Kyle Rudser

Fracture risk after parathyroidectomy among chronic hemodialysis patients

The impact of parathyroidectomy (PTX) on the long-term risks for hip and other fractures is unknown. Uncontrolled case series have reported an increase in bone mineral density after PTX. However, very low serum parathyroid hormone levels have been associated with decreased bone mineral density, adynamic bone disease, and fractures. This study compared long-term fracture rates among hemodialysis patients who underwent PTX with a matched control group. Data were obtained from the US Renal Data System. Patients who underwent a first PTX while receiving hemodialysis were matched with up to three control patients by age, race, gender, year of dialysis initiation, primary cause of renal failure, and the dosage of intravenous vitamin D used before PTX. Patients with a history of fracture or renal transplantation were excluded. Study outcomes were incident hip, vertebral, and distal radius-wrist fractures identified using hospitalization codes. Incident hip fracture rates in the PTX and matched control groups were 6.0 and 9.3 fractures per 1000 person-years, respectively. After adjustment, PTX was associated with a significant 32% lower risk for hip fracture (95% confidence interval 0.54 to 0.86; P = 0.001) and a 31% lower risk for any analyzed fracture (95% confidence interval 0.57 to 0.83; P < 0.001) compared with matched control subjects. Fracture risks were lower among hemodialysis patients who underwent PTX compared with matched control subjects. Surgical amelioration of secondary hyperparathyroidism may outweigh the risk of parathyroid hormone oversuppression in terms of bone health.

The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: a randomized, placebo-controlled, clinical trial.

IMPORTANCE Medical treatment options for pediatric obesity remain limited. Glucagon-like peptide-1 (GLP-1) receptor agonists induce weight loss by suppressing appetite and increasing satiety, but few studies have evaluated this therapy as a treatment for obesity. OBJECTIVE To evaluate the effects of exenatide on body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and cardiometabolic risk factors in adolescents with severe obesity. DESIGN Three-month, randomized, double-blind, placebo-controlled, multicenter clinical trial followed by a 3-month open-label extension. SETTING An academic medical center and an outpatient pediatric endocrinology clinic. PATIENTS A total of 26 adolescents (12-19 years of age) with severe obesity (BMI ≥ 1.2 times the 95th percentile or BMI ≥ 35). INTERVENTION All patients received lifestyle modification counseling and were equally randomized to exenatide or placebo injection, twice per day. MAIN OUTCOME MEASURES The primary end point was the mean percent change in BMI measured at baseline and 3 months. Secondary end points included absolute change in BMI, body weight, body fat, blood pressure, hemoglobin A1c, fasting glucose, fasting insulin, and lipids at 3 months. RESULTS Twenty-two patients completed the trial. Exenatide elicited a greater reduction in percent change in BMI compared with placebo (-2.70% [95% CI, -5.02% to -0.37%]; P = .03). Similar findings were observed for absolute change in BMI (-1.13 [95% CI, -2.03 to -0.24]; P = .02) and body weight (-3.26 kg [95% CI, -5.87 to -0.66 kg]; P = .02). Although not reaching the level of statistical significance, reduction in systolic blood pressure was observed with exenatide. During the open-label extension, BMI was further reduced in those initially randomized to exenatide (cumulative BMI reduction of 4%). CONCLUSIONS AND RELEVANCE These results provide preliminary evidence supporting the feasibility, safety, and efficacy of GLP-1 receptor agonist therapy for the treatment of severe obesity in adolescents. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01237197.

Differences in kidney function and incident hypertension: The multi-ethnic study of atherosclerosis

Context Evidence about whether early kidney dysfunction predates hypertension is scant. Contribution In this study, 2767 adults who were middle-aged or older and did not have clinically recognized hypertension or kidney or cardiovascular disease at baseline were followed for about 3 years. About 20% developed hypertension. Higher baseline levels of cystatin C were associated with higher incidence of hypertension, independent of other risk factors. Spot baseline measures of the urinary albumincreatinine ratio were not associated with hypertension incidence, independent of other risk factors. Implication Early renal impairment marked by higher cystatin C levels may play a role in the pathogenesis of hypertension. The Editors The kidneys play a central role in the regulation of blood pressure (1, 2). Although most individuals with established kidney disease have hypertension, the direction of the association between kidney dysfunction and elevated blood pressure remains controversial (37). Evidence suggests that early disturbances in kidney function may contribute to the development of hypertension. Transplantation of kidneys from Dahl and other hypertensive rat species transfers hypertension to recipient animals (8). Renal ischemia in early stages of kidney disease stimulates the reninangiotensinaldosterone and sympathetic nervous systems, which promotes sodium retention and increase peripheral resistance (9, 10). Evidence links low birthweight, a surrogate marker for reduced nephron number, with a greater risk for hypertension later in life (11). Accident victims with essential hypertension have a documented decrease in nephron number compared with matched control participants (12). The evaluation of early differences in kidney function has been hampered by the imprecision of traditional serologic methods and estimating equations (13). Cystatin C is an alternative marker of kidney function. It correlates with formal measurements of glomerular filtration and is more precise than serum creatinine levels in detecting early kidney dysfunction (14, 15). Urinary albumin excretion is a complementary marker to renal filtration and partially reflects hemodynamic disturbances within the glomerulus. We evaluated serum cystatin C levels and the urinary albumincreatinine ratio separately and in combination as predictors of incident hypertension in a multiethnic, community-based cohort without clinically recognized kidney or cardiovascular disease. Methods Study Population The MESA (Multi-Ethnic Study of Atherosclerosis) is a community-based study of subclinical cardiovascular disease among 6814 adults age 45 to 84 years (16). Between 2000 and 2002, the MESA researchers recruited participants from 6 communities: Forsyth County, North Carolina; northern Manhattan and Bronx, New York; the city of Baltimore and Baltimore County, Maryland; St. Paul, Minnesota; Chicago, Illinois; and Los Angeles County, California. The MESA researchers sampled eligible participants by self-reported race or ethnicity to create a cohort that was 38% white; 28% African American; 22% Hispanic; and 12% Asian, primarily of Chinese descent. The MESA researchers excluded participants if they had a previous diagnosis of cardiovascular disease (that is, physician-diagnosed heart attack, angina, stroke, transient ischemic attack, heart failure, or atrial fibrillation; were taking nitroglycerin; or had had angioplasty, coronary artery bypass grafting, valve replacement, pacemaker or defibrillator implantation, or any surgery on the heart or arteries.) We excluded MESA participants with baseline hypertension from our current analysis. Baseline hypertension was defined by any of the following criteria: systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, the use of medication for hypertension, or a self-reported history of hypertension. To focus the analyses on clinically unrecognized differences in kidney function, we excluded participants with clinical kidney disease, defined as an estimated glomerular filtration rate (GFR) less than 60 mL/min per 1.73 m2, or microalbuminuria, defined as a urinary albumincreatinine ratio of at least 25 mg/g for women or 17 mg/g for men (17, 18). We calculated estimated GFR by using the 4-variable Modification of Diet in Renal Disease equation (19). Participants with an estimated GFR greater than 90 mL/min per 1.73 m2 were examined separately in sensitivity analyses. Finally, we excluded participants who did not return for any follow-up MESA examinations. Figure 1 shows a flow diagram of the study participants. Figure 1. Study flow diagram. GFR = glomerular filtration rate; MESA = Multi-Ethnic Study of Atherosclerosis. Ascertainment of Exposure Variables The Laboratory for Clinical Biochemistry Research (University of Vermont, Burlington, Vermont) measured baseline cystatin C by using the BN II nephelometer (Dade Behring, Deerfield, Illinois) (20) and measured baseline urinary albumincreatinine ratio on a single spot morning collection by using nephelometry and the rate-Jaffe reaction, respectively. The coefficient of variation for cystatin C is 7.7%; cystatin C levels are stable through multiple freezethaw cycles (21). We reported the urinary albumincreatinine ratio as milligrams of albumin per gram of creatinine, which correlates with milligrams of albumin obtained from a 24-hour urine collection (22, 23). Studies have suggested that urinary albumincreatinine ratio values are higher in women because of lower creatinine excretion; therefore, we analyzed the values as sex-specific quartiles (18). Ascertainment of Outcome The MESA personnel assessed blood pressure and medication use during each MESA examination, each of which was conducted 18 months apart. They obtained 3 seated blood pressure measurements 5 minutes apart by using an automated sphygmomanometer. We calculated the mean of the second 2 measurements for analysis. The MESA personnel asked participants to bring all medications to each examination, and they assessed medication use by taking a medication inventory (24). We defined incident hypertension as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or the use of any antihypertensive medication during the second or third MESA follow-up examination (25). Because angiotensin-converting enzyme inhibitors and angiotensin II antagonists may be prescribed to individuals with diabetes but without hypertension, sensitivity analyses explored associations after excluding participants with diabetes. We also explored a second outcome, a clinically meaningful increase in blood pressure, defined as an increase in systolic blood pressure of at least 10 mm Hg, an increase in diastolic blood pressure of at least 5 mm Hg, or the introduction of an antihypertensive medication during follow-up. Ascertainment of Covariates We assessed covariates at the MESA baseline examination. Diabetes was defined as a reported history of diabetes, the use of any diabetes medication, or a fasting blood glucose level of at least 7 mmol/L (126 mg/dL) (26). Impaired fasting glucose was defined by a fasting glucose level of 5.6 to 6.99 mmol/L (100 to 125 mg/dL) without diabetes (26). The MESA investigators used a questionnaire to obtain histories of alcohol use and smoking. We analyzed smoking as the number of reported pack-years and alcohol use as the mean number of alcoholic drinks consumed per week. The MESA investigators obtained laboratory values after an 8- to 12-hour overnight fast. The Laboratory for Clinical Biochemistry Research measured high-sensitivity C-reactive protein levels by using the BN II nephelometer. Statistical Analysis We tabulated baseline participant characteristics by quartiles of cystatin C and urinary albumincreatinine ratio. We calculated risk time as the elapsed time from the baseline to the third MESA examination, unless a participant developed hypertension at the second examination or was lost to follow-up before the third examination, in which case we calculated risk time as the elapsed time from the baseline to the second examination. We calculated unadjusted hypertension rates as the number of events divided by person-years at risk, and we examined hypertension rates according to race or ethnicity, sex, and quartiles of cystatin C and urinary albumincreatinine ratio. We used Poisson (log-link) regression to model the incidence rate ratio of hypertension as a function of predictor covariates with robust variance estimation and an offset for follow-up time (27). We selected a 15-nmol/L increment in cystatin C levels for continuous analyses because it corresponded approximately to the intraquartile range for cystatin C. Variables that might be related to kidney function or hypertension were selected a priori (Table 1) and were added in blocks to progressive nested models. We used a Wald test to calculate P values and 95% CIs for model covariates and to evaluate the statistical significance of interactions. We used complete case analysis to handle missing data. Table 1. Baseline Characteristics, by Serum Cystatin C Level Searching MEDLINE from July 2007 through January 2008 did not yield any new references to the relationship of cystatin C levels with incident hypertension. Role of the Funding Source This study was supported by contracts from the National Heart, Lung, and Blood Institute and by a National Institutes of Health Career Development Award. The National Heart, Lung, and Blood Institute played a role in data collection, data management, and review and approval of the manuscript. Results Of the 6814 MESA participants, we excluded 3508 because of baseline hypertension, 151 because of an estimated GFR less than 60 mL/min per 1.73 m2, and 182 because of microalbuminuria (Figure 1). In addition, we excluded 43 participants because of a missing cystatin C value or urinary albumincreatinine ratio, 1 for an implausible cystatin C valu

Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study.

The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9–16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m2) were enrolled in a 6‐month, randomized, open‐label, crossover, clinical trial consisting of two, 3‐month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase‐order (i.e., starting with control or drug therapy) then crossed‐over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3‐, and 6‐months. The mean change over each 3‐month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (−1.7 kg/m2, 95% confidence interval (CI) (−3.0, −0.4), P = 0.01), body weight (−3.9 kg, 95% CI (−7.11, −0.69), P = 0.02), and fasting insulin (−7.5 mU/l, 95% CI (−13.71, −1.37), P = 0.02). Significant improvements were observed for OGTT‐derived insulin sensitivity (P = 0.02) and β‐cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well‐tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well‐controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.

Risk of lymphoma after renal transplantation varies with time : An analysis of the united states renal data system

Background. Characterization of the incidence of posttransplant lymphoma over time may help guide the timing and intensity of posttransplant monitoring. We analyzed the United States Renal Data System to describe the occurrence of lymphoma following renal transplantation. Methods. All end-stage renal disease patients placed on the transplant waiting list between January 1, 1990 and December 31, 1999 were considered. Survival analysis was used to estimate lymphoma risk in renal transplant patients. Results. Of 89,260 eligible patients, a total of 556 lymphoma cases were identified with 357 in transplant patients. The overall rate of posttransplant lymphoma was 33.3/10,000 person-years in transplant patients. There was variation in the duration and magnitude of increased lymphoma risk by age. The highest rates of lymphoma were among transplanted patients in the first 12 months, after which the rate of lymphoma decreased. Among Caucasian transplant recipients less than 25 years of age, the adjusted relative risk of lymphoma ranged from 13.82 [95% CI: (3.96, 48.15)] within 6 months posttransplant to 3.46 [95% CI: (0.69, 17.44)] within months 30-36 posttransplant. Only patients under 25 years had a notably increased risk beyond the first 2 posttransplant years. The risk of lymphoma differed by race, with Caucasian patients at nearly double the risk of African-Americans. Gender was not associated with lymphoma incidence. Conclusions. We found and quantified a time-varying relationship between renal transplant and lymphoma risk. This information can be used in combination with knowledge of established risk factors to guide the schedule of posttransplant monitoring.

Overall mortality, incremental life expectancy, and cause of death at 25 years in the program on the surgical control of the hyperlipidemias.

Objective:To present the longest follow-up report of any lipid-atherosclerosis intervention trial. Summary of Background Data:The Program on the Surgical Control of the Hyperlipidemias (POSCH), a secondary, clinical/arteriographic, randomized controlled trial, was the first lipid-atherosclerosis trial to demonstrate unequivocally that low density lipoprotein cholesterol reduction reduced the incidence of coronary heart disease death and myocardial infarction. Methods:We report POSCH 25 years follow-up for overall mortality, specific cause of death, and certain subgroup analyses, as well as a prediction for increase in life expectancy derived from the POSCH database, supplemented by the 2006 National Death Index, 1989–2006. Results:There were 838 patients randomized in POSCH (421 surgery, 417 control). At 25 years follow-up, the difference in the restricted mean survival and the logrank (Mantel-Haenszel) statistic was statistically significant, with survival probabilities of 0.57 (surgery) and 0.51 (controls). Cause of death data indicated a significant increase in cardiovascular deaths in the control group; cancer deaths were also greater in the control group but this was not significant. The most compelling subgroup analysis was a significant increase in survival, starting at 5 years after randomization, in the surgery group for patients with an ejection fraction ≥50%, with relative probabilities of 0.61 (surgery) and 0.51 (control). The estimated incremental increase in life expectancy over more than 25 years of follow-up was 1.0 year overall and 1.7 years in the cohort with an ejection fraction ≥50%. Conclusions:A 25-year mortality follow-up in POSCH shows statistically significant gains in overall survival, cardiovascular disease-free survival, and life expectancy in the surgery group compared with the control group.

Sodium nitroprusside enhanced cardiopulmonary resuscitation improves survival with good neurological function in a porcine model of prolonged cardiac arrest.

2261 Nighttime senior intensivist coverage is an important issue, discussed at the moment in many pediatric intensive care units (PICUs) worldwide. Therefore, studies on this topic are welcome. The specific local circumstances and organization of the PICU and the hospital dictate the optimal medical rosters. In this issue of Critical Care Medicine, Nishisaki et al (1) present their experiences with implementation of 24-hr in-hospital pediatric critical care attending coverage. The special features of their PICU are the following: no admissions of cardiac surgery patients and neonates after birth, low PICU mortality (2.2–2.5%), low proportion of ventilated patients, fairly high proportion of admissions after cardiopulmonary resuscitation on the floor (about 40 patients per year), and high proportion of admissions with malignancy. Senior consultant coverage during nighttime may be especially important in: 1) PICUs with postcardiac surgery patients because the nadir of cardiac function occurs typically 6–12 hrs after separation from cardiopulmonary bypass (2); 2) PICUs with admission of neonates directly after birth because childbirths happen to take place over night; and 3) PICUs with a high proportion of ventilated patients because of artificial ventilation–related complications. These risk factors are not present in the PICU described by Nishisaki et al (1). However, the PICU management of children after cardiac arrest on the ward may benefit from nighttime attendant presence. In a study from Australia, 20% of inhospital cardiac arrests were due to septic shock and 10% were due to upper airway obstruction (3). Because cardiac arrest is usually the culmination of prolonged hypoxemia or circulatory failure, there may be sufficient time to intervene and prevent it (3). Early detection of evolving, still compensated shock or respiratory failure is difficult and needs high clinical experience. Therefore, nighttime senior consultant coverage on the ward may be as important as in PICU. Too often, children need intensive care because of deficiencies in primary health care or care on general pediatric wards (4). Nishisaki et al (1) report on a significant decrease in PIUC length of stay and duration of mechanical ventilation. This fact alone is an important achievement because the duration of mechanical ventilation is associated with complications, such as ventilator associated pneumonia, sepsis, fluid overload and malnutrition, and renal failure. The authors claim that the shorter duration of mechanical ventilation and shorter length of stay are associated with the transition from a 12-hr to a 24-hr in-hospital pediatric critical care attending physician coverage model. I wonder whether this explanation is right or whether the authors should more cautiously state that there is just a significant improvement over time. For the standardized mortality ratio (SMR), calculated with Pediatric Index of Mortality 2 (5), many intensive care units observed an improvement over time and therefore are calling for a recalibration of the score (6). Obviously, intensive care units tend to improve with time. In our PICU in Zurich (around 1,300 admissions per year), we observed a steady improvement of the SMR, along with a decrease in the duration of intubation: mean duration of intubation (unfortunately, medians are not available any more): year 2000: 7.1 days, 2001: 6.6 days, 2002: 6.1 days, 2003: 5.3 days, 2004: 4.5 days, 2005: 5.6 days, 2006: 3.3 days, 2007: 2.6 days, 2008: 2.9 days, 2009: 2.8 days; SMR (95% confidence interval): 2004: 0.99 (0.75, 1.23), 2005: 1.27 (1.02, 1.52), 2006: 0.84 (0.59, 1.09), 2007: 0.74 (0.51, 0.97), 2008: 0.59 (0.36, 0.82), 2009: 0.53 (0.31, 0.75) (B. Frey, unpublished personal data). SMR is calculated from Pediatric Index of Mortality 2, which was released in 2003 (5). For the SMR, mean Pediatric Index of Mortality 2 values were used and the 95% confidence interval were calculated according to Rapoport et al (7). We had no major management changes such as the implementation of 24-hr in hospital attending coverage (in fact, consultants stay in hospital until 11 PM and thereafter are on call at home, obliged to return to the hospital within a maximum of 30 mins, if necessary). However, we had a multitude of subtle changes (improvements) over the last years, such as new guidelines, patient safety measures, improvements in resident/fellow/nursing teaching, strengthening of clinical pharmacy, and hospital hygiene. A further issue of nighttime attendant presence is related to fellow teaching. On one hand, there may be more bedside education provided at nighttime by attending physicians (1). On the other hand, fellows may be more tightly guided by their consultant; they may be less exposed to clinical problems, reducing their autonomy and decision-making skills. Education in intensive care medicine is a tightrope walk between direct supervision and autonomy of the fellow. In conclusion, it seems obvious that nighttime consultant presence improves quality and safety of care. The article by Nishisaki et al (1) adds at least some evidence to this assumption. It is difficult to argue that there is no need of experienced intensivists at the bedside of our sickest patients at night (i.e., half of a 24-hr day!).Objective: To assess the effectiveness of sodium nitroprusside (SNP)-“enhanced” cardiopulmonary resuscitation (SNPeCPR) on 24-hr survival rates compared to standard CPR in animals after cardiac arrest. SNPeCPR consists of large intravenous SNP bolus doses during CPR enhanced by active compression-decompression CPR, an inspiratory impedance threshold device (ITD), and abdominal binding (AB). The combination of active compression-decompression CPR+ITD+AB without SNP will be called “enhanced” or eCPR. Design: Randomized, blinded, animal study. Setting: Preclinical animal laboratory. Subjects: Twenty-four female farm pigs (30 ± 1 kg). Interventions: Isoflurane anesthetized and intubated pigs were randomized after 8 mins of untreated ventricular fibrillation to receive either standard CPR (n = 8), SNPeCPR (n = 8), or eCPR (n = 8) for 25 mins followed by defibrillation. Measurements and Main Results: The primary end point was carotid blood flow during CPR and 24-hr survival with good neurologic function defined as an overall performance category score of ≤2 (1 = normal, 5 = brain dead or dead). Secondary end points included hemodynamics and end-tidal CO2. SNPeCPR significantly improved carotid blood flow and 24-hr survival rates with good neurologic function compared to standard CPR or eCPR (six of eight vs. zero of eight vs. one of eight, p < .05). The improved survival rates were associated with higher coronary perfusion pressure and ETco2 during CPR. Conclusion: In pigs, SNPeCPR significantly improved hemodynamics, resuscitation rates, and 24-hr survival rates with good neurologic function after cardiac arrest when compared with standard CPR or eCPR alone.

Enzyme replacement is associated with better cognitive outcomes after transplant in Hurler syndrome

OBJECTIVE To investigate whether intravenous enzyme replacement therapy (ERT) benefits cognitive function in patients with mucopolysaccharidosis type IH (Hurler syndrome) undergoing hematopoietic cell transplantation (HCT). STUDY DESIGN Data were obtained for 9 children treated with HCT + ERT (ERT group) and 10 children treated with HCT only (no-ERT group) from neuropsychologic evaluations before HCT and at 1-year and 2-year post-HCT follow-up. RESULTS At 2 years after HCT, children in the ERT group lost 9.19 fewer IQ points per year compared with children in the no-ERT group (P = .031). Furthermore, the ERT group improved in nonverbal problem solving and processing, whereas the no-ERT group declined, resulting in a difference of 9.44 points per year between the 2 groups (P < .001). CONCLUSION ERT in association with HCT enhances cognitive outcomes, providing new evidence that ERT is a valuable addition to the standard transplantation protocol. Although the mechanism responsible for this improved outcome is unknown, both direct benefits and indirect effects must be considered.

A Prospective Natural History Study of Mucopolysaccharidosis Type IIIA.

OBJECTIVES To characterize the clinical course of mucopolysaccharidosis type IIIA (MPS IIIA), and identify potential endpoints for future treatment trials. STUDY DESIGN Children with a confirmed diagnosis of MPS IIIA, functioning above a developmental age of 1 year, were followed for up to 2 years. Cognitive status and brain atrophy were assessed by standardized tests and volumetric magnetic resonance imaging, respectively. Liver and spleen volumes and cerebrospinal fluid and urine biomarker levels were measured. RESULTS Twenty-five children, from 1.1 to 18.4 years old, were enrolled, and 24 followed for at least 12 months. 19 exhibited a rapidly progressing (RP) form of MPS IIIA, and 5, a more slowly progressing form. Children with RP plateaued in development by 30 months, followed by rapid regression after 40-50 months. In patients with RP, cognitive developmental quotients showed consistent steep declines associated with progressive cortical gray matter atrophy. Children with slowly progressing had a similar but more prolonged course. Liver and spleen volumes were approximately double normal size, and cerebrospinal fluid and urine heparin sulfate levels were elevated and relatively constant over time. CONCLUSION Developmental quotient and cortical gray matter volume are sensitive markers of disease progression in MPS IIIA, and may have utility as clinical endpoints in treatment trials. For optimal outcomes, treatment may need to be instituted in children before the onset of steep cognitive decline and brain atrophy. TRIAL REGISTRATION ClinicalTrials.gov: NCT01047306.

Changes in inflammation, oxidative stress and adipokines following bariatric surgery among adolescents with severe obesity

Background/Objectives:Inflammation, oxidative stress and dysregulation of adipokines are thought to be pathophysiological mechanisms linking obesity to the development of insulin resistance and atherosclerosis. In adults, bariatric surgery reduces inflammation and oxidative stress, and beneficially changes the levels of several adipokines, but little is known about the postsurgical changes among adolescents.Subjects/Methods:In two separate longitudinal cohorts we evaluated change from baseline of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemo-attractant protein-1 (MCP-1), oxidized low-density lipoprotein cholesterol (oxLDL), adiponectin, leptin and resistin up to 12 months following elective laparoscopic Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG) surgery in adolescents with severe obesity.Results:In cohort 1, which consisted of 39 adolescents (mean age 16.5±1.6 years; 29 females) undergoing either RYGB or VSG, IL-6 (baseline: 2.3±3.4 pg ml−1 vs 12 months: 0.8±0.6 pg ml−1, P<0.01), leptin (baseline: 178±224 ng ml−1 vs 12 months: 41.4±31.9 ng ml−1, P<0.001) and oxLDL (baseline: 41.6±11.6 U l−1 vs 12 months: 35.5±11.1 U l−1, P=0.001) significantly decreased and adiponectin significantly increased (baseline: 5.4±2.4 μg ml−1 vs 12 months: 13.5±8.9 μg ml−1, P<0.001). In cohort 2, which consisted of 13 adolescents (mean age 16.5±1.6 years; 10 females) undergoing RYGB, results were similar: IL-6 (baseline: 1.7±0.9 pg ml−1 vs 12 months: 0.4±0.9 pg ml−1, P<0.05) and leptin (baseline: 92.9±31.3 ng ml−1 vs 12 months: 37.3±33.4 ng ml−1, P<0.001) significantly decreased and adiponectin significantly increased (baseline: 6.1±2.9 μg ml−1 vs 12 months: 15.4±8.0 μg ml−1, P<0.001). When the cohorts were combined to evaluate changes at 12 months, oxLDL also significantly decreased (baseline: 39.8±16.7 U l−1 vs 12 months: 32.7±11.9 U l−1, P=0.03).Conclusions:Bariatric surgery produced robust improvements in markers of inflammation, oxidative stress and several adipokines among adolescents with severe obesity, suggesting potential reductions in risk for type 2 diabetes and cardiovascular disease.