Josephine Z. Kasa-Vubu

Denosumab treatment for fibrous dysplasia

Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)‐regulating protein, α‐subunit of the Gs stimulatory protein (Gsα). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF‐κB ligand (RANKL) is a cell‐surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD‐like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal‐related events from bone metastases. We present the case of a 9‐year‐old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross‐linked C‐telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD‐related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases.

Childhood body mass index and perioperative complications

Background:  Our aim was to describe the incidence of quality assurance events between overweight/obese and normal weight children.

Isolation of a New Mouse 3β-Hydroxysteroid Dehydrogenase Isoform, 3β-HSD VI, Expressed During Early Pregnancy1

The enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) is a key enzyme in the biosynthesis of steroid hormones. To date, this laboratory has isolated and characterized five distinct 3β-HSD complementary DNAs (cDNAs) in the mouse (3β-HSD I through V). These different forms are expressed in a tissue- and developmentally-specific manner and fall into two functionally distinct enzymes. 3β-HSD I and III, and most likely II, function as dehydrogenase/isomerases, whereas 3β-HSD IV and V function as 3-ketosteroid reductases. This study describes the isolation, characterization, and tissue-specific expression of a sixth member of this gene family, 3β-HSD VI. This new isoform functions as an NAD+-dependent dehydrogenase/isomerase exhibiting very low Michaelis-Menten constant (Km) values for pregnenolone (∼0.035 μm) and dehydroepiandrosterone (∼0.12μ m). 3β-HSD VI is the earliest isoform to be expressed during embryogenesis in cells of embryonic origin at 7 and 9.5 days postcoitum (pc), and is the major isoform express...

Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation

Permanent neonatal diabetes mellitus is a rare disorder known to be caused by activating mutations in KCNJ11 or ABCC8, inactivating mutations in INS, or very rarely in GCK or insulin promotor factor‐1 (IPF‐1) genes. We report a patient with permanent neonatal diabetes mellitus and severe exocrine pancreatic insufficiency. Ultrasound examination revealed pancreatic agenesis with a suggestion of a small amount of tissue in the head of the pancreas. Genetic testing revealed that the neonate had a homozygous Pro63fsX60 IPF‐1 mutation. This is the second reported case of neonatal diabetes mellitus secondary to a homozygous mutation in the IPF‐1 gene and supports the previously proposed biological role of IPF‐1 in the pancreatic development in human.

Differential Effects of Raloxifene and Estrogen on Insulin Sensitivity in Postmenopausal Women

OBJECTIVES: To test the hypothesis that both raloxifene and estrogen would improve insulin sensitivity in postmenopausal women and that the magnitude of the effect would be similar for both drugs.

Effects of denosumab treatment and discontinuation on human growth plates.

CONTEXT Denosumab is a humanized monoclonal antibody to receptor activator of nuclear factor-κB ligand used primarily for postmenopausal osteoporosis and skeletal-related events from metastatic cancer. Its safety in children has not been established. OBJECTIVE The objective of the study was to investigate the effects of denosumab treatment on skeletal growth and histology. DESIGN This was an observational case report with radiological and histopathological analyses. SETTING The study was conducted at a clinical research center. PATIENTS A 9-year-old boy with fibrous dysplasia treated with a 7-month course of denosumab participated in the study. INTERVENTION Histological analyses were performed and compared on growth plates from limbs that had been amputated before and 17 months after denosumab treatment. MAIN OUTCOME MEASURES Skeletal radiographs and bone histopathology from before and after treatment were measured. RESULTS After initiating denosumab, sclerotic metaphyseal bands appeared on radiographs. Posttreatment radiographs revealed migration of the bands away from the growth plates, consistent with continued linear growth. Histologically, the bands were composed of horizontally arranged trabeculae containing calcified cartilage. This cartilage appeared to derive from unresorbed primary spongiosa as a result of osteoclast inhibition by denosumab, similar to what has been observed with bisphosphonates. By 17 months after treatment, active bone resorption and formation had returned, as evidenced by the presence of active osteoclasts in resorption pits and osteoid surfaces. CONCLUSIONS Further studies are needed to determine the safety of denosumab on the growing skeleton. However, in this child there was continued epiphyseal activity both during and after treatment and reversal of bone turnover suppression after treatment discontinuation, suggesting that denosumab did not have significant adverse effects on growth.

Automated classification system for Bone Age X-ray images

Bone Age (BA) determination using radiological images of left hands and wrists is important in pediatric endocrinology to correctly assess growth and pubertal maturation. In this paper, we propose a fully automated Greulich and Pyle Atlas (GP) bone age determination system using feature extraction and machine learning classifiers. The original contributions of this paper are as follows: (i) We use commercially available morphing tools to create a modified GP atlas that has images regularly spaced at three month intervals, (ii) We propose a novel Singular Value Decomposition (SVD) based feature extractor to create a feature vector. We use the Scale Invariant Feature Transform (SIFT) to extract features from the images then apply SVD to compose the feature vectors. Then, we train a Neural Network classifier using the generated feature vectors. Our preliminary results show that, even with a small number of training data sets, we obtain promising results. Future direction is discussed.

Ghrelin Concentrations Reflect Body Mass Index Rather Than Feeding Status in Obese Girls

Ghrelin stimulates both appetite and secretion of growth hormone (GH). We hypothesized that fasting should increase ghrelin, thereby increasing GH concentrations in obesity. Eight obese girls underwent a 48-h fast, receiving 25% of calories for ideal body weight. Blood was obtained every 15 min for the last 24 h of the fast. Four months later, six obese girls had blood obtained in the fed state. Two additional obese and five lean girls had blood obtained in the fed state. Ghrelin was determined in 3-h pools. Mean ghrelin concentrations were 0.41 ± 0.03 ng/mL for lean girls and 0.16 ± 0.01 ng/mL in obese fed girls (p < 0.0001). Lean fed girls had diurnal variation of ghrelin whereas obese fed girls did not. Fasting neither increased ghrelin (0.18 ± 0.01 ng/mL) nor restored diurnal variation. Ghrelin concentrations were related to the body mass index (BMI) SD score (SDS) (r = 0.45, p = 0.005). For the six obese girls who participated in both fasting and fed studies, change in mean ghrelin concentration between studies was related to change in BMI SDS but not fed or fasting state. Ghrelin concentrations are, thus, a function of BMI rather than feeding status in obese girls.

Metformin as a Weight-Loss Tool in At-Risk Obese Adolescents : A Magic Bullet?

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Impact of fatness, insulin, and gynecological age on luteinizing hormone secretory dynamics in adolescent females

OBJECTIVE To study the link between fatness and gonadotropin secretion. Overweight status is linked to polycystic ovary syndrome (PCOS) in adolescents. We postulated that heavier adolescents without symptoms would secrete LH with: [1] increased pulse frequency (LHPF) and [2] exaggerated integrated concentrations (LHAUC). DESIGN Cross-sectional. SETTING General clinical research center. PATIENT(S) Eighty-seven postmenarcheal cyclic adolescents from lean to overweight recruited during the follicular phase. INTERVENTION(S) Luteinizing hormone sampling: [1] every 10 minutes/24 hours; [2] at 20-minute intervals after a GnRH challenge. MAIN OUTCOME MEASURE(S) The LHPF and LHAUC (calculated by the CLUSTER algorithm). Hormonal and metabolic covariates included percent body fat (PercentBF), insulin-like growth factor-I (IGF-I), fasting insulin, and the insulin resistance index HOMA-IR. The SAS software was used for analyses. RESULT(S) The PercentBF and younger gynecological age predicted faster LHPF. Fatness was negatively linked to LHAUC, which was best predicted by PercentBF and IGF-1 in multivariate modeling (R(2) = 0.25). The PercentBF and insulin predicted a lower 20-minute LH response to GnRH. CONCLUSION(S) [1] Higher adiposity and younger gynecological age predict rapid LHPF. [2] The early years after menarche represent a vulnerable window for an exaggerated LHPF with weight gain. [3] In healthy adolescents, higher adiposity is linked to lower LHAUC, thereby preserving pituitary stores.