Virilization at puberty in adolescent girls may reveal a 46,XY disorder of sexual development.

Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.

Frequency stabilization and noise-induced spectral narrowing in resonators with zero dispersion.

Mechanical resonators are widely used as precision clocks and sensitive detectors that rely on the stability of their eigenfrequencies. The phase noise is determined by different factors including thermal noise, frequency noise of the resonator and noise in the feedback circuitry. Increasing the vibration amplitude can mitigate some of these effects but the improvements are limited by nonlinearities that are particularly strong for miniaturized micro- and nano-mechanical systems. Here we design a micromechanical resonator with non-monotonic dependence of the eigenfrequency on energy. Near the extremum, where the dispersion of the eigenfrequency is zero, the system regains certain characteristics of a linear resonator, albeit at large amplitudes. The spectral peak undergoes narrowing when the noise intensity is increased. With the resonator serving as the frequency-selecting element in a feedback loop, the phase noise at the extremum amplitude is ~3 times smaller than the minimal noise in the conventional nonlinear regime.

[McCune-Albright syndrome revealed by Blaschko-linear café-au-lait spots on the back]. / Syndrome de McCune-Albright révélé par des taches café-au-lait blaschko-linéaires du dos.

BACKGROUND: McCune-Albright syndrome is a rare sporadic disease defined by the triad of café-au-lait spots, fibrous dysplasia of bone and endocrine disorder. Diagnosis is classically confirmed by the presence of bone lesions or precocious puberty. We report a case of McCune-Albright syndrome diagnosed solely on the basis of the cutaneous signs. PATIENTS AND METHODS: A four-year-old girl was seen in our clinic due to the presence of congenital café-au-lait spots on her back. These macules were irregular, with jagged borders, and were disposed in a broad band on the left shoulder and in the lumbar region, in a Blaschko-linear pattern. McCune-Albright syndrome was immediately suspected, despite the absence of other signs of the disease. Genetic assessment carried out a year and a half later confirmed the diagnosis, with arginine substitution at position 201 of Gs alpha protein. The child was still asymptomatic. Regular radiographic and endocrine assessments remained normal for three years until the sudden appearance at the age of seven years of precocious puberty and radiographic evidence of fibrous dysplasia of the right hand. DISCUSSION: Café-au-lait spots are very common in the general population. An underlying genetic disorder should only be sought when such spots are multiple. However, in the case of McCune-Albright syndrome, it is the irregular borders and the Blaschko-linear arrangement of the spots in broad irregular bands that are pathognomonic, reflecting as they do the genetic mosaicism characteristic of this disease.

Regular rather than chaotic origin of the resonant transport in superlattices.

We address the enhancement of electron transport in semiconductor superlattices that occurs in combined electric and magnetic fields when cyclotron rotation becomes resonant with Bloch oscillations. We show that the phenomenon is regular in origin, contrary to the widespread belief that it arises through chaotic diffusion. The theory verified by simulations provides an accurate description of earlier numerical results and suggests new ways of controlling resonant transport.

Maximal width of the separatrix chaotic layer.

The main goal of the paper is to find the absolute maximum of the width of the separatrix chaotic layer as function of the frequency of the time-periodic perturbation of a one-dimensional Hamiltonian system possessing a separatrix, which is one of the major unsolved problems in the theory of separatrix chaos. For a given small amplitude of the perturbation, the width is shown to possess sharp peaks in the range from logarithmically small to moderate frequencies. These peaks are universal, being the consequence of the involvement of the nonlinear resonance dynamics into the separatrix chaotic motion. Developing further the approach introduced in the recent paper by Soskin [Phys. Rev. E 77, 036221 (2008)], we derive leading-order asymptotic expressions for the shape of the low-frequency peaks. The maxima of the peaks, including in particular the absolute maximum of the width, are proportional to the perturbation amplitude times either a logarithmically large factor or a numerical, still typically large, factor, depending on the type of system. Thus, our theory predicts that the maximal width of the chaotic layer may be much larger than that predicted by former theories. The theory is verified in simulations. An application to the facilitation of global chaos onset is discussed.

Matching of separatrix map and resonant dynamics, with application to global chaos onset between separatrices.

We have developed a general method for the description of separatrix chaos, based on the analysis of the separatrix map dynamics. Matching it with the resonant Hamiltonian analysis, we show that, for a given amplitude of perturbation, the maximum width of the chaotic layer in energy may be much larger than it was assumed before. We use the above method to explain the drastic facilitation of global chaos onset in time-periodically perturbed Hamiltonian systems possessing two or more separatrices, previously discovered [S. M. Soskin, O. M. Yevtushenko, and R. Mannella, Phys. Rev. Lett. 90, 174101 (2003)]. The theory well agrees with simulations. We also discuss generalizations and applications. The method may be generalized for single-separatrix cases. The facilitation of global chaos onset may be relevant to a variety of systems, e.g., optical lattices, magnetic and semiconductor superlattices, meandering flows in the ocean, and spinning pendulums. Apart from dynamical transport, it may facilitate noise-induced transitions and the stochastic web formation.

Influence of rapamycin on rat macrophage viability and chemotaxis toward allogenic pancreatic islet supernates.

The aim of this work was to evaluate the effects of rapamycin on rat macrophage viability and chemotaxis toward allogereic pancreatic islet supernates. Macrophages were isolated from rats by peritoneal lavage at 3 days after intraperitoneal injection of thioglycolate. Macrophage viability was studied after 7 days of culture by Cell Titer assays in the presence of rapamycin at 0.1, 1, and 10 ng/mL (n = 6). After 48 hours of culture, pancreatic rat islet supernates were studied for there chemotactic properties toward freshly isolated macrophages in the presence of rapamycin at 0.1, 1, and 10 ng/mL. Chemotaxis was expressed as a migration index defined as the number of macrophages attracted by the test solution (islet supernate +/- rapamycin)/number of macrophages attracted by the supernate (n = 6). After 3 days of culture, macrophage viability decreased significantly by 22%, 36%, and 32% in the presence of 0.1, 1, and 10 ng/mL rapamycin, respectively (P = .008). Macrophage viability remained stable at about 70% after 7 days of culture. In the presence of islet supernates, macrophage migration increased two-fold compared with those obtained by culture medium. Rapamycin did not influence macrophage migration toward culture medium. However, the drug significantly reduced the migration of macrophages toward islet supernates from 2 +/- 0.6 to 0.9 +/- 0.4, 0.7 +/- 0.3, or 0.8 +/- 0.4 in the presence of 0.1, 1, or 10 ng/mL rapamycin, respectively (P = .04). Rapamycin decreased the survival of cultured rat macrophages and their migration toward allogenic islet supernates. These results suggested that, besides its anti-proliferative effect on T cells, rapamycin reduced macrophage attraction to the graft site.

Bilateral anorchia in infancy: occurence of micropenis and the effect of testosterone treatment.

OBJECTIVE: To analyze the clinical and histological findings in boys with bilateral anorchia and the response to testosterone treatment on penis length. STUDY DESIGN: Patients were divided into two groups according to the absence (group A, n = 29) or the presence (group B, n = 26) of palpable intrascrotal or inguinal mass at first clinical examination. RESULTS: A micropenis was found in 46% of patients (n = 24) with a similar proportion in both groups. Testosterone treatment induced a mean penis length gain of 1.9 +/- 1.3 SDS (standard deviation score). However, micropenis persisted in six patients. Histological examination (n = 18) confirmed the absence of any testicular structure with deferent ducts being present unilaterally or bilaterally in all but three patients. In these three patients, a hemorrhagic testis, probably as a result of a mechanical torsion, was found. CONCLUSIONS: The presence of isolated micropenis in almost half of patients with bilateral anorchia strongly suggests that the testicular damage frequently occurs during the second half of gestation after male sexual differentiation. In most cases, testosterone treatment stimulates the penile growth. Although the pathogenesis of bilateral anorchia may be heterogeneous, our study suggests that gonads may have been functionally abnormal before they disappeared, and suggests that some patients have an intrinsic endocrine disorder.

Divergence of the chaotic layer width and strong acceleration of the spatial chaotic transport in periodic systems driven by an adiabatic ac force.

We show for the first time that a weak perturbation in a Hamiltonian system may lead to an arbitrarily wide chaotic layer and fast chaotic transport. This generic effect occurs in any spatially periodic Hamiltonian system subject to a sufficiently slow ac force. We explain it and develop an explicit theory for the layer width, verified in simulations. Chaotic spatial transport as well as applications to the diffusion of particles on surfaces, threshold devices, and others are discussed.

Drastic facilitation of the onset of global chaos.

We show that the onset of global chaos in a time periodically perturbed Hamiltonian system may occur at unusually small magnitudes of perturbation if the unperturbed system possesses more than one separatrix. The relevant scenario is the combination of the overlap in the phase space between resonances of the same order and their overlap in energy with chaotic layers associated with separatrices of the unperturbed system. We develop the asymptotic theory and verify it in simulations.

Comment on "monostable array-enhanced stochastic resonance".

Lindner et al. [Phys. Rev. E 63, 051107 (2001)] have reported multiple stochastic resonances (SRs) in an array of underdamped monostable nonlinear oscillators. This is in contrast to the single SR observed earlier in a similar but isolated oscillator. Though the idea that such an effect might occur is intuitively reasonable, the notation and the interpretation of some of the major results seem confusing. These issues are identified and some of them are clarified. In addition, comments are made on two possible extensions of the central idea of Lindner et al.: one of these promises to provide much more striking manifestations of multiple SR in arrays; the other significantly widens the range of systems in which multiple SRs may be observed.

Strong enhancement of noise-induced escape by nonadiabatic periodic driving due to transient chaos.

We have found a mechanism by which a moderately weak nonadiabatic periodic driving may significantly facilitate noise-induced interwell transitions in an underdamped multiwell system. The mechanism is associated with the onset of a homoclinic tangle in the noise-free system: if the ratio of the driving amplitude A to the damping gamma exceeds a critical value approximately 1, then the basins of attraction of the linear responses related to different wells are mixed in a complex manner in some layer associated with the separatrix of the undriven nondissipative system, and the minimal energy in such layer is lower than the top of the barrier. Thus the energy to which the system needs to be activated by the noise, to be able to make a transition, is lower than the top of the barrier.

Short time scales in the Kramers problem: a stepwise growth of the escape flux.

We prove rigorously and demonstrate in simulations that, for a potential system staying initially at the bottom of a well, the escape flux over the barrier grows on times of the order of a period of eigenoscillation in a stepwise manner, provided that friction is small or moderate. If the initial state is not at the bottom of the well, then, typically, some of the steps transform into oscillations. The stepwise/oscillatory evolution at short times appears to be a generic feature of a noise-induced flux.

Noise-induced escape on time scales preceding quasistationarity: New developments in the Kramers problem.

Noise-induced escape from the metastable part of a potential is considered on time scales preceding the formation of quasiequilibrium within that part of the potential. It is shown that, counterintuitively, the escape flux may then depend exponentially strongly, and in a complicated manner, on time and friction. (c) 2001 American Institute of Physics.

Evaluation of gonadal function in 107 intersex patients by means of serum antimüllerian hormone measurement.

Fetal male sexual differentiation is driven by two testicular hormones: testosterone (synthesized by interstitial Leydig cells) and antimüllerian hormone (AMH; produced by Sertoli cells present in the seminiferous tubules). Intersex states result either from gonadal dysgenesis, in which both Leydig and Sertoli cell populations are affected, or from impaired secretion or action of either testosterone or AMH. Until now, only Leydig cell function has been assessed in children with ambiguous genitalia, by means of testosterone assay. To determine whether serum AMH would help in the diagnosis of intersex conditions, we assayed serum AMH levels in 107 patients with ambiguous genitalia of various etiologies. In XY patients, AMH was low when the intersex condition was caused by abnormal testicular determination (including pure and partial gonadal dysgenesis) but was normal or elevated in patients with impaired testosterone secretion, whereas serum testosterone was low in both groups. AMH was also elevated during the first year of life and at puberty in intersex states caused by androgen insensitivity. In 46,XX patients with a normal male phenotype or ambiguous genitalia, in whom the diagnosis of female pseudohermaphroditism had been excluded, serum AMH levels higher than 75 pmol/L were indicative of the presence of testicular tissue and correlated with the mass of functional testicular parenchyma. In conclusion, serum AMH determination is a powerful tool to assess Sertoli cell function in children with intersex states, and it helps to distinguish between defects of male sexual differentiation caused by abnormal testicular determination and those resulting from isolated impairment of testosterone secretion or action.

Factors associated with glycemic control. A cross-sectional nationwide study in 2,579 French children with type 1 diabetes. The French Pediatric Diabetes Group.

OBJECTIVE: To determine on a large scale the multiple medical and nonmedical factors that influence glycemic control in the general population of children with diabetes, we performed a nationwide French cross-sectional study. RESEARCH DESIGN AND METHODS: We enrolled 2,579 patients aged 1-19 years with type 1 diabetes of > 1 year's duration. The study was center based: 270 centers were identified, 206 agreed to participate, and 147 included at least 90% of their patients. Questionnaires were completed by physicians interviewing patients and family, and HbA1c measurements were centralized. To identify explanatory variables for HbA1c level and frequency of severe hypoglycemia, we performed multiple regression analysis using all the quantitative variables collected and stepwise logistic regression for the qualitative variables. RESULTS: Mean HbA1c value for the whole population was 8.97 +/- 1.98% (normal 4.7 +/- 0.7% [SD]). Only 19 children (0.7%) had ketoacidosis during the 6 months before the study, whereas 593 severe hypoglycemia events occurred in 338 children (13.8%). Control was better in university-affiliated hospitals and centers following > 50 patients, reflecting the importance of access to experienced diabetologists. Children had a mean of 2.3 injections, allegedly performed 2.8 glucose measurements per day, and were seen an average of 4.6 times per year at the center. In the multiple regression analysis, 94% of the variance of HbA1c was explained by our pool of selected variables, with the highest regression coefficient between HbA1c and age (Rc = 0.43, P < 0.0001), then with daily insulin dosage per kilogram (Rc = 0.28, P < 0.0001), mother's age (Rc = 0.26, P < 0.0001), frequency of glucose measurements (Rc = 0.21, P < 0.0001), and diabetes duration (Rc = 0.14, P < 0.0001). Logistic regression identified quality of family support and dietary compliance, two related qualitative and possibly subjective variables, as additional explanatory determinants of HbA1c. The frequency of severe hypoglycemia was 45 per 100 patient-years and correlated with diabetes duration, but not with HbA1c levels or other variables. CONCLUSIONS: Although overall results remain unsatisfactory, 33% of studied French children with type 1 diabetes had HbA1c < 8%, the value obtained in Diabetes Control and Complications Trial adolescents treated intensively. Diabetes management in specialized centers should be encouraged.

A 5-year prospective study of growth hormone (GH)-deficient children treated with GH before the age of 3 years. French Serono Study Group.

The aim of the study was to assess the efficacy of GH therapy in GH-deficient children treated before the age of 3 yr. A noncomparative multicenter prospective study included 49 children (22 girls and 27 boys) with isolated GH deficiency (n = 19) or multiple pituitary hormone deficiency (n = 30) treated with daily s.c. injections (0.6 U/kg.week) for 3-5 yr. They were divided into two groups according to their height SD score for chronological age (CA) at the initiation of therapy: group A consisted of 8 patients presenting an initial height within the normal range (< 2 SD below the mean) followed for 2-5 yr, and group B consisted of 25 children followed for 5 yr among 41 patients with initial growth retardation. In group A, the mean height SD score increased from -1.1 +/- 0.6 to 0.35 +/- 1.0 SD (P < 0.001) in the first year and remained in the normal range throughout the following 4 yr. In group B after 4 yr of treatment, the mean height SD score for age had increased from -3.6 +/- 1.0 SD (time zero) to -0.9 +/- 1.2 SD. During the fourth year of therapy, the mean height gain of 0.2 +/- 0.2 SD was significant (P < 0.001). After 5 yr of treatment, a plateau was reached with a corresponding height SD score (CA) of -0.8 +/- 1.2 SD (95% confidence interval between -1.3 and -0.2 SD). This value remained significantly below normal for age (P < 0.001), indicating that catch-up growth was incomplete. Only four patients (16%) remained below -2SD for CA. The 5-yr height gain was negatively correlated with the height SD score at the start of treatment (r = -0.6; P < 0.005) and the first year height gain was the most predictive parameter. There was no significant influence of intrauterine growth retardation, body mass index and age at the start of treatment, or parental target height. Bone maturation was significantly retarded over CA by a mean value of 1.1 +/- 0.9 yr (P < 0.0001), with a mean bone age/CA ratio of 0.8 +/- 0.2 after a mean treatment duration of 5.1 +/- 1.1 yr. In conclusion, the rapid and almost complete return to normal height obtained in this study supports the need for GH treatment in early diagnosed GH-deficient children. The present dosage may be considered the minimum to obtain satisfactory catch-up growth ensuring a favorable outcome for these children. In addition, it allowed growth at a rate normal for age in patients diagnosed before growth retardation.