Raphael David, M.D.

Age of onset of polycystic ovarian syndrome in girls may be earlier than previously thought
Bronstein, Jason; Tawdekar, Sonali; Liu, Yinghua; Pawelczak, Melissa; David, Raphael; Shah, Bina
2011 Feb;24(1):15-20, Journal of pediatric & adolescent gynecology
OBJECTIVES: To study the age at diagnosis of polycystic ovarian syndrome (PCOS) in a pediatric population. To compare risk factors involved in causing PCOS in preadolescent and adolescent girls. To review the current literature on the reported age of PCOS in girls. DESIGN: A retrospective chart review and systematic review of the literature. PARTICIPANTS: Patients included 58 girls (age </=18 yrs) with a diagnosis of PCOS based on the Rotterdam criteria. Girls were grouped as preadolescents (<13 yrs) or adolescents (13-18 yrs). Clinical and biochemical data were reviewed from the time of diagnosis. MAIN OUTCOME MEASURES: Age at diagnosis. Differences in risk factors for PCOS (Ethnicity, obesity, family history of PCOS, birth weight, age at pubarche, thelarche and menarche, evidence of hyperandrogenism and/or insulin resistance) were compared between the two groups. RESULTS: There were 26% (15/58) preadolescent girls (9-12 yrs) vs 74% (43/58) adolescents (13-18 yrs). There was no significant difference between the two groups in ethnicity, BMI z-score, family history of maternal PCOS, birth weight, hyperandrogenism, or insulin resistance. Preadolescents with PCOS had significantly earlier onset of pubarche and thelarche than adolescents with PCOS, by 1.9 and 1.5 yrs, respectively (P = 0.018, 0.030). In addition to earlier puberty, PCOS developed 2.1 years sooner after thelarche in preadolescents than in adolescents. (P = 0.008) Preadolescents were significantly taller for age than adolescents (72nd % vs 43rd %) (P = 0.005). A review of the 28 studies published in the last 3 years that included PCOS patients with age <=18 yrs described only 6.4% (27/425) of pediatric subjects with age <13 yrs. Four were primarily pediatric studies that included patients under the age of 13 yrs, with 9.4% (12/127) of the patients <13 yrs. CONCLUSION: Increased awareness of PCOS in young females is needed. PCOS may occur at a younger age in girls who develop early pubarche and thelarche. Therefore, the diagnosis and workup should be considered in young girls with risk factors suggestive of PCOS
— id: 121329, year: 2011, vol: 24, page: 15, stat: Journal Article,

Decreased Daytime Motor Activity Associated With Apathy in Alzheimer Disease: An Actigraphic Study
David R; Mulin E; Friedman L; Duff FL; Cygankiewicz E; Deschaux O; Garcia R; Yesavage JA; Robert PH; Zeitzer JM
2011 Oct 12;:?-? #, American journal of geriatric psychiatry
OBJECTIVE:: Across all stages of Alzheimer disease (AD), apathy is the most common neuropsychiatric symptom. Studies using the Neuropsychiatric Inventory (NPI) have found that apathy is present in up to 70% of individuals with Alzheimer disease. One of the main difficulties in assessing apathy and other neuropsychiatric symptoms is the absence of reliable, objective measures. Motor activity assessment using ambulatory actigraphy could provide an indirect, objective evaluation of apathy. The aim of our study was to assess the relationship between apathy and daytime motor activity in AD, using ambulatory actigraphy. METHODS:: One hundred seven AD outpatients wore a wrist actigraph (Motionlogger) during seven consecutive 24-hour periods to evaluate motor activity. Participants were divided into two subgroups according to their apathy subscores on the NPI: individuals with apathy (NPI-apathy subscores >4) and those without. Daytime mean motor activity scores were compared between the two subgroups. RESULTS:: Individuals with AD who had symptoms of apathy (n = 43; age = 79 +/- 4.7 years; Mini-Mental State Exam = 20.9 +/- 4.8) had significantly lower daytime mean motor activity than AD patients without apathy (n = 64; age = 76.3 +/- 7.7; Mini-Mental State Exam = 21.5 +/- 4.7), while nighttime mean motor activity did not significantly differ between the two subgroups. CONCLUSIONS:: Ambulatory actigraphy could be added to currently used questionnaires as a simple, objective technique for assessing apathy in the routine assessment of AD patients
— id: 147897, year: 2011, vol: , page: ?, stat: Journal Article,

Thyrotropin-secreting pituitary adenoma in an adolescent boy: challenges in management
Kessler, Marion; David, Raphael; Pawelczak, Melissa; Hanono, Anat; Shah, Bina
2010 Aug;126(2):e474-e478, Pediatrics
Thyrotropinomas tend to be aggressive, invasive tumors that are difficult to resect because of their marked fibrosis and their proximity to vital structures such as the optic chiasm. The latter characteristic also limits the use of radiation therapy. In the few cases reported of children younger than 18 years whose thyrotropinomas were treated surgically, the results were disappointing. We present here the case of a 16-year-old boy with a thyrotropin-secreting pituitary macroadenoma who underwent partial resection via a transsphenoidal approach and was left with significant residual tumor and continued hyperthyroidism. He subsequently received 4 years of long-acting release somatostatin therapy, during which he has remained euthyroid without requiring antithyroid medication. To our knowledge, this is thus far the longest duration of somatostatin therapy in the pediatric age group. This regimen also achieved a decrease in compression of the optic nerve and prevented further tumor growth. We review here the current literature on somatostatin analog treatment including molecular mechanisms and promising new treatment modalities, such as the heterodimerization of dopamine and somatostatin receptors. We conclude that this has been a useful adjuvant treatment for our adolescent patient
— id: 111543, year: 2010, vol: 126, page: e474, stat: Journal Article,

Outcomes of children and adolescents with well-differentiated thyroid carcinoma and pulmonary metastases following (1)(3)(1)I treatment: a systematic review
Pawelczak, Melissa; David, Raphael; Franklin, Bonita; Kessler, Marion; Lam, Leslie; Shah, Bina
2010 Oct;20(10):1095-1101, Thyroid
BACKGROUND: The optimal dose and efficacy of (1)(3)(1)I treatment of children and adolescents with well-differentiated thyroid carcinoma (WDTC) and pulmonary metastases are not well established. A therapeutic challenge is to achieve the maximum benefit of (1)(3)(1)I to decrease disease-related morbidity and obtain disease-free survival while avoiding the potential complications of (1)(3)(1)I therapy. SUMMARY: We systematically reviewed the published literature on children and adolescents with WDTC and pulmonary metastases treated with (1)(3)(1)I to examine outcomes after (1)(3)(1)I administration and the risks and benefits of therapy. After reviewing 14 published articles, 9 articles met our inclusion criteria encompassing 112 pediatric and adolescent patients with WDTC and pulmonary metastases 21 years of age or younger at diagnosis spanning a follow-up period of 0.6-45 years. (1)(3)(1)I therapy after surgery and thyrotropin suppression resulted in complete, partial, and no disease response in 47.32%, 38.39%, and 14.29% of patients, respectively. Five studies provided data on disease response in relation to (1)(3)(1)I dose. In general, nonresponders received the highest (1)(3)(1)I doses and complete responders received a higher dose than partial responders. The disease-specific mortality rate was 2.68%. Survival was 97.32%. A second primary malignancy occurred in one patient. One out of 11 patients studied experienced radiation fibrosis. CONCLUSIONS: This review confirms that the majority of pediatric and adolescent patients with WDTC and pulmonary metastases treated with (1)(3)(1)I do not achieve complete response to therapy, yet disease-specific morbidity and mortality appear to remain low. It is therefore prudent to use caution in the repeated administration of (1)(3)(1)I to such patients to ensure that adverse effects of therapy do not cause more harm than good in a disease that has an overall favorable natural course. Long-term prospective studies are needed to analyze disease-specific morbidity and mortality, recurrence rate, dose-specific response, and dose-related adverse effects of (1)(3)(1)I in this patient population
— id: 120833, year: 2010, vol: 20, page: 1095, stat: Journal Article,

Endometrial thickness, uterine, and ovarian ultrasonographic features in adolescents with polycystic ovarian syndrome
Shah, Bina; Parnell, Lauren; Milla, Sarah; Kessler, Marion; David, Raphael
2010 Jun;23(3):146-152, Journal of pediatric & adolescent gynecology
OBJECTIVE: Our aim was to evaluate uterine and ovarian ultrasonographic features including endometrial thickness (ET) in adolescent females with PCOS, which is limited in this population. METHODS: We performed a retrospective chart review of young females (n=51) ranging in age from 10 to 18 years with the diagnosis of PCOS. Clinical, biochemical and pelvic sonography data were reviewed. Sonographic data included uterine parameters of ET, length, and volume as well as ovarian volume and follicular morphologic features. RESULTS: Data in 51 girls were analyzed. Menstrual periods were reported as irregular in 26/51 (50.9%), amenorrheic in 19/51 (37.2%), regular in 4/51 (7.8%) and metrorrhagia in 2/51 (3.9%). Uterine features revealed that the endometrial stripe was enlarged (>7mm) in 16/51 (31.4%) of girls, all with homogeneous appearance. The uterine length was lower than normal in 22/51 (43.1%) of girls, normal in 21/51 (41.2%), and higher than normal in 8/51 (15.7%). Uterine volume was normal in 31/51 (60.7%) and higher in 20/51 (39.3%) of girls. Enlarged ovarian volume was found in 22/51 (43%) of patients. Mean ovarian volumes were 16.1cm(3) and 13.1cm(3) in bilateral and unilaterally enlarged ovaries, respectively. The morphology of ovarian follicles was studied in a subset of 40 patients. The location of ovarian follicles was peripheral in 81% and mixed in 19%. The number of follicles was also examined in 43 patients. They were few (<5) in 12%, moderate (5-10) in 5% and multiple (>10) in 84% cases. There was the presence of at least one >10mm cyst in 25% of girls. CONCLUSION: Majority of the adolescents with PCOS demonstrated multiple peripheral ovarian follicles, with large ovarian volumes in some, indicating an important role of ultrasonography in the diagnosis of PCOS, even at a younger age. Endometrial thickness, uterine length, ovarian size, and follicular morphology should be carefully examined in cases of adolescent PCOS
— id: 109786, year: 2010, vol: 23, page: 146, stat: Journal Article,

The prevalence of abnormal liver enzymes and metabolic syndrome in obese adolescent females with polycystic ovary syndrome
Barfield, Elaine; Liu, Ying-Hua; Kessler, Marion; Pawelczak, Melissa; David, Raphael; Shah, Bina
2009 Oct;22(5):318-322, Journal of pediatric & adolescent gynecology
OBJECTIVES: We sought to determine the prevalence of abnormal liver enzymes suggestive of nonalcoholic steatohepatitis and metabolic syndrome in obese adolescent females with polycystic ovary syndrome. DESIGN: A retrospective chart review. PARTICIPANTS: Patients included 39 obese (body mass index Z score >/= 2) adolescent females with a diagnosis of polycystic ovary syndrome. Clinical and biochemical data in these patients were reviewed. MAIN OUTCOME MEASURES: Aspartate and alanine aminotransferase levels, lipid panel, blood pressure, body mass index, and glucose intolerance were the main outcome measures of the study. RESULTS: The study showed that 15.4 % (6 of 39) of patients had elevated aminotransferase levels, suggestive of nonalcoholic steatohepatitis, and 43.6 % (17 of 39) of patients qualified as having metabolic syndrome. Finally, 10.2 % (4 of 39) of patients were found to have both liver dysfunction and metabolic syndrome. CONCLUSION: Liver dysfunction consistent with nonalcoholic steatohepatitis and metabolic syndrome are prevalent in obese adolescent females with polycystic ovary syndrome. Therefore, early screening and further work-up for both disease states are warranted in cases of young adolescent females with polycystic ovary syndrome
— id: 102156, year: 2009, vol: 22, page: 318, stat: Journal Article,

Late presentation, milder phenotype, of a novel CYP11B2 gene mutation in a Pakistani toddler with aldosterone synthase deficiency type 2 (ASD 2)
Brar, PC; Prasad, VK; Bista, R; Salameh, WA; Mikula, MX; Varghese, RM; David, R
2009 NOV ;72(3):68-68, Hormone research
— id: 106180, year: 2009, vol: 72, page: 68, stat: Journal Article,

Evaluation of adolescents for polycystic ovary syndrome in an urban population
Fingert, Sarabeth Broder; Shah, Bina; Kessler, Marion; Pawelczak, Melissa; David, Raphael
2009 Jun;1(4):188-193, JCRPE : Journal of Clinical Research in Pediatric Endocrinology
Objective: To assess the quality of diagnostic work-up received by patients with 'possible' polycystic ovary syndrome (PCOS).Design: A retrospective chart review.Setting: A hospital based Pediatric Clinic in New York City.Patients: Sixty female patients aged 13-19 years, with a primary ICD-9 diagnosis of ovarian dysfunction (256), menstrual irregularity (626), or hirsutism (704.1) were randomly selected for evaluation. In addition, 18 patients who were assigned the same ICD-9 codes at the Pediatric Endocrine Clinic were assessed.Main Outcome: Rates of assessment for diagnostic criteria of PCOS and selected co-morbidities.Results: Twenty-five percent (15/60) of the patients were evaluated for PCOS according to the Rotterdam Criteria, and only 2 were evaluated for common co-morbidities associated with PCOS. Of the 28 patients who presented with two or more signs of PCOS (menstrual irregularity plus either obesity, hirsutism and/or acne), 15 were evaluated for PCOS (54%), but only 7% were assessed for common co-morbidities.All patients referred to the Pediatric Endocrine Clinic received appropriate evaluation for PCOS. In addition, 89% of the study group underwent further assessment for selected complications of PCOS.Conclusions: Patients presenting to an inner-city pediatric clinic with 'possible' PCOS often do not receive a complete diagnostic evaluation. In addition, those evaluated for PCOS are often not adequately screened for the known health consequences associated with this condition. These findings suggest that PCOS is under evaluated and possibly under diagnosed in this pediatric population, which raises serious concerns regarding the potential for major longterm public health consequences.Conflict of interest:None declared
— id: 122540, year: 2009, vol: 1, page: 188, stat: Journal Article,

Antenatal treatment of fetal goiter: a therapeutic challenge
Hanono, Anat; Shah, Bina; David, Raphael; Buterman, Irving; Roshan, Daniel; Shah, Shetal; Lam, Leslie; Timor-Tritsch, Ilan
2009 Jan;22(1):76-80, Journal of maternal-fetal & neonatal medicine
OBJECTIVE: Pre-natal ultrasonography presents an opportunity for in-utero therapy of a fetal goiter. Because of the morbidity associated with a large goiter and the risks of repeated intra-amniotic injections, controversy arose about the precise indications of this mode of treatment. We describe our observations in treating a 22-week-old fetus with a large goiter because of dyshormogenesis, monitored with serial 3D high frequency, high resolution ultrasonography and amniotic hormonal measurements. Fetal hypothyroidism was confirmed by cordocentesis and amniotic hormone levels. After assessment of relevant risk factors and the criteria for in-utero intervention, including goiter volume, amniotic fluid index, polyhydramnios and tracheal compression, we determined that hormonal therapy was warranted. Levothyroxine was injected every 7-10 days, and its efficacy monitored by ultrasound changes and amniotic hormone sampling. RESULTS: Reduction in goiter volume restored normal neck flexion relieving the pressure on the trachea, polyhydramnios was prevented and amniotic hormone levels were normalised. The infant was euthyroid at birth, however, by age 4 days hypothyroidism was diagnosed, and treatment with l-thyroxine started. CONCLUSION: Advances in fetal ultrasonography permit judicious therapy of an enlarging goiter in a hypothyroid fetus, which may contribute to enhancing cognitive development. We discuss the value of amniotic hormone sampling, the objectives and risks of in-utero intervention in the light of recent literature and our own observations
— id: 96296, year: 2009, vol: 22, page: 76, stat: Journal Article,

Hemorrhagic pituitary apoplexy in an 18 year-old male presenting as non-ketotic hyperglycemic coma (NKHC)
Kamboj, Manmohan K; Zhou, Ping; Molofsky, Walter J; Franklin, Bonita; Shah, Bina; David, Raphael; Kohn, Brenda
2005 Jun;18(6):611-615, Journal of pediatric endocrinology & metabolism
Pituitary apoplexy is an acute clinical event usually caused by hemorrhage or infarction in a pituitary adenoma. We report the unusual case of hemorrhagic pituitary apoplexy in an 18 year-old male with previously undiagnosed type 2 diabetes mellitus who presented with unexplained hyperglycemia (glucose 49.2 mmol/l [887 mg/dl]) and obtundation and in whom an initial diagnosis of non-ketotic hyperglycemic coma (NKHC) was made. MRI revealed a heterogeneous mass arising from an expanded sella turcica into the suprasellar cistern. Despite well-controlled glucose levels on continuous insulin infusion, dexamethasone, and initiation of bromoergocriptine (parlodel) therapy, the patient's vision and pupillary responses deteriorated acutely. Following emergency transphenoidal surgery, the patient's vision and mental status improved. Data confirmed preoperative panhypopituitarism; serum prolactin was 396 ng/ml (microg/l). Immunostudies demonstrated tumoral labeling for prolactin, but not for ACTH, GH, TSH, LH, FSH, or P53
— id: 71609, year: 2005, vol: 18, page: 611, stat: Journal Article,

Hormonal effects in infants conceived by assisted reproductive technology
Rojas-Marcos, Patricia Martin; David, Raphael; Kohn, Brenda
2005 Jul;116(1):190-194, Pediatrics
OBJECTIVE: The purpose of this report is to describe 7 infants conceived by assisted reproductive technology (ART) who presented with breast development and/or pubic hair. The clinical presentation in these infants raises awareness that an altered intrauterine hormonal milieu may impact the fetal and infant stages of children conceived by ART. METHODS: Between May 2001 and April 2004, 7 children between the ages of 5 and 21 months conceived by ART were referred by their pediatricians to the Division of Pediatric Endocrinology at the New York University School of Medicine for evaluation of possible precocious puberty. Patients were evaluated for the possibility of centrally mediated precocious puberty and pseudoprecocious puberty, with a possible ovarian or adrenal origin. RESULTS: Endocrine evaluation in all patients indicated sex-steroid and hormone levels in the prepubertal range; pelvic sonography confirmed prepubertal ovaries with unstimulated uteri. Clinical follow-up of our patients thus far has not revealed progression of breast development, pubarche, or elevation in sex steroids. CONCLUSIONS: It is well established that the developing endocrine system in the fetus and maturation of endocrine-control systems are influenced by hormone concentrations in the fetus. Whether ART alters the intrauterine hormonal milieu for the growing fetus conceived by ART is as yet unknown and is an area of ongoing investigation. Patients conceived through ART, including our patients who presented with hormonal manifestations, will need to be monitored throughout childhood and into adolescence and adulthood to determine if any perturbation exists on the timing of puberty and later fertility
— id: 96297, year: 2005, vol: 116, page: 190, stat: Journal Article,

Letrozole significantly improves growth potential in a pubertal boy with growth hormone deficiency
Zhou, Ping; Shah, Bina; Prasad, Kris; David, Raphael
2005 Feb;115(2):e245-e248, Pediatrics
Clinical experience with using an aromatase inhibitor to suppress estrogen production during puberty for improvement of growth potential in adolescents with short stature is limited. This report documents treatment of such a patient with a combination of growth hormone and letrozole, a third-generation aromatase inhibitor. Our case demonstrates a favorable outcome on a short-term basis
— id: 51783, year: 2005, vol: 115, page: e245, stat: Journal Article,

Central precocious puberty in males
David R; Shah B
Encyclopedia of endocrine diseases Amsterdam ; Boston : Elsevier ; San Diego, Calif. : Academic Press, 2004,
— id: 4245, year: 2004, vol: 4, page: ?, stat: Chapter,

Massive hepatosplenomegaly and leukemoid reaction on prolonged high-dose decadron
Franklin, B; Kim, A; Moskowitz, N; Hart, D; Modduluru, M; Benkov, K; David, R
2004 APR ;55(4):162A-162A, Pediatric research
— id: 46532, year: 2004, vol: 55, page: 162A, stat: Journal Article,

Growth hormone treatment in children with familial dysautonomia
Kamboj, Manmohan K; Axelrod, Felicia B; David, Raphael; Geffner, Mitchell E; Novogroder, Michael; Oberfield, Sharon E; Turco, John H; Maayan, Channa; Kohn, Brenda
2004 Jan;144(1):63-67, Journal of pediatrics
OBJECTIVE: To assess experience with growth hormone (GH) therapy in patients with familial dysautonomia (FD).Study design Of 580 patients with FD registered at the Dysautonomia Center at New York University Medical Center, 13 patients (8 males, 5 females) aged 1.10 to 15.10 years received GH treatment. GH doses ranged from 0.2 to 0.3 mg/kg/wk; one patient received 0.14 mg/kg/wk. Information regarding auxologic data, skeletal age, pubertal status, and spinal deformity before and after GH therapy was obtained from center records and treating endocrinologists. Growth velocity was analyzed before and during GH treatment at 0 to 6 months, 6 to 12 months, 1 to 2 years, and >2 years. RESULTS: Before GH therapy, growth velocity was <5 cm/y in 10 patients and 5 to 6 cm/y in three patients. In the first six months of GH therapy, growth velocity exceeded pretreatment rates in all but one patient; 10 patients achieved an annualized growth rate >7 cm/y. Six of nine patients treated for more than one year grew >5 cm/y. Less than optimal treatment responses were attributed to poor compliance, intercurrent illness, scoliosis, or advanced puberty. CONCLUSION: The data demonstrate that GH treatment in patients with FD may increase growth velocity, at least in the short term. This experiential data supports a future prospective study
— id: 42620, year: 2004, vol: 144, page: 63, stat: Journal Article,

HER2/neu expression in adenoid cystic carcinoma of salivary gland origin: an immunohistochemical study
Dori, Shai; Vered, Marilena; David, Raphael; Buchner, Amos
2002 Sep;31(8):463-467, Journal of oral pathology & medicine
BACKGROUND: Adenoid cystic carcinoma (ACC) is a malignant tumor of salivary gland origin, which is characterized by a high rate of local recurrence and distant hematogenous metastasis. Despite aggressive surgical treatment and radiotherapy, the patient's long-term prognosis is dismal. Prompted by recent studies on the amplification of the oncogene HER2/neu in salivary gland tumors, we analyzed the immunohistochemical overexpression of HER2/neu in salivary glands ACC. If the tumor exhibits overexpression of HER2/neu, then treating it with the anti-HER2/neu therapeutic agent, Herceptin (Trastuzumab, Genentech, CA), could be considered. METHODS: The study comprised of 32 samples of formalin-fixed, paraffin-embedded specimens. All laboratory procedures and scoring criteria were performed according to currently approved FDA methods. RESULTS: HER2/neu overexpression was found in only five (16%) cases. Four cases (13%) scored 1+ and one case (3%) scored 2+. CONCLUSIONS: The low prevalence of HER2/neu overexpression in ACC limits the clinical utility of Herceptin therapy for salivary gland ACC
— id: 96298, year: 2002, vol: 31, page: 463, stat: Journal Article,

Iatrogenic Cushing's syndrome caused by super high potency topical steroid treatment
Kamboj, MK; Shah, BC; David, R
2002 Apr;51(4):678-, Pediatric research
— id: 27462, year: 2002, vol: 51, page: 678, stat: Journal Article,

Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency
Lutfallah, Chantal; Wang, Weihua; Mason, J Ian; Chang, Ying Tai; Haider, Anzar; Rich, Barry; Castro-Magana, Mariano; Copeland, Kenneth C; David, Raphael; Pang, Songya
2002 Jun;87(6):2611-2622, Journal of clinical endocrinology & metabolism
To define the hormonal criteria via genotypic proof for 3beta-hydroxysteroid dehydrogenase (3beta-HSD) deficiency in the adrenals and gonads, we investigated the type II 3beta-HSD genotype in 55 patients with clinical and/or hormonal presentation suggesting compromised adrenal with or without gonadal 3beta-HSD activity. Fourteen patients (11 males and 3 females) had ambiguous genitalia with or without salt wasting and with or without premature pubarche. One female neonate had salt wasting only. Twenty-five children (4 males and 21 females) had premature pubarche only. Fifteen adolescent and adult females had hirsutism with or without menstrual disorder. The type II 3beta-HSD gene, including the promoter region up to -1053 base, all exons I, II, III, IV, and exon and intron boundaries, was sequenced in all subjects. Eight patients had a proven or predictably deleterious mutation in both alleles of the type II 3beta-HSD gene, and 47 patients had no apparent mutation in the gene. ACTH-stimulated (1 h post iv bolus of 250 microg Cortrosyn) serum 17-hydroxypregnenolone (Delta5-17P) levels and basal and ACTH-stimulated ratios of Delta5-17P to cortisol (F) in the genotypic proven patients were unequivocally higher than those of age-matched or pubic hair stage matched genotype-normal patients or control subjects (n = 7-30 for each group). All other baseline and ACTH-stimulated hormone parameters, including dehydroepiandrosterone (DHEA) levels, ratios of Delta5-17P to 17-OHP and DHEA to androstenedione in the genotype-proven patients, overlapped with the genotype-normal patients or control subjects. The hormonal findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3beta-HSD deficiency congenital adrenal hyperplasia (numeric and graphic reference standards from infancy to adulthood are provided): ACTH-stimulated Delta5-17P levels in 1) neonatal infants with ambiguous genitalia at or greater than 378 nmol/liter equivalent to or greater than 5.3 SD above the control mean level [95 +/- 53 (SD) nmol/liter]; 2) Tanner I children with ambiguous genitalia at or greater than 165 nmol/liter equivalent to or greater than 35 SD above the control mean level [12 +/- 4.3 (SD) nmol/liter]; 3) children with premature pubarche at or greater than 294 nmol/liter equivalent to or greater than 54 SD above Tanner II pubic hair stage matched control mean level [17 +/- 5 (SD) nmol/liter]; and 4) adults with at or greater than 289 nmol/liter equivalent to or greater than 21 SD above the normal mean level [25 +/- 12 (SD) nmol/liter]. ACTH-stimulated ratio of Delta5-17P to F in 1) neonatal infants at or greater than 434 equivalent to or greater than 6.4 SD above the control mean ratio [88 +/- 54 (SD)]; 2) Tanner I children at or greater than 216 equivalent to or greater than 23 SD above the control mean ratio [12 +/- 9 (SD)]; 3) children with premature pubarche at or greater than 363 equivalent to or greater than 38 SD above the control mean ratio [20 +/- 9 (SD)]; and 4) adults at or greater than 4010 equivalent to or greater than 221 SD above the normal mean ratio [29 +/- 18 (SD)]. Conversely, the hormonal data in the genotype-normal patients suggest the following hormonal criteria are not consistent with 3beta-HSD deficiency congenital adrenal hyperplasia: ACTH-stimulated Delta5-17P levels in children with premature pubarche up to 72 nmol/liter equivalent to up to 11 SD above the control mean level, and in hirsute females up to 150 nmol/liter equivalent to up to 12 SD above the normal female mean level [28 +/- 10 (SD) nmol/liter]; and ACTH-stimulated Delta5-17P to F ratio in children with premature pubarche up to 67 equivalent to up to 5 SD above the control mean ratio, and in hirsute females up to 151 equivalent to up to 10 SD above the normal mean ratio [32 +/- 12 (SD)]. These findings help define newly proposed hormonal criteria to accurately predict inherited 3beta-HSD deficiency
— id: 71768, year: 2002, vol: 87, page: 2611, stat: Journal Article,

A novel nonstop mutation in the stop codon and a novel missense mutation in the type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing, respectively, nonclassic and classic 3beta-HSD deficiency congenital adrenal hyperplasia
Pang, Songya; Wang, Weihua; Rich, Barry; David, Raphael; Chang, Ying Tai; Carbunaru, Goldy; Myers, Susan E; Howie, A Forbes; Smillie, Karen J; Mason, J Ian
2002 Jun;87(6):2556-2563, Journal of clinical endocrinology & metabolism
We investigated two novel point mutations in the human type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing a mild and a severe form of 3beta-HSD deficiency congenital adrenal hyperplasia. The first is a nonstop mutation in the normal stop codon 373 of the gene in exon IV [TGA (Stop) --> TGC (Cys) = Stop373C) identified from one allele of a female child with premature pubarche whose second allele had an E142K mutation. The Stop373C mutation predictably results in an open reading frame and a mutant-type (MT) II 3beta-HSD protein containing 467 amino acid residues, compared with the 372 amino acid residues of wild-type (WT) protein. The second is a homozygous missense mutation in codon 222 [CCA (Pro) --> ACT (Thr) = P222T] in the gene identified from a female neonate with salt-wasting disorder. The pcDNA vectors containing the constructs of WT II 3beta-HSD cDNA, WT cDNA with the open reading frame (WT cDNA(+)), MT Stop373C with the open reading frame (Stop373C(+)) and MT P222T cDNA were transfected in COS-I and 293T cells and expressed a similar amount of 3beta-HSD mRNA. The enzyme activity in intact cells using pregnenolone and dehydroepiandrosterone as substrate in the medium (1 micromol/liter) was identical between the WT cDNA and the WT cDNA(+), but was decreased to 27% of the WT enzymes at 6 h by MT Stop373C(+) enzyme, and was undetectable by P222T enzyme. In the homogenates of the cells, both MT Stop373C(+) and P222T enzyme activities and enzymes were undetectable despite clear detection of WT enzyme activities and WT enzymes. LH response to an LHRH analog stimulation in the pubertal female with the Stop373C/E142K genotypes and in a pubertal female with compound 273/318 frameshift genotypes were comparable to and higher than control females, respectively. In conclusion, a structurally lengthy MT II 3beta-HSD enzyme due to a nonstop mutation was relatively detrimental in intact cells causing the nonclassic phenotype of 3beta-HSD deficiency. A missense P222T mutation was seriously detrimental, causing the classic phenotype of 3beta-HSD deficiency. The undetectable Stop373C and P222T enzymes on Western blottings, together with the respective in vivo and in vitro data, suggest that a relative instability of Stop373C enzyme and a profound instability of the P222T enzyme are likely the detrimental molecular mechanisms. The increased LH in the female with the frameshift genotype and the appropriate LH response in the female with the nonstop genotype correlated with predictably severe and mild ovarian type II 3beta-HSD deficiency, respectively
— id: 71769, year: 2002, vol: 87, page: 2556, stat: Journal Article,

Increased 5alpha-reductase and normal 11beta-hydroxysteroid dehydrogenase metabolism of C19 and C21 steroids in a young population with polycystic ovarian syndrome
Chin D; Shackleton C; Prasad VK; Kohn B; David R; Imperato-McGinley J; Cohen H; McMahon DJ; Oberfield SE
2000 Mar;13(3):253-259, Journal of pediatric endocrinology & metabolism
OBJECTIVE: To test the hypothesis that 5alpha-reductase (5alphaR) and 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity are increased in adolescent and young-adult women with PCOS and that an altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis occurred in these subjects. DESIGN: Prospective non-randomized study in an academic research environment. PATIENTS: Eleven women, aged 14 to 25 years, were studied who were at least one year post-menarche and who had a diagnosis of PCOS based on a history of oligomenorrhea and elevated total and or free serum testosterone. INTERVENTION: 24-Hour urinary metabolites were assessed in nine subjects and five underwent stimulation with ovine corticotropin releasing factor (oCRF). OUTCOME MEASURES: C19 and C21 steroid urinary metabolite 5-alpha/5-beta pairs, 11-oxo/11-hydroxy products and the ratio of the total 5-alpha/5-beta reduced and 11-oxo/11-hydroxy products were compared to values in control women. Urinary cortisol (F) (sum of conjugated and free, and free F) and total F metabolites (the sum of THE, THF, 5alpha-THF, cortolones, and cortols) were determined. A 1 microg/kg oCRF stimulation test was performed with timed samples determined for plasma ACTH and serum F levels. RESULT: The 24-hour total and free urinary F were not different from control. However, the total F metabolites were markedly elevated (7922+/-2666 vs 5418+/-1549 microg/24 h, p<0.01). A marked increase in the total 5-alpha reduced C19 and C21 metabolites was observed in the PCOS population vs control (5084+/-1977 vs 2681+/-1188 microg/24 h, p<0.01). The total urinary 11-oxo/11-hydroxy metabolite ratio was not different, p=0.23. The basal values and response of both ACTH and F to oCRF stimulation were not different from those of controls. CONCLUSION: There is a marked increase in 5alphaR metabolism of both C19 and C21 steroids in younger women with PCOS
— id: 11803, year: 2000, vol: 13, page: 253, stat: Journal Article,

Hypertension and virilization caused by a unique desoxycorticosterone- and androgen-secreting adrenal adenoma
Soranno D; Prasad V; David R; Oberfield S; Greco A; Sivaraman N; Drucker W
1999 Mar-Apr;12(2):215-220, Journal of pediatric endocrinology & metabolism
We describe a rare androgen and desoxycorticosterone (DOC)-secreting adrenal tumor in a non-Cushingoid 14 year-old Haitian girl with secondary amenorrhea, hypertension and virilization. Her steroid pattern simulated an 11 beta-hydroxylation defect with notable elevation of adrenal androgens, 11-desoxycortisol (S), DOC, 17 alpha-hydroxyprogesterone and pregnenelone. Exogenous ACTH stimulated steroidogenesis. A CAT scan unfortunately failed to delineate an adrenal mass. Dexamethasone (DEX) was administered, therefore, which partially suppressed androgen levels, reduced DOC and S by 80% and 82% respectively, and normalized blood pressure. Nevertheless, the response to glucocorticoid was incomplete and an MRI was obtained, which revealed a right adrenal tumor. Post surgery, the patient promptly resumed menses and became normotensive. This case illustrates that ACTH and DEX cannot reliably differentiate tumor from hyperplasia, whereas the simultaneous increase of delta 4 and delta 5 steroids, present here, may favor a tumor. This case also allows speculation that the hypersecretion of DOC may result from inhibition of 11 beta-hydroxylase activity by excess androgens. The importance of appropriate imaging for diagnosis is underscored
— id: 6153, year: 1999, vol: 12, page: 215, stat: Journal Article,

Study of a kindred with classic congenital adrenal hyperplasia: diagnostic challenge due to phenotypic variance
Chin D; Speiser PW; Imperato-McGinley J; Dixit N; Uli N; David R; Oberfield SE
1998 Jun;83(6):1940-1945, Journal of clinical endocrinology & metabolism
We sought to determine the concordance of the phenotype and genotype in a kindred with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The variation in phenotypic expression within this family underscores the difficulty of establishing the diagnosis in the absence of newborn screening, even with a heightened index of suspicion. Steroidogenic profiles were obtained for the three affected siblings. The available clinical history of the two affected aunts was retrieved. Genotyping was performed on several members of the kindred. Detailed sequencing of the entire CYP21 gene of two clinically dissimilar subjects in this family was undertaken to explore the possibility of other mutations or polymorphisms. PCR with ligase detection reaction analysis of CYP21 revealed that the affected family members III-2, III-3, III-4, II-3, and II-4, all were compound heterozygotes carrying the intron 2 point mutation known to interfere with splicing (nucleotide 656 A to G) and the exon 4 point mutation causing a nonconservative substitution of asparagine for isoleucine at codon 172 (I172N). Detailed sequencing of the gene was performed for the two most phenotypically dissimilar subjects. A single silent polymorphism was found in the third nucleotide for codon 248 in patient II-4, but not in patient III-4, and no additional mutations were found. Classic congenital adrenal hyperplasia remains a difficult diagnosis to make in the absence of newborn screening because of the variability of phenotypic expression. Likewise, the variable degree of genital ambiguity in affected females in this family serves to question universal advocacy of prenatal steroid treatment in pregnancies at risk for congenital adrenal hyperplasia. Extensive molecular exploration did not provide an explanation of the phenotypic heterogeneity and supports the possibility of influences other than the CYP21 gene for the observed divergence
— id: 7941, year: 1998, vol: 83, page: 1940, stat: Journal Article,

2-Ethylhexanoic acid: subchronic oral toxicity studies in the rat and mouse
Juberg, D R; David, R M; Katz, G V; Bernard, L G; Gordon, D R; Vlaovic, M S; Topping, D C
1998 May;36(5):429-436, Food & chemical toxicology
Groups of 10 male and 10 female Fischer 344 rats and B6C3F1 mice were fed diets containing either 0.0, 0.1, 0.5 or 1.5% 2-ethylhexanoic acid (EHA) for 13 wk. Additional groups of 10 male and 10 female rats or mice. were fed either 0.0 or 1.5% EHA for 13 wk followed by a 4-wk recovery (non-treatment) period. Based on food consumption and body weight, the EHA diets provided doses of 61, 303 or 917 mg/kg/day for male rats and 71, 360 or 1068 mg/kg/day for female rats. The EHA diets provided doses of 180, 885 or 2728 mg/kg/day for male mice and 205, 1038 or 3139 mg/kg/day for female mice. No mortality or significant clinical signs of toxicity were observed during the study. Body weights and food consumption of both rats and mice fed 1.5% EHA were lower beginning after the first week of treatment, consistent with a reduction in food consumption. Other groups were unaffected by treatment. After 13 wk, lower triglyceride levels occurred in male mice fed 1.5% EHA and female mice fed 0.5 or 1.5% EHA, but not in other groups. Cholesterol levels were higher in all male rat test groups and in female rats and male and female mice fed either 0.5 or 1.5% EHA, although this effect was reversible following a 28-day recovery period. The principal effects of EHA involved the liver or metabolic processes associated with the liver. The 0.5 and 1.5% diets in both rats and mice were associated with increased relative liver weight and histological changes in hepatocytes, specifically hepatocyte hypertrophy and reduced cytoplasmic vacuolization. Observed histopathological and clinical pathological changes were reversible following recovery. These results indicate that EHA does not produce persistent. overt toxicity in rats or mice following subchronic dietary exposure at concentrations up to 1.5% in feed. The no-observed-adverse-effect level (NOAEL) for male rats was 61 mg/kg/day and the no-observed-effect level (NOEL) for female rats was 71 mg/kg/day, while 180 and 205 mg/kg/day represent NOELs for male and female mice, respectively
— id: 121930, year: 1998, vol: 36, page: 429, stat: Journal Article,

Thyroid dysfunction as a late effect in survivors of pediatric medulloblastoma/primitive neuroectodermal tumors: a comparison of hyperfractionated versus conventional radiotherapy
Chin D; Sklar C; Donahue B; Uli N; Geneiser N; Allen J; Nirenberg A; David R; Kohn B; Oberfield SE
1997 Aug 15;80(4):798-804, Cancer
BACKGROUND: Primary hypothyroidism is a common sequela of craniospinal radiotherapy in the treatment of pediatric brain tumors. METHODS: The authors compared the incidence of primary hypothyroidism after hyperfractionated radiotherapy (HFRT) (n = 14 patients) versus conventionally fractionated radiotherapy (CRT) (n = 34 patients) in a group of pediatric patients with medulloblastoma/primitive neuroectodermal tumors (MB/PNET). RESULTS: The mean age at the time of tumor diagnosis was 7.9 years in the HFRT group and 8.4 years in the CRT group. The patients were followed for a mean of 4.6 years (HFRT) and 8.3 years (CRT) after diagnosis. Mean radiation doses to the thyroid were similar in both radiotherapy groups (29 gray [Gy] [HFRT] vs. 24 Gy [CRT]). Approximately 14% of the HFRT and 62% of the CRT patients developed primary hypothyroidism within a similar period after irradiation (3.2 years [HFRT] vs. 3.0 years [CRT]). Analysis by cumulative incidence function demonstrated a significant difference in the risk of developing thyroid dysfunction between these two groups of patients (P = 0.02). CONCLUSIONS: The current study findings suggest that the use of HFRT in the treatment of pediatric patients with MB/PNET is associated with a lower risk of these patients developing primary hypothyroidism
— id: 56932, year: 1997, vol: 80, page: 798, stat: Journal Article,

Subchronic inhalation toxicity study of a water-dispersible polyester in rats
Katz, G V; Faber, W D; Bernard, L G; Moulton, R A; David, R M; Vlaovic, M S; Dyer, W M Jr
1997 Oct-Nov;35(10-11):1023-1030, Food & chemical toxicology
AQ55 is a high molecular weight, water-dispersible, amorphous polyester used in applications where the exclusion of solvents and conventional surfactants is desirable, such as water-based adhesives, coatings, emulsions, paint primers, cosmetics and detergents. Potential health effects were evaluated in rats exposed by inhalation for about 13 wk to mean concentrations of 0, 2.4, 19.6 or 199 mg/m3 AQ55 polymer. No mortality occurred and body weights were unaffected. Mean relative liver weights in all treated male groups were slightly higher than control weights, but were not judged to be treatment related. Absolute liver weights and all other organ weights except lung weights were normal. Haematology, clinical chemistries and gross pathology were unremarkable. Exposure-related changes in the 199 mg/m3 groups included increased mean absolute and relative lung weights, accumulations of macrophages and acute inflammatory cells in alveolar and bronchial lumina, and increased numbers of macrophages in sinusoids of peribronchial lymph nodes. Minor accumulation of macrophages in alveolar lumina was the only exposure-related change in the 19.6 mg/m3 group. No exposure-related effects were seen in the 2.4 mg/m3 group. AQ55 produced no systemic toxicity, and aerosols of AQ55 do not appear to be toxic to pulmonary tissues following subchronic inhalation exposure
— id: 121931, year: 1997, vol: 35, page: 1023, stat: Journal Article,

Endocrine late effects of childhood cancers
Oberfield SE; Chin D; Uli N; David R; Sklar C
1997 Jul;131(1 Pt 2):S37-S41, Journal of pediatrics
Long-term survival in children with cancer has increased markedly in the past 15 years. However, impaired linear growth and thyroid dysfunction that vary according to the age at diagnosis and treatment and to the dose and duration of radiation and chemotherapy have been described in these patients. The impact of cranial irradiation on the hypothalamic-pituitary-adrenal axis and on pubertal maturation has been less well studied. A positive correlation between the age at diagnosis and the age at onset of puberty in children who have been treated with high-dose cranial radiation therapy for central nervous system (CNS) tumors has been found recently. Frank adrenal insufficiency is uncommon after high-dose CNS irradiation, but alterations in the hypothalamic-pituitary-adrenal axis do occur. Assessments of the effects of newer modes of radiation therapy such as hyperfractionated craniospinal radiation suggest a lower incidence of primary hypothyroidism in the long term
— id: 7229, year: 1997, vol: 131, page: S37, stat: Journal Article,

Hypothalamic-pituitary-adrenal function following cranial irradiation
Oberfield SE; Nirenberg A; Allen JC; Cohen H; Donahue B; Prasad V; Schiff R; Pang S; Ghavimi F; David R; Chrousos G; Sklar C
1997 ;47(1):9-16, Hormone research
We assessed the effect of cranial irradiation on hypothalamic-pituitary (HP)-adrenal function in 17 patients (12 females, 5 males) treated with cranial/ craniospinal irradiation for acute leukemia (2 patients) or tumors distant from the hypothalamus and pituitary (8 medulloblastoma, 3 astrocytoma, 3 rhabdomyosarcoma, 1 ependymoma). Estimated doses of radiation (RT) to the HP region ranged from 18 to 72 Gy. Thirteen of seventeen patients were also treated with chemotherapy. Patients were a median of 3.75 years of age (1.5-19 years) at diagnosis and were studied at a median of 5 years (0.1-20 years) after RT. Patients received corticotropin-releasing factor (oCRF, 1 microgram/kg i.v.), and sampling for cortisol and ACTH levels was performed at -15, 0, 15, 30, 60, 90 and 120 min. The-5- and 0-min levels were combined for a standardized baseline value (Base). Cortisol levels at 0, Base, 30 and 120 min, as well as the peak cortisol response, were significantly lower in the patients. Twelve of seventeen patients' peak cortisol levels fell below the normal range. The patients' mean integrated values for cortisol (area under the curve) were not, however, different from controls. The ACTH responses to oCRF did not differ between patients and controls. No relationship was observed between ACTH or cortisol responses and the time elapsed from treatment or dose of HP RT. Further, in 10 of 12 patients, 0-min dehydroepiandrosterone sulfate levels were lower than the expected normal mean levels for age, sex and pubertal status, and in 4 of these 10 patients the values were below the normal range. These data suggest that some patients treated with HP RT may be at risk for adrenal insufficiency
— id: 12423, year: 1997, vol: 47, page: 9, stat: Journal Article,

Impaired early growth of infants perinatally infected with human immunodeficiency virus: correlation with viral load
Pollack H; Glasberg H; Lee E; Nirenberg A; David R; Krasinski K; Borkowsky W; Oberfield S
1997 Jun;130(6):915-922, Journal of pediatrics
OBJECTIVE: To evaluate the effect of viral load on the early growth of infants infected with human immunodeficiency virus (HIV). METHODS: Plasma concentrations of p24-antigen and HIV ribonucleic acid were measured retrospectively and correlated with growth parameters for the first 18 months of life in a cohort of 47 term infants born to HIV-infected mothers prospectively enrolled in a study of perinatal HIV transmission. Comparisons of the mean weight and length of the 18 HIV-infected and 29 uninfected infants for each interval and across intervals were made. Viral load was correlated with standard deviation scores. Infants were stratified by high and low viral load during the first 6 months of life. RESULTS: At birth, no difference in weight and length was observed between HIV-infected and uninfected infants. Between birth and 6 months of age, the infected infants grew less rapidly than the uninfected infants, a finding temporally associated with an exponential increase in HIV viremia. The linear growth of infected infants remained consistently less than that of the uninfected infants after 6 months of life, although the differences were no longer statistically significant and tended to decrease with age in parallel with declines in viral load. The median plasma concentration of HIV ribonucleic acid was significantly higher at 3, 6, 12, and 18 months in infected infants in whom growth failure developed. Infants who had a high viral load in the first 6 months of life were significantly more likely to have severe growth failure. Though the mean SD for weight of the infected infants was always less than that of the uninfected infants, the differences were small and not significant. CONCLUSIONS: Our results confirm the observation that stunting is an early frequent finding in perinatal HIV infection. The deleterious effect of HIV on linear growth appears to be correlated with the level of postnatal HIV viremia, although the exact mechanism of this association remains to be elucidated
— id: 7235, year: 1997, vol: 130, page: 915, stat: Journal Article,

Testicular arginine vasopressin in the developing rat: a possible physiological role
Tyson DL; Landin LM; David R; Yoon DJ
1997 ;71(6):379-384, Biology of the neonate
Testicular immunoreactive arginine vasopressin (irAVP) has been shown to inhibit testosterone production by the Leydig cell in vitro. We studied pre- and postpubertal rats and the results are in agreement with the notion that such inhibition might occur in vivo and, therefore, could have physiological significance. Testicular irAVP and serum testosterone levels were measured in 14-, 21-, 28-, 35-, 42-, and 70-day-old rats. The testicular irAVP concentration was lowest in early prepubertal rats, increased significantly to the highest level at 35 days, then decreased at 42 days, and plateaued at 70 days of age. A pubertal increase in serum testosterone was observed at 42 days when AVP was decreasing. Thus, an inverse relationship was observed at the onset of pubertal maturation. These parameters were also measured in 3 groups of rats 1 week after hemicastration which was performed at the ages of 28, 35 and 70 days. In the 28-day-old rats there was a significant decrease in irAVP 1 week later, in contrast to the intact animal, whereas hemicastration performed at 35 and 70 days of age had no impact on irAVP. Our data suggest that the role of AVP may be physiologically relevant during the peripubertal period of testicular maturation in the rat
— id: 12407, year: 1997, vol: 71, page: 379, stat: Journal Article,

Menstrual bleeding in a female infant with congenital adrenal hyperplasia: altered maturation of the hypothalamic-pituitary-ovarian axis
Uli N; Chin D; David R; Geneiser N; Roche K; Marino F; Shapiro E; Prasad K; Oberfield S
1997 Oct;82(10):3298-3302, Journal of clinical endocrinology & metabolism
Vaginal bleeding during the neonatal period is commonly related to the withdrawal of maternal estrogens. Vaginal bleeding has also been reported in female infants with congenital adrenal hyperplasia and has been proposed to be due to a treatment-induced activation of the hypothalamic-pituitary-ovarian axis. We report a female infant with the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, who had the onset of vaginal bleeding at 3 months of life. Adrenal steroid suppression had been achieved by 2.5 weeks of age. At the time of bleeding, imaging studies revealed an enlarged right ovary with a dominant 3-cm cyst and additional small cysts that had not been seen on the newborn sonogram. The uterus was enlarged and stimulated. Three weeks later (1 week after the cessation of bleeding), repeat ultrasound demonstrated a marked decrease in the size of the right ovary, and the dominant cyst was no longer seen. The patient had a heightened FSH response to GnRH and elevated levels of estradiol for age. At 5 months of age, no further episodes of sustained vaginal bleeding were observed. Repeat hormonal levels were prepubertal, and pelvic sonogram demonstrated no evidence of stimulation. The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels, which then triggered a transient and augmented end-organ response (menses). Further, we suggest that our infant's hormonal findings may reflect a delay in the timely development of the negative restraint by sex steroids on gonadotropins that is normally observed in infancy
— id: 12247, year: 1997, vol: 82, page: 3298, stat: Journal Article,

Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies
Brown, RS; Bellisario, RL; Botero, D; Fournier, L; Abrams, CAL; Cowger, ML; David, R; Fort, P; Richman, RA
1996 MAR ;81(3):1147-1151, Journal of clinical endocrinology & metabolism
To determine the incidence of transient congenital hypothyroidism due to TSH receptor-blocking antibodies, we screened dried blood specimens obtained from 788 neonates identified as having possible congenital hypothyroidism (from a total population of 1,614,166 babies) and 121 controls. ARRA was used. The potency of blood spot TSH binding inhibitory activity was compared with the severity of congenital hypothyroidism to assess the possible etiological relationship. Maternal serum was studied to confirm the presence of blocking antibodies by both RRA and bioassay. Blood spots obtained from 9 infants contained potent TSH receptor-blocking activity. Samples from 2 additional babies, studied because of clinical suspicion of the disease, were also positive. Long term outcome was known in of the 11 babies, and all had transient disease. Neonates with TSH receptor-blocking activity greater than 132 U/L had a significantly lower T-4 level (P < 0.05) and higher TSH (P < 0.005) than those in whom TSH binding-inhibitory activity was less than 132 U/L. All 9 mothers had autoimmune thyroid disease, and 3 had more than 1 affected child. Potent blocking activity was present in 7 maternal serum samples as long as 7 yr after the births of their affected babies. We conclude that measurement of TSH binding-inhibitory activity in dried neonatal blood specimens is a simple and effective method to predict the occurrence of transient congenital hypothyroidism. The incidence of this disorder in North America is 1 in 180,000 normal infants, or approximately 2% of babies with congenital hypothyroidism
— id: 53046, year: 1996, vol: 81, page: 1147, stat: Journal Article,

Age at onset of puberty following high-dose central nervous system radiation therapy
Oberfield SE; Soranno D; Nirenberg A; Heller G; Allen JC; David R; Levine LS; Sklar CA
1996 Jun;150(6):589-592, Archives of pediatrics & adolescent medicine
OBJECTIVE: To determine if a relationship exists between age at irradiation, sex of the patient, and age at onset of puberty and pubarche in children treated with high-dose radiation to the central nervous system. DESIGN: Case series. SETTING: Tertiary care institutional practices and clinics. PATIENTS: Thirty-six children treated with high-dose irradiation (hypothalamic pituitary dose, 30-72 Gy) by conventional (n = 29) or hyperfractionated (n = 7) schedules. Girls were treated before age 8 years and boys before age 9 years. Twenty-six of the 36 children also received chemotherapy. All tumors were distant from the hypothalamic-pituitary region. MAIN OUTCOME MEASURE: Age at onset of puberty and pubarche. RESULTS: In girls, the median age at onset of puberty was 9.3 years vs 10.9 years for controls (P < .01); pubarche occurred at 9.4 years vs 11.2 years for controls (P < .01). In boys, the median age at onset of puberty--genital II--was 11.0 years vs 11.5 years for controls (P = .30); pubarche occurred at a median age of 10.5 years vs 12 years for controls (P = .25). A censored-data normal linear regression model was used to account for children (n = 6) who had not reached puberty. Age at diagnosis (P < .01) and sex (P = .01) were significant predictors of age at onset of puberty. Body mass index SD score (z score) was inversely related to age at onset of puberty (r = -0.77) and was greater at onset of puberty in girls than in boys. CONCLUSION: In children who have received high-dose cranial radiation therapy, a significant positive correlation exists between age at diagnosis and age at onset of puberty in boys and girls
— id: 7028, year: 1996, vol: 150, page: 589, stat: Journal Article,

Neurodevelopment, growth, and viral load in HIV-infected infants
Pollack H; Kuchuk A; Cowan L; Hacimamutoglu S; Glasberg H; David R; Krasinski K; Borkowsky W; Oberfield S
1996 Sep;10(3):298-312, Brain, behavior & immunity
The relation of HIV-1 infection to infant growth and neurodevelopment was studied prospectively in a cohort of 65 infants born to women at risk for HIV infection. No differences were observed at birth between infected infants (INF) and uninfected infants (SR) of HIV-infected women, and infants of uninfected women (SN) with similar socioeconomic background and exposure to drugs. However, postnatal linear growth and cognitive-motor development of INF infants were impaired when compared to SR and SN infants. Declines in linear growth were observed within the first 6 months of life, whereas delays in neurodevelopment were first appreciated at 12 months. In INF infants, decreased linear growth was positively correlated with developmental delay. Moreover, growth and development were both correlated with HIV viral load. INF infants with high plasma HIV RNA copies (> 5 x 10(5)/ ml) at 6 months of life were more likely to exhibit severe growth and developmental delay than infants with a lower viral burden. The implications of these findings with respect to the mechanism of action of HIV-related growth and neurodevelopmental impairments are discussed
— id: 12544, year: 1996, vol: 10, page: 298, stat: Journal Article,

Delayed neonatal hypothalamic/pituitary/ovarian maturation in a female infant with CAH and menstrual bleeding
Uli, N; Chin, D; David, R; Geneiser, N; Marino, F; Shapiro, E; Oberfield, S
1996 APR ;39(4):585-585, Pediatric research
— id: 52989, year: 1996, vol: 39, page: 585, stat: Journal Article,

HIGH-DOSE CNS RADIATION AND AGE AT ONSET OF PUBERTY
OBERFIELD, SE; SORANNO, D; NIRENBERG, A; ALLEN, J; DAVID, R; LEVINE, LS; HELLER, G; HORLICK, M; SKLAR, C
1995 APR ;37(4):A163-A163, Pediatric research
— id: 86761, year: 1995, vol: 37, page: A163, stat: Journal Article,

Relationship of growth hormone deficiency and leukemia
Rapaport R; Oberfield SE; Robison L; Salisbury S; David R; Rao J; Redmond GP
1995 May;126(5 Pt 1):759-761, Journal of pediatrics
The use of growth hormone (GH) has been implicated as a possible risk factor for leukemia. We present data from six patients that support a working hypothesis that an increased risk of leukemia may exist in patients with GH deficiency not related to exogenous use of GH
— id: 6722, year: 1995, vol: 126, page: 759, stat: Journal Article,

Effect of brimonidine 0.5% on intraocular pressure spikes following 360 degrees argon laser trabeculoplasty
Robin, AL; David, R; Shani, L; Barnebey, H; Clevenger, CE; Zimmerman, TJ; Nardin, G; Hersh, SB; Morrison, JC; Spaeth, GL; Katz, LJ; Perell, HF; Siegel, LI; Lewis, RA; Henry, JC; Coleman, AL; Lee, DA; Stiles, MC; Passo, MS; Cinotti, DJ; Stamper, RL; Yaldo, MK; Kelley, EP; Walt, JG; Chen, KS
1995 ;26(5):404-409, Ophthalmic surgery
BACKGROUND AND OBJECTI
— id: 103772, year: 1995, vol: 26, page: 404, stat: Journal Article,

Monitoring of girls undergoing medical therapy for isosexual precocious puberty
Ambrosino MM; Hernanz-Schulman M; Genieser NB; Sklar CA; Fefferman NR; David R
1994 Jul;13(7):501-508, Journal of ultrasound in medicine
We evaluated the use of sonography in monitoring the efficacy of suppressive therapy with a gonadotropin releasing hormone analogue in girls being treated for isosexual precocious puberty. Ten girls 5 to 9 years of age underwent serial sonography and hormonal stimulation tests on the same day. Sonographic trends of decreasing ovarian volume and uterine length indicated early suppression even when absolute values were above threshold. Changes in ovarian volume were the most sensitive predictor of pituitary-gonadal suppression. Sonography is a sensitive and accurate method of monitoring medical therapy; ovarian volume and analysis of interval change are the most sensitive barometers of change
— id: 6566, year: 1994, vol: 13, page: 501, stat: Journal Article,

Necrotizing enterocolitis and hypothyroidism in a newborn infant: treatment with intravenous L-thyroxine
Amer T; David R; Oberfield SE
1994 Jan;11(1):30-32, American journal of perinatology
Gastrointestinal complications of hypothyroidism are well documented and include constipation, obstipation, and abdominal distention, as well as ileus, pseudo-obstruction, tumor-like mass of the intestine, and megacolon. We report herein on a 2-week-old, full-term female infant, who had both necrotizing enterocolitis (NEC) and congenital hypothyroidism. We further describe the response to therapy with intravenous L-thyroxine. To our knowledge, the patient's course is the first report of intravenous L-thyroxine in the management of congenital hypothyroidism when oral replacement is not an option. The possible causal relationship between NEC and hypothyroidism is discussed
— id: 6308, year: 1994, vol: 11, page: 30, stat: Journal Article,

Abnormalities of water metabolism in children and adolescents following craniotomy for a brain tumor
Blumberg DL; Sklar CA; Wisoff J; David R
1994 Nov;10(8):505-508, Child's nervous system : ChNS
We conducted a retrospective analysis of the cases of 122 children operated on for various brain tumors, to determine the incidence and natural history of postoperative diabetes insipidus (DI), and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Abnormalities of water homeostasis were observed in 15 patients (12%). DI, with or without SIADH, was observed in 10 patients (8%), while SIADH alone was seen in five (4%). DI was permanent in five subjects (50%), whereas SIADH resolved completely in all affected individuals. Parenteral desmopressin (dDAVP) was an effective mode of therapy in the postoperative period. The effect did not correlate with a dosage strictly based on body weight
— id: 6581, year: 1994, vol: 10, page: 505, stat: Journal Article,

Altered sensitivity to low dose dexamethasone in a subset of patients with premature adrenarche
Oberfield SE; Amer T; Tyson D; Soranno D; David R; Lee E; Levine LS
1994 Oct;79(4):1102-1104, Journal of clinical endocrinology & metabolism
During adrenarche, levels of adrenal androgens increase. Although the regulatory mechanisms of adrenarche and premature adrenarche (PA) are not fully understood, it has been suggested that, unlike the cortisol (F) response to glucocorticoid suppression, which is not age dependent, before adrenarche the major adrenal androgen, dehydroepiandrosterone sulfate, is not suppressible by glucocorticoid. As these studies were performed using long term, high dose glucocorticoids, we sought to evaluate the F and adrenal androgen or androgen precursor suppression in response to low dose glucocorticoids [a single evening dose of dexamethasone (DEX), 0.3 mg/m2]. Twenty-four children (aged 1.3-8.75 yr; 4 males and 20 females) known to have PA, as determined by their response to ACTH-(1-24) (Cortrosyn; 0.25 mg, given by iv bolus), were studied. The children with PA could be divided into two groups, as defined by their morning F level after DEX administration: group I (n = 12), F levels below 5 micrograms/dL; and group II (n = 12), F levels of 5 micrograms/dL or more. Although the mean baseline values of F, testosterone, dehydroepiandrosterone, delta 4-androstenedione, 17-hydroxyprogesterone, and delta 5-17-hydroxypregnenolone did not differ between groups I and II, the mean levels in group I vs. group II of dehydroepiandrosterone, delta 4-androstenedione, and delta 5-17-hydroxypregnenolone were significantly greater in response to ACTH and lower in response to DEX (P < 0.05). Although no clinical difference was noted between the 2 groups, the mean SD for bone age adjusted for chronological age was greater and approached significance in group I, suggesting a greater degree of biological maturity in this group. These results suggest an increased sensitivity of the hypothalamic-pituitary-adrenal axis to changes in ACTH secretion in this subgroup of patients with PA
— id: 56693, year: 1994, vol: 79, page: 1102, stat: Journal Article,

Altered cortisol response and hippocampal atrophy in pediatric HIV disease
Oberfield SE; Cowan L; Levine LS; George A; David R; Litt A; Rojas V; Kairam R
1994 Jan;7(1):57-62, Journal of acquired immune deficiency syndrome
The hippocampus is a major center for the regulation of the hypothalamic-pituitary-adrenal axis. There is experimental evidence that chronic exposure to high levels of glucocorticoids may be toxic to the hippocampus. We observed elevated mean basal and 60-min cortisol (F) levels in response to adrenocorticotropin stimulation (0.25 mg cortrosyn, i.v. bolus infusion) in 15 children with HIV infection. Furthermore, in eight of the children for whom data was available, in addition to high peripheral cortisol levels, neurologic dysfunction and hippocampal atrophy were noted on CT scan. These preliminary data suggest that in HIV-infected children an altered cortisol secretion may be associated with specific central nervous system damage
— id: 56570, year: 1994, vol: 7, page: 57, stat: Journal Article,

HYPOTHALAMIC-PITUITARY (HP)-ADRENAL FUNCTION FOLLOWING HIGH-DOSE CRANIAL IRRADIATION (RT)
OBERFIELD, S; SKLAR, C; NIRENBERG, A; ALLEN, J; GHAVIMI, F; DONAHUE, B; COHEN, H; PANG, S; DAVID, R; CHROUSOS, G
1994 APR ;35(4):A104-A104, Pediatric research
— id: 52463, year: 1994, vol: 35, page: A104, stat: Journal Article,

Prolactin-secreting macroadenomas in adolescents. Response to bromocriptine therapy
Tyson D; Reggiardo D; Sklar C; David R
1993 Oct;147(10):1057-1061, American journal of diseases of children
OBJECTIVE--To report five cases of prolactin (PRL)-secreting macroadenomas in adolescents, including their presentations and responses to bromocriptine mesylate treatment. PATIENTS--Five adolescents (three females and two males) aged between 12.5 and 17 years were diagnosed as having PRL-secreting macroadenomas at the pediatric endocrine service at New York University Medical Center between 1987 and 1989. Presenting complaints included visual field deficits, gynecomastia, and amenorrhea, both primary and secondary. All patients demonstrated some feature of hypogonadism or pubertal arrest. Diagnostic criteria included an elevated serum PRL level (mean, 1670 micrograms/L; range, 610 to 3700 micrograms/L) and visualization of a pituitary tumor that measured greater than 1 cm by either a computed tomographic scan or magnetic resonance imaging (mean size, 2.7 cm; range, 1.4 to 4 cm). INTERVENTIONS--Each patient was treated with bromocriptine mesylate at an oral dose of 7.5 mg/d. The patients continued with that treatment for the duration of the study period. MEASUREMENTS AND RESULTS--Anterior pituitary function was evaluated in four of five patients before treatment. All four were growth hormone deficient. Three patients were also gonadotropin deficient. Thyrotropin (thyroid-stimulating hormone) and corticotropin (adrenocorticotropic hormone) deficiencies were demonstrated in three patients who had multiple pituitary deficits. Follow-up testing included serial PRL measurements and radiographic imaging of tumor size. All patients demonstrated a marked decrease in PRL levels, as well as in tumor size (mean shrinkage, 70%). The three patients who initially had visual field deficits showed significant improvement of vision with bromocriptine therapy. Follow-up study of anterior pituitary function showed significant improvement with bromocriptine treatment in three patients. CONCLUSIONS--Bromocriptine was quite effective in the shrinkage of PRL-secreting macroadenomas in all our patients. It is a noninvasive treatment that can preserve and restore vision, as well as pituitary function, which is integral to continued growth and sexual maturation of the adolescent. Bromocriptine is preferable to surgery or radiation in the treatment of PRL-secreting macroadenomas in the adolescent
— id: 6544, year: 1993, vol: 147, page: 1057, stat: Journal Article,

Juvenile autoimmune thyroiditis and mitral valve prolapse
Blumberg D; Rutkowski M; Sklar C; Reggiardo D; Friedman D; David R
1992 Apr;13(2):89-91, Pediatric cardiology
An increased incidence of mitral valve prolapse (MVP) has been reported in adult patients with autoimmune thyroid disease. The aim of this study was to assess the incidence of MVP in children and adolescents with juvenile autoimmune thyroiditis (JAT). Cardiac echo studies using M-mode, 2D, and Doppler examinations were performed on 23 patients (21 females, 2 males). The patients were studied at a median age of 12 years (range 5-20 years). Only one patient was found to have evidence suggestive of MVP, an incidence (4.3%) similar to that seen in the normal pediatric population. We, therefore, conclude that the incidence of MVP in children and adolescence with JAT is not increased
— id: 13634, year: 1992, vol: 13, page: 89, stat: Journal Article,

Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion
Sklar CA; Rothenberg S; Blumberg D; Oberfield SE; Levine LS; David R
1991 Oct;73(4):734-738, Journal of clinical endocrinology & metabolism
To assess further the relationship between gonadal sex steroids and PRL, GH, and insulin-like growth factor-I (IGF-I) secretion and to help clarify the mechanism underlying the pubertal growth spurt, we studied 11 children (10 girls) with central precocious puberty before and during gonadal suppression with the GnRH agonist (GnRH-a) leuprolide acetate. Nocturnal sampling for plasma levels of GH and PRL, GH response to GH-releasing factor-(1-44), and plasma IGF-I levels were determined before and 3-6 months after pituitary-gonadal suppression. Treatment caused a significant decrease in the LH and FSH responses to GnRH (P less than 0.01) and the plasma concentration of estradiol (P less than 0.05). The patients' mean height velocity SD score for chronological age, initially 3.8 +/- 1.9, decreased significantly to 0.9 +/- 0.9 with treatment (P less than 0.005). Nocturnal GH secretion (mean GH concentration, sum of GH pulse areas, sum of GH pulse amplitudes, and GH pulse frequency) and mean IGF-I levels (1.38 +/- 0.6 vs. 1.72 +/- 0.34 U/mL) were not significantly altered by treatment. However, the mean peak GH response to GH-releasing factor-(1-44) was 29.2 +/- 6.8 micrograms/L before treatment and declined significantly to 17.7 +/- 3.4 micrograms/L after gonadal suppression (P less than 0.05). PRL secretion was similar before and after GnRH-a-induced suppression. These results indicate that the decrease in height velocity noted during GnRH-a treatment occurred independently of changes in nocturnal GH secretion and IGF-I levels. These data are consistent with the premise that sex steroids can modulate growth by a direct action on skeletal growth
— id: 13880, year: 1991, vol: 73, page: 734, stat: Journal Article,

IMPROVED HEIGHT PROGNOSIS IN CHILDREN WITH PRECOCIOUS PUBERTY AND GROWTH-HORMONE (GH) DEFICIENCY TREATED WITH A GNRH AGONIST (GNRHA) AND GH
Sklar, CA; David, R
1990 Apr;27(4):A86-A86, Pediatric research
— id: 31990, year: 1990, vol: 27, page: A86, stat: Journal Article,

Available FSH receptors in adult rat testis in vivo
Yoon DJ; Reggiardo D; David R
1990 May;125(2):293-299, Journal of endocrinology
It has been suggested that the tight junctions formed between Sertoli cells during the peripubertal period constitute a barrier to circulating FSH in the adult testis, limiting its access to the lumen of the seminiferous tubules. There are also reports of FSH receptor-binding inhibitors. These observations prompted us to study the extent of FSH receptor availability in vivo in the adult rat. Experimental rats were given an intracardiac injection of rat FSH (rFSH), and the occupied receptor was measured by radioimmunoassay of acid-released rFSH from the testis. In the saline-injected control animals, there were 247 fmol occupied FSH receptors/g testis, and as much as 1788 fmol of the unoccupied high-affinity receptors/g testis, as measured by in-vitro binding studies. After intracardiac injection of increasing amounts of rFSH (up to 606 pmol), receptor occupancy increased to a maximum plateau of only 448 fmol/g testis. In contrast, when rFSH was given by intratesticular injection in order to achieve pharmacological doses in the testis, the maximum binding was 662 fmol/g testis. Scatchard analysis of the in-vivo data revealed, however, that the maximum concentration of the high-affinity receptor was 452 fmol/g testis, a value concordant with the highest in-vivo binding observed in animals given intracardiac rFSH (448 fmol/g). A single injection of the hormone did not induce down-regulation of FSH receptors, regardless of the dose, whereas multiple injections of menotrophin were effective, at least to some extent. Despite the receptor loss, the immediate receptor availability was maintained, suggesting the presence of a receptor pool.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 62211, year: 1990, vol: 125, page: 293, stat: Journal Article,

Acromegaly in an infant
Blumberg DL; Sklar CA; David R; Rothenberg S; Bell J
1989 Jun;83(6):998-1002, Pediatrics
Serial hormonal studies were carried out in a girl with a growth hormone-secreting pituitary adenoma and hyperprolactinemia diagnosed at 21 months of age, the youngest verified case of acromegaly. The child had progressive macrocephaly, noted at 6 months of age, which preceded the rapid acceleration of linear growth by nearly 1 year. At 21 months of age, the girl's head circumference measured 55 cm (+5.5 SD) and her height was 97.6 cm (+4.4 SD). Preoperative serum growth hormone level was 135 ng/mL, somatomedin C was 1,540 ng/mL (normal for bone age 18 to 97 ng/mL), and prolactin was 370 ng/mL (normal less than 20 ng/mL). Following total resection of a large adenoma, immunohistochemical staining of the tumor showed growth hormone but not prolactin. With longitudinal monitoring of the child for 2 years postoperatively, persistently low growth hormone levels were demonstrated and normal growth velocity (6 cm/yr). Peak serum growth hormone levels ranged from 2.8 to 4.1 ng/mL after stimulation tests with insulin, arginine, and L-dopa. Maximum sleep-entrained growth hormone level was 3.4 ng/mL. At the same time, serum somatomedin C levels measured serially were normal (29 to 111 ng/mL), whereas simultaneous prolactin levels were moderately increased (30 to 147 ng/mL). The data support the hypothesis that hyperprolactinemia may have contributed to stimulating somatomedin C and sustaining the normal growth rate in this child
— id: 10603, year: 1989, vol: 83, page: 998, stat: Journal Article,

SUCCESSFUL THERAPY OF PROLACTIN (PRL) SECRETING MACROADENOMAS IN ADOLESCENTS
Reggiardo, DB; Sklar, CA; David, R
1989 Apr;25(4):A8-A8, Pediatric research
— id: 31729, year: 1989, vol: 25, page: A8, stat: Journal Article,

Congenital adrenal hyperplasia and fertility
Blumberg, D L; Reggiardo, D; Sklar, C; David, R
1988 Oct 6;319(14):951-951, New England journal of medicine
— id: 71770, year: 1988, vol: 319, page: 951, stat: Journal Article,

SONOGRAPHIC EVALUATION OF EFFICACY OF MEDICAL-TREATMENT FOR ISOSEXUAL PRECOCIOUS PUBERTY - COMPARATIVE CLINICAL AND IMAGING STUDY
Hernanzschulman, M; Sklar, C; Ambrosino, M; Blumberg, D; David, R; Genieser, N
1988 Sep;151(3):619-619, American journal of roentgenology
— id: 31466, year: 1988, vol: 151, page: 619, stat: Journal Article,

SONOGRAPHIC EVALUATION OF EFFICACY OF MEDICAL-TREATMENT FOR ISOSEXUAL PRECOCIOUS PUBERTY - COMPARATIVE CLINICAL AND IMAGING STUDY
Hernanzschulman, M; Sklar, C; Ambrosino, M; Blumberg, D; David, R; Genieser, N
1988 Jul;18(5):438-438, Pediatric radiology
— id: 31467, year: 1988, vol: 18, page: 438, stat: Journal Article,

Adrenal androgens in children with short stature
Lew LQ; Sklar CA; Yoon DJ; David R
1988 ;29(4):151-155, Hormone research
Recent data suggest that adolescent individuals with growth hormone (GH) deficiency have subnormal levels of adrenal androgens (AA). In order to determine the developmental pattern of AA in GH deficiency and to assess whether AA levels can help identify children with GH deficiency, we measured plasma concentrations of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), delta 4-androstenedione (delta 4A), and cortisol in the basal state and during prolonged adrenocorticotropin (ACTH) infusion (8 h) in a group of 34 individuals, 26 males and 8 females, with short stature. Their chronological ages (CA) ranged from 1.75 to 17.5 years (median 10.35 years). The subjects were grouped into two categories according to the results of pituitary testing: group 1 = short, non-GH-deficient (n = 16), and group 2 = GH-deficient, ACTH-sufficient (n = 18). Patients in groups 1 and 2 had similar bone ages (BA: 7.2 +/- 0.7 vs. 7.5 +/- 1.0 years) and Z scores for height (-3.0 +/- 0.2 vs. -3.2 +/- 0.3 units) and height velocity (-2.5 +/- 0.4 vs. -2.6 +/- 0.2 units). For both groups there were significant increases from basal to peak levels for DHEA, DHEA-S, delta 4A and cortisol following prolonged ACTH infusion. Although both basal and peak levels of DHEA-S overlapped in groups 1 and 2 for all CA and BA, levels in group 2 tended to be lower, especially for BA greater than 10 years.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 11282, year: 1988, vol: 29, page: 151, stat: Journal Article,

Presence of immunoreactive corticotropin-releasing factor in rat testis
Yoon DJ; Sklar C; David R
1988 Feb;122(2):759-761, Endocrinology
We attempted to demonstrate the presence of immunoreactive (ir) CRF in rat testis by RIA, and by an immunocytochemical technique. The RIA was performed on 27,000 x g supernatants of phosphate buffer extracts of adult rat testes, and revealed a high concentration of irCRF (51 - 74 ng/g testis), with a clear parallelism to the standard curve prepared with synthetic rat CRF. In contrast, the peripheral blood level of irCRF was extremely low (less than 0.05 ng/ml). Immunocytochemical studies of irCRF revealed strong specific staining in the Leydig cells and germ cells in normal adult rat testis. Epididymal spermatozoa also stained positive. Testicular irCRF fluctuated significantly with age. The levels (mean +/- SD) assayed in 10, 20, 60 and 90-day-old rats were 41.6 +/- 4.7, 8.7 +/- 0.2, 55.5 +/- 3.3 and 71.3 +/- 3.4 ng/g testis, respectively (P less than 0.01). The level was drastically reduced after abdominal translocation of a testis (9.6 +/- 1.3 ng/g testis), and after hypophysectomy (16.7 +/- 1.6 ng/g testis) in adult rats. However, neither hemicastration nor unilateral cryptorchidism influenced the irCRF levels in the contralateral testis. These data suggest a local production of irCRF which may play a role in regulation of Leydig cell function and sperm maturation in testis and epididymis
— id: 11198, year: 1988, vol: 122, page: 759, stat: Journal Article,

TESTICULAR IMMUNOREACTIVE CORTICOTROPIN-RELEASING FACTOR (IRCRF) - EVIDENCE FOR SERTOLI-CELL AS ITS PRODUCTION SITE
YOON, DJ; DAVID, R
1988 JAN-FEB ;9(1):P22-P22, Journal of andrology
— id: 41824, year: 1988, vol: 9, page: P22, stat: Journal Article,

ACROMEGALY PRESENTING IN INFANCY
Blumberg, D; Sklar, C; Bell, J; David, R
1987 Apr;21(4):A244-A244, Pediatric research
— id: 31241, year: 1987, vol: 21, page: A244, stat: Journal Article,

GROWTH AND PUBERTY IN A 36 YR OLD MALE AFTER INTRAVENOUS ALIMENTATION
Sansaricq, C; Snyderman, SE; David, R; Shaha, M; Pulmones, TM
1987 Apr;21(4):A277-A277, Pediatric research
— id: 31242, year: 1987, vol: 21, page: A277, stat: Journal Article,

Adrenal function in thalassemia major following long-term treatment with multiple transfusions and chelation therapy. Evidence for dissociation of cortisol and adrenal androgen secretion
Sklar, C A; Lew, L Q; Yoon, D J; David, R
1987 Mar;141(3):327-330, American journal of diseases of children
Eight patients with beta-thalassemia who were given long-term treatment with combined multiple transfusions and chelation therapy underwent adrenal testing. The six male and two female patients ranged in age from 7 to 19 years. Six of eight patients had delayed bone ages and height greater than 2.5 SDs below the mean. Of the six patients more than 13 years of age, two had clinical evidence of isolated adrenarche and only one had evidence of true puberty. Cortisol levels were similar in patients and controls at zero time (10.6 +/- 1.8 micrograms/dL [292 +/- 50 nmol/L] vs 10.8 +/- 1.4 micrograms/dL [298 +/- 39 nmol/L]) and at 60 minutes (26.6 +/- 2.5 micrograms/dL [734 +/- 69 nmol/L] vs 24.9 +/- 1.9 micrograms/dL [687 +/- 52 nmol/L]) after insulin hypoglycemia (all values are the mean +/- SE). During an eight-hour infusion of ACTH, cortisol responses in the patients with thalassemia were not significantly different from those of controls. Baseline levels of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were significantly lower in the subjects with thalassemia compared with controls of similar bone age and pubertal status. The prolonged ACTH infusion caused a significant increase in the DHEA level (79.2 +/- 14.7 ng/dL [2.74 +/- 0.51 nmol/L] vs 538.6 +/- 38.1 ng/dL [18.67 +/- 4.79 nmol/L]) and the DHEA-S level (37.5 +/- 10.8 micrograms/dL [1.02 +/- 0.29 mumol/L] vs 70.5 +/- 18.3 micrograms/dL [1.19 +/- 0.50 mumol/L]) in the patients. The patients' peak stimulated levels of DHEA-S were significantly lower than those of the controls, whereas peak levels of DHEA were similar in the patients and the controls. These results indicate that combined multiple transfusions and chelation therapy preserve the integrity of the ACTH-cortisol axis in patients with thalassemia. The reduced levels of adrenal androgens, short stature, and delayed puberty noted in our patients suggest, however, that alternative approaches to the therapy of thalassemia are needed
— id: 71771, year: 1987, vol: 141, page: 327, stat: Journal Article,

Immunocytochemical localization of hFSH as an index of Sertoli cell function in the human testis
Yoon DJ; Golimbu M; Schinella R; Stein B; Sklar CA; David R
1987 Nov;116(3):333-338, Acta endocrinologica (Copenhagen)
The FSH receptor in the human testis has not been well characterized in vivo. Using an immunoperoxidase technique we have attempted the immunocytochemical localization of FSH in testicular tissue from patients with a variety of disorders including oligo- or azoospermia (N = 6), cryptorchidism (N = 3), and prostatic carcinoma (N = 3). Specific staining for hFSH was observed inside the seminiferous tubule, generally near the basal membrane in all except the cryptorchid patients. Specific staining was also localized in the luminal area of the seminiferous tubule. In most cases, FSH-positive cells were also found in the interstitium, with a minority of the cells being macrophages. The latter were more prevalent in the undescended testes and in orchiectomy specimens from patients with prostatic cancer. The pattern of FSH localization observed in this study probably represents receptorbound hormone, and may reflect damage to the Sertoli cell and its tight junctions. Further study of the changes in receptor distribution as an indication of Sertoli cell malfunction, may be helpful in our understanding of human testicular disorders
— id: 11338, year: 1987, vol: 116, page: 333, stat: Journal Article,

ADRENAL ANDROGENS (AA) IN THE DIFFERENTIAL-DIAGNOSIS OF SHORT STATURE
LEW, LQ; SKLAR, CA; YOON, DJ; DAVID, R
1986 APR ;20(4):A217-A217, Pediatric research
— id: 41460, year: 1986, vol: 20, page: A217, stat: Journal Article,

Juvenile autoimmune thyroiditis. Hormonal status at presentation and after long-term follow-up
Sklar, C A; Qazi, R; David, R
1986 Sep;140(9):877-880, American journal of diseases of children
Thirty children and adolescents with the clinical diagnosis of juvenile autoimmune thyroiditis (JAT) were studied. Twenty-six patients were female and four were male. The median age at diagnosis was 12.9 years (range, 7.5 to 17.3 years). At the initial evaluation, endocrine studies revealed that 40% of the patients were euthyroid, while 33% had compensated hypothyroidism and 27% had overt hypothyroidism. Seventeen patients, 16 of whom received thyroid hormone replacement therapy for a median period of 26 months, were followed up on a long-term basis after discontinuation of therapy. Seven (87%) of eight patients who were initially euthyroid have remained so for a median period of 28 months after treatment and a median period of 50 months since diagnosis. Four (44%) of nine patients who initially had hypothyroidism (either compensated or overt) have reverted to a euthyroid state and have remained so for a median period of 33 months after discontinuation of therapy. Neither the size of the thyroid gland nor the pattern or absolute titer of thyroid autoantibodies correlated with functional status. These results indicate that individuals with euthyroid JAT may remain euthyroid for many years and that a substantial percentage of patients with hypothyroid JAT will experience resolution of thyroid dysfunction
— id: 71772, year: 1986, vol: 140, page: 877, stat: Journal Article,

JUVENILE AUTOIMMUNE-THYROIDITIS (JAT) - HORMONAL STATUS AT PRESENTATION AND AFTER LONG-TERM FOLLOW-UP
SKLAR, CA; QAZI, R; DAVID, R
1986 APR ;20(4):A222-A222, Pediatric research
— id: 41461, year: 1986, vol: 20, page: A222, stat: Journal Article,

Down's syndrome and testicular cancer: a possible association
Braun DL; Green MD; Rausen AR; David R; Wolman SR; Alba Greco M; Muggia FM
1985 Summer;7(2):208-211, American journal of pediatric hematology-oncology
— id: 18128, year: 1985, vol: 7, page: 208, stat: Journal Article,

Plasma growth hormone response to oral l-dopa in infantile autism
Deutsch, S I; Campbell, M; Sachar, E J; Green, W H; David, R
1985 Jun;15(2):205-212, Journal of autism & developmental disorders
In order to assess further the occurrence of hypothalamic dysfunction in infantile autism and its possible relationship to dopaminergic abnormalities, the l-dopa provocative test was performed in 22 patients fulfilling DSM-III criteria for this disorder. The results indicate a high incidence (at least 30%) of blunted plasma growth hormone (GH) responses following oral administration of l-dopa in this sample. These data suggest an alteration of hypothalamic dopamine receptor sensitivity in the patients with blunted responses. Thus, a subgroup of autistic patients within a descriptively homogeneous diagnostic category shows evidence of hypothalamic dysregulation and dopaminergic abnormalities
— id: 120765, year: 1985, vol: 15, page: 205, stat: Journal Article,

Chronic syndrome of inappropriate secretion of antidiuretic hormone in childhood
Sklar, C; Fertig, A; David, R
1985 Jul;139(7):733-735, American journal of diseases of children
Chronic forms of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occur infrequently in childhood. We describe three pediatric patients with chronic SIADH. In two patients the persistent SIADH was associated with neoplasms of the central nervous system while in the third patient it was due to congenital anomalies of the central nervous system. We describe the clinical course and management of each patient, including the long-term use of furosemide taken orally once a day
— id: 71773, year: 1985, vol: 139, page: 733, stat: Journal Article,

PROLACTIN (PRL) SECRETION IN LONG-TERM SURVIVORS OF ACUTE LYMPHOBLASTIC-LEUKEMIA (ALL)
Sklar, CA; Rothenberg, SA; Avruskin, TW; Rausen, A; David, R
1985 ;19(6):613-613, Pediatric research
— id: 30905, year: 1985, vol: 19, page: 613, stat: Journal Article,

A syndrome of gonadotropin resistance possibly due to a luteinizing hormone receptor defect
David R; Yoon DJ; Landin L; Lew L; Sklar C; Schinella R; Golimbu M
1984 Jul;59(1):156-160, Journal of clinical endocrinology & metabolism
An 18-yr-old 46,XY man with primary hypogonadism and a microphallus is described whose Leydig cells appear to be partially insensitive to gonadotropin action. The external genitalia were well differentiated though abnormally small. The mean +/- SE baseline plasma testosterone (T) level was 62 +/- 3.9 ng/dl, and androstenedione was 34.5 +/- 7.3 ng/dl. Plasma levels of dehydroepiandrosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, 17-hydroxypregnenolone, corticosterone, deoxycorticosterone, and 17 beta-estradiol were all normal. After the im administration of hCG, plasma T increased insignificantly from 71 to 78 ng/dl, and androstenedione increased from 22 to 47 ng/dl; there was no significant change in the levels of precursor steroids. The mean +/- SE serum FSH level was 17.4 +/- 3.6 mIU/ml, and LH was 15.4 +/- 1.1 mIU/ml (normal, 5-20); both responded briskly to iv GnRH. Exogenous T therapy resulted in normal virilization, whereas therapy with hCG was ineffectual. Testicular biopsy revealed Leydig cells in normal numbers, some spermatogenesis, and thickened tubular basement membranes. In vitro binding studies using [125I]hCG were performed with testicular homogenates from the patient and three normal subjects. With 7.4 fmol labeled hCG, the specific binding (mean +/- SD), expressed as femtomoles of hCG per mg protein, was 1.16 +/- 0.44 compared to 2.49 +/- 0.41 in normal subjects (P less than 0.05). These data demonstrate partial resistance to hCG and suggest that the defect in Leydig cell function may be at the LH receptor or postreceptor level
— id: 62206, year: 1984, vol: 59, page: 156, stat: Journal Article,

ABNORMALITIES OF THYROID-FUNCTION IN INFANTS WITH DOWN SYNDROME
FORT, P; LIFSHITZ, F; BELLISARIO, R; DAVIS, J; LANES, R; PUGLIESE, M; RICHMAN, R; POST, EM; DAVID, R
1984 ;104(4):545-549, Journal of pediatrics
— id: 41091, year: 1984, vol: 104, page: 545, stat: Journal Article,

Psychosocial dwarfism: a critical review of the evidence
Green, W H; Campbell, M; David, R
1984 Jan;23(1):39-48, Journal of the American Academy of Child Psychiatry
— id: 120769, year: 1984, vol: 23, page: 39, stat: Journal Article,

EFFECT OF ADRENAL ANDROGENS ON BONE RUDIMENTS IN ORGAN-CULTURE
Drucker, WD; Banerjee, S; Mcmorrow, L; David, R
1981 ;15(12):1557-1557, Pediatric research
— id: 30231, year: 1981, vol: 15, page: 1557, stat: Journal Article,

Cushing's syndrome in infancy: difficulties in diagnosis and adrenal autotransplantation after therapeutic adrenalectomy
Avruskin, T W; Tang, S C; Juan, C S; Mestel, A L; Kishida, S; David, R; Drucker, W D
1980 Sep-Oct;280(2):101-108, American journal of the medical sciences
A two-month-old female with clinical manifestations of Cushing's syndrome including mild virilization exhibited an unusual steroid pattern illustrating difficulties in diagnosis of this disorder in infancy. Unequivocal abnormalities were limited to serial elevations of serum cortisol concentration, hyperresponsiveness to ACTH, resistance of serum cortisol to dexamethasone suppression, and elevation of testosterone and dehydroepiandrosterone sulfate concentration. On the other hand, twenty-four hour urinary 17-hydroxysteroid, 17-ketosteroid, free cortisol, and 6B-hydroxycortisol excretion were normal for the age. At laparotomy the adrenals were only minimally enlarged, and their architecture was normal by light microscopy. Following total adrenalectomy, adrenal slices were transplanted into the rectus abdominis muscles. Progressive hypertension developed three weeks later, suggesting adrenal regeneration. The infant then developed acute Salmonella enteritis and expired. At autopsy, the adrenal transplant showed outer cortical preservation, inner zone degeneration, and some growth into the surrounding tissue. The unfavorable outcome notwithstanding, this study adds to existing data in the adult that adrenal autotransplantation may have significant therapeutic value in Cushing's syndrome treated by bilateral adrenalectomy
— id: 122853, year: 1980, vol: 280, page: 101, stat: Journal Article,

Some physical parameters of young autistic children
Campbell, M; Petti, T A; Green, W H; Cohen, I L; Genieser, N B; David, R
1980 Spring;19(2):193-212, Journal of the American Academy of Child Psychiatry
— id: 120772, year: 1980, vol: 19, page: 193, stat: Journal Article,

Aberrant testicular differentiation in 46,XY gonadal dysgenesis: morphology, endocrinology, serology
Wolman SR; McMorrow LE; Roy S; Koo GC; Wachtel SS; David R
1980 ;55(3):321-325, Human genetics
In an infant with gonadal dysgenesis and somatic anomalies, the internal and external genitalia were female but the gonads contained tubular structures suggesting male differentiation. The karyotype was 46,XY with no evidence of structural aberration or mosaicism. Hormonal metabolism and H-Y antigen expression were assayed in cultured gonadal cells. Although unable to synthesize testosterone, the cultured cells were able to convert it to dihydrotestosterone. H-Y antigen was present, perhaps at a level lower than that in cells from normal XY males. Our observations indicate that a modicum of testicular organogenesis may precede the involution that results in a streak gonad in some cases of gonadal dysgenesis
— id: 27823, year: 1980, vol: 55, page: 321, stat: Journal Article,

Passive avoidance learning in Lesch-Nyhan disease: effect of 1-desamino-8-arginine-vasopressin
Anderson LT; David R; Bonnet K; Dancis J
1979 Mar 5;24(10):905-910, Life sciences
— id: 43319, year: 1979, vol: 24, page: 905, stat: Journal Article,

PLASMA DEHYDROEPIANDROSTERONE SULFATE IN NORMAL, HYPERTENSIVE AND HYPERPROLACTINEMIC SUBJECTS
Drucker, WD; David, R
1979 ;27(4):A678-A678, Clinical research
— id: 29998, year: 1979, vol: 27, page: A678, stat: Journal Article,

EFFECT OF DDAVP ON PASSIVE-AVOIDANCE LEARNING IN LESCH-NYHAN DISEASE
Anderson, LT; David, R; Bonnet, KA; Dancis, J
1978 ;12(4):367-367, Pediatric research
— id: 29937, year: 1978, vol: 12, page: 367, stat: Journal Article,

HYPERCALCEMIA AS A PRESENTING MANIFESTATION OF LEUKEMIA - EVIDENCE OF EXCESSIVE
JAYARAMAN, J; DAVID, R
1977 ;90(4):609-610, Journal of pediatrics
— id: 39990, year: 1977, vol: 90, page: 609, stat: Journal Article,

Levodopa and levoamphetamine: a crossover study in young schizophrenic children
Campbell M; Small AM; Collins PJ; Friedman E; David R; Genieser N
1976 Jan;19(1):70-86, Current therapeutic research
— id: 66992, year: 1976, vol: 19, page: 70, stat: Journal Article,

DERMATOGLYPHICS IN 45X-46XX GONADAL DYSGENESIS
WOLMAN, SR; HORLAND, AA; DAVID, R
1976 ;9(4):441-443, Clinical genetics
— id: 98722, year: 1976, vol: 9, page: 441, stat: Journal Article,

EARLY DIAGNOSIS OF CONGENITAL ADRENAL-HYPERPLASIA BY MEASUREMENT OF 17-HYDROXYPROGESTERONE
Youssefnejadian, E; David, R
1975 ;4(4):451-454, Clinical endocrinology
— id: 28607, year: 1975, vol: 4, page: 451, stat: Journal Article,

INFANTILE RICKETS WITH SEVERE PROXIMAL RENAL TUBULAR-ACIDOSIS, RESPONSIVE TO VITAMIN-D
HUGUENIN, M; SCHACHT, R; DAVID, R
1974 ;49(12):955-959, Archives of disease in childhood
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24 HOUR PATTERNS OF PLASMA LUTEINIZING-HORMONE AND FOLLICLE-STIMULATING HORMONE IN SEXUAL PRECOCITY
BOYAR, RM; FINKELST.JW; DAVID, R; ROFFWARG, H; KAPEN, S; WEITZMAN, ED; HELLMAN, L
1973 ;289(6):282-286, New England journal of medicine
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Liothyronine treatment in psychotic and nonpsychotic children under 6 years
Campbell M; Fish B; David R; Shapiro T; Collins P; Koh C
1973 Nov;29(5):602-608, Archives of general psychiatry
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Response to triiodothyronine and dextroamphetamine: a study of preschool schizophrenic children
Campbell M; Fish B; David R; Shapiro T; Collins P; Koh C
1972 Oct-Dec;2(4):343-358, Journal of autism & childhood schizophrenia
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