Nemours Children's Clinic

Neurodegenerative disorders are characterized by progressive loss of selectively vulnerable populations of neurons, which contrasts with select static neuronal loss because of metabolic or toxic disorders. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormality. The most common neurodegenerative disorders are amyloidoses, tauopathies, α-synucleinopathies, and TDP-43 proteinopathies. The protein abnormalities in these disorders have abnormal conformational properties. Growing experimental evidence suggests that abnormal protein conformers may spread from cell to cell along anatomically connected pathways, which may in part explain the specific anatomical patterns observed at autopsy. In this review, we detail the human pathology of select neurodegenerative disorders, focusing on their main protein aggregates.

BACKGROUND: Previous reports have indicated high complication rates associated with non-fusion surgery in patients with early-onset scoliosis. This study was performed to evaluate the clinical and radiographic complications associated with growing-rod treatment. METHODS: Data from the multicenter Growing Spine Study Group database were evaluated. Inclusion criteria were growing-rod treatment for early-onset scoliosis and a minimum of two years of follow-up. Patients were divided into treatment groups according to rod type (single or dual) and rod location (subcutaneous or submuscular). Complications were categorized as wound, implant, alignment, and general (surgical or medical). Surgical procedures were classified as planned and unplanned. RESULTS: Between 1987 and 2005, 140 patients met the inclusion criteria and underwent a total of 897 growing-rod procedures. The mean age at the initial surgery was six years, and the mean duration of follow-up was five years. Eighty-one (58%) of the 140 patients had a minimum of one complication. Nineteen (27%) of the seventy-one patients with a single rod had unplanned procedures because of implant complications, compared with seven (10%) of the sixty-nine patients with dual rods (p ≤ 0.05). Thirteen (26%) of the fifty-one patients with subcutaneous rod placement had wound complications compared with nine of the eighty-eight patients (10%) with submuscular rod placement (p ≤ 0.05). The patients with subcutaneous dual rods had more wound complications, more prominent implants, and more unplanned surgical procedures than did those with submuscular dual rods (p ≤ 0.05). The risk of complications occurring during the treatment period decreased by 13% for each year of increased patient age at the initiation of treatment. The complication risk increased by 24% for each additional surgical procedure performed. CONCLUSIONS: Regardless of treatment modality, the management of early-onset scoliosis is prolonged; therefore, complications are frequent and should be expected. Complications can be reduced by delaying initial implantation of the growing rods if possible, using dual rods, and limiting the number of lengthening procedures. Submuscular placement reduces wound and implant-prominence complications and reduces the number of unplanned operations.

BACKGROUND: Uncuffed endotracheal tubes are routinely used in young children. This study tests a formula for selecting appropriately sized cuffed endotracheal tubes and compares the use of cuffed versus uncuffed endotracheal tubes for patients whose lungs are mechanically ventilated during anesthesia. METHODS: Full-term newborns and children (n = 488) through 8 yr of age who required general anesthesia and tracheal intubation were assigned randomly to receive either a cuffed tube sized by a new formula [size(mm internal diameter) = (age/4) + 3], or an uncuffed tube sized by the modified Cole's formula [size(mm internal diameter) = (age/4) + 4]. The number of intubations required to achieve an appropriately sized tube, the need to use more than 21.min-1 fresh gas flow, the concentration of nitrous oxide in the operating room, and the incidence of croup were compared. RESULTS: Cuffed tubes selected by our formula were appropriate for 99% of patients. Uncuffed tubes selected by Cole's formula were appropriate for 77% of patients (P < 0.001). The lungs of patients with cuffed tubes were adequately ventilated with 2 1.min-1 fresh gas flow, whereas 11% of those with uncuffed tubes needed greater fresh gas flow (P < 0.001). Ambient nitrous oxide concentration exceeded 25 parts per million in 37% of cases with uncuffed tubes and in 0% of cases with cuffed tubes (P < 0.001). Three patients in each group were treated for croup symptoms (1.2% cuffed; 1.3% uncuffed). CONCLUSIONS: Our formula for cuffed tube selection is appropriate for young children. Advantages of cuffed endotracheal tubes include avoidance of repeated laryngoscopy, use of low fresh gas flow, and reduction of the concentration of anesthetics detectable in the operating room. We conclude that cuffed endotracheal tubes may be used routinely during controlled ventilation in full-term newborns and children during anesthesia.

Body composition exhibits marked variations across the early human lifetime. The precise physiological mechanisms that drive such developmental adaptations are difficult to establish. This clinical challenge reflects an array of potentially confounding factors, such as marked intersubject differences in tissue compartments; the incremental nature of longitudinal intrasubject variations in body composition; technical limitations in quantitating the unobserved mass of mineral, fat, water, and muscle ad seriatim; and the multifold contributions of genetic, dietary, environmental, hormonal, nutritional, and behavioral signals to physical and sexual maturation. From an endocrine perspective (reviewed here), gonadal sex steroids and GH/IGF-I constitute prime determinants of evolving body composition. The present critical review examines hormonal regulation of body composition in infancy, childhood, and puberty.

Prednisone treatment causes protein wasting and adds additional risks to a patient, whereas human growth hormone (hGH) treatment causes positive nitrogen balance. To determine whether concomitant administration of hGH prevents the protein catabolic effects of prednisone, four groups of eight healthy volunteers each were studied using isotope dilution and nitrogen balance techniques after 7 d of placebo, hGH alone (0.1 mg.kg-1.d-1), prednisone alone (0.8 mg.kg-1.d-1), or prednisone plus hGH (n = 8 in each group). Whether protein balance was calculated from the leucine kinetic data or nitrogen balance values, prednisone alone induced protein wasting (P less than 0.001), whereas hGH alone resulted in positive (P less than 0.001) protein balance, when compared to the placebo-treated subjects. When hGH was added to prednisone therapy, the glucocorticoid-induced protein catabolism was prevented. Using leucine kinetic data, negative protein balance during prednisone was due to increased (P less than 0.05) proteolysis, whereas hGH had no effect on proteolysis and increased (P less than 0.01) whole body protein synthesis. During combined treatment, estimates of proteolysis and protein synthesis were similar to those observed in the placebo treated control group. In conclusion, human growth hormone may have a distinct role in preventing the protein losses associated with the administration of pharmacologic doses of glucocorticosteroids in humans.

To investigate specific effects of androgens on whole body metabolism, we studied six healthy lean men (mean +/- SEM age, 23.2 +/- 0.5 yr) before and after gonadal steroid suppression with a GnRH analog (Lupron), given twice, 3 weeks apart. Primed infusions of [13C]leucine, indirect calorimetry, isokinetic dynamometry, growth factor measurements, and percutaneous muscle biopsies were performed at baseline (D1) and after 10 weeks of treatment (D2); each subject served as his own control. Testosterone concentrations were markedly suppressed after 10 weeks of treatment (D1, 535 +/- 141 ng/dL; D2, 31 +/- 9). Leucine's rate of appearance (index of proteolysis) was markedly suppressed after 10 weeks of hypogonadism (-13%; P = 0.01) as well as the nonoxidative leucine disposal, an index of whole body protein synthesis (-13%; P = 0.01) without any changes in plasma amino acid concentrations. All subjects studied after 10 weeks showed a decrease in fat-free mass, as measured by skinfold calipers and dual emission x-ray absortiometry scans (D1, 56.5 +/- 2.9 kg; D2, 54.4 +/- 2.5; P = 0.005), and an increase in percent fat mass (D1, 19.2 +/- 2.5%; D2, 22.2 +/- 2.5; P = 0.001). Rates of lipid oxidation decreased (-31%; P = 0.05) after treatment, with parallel changes in resting energy expenditure (-9%; P = 0.05). Mean and peak GH concentrations (measured every 10 min for 6 h) and GH production rates did not decrease after testosterone deficiency, with an actual increase in basal secretion (P < 0.02). Plasma insulin-like growth factor I (IGF-I) concentrations did not change significantly after 10 weeks of treatment (D1, 227 +/- 44 micrograms/L; D2, 291 +/- 60; P = 0.08). Isokinetic dynamometry of leg extensors at 60 degrees and 180 degrees/s was also decreased after 10 weeks of hypogonadism. Total ribonucleic acid (RNA) was isolated from muscle biopsy samples, and ribonuclease protection assays were performed using human complementary DNA clones for IGF-I, IGF-binding protein-4, myosin, and actin. Ten weeks after Lupron treatment, messenger RNA (mRNA) concentrations of IGF-I decreased significantly, whereas there was a trend toward higher IGF-binding protein-4 concentrations, with no change in myosin or actin mRNA concentrations. In conclusion, testosterone deficiency in young men is associated with a marked decrease in measures of whole body protein anabolism, decreased strength, decreased fat oxidation, and increased adiposity. These effects of testosterone deficiency are independent of changes in peripheral GH production and IGF-I concentrations, even though im IGF-I mRNA concentrations decrease. These data suggest a direct effect of androgens on whole body lipid and protein metabolism.

Probiotics are widely used by patients with Crohn's disease (CD) in an attempt to improve their health, but few controlled studies have been done to evaluate the efficacy of these therapies. We conducted a randomized, placebo-controlled trial of the probiotic Lactobacillus rhamnosus strain GG (LGG) to see if the addition of LGG to standard therapy prolonged remission in children with CD. Concomitant medications allowed in the study included aminosalicylates, 6-mercaptopurine, azathioprine, and low-dose alternate day corticosteroids. Seventy-five children (age range, 5-21 yr) with CD in remission were randomized to either LGG (n=39) or placebo (n=36) and followed for up to 2 years. The median time to relapse was 9.8 months in the LGG group and 11.0 months in the placebo group (P=0.24); 31% (12/39) of patients in the LGG group developed a relapse compared with 6/36 (17%) of the placebo group (P=0.18). The LGG was well tolerated, with a side effect profile comparable with placebo. This study suggests that LGG does not prolong time to relapse in children with CD when given as an adjunct to standard therapy.

BACKGROUND AND OBJECTIVES: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions. METHODS: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol. RESULTS: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean +/- SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 +/- 10.4, 32.2 +/- 12.7, and 47.8 +/- 14.9, respectively (P < 0.001 for all comparisons). Mean +/- SD PCDAI for inactive disease after treatment was 5.2 +/- 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of > or = 30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of > or = 12.5 points, and 3) a PCDAI < 10 best reflected inactive disease. CONCLUSIONS: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of > or = 30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

OBJECTIVE: To review key advances in the behavioral science literature related to psychosocial issues and therapies for persons with diabetes, to discuss barriers to research progress, and to make recommendations for future research. RESEARCH DESIGN AND METHODS: Key findings from the literature on psychosocial research in diabetes are reviewed separately for children and adults. Specific issues covered include psychosocial adjustment and psychiatric disorders, neurocognitive functioning, quality of life, and psychosocial therapies. Barriers that must be addressed to allow research in this area to progress are discussed. Recommendations are then made concerning high-priority areas for advancing research in the field. CONCLUSIONS: A substantial amount of behavioral science research has demonstrated that psychosocial factors play an integral role in the management of diabetes in both children and adults. Research has also shown the efficacy of a number of psychosocial therapies that can improve regimen adherence, glycemic control, psychosocial functioning, and quality of life. More research in this area is needed to develop psychosocial intervention programs for specific patient populations and to demonstrate the cost-effectiveness of these approaches.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

BACKGROUND: We evaluated the psychometric performance of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in a real-life cohort from the Pediatric IBD Collaborative Research Group. METHODS: Two consecutive visits of 215 children with ulcerative colitis (UC) were included (mean age 11.2 +/- 3.6 years; 112 (52%) males; 63 (29%) newly diagnosed and the others after disease duration of 24 +/- 15.6 months). Validity was assessed using several constructs of disease activity. Distributional and anchor-based strategies were used to assess the responsiveness of the PUCAI to change over time following treatment. RESULTS: Reflecting feasibility, 97.6% of 770 eligible registry visits had a completed PUCAI score versus only 47.6% for a contemporaneously collected Pediatric Crohn's Disease Activity Index (odds ratio = 45.8, 95% confidence interval [CI] 28.6-73.5) obtained for children with Crohn's disease accessioned into the same database. The PUCAI score was significantly higher in patients requiring escalation of medical therapy (45 points [interquartile range, IQR, 30-60]) versus those who did not, (0 points [IQR 0-10]; P < 0.001), and was highly correlated with physician's global assessment of disease activity (r = 0.9, P < 0.001). The best cutoff to differentiate remission from active disease was 10 points (area under receiver operating characteristic curve [AUC] 0.94; 95% CI 0.90-0.97). Test-retest reliability was excellent (intraclass correlation coefficient = 0.89; 95% CI 0.84-0.92, P < 0.001) as well as responsiveness to change (AUC 0.96 [0.92-0.99]; standardized response mean 2.66). CONCLUSION: This study on real-life, prospectively obtained data confirms that the PUCAI is highly feasible by virtue of the noninvasiveness, valid, and responsive index. The PUCAI can be used as a primary outcome measure to reflect disease activity in pediatric UC.

Previous classification systems of failure of limb salvage focused primarily on endoprosthetic failures and lacked sufficient depth for the effective study of the causes of failure. In order to address these inadequacies, the International Society of Limb Salvage (ISOLS) formed a committee to recommend revisions of the previous systems. The purpose of this study was to report on their recommendations. The modifications were prepared using an earlier, evidence-based model with subclassification based on the existing medical literature. Subclassification for all five primary types of failure of limb salvage following endoprosthetic reconstruction were formulated and a complementary system was derived for the failure of biological reconstruction. An additional classification of failure in paediatric patients was also described. Limb salvage surgery presents a complex array of potential mechanisms of failure, and a complete and precise classification of types of failure is required. Earlier classification systems lacked specificity, and the evidence-based system outlined here is designed to correct these weaknesses and to provide a means of reporting failures of limb salvage in order to allow the interpretation of outcome following reconstructive surgery.

OBJECTIVE: Treatment of IDDM in youth emphasized balancing children's self-care autonomy with their psychological maturity. However, few data exist to guide clinicians or parents, and little is known about correlates of deviations from this ideal. RESEARCH DESIGN AND METHODS: In this cross-sectional study, IDDM self-care autonomy of 100 youth was assessed using two well-validated measures. Three measures of psychological maturity (cognitive function, social-cognitive development, and academic achievement) were also collected for each child. Composite indexes of self-care autonomy and of psychological maturity were formed, and the ratio of the self-care autonomy index to the psychological maturity index quantified each child's deviation from developmentally appropriate IDDM self-care autonomy. Based on these scores, participants were categorized as exhibiting constrained (lower tertile), appropriate (middle tertile), or excessive (higher tertile) self-care autonomy. Between-group differences in treatment adherence, diabetes knowledge, glycemic control, and hospitalization rates were explored. RESULTS: Analysis of covariance controlling for age revealed that the excessive self-care autonomy group demonstrated less favorable treatment adherence, diabetes knowledge, hospitalization rates, and, marginally, glycemic control. Excessive self-care autonomy increased with age and was less common among intact two-parent families but was unrelated to other demographic factors. CONCLUSIONS: The findings indicate caution about encouragement of maximal self-care autonomy among youth with IDDM and suggest that families who succeed in maintaining parental involvement in diabetes management may have better outcomes.

PURPOSE: To assess neurocognitive and behavioral performance in children with idiopathic epilepsy (CWE, n = 74), their siblings without epilepsy (control, n = 23), and children with migraine (CWM, n = 13), and to identify medical factors related to learning or behavioral problems in CWE. METHODS: Subjects, ages 8-13 years with IQs of >/=80, completed a neurocognitive test battery annually for </=3 years. For CWE, age at seizure onset, most recent EEG results, seizure type, seizure frequency, current antiepileptic drug (AED), and most recent AED serum levels were documented at each visit. RESULTS: CWE and CWM had high rates of grade retention and placement in special education compared with sibling controls. CWE performed worse than controls on numerous neurocognitive variables. These differences persisted over time. CWE with abnormal EEGs scored lower than CWE with normal EEGs on reading and spelling measures, even with comparable IQs. Age at seizure onset, seizure type, and seizure frequency were not related to neurocognitive or behavioral test scores. CWE taking carbamazepine (CBZ) performed better than CWE taking valproate (VPA) on academic achievement measures, although the study lacked controls necessary to assess this finding thoroughly. CWM did not differ from CWE or controls in cognitive or academic achievement skills. CONCLUSIONS: Long-term risk of learning problems exists among CWE as compared with controls, even with normal IQs and well-controlled seizures. Predicting learning problems in CWE based on medical factors remains elusive. Monitoring of educational progress and neurocognitive screening may be most effective in assessing academic risk for CWE.

STUDY DESIGN: Retrospective review. OBJECTIVE: To compare the incidence of and risk factors for proximal junctional kyphosis (PJK) in adolescent idiopathic scoliosis (AIS) following posterior spinal fusion using hook, pedicle screw, or hybrid constructs. SUMMARY OF BACKGROUND DATA: Proximal junctional kyphosis is a recently recognized phenomenon in adults and adolescents after AIS surgery. The postoperative effect on PJK with the use of hooks, hybrid constructs, or screws has not been compared in a multicenter study to date. METHODS: From a multicenter database, the preoperative and 2-year follow-up radiographic measurements from 283 patients with AIS treated with posterior spinal fusion using hooks (group 1, n = 51), hybrid constructs (group 2, n = 177), pedicle screws (group 3, n = 37), and pedicle screws with hooks only at the top level (group 4, n = 18) were compared. RESULTS: The average proximal level kyphosis at 2 years after surgery was 8.2 degrees (range -1 to 18) in the all screw constructs, representing a significant increase when compared with hybrid and all hook constructs, 5.7 degrees (P = 0.02) and 5.0 degrees (P = 0.014), respectively. Conversely, average postoperative T5-T12 kyphosis was significantly less (P = 0.016) in the screw group compared with the all hook group. Of potential interest, but currently not statistically significant, was the trend towards a decrease in proximal kyphosis in constructs with all pedicle screws except hooks at the most cephalad segment, 6.4 degrees . The incidence of PJK (assuming PJK is a kyphotic deformity greater than 15 degrees ) was 0% in group 1, 2.3% in group 2, 8.1% in group 3, and 5.6% in group 4 (P = 0.18). Patients with PJK had an increased body mass index compared with those who did not meet criteria for PJK (P = 0.013). CONCLUSION: Adjacent level proximal kyphosis was significantly increased with pedicle screws, but the clinical significance of this is unclear. A potential solution is the substitution of hooks at the upper-instrumented vertebrae, but further investigation is required.

OBJECTIVE: To describe the short-term results of a controlled trial of Behavioral Family Systems Therapy (BFST) for families of adolescents with diabetes. METHODS: We randomized 119 families of adolescents with diabetes to 3 months' treatment with either BFST, an education and support Group (ES), or current therapy (CT). Family relationships, psychological adjustment to diabetes, treatment adherence and diabetic control were assessed at baseline, after 3 months of treatment (reported here), and 6 and 12 months later. RESULTS: Compared with CT and ES, BFST yielded more improvement in parent-adolescent relations and reduced diabetes-specific conflict. Effects on psychological adjustment to diabetes and diabetic control were less robust and depended on the adolescent's age and gender. There were no effects on treatment adherence. CONCLUSIONS: BFST yielded some improvement in parent-adolescent relationships; its effects on diabetes outcomes depended on the adolescent's age and gender. Factors mediating the effectiveness of BFST must be clarified.

Patient satisfaction is an individual's cognitive evaluation of, and emotional reaction to, his or her health-care experience. This concept is increasing in importance as survey data are being used by health-care facilities for self-assessment, accreditation requirements, and compensation formulas. High patient satisfaction is associated with increased market share, financial gains, decreased malpractice claims, and improved reimbursement rates. Modifiable factors that contribute to satisfaction include physician-patient communication, the setting of appropriate expectations, minimization of waiting times, and provision of continuity of care. There are also factors that are less amenable to change, including chronic illness, opioid dependence, and sociodemographic status. Satisfaction with a surgical outcome differs from satisfaction with an office visit. Accurate expectations and patient-reported outcome measures are important determinants of satisfaction after a surgical procedure. Physicians can improve patient satisfaction in their practice by understanding the implications of satisfaction and the predictors of success.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

CONTEXT: Retinol binding protein (RBP4), secreted primarily from the liver and adipose tissues, was recently proposed as a link between obesity and insulin resistance. The role of RBP4 in pediatric obesity, its relationship with subclinical inflammation, and its response to lifestyle changes are not elucidated. OBJECTIVE: The objective of the study was to determine in children: 1) the status of RBP4 levels in lean vs. obese; 2) the relationship between RBP4 levels and subclinical inflammation; and 3) the effect of lifestyle-only intervention on RBP4 levels. DESIGN, SETTING, AND PATIENTS: Lean and obese children (n = 21) matched for age (>14 yr to < 18 yr) and maturity stage (Tanner IV) were studied at baseline and with lifestyle intervention in obese subjects only (n = 15). INTERVENTION: Patients received 3 months of randomized and controlled physical activity-based lifestyle intervention. MAIN OUTCOME MEASURE: RBP4 levels in children before and after intervention and the relationship between RBP4 and subclinical inflammation were measured. RESULTS: Higher RBP4 levels were found in the obese group vs. lean group (P = 0.005). RBP4 correlated with not only indices of obesity and insulin resistance but also inflammatory factors (r = 0.63 and 0.64 for C-reactive protein and IL-6, respectively, P < 0.01). Intervention reduced RBP4 levels by approximately 30% (P = 0.001), and RBP4 reduction was correlated with the magnitude of decrease in inflammatory factors (P = 0.01). CONCLUSION: Alterations in serum RBP4 occur at an early age in the clinical course of obesity and appear to correlate with subclinical inflammation. Lifestyle intervention almost entirely reversed the raised RBP4 levels in obese children. Future studies should determine whether elevation of RBP4 is a direct trigger for the insulin resistance and subclinical inflammation implicated in the premature development of cardiovascular disease and diabetes.

Activation of the gonadotropic and somatotropic axes in puberty is marked by striking amplification of pulsatile neurohormone secretion. In addition, each axis, as a whole, constitutes a regulated network whose feedback relationships are likely to manifest important changes at the time of puberty. Here, we use the regularity statistic, approximate entropy (ApEn), to assess feedback activity within the somatotropic (hypothalamo-pituitary/GH-insulin-like growth factor I) axis indirectly. To this end, we studied pubertal boys and prepubertal girls or boys with sex-steroid hormone deficiency treated short-term with estrogen, testosterone, or a nonaromatizable androgen in a total of 3 paradigms. First, our cross-sectional analysis of 53 boys at various stages of puberty or young adulthood revealed that mean ApEn, taken as a measure of feedback complexity, of 24-h serum GH concentration profiles is maximal in pre- and mid-late puberty, followed by a significant decline in postpubertal adolescence and young adulthood (P = 0.0008 by ANOVA). This indicates that marked disorderliness of the GH release process occurs in mid-late puberty at or near the time of peak growth velocity, with a return to maximal orderliness thereafter at reproductive maturity. Second, oral administration of ethinyl estradiol for 5 weeks to 7 prepubertal girls with Turner's syndrome also augmented ApEn significantly (P = 0.018), thus showing that estrogen per se can induce greater irregularity of GH secretion. Third, in 5 boys with constitutionally delayed puberty, im testosterone administration also significantly increased ApEn of 24-h GH time series (P = 0.0045). In counterpoint, 5 alpha-dihydrotestosterone, a nonaromatizable androgen, failed to produce a significant ApEn increase (P > 0.43). We conclude from these three distinct experimental contexts that aromatization of testosterone to estrogen in boys, or estrogen itself in girls, is likely the proximate sex-steroid stimulus amplifying secretory activity of the GH axis in puberty. In addition, based on inferences derived from mathematical models that mechanistically link increased disorderliness (higher ApEn) to network changes, we suggest that sex-steroid hormones in normal puberty modulate feedback within, and hence network function of, the hypothalamo-pituitary/GH-insulin-like growth factor I axis.