Synthesis, Biological Evaluation, and Binding Mode of a New Class of Oncogenic K-Ras4b Inhibitors.

Ras proteins are implicated in some of the most common life-threatening cancers. Despite intense research during the past three decades, progress towards small-molecule inhibitors of mutant Ras proteins still has been limited. Only recently has significant progress been made, in particular with ligands for binding sites located in the switch II and between the switch I and switch II region of K-Ras4B.

Normal insulin-like peptide-3 levels despite low testosterone in adult males with Prader-Willi syndrome: variations in Leydig cell function from infancy through adulthood.

Background: Cryptorchidism, incomplete pubertal development, and low testosterone are manifestations of hypogonadism in Prader-Willi syndrome (PWS). Insulin-like peptide-3 (INSL3) facilitates testicular descent in the fetus and reflects Leydig cell number in adults. INSL3 levels in PWS have not been previously reported.

Environmental home inspection services in Western Europe.

This review deals with environmental home inspection services in Western Europe provided for patients at the request of attending physicians to improve patient management. Such requests are usually motivated by respiratory or general symptoms which occur or worsen at home. The visit includes a standardised questionnaire as well as environmental sampling such as mite-allergen measurement, mould identification and volatile organic compound (VOC) measurements.

Clinical and hormonal status of infants with nonmosaic XXY karyotype.

Aim: To compare our recent findings in a cohort of 77 nonmosaic XXY infants <2 years of age with clinical and biological features already reported.

Results: The majority of reported XXY neonates had normal external genitalia. Only undescended testes and/or micropenis were identified reasons for referral.

Assessment of Leydig and Sertoli cell functions in infants with nonmosaic Klinefelter syndrome: insulin-like peptide 3 levels are normal and positively correlated with LH levels.

Context: Klinefelter syndrome (KS) is the most common sex chromosome disorder and a major cause of male infertility. In adult patients, serum inhibin B and anti-Mullerian-hormone (AMH) are undetectable, testosterone secretion is often impaired, and the tubules are depleted of germ cells. Before puberty, inhibin B, AMH, and testosterone levels are within the normal range.

Impact level of dihydrotestosterone on the hypothalamic-pituitary-leydig cell axis in men.

Dihydrotestosterone (DHT) the physiologically most potent androgen cannot be aromatised into oestrogen. DHT is used as a treatment for idiopathic gynaecomastia. In order to investigate the different sites of action of DHT on the hypothalamic-pituitary-testicular axis, two groups of adult men were studied.

Screening for Down syndrome using first-trimester combined screening followed by second-trimester ultrasound examination in an unselected population.

Objective: Recent studies have reported the efficacy of first-trimester combined screening for Down syndrome based on maternal age, serum markers (human chorionic gonadotropin, pregnancy-associated plasma protein A), and ultrasound measurement of fetal nuchal translucency. However, those do not incorporate the value of the widely accepted routine 20-22 weeks' anomaly scan.

Study Design: We carried out a multicenter, interventional study in the unselected population of a single health authority in order to assess the performance of first-trimester combined screening, followed by routine second trimester ultrasound examination and/or screening by maternal serum markers (free beta-hCG and alpha-fetoprotein measurement or total hCG, alpha-fetoprotein, and unconjugated estriol measurement) when incidentally performed.

Activating mutations in the luteinizing hormone receptor gene: a human model of non-follicle-stimulating hormone-dependent inhibin production and germ cell maturation.

Context: Familial male-limited precocious puberty is a dominant autosomal genetic disease caused by activating LH receptor gene mutations, clinically expressed only in males. In preliminary studies, in addition to the expected testosterone increase, we found high inhibin B levels before the age of normal puberty.

Objectives: The objective of the study was to assess the cellular origin of serum inhibin thanks to testis section immunostaining.

Adult height after ketoconazole treatment in patients with familial male-limited precocious puberty.

Familial male-limited precocious puberty is a rare cause of precocious puberty due to activating mutations of the LH receptor, leading to early onset virilization and short stature. Two therapeutic approaches have been proposed: the P450 cytochrome inhibitor ketoconazole or combined treatment with spironolactone and testolactone. Results on adult heights have not been reported to date after these two treatments, and in this study we present results from five patients treated with ketoconazole at a median dose of 16.

Inhibin B in pubertal development and pubertal disorders.

The inhibin B pubertal surge is a prominent signal of gonadal maturation in females as well as in males. In boys, it denotes the final functional maturation of Sertoli cells, which is accompanied by a progressive suppression of antimüllerian hormone production. In girls it reflects the initial recruitment of preantral follicles and their evolution to the antral stage.

Precocious puberty and statural growth.

Precocious puberty results mostly from the precocious activation of the gonadotropic axis. Although the age limits have recently been discussed, most physicians consider that onset of pubertal development before the age of 8 years in a girl or 9 years in a boy warrants at least a clinical and bone age evaluation by a paediatric endocrinologist. The major concern in precocious puberty is the underlying condition, and central nervous system or gonadal neoplasm have to be formally excluded as a first step in the diagnosis.

Inhibin B and anti-Müllerian hormone, but not testosterone levels, are normal in infants with nonmosaic Klinefelter syndrome.

Klinefelter syndrome is a major cause of infertility in the male. Nevertheless, pregnancies were recently obtained by intracytoplasmic injection of sperm retrieved by surgery or ejaculation, underscoring the need to understand the role of Sertoli and Leydig cell secretions during development. In 18 infants with prenatally diagnosed homogenous 47,XXY karyotype, blood samples were taken from birth to 3 yr of age.

Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants.

Objective: Many extremely preterm infants develop hyperglycemia in the first week of life during continuous glucose infusion. The objective of this study was to determine whether defective insulin secretion or resistance to insulin was the primary factor involved in transient hyperglycemia of extremely preterm infants.

Methods: A prospective comparative study was conducted in appropriate-for-gestational-age preterm infants <30 weeks of gestational age with the aim specifically to evaluate the serum levels of proinsulin, insulin, and C-peptide secreted during transient hyperglycemia by specific immunoassays.

Mutations in the human leptin and leptin receptor genes as models of serum leptin receptor regulation.

A part of serum Ob leptin, an adipocyte-secreted peptide, is bound to a soluble Ob receptor (sObR). Immunoreactive sObR was measured in 125 lean or obese control subjects (group 1), 18 individuals with a mutation in the leptin gene impairing leptin secretion (group 2), and 10 individuals with a mutation in the ObR gene, leading to production of a truncated ObR not anchored to cell membranes (group 3). In group 1, sObR levels were negatively correlated with age and BMI in children and with BMI in adults.