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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.

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.

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.

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.

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.)

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.

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.)

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.

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.

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.

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.