1(6):231-237

Department of Dermatology, University of California Davis School of Medicine , Sacramento, California. ; Department of Ophthalmology, University of California Davis School of Medicine , Sacramento, California. ; Institute for Regenerative Cures, University of California Davis School of Medicine , Sacramento, California.

Background: Interleukin 22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) are two important regulators of inflammation. Crohn's disease and ulcerative colitis are considered inflammatory bowel diseases (IBDs), due to the belief that these diseases result from dysregulated responses of the intestinal immune system to bacteria present in the commensal flora.

The Problem: It is debated whether a breakdown of immune tolerance is the primary cause of these diseases or occurs downstream of an initial defect of the intestinal barrier and intestinal epithelial cells (IECs).

Basic/clinical Science Advances: Recent reports suggest a crucial role for IL-22 in the regulation of gut inflammation as well as epithelial barrier integrity. Local gene delivery enhances expression of its downstream effector, , within colonic epithelial cells and induces both STAT3-dependent expression of mucus-associated molecules and restitution of mucus-producing goblet cells. IEC-specific deletion of results in significant susceptibility to experimental colitis with a striking defect in epithelial restitution. STAT3 activation, thus, may regulate immune homeostasis in the gut by promoting IL-22-dependent mucosal wound healing.

Clinical Care Relevance: The importance of IL-22/STAT3 signaling in IEC wound healing suggests a critical role for epithelial homeostasis in IBDs.

Conclusion: Effective healing of the IECs could be considered a primary target in the development of treatments for IBDs. IL-22/STAT3 signaling exerts a protective role in the process of intestinal mucosal wound healing and may thereby provide a promising therapeutic approach to the treatment of IBDs.
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http://dx.doi.org/10.1089/wound.2011.0334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623586PMC
December 2012

Metabolic syndrome and arterial elasticity in youth.

Metabolism 2013 Mar 9;62(3):424-31. Epub 2012 Nov 9.

CMRI Diabetes and Metabolic Research Program, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.

Objective: To compare arterial elasticity in children, adolescents, and young adults with and without metabolic syndrome (MetS), and to assess which MetS components, demographic measures, and body composition measures are associated with arterial elasticity.

Materials/methods: Two-hundred six subjects (107 females and 99 males) between the ages of 10 and 20years were recruited by local newspaper advertisements, university email advertisements, and informational flyers. Subjects were assessed on MetS components, demographic measures, body composition measures, and arterial elasticity via radial tonometry. Forty-five subjects (22%) had MetS, as defined by the International Diabetes Federation, and 161 subjects (78%) did not.

Results: The primary novel finding was that group differences were not observed for large artery elasticity index (LAEI) (MetS=16.1±4.4 (ml×mmHg(-1))×10 (mean±SD), control=15.4±4.9, (ml×mmHg(-1))×10, p=0.349), and small artery elasticity index (SAEI) (MetS=9.2±2.7 (ml×mmHg(-1))×100, control=8.4±2.9, (ml×mmHg(-1))×100, p=0.063). In the MetS group, fat free mass was positively associated with arterial elasticity, and was the strongest multivariate predictor of LAEI (partial R(2)=0.41) and SAEI (partial R(2)=0.29).

Conclusions: Youth with MetS did not exhibit differences in LAEI and SAEI compared to controls. Furthermore, fat free mass of youth with MetS was positively associated with arterial elasticity, and was the strongest predictor of both LAEI and SAEI. The clinical implication is that exercise intervention designed to increase fat free mass might increase arterial elasticity in youth, particularly in youth with MetS.
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http://dx.doi.org/10.1016/j.metabol.2012.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572292PMC
March 2013

Electric fields guide migration of epidermal stem cells and promote skin wound healing.

Wound Repair Regen 2012 Nov-Dec;20(6):840-51. Epub 2012 Oct 19.

State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.

Migration of epidermal stem cells (EpSCs) into wounds may play an important role in wound healing. Endogenous electric fields (EFs) arise naturally at wounds. Consistent with previous reports, we measured outward electric currents at rat skin wounds using vibrating probes. Topical use of prostaglandin E2 significantly promoted wound healing. However, it is not known whether EpSCs respond to EFs. We first isolated and characterized EpSCs from rat skin. We then demonstrated that EpSCs isolated from the epidermis migrated directionally toward the cathode in EFs of 50-400 mV/mm. The directedness values increased in a dose- and time-dependent fashion. The migration speed of EpSCs was significantly increased in EFs. EFs induced asymmetric polymerization of intracellular F-actin and activation of the extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3-kinase (PI3K)/protein kinase B pathways. Inhibition of epidermal growth factor receptor, extracellular signal-regulated kinase 1/2, or PI3K significantly inhibited the cathodal distribution of F-actin and the electrotactic response of EpSCs. These data for the first time show that EpSCs possess obvious electrotaxis, in which the epidermal growth factor receptor-mitogen activated protein kinase-PI3K pathways are involved. These data thus suggest a novel aspect of electric signaling in wound healing-to stimulate and guide migration of EpSCs and to regulate wound healing.
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http://dx.doi.org/10.1111/j.1524-475X.2012.00829.xDOI Listing
April 2013

Metabolic syndrome and daily ambulation in children, adolescents, and young adults.

Med Sci Sports Exerc 2013 Jan;45(1):163-9

CMRI Diabetes and Metabolic Research Program, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.

Purposes: To compare daily ambulatory measures in children, adolescents, and young adults with and without metabolic syndrome and to assess which metabolic syndrome components, demographic measures, and body composition measures are associated with daily ambulatory measures.

Methods: Two-hundred fifty subjects between the ages of 10 and 30 yr were assessed on metabolic syndrome components, demographic and clinical measures, body fat percentage, and daily ambulatory strides, durations, and cadences during seven consecutive days. Of the 250 subjects, 45 had metabolic syndrome, as defined by the International Diabetes Federation.

Results: Subjects with metabolic syndrome ambulated at a slower daily average cadence than those without metabolic syndrome (13.6 ± 2.2 vs 14.9 ± 3.2 strides per minute; P = 0.012), and they had slower cadences for continuous durations of 60 min (P = 0.006), 30 min (P = 0.005), 20 min (P = 0.003), 5 min (P = 0.002), and 1 min (P = 0.001). However, the total amount of time spent ambulating each day was not different (P = 0.077). After adjustment for metabolic syndrome status, average cadence is linearly associated with body fat percentage (P < 0.001) and fat mass (P < 0.01). Group difference in average cadence was no longer significant after adjusting for body fat percentage (P = 0.683) and fat mass (P = 0.973).

Conclusions: Children, adolescents, and young adults with metabolic syndrome ambulate more slowly and take fewer strides throughout the day than those without metabolic syndrome, although the total amount of time spent ambulating is not different. Furthermore, the detrimental influence of metabolic syndrome on ambulatory cadence is primarily a function of body fatness.
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http://dx.doi.org/10.1249/MSS.0b013e3182699239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521853PMC
January 2013

Transition from pediatric to adult care for adolescents and young adults with a disorder of sex development.

J Pediatr Adolesc Gynecol 2012 Apr;25(2):155-7

Department of Psychology, Oklahoma State University, Stillwater, Oklahoma, USA.

Over the past twenty years, there has been an increasing awareness of the transition to adult-oriented health care in adolescents and young adults with a chronic illness. While general guidelines for health care transition have been established, some have called for illness-specific guidelines which are tailored to the needs of specific illness populations. The current paper sought to outline illness-specific guidelines for health care transition in adolescents and young adults with disorders of sex development based upon the recent American Academy of Pediatrics guidelines. We also suggest indicators of successful transition for adolescents and young adults with disorders of sex development as well as areas for future research.
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http://dx.doi.org/10.1016/j.jpag.2011.11.003DOI Listing
April 2012

Electric field-controlled directed migration of neural progenitor cells in 2D and 3D environments.

J Vis Exp 2012 Feb 16(60):3453. Epub 2012 Feb 16.

School of Dentistry, Cardiff Institute of Tissue Engineering & Repair, Cardiff University.

Endogenous electric fields (EFs) occur naturally in vivo and play a critical role during tissue/organ development and regeneration, including that of the central nervous system(1,2). These endogenous EFs are generated by cellular regulation of ionic transport combined with the electrical resistance of cells and tissues. It has been reported that applied EF treatment can promote functional repair of spinal cord injuries in animals and humans(3,4). In particular, EF-directed cell migration has been demonstrated in a wide variety of cell types(5,6), including neural progenitor cells (NPCs)(7,8). Application of direct current (DC) EFs is not a commonly available technique in most laboratories. We have described detailed protocols for the application of DC EFs to cell and tissue cultures previously(5,11). Here we present a video demonstration of standard methods based on a calculated field strength to set up 2D and 3D environments for NPCs, and to investigate cellular responses to EF stimulation in both single cell growth conditions in 2D, and the organotypic spinal cord slice in 3D. The spinal cordslice is an ideal recipient tissue for studying NPC ex vivo behaviours, post-transplantation, because the cytoarchitectonic tissue organization is well preserved within these cultures(9,10). Additionally, this ex vivo model also allows procedures that are not technically feasible to track cells in vivo using time-lapse recording at the single cell level. It is critically essential to evaluate cell behaviours in not only a 2D environment, but also in a 3D organotypic condition which mimicks the in vivo environment. This system will allow high-resolution imaging using cover glass-based dishes in tissue or organ culture with 3D tracking of single cell migration in vitro and ex vivo and can be an intermediate step before moving onto in vivo paradigms.
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http://dx.doi.org/10.3791/3453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376928PMC
February 2012

A model of delivering multi-disciplinary care to people with 46 XY DSD.

J Pediatr Urol 2012 Feb 9;8(1):7-16. Epub 2011 Nov 9.

Pediatric Urology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

In 2006, a consensus statement was jointly produced by the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society of Paediatric Endocrinology (ESPE) concerning the management of disorders of sex development (DSD) [1]. A recommendation provided by this consensus was that evaluation and long-term care for people affected by DSD should be performed at medical centers with multi-disciplinary teams experienced in such conditions. Here we provide our team's interpretation of the 2006 consensus statement recommendations and its translation into a clinical protocol for individuals affected by 46 XY DSD with either female, or ambiguous, genitalia at birth. Options for medical and surgical management, transitioning of care, and the use of mental health services and peer support groups are discussed. Finally, we provide preliminary data to support the application of our model for delivering multi-disciplinary care and support to patients and their families.
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http://dx.doi.org/10.1016/j.jpurol.2011.08.013DOI Listing
February 2012

Electrical signaling in control of ocular cell behaviors.

Prog Retin Eye Res 2012 Jan 17;31(1):65-88. Epub 2011 Oct 17.

Department of Dermatology, UC Davis School of Medicine, 2921 Stockton Blvd., Sacramento, CA 95817, USA.

Epithelia of the cornea, lens and retina contain a vast array of ion channels and pumps. Together they produce a polarized flow of ions in and out of cells, as well as across the epithelia. These naturally occurring ion fluxes are essential to the hydration and metabolism of the ocular tissues, especially for the avascular cornea and lens. The directional transport of ions generates electric fields and currents in those tissues. Applied electric fields affect migration, division and proliferation of ocular cells which are important in homeostasis and healing of the ocular tissues. Abnormalities in any of those aspects may underlie many ocular diseases, for example chronic corneal ulcers, posterior capsule opacity after cataract surgery, and retinopathies. Electric field-inducing cellular responses, termed electrical signaling here, therefore may be an unexpected yet powerful mechanism in regulating ocular cell behavior. Both endogenous electric fields and applied electric fields could be exploited to regulate ocular cells. We aim to briefly describe the physiology of the naturally occurring electrical activities in the corneal, lens, and retinal epithelia, to provide experimental evidence of the effects of electric fields on ocular cell behaviors, and to suggest possible clinical implications.
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http://dx.doi.org/10.1016/j.preteyeres.2011.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242826PMC
January 2012

Normal sex differences in prenatal growth and abnormal prenatal growth retardation associated with 46,XY disorders of sex development are absent in newborns with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Biol Sex Differ 2011 May 5;2. Epub 2011 May 5.

Department of Pediatrics, The University of Oklahoma College of Medicine-Tulsa, Tulsa, OK 74135, USA.

Background: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is the most common presentation of a disorder of sex development (DSD) in genetic females. A report of prenatal growth retardation in cases of 46,XY DSD, coupled with observations of below-optimal final height in both males and females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, prompted us to investigate prenatal growth in the latter group. Additionally, because girls with congenital adrenal hyperplasia are exposed to increased levels of androgens in the absence of a male sex-chromosome complement, the presence or absence of typical sex differences in growth of newborns would support or refute a hormonal explanation for these differences.

Methods: In total, 105 newborns with congenital adrenal hyperplasia were identified in our database. Gestational age (weeks), birth weight (kg), birth length (cm) and parental heights (cm) were obtained. Mid-parental height was considered in the analyses.

Results: Mean birth weight percentile for congenital adrenal hyperplasia was 49.26%, indicating no evidence of a difference in birth weight from the expected standard population median of 50th percentile (P > 0.05). The expected sex difference in favor of heavier males was not seen (P > 0.05). Of the 105 subjects, 44 (27%; 34 females, 10 males) had birth length and gestational age recorded in their medical chart. Mean birth length for this subgroup was 50.90 cm (63rd percentile), which differed from the expected standard population median of 50th percentile (P = 0.0082). The expected sex difference in favor of longer males was also not seen (P > 0.05).

Conclusion: The prenatal growth retardation patterns reported in cases of 46,XY disorders of sex development do not generalize to people with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Sex differences in body weight and length typically seen in young infants were not seen in the subjects who participated in this study. We speculate that these differences were ameliorated in this study because of increased levels of prenatal androgens experienced by the females infants.
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http://dx.doi.org/10.1186/2042-6410-2-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113712PMC
May 2011

Paradoxical increase in arterial compliance in obese pubertal children.

Angiology 2011 Oct 18;62(7):565-70. Epub 2011 Mar 18.

CMRI Diabetes and Metabolic Research Program, Section of Diabetes/Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

We determined whether arterial compliance measured by pulse wave analysis is impaired in obese pubertal children compared to normal weight controls, and assessed whether arterial compliance is associated with ambulatory activity. Body fat percentage was significantly different between the normal (n = 33) and obese (n = 34) participants (P < .001). Large (P = .012) and small (P < .001) arterial compliance were lower in the normal-weight group. After adjusting for height, systolic and diastolic blood pressure, race, sex, and Tanner stage, large arterial compliance was no longer different between groups (P = .066), whereas small arterial compliance remained higher in the obese group (P < .001). Obese pubertal children have paradoxically increased small arterial compliance compared to that of normal weight children, even after adjusting for height, blood pressure, race, sex, and Tanner stage. Thus, obesity in adolescence is not associated with impairments in small arterial compliance.
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http://dx.doi.org/10.1177/0003319711399117DOI Listing
October 2011

An Evidence-Based Model of Multidisciplinary Care for Patients and Families Affected by Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency.

Int J Pediatr Endocrinol 2010 18;2010:692439. Epub 2010 Mar 18.

Pediatric Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

In 2002 a consensus statement pertaining to the management of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency was jointly produced by the Lawson Wilkins Pediatric Endocrine Society and the European Society of Pediatric Endocrinology. One of the recommendations of this consensus was that centers should maintain multidisciplinary teams for providing care and support to these patients and their families. However, the specifics for how this should be accomplished were not addressed in the original consensus statement. Here we interpret and translate the 2002 consensus statement recommendations into medical, surgical and mental health protocols. Additionally, we provide preliminary evidence that such protocols result in improved care and support for patients and families.
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http://dx.doi.org/10.1155/2010/692439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842898PMC
July 2011

Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism.

J Am Coll Cardiol 2009 Sep;54(14):1309-16

Department of Medicine, University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104, USA.

Objectives: We studied activating autoantibodies to beta-1 adrenergic receptors (AAbeta1AR) and activating autoantibodies to M2 muscarinic receptors (AAM2R) in the genesis of atrial fibrillation (AF) in Graves' hyperthyroidism.

Background: Atrial fibrillation frequently complicates hyperthyroidism. Both AAbeta1AR and AAM2R have been described in some patients with dilated cardiomyopathy and AF. We hypothesized that their copresence would facilitate AF in autoimmune Graves' hyperthyroidism.

Methods: Immunoglobulin G purified from 38 patients with Graves' hyperthyroidism with AF (n=17) or sinus rhythm (n=21) and 10 healthy control subjects was tested for its effects on isolated canine Purkinje fiber contractility with and without atropine and nadolol. Immunoglobulin G electrophysiologic effects were studied using intracellular recordings from isolated canine pulmonary veins. Potential cross-reactivity of AAbeta1AR and AAM2R with stimulating thyrotropin receptor (TSHR) antibodies was evaluated before and after adsorption to Chinese hamster ovary cells expressing human TSHRs using flow cytometry and enzyme-linked immunosorbent assays.

Results: The frequency of AAbeta1AR and/or AAM2R differed significantly between patients with AF and sinus rhythm (AAbeta1AR=94% vs. 38%, p<0.001; AAM2R=88% vs. 19%, p<0.001; and AAbeta1AR+AAM2R=82% vs. 10%, p<0.001). The copresence of AAbeta1AR and AAM2R was the strongest predictor of AF (odds ratio: 33.61, 95% confidence interval: 1.17 to 964.11, p=0.04). Immunoglobulin G from autoantibody-positive patients induced hyperpolarization, decreased action potential duration, enhanced early afterdepolarization formation, and facilitated triggered firing in pulmonary veins by local autonomic nerve stimulation. Immunoadsorption studies showed that AAbeta1AR and AAM2R were immunologically distinct from TSHR antibodies.

Conclusions: When present in patients with Graves' hyperthyroidism, AAbeta1AR and AAM2R facilitate development of AF.
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http://dx.doi.org/10.1016/j.jacc.2009.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801559PMC
September 2009

Prolongation of growth by treatment of 11-hydroxylase deficiency with depot-leuprolide, growth hormone, and hydrocortisone.

J Pediatr Endocrinol Metab 2006 Oct;19(10):1251-5

Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104 , USA.

A 4-10/12 year-old boy presented with tall stature and advanced secondary sexual characteristics. His bone age was 13 years giving him a height prediction of 147 cm. An initial 11-deoxycortisol level of 13,770 ng/dl and associated hypertension suggested the diagnosis of 11-hydroxylase deficiency, which was confirmed by dexamethasone suppression and genotyping. Treatment strategy was based on the premise that known hypothalamic priming resulting in early pubertal development could be averted by delaying puberty with leuprolide; also that effects of hydrocortisone and leuprolide on attenuating growth could be counteracted by growth hormone. The combined treatment resulted in a final height at age 12 years which was 25.4 cm greater than predicted, and bone density above average. We conclude that delaying puberty until an appropriate age, offsetting growth suppression, and improving bone mineralization can be effectively achieved using glucocorticoids, leuprolide and growth hormone in patients with 11-hydroxylase deficiency.
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http://dx.doi.org/10.1515/jpem.2006.19.10.1251DOI Listing
October 2006

The role of obesity and its bioclinical correlates in the progression of chronic kidney disease.

Adv Chronic Kidney Dis 2006 Oct;13(4):352-64

Department of Pediatrics, Oklahoma University Health Science Center, Oklahoma City, OK 73104, USA.

In spite of a progressive fall in the incidence of traditional risk factors of cardiovascular morbidity (cigarette smoking, high blood pressure, and hyperlipidemia), there is an upward trend in the prevalence of obesity and chronic kidney disease (CKD). Furthermore, there is a strong correlation between body mass indices and the relative risk of progression of CKD. The close biophysiological interaction between obesity and CKD is evident by a similar occurrence of comorbidities including insulin resistance, hyperlipidermia, endothelial dysfunction, and sleep disorders. Truncal obesity is a primary component of metabolic syndrome; unlike peripheral fat, the visceral adipocytes are more resistant to insulin. In addition, lipolysis results in a release of free fatty acid and TG, whereas hypertriglycedemia is potentiated by uremic activation of fatty acid synthase. Hypertriglycedemia and low HDL cholesterol increase the relative risk of progression of CKD. Furthermore, endothelial inflammation and premature atherosclerosis are promoted by hyperhomocysteinemia and oxidation of LDL, both of which are commonly observed in CKD and obesity. Predominance of oxidative stress in both obesity and azotemia stimulate synthesis of angiotensin II, which in turn increases TGF-B and plasminogen activator inhibitor-1, thereby propagating glomerular fibrosis. Furthermore, local synthesis of angiotensinogen by adipocytes, leptin activation of sympathetic nervous system, and hyperinsulinemia contribute to the development of hypertension in obesity and CKD. In addition, increased renal tubular expression of Na-K-ATPase and a blunted response to natiuretic hormones in obesity promote salt and water retention. Glomerular hyperfiltration from systemic volume load and hypertension results in mesangial cellular proliferation and progressive renal fibrosis. In addition, maternal nutritional deprivation increases the incidence of obesity, hypertension, and diabetes in adulthood. Reduced fetal protein synthesis contributes to oxidative glomerular injury and impairment of renal morphogenesis. Thus, kidneys are poorly equipped to handle physiologic stress that may result from the rapid body growth and programmed metabolic dysfunction later in life. Finally, in order to minimize morbidity of obesity-related kidney disease, preventive strategy must include optimal maternal health care, promotion of healthy nutrition and routine physical exercise, and early detection of CKD.
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http://dx.doi.org/10.1053/j.ackd.2006.07.010DOI Listing
October 2006

Type 2 diabetes in children: oxymoron or medical metamorphosis?

Pediatr Ann 2005 Sep;34(9):686-97

Section of Diabetes and Endocrinology, Department of Pediatrics, University of Oklahoma Health Science Center, Oklahoma City 73104, USA.

The full public health effects of the new epidemic of obesity and diabetes in children and adolescents may not be known for many years but are certain to be substantial. Diagnosed diabetes, which is present in only 4.2% of the US population, along with its consequences, already represents approximately 19% of the total personal healthcare expenditures in this country. Between 1997 and 2002, the estimated direct medical cost of diabetes increased from 44 billion dollars to 92 billion dollars, a staggering increase of 8 billion dollars a year. In 2002, diabetes annual costs per capita rose by more than 30% to 13,243 dollars per person, compared with the average annual health care costs for persons without diabetes of 2560.92 dollars. An estimate from the CDC indicates that approximately one-third of children born in 2000 will develop diabetes at some time in their life, and nearly one-half of all Hispanic children born in 2000 will develop diabetes. As type 2 diabetes is being diagnosed at an earlier age, more young people can expect to live many more years with diabetes and its complications, adding even further to this already enormous health burden. An appropriate starting place is recognition of the magnitude of the problem by physicians, politicians, public health policy makers, and other healthcare workers. An aggressive approach to management of diabetes must begin well before the appearance of cardiovascular, eye, renal, and other complications of diabetes appear, and even before obesity leads to diabetes. Currently, physicians and other healthcare workers are poorly reimbursed for management of obesity, for diabetes education, and for ongoing telephone contact with diabetic patients and families, essential for optimal diabetes management. National policies and priorities must be readjusted to emphasize prevention, rather than crisis management, if we are to avoid a catastrophic public health crisis within the next several decades.
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http://dx.doi.org/10.3928/0090-4481-20050901-09DOI Listing
September 2005