Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay

Although delayed puberty is relatively common and often familial, its molecular and pathophysiologic basis is poorly understood. In contrast, the molecular mechanisms underlying some forms of hypogonadotropic hypogonadism (HH) are clearer, following the description of mutations in the genes KAL, GNRHR, and PROP1. Mutations in another gene, DAX1 (AHC), cause X-linked adrenal hypoplasia congenita and HH. Affected boys usually present with primary adrenal failure in infancy or childhood and HH at the expected time of puberty.DAX1 mutations have also been reported to occur with a wider spectrum of clinical presentations. These cases include female carriers of DAX1 mutations with marked pubertal delay and a male with incomplete BH and mild adrenal insufficiency in adulthood. Given this emerging phenotypic spectrum of clinical presentation in men and women with DAX1 mutations, we hypothesized that DAX1 might be a candidate gene for mutation in patients with idiopathic sporadic or familial HH or constitutional delay of puberty. Direct sequencing of DAX1 was performed in 106 patients, including 85 (80 men and 5 women) with sporadic HH or constitutional delay of puberty and patients from 21 kindreds with familial forms of these disorders. No DAX1 mutations were found in these groups of patients, although silent single nucleotide polymorphisms were identified (T114C, G498A). This study suggests that mutations in DAX1 are unlikely to be a common cause of HH or pubertal delay in the absence of a concomitant history of adrenal insufficiency

X-linked adrenal hypoplasia congenita: A mutation in DAX1 expands the phenotypic spectrum in males and females

X-linked adrenal hypoplasia congenita (AHC) is a disorder associated with primary adrenal insufficiency and hypogonadotropic hypogonadism (HH). The gene responsible for X-linked AHC, DAX1, encodes a member of the nuclear hormone receptor superfamily. We studied an extended kindred with AHC and HH in which two males (the proband and his nephew) were affected with a nucleotide deletion (501delA). The proband's mother, sister, and niece were heterozygous for this frameshift mutation. At age 27 yr, after 7 yr of low dose hCG therapy, the proband underwent a testicular biopsy revealing rare spermatogonia and Leydig cell hyperplasia. Despite steadily progressive doses of hCG and Pergonal administered over a 3-yr period, the proband remained azoospermic. The proband's mother, sister (obligate carrier), and niece all had a history of delayed puberty, with menarche occurring at ages 17-18 yr.Baseline patterns of pulsatile gonadotropin secretion and gonad otropin responsiveness to exogenous pulsatile GnRH were examined in the affected males. LH, FSK, and free alpha-subunit were determined during 12.5-24 h of frequent blood sampling (every 10 min). Both patients then received pulsatile GnRH (25 ng/kg) sc every 2 h for 6-7 days. Gonadotropin responses to a single GnRH pulse iv were monitored daily to assess the pituitary responsiveness to exogenous GnRH. In the proband, FSH and LH levels demonstrated a subtle, but significant, response to GnRH over the week of pulsatile GnRH therapy. Free alpha-subunit levels demonstrated an erratic pattern of secretion at baseline and no significant response to pulsatile GnRH.We conclude that 1) affected males with AHC/HH may have an intrinsic defect in spermatogenesis that is not responsive to gonadotropin therapy; 2) female carriers of DAX1 mutations may express the phenotype of delayed puberty; and 3) although affected individuals display minimal responses to pulsatile GnRH, as observed in other AHC kindreds, subtle differences in gonadotropin patterns may nevertheless exist between affected individuals within a kindred

Carbon and climate system coupling on timescales from the Precambrian to the Anthropocene

Author Posting. © Annual Reviews, 2007. This is the author's version of the work. It is posted here by permission of Annual Reviews for personal use, not for redistribution. The definitive version was published in Annual Review of Environment and Resources 32 (2007): 31-66, doi:10.1146/annurev.energy.32.041706.124700.The global carbon and climate systems are closely intertwined, with biogeochemical processes responding to and driving climate variations. Over a range of geological and historical time-scales, warmer climate conditions are associated with higher atmospheric levels of CO2, an important climate-modulating greenhouse gas. The atmospheric CO2-temperature relationship reflects two dynamics, the planet’s climate sensitivity to a perturbation in atmospheric CO2 and the stability of non-atmospheric carbon reservoirs to evolving climate. Both exhibit non-linear behavior, and coupled carbon-climate interactions have the potential to introduce both stabilizing and destabilizing feedback loops into the Earth System. Here we bring together evidence from a wide range of geological, observational, experimental and modeling studies on the dominant interactions between the carbon cycle and climate. The review is organized by time-scale, spanning interannual to centennial climate variability, Holocene millennial variations and Pleistocene glacial-interglacial cycles, and million year and longer variations over the Precambrian and Phanerozoic. Our focus is on characterizing and, where possible quantifying, the emergent behavior internal to the coupled carbon-climate system as well as the responses of the system to external forcing from tectonics, orbital dynamics, catastrophic events, and anthropogenic fossil fuel emissions. While there are many unresolved uncertainties and complexity in the carbon cycle, one emergent property is clear across time scales: while CO2 can increase in the atmosphere quickly, returning to lower levels through natural processes is much slower, so the consequences of the human perturbation will far outlive the emissions that caused them.S. Doney acknowledges support from the NSF Geosciences Carbon and Water program (NSF ATM-0628582) and the WHOI W. Van Alan Clark Sr. Chair. D. Schimel acknowledges support from the NSF Biocomplexity in the Environment program (NSF EAR-0321918)

CubeNet: Equivariance to 3D Rotation and Translation

3D Convolutional Neural Networks are sensitive to transformations applied to their input. This is a problem because a voxelized version of a 3D object, and its rotated clone, will look unrelated to each other after passing through to the last layer of a network. Instead, an idealized model would preserve a meaningful representation of the voxelized object, while explaining the pose-difference between the two inputs. An equivariant representation vector has two components: the invariant identity part, and a discernable encoding of the transformation. Models that can't explain pose-differences risk "diluting" the representation, in pursuit of optimizing a classification or regression loss function. We introduce a Group Convolutional Neural Network with linear equivariance to translations and right angle rotations in three dimensions. We call this network CubeNet, reflecting its cube-like symmetry. By construction, this network helps preserve a 3D shape's global and local signature, as it is transformed through successive layers. We apply this network to a variety of 3D inference problems, achieving state-of-the-art on the ModelNet10 classification challenge, and comparable performance on the ISBI 2012 Connectome Segmentation Benchmark. To the best of our knowledge, this is the first 3D rotation equivariant CNN for voxel representations.Comment: Preprin

Multiscale Shape Description with Laplacian Profile and Fourier Transform

International audienceWe propose a new local multiscale image descriptor of vari-able size. The descriptor combines Laplacian of Gaussian values at dif-ferent scales with a Radial Fourier Transform. This descriptor provides a compact description of the appearance of a local neighborhood in a manner that is robust to changes in scale and orientation. We evaluate this descriptor by measuring repeatability and recall against 1-precision with the Affine Covariant Features benchmark dataset and as well as with a set of textureless images from the MIRFLICKR Retrieval Evalu-ation dataset. Experiments reveal performance competitive to the state of the art, while providing a more compact representation

Predictive use of the Maximum Entropy Production principle for Past and Present Climates

In this paper, we show how the MEP hypothesis may be used to build simple climate models without representing explicitly the energy transport by the atmosphere. The purpose is twofold. First, we assess the performance of the MEP hypothesis by comparing a simple model with minimal input data to a complex, state-of-the-art General Circulation Model. Next, we show how to improve the realism of MEP climate models by including climate feedbacks, focusing on the case of the water-vapour feedback. We also discuss the dependence of the entropy production rate and predicted surface temperature on the resolution of the model

A Hierarchical Framework for Collaborative Artificial Intelligence

We propose a hierarchical framework for collaborative intelligent systems. This framework organizes research challenges based on the nature of the collaborative activity and the information that must be shared, with each level building on capabilities provided by lower levels. We review research paradigms at each level, with a description of classical engineering-based approaches and modern alternatives based on machine learning, illustrated with a running example using a hypothetical personal service robot. We discuss cross-cutting issues that occur at all levels, focusing on the problem of communicating and sharing comprehension, the role of explanation and the social nature of collaboration. We conclude with a summary of research challenges and a discussion of the potential for economic and societal impact provided by technologies that enhance human abilities and empower people and society through collaboration with intelligent systems

Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2.

A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4; 14) and del17p, and detection by fluorescence in situ hybridization of t(4; 14), t(14; 16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum beta(2)-microglobulin level and International Staging System stages II and III, incorporating high beta(2)-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations. (Blood. 2011; 117(18): 4696-4700

Effect of weekend admission on in-hospital mortality and functional outcomes for patients with acute subarachnoid haemorrhage (SAH)

BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) is an acute cerebrovascular event with high socioeconomic impact as it tends to affect younger patients. The recent NCEPOD study looking into management of aSAH has recommended that neurovascular units in the United Kingdom should aim to secure cerebral aneurysms within 48 h and that delays because of weekend admissions can increase the mortality and morbidity attributed to aSAH. METHOD: We used data from a prospective audit of aSAH patients admitted between January 2009 and December 2011. The baseline demographic and clinical features of the weekend and weekday groups were compared using the chi-squared test and T-test. Cox proportional hazards models (Proc Phreg in SAS) were used to calculate the adjusted overall hazard of in-hospital death associated with admission on weekend, adjusting for age, sex, baseline WFNS grade, type of treatment received and time from scan to treatment. Sliding dichotomy analysis was used to estimate the difference in outcomes after SAH at 3 months in weekend and weekday admissions. RESULTS: Those admitted on weekends had a significantly higher scan to treatment time (83.05 ± 83.4 h vs 40.4 ± 53.4 h, P < 0.0001) and admission to treatment (71.59 ± 79.8 h vs 27.5 ± 44.3 h, P < 0.0001) time. After adjustments for adjusted for relevant covariates weekend admission was statistically significantly associated with excess in-hospital mortality (HR = 2.1, CL [1.13–4.0], P = 0.01). After adjustments for all the baseline covariates, the sliding dichotomy analysis did not show effects of weekend admission on long-term outcomes on the good, intermediate and worst prognostic bands. CONCLUSIONS: This study provides important data showing excess in-hospital mortality of patients with SAH on weekend admissions served by the United Kingdom’s National Health Service.; However, there were no effects of weekend admission on long-term outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00701-016-2746-z) contains supplementary material, which is available to authorized users