Paediatric Cushing’s disease: long-term outcome and predictors of recurrence

Paediatric Cushing’s disease (CD) is characterized by excess ACTH secretion from a pituitary adenoma, leading to hypercortisolism. It has approximately 5% of the incidence of adult CD and is a rare disorder in the paediatric age range. The four most specific presenting features of hypercortisolism are: change in facial appearance, weight gain, decreased linear growth and virilisation shown by advanced pubic hair for the stage of breast development or testicular volume. The main diagnostic priority is the demonstration of hypercortisolism followed by distinction between its ACTH-dependent and ACTH-independent origin, thus leading to identification of aetiology. All treatment options aim to resolve or control hypercortisolism. Consensus favours transsphenoidal (TSS) pituitary surgery with selective removal of the corticotroph adenoma. TSS in children with CD is now well established and induces remission in 70-100% of cases. External pituitary radiotherapy and bilateral adrenalectomy are second-line therapeutic approaches in subjects not responding to TSS. Long-term medical treatment is less frequently adopted. Recurrence in paediatric CD cases is low with factors predicting relapse being higher post-TSS cortisol and ACTH levels and rapid recovery of the hypothalamic-pituitary-adrenal axis after TSS. In summary, complete excision of the microadenoma with histological and biochemical evidence for this, predicts a low rate of recurrence of CD. Due to the need for rapid diagnosis and management to avoid the burden of prolonged exposure to hypercortisolism, tertiary university centres comprising both paediatric and adult endocrinology specialists together with experienced pituitary surgery and, eventually, radiotherapy units are recommended for referral of these patients

Classification of irreducible quasifinite modules over map Virasoro algebras

We give a complete classification of the irreducible quasifinite modules for algebras of the form Vir \otimes A, where Vir is the Virasoro algebra and A is a Noetherian commutative associative unital algebra over the complex numbers. It is shown that all such modules are tensor products of generalized evaluation modules. We also give an explicit sufficient condition for a Verma module of Vir \otimes A to be reducible. In the case that A is an infinite-dimensional integral domain, this condition is also necessary.Comment: 25 pages. v2: Minor changes, published versio

Genetic Defects in the Growth Hormone–IGF-I Axis Causing Growth Hormone Insensitivity and Impaired Linear Growth

Human genetic defects in the growth hormone (GH)–IGF-I axis affecting the IGF system present with growth failure as their principal clinical feature. This is usually associated with GH insensitivity (GHI) presenting in childhood as severe or mild short stature. Dysmorphic features and metabolic abnormalities may also be present. The field of GHI due to mutations affecting GH action has evolved rapidly since the first description of the extreme phenotype related to homozygous GH receptor (GHR) mutations in 1966. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The mechanisms of the GH–IGF-I axis in the regulation of normal human growth is discussed followed by descriptions of mutations in GHR, STAT5B, IGF-I, IGFALS, IGF1R, and GH1 defects causing bio-inactive GH or anti-GH antibodies. These GH–IGF-I axis defects are associated with a range of clinical, and hormonal characteristics. An up-dated approach to the clinical assessment of the patient with GHI focusing on investigation of the GH–IGF-I axis and relevant molecular studies contributing to the identification of causative genetic defects is also discussed

Characterization of thermal effects in the Enhanced LIGO Input Optics

We present the design and performance of the LIGO Input Optics subsystem as implemented for the sixth science run of the LIGO interferometers. The Initial LIGO Input Optics experienced thermal side effects when operating with 7 W input power. We designed, built, and implemented improved versions of the Input Optics for Enhanced LIGO, an incremental upgrade to the Initial LIGO interferometers, designed to run with 30 W input power. At four times the power of Initial LIGO, the Enhanced LIGO Input Optics demonstrated improved performance including better optical isolation, less thermal drift, minimal thermal lensing and higher optical efficiency. The success of the Input Optics design fosters confidence for its ability to perform well in Advanced LIGO

Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification

Dynamic localization of a helper NLR at the plant-pathogen interface underpins pathogen recognition

Plants employ sensor-helper pairs of NLR immune receptors to recognize pathogen effectors and activate immune responses (1). Yet the subcellular localization of NLRs pre- and post-activation during pathogen infection remains poorly understood. Here we show that NRC4, from the ‘NRC’ solanaceous helper NLR family (1), undergoes dynamic changes in subcellular localization by shuttling to and from the plant-pathogen haustorium interface established during infection by the Irish potato famine pathogen Phytophthora infestans. Specifically, prior to activation, NRC4 accumulates at the extra-haustorial membrane (EHM), presumably to mediate response to perihaustorial effectors, that are recognized by NRC4- dependent sensor NLRs. However not all NLRs accumulate at the EHM, as the closely related helper NRC2, and the distantly related ZAR1, did not accumulate at the EHM. NRC4 required an intact N-terminal coiled coil domain to accumulate at the EHM, whereas the functionally conserved MADA motif implicated in cell death activation and membrane insertion was dispensable for this process. Strikingly, a constitutively autoactive NRC4 mutant did not accumulate at the EHM and showed punctate distribution that mainly associated with the plasma membrane, suggesting that post-activation, NRC4 may undergo a conformation switch to form clusters that do not preferentially associate with the EHM. When NRC4 is activated by a sensor NLR during infection however, NRC4 forms puncta mainly at the EHM and to a lesser extent at the plasma membrane. We conclude that following activation at the EHM, NRC4 may spread to other cellular membranes from its primary site of activation to trigger immune responses

Nucleons Properties at Finite Lattice Spacing in Chiral Perturbation Theory

Properties of the proton and neutron are studied in partially-quenched chiral perturbation theory at finite lattice spacing. Masses, magnetic moments, the matrix elements of isovector twist-2 operators and axial-vector currents are examined at the one-loop level in a double expansion in the light-quark masses and the lattice spacing. This work will be useful in extrapolating the results of simulations using Wilson valence and sea quarks, as well as simulations using Wilson sea quarks and Ginsparg-Wilson valence quarks, to the continuum.Comment: 16 pages LaTe

n+p -> d+gamma for Big-Bang Nucleosynthesis

The cross section for n+p -> d+gamma is calculated at energies relevant to big bang nucleosynthesis using the recently developed effective field theory that describes the two-nucleon sector. The E1 amplitude is computed up to NNNLO and depends only upon nucleon-nucleon phase shift data. In contrast, the M1 contribution is computed up to NLO, and the four-nucleon-one-magnetic-photon counterterm that enters is determined by the cross section for cold neutron capture. The uncertainty in the calculation for nucleon energies up to E ~ 1 MeV is estimated to be < 4%.Comment: 11 pages, 3 figures, late

A nonlinear hydrodynamical approach to granular materials

We propose a nonlinear hydrodynamical model of granular materials. We show how this model describes the formation of a sand pile from a homogeneous distribution of material under gravity, and then discuss a simulation of a rotating sandpile which shows, in qualitative agreement with experiment, a static and dynamic angle of repose.Comment: 17 pages, 14 figures, RevTeX4; minor changes to wording and some additional discussion. Accepted by Phys. Rev.

Constraints on Low-Mass WIMP Interactions on 19F from PICASSO

Recent results from the PICASSO dark matter search experiment at SNOLAB are reported. These results were obtained using a subset of 10 detectors with a total target mass of 0.72 kg of 19F and an exposure of 114 kgd. The low backgrounds in PICASSO allow recoil energy thresholds as low as 1.7 keV to be obtained which results in an increased sensitivity to interactions from Weakly Interacting Massive Particles (WIMPs) with masses below 10 GeV/c^2. No dark matter signal was found. Best exclusion limits in the spin dependent sector were obtained for WIMP masses of 20 GeV/c^2 with a cross section on protons of sigma_p^SD = 0.032 pb (90% C.L.). In the spin independent sector close to the low mass region of 7 GeV/c2 favoured by CoGeNT and DAMA/LIBRA, cross sections larger than sigma_p^SI = 1.41x10^-4 pb (90% C.L.) are excluded.Comment: 23 pages, 7 figures, to be published in Phys. Lett.