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Context Mutations in type I collagen or collagen-related proteins cause osteogenesis imperfecta (OI). Energy expenditure and body composition in OI could reflect reduced mobility or intrinsic defects in osteoblast differentiation increasing adipocyte development. Objective This study compares adiposity and resting energy expenditure (REE) in OI and healthy controls (HC), for OI genotype- and Type-associated differences. Methods We studied 90 participants, 30 with OI (11 COL1A1 Gly, 8 COL1A2 Gly, 4 COL1A1 non-Gly, 1 COL1A2 non-Gly, 6 non-COL; 8 Type III, 16 Type IV, 4 Type VI, 1 Type VII, 1 Type XIV) and 60 HC with sociodemographic characteristics/BMI/BMIz similar to the OI group. Participants underwent dual-energy x-ray absorptiometry to determine lean mass and fat mass percentage (FM%) and REE. FM% and REE were compared, adjusting for covariates, to examine the relationship of OI genotypes and phenotypic Types. Results FM% did not differ significantly in all patients with OI vs HC (OI: 36.6% ± 1.9%; HC: 32.7% ± 1.2%; P = 0.088). FM% was, however, greater than HC for those with non-COL variants (P = 0.016). FM% did not differ from HC among OI Types (P values > 0.05). Overall, covariate-adjusted REE did not differ significantly between OI and HC (OI: 1376.5 ± 44.7 kcal/d; HC: 1377.0 ± 96 kcal/d; P = 0.345). However, those with non-COL variants (P = 0.016) and Type VI OI (P = 0.04) had significantly lower REE than HC. Conclusion Overall, patients with OI did not significantly differ in either extra-marrow adiposity or REE from BMI-similar HC. However, reduced REE among those with non-COL variants may contribute to greater adiposity.

Little is known regarding the long-term effects of antiretroviral (ARV) exposure on body composition for people living with HIV (PLWH) since early childhood. This study explores changes in body fat distribution in relation to ARV exposure.We conducted a prospective study of adults with perinatal HIV (n = 70) using dual-energy X-ray absorptiometry and standard anthropometrics. Trunk to limb fat ratio and waist to hip ratio were compared cross-sectionally to 47 matched controls. Furthermore, changes in body composition and ARV exposure were evaluated longitudinally in a subset of 40 PLWH with a median follow-up of 7 years.Cross-sectional comparisons of PLWH with controls revealed significantly higher waist to hip ratio, trunk to limb fat ratio, HOMA-IR, and triglycerides, whereas BMI did not differ. Among PLWH with longitudinal follow-up, the prevalence of overweight increased from 27.5% to 52.5% and obesity from 12.5% to 25%; waist to hip and trunk to limb fat ratios also increased (P0.0001). Changes in waist to hip ratio were positively correlated with longer exposure during follow-up to darunavir (r = 0.36; P = 0.02), whereas increases in trunk to limb fat ratio were positively correlated with longer exposure to stavudine (r = 0.39; P = 0.01) and didanosine (r = 0.39; P = 0.01) but inversely associated with emtricitabine (r = -0.33; P = 0.04). Increases in waist to hip ratio were correlated with increases in triglyceride levels (r = 0.35; P = 0.03).This study presents strong evidence for persistent and worsening central adiposity in young adults with lifelong HIV and extensive ARV exposure. As this cohort ages, continued evaluation of the body composition and metabolic impact of lifelong ARV therapy is warranted to optimize long-term health.

Background Fatty acids, specifically polyunsaturated fatty acids (PUFAs) play an important role in inflammation and its resolution, however, their interaction with the epigenome is relatively unexplored. Here we investigate the relationship between circulating blood fatty acids and the DNA methylation of the cytokine encoding gene tumour necrosis factor (TNF, OMIM 191160). Methods Using a cross‐sectional study approach, we collected blood samples from adults (N=88 (30 males, 58 females); 18–74 years old) for DNA methylation pyrosequencing analysis at four sites in TNF exon 1 and gas‐chromatography mass‐spectrometry analysis of the fatty acid profile of dried blood spots (DBS). Results Methylation levels of TNF exon 1 are significantly correlated with specific fatty acids in a gender‐specific manner. In the males the PUFAs Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) were positively associated with TNF methylation, as was the saturated fatty acid (SFA) Stearic Acid; in contrast, mono‐unsaturated fatty acids (MUFAs) had a negative association. In the females, omega‐6 PUFA γ‐Linolenic acid (GLA) was negatively correlated with TNF methylation; Adrenic acid and Eicosadienoic Acid were positively correlated with TNF methylation. Conclusion These results suggest that one way that fatty acids interact with the inflammation is through altered methylation profiles of cytokine genes; thus, providing potential therapeutic targets for nutritional and health interventions., Methylation levels of TNF exon 1 are significantly correlated with specific fatty acids in a gender‐specific manner. In the males the PUFAs Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) were positively associated. In females, omega‐6 PUFA γ‐Linolenic acid (GLA) was negatively correlated with TNF methylation. These results suggest that one way that fatty acids interact with the inflammation is through altered methylation profiles of cytokine genes; thus, providing potential therapeutic targets for nutritional and health interventions.

Background Systemic mastocytosis (SM), a clonal expansion of mast cells affecting multiple organs including the skeletal system, puts patients at risk for osteoporosis and fractures. Various aspects of skeletal disease in SM have been reported among European cohorts. Objective To determine fracture prevalence and risk predictors in SM in a North American (NA) cohort and compare findings with studies of other populations. Methods Fifty patients, aged 25-74 years, were grouped based on fracture type and history. Data collected included laboratory findings and radiographic markers such as serum tryptase, bone turnover markers, dual-energy x-ray absorptiometry images, and trabecular bone scores. We performed univariate and multivariate analyses of these findings. Results Fracture history was found in 74% of patients. Significantly different median age, body mass index, dual-energy x-ray absorptiometry scores, and alkaline phosphatase levels were observed between fracture groups, consistent with French and Dutch studies. Significant findings included the difference in trabecular bone scores among fracture groups, the association between alkaline phosphatase and fracture type and occurrence, and the model for predicting fracture risk based on DXA spine T-scores, alkaline phosphatase, and age (81.3% accuracy and 77.1% sensitivity). Conclusions Our findings in an NA cohort are in overall agreement with those reported in European studies of skeletal disease and fracture risk for individuals with SM. We include an interactive calculator designed from a predictive model based on the NA cohort, which may be used for improved screening for fracture risk.

Objective Pretreatment with lithium (Li) is associated with an increased residence time of radioactive iodine (RAI) in differentiated thyroid cancer (DTC) metastases. There are no data translating this observation into long-term outcomes. The study goal was to compare the efficacy of three methods of preparation for RAI therapy in metastatic DTC-thyroid hormone withdrawal (THW), THW with pretreatment with Li (THW+Li), and recombinant human TSH (rhTSH). Design/patients/measurements We performed a cohort study comparing overall survival (OS) and progression-free survival (PFS) between the three groups: THW (n = 52), THW+Li (n = 41) and rhTSH (n = 42). Kaplan-Meier analyses were performed to compare OS and PFS between the groups. Cox proportional hazards regression model with a stepwise variable selection was performed to study the contribution of age, gender, histology, TNM status, a location of distant metastases and RAI dose. Results During the follow-up of median 5.1 (IQR = 3.0-8.1) years, 52% of patients had disease progression and 12.6% died. Although THW+Li group was characterized by the longest OS (P = 0.007), only age (HR 1.05, CI 1.01-1.09, P = 0.01) and widespread disease (HR 3.8, CI 1.2-11.8, P = 0.02) were found to affect OS in a multivariate model. There was no difference in PFS between the groups (P = 0.47). Presence of distant metastases limited to the lungs only was associated with longer PFS (PFS HR 0.35, CI 0.20-0.60, P = 0.0002). Conclusion The older age is associated with shorter OS, while disease burden affects OS and PFS in patients with metastatic thyroid cancer. The method of preparation for RAI therapy does not affect the outcome.

The majority of Americans use the Internet daily, if not more often, and many search online for health information to better understand a diagnosis they have been given or to research treatment options. The average American reads at an eighth-grade level. The purpose of this study is to evaluate the readability of online patient education materials on the websites of 14 professional organizations representing the major internal medicine subspecialties. We used ten well-established quantitative readability scales to assess written text from patient education materials published on the websites of the major professional organizations representing the following subspecialty groups: allergy and immunology, cardiology, endocrinology, gastroenterology, geriatrics, hematology, hospice and palliative care, infectious disease, nephrology, oncology, pulmonology and critical care, rheumatology, sleep medicine, and sports medicine. Collectively the 540 articles analyzed were written at an 11th-grade level (SD 1.4 grade levels). The sleep medicine and nephrology websites had the most readable materials, written at an academic grade level of 8.5 ± 1.5 and 9.0 ± 0.2, respectively. Material at the infectious disease site was written at the most difficult level, with average readability corresponding to grades 13.9 ± 0.3. None of the patient education materials we reviewed conformed to the American Medical Association (AMA) and the National Institutes of Health (NIH) guidelines requiring that patient education articles be written at a third- to seventh-grade reading level. If these online resources were rewritten, it is likely that more patients would derive benefit from reading them.

Background/Aims: Animal studies suggest that leptin may adversely affect bone mineral density (BMD). Clinical studies have yielded conflicting results. We therefore investigated associations between leptin and bone parameters in children. Methods: 830 healthy children (age = 11.4 ± 3.1 years; 75% female; BMI standard deviation score [BMIz] = 1.5 ± 1.1) had fasting serum leptin measured with ELISA and body composition by dual-energy X-ray absorptiometry. The main effects for leptin and BMIz plus leptin’s interactions with sex and BMIz were examined using hierarchical linear regressions for appendicular, pelvis, and lumbar spine BMD as well as bone mineral content (BMC), and bone area (BA). Results: Accounting for demographic, pubertal development, and anthropometric variables, leptin was negatively and independently associated with lumbar spine BMC and BA, pelvis BA, and leg BA (p < 0.05 for all). Sex, but not BMIz, moderated the associations of leptin with bone parameters. In boys, leptin was negatively correlated with leg and arm BMD, BMC at all bone sites, and BA at the subtotal and lumbar spine (p < 0.01 for all). In girls, leptin was positively correlated with leg and arm BMD (p < 0.05 for both). Conclusion: Independent of body size, leptin is negatively associated with bone measures; however, these associations are moderated by sex: boys, but not girls, have a negative independent association between leptin and BMD.

SummaryObjective Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that has antiproliferative effects on several types of cancer, including thyroid cancer. In addition, VA has been reported to upregulate the sodium-iodine symporter in thyroid cancer cells and increases radioiodine uptake in preclinical studies. The aim of this study was to assess the antiproliferative effects of VA and to evaluate if VA can increase the radioiodine uptake in patients with advanced, radioiodine-negative thyroid cancer. Design An open-label Simon two-stage phase II trial. Patients and Measurements Valproic acid was administered orally, and doses were adjusted to maintain serum trough levels between 50 and 100 mg/l for 10 weeks, followed by injections of recombinant human thyroid-stimulating hormone and a radioiodine uptake scan. Anatomical imaging studies were performed at week 16 to assess tumour response and radioiodine therapy in patients with increased radioiodine uptake. Results Thirteen patients with a median age of 66 years (50–78 years) were enrolled and evaluated. Seven patients had papillary thyroid cancer (PTC), two had follicular variant PTC, two had follicular thyroid cancer, and two had Hurthle cell carcinoma. None of the 10 patients who completed the 10-week treatment had increased radioiodine uptake at their tumour sites. Three patients were taken off the study prior to the 10-week radioiodine uptake scan: one with grade-3 hepatic toxicity, one with disease progression and one for noncompliance. Four of 13 patients had decreased stimulated serum thyroglobulin with VA treatment. None of the patients had complete or partial responses based on Response Evaluation Criteria in Solid Tumors (RECIST), and six patients had disease progression. Conclusions Valproic acid does not increase radioiodine uptake and does not have anticancer activity in patients with advanced, radioiodine-negative thyroid cancer of follicular cell origin.

The influence of insulin and insulin resistance (IR) on children's weight and fat gain is unclear.To evaluate insulin and IR as predictors of weight and body fat gain in children at high risk for adult obesity. We hypothesized that baseline IR would be positively associated with follow-up body mass index (BMI) and fat mass.Two hundred and forty-nine healthy African American and Caucasian children aged 6-12 years at high risk for adult obesity because of early-onset childhood overweight and/or parental overweight were followed for up to 15 years with repeated BMI and fat mass measurements. We examined baseline serum insulin and homeostasis model of assessment-IR (HOMA-IR) as predictors of follow-up BMI Z-score and fat mass by dual-energy X-ray absorptiometry in mixed model longitudinal analyses accounting for baseline body composition, pubertal stage, sociodemographic factors and follow-up interval.At baseline, 39% were obese (BMI⩾95th percentile for age/sex). Data from 1335 annual visits were examined. Children were followed for an average of 7.2±4.3 years, with a maximum follow-up of 15 years. After accounting for covariates, neither baseline insulin nor HOMA-IR was significantly associated with follow-up BMI (Ps0.26), BMIz score (Ps0.22), fat mass (Ps0.78) or fat mass percentage (Ps0.71). In all models, baseline BMI (P0.0001), body fat mass (P0.0001) and percentage of fat (P0.001) were strong positive predictors for change in BMI and fat mass. In models restricted to children without obesity at baseline, some but not all models had significant interaction terms between body adiposity and insulinemia/HOMA-IR that suggested less gain in mass among those with greater insulin or IR. The opposite was found in some models restricted to children with obesity at baseline.In middle childhood, BMI and fat mass, but not insulin or IR, are strong predictors of children's gains in BMI and fat mass during adolescence.

Summary Background In adults, obesity is associated with abnormalities of thyroid function; there are fewer studies in paediatric cohorts. Objectives To examine associations of weight and adiposity with indices of thyroid function and thyroid-related metabolic factors in children. Design/Methods A sample of 1203 children without obesity (body mass index [BMI]

Background: In adults with primary focal segmental glomerulosclerosis (FSGS), daily prednisone may induce complete remissions (CR) and partial remissions (PR), but relapses are frequent and adverse events are common. Methods: We carried out 2 open-label, uncontrolled trials to explore the efficacy and tolerability of pulse oral dexamethasone as an alternative to daily prednisone. We enrolled adult patients with proteinuria > 3.5 g/day despite the use of renin-angiotensin-aldosterone blockade. In the first trial, we enrolled 14 subjects with FSGS and administered 4 dexamethasone doses (25 mg/m2) daily for 4 days, repeated every 28 days over 32 weeks. The second trial involved a more intensive regimen. Eight subjects received 4 dexamethasone doses of 50 mg/m2 every 4 weeks for 12 weeks, followed by 4 doses of 25 mg/m2 every 4 weeks for 36 weeks; subjects were randomized to 2 doses every 2 weeks or 4 doses every 4 weeks. Results: In the first trial, we enrolled 13 subjects with FSGS and 1 with minimal change disease and found a combined CR and PR rate of 36%. In the second trial, we enrolled 8 subjects. The combined CR and PR rate was 29%. Analysis combining both trials showed a combined CR and PR rate of 33%. Adverse events were observed in 32% of subjects, with mood symptoms being most common. There were no serious adverse events related to the study. Conclusion: We conclude that high dose oral dexamethasone is well tolerated by adults with idiopathic nephrotic syndrome and may have some efficacy.

Objective Pediatric loss of control (LOC) eating prospectively predicts the worsening of metabolic syndrome components. However, it is unknown if remission of LOC eating is associated with improvements in metabolic health. Therefore, we conducted a secondary analysis of a trial that enrolled adolescent girls with LOC eating, examining whether LOC remission (vs. persistence) at end-of-treatment was associated with changes in metabolic syndrome components at 6-month follow-up. Method One hundred three adolescent girls (age 14.5 ± 1.7 years; BMI-z 1.5 ± 0.3; 56.3% non-Hispanic White, 24.3% non-Hispanic Black) with elevated weight (75th-97th BMI %ile) and reported LOC eating were assessed for metabolic syndrome components at baseline and again six months following the interventions. The main effects of LOC status at end-of-treatment (persistence vs. remission) on metabolic syndrome components (waist circumference, lipids, glucose, and blood pressure) at 6-month follow-up were examined, adjusting for baseline age, depressive symptoms, LOC frequency, fat mass, and height, as well as race, change in height, change in fat mass, and the baseline value of each respective component. Results Youth with LOC remission at end-of-treatment had lower glucose (83.9 ± 6.4 vs. 86.5 ± 5.8 mg/dL; p = .02), higher high-density lipoprotein cholesterol (50.3 ± 11.8 vs. 44.8 ± 11.9 mg/dL; p = .01), and lower triglycerides (84.4 ± 46.2 vs. 96.9 ± 53.7 mg/dL; p = .02) at 6-month follow-up when compared with youth with persistent LOC, despite no baseline differences in these components. No other component significantly differed by LOC eating status (ps > .05). Discussion Reducing LOC eating in adolescent girls may have a beneficial impact on some components of the metabolic syndrome.

BACKGROUND: Alström syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body–associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements. OBJECTIVE: We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI)–matched controls. METHODS: We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed. RESULTS: Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two-thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps ≤ 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001). CONCLUSION: Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development.

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01724580","term_id":"NCT01724580"}}NCT01724580 and {"type":"clinical-trial","attrs":{"text":"NCT02974595","term_id":"NCT02974595"}}NCT02974595. FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.

Context HIV antiretroviral (ARV) therapy is associated with renal and bone toxicity, but little is known about the potential cumulative effects in adults exposed to ARVs from birth. Objective To prospectively evaluate renal and bone health in young adults with lifelong HIV and extensive ARV exposure. Design Cross-sectional comparison of bone mineral density (BMD) by dual-energy X-ray absorptiometry, bone turnover, and renal function in young adults infected with HIV in early life (n = 65) to matched healthy controls (n = 23) and longitudinal evaluation (mean follow-up = 4.4 years) within a subset of the HIV cohort (n = 33). Setting Government outpatient research clinic. Results Albumin/creatinine ratio, protein/creatinine ratio, anion gap, N-terminal telopeptides, and osteocalcin were significantly increased in persons with HIV compared with controls, whereas whole-body BMD and BMD z scores were lower. Within the HIV group, duration of tenofovir disoproxil fumarate (TDF) correlated with higher anion gap but did not correlate with bone parameters. Longer duration of didanosine and stavudine use correlated with lower BMD and BMD z scores. Longitudinal analyses revealed that BMD and bone metabolism significantly improved over time. No subject had an estimated glomerular filtration rate (eGFR)

Women with primary ovarian insufficiency have significantly lower serum estradiol and T levels compared with regularly menstruating women. They also have significantly reduced bone mineral density (BMD).The objective of the study was to evaluate the efficacy of hormone replacement in maintaining BMD in these young women.This was a randomized, double-blind, single-center, placebo-controlled clinical trial at the National Institutes of Health clinical center (Bethesda, Maryland).Young women with primary ovarian insufficiency participated in the study.We compared the effect of estradiol and progestin replacement (n = 72) vs estradiol, progestin, and T replacement (n = 73) on BMD. We also compared findings with a contemporaneous control group of normal women (n = 70). All patients received transdermal estradiol (100 μg/d) plus oral medroxyprogesterone acetate 10 mg/d (12 d/mo) for a 3-month run-in period before being randomized in a double-blinded fashion to the addition of transdermal T (150 μg/d) or placebo.Change in BMD at the femoral neck was measured by dual-energy x-ray absorptiometry.At screening, patients had significantly lower femoral neck BMD compared with control women (0.77 vs 0.81 g/cm(2), P = .001) and did not differ in body mass index, age at menarche, or education level. Normal control women lost femoral neck BMD over the study period, whereas patients on estradiol and progestin therapy gained BMD; and at the end of the study period, femoral neck BMD of patients on estradiol and progestin therapy did not differ from that of control women (0.80 g/cm(2) in both groups, P = .9). The addition of T showed no further benefit (percentage change in BMD 3.9 vs 2.4, respectively, P = .9). Nonetheless, using a repeated-measures model, the T group achieved a mean BMD in the femoral neck 0.015 g/cm(2) higher than the placebo group at 3 years (95% confidence interval -0.005 to 0.034, P = .13). Similar findings were observed in the lumbar spine BMD as well.Long-term physiological transdermal estradiol replacement in combination with oral medroxyprogesterone acetate restores mean femoral neck BMD to normal in young women with spontaneous 46,XX primary ovarian insufficiency. However, the addition of physiological transdermal T replacement did not provide additional benefit.

The lay public frequently access and rely on online information as a source of their medical knowledge. Many medical societies are unaware of national patient education material guidelines and subsequently fail to meet them. The goal of the present study was to evaluate the readability of patient education materials within the medical field of gastroenterology.Two hundred fourteen articles pertaining to patient education materials were evaluated with ten well-established readability scales. The articles were available on the websites for the American College of Gastroenterology (ACG), the American Gastroenterological Association (AGA), the American Society of Gastrointestinal Endoscopy (ASGE), the British Society of Gastroenterology (BSG), and the NIH section National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). One-way analysis of variance (ANOVA) and Tukey's honest significant difference (HSD) post hoc analysis were conducted to determine any differences in level of readability between websites.The 214 articles were written at an 11.8 ± 2.1 grade level with a range of 8.0 to 16.0 grade level. A one-way ANOVA and Tukey's HSD post hoc analysis determined the ACG was written at a significantly (p 0.05) more difficult level when compared to the AGA, the BSG, and the NIDDK websites. No differences were noted when comparing the ASGE website.None of the patient education materials were written at a level that met national guidelines. If the materials are redrafted, the general American public will likely have a greater understanding of the gastroenterology content.

Purpose: Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers. Experimental Design: Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes. Results: Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m2 on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors–defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21–112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases. Conclusions: A romidepsin dose of 7 mg/m2 administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors. Clin Cancer Res; 19(16); 4499–507. ©2013 AACR.

Patients with congenital adrenal hyperplasia (CAH) often suffer from long-term complications secondary to chronic glucocorticoid therapy and suboptimal treatment regimens.The aim of the study was to describe clinical characteristics of a large cohort of pediatric and adult CAH patients.We conducted a cross-sectional study of 244 CAH patients [183 classic, 61 nonclassic (NC)] included in a Natural History Study at the National Institutes of Health.Outcome variables of interest were height sd score, obesity, hypertensive blood pressure (BP), insulin resistance, metabolic syndrome, bone mineral density, hirsutism (females), and testicular adrenal rest (TART).The majority had elevated or suppressed androgens, with varied treatment regimens. Mean adult height SD score was -1.0 ± 1.1 for classic vs. -0.4 ± 0.9 for NC patients (P = 0.015). Obesity was present in approximately one third of patients, across phenotypes. Elevated BP was more common in classic than NC patients (P ≤ 0.01); pediatric hypertensive BP was associated with suppressed plasma renin activity (P = 0.001). Insulin resistance was common in classic children (27%) and adults (38% classic, 20% NC); 18% of adults had metabolic syndrome. The majority (61%) had low vitamin D; 37% of adults had low bone mineral density. Hirsutism was common (32% classic; 59% NC women). TART was found in classic males (33% boys; 44% men).Poor hormonal control and adverse outcomes are common in CAH, necessitating new treatments. Routine monitoring of classic children should include measuring BP and plasma renin activity. Osteoporosis prophylaxis and TART screening should begin during childhood. A longitudinal study is under way.

Steady-state population pharmacokinetics of a noncommercial immediate-release metformin (hydrochloride) drug product were characterized in 28 severely obese children with insulin resistance. The concentration-time profiles with double peaks were well described by a 1-compartment model with 2 absorption sites. Mean population apparent clearance (CL/F) was 68.1 L/h, and mean apparent volume of distribution (V/F) was 28.8 L. Body weight was a covariate of CL/F and V/F. Estimated glomerular filtration rate was a significant covariate of CL/F (P

OBJECTIVE Metformin can decrease adiposity and ameliorate obesity-related comorbid conditions, including abnormalities in glucose homeostasis in adolescents, but there are few data evaluating the efficacy of metformin among younger children. Our objective was to determine whether metformin treatment causes weight loss and improves obesity-related comorbidities in obese children, who are insulin-resistant. RESEARCH DESIGN AND METHODS This study was a randomized double-blind placebo-controlled trial consisting of 100 severely obese (mean BMI 34.6 ± 6.6 kg/m2) insulin-resistant children aged 6–12 years, randomized to 1,000 mg metformin (n = 53) or placebo (n = 47) twice daily for 6 months, followed by open-label metformin treatment for 6 months. All children and their parents participated in a monthly dietitian-administered weight-reduction program. RESULTS Eighty-five percent completed the 6-month randomized phase. Children prescribed metformin had significantly greater decreases in BMI (difference −1.09 kg/m2, CI −1.87 to −0.31, P = 0.006), body weight (difference −3.38 kg, CI −5.2 to −1.57, P < 0.001), BMI Z score (difference between metformin and placebo groups −0.07, CI −0.12 to −0.01, P = 0.02), and fat mass (difference −1.40 kg, CI −2.74 to −0.06, P = 0.04). Fasting plasma glucose (P = 0.007) and homeostasis model assessment (HOMA) insulin resistance index (P = 0.006) also improved more in metformin-treated children than in placebo-treated children. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17%. During the 6-month open-label phase, children treated previously with placebo decreased their BMI Z score; those treated continuously with metformin did not significantly change BMI Z score further. CONCLUSIONS Metformin had modest but favorable effects on body weight, body composition, and glucose homeostasis in obese insulin-resistant children participating in a low-intensity weight-reduction program.

[¹³¹I]meta-iodobenzylguanidine ([¹³¹I]MIBG) is the most commonly used treatment for metastatic pheochromocytoma and paraganglioma. It enters the chromaffin cells via the membrane norepinephrine transporter; however, its success has been modest. We studied the ability of histone deacetylase (HDAC) inhibitors to enhance [¹²³I]MIBG uptake by tumors in a mouse metastatic pheochromocytoma model. HDAC inhibitors are known to arrest growth, induce differentiation and apoptosis in various cancer cells, and further inhibit tumor growth. We report the in vitro and in vivo effects of two HDAC inhibitors, romidepsin and trichostatin A, on the uptake of [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in mouse pheochromocytoma (MPC) cells by using the transporter-blocking agent desipramine and the vesicular-blocking agent reserpine. HDAC inhibitors increased [(3)H]norepinephrine, [¹²³I]MIBG, and [(18)F]fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in significantly increased uptake of [(18)F]fluorodopamine positron emission tomography (PET) in pheochromocytoma liver metastases (19.1 ± 3.2% injected dose per gram of tumor (%ID/g) compared to liver metastases in pretreatment scans 5.9 ± 0.6%; P

Objective Major depressive disorder (MDD) is associated with immune system dysfunction and disruption of multiple circadian systems. Adiponectin is an adipocytokine with anti-inflammatory and antiatherogenic effects. Circulating concentrations are inversely related to adiposity and risks of metabolic syndrome and diabetes mellitus. Our goals were (1) to establish whether premenopausal women with MDD exhibit decreased plasma adiponectin concentrations and/or disruption of circadian adiponectin rhythmicity; (2) to assess whether there is a relationship between adiponectin and MDD; and (3) to explore the temporal relationships among adiponectin, leptin, corticotropin, and cortisol secretion. Method We conducted a case-control study of community-dwelling premenopausal women with DSM-IV MDD (n = 23) and age- and body mass index (BMI)-matched control subjects (n = 23). Main outcome measures were circulating concentrations of adiponectin, leptin, corticotropin, and cortisol measured hourly for 24 hours. Subjects were recruited from July 1, 2001, to February 28, 2003. Results Women with MDD had approximately 30% lower mean 24-hour concentration of adiponectin than did control subjects. Adiponectin concentration was inversely related to depression severity and total duration of disease, suggesting a causal link. In contrast, mean nocturnal leptin concentration was higher in the MDD versus control groups. Mean leptin concentration was inversely related to cortisol and adiponectin concentrations, both in subjects with depression and in control subjects. In cross-correlation analyses, the relationship between corticotropin and cortisol concentrations was stronger in women with MDD than in control subjects, a finding consistent with hypothalamic-pituitary-adrenal (HPA) axis activation in MDD. Conclusions In premenopausal women with MDD, reduced daily adiponectin production may increase the risk of diabetes mellitus, and elevated leptin may contribute to osteoporosis.

Background: Human obesity is associated with increased heat production; however, subcutaneous adipose tissue provides an insulating layer that impedes heat loss. To maintain normothermia, therefore, obese individuals must increase their heat dissipation. Objective: The objective was to test the hypothesis that temperature in a heat-dissipating region of the hand is elevated in obese adults. Design: Obese [body mass index (in kg/m 2 ) 30] and normalweight (NW; body mass index = 18–25) adults were studied under thermoneutral conditions at rest. Core body temperature was measured by using ingested telemetric capsules. The temperatures of the third fingernail bed of the right hand and of abdominal skin from an area 1.5 cm inferior to the umbilicus were determined by using infrared thermography. Abdominal skin temperatures were also measured via adhesive thermistors that were placed over a prominent skin-surface blood vessel and over an adjacent nonvessel location. The groups were compared by analysis of covariance with age, sex, race, and room temperature as covariates. Results: Core temperature did not differ significantly between the 23 obese and 13 NW participants (P = 0.74). However, infrared thermography–measured fingernail-bed temperature was significantly higher in obese subjects than in NW subjects (33.9 6 0.7C compared with 28.6 6 0.9C; P , 0.001). Conversely, infrared thermography–measured abdominal skin temperature was significantly lower in obese subjects than in NW subjects (31.8 6 0.2C compared with 32.8 6 0.3C; P = 0.02). Nonvessel abdominal skin temperatures measured by thermistors were also lower in obese subjects (P = 0.04). Conclusions: Greater subcutaneous abdominal adipose tissue in obese adults may provide a significant insulating layer that blunts abdominal heat transfer. Augmented heat release from the hands may offset heat retention in areas of the body with greater adiposity, thereby helping to maintain normothermia in obesity. This trial was registered at clinicaltrials.gov as NCT00266500. Am J Clin Nutr 2009;90:1124–31.

Context: Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density. Objective: The aim of the study was to assess bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model. Design and Setting: We conducted a cross-sectional study at a tertiary care research center. Participants: We studied women with POI (n = 442), concurrent controls (n = 70), and matched controls from NHANES III (n = 353). Primary Outcome Measure: We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry. Results: Patients on average had 2–3% lower BMD at L1–L4, femoral neck, and total hip (P < 0.01 at all sites). The modifiable risk factors for BMD below the expected range for age (Z-score

To examine the relationships between cognitive eating restraint and both bone mineral density (BMD) and markers of bone turnover in overweight adolescents.One hundred thirty-seven overweight (BMI 39.1 +/- 6.8 kg/m(2)) African American and Caucasian adolescent (age = 14.4 +/- 1.4 years) girls (66.4%) and boys were administered the Eating Disorder Examination (EDE) interview and Eating Inventory (EI) questionnaire and underwent dual energy X-ray absorptiometry (DXA) to measure total lumbar spine BMD. Markers of bone formation (serum bone specific alkaline phosphatase and osteocalcin), bone resorption (24-hour urine N-telopeptides), and stress (urine free cortisol) were measured.After accounting for the contribution of demographics, height, weight, serum 25-hydroxyvitamin D, and depressive symptoms, adolescents' weight concern, as assessed by interview, was a significant contributor to the model of urine free cortisol (beta = .30, p.05). Shape concern, as also assessed by interview, was significantly associated with lumbar spine bone mineral density (beta = -.15, p.05). Dietary restraint was not a significant predictor in any of these models.These findings suggest that among severely overweight adolescents, dissatisfaction with shape and weight may be salient stressors. Future research is required to illuminate the relationship between bone health and disordered-eating attitudes in overweight adolescents.

We report that osteopenia is a prominent and previously unappreciated clinical feature of patients with X-linked hyper-IgM syndrome, an inherited immune deficiency disorder caused by mutations in the gene encoding CD40 ligand (CD40L). We therefore conducted studies to determine the relationship between CD40L and osteoclastogenesis. Recognizing that activated T cells express surface receptor activator of NF-κB ligand (RANKL) and can induce osteoclast differentiation of myeloid cells expressing RANK, we assessed the capacity of wild-type T cells and CD40L −/− T cells to induce osteoclastogenesis in vitro . Relative to wild-type T cells, activated CD40L −/− T cells from both humans and mice promoted robust osteoclast differentiation of myeloid cells. Whereas activated CD40L −/− T cells had normal expression of RANKL, they were deficient in IFN-γ production. In subsequent studies, we cultured activated CD40L −/− T cells in the presence of IFN-γ, and we found that the osteoclastic capacity of CD40L −/− T cells could be greatly diminished. These results show that CD40L can influence RANKL signaling through T cell priming, and thus they demonstrate a regulatory role for CD40L in bone mineralization that is absent in patients with X-linked hyper-IgM syndrome.

Purpose To assess health and musculoskeletal function in survivors of pediatric sarcomas. Patients and Methods Thirty-two individuals treated for Ewing sarcoma family of tumors (ESFT), rhabdomyosarcoma (RMS), or non-rhabdomyosarcoma soft tissue sarcomas (NR-STS) with multi-modality therapy were enrolled on this cross-sectional study. Median age at the time of therapy was 15.4 years (range 7.1–34.2), median age at the time of analysis was 37.4 years (17.5–55.4), and median duration of time elapsed from completion of therapy was 17.3 years (2.9–32.6). Participants underwent assessments of musculoskeletal functioning, cardiac function, metabolic and lipid analyses, renal and gonadal function, and psychological evaluation. Results This cohort of sarcoma survivors shows expected locoregional limitations in function of the area affected by sarcoma, and impaired global musculoskeletal functioning as evidenced by limited endurance and limited overall activity levels. The cohort also demonstrated substantial rates of cardiac dysfunction, elevated body fat index, hyperlipidemia, chronic psychological distress, and infertility in men (76%) and premature menopause (49%) in women. Conclusion Sarcoma survivors demonstrate diminished locoregional and global musculoskeletal functioning which likely limit occupational opportunities and socioeconomic health. In addition, the combination of diminished cardiac reserve, limited activity levels, and lipid dysregulation in sarcoma survivors suggests that this population is at increased risk for cardiovascular disease, even many years following completion of sarcoma therapy. Sarcoma survivors may benefit from life long follow-up for cardiovascular disease and from occupational counseling upon completion of therapy. Pediatr Blood Cancer 2007;48:192–199. Published 2006 Wiley-Liss, Inc.

African ancestry is associated with low vitamin D levels but high bone density. Fifty percent of African immigrants had low vitamin D levels, but10 % had evidence of deficiency. The value of providing vitamin D supplementation to African immigrants without evidence of deficiency needs to be determined.The Endocrine Society and Institute of Medicine (IOM) have concluded from studies in largely white populations that 25(OH)D is necessary for bone health. However, their definition of vitamin D insufficiency differs. The Endocrine Society recommends a 25(OH)D threshold of30 ng/mL. The IOM uses a lower threshold of 25(OH)D of20 ng/mL. As African ancestry is associated with decreased 25(OH)D but increased bone mineral density (BMD), the applicability of these thresholds to Africans is unknown. Therefore, we examined in African immigrants the relationship of 25(OH)D to parathyroid hormone (PTH) and BMD.One hundred eighty-six African immigrants(69 % male, age 38 ± 10 (mean ± SD), range 20-64 years) living in metropolitan Washington, DC, were enrolled. BMD was determined from whole-body dual-energy X-ray absorptiometry (DXA) scans. Decreased BMD required T-scores ≤-1.0. The threshold for low 25(OH)D was the concentration of 25(OH)D at which PTH became suppressed. This is known as the inflection point. Biochemical deficiency required low 25(OH)D and PTH of65 pg/mL. Clinical deficiency required low 25(OH)D and T-scores ≤-1.0.25(OH)D30 and20 ng/mL occurred in 83 and 46 % of African immigrants, respectively. PTH inversely correlated with 25(OH)D (r = -0.31, P = 0.002). The inflection point occurred at a 25(OH)D concentration of 20 ng/mL. Biochemical and clinical deficiency occurred in only 8 and 3 % of immigrants, respectively.As PTH became suppressed at 25(OH)D of 20 ng/mL, the 25(OH)D20 ng/mL threshold for insufficiency may apply to African immigrants. However, ~50 % of African immigrants have 25(OH)D20 ng/mL, but only10 % had evidence of deficiency. The value of providing vitamin D supplementation to the large number of African immigrants with 25(OH)D20 ng/mL and no detectable evidence of deficiency needs to be determined.

The long-term effects on bone and fat mass in children with endogenous CS are unknown. In 14 children followed for 3-7 years into young adulthood after cure of CS, whereas bone mass largely recovered, persisting increases in total body and visceral fat suggests an increase risk of the metabolic syndrome.Endogenous Cushing syndrome (CS) is associated with decreased bone mass and increased central fat mass. Whereas bone mass seems to improve after successful treatment, little is known about whether central fat persists.This was a prospective study of 14 children (10 girls and 4 boys) and adolescents with CS who were successfully treated and remained eucortisolemic. Growth, puberty, bone mass, and body composition were evaluated at baseline and during regular follow-up for 3 years and in seven children for a further 4 years of remission to assess final adult height (FH), BMI, bone mass, and body composition.CS compromised growth, leading to about a -0.8 SD loss of FH and 0.9 SD increase in weight and BMI. BMD apparent density (BMAD) SD Score (SDS) at the lumbar spine (LS) at diagnosis were -1.8 and -1.25, respectively, and after 3 years of follow-up approached the mean with no further increase apparent up to 7 years of follow-up. Whereas hip BMD SDS increased from -1.3 at diagnosis to -0.40 at 3 years and 0 at 7 years of follow-up, femoral neck BMAD remained at or around 0 SDS at diagnosis and during follow-up. BMI was25 kg/m(2) in five of seven adult subjects, most of whom were women. Total body fat and the ratio of visceral to subcutaneous was abnormally high in the majority of these subjects, whereas LS volumetric BMD was -0.7 SDS.Despite remission of CS, children and adolescents have significant alterations in body composition that result in a small but significant decrease in bone mass and increase in visceral adiposity. Although bone mass largely recovers after endogenous CS, changes in total and visceral fat suggest these subjects are at increased risk of the metabolic syndrome. Therefore, long-term monitoring of body fat and bone mass is mandatory after treatment of CS.

Context: Raloxifene is a promising breast cancer prevention agent in postmenopausal women at increased risk for breast cancer. The effects of raloxifene in premenopausal women are unknown. Objective: We evaluated the effect of raloxifene in premenopausal women at increased risk for breast cancer on bone mineral density (BMD). Design: This was a phase II clinical trial. Setting: This study was conducted at an academic medical center. Participants: Thirty-seven premenopausal women at increased risk for breast cancer enrolled in the trial. Thirty subjects began treatment and 27 were evaluable. Intervention: Raloxifene (60 mg daily) and elemental calcium (500 mg daily) were given for 2 yr. Subjects were followed up off medications for 1 yr. Main Outcome Measure: The primary end point was the intrasubject percent change in BMD at 1 yr measured by dual-energy x-ray absorptiometry. Results: The mean baseline lumbar spine density was 1.027 g/cm2. Lumbar spine density decreased 2.3% at 1 yr (P < 0.00001) and 3.5% at 2 yr (P < .00001). Percent change from yr 2 to 3 was +1.4%. The mean baseline total hip bone density was 0.905 g/cm2. Total hip density decreased 0.3% at 1 yr and 1.0% at 2 yr (P = 0.033). Percent change from yr 2 to 3 was +1.7%. Conclusions: Raloxifene use is associated with a decrease in BMD in premenopausal women at increased risk for breast cancer. The clinical significance of this decrease is unknown and is attenuated with stopping raloxifene.

OBJECTIVE. Limited data suggest that psychological factors, including binge eating, dieting, and depressive symptoms, may predispose children to excessive weight gain. We investigated the relationship between baseline psychological measures and changes in body fat (measured with dual-energy x-ray absorptiometry) over time among children thought to be at high risk for adult obesity. METHODS. A cohort study of a convenience sample of children (age: 6–12 years) recruited from Washington, DC, and its suburbs was performed. Subjects were selected to be at increased risk for adult obesity, either because they were overweight when first examined or because their parents were overweight. Children completed questionnaires at baseline that assessed dieting, binge eating, disordered eating attitudes, and depressive symptoms; they underwent measurements of body fat mass at baseline and annually for an average of 4.2 years (SD: 1.8 years). RESULTS. Five hundred sixty-eight measurements were obtained between July 1996 and December 2004, for 146 children. Both binge eating and dieting predicted increases in body fat. Neither depressive symptoms nor disturbed eating attitudes served as significant predictors. Children who reported binge eating gained, on average, 15% more fat mass, compared with children who did not report binge eating. CONCLUSIONS. Children’s reports of binge eating and dieting were salient predictors of gains in fat mass during middle childhood among children at high risk for adult obesity. Interventions targeting disordered eating behaviors may be useful in preventing excessive fat gain in this high-risk group.

Enlargement of the vestibular aqueduct (EVA) and its contents, the endolymphatic sac and duct, is the most common radiologic malformation of the inner ear associated with sensorineural hearing loss.1 It may occur alone or in combination with an incomplete partition of the apical turn of the cochlea as part of a complex of malformations known as a Mondini deformity.2 Hearing loss in ears with EVA is typically pre- or perilingual in onset, sensorineural or mixed, and fluctuating or progressive. EVA may be unilateral or bilateral; asymmetry of the hearing loss and the anatomic defect is common in bilateral cases.3–5 EVA has been observed in Pendred syndrome (PS; MIM 274600),6 branchio-oto-renal syndrome (MIM 113650),7 CHARGE (MIM 214800),8 Waardenburg syndrome (MIM 193500, 193510, 600193, 606662),9 and distal renal tubular acidosis with deafness (MIM 267300).10 Familial non-syndromic hearing loss with EVA was described in 199611 and numerous subsequent reports (DFNB4 (MIM 600791), enlarged vestibular aqueduct syndrome (MIM 603545)). EVA is always detected when the ears of individuals with PS are evaluated by both computed tomography (CT) and magnetic resonance imaging (MRI),6 and it has been estimated that PS may comprise up to 10% of prelingual deafness worldwide.3,12,13 PS is inherited in an autosomal recessive manner and is comprised of bilateral hearing loss, EVA, and an iodine organification defect in the thyroid gland, which may lead to goitre. PS is clinically differentiated from non-syndromic EVA by the presence of the thyroid iodine organification defect because goitre is an incompletely penetrant feature of PS.3 When goitre does occur in PS, it is most often euthyroidal and not evident until the second decade of life.3,12,14,15 There can be intrafamilial variability of the goitre, and PS phenocopies with …

Background: Little is known about how simpler and more available methods to measure change in body fatness compare with criterion methods such as dual-energy X-ray absorptiometry (DXA) in children. Objective: Our objective was to determine the ability of airdisplacement plethysmography (ADP) and formulas based on triceps skinfold thickness (TSF) and bioelectrical impedance analysis (BIA) to estimate changes in body fat over time in children. Design: Eighty-six nonoverweight and overweight boys (n 34) and girls (n 52) with an average age of 11.0 2.4 y underwent ADP, TSF measurement, BIA, and DXA to estimate body fatness at baseline and 1 0.3 y later. Recent equations were used to estimate percentage body fat by TSF measurement (Dezenberg equation) and by BIA (Suprasongsin and Lewy equations). Percentage body fat estimates by ADP, TSF measurement, and BIA were compared with those by DXA. Results: All methods were highly correlated with DXA (P 0.001). No mean bias for estimates of percentage body fat change was found for ADP (Siri equation) compared with DXA for all subjects examined together, and agreement between body fat estimation by ADP and DXA did not vary with race or sex. Magnitude bias was present for ADP relative to DXA (P 0.01). Estimates of change in percentage body fat were systematically overestimated by BIA equations (1.37 6.98%; P 0.001). TSF accounted for only 13% of the variance in percentage body fat change. Conclusion: Compared with DXA, there appears to be no noninvasive and simple method to measure changes in children’s percentage body fat accurately and precisely, but ADP performed better than did TSF or BIA. ADP could prove useful for measuring changes in adiposity in children. Am J Clin Nutr 2004;80:64 –9.

Leptin, an adipocyte hormone, when replaced in patients with lipodystrophy, improves insulin resistance, hyperglycemia, dyslipidemia, and hepatic steatosis. Changes in body composition accompany this metabolic improvement. We studied 14 patients (3 men and 11 women); 12 of who had generalized lipodystrophy (7 congenital, 5 acquired), and 2 patients had partial lipodystrophy. Body composition and related parameters were evaluated at baseline and after 4 and 12 months of leptin therapy. Baseline body mass index (BMI) was 21.7 +/- 0.8 kg/m(2), the percent body fat was 9.5% +/- 1.6%, and the serum leptin level was 1.7 +/- 0.3 ng/mL. On treatment, serum leptin levels increased by 10-fold. All patients reported a decrease in appetite on therapy. After 4 months, both daily caloric intake and resting energy expenditure (REE) decreased. The liver volume decreased (baseline = 3,055 +/- 281 cm(3); 4 months = 2,433 +/- 243 cm(3), P =.006). Dual energy x-ray absorptiometry (DEXA) demonstrated significant decreases in fat mass (5.4 +/- 0.8 kg to 5.0 +/- 0.8 kg; P =.003) and lean body mass (51.2 +/- 3.2 kg to 48.3 +/- 3.4 kg; P =.003) at 4 months on therapy. There was no impact of leptin therapy on bone mineral content, mineral density, and metabolism. Changes in body composition occurred during the first 4 months of leptin therapy, but then stabilized and were sustained thereafter.

Little is known of the natural history of thymic carcinoids in multiple endocrine neoplasia type 1 (MEN1). This is important because in 1993 they were identified as a frequent cause of death, yet only small retrospective studies and case reports exist. We report results of a prospective study of 85 patients with MEN1 evaluated for pancreatic endocrine tumors and followed over a mean of 8 yr with serial chest computed tomography, magnetic resonance imaging (MRI), chest x-ray, and, since 1994, octreoscans [somatostatin receptor scintigraphy (SRS)]. Seven patients (8%) developed thymic carcinoids. Patients with and without carcinoids did not differ in clinical, laboratory, or MEN1 tumor features, except for male gender and the presence of a gastric carcinoid. All thymic tumors were hormonally inactive. Four thymic carcinoids lacked 11q loss of heterozygosity, although it was found in three pancreatic endocrine tumors. Computed tomography and/or MRI were more sensitive than SRS or chest x-ray in detecting tumors initially or with recurrence. All patients underwent resection of the thymic carcinoid, and in all patients followed more than 1 yr, the tumor recurred. Bone metastases developed in two patients and were detected early only on MRI, not SRS. This study provides information on early thymic carcinoids and allows modifications of existing guidelines to be recommended for their diagnosis, surveillance, and treatment.

Extreme short stature is a cardinal feature of severe osteogenesis imperfecta (OI), types III and IV. We conducted a treatment trial of growth hormone in children with OI and followed linear growth velocity, bone metabolism markers, histomorphometrics, and vertebral bone density. Twenty-six children with types III and IV OI, ages 4.5-12 years, were treated with recombinant growth hormone (rGH), 0.1-0.2 IU/kg per day for 6 days/week, for at least 1 year. Length, insulin-like growth factor (IGF-I), insulin-like growth factor binding protein (IGFBP-3), bone metabolic markers, and vertebral bone density by DXA were evaluated at 6-month intervals. An iliac crest biopsy was obtained at baseline and 12 months. Approximately one-half of the treated OI children sustained a 50% or more increase in linear growth over their baseline growth rate. Most responders (10 of 14) had moderate type IV OI. All participants had positive IGF-I, IGFBP-3, osteocalcin, and bone-specific alkaline phosphatase responses. Only the linear growth responders had a significant increase in vertebral DXA z-score and a significant decrease in long bone fractures. After 1 year of treatment, responders' iliac crest biopsy showed significant increases in cancellous bone volume, trabecular number, and bone formation rate. Responders were distinguished from nonresponders by higher baseline carboxyterminal propeptide (PICP) values (p < 0.05), suggesting they have an intrinsically higher capacity for collagen production. The results show that growth hormone can cause a sustained increase in the linear growth rate of children with OI, despite the abnormal collagen in their bone matrix. In the first year of treatment, growth responders achieve increased bone formation rate and density, and decreased fracture rates. The baseline plasma concentration of PICP was an excellent predictor of positive response.

BACKGROUND Men are believed to have more visceral adipose tissue (VAT) than women have, but studies in African Americans that measured VAT from a single computed tomography (CT) slice found no sex difference. OBJECTIVE We used a serial-slice CT scan to investigate whether there is a sex difference in VAT volume among African Americans. DESIGN Single-slice CT measurements of VAT area at lumbar spine L2-3 and L4-5 levels were taken in 110 African Americans (44 men, 66 women). In 59 subjects (24 men, 35 women), VAT volume was also measured with contiguous CT slices from the diaphragm to the iliac crest. Fat mass was determined by dual-energy X-ray absorptiometry. RESULTS Men and women had similar ages (x +/- SD: 36.1 +/- 7.8 and 35.6 +/- 7.8 y, respectively) and body mass indexes in kg/m(2) (29.5 +/- 6.9 and 32.0 +/- 8.9). The percentage of body fat was lower (P < 0.0001) in men (21.8 +/- 7.3%) than in women (37.4 +/- 7.9%). The VAT volume was greater (P = 0.01) in men (1443 +/- 931 cm(3)) than in women (940 +/- 821 cm(3)). There was no sex difference in unadjusted VAT area at L2-3 (men, 88.6 +/- 63.5 cm(2); women, 57.2 +/- 45.4 cm(2)) or L4-5 (men, 65.6 +/- 53.3 cm(2); women, 55.0 +/- 38.3 cm(2)). After adjustment for percentage of body fat or fat mass, men had larger VAT area at both levels (P < 0.01). After adjustment for body mass index, the sex difference in VAT area was detectable at L2-3 (P < 0.001) but not at L4-5 (P = 0.22). CONCLUSIONS VAT volume is greater in men than in women. Detection of sex differences in VAT area among African Americans on single-slice CT requires adjustment for body fat content. At L2-3, adjustment for body mass index alone is adequate to detect sex differences in VAT.

Esophageal adenocarcinoma, the most lethal complication of gastroesophageal reflux disease, develops in the most common premalignant disorder of the upper gastrointestinal tract, Barrett’s esophagus. Unfortunately, most patients present with advanced disease and have a very poor prognosis. Recent increased interest in Barrett’s and the risks of gastroesophageal reflux have had little impact on identifying patients with adenocarcinoma at an early stage [1]. Gaining better understanding of the clinical factors responsible for the progression of Barrett’s metaplasia to adenocarcinoma will provide important insights into the mechanisms of carcinogenesis and provide opportunities for clinicians to prevent deaths from this highly lethal cancer. Identification of these risks is also likely to lead to understanding of factors that alter the frequency of cancers in our society. The incidence of adenocarcinoma is increasing in epidemic proportions throughout the United States and the western world [2–10]. Nearly all of this increase in the incidence of adenocarcinoma has occurred over the past three decades. Since the mid-1970s, the incidence of esophageal adenocarcinoma rose more than 350% [7]. At the Mayo Clinic, the percentage of esophageal cancers that are adenocarcinomas has increased from 3.3% between 1946 and 1963 to its current ratio of over 60% [6]. Recent studies indicated that there has been a 10-fold increase in the incidence of adenocarcinoma over the past 30 years [6]. There has also been an increase in the incidence of gastric cardia adenocarcinoma that may be related to Barrett’s-like intestinal metaplasia. Although cancer incidence is rising among females and nonCaucasians, the greatest risk continues to be for white males [2,3,8]. The

Our goal is to eliminate gastrointestinal cancer. This may be achieved by the prevention of new tumors or by the recognition and treatment of premalignant lesions or biological early cancers. The identification of individuals at risk for gastrointestinal cancer should also involve therapies to avoid the development and progression of these tumors. Screening and surveillance Screening allows the detection of tumors when they are treatable, at an early stage of invasiveness or, even better, before they have become malignant or invasive. The importance of screening is to reduce the consequences and mortality of the tumor. Screening is one way of combating cancer. Although there are apparent benefits to screening, there are also inaccuracies and negative factors involved. The utility and reality of screening and surveillance programs in increasing life expectancy has been questioned. Craanen and Kuipers [1] point out the advantages, disadvantages, and uncertainties of mass screening and surveillance of high-risk groups. The epidemiologic problems are eloquently presented. The natural history of disease is emphasized, and it is shown how this influences the purported benefits of screening and surveillance techniques. There are limitations in detecting early lesions in asymptomatic individuals. If there is a well-defined sequential process at the time of biological onset, the disease is present but not

Context: Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. Patients with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement. Objective: To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism. Design and Setting: An open-label nonrandomized study at the National Institutes of Health. Patients: Thirty-one patients with CGL (ages 4.3 to 46.7 y). Intervention: Metreleptin (0.06 to 0.24 mg/kg/d) for 6 months to 11 years. Outcome Measures: BMC was assessed by dual-energy x-ray absorptiometry. SD scores (SDS) for BMC were calculated based on height, race, sex, and age using population normative data. Calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at baseline and follow-up. Results: At baseline, patients demonstrated significantly increased total body less head BMC (mean SDS, 1.8 ± 0.7), height (mean SDS, 1.3 ± 1.3), and lean mass index, defined as lean body mass per height squared (mean SDS, 1.5 ± 0.83), vs population normative data. No change in total body less head BMC was observed after metreleptin. Lean mass index decreased with metreleptin. Serum calcium decreased with metreleptin, but remained within normal limits. No changes were seen in phosphorus, PTH, or vitamin D. Conclusions: In contrast to rodent models, CGL patients have increased BMC in the leptin-deficient state, which does not change with leptin replacement. The high BMC in these patients is partially explained by high lean mass and tall stature.

BACKGROUND Prior studies reveal that bone mineral density (BMD) in congenital adrenal hyperplasia (CAH) is mostly in the osteopaenic range and is associated with lifetime glucocorticoid dose. The forearm, a measure of cortical bone density, has not been evaluated. OBJECTIVE We aimed to evaluate BMD at various sites, including the forearm, and the factors associated with low BMD in CAH patients. METHODS Eighty CAH adults (47 classic, 33 nonclassic) underwent dual-energy-x-ray absorptiometry and laboratory and clinical evaluation. BMD Z-scores at the AP spine, total hip, femoral neck, forearm and whole body were examined in relation to phenotype, body mass index, current glucocorticoid dose, average 5-year glucocorticoid dose, vitamin D, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone and dehydroepiandrosterone sulphate (DHEAS). RESULTS Reduced BMD (T-score

Thyroid dysfunction is a common adverse event associated with tyrosine kinase inhibitors (TKI), but its underlying pathophysiology is unclear. Cabozantinib is a novel TKI currently Food and Drug Administration approved for advanced medullary thyroid cancer and tested in clinical trials on solid tumors including prostate, liver, bladder, breast, and ovarian cancer.We analyzed the thyroid function of patients enrolled in two phase 2 clinical trials using cabozantinib at the National Institutes of Health Clinical Center. Two cases of thyroiditis associated with cabozantinib therapy are presented in detail, and a systematic review of the literature on TKI-associated thyroid dysfunction is also discussed.Between September 2012 and September 2013, 33 patients were treated with cabozantinib, and follow-up thyroid function tests were available for 31 (20 males, 11 females; age 59±1 years). Thyroid dysfunction was recorded in the majority of patients (93.1%), with a predominance of subclinical hypothyroidism. Two cases showed a biphasic pattern of thyroid dysfunction characterized by a transient thyrotoxicosis followed by hypothyroidism. Color Doppler demonstrated an increase in vascularization during the thyrotoxic phase, but no uptake was visualized on nuclear medicine imaging. A systematic review of the literature resulted in the identification of 40 original manuscripts, of which 13 were case series and 6 were case reports describing TKI-associated thyroid dysfunction.TKI therapy often results in clinically significant thyroid dysfunction. Cabozantinib treatment commonly results in thyroid dysfunction varying from subclinical hypothyroidism to symptomatic thyrotoxicosis. Early detection and characterization of cabozantinib-associated thyroid dysfunction and close follow-up are essential to provide adequate management of this common adverse event.

Barrett's esophagus is the most common premalignant lesion of the upper gastrointestinal tract. This metaplastic change in the normal esophageal epithelium occurs in 10% to 15% of patients with chronic reflux esophagitis and is associated with a 30- to 40-fold increased risk of developing esophageal cancer. Cancers of the esophagus and gastroesophageal junction are increasing in incidence faster than any other cancer in the Western world. Despite the importance of this cancer epidemic and its well-known precursor lesion, most investigators have taken a subjective approach to quantifying the extent of disease, the location of abnormal tissues, and the effect of ablation techniques. Our ability to impact on this epidemic may be dependent on our ability to apply modern technologies to document quantitatively both the extent of disease and the severity of molecular derangement of the intrinsic growth regulatory mechanism of the metaplastic cells. This review will focus on the challenge of addressing the quantitative endoscopic findings in Barrett's esophagus.

Endogenous Cushing's syndrome (CS) in children causes growth retardation, decreased bone mass, and increased total body fat. No prospective controlled studies have been performed in children to determine the long-term sequelae of CS on peak bone mass and body composition. A 15-year-old girl with Cushing disease (CD), and her healthy identical co-twin, were followed for 6 years after the CD was cured. At the 6-year follow-up both twins had areal bone mineral density (BMD) and body composition determined by dual-energy X-ray absorptiometry (DXA) and three-dimensional quantitative computed tomography (3DQCT). Z scores for height, weight, and body mass index (BMI) were -2.3, -0.8 and 0.2, and 1.2, 0.2, and -0.6, in the twin with CD and her co-twin, respectively. In the twin with CD, areal BMD and bone mineral apparent density (BMAD) at different sites varied from 0.7 to 3 SD below her co-twin. Volumetric lumbar spine bone density Z score was -0.75 and 1.0, and total body, abdominal visceral, and subcutaneous fat (%) was 42, 10, and 41 versus 26, 4, and 17 in the twin with CD and her co-twin, respectively. The relationship between total body fat and L2-L4 BMAD was inverse in the twin with CD (p < 0.05), which by contrast in her co-twin was opposite and direct (p < 0.001). In the twin with CD, despite cure, there was a persistent deficit in bone mass and increase in total and visceral body fat. These observations suggest that hypercortisolism (exogenous or endogenous) during adolescence may have persistent adverse effects on bone and fat mass.

Objectives: Acanthosis nigricans (AN) has been proposed as a reliable marker of hyperinsulinemia, but its utility for predicting hyperinsulinism has not been systematically evaluated in overweight children. We examined the relationship of AN to hyperinsulinemia and body adiposity. Study design: One hundred thirty-nine children underwent physical examination for AN, body composition studies, an oral glucose tolerance test, and a hyperglycemic clamp. Results: Thirty-five children (25%) had AN. AN was more prevalent in African Americans (50.1%) than in white subjects (8.2%, P P P P P 20 μU/mL and 50% with fasting insulin levels >15 μU/mL did not have AN. Eighty-eight percent of children with fasting insulin levels ≥15 μU/mL had a body mass index SD score ≥3.0. Conclusions: AN is not a reliable marker for hyperinsulinemia in overweight children. Children with a race-, sex-, and age-specific body mass index SD scores ≥3.0 should be screened for hyperinsulinemia, whether or not they have AN. (J Pediatr 2001;138:474-80)