The effects of anorexia nervosa on bone metabolism in female adolescents

Osteopenia is a frequent, often persistent, complication of anorexia nervosa (AN) in adolescent girls and occurs during a critical time in bone development. Little is known about bone metabolism in this patient population. Therefore, we measured bone density (BMD) and body composition by dual energy x-ray absorptiometry, nutritional status, bone turnover, calcium, and hormonal status in 19 adolescent girls with AN (mean +/- SEM, 16.0+/-0.4 yr) and 19 bone age-matched controls. The mean duration of AN was 19+/-5 months. Spinal (L1-L4) osteopenia was common in AN. Lumbar anterioposterior BMD was more than 1 SD below the mean in 42% of patients, and lateral spine BMD was more than 1 SD below in 63% of patients compared with controls. Lean body mass significantly predicted lumbar bone mineral content (r = 0.75; P \u3c 0.0001) in controls only. In AN, duration of illness was the most significant predictor of spinal BMD (lumbar: r = -0.44; P = 0.06; lateral: r = -0.59; P = 0.008). AN adolescents with mature BA (15 yr and greater) were hypogonadal [estradiol, 16.2+/-1.9 vs. 23.3+/-1.6 pg/mL (P = 0.01); free testosterone, 0.70+/-0.17 vs. 1.36+/-0.14 pg/mL (P = 0.01)] although dehydroepiandrosterone sulfate and urinary free cortisol levels did not differ. Leptin levels were reduced in AN (2.9+/-2.1 vs. 16.5+/-1.8 ng/mL; P \u3c 0.0001). Insulin-like growth factor I (IGF-I) was reduced in AN to 50% of control levels (219+/-41 vs. 511+/-35 ng/mL; P \u3c 0.0001) and correlated with all measures of nutritional status, particularly leptin (r = 0.80; P \u3c 0.0001). Surrogate markers of bone formation, serum osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), were significantly (P = 0.02) reduced in AN vs. controls (OC, 39.1+/-6.4 vs. 59.2+/-5.2 ng/mL; BSAP, 27.9+/-4.0 vs. 40.6+/-3.4 U/L). The majority of the variation in bone formation in AN was due to IGF-I levels (OC: r2 = 0.72; P = 0.002; BSAP: r2 = 0.53; P = 0.01) in stepwise regression analyses. Bone resorption was comparable in patients and controls. These data demonstrate that bone formation is reduced and uncoupled to bone resorption in mature adolescents with AN in association with low bone density. Lean body mass was a significant predictor of BMD in controls, but not AN patients. The major correlate of bone formation in AN was the nutritionally dependent bone trophic factor, IGF-I. Reduced IGF-I during the critical period of bone mineral accumulation may be an important factor in the development of osteopenia in adolescents with AN

Abnormal bone mineral accrual in adolescent girls with anorexia nervosa

Anorexia nervosa (AN) is increasingly common in adolescent girls and occurs at a time of peak bone mass formation. Osteopenia is common in adolescent girls with AN, and in a cross-sectional study, we have reported low bone formation markers in such girls. To determine the impact of chronic undernutrition on bone mineral accrual in contrast to healthy controls, we prospectively measured bone mineral density (BMD) and body composition by dual energy x-ray absorptiometry, bone metabolism markers, and nutritional and hormonal status at baseline, 6 months, and 12 months in 19 adolescent girls with AN (mean +/- SEM, 15.4 +/- 0.4 yr) and 19 controls of comparable chronological and skeletal age. Overall, nutritional status in subjects with AN improved (mean percentage increase in body mass index from baseline, 9.2 +/- 1.9% and 15.2 +/- 2.6% at 6 and 12 months, respectively), with 11 subjects having recovered weight at 12 months. However, lumbar BMD at 12 months (AN, 0.88 +/- 0.02 g/cm(2), vs. control, 0.98 +/- 0.03 g/cm(2); P = 0.008) remained significantly reduced in AN compared with controls, even in recovered subjects. This was due to significant increases in lumbar BMD in controls vs. no change in AN subjects over the year (0.003 +/- 0.001 g/cm(2).month vs. 0.000 +/- 0.001 g/cm(2).month, respectively; P = 0.04). The most significant determinant of change in lumbar BMD at 12 months was change in lean body mass in both AN (r = 0.62; P = 0.008) and control (r = 0.80; P = 0.0006) groups. There were significant increases in surrogate markers of bone turnover in subjects with AN compared with controls as assessed by osteocalcin (AN, 0.9 +/- 0.4 micro g/liter.month, vs. control, -1.1 +/- 0.4 micro g/liter.month; P = 0.0007), bone-specific alkaline phosphatase (AN, 0.6 +/- 0.5 U/liter.month, vs. control, -1.5 +/- 0.4 U/liter.month; P = 0.002), deoxypyridinoline [AN, 0.1 +/- 0.1 nmol/mmol creatinine (cr).month, vs. control, -0.4 +/- 0.1 nmol/mmol cr.month; P = 0.005], and N-telopeptide (AN, 4 +/- 4 nmol BCE/mmol cr/month, vs. control, -9 +/- 4 nmol BCE/mmol cr/month; P = 0.01). Changes in IGF-I levels over the year were highly correlated with changes in bone turnover over the same period in AN (osteocalcin, r = 0.77; P = 0.001; deoxypyridinoline, r = 0.66; P = 0.01). A rise in N-telopeptide over the year was correlated with an increase in all bone mineral measures, including lumbar bone mineral content (r = 0.58; P = 0.03) and BMD (r = 0.53; P = 0.05) and total bone mineral content (r = 0.69; P = 0.006) and BMD (r = 0.69; P = 0.006) in the AN group. Therefore, despite recovery over 1 yr, poor bone mineral accrual persists in adolescent girls with AN in contrast to rapid bone accrual in healthy girls. Normalization of bone turnover markers occurs in association with nutritional recovery and an increase in the nutritionally dependent bone trophic factor IGF-I. A rise in bone turnover markers may be an early indicator of increase in BMD in recovering girls with AN

Determinants of Smoking and Quitting in HIV-Infected Individuals

Background: Cigarette smoking is widespread among HIV-infected patients, who confront increased risk of smoking-related co-morbidities. The effects of HIV infection and HIV-related variables on smoking and smoking cessation are incompletely understood. We investigated the correlates of smoking and quitting in an HIV-infected cohort using a validated natural language processor to determine smoking status. Method We developed and validated an algorithm using natural language processing (NLP) to ascertain smoking status from electronic health record data. The algorithm was applied to records for a cohort of 3487 HIV-infected from a large health care system in Boston, USA, and 9446 uninfected control patients matched 3:1 on age, gender, race and clinical encounters. NLP was used to identify and classify smoking-related portions of free-text notes. These classifications were combined into patient-year smoking status and used to classify patients as ever versus never smokers and current smokers versus non-smokers. Generalized linear models were used to assess associations of HIV with 3 outcomes, ever smoking, current smoking, and current smoking in analyses limited to ever smokers (persistent smoking), while adjusting for demographics, cardiovascular risk factors, and psychiatric illness. Analyses were repeated within the HIV cohort, with the addition of CD4 cell count and HIV viral load to assess associations of these HIV-related factors with the smoking outcomes. Results: Using the natural language processing algorithm to assign annual smoking status yielded sensitivity of 92.4, specificity of 86.2, and AUC of 0.89 (95% confidence interval [CI] 0.88–0.91). Ever and current smoking were more common in HIV-infected patients than controls (54% vs. 44% and 42% vs. 30%, respectively, both P<0.001). In multivariate models HIV was independently associated with ever smoking (adjusted rate ratio [ARR] 1.18, 95% CI 1.13–1.24, P <0.001), current smoking (ARR 1.33, 95% CI 1.25–1.40, P<0.001), and persistent smoking (ARR 1.11, 95% CI 1.07–1.15, P<0.001). Within the HIV cohort, having a detectable HIV RNA was significantly associated with all three smoking outcomes. Conclusions: HIV was independently associated with both smoking and not quitting smoking, using a novel algorithm to ascertain smoking status from electronic health record data and accounting for multiple confounding clinical factors. Further research is needed to identify HIV-related barriers to smoking cessation and develop aggressive interventions specific to HIV-infected patients

Serum osteoprotegerin in adolescent girls with anorexia nervosa

Low bone mineral density (BMD) in adolescents with anorexia nervosa (AN) is associated with a low bone turnover state. Osteoprotegerin (OPG), a cytokine that acts as a decoy receptor for receptor activator of nuclear factor-kappaB ligand, decreases bone resorption by inhibiting differentiation of osteoclast precursors and activation of mature osteoclasts, and by stimulating osteoclast apoptosis. We compared OPG levels in 43 adolescent girls with AN with 38 controls and examined bone density, bone turnover, and hormonal parameters. Girls with AN had lower fat mass, lean body mass, lumbar BMD z-scores, and lumbar bone mineral apparent density than controls. OPG levels were higher in girls with AN than in controls (44.5 +/- 22.5 pg/ml vs. 34.5 +/- 12.7 pg/ml, P = 0.02). Osteocalcin, deoxypyridinoline, estradiol, free testosterone, IGF-I, and leptin were lower in AN than in healthy adolescents. OPG values correlated negatively with body mass index (r = -0.27, P = 0.02), percent fat mass (r = -0.35, P = 0.0002), leptin (r = -0.28, P = 0.02), lumbar BMD z-scores (r = -0.25, P = 0.03), and lumbar bone mineral apparent density (r = -0.26, P = 0.03). In conclusion, adolescent girls with AN have higher serum OPG values than controls. OPG values correlate negatively with markers of nutritional status and lumbar bone density z-scores and may be a compensatory response to the bone loss seen in this population

Increased Coronary Atherosclerotic Plaque Vulnerability by Coronary Computed Tomography Angiography in HIV-Infected Men

a Objective: Among HIV-infected patients, high rates of MI and sudden cardiac death have been observed. Exploring potential underlying mechanisms, we used multidetector spiral coronary computed tomography angiography (coronary CTA) to compare atherosclerotic plaque morphology in HIV-infected subjects and non-HIVinfected controls. Methods: Coronary atherosclerotic plaques visualized by CTA in HIV-infected (101) and non-HIV-infected (41) men without clinically apparent heart disease matched on cardiovascular risk factors were analyzed for 3 vulnerability features: low attenuation, positive remodeling, and spotty calcification. Results: 95% of HIV-infected subjects were receiving ART (median duration 7.9 years) and had well-controlled disease (median CD4 473 cells/mm3, median HIV RNA &lt;50 copies/ml). Age and traditional cardiovascular risk factors were similar in HIV-infected subjects and controls. Among the HIV-infected (versus control) group, there was a higher prevalence of subjects with at least one: 1) low attenuation plaque (22.8% versus 7.3%, p ¼ 0.02), 2) positively remodeled plaque (49.5% versus 31.7%, p ¼ 0.05) and 3) high-risk 3-feature plaque (7.9% versus 0%, p ¼ 0.02). Moreover, subjects in the HIVinfected (versus control) group demonstrated a higher number of low attenuation plaques (p ¼ 0.01) and positively remodeled plaques (p ¼ 0.03) per subject. Conclusions: Our data demonstrate an increased prevalence of vulnerable plaque features among relatively young HIV-infected patients. Differences in coronary atherosclerotic plaque morphology -namely, increased vulnerable plaque among HIVinfected subjects -are here for the first time reported and may contribute to increased rates of MI and sudden cardiac death in this population

Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy

miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. the endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and whitening of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte-like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.NIHEllison FoundationJoslin Diabetes and Endocrinology Research Center coresMary K. Iacocca ProfessorshipAcademy of FinlandSigrid Juselius FoundationFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USAUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilUniversidade Federal de São Paulo, Program Mol Biol, São Paulo, BrazilAstraZeneca R&D, Cardiovasc & Metab Dis iMed, Molndal, SwedenUniv Helsinki, Dept Med, Helsinki, FinlandMinerva Fdn, Inst Med Res, Helsinki, FinlandUniv Massachusetts, Sch Med, Program Mol Med, Worcester, MA USAMassachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USAHarvard Univ, Sch Med, Boston, MA USAUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilUniversidade Federal de São Paulo, Program Mol Biol, São Paulo, BrazilNIH: DK082659NIH: DK033201NIH: AI060354NIH: DK040561NIH: U24-DK093000Joslin Diabetes and Endocrinology Research Center cores: DK036836FAPESP: 2010/52557-0Web of Scienc

Ideal cardiovascular health, biomarkers, and coronary artery disease in persons with HIV

OBJECTIVE: To investigate relationships between Life\u27s Simple 7 (LS7), an assessment of cardiovascular health (CVH), and coronary plaque among people with HIV (PWH). DESIGN: Cross-sectional. METHODS: Coronary computed tomography angiography, immune/inflammatory biomarkers, and characterization of LS7 were collected among a subset of ART-treated PWH enrolled in REPRIEVE, a primary prevention trial. Analyses adjusted for cardiovascular disease risk (ASCVD score). RESULTS: Median age of the 735 participants was 51(±6) years, 16% female, and median (Q1-Q3) CVD risk was 4.5% (2.6-6.9). Forty percent had poor (≤2 ideal components), 51% had intermediate (three or four ideal components), and only 9% had ideal CVH (≥5). Coronary plaque was present in 357 (49%); 167 (23%) had one or more vulnerable plaque features, 293 (40%) had noncalcified plaque, and 242 (35%) had a coronary artery calcium score \u3e0. All three phenotypes were increasingly more prevalent with poorer CVH and these relationships remained after adjusting for ASCVD risk. Poor CVH was associated with higher high-sensitivity C-reactive protein, oxidized low-density cholesterol, and interleukin-6. The relationship of LS7 to plaque remained after adjusting for these biomarkers. CONCLUSIONS: Among PWH, poor CVH as measured by LS7 was associated with coronary plaque presence, vulnerable features, and calcification. LS7 was also associated with selected biomarkers; adjustment for these and ASCVD score reduced but did not eliminate LS7\u27s association with plaque, suggesting the possibility of additional protective mechanisms against atherogenesis and plaque remodeling. Clinical use of LS7 and further exploration of its relationships with coronary artery disease may enhance efforts to reduce cardiovascular morbidity and mortality in PWH. CLINICAL TRIALS REGISTRATION: NCT02344290

From Harm to Robustness: A Principled Approach to Vice Regulation

John Stuart Mill’s harm principle maintains that adult behavior cannot justifiably be subject to social coercion unless the behavior involves harm or a significant risk of harm to non-consenting others. The absence of harms to others, however, is one of the distinguishing features of many manifestations of “vices” such as the consumption of alcohol, nicotine, recreational drugs, prostitution, pornography, and gambling. It is with respect to vice policy, then, that the harm principle tends to be most constraining, and some current vice controls, such as prohibitions on drug possession and prostitution, violate Mill’s precept. In the vice arena, we seem to be willing to accept social interference with what Mill termed “self-regarding” behavior. But does that willingness then imply that any social intervention into private affairs is justifiable, that the government has just as much right to outlaw Protestantism, or shag carpets, or spicy foods, as it does to outlaw drugs? In this paper I argue that advances in neuroscience and behavioral economics offer strong evidence that vices and other potentially addictive goods or activities frequently involve less-than-rational choices, and hence are exempt from the full force of the harm principle. As an alternative guide to vice policy, and following some guidance from Mill, I propose the “robustness principle”: public policy towards addictive or vicious activities engaged in by adults should be robust with respect to departures from full rationality. That is, policies should work pretty well if everyone is completely rational, and policies should work pretty well even if many people are occasionally (or frequently) irrational in their vice-related choices. The harm and robustness principles cohere in many ways, but the robustness principle offers more scope for policies that try to direct people “for their own good,” without opening the door to tyrannical inroads upon self-regarding behavior

Risk of coronary heart disease in patients with HIV infection

The lives of individuals infected with HIV who have access to combination antiretroviral therapy (cART) are substantially prolonged, which increases the risk of developing non-AIDS comorbidities, including coronary heart disease (CHD). In Europe and the USA, individuals with HIV infection have a ∼1.5-fold increased risk of myocardial infarction relative to uninfected individuals. In Africa, the relative risk of myocardial infarction is unknown, but broadened access to life-extending cART suggests that rates of CHD will rise in this and other resource-constrained regions. Atherogenesis in HIV is affected by complex interactions between traditional and immune risk factors. cART has varied, regimen-specific effects on metabolic risk factors. Overall, cART seems to lessen proatherogenic immune activation, but does not eliminate it even in patients in whom viraemia is suppressed. Current strategies to decrease the risk of CHD in individuals infected with HIV include early initiation of cART regimens with the fewest metabolic adverse effects, and careful management of traditional CHD risk factors throughout treatment. Future strategies to prevent CHD in patients with HIV infection might involve the use of HIV-tailored CHD risk-prediction paradigms and the administration of therapies alongside cART that will further decrease proatherogenic HIV-specific immune activatio

Comparison of Ischemic Stroke Incidence in HIV-Infected and Non–HIV-Infected Patients in a US Health Care System

BackgroundCardiovascular disease is increased among HIV-infected patients, but little is known regarding ischemic stroke rates. We sought to compare stroke rates and determine stroke risk factors in HIV-infected versus non-HIV-infected patients.MethodsAn HIV cohort and matched non-HIV comparator cohort seen between 1996 and 2009 were identified from a Boston health care system. The primary endpoint was ischemic stroke, defined using International Classification of Diseases (ICD) codes. Unadjusted stroke incidence rates were calculated. Cox proportional hazards modeling was used to determine adjusted hazard ratios (HRs).ResultsThe incidence rate of ischemic stroke was 5.27 per 1000 person-years in HIV-infected compared with 3.75 in non-HIV-infected patients, with an unadjusted HR of 1.40 [95% confidence interval (CI): 1.17 to 1.69, P &lt; 0.001]. HIV remained an independent predictor of stroke after controlling for demographics and stroke risk factors (HR: 1.21, 95% CI: 1.01 to 1.46, P = 0.043). The relative increase in stroke rates (HIV vs. non-HIV) was significantly higher in younger HIV patients (incidence rate ratio: 4.42, 95% CI: 1.56 to 11.09, age 18-29; 2.96, 1.69-4.96, age: 30-39; 1.53, 1.06-2.17, age: 40-49), and in women [HR: 2.16 (95% CI: 1.53 to 3.04) for women vs. HR: 1.18 (95% CI: 0.95 to 1.47) for men]. Among HIV patients, increased HIV RNA (HR: 1.10, 95% CI: 1.04 to 1.17, P = 0.001) was associated with an increased risk of stroke.ConclusionsStroke rates were increased among HIV-infected patients, independent of common stroke risk factors, particularly among young patients and women