Showing papers by "Boston Children's Hospital published in 2003"

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

Abstract: DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.

Abstract: Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells Together our data indicate that ACE2 is a functional receptor for SARS-CoV

TRP channels as cellular sensors

Abstract: TRP channels are the vanguard of our sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory apparatus for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.

Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.

Abstract: Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common disease1,2,3,4, but are plagued by the impression that they are not consistently reproducible5,6. In principle, the inconsistency may be due to false positive studies, false negative studies or true variability in association among different populations4,5,6,7,8. The critical question is whether false positives overwhelmingly explain the inconsistency. We analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations (P < 10−14). This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. For 8 of these 11 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. Thus, a sizable fraction (but under half) of reported associations have strong evidence of replication; for these, false negative, underpowered studies probably contribute to inconsistent replication. We conclude that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.

Cell fusion is the principal source of bone-marrow-derived hepatocytes

Abstract: Evidence suggests that haematopoietic stem cells might have unexpected developmental plasticity, highlighting therapeutic potential. For example, bone-marrow-derived hepatocytes can repopulate the liver of mice with fumarylacetoacetate hydrolase deficiency and correct their liver disease. To determine the underlying mechanism in this murine model, we performed serial transplantation of bone-marrow-derived hepatocytes. Here we show by Southern blot analysis that the repopulating hepatocytes in the liver were heterozygous for alleles unique to the donor marrow, in contrast to the original homozygous donor cells. Furthermore, cytogenetic analysis of hepatocytes transplanted from female donor mice into male recipients demonstrated 80,XXXY (diploid to diploid fusion) and 120,XXXXYY (diploid to tetraploid fusion) karyotypes, indicative of fusion between donor and host cells. We conclude that hepatocytes derived form bone marrow arise from cell fusion and not by differentiation of haematopoietic stem cells.

Ten-year research update review: child sexual abuse.

Abstract: OBJECTIVE To provide clinicians with current information on prevalence, risk factors, outcomes, treatment, and prevention of child sexual abuse (CSA). To examine the best-documented examples of psychopathology attributable to CSA. METHOD Computer literature searches of and for key words. All English-language articles published after 1989 containing empirical data pertaining to CSA were reviewed. RESULTS CSA constitutes approximately 10% of officially substantiated child maltreatment cases, numbering approximately 88,000 in 2000. Adjusted prevalence rates are 16.8% and 7.9% for adult women and men, respectively. Risk factors include gender, age, disabilities, and parental dysfunction. A range of symptoms and disorders has been associated with CSA, but depression in adults and sexualized behaviors in children are the best-documented outcomes. To date, cognitive-behavioral therapy (CBT) of the child and a nonoffending parent is the most effective treatment. Prevention efforts have focused on child education to increase awareness and home visitation to decrease risk factors. CONCLUSIONS CSA is a significant risk factor for psychopathology, especially depression and substance abuse. Preliminary research indicates that CBT is effective for some symptoms, but longitudinal follow-up and large-scale "effectiveness" studies are needed. Prevention programs have promise, but evaluations to date are limited.

Compensation mechanism in tumor cell migration: mesenchymal–amoeboid transition after blocking of pericellular proteolysis

Abstract: Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.

Sleep duration from infancy to adolescence: reference values and generational trends.

Abstract: Objective. The main purpose of the present study was to calculate percentile curves for total sleep duration per 24 hours, for nighttime and for daytime sleep duration from early infancy to late adolescence to illustrate the developmental course and age-specific variability of these variables among subjects. Methods. A total of 493 subjects from the Zurich Longitudinal Studies were followed using structured sleep-related questionnaires at 1, 3, 6, 9, 12, 18, and 24 months after birth and then at annual intervals until 16 years of age. Gaussian percentiles for ages 3 months to 16 years were calculated for total sleep duration (time in bed) and nighttime and daytime sleep duration. The mean sleep duration for ages 1 to 16 years was estimated by generalized additive models based on the loess smoother; a cohort effect also had to be included. The standard deviation (SD) was estimated from the loess smoothed absolute residuals from the mean curve. For ages 3, 6, and 9 months, an alternative approach with a simple model linear in age was used. For age 1 month, empirical percentiles were calculated. Results. Total sleep duration decreased from an average of 14.2 hours (SD: 1.9 hours) at 6 months of age to an average of 8.1 hours (SD: 0.8 hours) at 16 years of age. The variance showed the same declining trend: the interquartile range at 6 months after birth was 2.5 hours, whereas at 16 years of age, it was only 1.0 hours. Total sleep duration decreased across the studied cohorts (1974–1993) because of increasingly later bedtime but unchanged wake time across decades. Consolidation of nocturnal sleep occurred during the first 12 months after birth with a decreasing trend of daytime sleep. This resulted in a small increase of nighttime sleep duration by 1 year of age (mean 11.0 ± 1.1 hours at 1 month to 11.7 ± 1.0 hours at 1 year of age). The most prominent decline in napping habits occurred between 1.5 years of age (96.4% of all children) and 4 years of age (35.4%). Conclusions. Percentile curves provide valuable information on developmental course and age-specific variability of sleep duration for the health care professional who deals with sleep problems in pediatric practice.

Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia

Abstract: We report here that individuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic mutations in PTPN11 account for 34% of non-syndromic JMML. Furthermore, we found mutations in PTPN11 in a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML). Functional analyses documented that the two most common mutations in PTPN11 associated with JMML caused a gain of function.

PIM2: a revised version of the Paediatric Index of Mortality

Abstract: To revise the Paediatric Index of Mortality (PIM) to adjust for improvement in the outcome of paediatric intensive care. International, multi-centre, prospective, observational study. Twelve specialist paediatric intensive care units and two combined adult and paediatric units in Australia, New Zealand and the United Kingdom. All children admitted during the study period. In the analysis, 20,787 patient admissions of children less than 16 years were included after 220 patients transferred to other ICUs and one patient still in ICU had been excluded. None. A revised model was developed by forward and backward logistic regression. Variable selection was based on the effect of including or dropping variables on discrimination and fit. The addition of three variables, all derived from the main reason for ICU admission, improved the fit across diagnostic groups. Data from seven units were used to derive a learning model that was tested using data from seven other units. The model fitted the test data well (deciles of risk goodness-of-fit χ2 8.14, p=0.42) and discriminated between death and survival well [area under the receiver operating characteristic (ROC) plot 0.90 (0.89–0.92)]. The final PIM2 model, derived from the entire sample of 19,638 survivors and 1,104 children who died, also fitted and discriminated well [χ2 11.56, p=0.17; area 0.90 (0.89–0.91)]. PIM2 has been re-calibrated to reflect the improvement that has occurred in intensive care outcome. PIM2 estimates mortality risk from data readily available at the time of ICU admission and is therefore suitable for continuous monitoring of the quality of paediatric intensive care.

Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using 'real-time' quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) - a Europe against cancer program

Abstract: Real-time quantitative RT-PCR (RQ-PCR) is a sensitive tool to monitor minimal residual disease (MRD) in leukemic patients through the amplification of a fusion gene (FG) transcript. In order to correct variations in RNA quality and quantity and to calculate the sensitivity of each measurement, a control gene (CG) transcript should be amplified in parallel to the FG transcript. To identify suitable CGs, a study group within the Europe Against Cancer (EAC) program initially focused on 14 potential CGs using a standardized RQ-PCR protocol. Based on the absence of pseudogenes and the level and stability of the CG expression, three genes were finally selected: Abelson (ABL), beta-2-microglobulin (B2M), and beta-glucuronidase (GUS). A multicenter prospective study on normal (n=126) and diagnostic leukemic (n=184) samples processed the same day has established reference values for the CG expression. A multicenter retrospective study on over 250 acute and chronic leukemia samples obtained at diagnosis and with an identified FG transcript confirmed that the three CGs had a stable expression in the different types of samples. However, only ABL gene transcript expression did not differ significantly between normal and leukemic samples at diagnosis. We therefore propose to use the ABL gene as CG for RQ-PCR-based diagnosis and MRD detection in leukemic patients. Overall, these data are not only eligible for quantification of fusion gene transcripts, but also for the quantification of aberrantly expressed genes.

Human Decidual Natural Killer Cells Are a Unique NK Cell Subset with Immunomodulatory Potential

Abstract: Natural killer cells constitute 50–90% of lymphocytes in human uterine decidua in early pregnancy. Here, CD56bright uterine decidual NK (dNK) cells were compared with the CD56bright and CD56dim peripheral NK cell subsets by microarray analysis, with verification of results by flow cytometry and RT-PCR. Among the ∼10,000 genes studied, 278 genes showed at least a threefold change with P ≤ 0.001 when comparing the dNK and peripheral NK cell subsets, most displaying increased expression in dNK cells. The largest number of these encoded surface proteins, including the unusual lectinlike receptors NKG2E and Ly-49L, several killer cell Ig-like receptors, the integrin subunits αD, αX, β1, and β5, and multiple tetraspanins (CD9, CD151, CD53, CD63, and TSPAN-5). Additionally, two secreted proteins, galectin-1 and progestagen-associated protein 14, known to have immunomodulatory functions, were selectively expressed in dNK cells.

ACTN3 Genotype Is Associated with Human Elite Athletic Performance

Abstract: There is increasing evidence for strong genetic influences on athletic performance and for an evolutionary “trade-off” between performance traits for speed and endurance activities. We have recently demonstrated that the skeletal-muscle actin-binding protein α-actinin-3 is absent in 18% of healthy white individuals because of homozygosity for a common stop-codon polymorphism in the ACTN3 gene, R577X. α-Actinin-3 is specifically expressed in fast-twitch myofibers responsible for generating force at high velocity. The absence of a disease phenotype secondary to α-actinin-3 deficiency is likely due to compensation by the homologous protein, α-actinin-2. However, the high degree of evolutionary conservation of ACTN3 suggests function(s) independent of ACTN2. Here, we demonstrate highly significant associations between ACTN3 genotype and athletic performance. Both male and female elite sprint athletes have significantly higher frequencies of the 577R allele than do controls. This suggests that the presence of α-actinin-3 has a beneficial effect on the function of skeletal muscle in generating forceful contractions at high velocity, and provides an evolutionary advantage because of increased sprint performance. There is also a genotype effect in female sprint and endurance athletes, with higher than expected numbers of 577RX heterozygotes among sprint athletes and lower than expected numbers among endurance athletes. The lack of a similar effect in males suggests that the ACTN3 genotype affects athletic performance differently in males and females. The differential effects in sprint and endurance athletes suggests that the R577X polymorphism may have been maintained in the human population by balancing natural selection.

Theta and Gamma Oscillations during Encoding Predict Subsequent Recall

Abstract: Electrophysiological and hemodynamic measures of human brain activity have been shown to distinguish between episodes of encoding items that are later recalled versus those that are not recalled (Paller and Wagner, 2002). Using intracranial recordings from 793 widespread cortical and subcortical sites in 10 epileptic patients undergoing invasive monitoring, we compared oscillatory power at frequencies ranging from 2 to 64 Hz as participants studied lists of common nouns. Significant increases in oscillatory power during encoding predicted subsequent recall, with this effect predominantly in the 4-8 Hz (theta) and 28-64 Hz (gamma) frequency bands. Sites exhibiting increased theta activity during successful encoding were clustered in right temporal and frontal cortex, whereas those exhibiting increased gamma activity appeared bilaterally at widespread cortical locations. These findings implicate theta and gamma oscillatory activity, across a widespread network of cortical regions, in the formation of new episodic memories.

The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.

Abstract: Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon γ–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

Diagnosis and phenotypic classification of Wilson disease

Abstract: Wilson disease is an inherited autosomal recessive disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs such as the brain and the cornea. Originally Wilson disease was described as a neurodegerative disorder associated with cirrhosis of the liver. Later, Wilson disease was observed in children and adolescents presenting with acute or chronic liver disease without any neurologic symptoms. While diagnosis of neurologic Wilson disease is straightforward, it may be quite difficult in non-neurologic cases. Up to now, no single diagnostic test can exclude or confirm Wilson disease with 100% certainty. In 1993, the gene responsible for Wilson disease was cloned and localized on chromosome 13q14.3 (MIM277900) (1, 2). The Wilson disease gene ATP7B encodes a P-type ATPase. More than 200 disease causing mutations of this gene have been described so far (3). Most of these mutations occur in single families, only a few are more frequent (like H1069Q, 3400delC and 2299insC in Caucasian (4-6) or R778L in Japanese (7), Chinese and Korean patients). Studies of phenotype-genotype relations are hampered by the lack of standard diagnostic criteria and phenotypic classifications. To overcome this problem, a working party discussed these problems in depth at the 8th International Meeting on Wilson disease and Menkes disease in Leipzig/Germany (April 16-18, 2001). After the meeting, a preliminary draft of a consensus report was mailed to all active participants and their comments were incorporated in the final text.

A readers' guide to the interpretation of diagnostic test properties: clinical example of sepsis.

Abstract: One of the most challenging practical and daily problems in intensive care medicine is the interpretation of the results from diagnostic tests. In neonatology and pediatric intensive care the early diagnosis of potentially life-threatening infections is a particularly important issue. A plethora of tests have been suggested to improve diagnostic decision making in the clinical setting of infection which is a clinical example used in this article. Several criteria that are critical to evidence-based appraisal of published data are often not adhered to during the study or in reporting. To enhance the critical appraisal on articles on diagnostic tests we discuss various measures of test accuracy: sensitivity, specificity, receiver operating characteristic curves, positive and negative predictive values, likelihood ratios, pretest probability, posttest probability, and diagnostic odds ratio. We suggest the following minimal requirements for reporting on the diagnostic accuracy of tests: a plot of the raw data, multilevel likelihood ratios, the area under the receiver operating characteristic curve, and the cutoff yielding the highest discriminative ability. For critical appraisal it is mandatory to report confidence intervals for each of these measures. Moreover, to allow comparison to the readers' patient population authors should provide data on study population characteristics, in particular on the spectrum of diseases and illness severity.

Primary Metastatic Osteosarcoma: Presentation and Outcome of Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols

Abstract: Purpose: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. Patients and Methods: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. Results: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respe...

Pulmonary Alveolar Proteinosis

Abstract: Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterised by alveolar accumulation of surfactant. It may result from mutations in surfactant proteins or granulocyte macrophage-colony stimulating factor (GM-CSF) receptor genes, it may be secondary to toxic inhalation or haematological disorders, or it may be auto-immune, with anti- GM-CSF antibodies blocking activation of alveolar macrophages. Auto-immune alveolar proteinosis is the most frequent form of PAP, representing 90% of cases. Although not specific, high-resolution computed tomography shows a characteristic ''crazy paving'' pattern. In most cases, bronchoalveolar lavage findings establish the diagnosis. Whole lung lavage is the most effective therapy, especially for auto-immune disease. Novel therapies targeting alveolar macrophages (recombinant GM-CSF therapy) or anti-GM-CSF antibodies (rituximab and plasmapheresis) are being investigated. Our knowledge of the pathophysiology of PAP has improved in the past 20 yrs, but therapy for PAP still needs improvement.

Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen.

Abstract: Splenectomized and asplenic patients have a high incidence of infections by encapsulated bacteria and do not respond to polysaccharide vaccines. To understand whether the absence of the spleen is associated with a defined B cell defect, we analyzed B cell subsets in the peripheral blood. We found that a population of B cells known as immunoglobulin (Ig)M memory is lacking in patients without spleen. The absence of IgM memory B cells correlates with an impaired immune response to encapsulated bacteria not only in splenectomized patients, but also in individuals with an intact spleen. We show that the physiological and transient predisposition to pneumococcal infections of young children (0-2 yr) is associated with the lack of circulating IgM memory B cells and of serum antipolysaccharide IgM. We also demonstrate that IgM memory B cells are undetectable in a fraction of patients with common variable immunodeficiency, who have recurrent and invasive infections by encapsulated bacteria. IgM memory B cells, therefore, require the spleen for their generation and/or survival and are responsible for the protection against encapsulated bacteria.

Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis—State of the Art: Cystic Fibrosis Foundation Consensus Conference

Abstract: Because of the difficulties of recognizing allergic bronchopulmonary aspergillosis (ABPA) in the context of cystic fibrosis (because of overlapping clinical, radiographic, microbiologic, and immunologic features), advances in our understanding of the pathogenesis of allergic aspergillosis, new possibilities in therapy, and the need for agreed-upon definitions, an international consensus conference was convened. Areas addressed included fungal biology, immunopathogenesis, insights from animal models, diagnostic criteria, epidemiology, the use of new immunologic and genetic techniques in diagnosis, imaging modalities, pharmacology, and treatment approaches. Evidence from the existing literature was graded, and the consensus views were synthesized into this document and recirculated for affirmation. Virulence factors in Aspergillus that could aggravate these diseases, and particularly immunogenetic factors that could predispose persons to ABPA, were identified. New information has come from transgenic animals and recombinant fungal and host molecules. Diagnostic criteria that could provide a framework for monitoring were adopted, and helpful imaging features were identified. New possibilities in therapy produced plans for managing diverse clinical presentations.

Relation between dieting and weight change among preadolescents and adolescents.

Abstract: Objective. To assess whether dieting to control weight was associated with weight change among children and adolescents. Methods. A prospective study was conducted of 8203 girls and 6769 boys who were 9 to 14 years of age in 1996, were in an ongoing cohort study, and completed at least 2 annual questionnaires between 1996 and 1999. Dieting to control weight, binge eating, and dietary intake were assessed annually from 1996 through 1998 with instruments designed specifically for children and adolescents. The outcome measure was age- and sex-specific z score of body mass index (BMI). Results. In 1996, 25.0% of the girls and 13.8% of the boys were infrequent dieters and 4.5% of the girls and 2.2% of the boys were frequent dieters. Among the girls, the percentage of dieters increased over the following 2 years. Binge eating was more common among the girls, but in both sexes, it was associated with dieting to control weight (girls: infrequent dieters, odds ratio [OR]: 5.10; frequent dieters, OR: 12.4; boys: infrequent dieters, OR: 3.49; frequent dieters, OR: 7.30). During 3 years of follow-up, dieters gained more weight than nondieters. Among the girls, frequency of dieting was positively associated with increases in age- and sex-specific z scores of BMI (β = 0.05 and β = 0.04 for frequent and infrequent dieters vs nondieters). Among the boys, both frequent and infrequent dieters gained 0.07 z scores of BMI more than nondieters. In addition, boys who engaged in binge eating gained significantly more weight than nondieters. Conclusions. Although medically supervised weight control may be beneficial for overweight youths, our data suggest that for many adolescents, dieting to control weight is not only ineffective, it may actually promote weight gain.