18 results on '"Motaghedi R"'
Search Results
2. Validity and Reliability Assessment of the Persian Version of Therapy-Related Symptom Checklist.
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Mansouri A, Motaghedi R, Rashidian A, Ashouri A, Kagrar M, Hajibabaei M, Gholami K, and Ansari S
- Abstract
Therapy-related symptom checklist for children (TRSC-C) was developed as a symptom assessment tool in children receiving chemotherapy. The objective of the present study was to evaluate the validity and reliability of the Persian version of TRSC-C. This cross-sectional study was conducted in 2013-2014 in Tehran, Iran. TRSC-C was translated using backward-forward approach. The content validity, face validity, and comprehensiveness were investigated based on the opinion of experts. The item content validity index (I-CVI) and scale content validity index (S-CVI) were calculated by the mean approach and inter-rater agreement. The scale was revised based on the comments from a team of five experts, after which it was evaluated by an additional group of four experts. To assess the inter-rater reliability, two raters filled the scale with 29 and 30 patients in the outpatient clinic of Hazrat-e Ali Asghar Hospital. The Cronbach's alpha was calculated and factor analysis was performed. The scores of content validity were analyzed in Excel. Other statistical analyses were performed using the SPSS software version 20.0. Based on the initial assessment, the S-CVI with less conservative approach was 60% for clarity, 33% for relevancy, and 60% for simplicity. After revising the scale, the S-CVI reached 100%. The comprehensiveness and face validity of the scale were appropriate. The scale was inter-rater reliable and the Cronbach's alpha was 0.803. Eleven subscales were found in the TRSC-C. It is concluded that the Persian TRSC-C is a valid and reliable tool for measuring children symptoms. Availability of a valid and reliable checklist is a fundamental step in monitoring the symptoms of patients while receiving chemotherapy.
- Published
- 2017
3. Effect of Marijuana Use on Thyroid Function and Autoimmunity.
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Malhotra S, Heptulla RA, Homel P, and Motaghedi R
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- Adolescent, Adult, Aged, Autoantibodies immunology, Autoantigens immunology, Autoimmunity immunology, Cross-Sectional Studies, Female, Humans, Hypothyroidism blood, Hypothyroidism immunology, Iodide Peroxidase immunology, Iron-Binding Proteins immunology, Male, Marijuana Use blood, Marijuana Use immunology, Middle Aged, Nutrition Surveys, Odds Ratio, Thyroiditis, Autoimmune blood, Thyroiditis, Autoimmune immunology, Thyrotropin blood, United States epidemiology, Young Adult, Hypothyroidism epidemiology, Marijuana Use epidemiology, Thyroiditis, Autoimmune epidemiology
- Abstract
Background: Marijuana is legalized for medical use in 24 states and for recreational use in 5. However, effects of marijuana use on thyroid function and autoimmunity are unknown., Methods: We performed a cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2012 to assess the effects of marijuana on thyroid function and autoimmunity in users. We included 5280 adults ages 18 to 69 years, who responded to questions related to marijuana use and had laboratory results related to thyroid parameters. Subjects were categorized as nonusers (never used), past users (used prior to 30 days ago), and recent users (used within last 30 days). Using NHANES normative cut offs for thyroid parameters, we compared recent users with nonusers and past users and calculated the odds ratios for the relative rate of clinically significant thyroid dysfunction in those groups. Multivariate logistic regression was then performed to control for confounders., Results: Fifty-four percent of subjects reported lifetime cannabis use, with 15% using it recently. Univariate regression analysis showed that recent marijuana users had significantly lower frequency of elevated thyrotropin (TSH) and positive anti-thyroperoxidase antibody (TPOAb) versus nonusers/past users. After controlling for confounders, recent marijuana use remained an independent predictor for TSH <5.6 μIU/mL (odds ratio of 0.344 with 95% CI of 0.127-0.928; p = 0.04) but not for negative TPOAb., Conclusion: Recent marijuana use was not associated with thyroid dysfunction but was significantly associated with lower levels of TSH.
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- 2017
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4. Seronegative Myasthenia Gravis, as a Rare Autoimmune Condition in Turner Syndrome.
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Sharief R, Miodovnik A, and Motaghedi R
- Abstract
Girls with Turner syndrome (TS), especially with isochromosome 46,X,i(X)(q10), are prone to develop autoimmunity. Associations of several autoimmune conditions with TS have been frequently described in the past. However, the unique combination of TS and myasthenia gravis (MG) has been reported only once before in a girl with mosaic monosomy 45,X/46,XX. Here, we present the second case of a girl affected with seronegative MG but with mosaic isochromosome TS. This is a child with developmental delay presented with muscle weakness, frequent fall, and bilateral ptosis. Diagnosis of MG was made based on positive Tensilon and electromyography tests and excellent response to intravenous immunoglobulin. At the age of 11 years due to short stature and developmental delay, a karyotype was done and revealed the mosaic isochromosome 45,X/46,X,i(X)(q10). Overall, clinicians should be aware of the vulnerability of girls with TS to autoimmunity, especially if the isochromosome 46,X,i(X)(q10) karyotype is identified. Furthermore, if a child with TS develops muscle weakness, ptosis, or ophthalmoplegia, MG should also be included in the differential diagnosis, particularly if other concurrent autoimmune conditions are present.
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- 2017
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5. Topical Iodine-Induced Thyrotoxicosis in a Newborn with a Giant Omphalocele.
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Malhotra S, Kumta S, Bhutada A, Jacobson-Dickman E, and Motaghedi R
- Abstract
Introduction: Neonatal thyrotoxicosis is a life-threatening condition with potentially irreversible neurologic sequelae. Most cases are seen in neonates born to mothers with Graves' disease. Topical iodine-induced hypothyroidism has been reported in neonates, but iodine-induced neonatal hyperthyroidism has not been described; albeit a familiar entity in adults., Case Description: Herein we present a unique case of a neonate, born with a giant omphalocele, who was treated with topical povidone-iodine dressings to promote escharification, in preparation for delayed surgical closure. By third day of life (DOL), the baby presented with a suppressed thyroid stimulating hormone of 0.59 µIU/mL, elevated free thyroxine of 5.63 ng/dL, and frank cardiovascular manifestations of thyrotoxicosis. After replacement of the topical iodine dressings with iodine-free silver sulfadiazine, the thyroid status gradually improved with complete resolution of hyperthyroidism by 17th DOL., Conclusion: This case emphasizes that significant topical iodine exposure can result in both hypothyroidism and hyperthyroidism, and therefore, vigilance in monitoring thyroid function is imperative.
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- 2016
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6. Should children with isolated premature adrenarche be routinely evaluated for non-classical congenital adrenal hyperplasia?
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Ghanny BA, Malhotra S, Kumta S, Kazachkova I, Homel P, Jacobson-Dickman E, and Motaghedi R
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- Adrenal Hyperplasia, Congenital etiology, Adrenal Hyperplasia, Congenital metabolism, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Male, Prognosis, Retrospective Studies, Steroid 21-Hydroxylase genetics, 17-alpha-Hydroxyprogesterone metabolism, Adrenal Hyperplasia, Congenital diagnosis, Adrenarche, Puberty, Precocious complications
- Abstract
Background: Current clinical practice is to evaluate children presenting with premature adrenarche (PA) for non-classical congenital adrenal hyperplasia (NC-CAH). Our main objective was to assess the prevalence of NC-CAH among children presented with PA. Additional objectives were to ascertain whether subpopulations were prone to NC-CAH, and therefore justified to be tested, and if obesity is a factor that can exclude the need for CAH testing., Methods: A retrospective chart review of all children ≤11 years, who presented to our clinic with PA between January 2012 and May 2015 (n=103) was conducted. PA was defined based on commonly accepted clinical criteria., Results: We did not identify any subjects with NC-CAH but one was affected with previously undiagnosed classical simple virilizing CAH (SV-CAH). The subject was born prior to the implementation of CAH newborn screening in the state of birth. The affected subject was of Middle Eastern origin and also obese (BMI >95 percentile for age and sex)., Conclusions: Undiagnosed CAH is an uncommon cause of PA, and therefore routine screening for NC-CAH in every case of PA may not be justified, although, perhaps, should still be considered in high risk ethnicities. Obesity does not appear to exclude the possibility of being affected with mild or NC-CAH.
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- 2016
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7. Association of obesity with inflammation and pain after total hip arthroplasty.
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Motaghedi R, Bae JJ, Memtsoudis SG, Kim DH, Beathe JC, Paroli L, YaDeau JT, Gordon MA, Maalouf DB, Lin Y, Ma Y, Cunningham-Rundles S, and Liu SS
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- Aged, Analgesics therapeutic use, Biomarkers blood, Body Mass Index, Cells, Cultured, Cross-Sectional Studies, Cytokines blood, Elective Surgical Procedures, Female, Humans, Inflammation blood, Inflammation diagnosis, Inflammation immunology, Leukocytes, Mononuclear immunology, Male, Middle Aged, Obesity diagnosis, Obesity immunology, Pain Measurement, Pain, Postoperative diagnosis, Pain, Postoperative drug therapy, Prospective Studies, Risk Factors, Severity of Illness Index, Time Factors, Treatment Outcome, Arthroplasty, Replacement, Hip adverse effects, Inflammation etiology, Obesity complications, Pain, Postoperative etiology
- Abstract
Background: The prevalence of obesity is increasing, and obesity often leads to degenerative joint disease requiring total hip arthroplasty (THA). Obesity is a proinflammatory state associated with an increase in chronic, low-grade inflammatory response. As such, it may augment the postoperative inflammatory response, which has been associated with postoperative pain and complications., Questions/purposes: We determined whether severity of obesity was associated with (1) severity of inflammatory response, as measured by the in vivo circulating levels of cytokines and ex vivo functional reactivity of mononuclear blood cells, and (2) severity of pain, as measured by verbal pain scores and analgesic consumption, in the first 24 hours after THA., Methods: We studied 60 patients (20 normal weight, 20 overweight, 20 obese) undergoing elective primary unilateral THA in this prospective cross-sectional study. Blood samples were collected for C-reactive protein and cytokine levels, including IL-1β, IL-2, IL-6, IL-8, and tumor necrosis factor α (TNF-α), from patients before and 24 hours after surgery. Cytokine response of whole blood was evaluated ex vivo with or without two standard activators, phorbol-12-myristate-13-acetate and lipopolysaccharide, using standardized blood sample from patients at 24 hours. These standard immune activators are implicated in the inflammatory response to gram-negative infection, translocation of microbial products, pathophysiology of septic shock syndrome in human, and tumor promotion. Pain response was gauged using verbal pain scores (on a 0- to 10-point scale, where 0 = no pain and 10 = worst pain) at rest and with activity at 24 hours after surgery and analgesic consumption of volume of epidural analgesic solution for the first 24 hours after surgery., Results: No correlation was found between BMI and postoperative spontaneous circulating cytokine levels. However, after activation of blood leukocytes with lipopolysaccharide, there was a significant positive correlation between the BMI and IL-1β, IL-6, and TNF-α levels (r = 0.26-0.32; p = 0.03, p = 0.03, and p = 0.01, respectively), suggesting priming of the innate immune system in obesity and potential for excessive postoperative inflammatory response. Obesity was not associated with increased pain or analgesic consumption in the first 24 hours after surgery., Conclusions: Obesity is associated with a proinflammatory state after THA as demonstrated by enhanced cytokine reactivity. Larger studies exploring the specific impact of obesity and inflammation on surgical outcomes, including pain, are warranted., Level of Evidence: Level II, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.
- Published
- 2014
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8. Whole-exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity.
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Gill R, Cheung YH, Shen Y, Lanzano P, Mirza NM, Ten S, Maclaren NK, Motaghedi R, Han JC, Yanovski JA, Leibel RL, and Chung WK
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- Acanthosis Nigricans etiology, Adolescent, Body Mass Index, Child, Consanguinity, Family Health, Female, Homozygote, Humans, Infant, Insulin blood, Leptin blood, Male, Pediatric Obesity blood, Pediatric Obesity metabolism, Pediatric Obesity physiopathology, Pedigree, Receptors, Leptin chemistry, Receptors, Leptin metabolism, Sequence Analysis, DNA, Exome, Frameshift Mutation, Pediatric Obesity genetics, Receptors, Leptin genetics
- Abstract
Objective: Obesity is a major public health problem that increases the risk for a broad spectrum of co-morbid conditions. Despite evidence for a strong genetic contribution to susceptibility to obesity, previous efforts to discover the relevant genes using positional cloning have failed to account for most of the apparent genetic risk variance., Design and Methods: Deploying a strategy combining analysis of exome sequencing data in extremely obese members of four consanguineous families with segregation analysis, we screened for causal genetic variants. Filter-based analysis and homozygosity mapping were used to identify and prioritize putative functional variants., Results: Two novel frameshift mutations in the leptin receptor in two of the families were identified., Conclusions: These results provide proof-of-principle that whole-exome sequencing of families segregating for extreme obesity can identify causal pathogenic mutations. The methods described here can be extended to additional families segregating for extreme obesity and should enable the identification of mutations in novel genes that predispose to obesity., (Copyright © 2013 The Obesity Society.)
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- 2014
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9. Anti-cytokine autoantibodies preceding onset of autoimmune polyendocrine syndrome type I features in early childhood.
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Wolff AS, Sarkadi AK, Maródi L, Kärner J, Orlova E, Oftedal BE, Kisand K, Oláh E, Meloni A, Myhre AG, Husebye ES, Motaghedi R, Perheentupa J, Peterson P, Willcox N, and Meager A
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- Adolescent, Adult, Autoantibodies biosynthesis, Child, Child, Preschool, Early Diagnosis, Female, Humans, Infant, Interferon-alpha immunology, Interleukin-17 immunology, Interleukins immunology, Male, Polyendocrinopathies, Autoimmune metabolism, Syndrome, Young Adult, Interleukin-22, Autoantibodies blood, Cytokines immunology, Polyendocrinopathies, Autoimmune diagnosis, Polyendocrinopathies, Autoimmune immunology
- Abstract
Purpose: Almost all patients with autoimmune polyendocrine syndrome (APS)-I have high titer neutralizing autoantibodies to type I interferons (IFN), especially IFN-ω and IFN-α2, whatever their clinical features and onset-ages. About 90 % also have antibodies to interleukin (IL)-17A, IL-17F and/or IL-22; they correlate with the chronic mucocutaneous candidiasis (CMC) that affects ~90 % of patients. Our aim was to explore how early the manifestations and endocrine and cytokine autoantibodies appear in young APS-I patients. That may hold clues to very early events in the autoimmunization process in these patients., Methods: Clinical investigations and autoantibody measurements in 13 APS-I patients sampled before age 7 years, and 3 pre-symptomatic siblings with AIRE-mutations in both alleles., Results: Antibody titers were already high against IFN-α2 and IFN-ω at age 6 months in one sibling-8 months before onset of APS-I-and also against IL-22 at 7 months in another (still unaffected at age 5 years). In 12 of the 13 APS-I patients, antibody levels were high against IFN-ω and/or IL-22 when first tested, but only modestly positive against IFN-ω in one patient who had only hypo-parathyroidism. Endocrine organ-specific antibodies were present at age 6 months in one sibling, and as early as 36 and 48 months in two of the six informative subjects., Conclusion: This is the first study to collate the onset of clinical features, cytokine and endocrine autoantibodies in APS-I infants and siblings. The highly restricted early autoantibody responses and clinical features they show are not easily explained by mere loss of broad-specific self-tolerance inducing mechanisms, but hint at some more sharply focused early event(s) in autoimmunization.
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- 2013
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10. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans.
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Menard L, Saadoun D, Isnardi I, Ng YS, Meyers G, Massad C, Price C, Abraham C, Motaghedi R, Buckner JH, Gregersen PK, and Meffre E
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- Autoantibodies immunology, Autoimmune Diseases genetics, Autoimmune Diseases immunology, B-Lymphocytes cytology, Genetic Predisposition to Disease, Humans, Isoenzymes metabolism, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 22 metabolism, Risk Factors, Self Tolerance genetics, Self Tolerance immunology, Alleles, Autoimmunity immunology, B-Lymphocytes immunology, Isoenzymes genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics
- Abstract
Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms are associated with many autoimmune diseases. The major risk allele encodes an R620W amino acid change that alters B cell receptor (BCR) signaling involved in the regulation of central B cell tolerance. To assess whether this PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s) encoding the PTPN22 R620W variant. We found that new emigrant/transitional and mature naive B cells from carriers of this PTPN22 risk allele contained high frequencies of autoreactive clones compared with those from non-carriers, revealing defective central and peripheral B cell tolerance checkpoints. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection before any onset of autoimmunity. In addition, gene array experiments analyzing mature naive B cells displaying PTPN22 risk allele(s) revealed that the association strength of PTPN22 for autoimmunity may be due not only to the impaired removal of autoreactive B cells but also to the upregulation of genes such as CD40, TRAF1, and IRF5, which encode proteins that promote B cell activation and have been identified as susceptibility genes associated with autoimmune diseases. These data demonstrate that early B cell tolerance defects in autoimmunity can result from specific polymorphisms and precede the onset of disease.
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- 2011
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11. Psychiatric adverse effects of rimonobant in adults with Prader Willi syndrome.
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Motaghedi R, Lipman EG, Hogg JE, Christos PJ, Vogiatzi MG, and Angulo MA
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- Adipose Tissue drug effects, Adipose Tissue metabolism, Adolescent, Adult, Body Weight drug effects, Cannabinoid Receptor Antagonists, Double-Blind Method, Fasting blood, Female, Ghrelin blood, Humans, Insulin-Like Growth Factor Binding Protein 3 blood, Insulin-Like Growth Factor I metabolism, Leptin blood, Male, Paranoid Disorders chemically induced, Pilot Projects, Piperidines adverse effects, Psychotic Disorders etiology, Pyrazoles adverse effects, Radioimmunoassay, Rimonabant, Treatment Outcome, Young Adult, Piperidines therapeutic use, Prader-Willi Syndrome drug therapy, Pyrazoles therapeutic use
- Abstract
Background: Prader Willi syndrome (PWS) without strict environmental modifications can lead to obesity associated with significant morbidity and mortality. In addition to increased appetite, these individuals have decreased energy expenditure with lower insulin like growth factor 1 (IGF1), which contributes to adiposity. No effective treatment is available for this condition. Endocannabinoid receptor CB1 antagonist, rimonobant, has been effective for treatment of obesity in adult subjects. Rimonabant promotes weight loss by multiple proposed mechanisms, including decreased appetite and lipogenesis, and increased energy expenditure. Therefore, we conducted this pilot study to evaluate the effect of rimonabant on body weight and composition of adults with PWS., Method: This was a double blind placebo controlled study. Body weight, total fat mass, fasting ghrelin, leptin, IGF1 and insulin like growth factor binding protein (IGFBP-3) were collected at baseline, and after 90 and 180 days of treatment with placebo or 20 mg of rimonabant., Results: Due to psychiatric adverse effects, 50% of subjects in the rimonabant group withdrew, and the study was terminated early (N=10) for safety concerns. There was a trend for weight loss, lower fat mass and higher IGF1 level at the end of study in this group. Leptin followed the fat mass and decreased with rimonabant treatment., Conclusion: Rimonabant administration may be efficacious for weight loss in adults with PWS; unfortunately it is associated with an unacceptably high risk of psychiatric side effects. Future CB1 antagonists will need a better psychiatric profile before considered in the treatment of obesity in this genetic condition., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)
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- 2011
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12. Large islets, beta-cell proliferation, and a glucokinase mutation.
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Kassem S, Bhandari S, Rodríguez-Bada P, Motaghedi R, Heyman M, García-Gimeno MA, Cobo-Vuilleumier N, Sanz P, Maclaren NK, Rahier J, Glaser B, and Cuesta-Muñoz AL
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- Cell Proliferation, Congenital Hyperinsulinism pathology, Female, Humans, Infant, Newborn, Mutation, Pancreas pathology, Congenital Hyperinsulinism genetics, Glucokinase genetics, Insulin-Secreting Cells cytology, Islets of Langerhans pathology
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- 2010
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13. Screening markers of impaired glucose tolerance in the obese pediatric population.
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Tsay J, Pomeranz C, Hassoun A, Zandieh SO, Rutledge J, Vogiatzi MG, Oberfield SE, and Motaghedi R
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- Adolescent, Adult, Algorithms, Biomarkers, Child, Child, Preschool, Diabetes Mellitus diagnosis, Diabetes Mellitus metabolism, Female, Glucose metabolism, Glucose Intolerance complications, Glucose Intolerance epidemiology, Glycated Hemoglobin metabolism, Humans, Male, Obesity complications, Pilot Projects, Predictive Value of Tests, Sensitivity and Specificity, Young Adult, Glucose Intolerance diagnosis, Glucose Tolerance Test standards, Glycated Hemoglobin analysis
- Abstract
Background: With the epidemic of childhood obesity, it is crucial to devise a simple screening protocol to predict impaired glucose tolerance (IGT) or pre-diabetes. The oral glucose tolerance test (OGTT), which is the gold standard for the diagnosis of IGT, is impractical for screening purposes. This pilot study was designed to formulate a simple, sensitive algorithm to predict IGT using clinical and laboratory parameters., Methods: Ethnicity, family history of diabetes, pubertal status, BMI z-score, blood pressure, lipids, hemoglobin A1c (HbA1c) and OGTT data were retrospectively collected from 209 overweight multi-ethnic subjects aged 3-21 years. Multivariate logistic regression was used to determine independent predictors of IGT., Results: HbA1c was the only significant predictor of IGT (p = 0.001), whereas fasting glucose was not. A cut-off of 5.5% had the best combined sensitivity (85.7%) and specificity (56.9%) with an odds ratio of 7.9 of having IGT when HbA1c is > or =5.5%. The remaining clinical parameters were not significant predictors of IGT., Conclusion: While fasting blood glucose does not seem to be a predictor of IGT, we propose that HbA1c > or =5.5% can be used as a screening test to assess the risk of IGT and to determine who should undergo diagnostic OGTT. Large prospective studies validating our findings are warranted., (Copyright 2010 S. Karger AG, Basel.)
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- 2010
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14. Autoimmune type I diabetes mellitus in a perinatally HIV infected patient with a well-preserved immune system.
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Bargman R, Freedman A, Vogiatzi M, and Motaghedi R
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- Anti-Retroviral Agents therapeutic use, Diabetes Mellitus, Type 1 etiology, Female, HIV Infections complications, HIV Infections drug therapy, Humans, Autoantibodies immunology, Diabetes Mellitus, Type 1 immunology, HIV Infections immunology
- Abstract
We report an 8 year-old girl with well-controlled perinatally acquired HIV infection who developed autoimmune type 1 diabetes mellitus (DM1A) confirmed by the presence of diabetes-related auto-antibodies. Although non-autoimmune insulin dependent diabetes mellitus (DM1B) and more frequently type 2 DM has been reported in patients affected with HIV, this is the first report of DM1A diagnosed in an HIV positive patient.
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- 2009
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15. IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans.
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Isnardi I, Ng YS, Srdanovic I, Motaghedi R, Rudchenko S, von Bernuth H, Zhang SY, Puel A, Jouanguy E, Picard C, Garty BZ, Camcioglu Y, Doffinger R, Kumararatne D, Davies G, Gallin JI, Haraguchi S, Day NK, Casanova JL, and Meffre E
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- Antibodies, Antinuclear immunology, Antibodies, Antinuclear metabolism, Autoantibodies immunology, Autoantibodies metabolism, B-Lymphocytes metabolism, Child, Female, Gene Expression Profiling, Humans, Infant, Interleukin-1 Receptor-Associated Kinases deficiency, Lymphocyte Activation, Male, Membrane Transport Proteins deficiency, Myeloid Differentiation Factor 88 deficiency, Oligonucleotide Array Sequence Analysis, Recombinant Proteins immunology, Toll-Like Receptors metabolism, Young Adult, Autoimmunity, B-Lymphocytes immunology, Interleukin-1 Receptor-Associated Kinases metabolism, Membrane Transport Proteins metabolism, Myeloid Differentiation Factor 88 metabolism, Self Tolerance, Toll-Like Receptors immunology
- Abstract
Most autoreactive B cells are normally counterselected during early B cell development. To determine whether Toll-like receptors (TLRs) regulate the removal of autoreactive B lymphocytes, we tested the reactivity of recombinant antibodies from single B cells isolated from patients deficient for interleukin-1 receptor-associated kinase 4 (IRAK-4), myeloid differentiation factor 88 (MyD88), and UNC-93B. Indeed, all TLRs except TLR3 require IRAK-4 and MyD88 to signal, and UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9. All patients suffered from defective central and peripheral B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive mature naive B cells in their blood. Hence, TLR7, TLR8, and TLR9 may prevent the recruitment of developing autoreactive B cells in healthy donors. Paradoxically, IRAK-4-, MyD88-, and UNC-93B-deficient patients did not display autoreactive antibodies in their serum or develop autoimmune diseases, suggesting that IRAK-4, MyD88, and UNC-93B pathway blockade may thwart autoimmunity in humans.
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- 2008
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16. The CB1 endocannabinoid system modulates adipocyte insulin sensitivity.
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Motaghedi R and McGraw TE
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- 3T3-L1 Cells, Adipocytes cytology, Animals, Arachidonic Acids pharmacology, Cannabinoid Receptor Modulators pharmacology, Cell Membrane metabolism, Dose-Response Relationship, Drug, Endocannabinoids, Glucose Transporter Type 4 metabolism, Glycerides pharmacology, Insulin Resistance, Mice, Pertussis Toxin pharmacology, Piperidines pharmacology, Proto-Oncogene Proteins c-akt metabolism, Pyrazoles pharmacology, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptor, Insulin metabolism, Rimonabant, Adipocytes drug effects, Adipocytes metabolism, Insulin physiology, Receptor, Cannabinoid, CB1 metabolism
- Abstract
Mounting evidence suggests that the endocannabinoid system regulates energy metabolism through direct effects on peripheral tissues as well as central effects that regulate appetite. Here we examined the effect of cannabinoid receptor 1 (CB1) signaling on insulin action in fat cells. We examined effects of the natural CB1 agonist, 2-Arachidonoylglycerol (2-AG), and the synthetic CB1 antagonist, SR141716, on insulin action in cultured adipocytes. We used translocation of glucose transporter GLUT4 to plasma membrane (PM) as a measure of insulin action. 2-AG activation of the CB1 receptor promoted insulin sensitivity whereas antagonism by SR141716 reduced insulin sensitivity. Neither drug affected GLUT4 translocation in the absence of insulin or with high doses of insulin. Consistent with these results we found that insulin-stimulated phosphorylation of the protein kinase Akt was increased by 2-AG, attenuated by SR141716, and unaffected in the absence of insulin or by addition of high-dose insulin. These data provide a functional and molecular link between the CB1 receptor and insulin sensitivity, because insulin-stimulated phosphorylation of Akt is required for GLUT4 translocation to the PM. The sensitizing effects of 2-AG were abrogated by SR141716 and Pertussis toxin, indicating that the effects are mediated by CB1 receptor. Importantly, neither 2-AG nor SR141716 alone or in combination with maximal dose of insulin had effects on GLUT4 translocation and Akt phosphorylation. These data are consistent with a model in which the endocannabinoid system sets the sensitivity of the insulin response in adipocytes rather than directly regulating the redistribution of GLUT4 or Akt phosphorylation.
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- 2008
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17. Insulin-like growth factor binding protein-1 to screen for insulin resistance in children.
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Motaghedi R, Gujral S, Sinha S, Sison C, Ten S, and Maclaren NK
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- Adolescent, Adult, Biomarkers blood, Child, Child, Preschool, Diabetes Mellitus prevention & control, Female, Glucose Tolerance Test, Humans, Insulin physiology, Liver physiology, Male, Mass Screening methods, Overweight physiology, Sensitivity and Specificity, Statistics, Nonparametric, Insulin Resistance physiology, Insulin-Like Growth Factor Binding Protein 1 blood, Insulin-Like Growth Factor Binding Protein 3 blood
- Abstract
Background: Diabetes and atherosclerosis are burgeoning health problems complicating obesity-associated insulin resistance (IR). Early detection of IR in children is a key to preventative strategies. Since peripheral insulin levels insensitively reflect hepatic insulin fluxes, we studied the insulin-regulated hepatic insulin-like growth factor binding proteins (IGFBPs)-1 and -3 as possible screening markers of childhood IR., Methods: The tolbutamide-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) and the oral glucose tolerance test (OGTT) were performed in 118 subjects < 21 years old with obesity. The relationships between insulin sensitivity index by minimal modeling (SiIVGTT), other Sis derived from fasting and OGTT insulin and glucose values, and the candidate serum markers were sought., Results: Significant correlation was found between IGFBP-1 and SiIVGTT, similar to the correlations of insulin sensitivity indices with SiIVGTT. In children < or = 10 years old, correlation of IGFBP-1 with SiIVGTT was the strongest. All (100%) subjects with IR defined by SiIVGTT < 4.5 +/- 0.5 x 10(-4) min(-1) /(microIU/mL) had inappropriately low IGFBP-1 levels. IGFBP-3 was not correlated with SiIVGTT., Conclusions: IGFBP-1 levels decrease with obesity and IR. We propose that in young subjects, especially children under the age of 10 years, IGFBP-1 is a convenient and sensitive marker of IR, whereas elevated fasting insulin is less sensitive but more specific.
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- 2007
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18. Update on the prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency.
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Motaghedi R, Betensky BP, Slowinska B, Cerame B, Cabrer M, New MI, and Wilson RC
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- Adolescent, Adrenal Hyperplasia, Congenital therapy, Amniocentesis, Child, Chorionic Villi Sampling, Consanguinity, DNA Mutational Analysis, Dexamethasone therapeutic use, Female, Fetal Diseases drug therapy, Genetic Carrier Screening methods, Glucocorticoids therapeutic use, Humans, Infant, Infant, Newborn, Male, Mutation, Pedigree, Pregnancy, Prenatal Diagnosis, Virilism genetics, Virilism prevention & control, Adrenal Hyperplasia, Congenital diagnosis, Adrenal Hyperplasia, Congenital genetics, Chromosomes, Human, Pair 8 genetics, Fetal Diseases diagnosis, Fetal Diseases genetics, Steroid 11-beta-Hydroxylase genetics
- Abstract
11beta-Hydroxylase deficiency is a common form of congenital adrenal hyperplasia causing virilization of the female fetus and hypertension. DNA analysis of the gene (CYP11B1) encoding 11beta-hydroxylase has been reported previously to be effective in the prenatal diagnosis of one affected female fetus. In that case, prenatal treatment with dexamethasone resulted in normal female genitalia. We now report five new pregnancies that underwent prenatal diagnosis for 11beta-hydroxylase deficiency. In the first family, the proband is homozygous for a T318M mutation and all fetuses from four subsequent pregnancies are carriers. In a second family, the mother is homozygous for a A331V mutation and was started on dexamethasone, but identification of a homozygous normal fetus led to the discontinuation of treatment. In another family, the fetus was a male homozygous for R384Q and treatment was discontinued. Lastly, a novel G444D mutation in exon 8 was identified and proven to reduce 11beta-hydroxylase activity.
- Published
- 2005
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