Next Level Health: a holistic health and wellbeing program to empower New Zealand women.

Improving equity in women's health requires gender-specific and empowering approaches. However, health programs often disempower women by adopting a 'one-size-fits-all' approach that emphasizes diet, exercise and weight loss over other important aspects like sleep and mental wellbeing. This article reports on the design of Next Level Health (NLH), a program that aims to empower women through developing a wide range of health behaviors to support their holistic wellbeing. NLH is grounded by ethics, theory and evidence to support women to make achievable, sustainable changes that are relevant to their everyday lives. Women utilized the NLH framework to develop an integrative health routine across six domains: physical activity, sleep, nutrition, eating behavior, self-care and stress management. The framework guided them to set small, incremental goals that were adaptive to their needs and built from their existing circumstances. Participants reflected on their progress with a facilitator during monthly meetings, accessed a social media support page and received monthly text messages. Health programs remain an essential approach to improving women's health alongside community- and policy-level strategies. The development of NLH exemplifies how evidence may partner with modern health promotion values to inform relevant and ethical program design for women.

In western societies, health programs often focus on weight loss through exercise and diet to promote women's health. Such approaches disempower women by undervaluing important factors affecting their health like stress and sleep and narrow their scope for 'health success'. This article reports on the development of Next Level Health (NLH) that aims to help women gain greater health-related control by broadening their approach to health. The program is designed to support women to set small, achievable goals across six domains (physical activity, sleep, nutrition, eating behavior, self-care, and stress management) toward developing positive and sustainable health behaviors. Although women work with a facilitator each month to set goals, they are ultimately in control of formulating their health plans and their progression through NLH. Women can support each other by joining a community of other NLH participants through a social media group. NLH offers a novel program that is responsive to women's individual health needs and broadens their potential for health success.

Long-Term Continuous Suppression With Once-Yearly Histrelin Subcutaneous Implants for the Treatment of Central Precocious Puberty: A Final Report of a Phase 3 Multicenter Trial.

CONTEXT AND OBJECTIVE: The histrelin implant has proven to be an effective method of delivering GnRH analog (GnRHa) therapy to children with central precocious puberty (CPP), yet there are limited data available regarding hormonal suppression and auxological changes during an extended course of therapy. DESIGN: This was a phase 3, prospective, open-label study. SETTING AND PARTICIPANTS: Thirty-six children with CPP who participated in a phase 3, open-label study and required further GnRHa therapy were eligible to continue treatment receiving a new implant upon removal of the prior 12-month histrelin implant during a long-term extension phase. OUTCOME MEASURES: Hormone levels and auxologic parameters were measured periodically for up to 6 years of treatment and up to 1 year of posttreatment follow-up. RESULTS: Hormonal suppression was maintained throughout the study in patients who had prior GnRHa therapy (n = 16) and in treatment-naive patients (n = 20). Bone age to chronological age ratio decreased from 1.417 (n = 20) at baseline to 1.18 (n = 8) at 48 months in treatment-naive children (P < .01). Predicted adult height in girls increased from 151.9 cm at baseline to 166.5 cm at month 60 (n = 6; P < .05), with a 10.7-cm height gain observed among treatment-naive children (n = 5). No adverse effect on growth or recovery of the hypothalamic-pituitary-gonadal axis was observed with hormonal suppression. The histrelin implant was generally well tolerated during long-term therapy. CONCLUSIONS: Long-term histrelin implant therapy provided sustained gonadotropin suppression safely and effectively and improved predicted adult height in children with CPP.

Precocious puberty.

PURPOSE OF REVIEW: Precocious puberty continues to elicit great interest and concern among medical practitioners, as well as the public. RECENT FINDINGS: Studies have elucidated neural regulation of puberty by kisspeptin, neurokinin B, and other factors. Cohort studies from the North America and Europe suggest that the age of thelarche may be earlier than determined 2 decades ago, and menarche may be slightly earlier, but the causes are unclear. Long-term outcomes of gonadotropin-releasing hormone analog therapy demonstrate increases in final height in the youngest treated patients, with no apparent adverse bone or reproductive consequences. SUMMARY: Although the appropriate threshold age of onset of central puberty remains uncertain, gonadotropin-releasing hormone analog therapy is well tolerated and effective in suppressing luteinizing hormone pulses and ovarian activity.

Letrozole vs anastrozole for height augmentation in short pubertal males: first year data.

CONTEXT: Aromatase inhibitors are used off-label to treat short stature in peripubertal boys. OBJECTIVE: To investigate short- and long-term hormonal and auxologic differences in short pubertal boys treated with letrozole (L) or anastrozole (A). DESIGN: PATIENTS are seen for laboratory evaluation and physical examination every 6 months, bone age yearly, DEXA and spine film every 2 years. They will be followed until they reach their final height. This is a preliminary report after 1 year of treatment. SETTING: A single academic children's hospital outpatient clinic. PATIENTS: Boys with age >10 years, bone age ≤ 14 years, clinical and hormonal evidence of central puberty, and either height < fifth percentile or predicted adult height (PAH) more than 10 cm below mid-parental height (MPH). INTERVENTION: Letrozole (2.5 mg) or anastrozole (1 mg) was administered orally each day. MAIN OUTCOME MEASURES: Hormonal and clinical parameters, growth velocity, and change in bone age and PAH. RESULTS: Thirty-nine boys have completed 1 year of treatment. Baseline means were age 14.1 years, PAH 166 cm, and testosterone 198 ng/dL. At 1 year, letrozole resulted in higher LH (L 6.1 ± 2.5 vs A 3.2 ± 1.7 IU/L) and testosterone (1038 ± 348 vs 536 ± 216 ng/dL) with lower estradiol (2.8 ± 2.8 vs 5.6 ± 2.9 pg/mL) and IGF-1 (237 ± 51 vs 331 ± 79 ng/mL). First year growth velocities were identical (7.2 cm/year), but an increase in PAH was greater in the anastrozole group (4.2 ± 3.5 vs 1.4 ± 4.4 cm, p = 0.03) after 1 year. CONCLUSIONS: We present first-year data from a direct comparison of anastrozole and letrozole for height augmentation in short pubertal boys. Letrozole was more potent in hormonal manipulation than anastrozole. First-year growth velocities were comparable, but improvement in PAH was greater in the anastrozole group. It remains to be seen if positive PAH trends will translate to increase in final height in either group.

A randomized trial of transdermal and oral estrogen therapy in adolescent girls with hypogonadism.

BACKGROUND: Adolescent females with ovarian failure require estrogen therapy for induction of puberty and other important physiologic effects. Currently, health care providers have varying practices without evidence-based standards, thus investigating potential differences between oral and transdermal preparations is essential. The purpose of this study was to compare the differential effects of treatment with oral conjugated equine estrogen (OCEE), oral 17ß estradiol (OBE), or transdermal 17ß estradiol (TBE) on biochemical profiles and feminization in girls with ovarian failure. STUDY DESIGN: 20 prepubertal adolescent females with ovarian failure, ages 12-18 years, were randomized to OCEE (n = 8), OBE (n = 7), or TBE (n = 5) for 24 months. Estrogen replacement was initiated at a low dose (0.15 mg OCEE, 0.25 mg OBE, or 0.0125 mg TBE) and doubled every 6 months to a maximum dose of 0.625 mg/d OCEE, 1 mg/d OBE, or 0.05 mg/d TBE. At 18 months, micronized progesterone was added to induce menstrual cycles. Biochemical markers including sex hormones, inflammatory markers, liver enzymes, coagulation factors, and lipids were obtained at baseline and 6 month intervals. Differences in levels of treatment parameters between the groups were evaluated with one-way analysis of variance (ANOVA). The effect of progesterone on biochemical markers was evaluated with the paired t-test. RESULTS: Mean (±SE) estradiol levels at maximum estrogen dose (18 months) were higher in the TBE group (53 ± 19 pg/mL) compared to OCEE (14 ± 5 pg/mL) and OBE (12 ± 5 pg/mL) (p ≤ 0.01). The TBE and OBE groups had more effective feminization (100% Tanner 3 breast stage at 18 months). There were no statistical differences in other biochemical markers between treatment groups at 18 months or after the introduction of progesterone. CONCLUSIONS: Treatment with transdermal 17ß estradiol resulted in higher estradiol levels and more effective feminization compared to oral conjugated equine estrogen but did not result in an otherwise different biochemical profile in this limited number of heterogeneous patients. OBE and TBE provide safe and effective alternatives to OCEE to induce puberty in girls, but larger prospective randomized trials are required. CLINICAL TRIALS IDENTIFIER: NCT01023178.

Review of outcomes after cessation of gonadotropin-releasing hormone agonist treatment of girls with precocious puberty.

Although gonadotropin-releasing hormone agonists (GnRHa) have been the standard of care of central precocious puberty (CPP) management for many years, there are still questions about the long-term consequences of treatment. With increased utilization of GnRHa treatment, it is now possible to assess posttreatment outcomes in the immediate posttreatment period and into adulthood. This literature review reports on the long-term effects of GnRHa therapy in girls with CPP after therapy has been discontinued. Published reports confirm the reversibility of hypothalamic-pituitary-ovarian axis suppression in females after cessation of GnRHa therapy, with the majority of patients achieving ovulatory menstrual cycles of normal timing and duration. GnRHa therapy does not appear to induce polycystic ovary syndrome or have long-term negative repercussions on either bone mineral density or body composition. Evidence is currently insufficient to identify agent-specific differences in outcomes, reproductive function, and health of offspring.

Random unstimulated pediatric luteinizing hormone levels are not reliable in the assessment of pubertal suppression during histrelin implant therapy.

BACKGROUND: Gonadotropin-releasing hormone agonist (GnRHa)-stimulated luteinizing hormone (LH) is the standard hormonal assessment for both diagnosis and therapeutic monitoring of children with central precocious puberty (CPP). Use of unstimulated (random) LH levels may be helpful in diagnosis and has gained popularity in monitoring GnRHa therapy despite lack of validation against stimulated values. The objective of this investigation was to assess the suitability of random LH for monitoring pubertal suppression during GnRHa treatment. METHODS: Data from a multi-year, multicenter, open-label trial of annual histrelin implants for CPP was used for our analysis. Children meeting clinical and hormonal criteria for CPP, either naïve to GnRHa therapy or previously treated with another GnRHa for at least 6 months who were being treated at academic pediatric centers were included in the study. Subjects received a single 50-mg subcutaneous histrelin implant annually until final explant at an age determined at the discretion of each investigator. Monitoring visits for physical examination and GnRHa-stimulation testing were performed at regular intervals. The main outcome measure was pubertal suppression during treatment defined by peak LH < 4 mIU/mL after GnRHa stimulation. RESULTS: During histrelin treatment, 36 children underwent a total of 308 monitoring GnRHa stimulation tests. Unstimulated and peak LH levels were positively correlated (r = 0.798), and both declined from the first to second year of treatment. Mean ± SD peak LH level during therapy was 0.62 ± 0.43 mIU/mL (range, 0.06-2.3), well below the normal prepubertal mean. Mean random LH was 0.35 ± 0.25 mIU/mL (range, 0.04-1.5), 10-fold higher than the normal prepubertal mean. The random LH levels were above the prepubertal upper threshold (<0.3 mIU/mL) in 48.4% of all tests and in 88.9% of subjects at some point during therapy. CONCLUSIONS: In contrast with GnRHa-stimulated LH, unstimulated LH values frequently fail to demonstrate suppression to prepubertal values during GnRHa therapy for CPP, despite otherwise apparent pubertal suppression, and are thus unsuitable for therapeutic monitoring. TRIAL REGISTRATION: ClinicalTrial.gov NCT00779103.

Pharmacodynamics of aqueous leuprolide acetate stimulation testing in girls: correlation between clinical diagnosis and time of peak luteinizing hormone level.

We assessed the pharmacodynamics of a 3-hour leuprolide stimulation test in 11 girls with precocious puberty to determine an optimal single sampling time. Luteinizing hormone level following leuprolide stimulation was near maximum by 30 minutes in girls with central precocious puberty, whereas it continued to rise slowly in girls with nonprogressive puberty.

Efficacy and safety of leuprolide acetate 3-month depot 11.25 milligrams or 30 milligrams for the treatment of central precocious puberty.

CONTEXT: GnRH agonist (GnRHa) monthly injections are frequently used in the treatment of central precocious puberty (CPP). The 3-month leuprolide depot 11.25- and 30-mg formulations are newly approved treatment options. OBJECTIVE: The aim of the study was to investigate the safety and efficacy of leuprolide acetate 3-month depot formulations for the treatment of CPP in children. DESIGN: This was a phase III, randomized, open-label, dose-ranging 6-month study. SETTING: Twenty-two U.S. medical centers (including Puerto Rico) participated. PATIENTS: Children diagnosed with CPP (n = 84), who were either treatment naive or previously treated with GnRHa, were recruited. Chronological age at onset of pubertal signs was less than 8 yr in girls and less than 9 yr in boys, and bone age was advanced over chronological age at least 1 yr. INTERVENTION: Leuprolide acetate depot (11.25 or 30 mg) was administered im every 3 months. MAIN OUTCOME MEASURES: Biochemical [peak-stimulated LH, estradiol (girls), and testosterone (boys)] and anthropometric (growth rate, bone age acceleration, pubertal progression) parameters and safety were assessed. RESULTS: Peak-stimulated LH was suppressed in the 11.25- and 30-mg dose groups in 78.4 and 95.2%, respectively, of children from months 2 through 6. There were nine treatment failures (peak-stimulated LH >4 IU/liter) in the 11.25-mg group and two in the 30-mg group. Basal sex steroid suppression, growth rates, pubertal progression, bone age advancement, and adverse events were similar with either dose. CONCLUSIONS: Treatment with leuprolide acetate 3-month depot formulations (11.25 and 30 mg) effectively suppressed the GnRH axis, was well tolerated, and may positively impact patient convenience and compliance.

Efficacy of Leuprolide Acetate 1-Month Depot for Central Precocious Puberty (CPP): Growth Outcomes During a Prospective, Longitudinal Study.

INTRODUCTION: Gonadotropin-releasing hormone analogs (GnRHa) are the treatment of choice for CPP. We investigated growth in GnRHa-naïve subjects, treated with leuprolide acetate 1-month depot for CPP. METHODS: This prospective, open-label study had a long-term, observational, follow-up period. Forty-nine females and 6 males were enrolled. Leuprolide acetate depot was administered intramuscularly every 28 days. Height and growth rate during and after treatment until adulthood were measured. RESULTS: Among 30 of 49 females having an adult height (AH) measurement, 29 had target heights available (mean = 163.8 cm) and 27 had pretreatment predicted adult heights (PAHs; mean = 157.4 cm). After treatment, the mean AH at mean age 21.8 years [range 13.7-26.7 years] was 162.5 cm, a mean height gain over baseline PAH of 4.0 cm. The mean height standard deviation score was -0.1 at AH. CONCLUSIONS: Treatment of CPP with leuprolide acetate 1-month depot had beneficial effects on growth rate and preservation of AH. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00660010.

Biodegradation of polyester polyurethane by endophytic fungi.

Bioremediation is an important approach to waste reduction that relies on biological processes to break down a variety of pollutants. This is made possible by the vast metabolic diversity of the microbial world. To explore this diversity for the breakdown of plastic, we screened several dozen endophytic fungi for their ability to degrade the synthetic polymer polyester polyurethane (PUR). Several organisms demonstrated the ability to efficiently degrade PUR in both solid and liquid suspensions. Particularly robust activity was observed among several isolates in the genus Pestalotiopsis, although it was not a universal feature of this genus. Two Pestalotiopsis microspora isolates were uniquely able to grow on PUR as the sole carbon source under both aerobic and anaerobic conditions. Molecular characterization of this activity suggests that a serine hydrolase is responsible for degradation of PUR. The broad distribution of activity observed and the unprecedented case of anaerobic growth using PUR as the sole carbon source suggest that endophytes are a promising source of biodiversity from which to screen for metabolic properties useful for bioremediation.

A randomized trial of 1- and 3-month depot leuprolide doses in the treatment of central precocious puberty.

OBJECTIVE: To compare 1-month and 3-month depot formulations of leuprolide acetate (DL), a gonadotropin-releasing hormone analog, in the treatment of central precocious puberty (CPP). STUDY DESIGN: Subjects with CPP naïve to therapy were randomized to 7.5 mg of 1-month DL, 11.25 mg of 3-month DL, or 22.5 mg of 3-month DL. Stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and estradiol levels, growth velocity, and bone age progression were examined in a 2-year period. RESULTS: Forty-nine female and 5 male subjects with CPP were randomized. Mean stimulated LH and FSH levels during treatment were higher in the low-dose 11.25-mg 3-month DL group, and more LH levels >4 IU/L were observed, in comparison with the other two dose groups. Mean LH and FSH levels in the 22.5-mg 3-month group were not different from the monthly DL. No differences in estradiol levels, growth velocity, or bone age progression were observed in dosing groups. CONCLUSIONS: All DL doses resulted in prompt and effective suppression of puberty, but higher LH and FSH levels were seen with the 11.25-mg 3-month DL dose. Multi-monthly DL is effective in treating CPP, but higher dosing may be required in some circumstances.

Nodal endosalpingiosis in ovarian serous tumors of low malignant potential with lymph node involvement: a case for a precursor lesion.

Lymph node involvement (LNI) in ovarian serous tumors of low malignant potential (OSLMP) upstages 22% of patients. The origin of LNI has been a subject of debate in the literature. The purpose of this study was to investigate the role of nodal endosalpingiosis in the pathogenesis of this entity. We first examined the frequency of nodal endosalpingiosis in 30 OSLMP cases, 30 cervical adenocarcinoma cases, and 30 endometrial endometrioid adenocarcinoma cases. The rate of nodal endosalpingiosis was significantly higher in OSLMP cases (33%) compared with both cervical (0%, P<0.0001) and endometrial tumor cases (3%, P=0.0015). We then compared the frequency of nodal endosalpingiosis in 36 cases of OSLMP with LNI and 36 cases of OSLMP without LNI. The rate of nodal endosalpingiosis was significantly higher in OSLMP with LNI (66%) than in OSLMP without LNI (14%, P<0.0001). We further investigated the cohort cases of OSLMP with LNI by recording the presence of nodal endosalpingiosis and LNI in each individual lymph node in every case. This analysis revealed that nodal endosalpingiosis and LNI appear together in the same lymph nodes at a much higher rate than would be expected by random chance alone (OR=71.2, P<0.0001). Lastly, in OSLMP cases with LNI, we recorded the types of LNI patterns. We found that the intraglandular pattern was present in a higher percentage of cases with nodal endosalpingiosis (50%) than in cases without nodal endosalpingiosis (8%, P=0.0253). Overall, the intraglandular pattern of LNI appeared in 36% of OSLMP cases with LNI. In this study, we show that nodal endosalpingiosis not only occurs more commonly in OSLMP compared with other Müllerian malignancies, but also in OSLMP with LNI compared with OSLMP without LNI. For the first time, we demonstrate a statistically significant association between endosalpingiosis and the intraglandular pattern of LNI, and we propose that in up to a third of patients with OSLMP and LNI, nodal foci of serous tumor of low malignant potential may derive independently, from nodal endosalpingiosis. This result contributes to the understanding of the pathogenesis of extraovarian disease in cases of OSLMP and has important implications for patient management and follow-up.

Leuprolide acetate 1-month depot for central precocious puberty: hormonal suppression and recovery.

Methods. This prospective US multicenter trial of leuprolide acetate 1-month depot (7.5-15 mg) for central precocious puberty utilized an open-label treatment period, long-term follow-up, and adult callback. Forty-nine females <9 years old with Tanner breast stage ≥2 before 8 years and 6 males <10 years old with Tanner genital stage ≥2 before 9 years with stimulated LH ≥10 IU/L and bone age advance ≥1 year were enrolled. Results. Subjects were treated for 3.9 ± 2.0 years. Mean peak GnRH-stimulated LH and FSH were prepubertal after the first dose and remained suppressed throughout treatment. During treatment, mean estradiol decreased to the limit of detection and mean testosterone decreased but remained above prepubertal norms. During posttreatment follow-up (3.5 ± 2.2 years), all patients achieved a pubertal hormonal response within 1 year and menses were reported in all females ≥12 years old. No impairment of reproductive function was observed at adulthood (mean age: 24.8 years).

Results of a second year of therapy with the 12-month histrelin implant for the treatment of central precocious puberty.

Background. Gonadotropin releasing hormone analogs (GnRHas) are standard of care for central precocious puberty (CPP). The histrelin subcutaneous implant is safe and effective in the treatment of CPP for one year. Objective. The study evaluates a second year of therapy in children with CPP who received a new implant after one year of treatment. Methods. A prospective one-year study following an initial 12-month treatment period was conducted. Results. Thirty-one patients (29 girls) aged 7.7 +/- 1.5 years received a second implant. Eighteen were naïve to GnRHa therapy at first implantation. Peak LH declined from 0.92 +/- 0.58 mIU/mL at 12 months to 0.51 +/- 0.33 mIU/mL at 24 months (P < .0001) in naïve subjects, and from 0.74 +/- 0.50 mIU/mL at 12 months to 0.45 +/- 0.35 mIU/mL at 24 months (P = .0081) in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months (P = .0001). Minor implant site reactions occurred in 61%, while minor difficulties with explantation occurred in 32.2% of subjects. Conclusion. The histrelin implant demonstrates profound hypothalamic-pituitary-gonadal axis suppression when a new implant is placed for a second year of treatment. Prospective follow-up of this therapeutic modality for the treatment of CPP is needed.

Consensus statement on the use of gonadotropin-releasing hormone analogs in children.

OBJECTIVE: Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents. PARTICIPANTS: When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe, an equal male/female ratio, and a balanced spectrum of professional seniority and expertise. EVIDENCE: Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence was insufficient, conclusions were based on expert opinion. CONSENSUS PROCESS: Participants were put into working groups with assigned topics and specific questions. Written materials were prepared and distributed before the conference, revised on the basis of input during the meeting, and presented to the full assembly for final review. If consensus could not be reached, conclusions were based on majority vote. All participants approved the final statement. CONCLUSIONS: The efficacy of gonadotropin-releasing hormone analogs in increasing adult height is undisputed only in early-onset (girls <6 years old) central precocious puberty. Other key areas, such as the psychosocial effects of central precocious puberty and their alteration by gonadotropin-releasing hormone analogs, need additional study. Few controlled prospective studies have been performed with gonadotropin-releasing hormone analogs in children, and many conclusions rely in part on collective expert opinion. The conference did not endorse commonly voiced concerns regarding the use of gonadotropin-releasing hormone analogs, such as promotion of weight gain or long-term diminution of bone mineral density. Use of gonadotropin-releasing hormone analogs for conditions other than central precocious puberty requires additional investigation and cannot be suggested routinely.

Correlation of clinical and biochemical findings with diabetic ketoacidosis-related cerebral edema in children using magnetic resonance diffusion-weighted imaging.

OBJECTIVE: To determine clinical and biochemical factors influencing cerebral edema formation during diabetic ketoacidosis (DKA) in children. STUDY DESIGN: We used magnetic resonance diffusion-weighted imaging to quantify edema formation. We measured the apparent diffusion coefficient (ADC) of brain water during and after DKA treatment in 26 children and correlated ADC changes with clinical and biochemical variables. RESULTS: Mean ADC values were elevated during DKA treatment compared with baseline (8.13 +/- 0.47 vs 7.74 +/- 0.49 x 10(-4) mm(2)/sec, difference in means 0.40, 95% CI: 0.25 to 0.55, P < .001). Children with altered mental status during DKA had greater elevation in ADC. ADC elevation during DKA was positively correlated with initial serum urea nitrogen concentration (correlation coefficient 0.41, P = .03) and initial respiratory rate (correlation coefficient 0.61, P < .001). ADC elevation was not significantly correlated with initial serum glucose, sodium or effective osmolality, nor with changes in glucose, sodium or osmolality during treatment. Multivariable analyses identified the initial urea nitrogen concentration and respiratory rate as independently associated with ADC elevation. CONCLUSIONS: The degree of edema formation during DKA in children is correlated with the degree of dehydration and hyperventilation at presentation, but not with factors related to initial osmolality or osmotic changes during treatment. These data support the hypothesis that CE is related to cerebral hypoperfusion during DKA, and that osmotic fluctuations during DKA treatment do not play a primary causal role.

Elevated serum amylase and lipase in pediatric diabetic ketoacidosis.

OBJECTIVES: Pancreatic enzyme concentrations are frequently elevated in children with diabetic ketoacidosis (DKA). We sought to determine the clinical and biochemical characteristics associated with patients with these elevations. Our hypothesis was that pancreatic enzyme elevations would be associated with biochemical markers of hypoperfusion. DESIGN: Prospective cohort study. SETTING: Three university-affiliated children's hospitals. PATIENTS: We collected data on consecutive children <18 yrs of age hospitalized with the diagnosis of DKA. INTERVENTIONS: Serum electrolyte and lactate concentrations and venous pH and Pco2 were measured every 3 hrs from hours 0 to 12 and then every 6 hrs until hour 24. Serum calcium, phosphate, and magnesium concentrations were measured every 6 hrs from hours 0 to 24. Serum amylase, lipase, and triglyceride concentrations were measured at hour 0 and then 12, 24, and 48 hrs after the initiation of therapy. MEASUREMENTS AND MAIN RESULTS: We performed multivariable analyses to test for associations between clinical variables and pancreatic enzyme elevation in 67 children with DKA. Lipase was elevated in 21 (31%) and amylase in 16 (24%) of the children. Pancreatic enzyme values peaked 12-24 hrs after admission. There was no significant correlation between pancreatic enzyme elevation and abdominal pain. In multivariable analyses, an elevated blood urea nitrogen (BUN) concentration was associated with elevated serum amylase (odds ratio 1.04 per unit increase; 95% confidence interval, 1.01-1.09; p = .02), and elevated BUN concentrations and hypophosphatemia were associated with elevated serum lipase (odds ratio 1.04 per unit increase; 95% confidence interval, 1.00-1.08; p = .04; and odds ratio 0.35 per unit increase; 95% confidence interval, 0.15-0.81; p = .01, respectively). CONCLUSIONS: Elevation of pancreatic enzymes is common in children with DKA, but clinical pancreatitis is rare. Pancreatic enzyme levels reach a peak 12-24 hrs after initiation of treatment for DKA. Pancreatic enzyme elevation is associated with increased BUN concentrations at presentation but is not associated with abdominal pain.

Cerebral proton magnetic resonance spectroscopy in children with diabetic ketoacidosis.

BACKGROUND AND PURPOSE: Subclinical cerebral edema occurs in many, if not most, children with diabetic ketoacidosis (DKA) and may be an indicator of subtle brain injury. Brain ratios of N-acetylaspartate (NAA) to creatine (Cr), measured by proton MR spectroscopy, decrease with neuronal injury or dysfunction. We hypothesized that brain NAA/Cr ratios may be decreased in children in DKA, indicating subtle neuronal injury. MATERIALS AND METHODS: Twenty-nine children with DKA underwent cerebral proton MR spectroscopy during DKA treatment (2-12 hours after initiating therapy) and after recovery from the episode (72 hours or more after the initiation of therapy). We measured peak heights of NAA, Cr, and choline (Cho) in 3 locations within the brain: the occipital gray matter, the basal ganglia, and periaqueductal gray matter. These regions were identified in previous studies as areas at greater risk for neurologic injury in DKA-related cerebral edema. We calculated the ratios of NAA/Cr and Cho/Cr and compared these ratios during the acute illness and recovery periods. RESULTS: In the basal ganglia, the ratio of NAA/Cr was significantly lower during DKA treatment compared with that after recovery (1.68 +/- 0.24 versus 1.86 +/- 0.28, P<.005). There was a trend toward lower NAA/Cr ratios during DKA treatment in the periaqueductal gray matter (1.66 +/- 0.38 versus 1.91 +/- 0.50, P=.06) and the occipital gray matter (1.97 +/- 0.28 versus 2.13 +/- 0.18, P=.08). In contrast, there were no significant changes in Cho/Cr ratios in any region. CONCLUSIONS: NAA/Cr ratios are decreased in children during DKA and improve after recovery. This finding suggests that during DKA neuronal function or viability or both are compromised and improve after treatment and recovery.

Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial.

CONTEXT: GnRH analog (GnRHa) therapy for central precocious puberty (CPP) typically involves im injections. The histrelin implant is a new treatment that provides a continuous slow release of the GnRHa histrelin. OBJECTIVE: The objective of the study was to investigate the safety and efficacy of the subdermal histrelin implant for the treatment of CPP in treatment naive and previously treated children. DESIGN: This was a phase III, open-label, prospective study of 1-yr duration. SETTING: The study was conducted at nine U.S. medical centers. PATIENTS: Girls ages 2-8 yr (naive) or 2-10 yr (previously treated) and boys 2-9 yr (naive) or 2-11 yr (previously treated) with clinical evidence of CPP and a pretreatment pubertal response to leuprolide stimulation were eligible. INTERVENTION: A 50-mg histrelin implant was inserted sc in the inner upper arm. MAIN OUTCOME MEASURES: Peak LH after GnRHa stimulation testing and estradiol (girls) and testosterone (boys) were the main outcome measures. RESULTS: Thirty-six subjects (20 naive) were enrolled. By 1 month, peak LH fell from 28.2 +/- 19.97 (naive) to 0.8 +/- 0.39 mIU/ml (P < 0.0001) and from 2.1 +/- 2.15 (previously treated) to 0.5 +/- 0.32 mIU/ml (P < 0.0056). Estradiol suppressed from 24.5 +/- 22.27 (naive) to 5.9 +/- 2.37 pg/ml (P = 0.0016) and remained suppressed in previously treated subjects, as did testosterone. Suppression was maintained throughout the study. No significant adverse events occurred. CONCLUSIONS: The subdermal histrelin implant achieves and maintains excellent suppression of peak LH and sex steroid levels for 1 yr in children with CPP. The treatment is well tolerated. Long-term studies are needed to confirm these results.