Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders

Fuzzy Characterization of Near-Earth-Asteroids

Due to close encounters with the inner planets, Near-Earth-Asteroids (NEAs) can have very chaotic orbits. Because of this chaoticity, a statistical treatment of the dynamical properties of NEAs becomes difficult or even impossible. We propose a new way to classify NEAs by using methods from Fuzzy Logic. We demonstrate how a fuzzy characterization of NEAs can be obtained and how a subsequent analysis can deliver valid and quantitative results concerning the long-term dynamics of NEAs.Comment: 11 pages, presented at the 7th Alexander von Humboldt Colloquium on Celestial Mechanics (2008), accepted for publication in "Celestial Mechanics and Dynamical Astronomy

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Mechanical Properties and Microstructural Characterization of Aged Nickel-based Alloy 625 Weld Metal

The aim of this work was to evaluate the different phases formed during solidification and after thermal aging of the as-welded 625 nickel-based alloy, as well as the influence of microstructural changes on the mechanical properties. The experiments addressed aging temperatures of 650 and 950 A degrees C for 10, 100, and 200 hours. The samples were analyzed by electron microscopy, microanalysis, and X-ray diffraction in order to identify the secondary phases. Mechanical tests such as hardness, microhardness, and Charpy-V impact test were performed. Nondestructive ultrasonic inspection was also conducted to correlate the acquired signals with mechanical and microstructural properties. The results show that the alloy under study experienced microstructural changes when aged at 650 A degrees C. The aging was responsible by the dissolution of the Laves phase formed during the solidification and the appearance of gamma aEuro(3) phase within interdendritic region and fine carbides along the solidification grain boundaries. However, when it was aged at 950 A degrees C, the Laves phase was continuously dissolved and the excess Nb caused the precipitation of the delta-phase (Ni3Nb), which was intensified at 10 hours of aging, with subsequent dissolution for longer periods such as 200 hours. Even when subjected to significant microstructural changes, the mechanical properties, especially toughness, were not sensitive to the dissolution and/or precipitation of the secondary phases

Recurrent frameshift neoantigen vaccine elicits protective immunity with reduced tumor burden and improved overall survival in a Lynch syndrome mouse model

BACKGROUND AND AIMS: DNA mismatch repair deficiency (MMRD) drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20-25 million individuals worldwide. LS individuals are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a Phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not been demonstrated so far. METHODS: A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression and mutation frequency. In silico prediction, in vivo immunogenicity testing and epitope mapping was used to identify candidates for FSP vaccination. RESULTS: We identified four shared FSP neoantigens [Nacad(FSP-1), Maz(FSP-1), Senp6(FSP-1), Xirp1(FSP-1)] that induced CD4/CD8 T cell responses in naïve C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only four FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth and prolonged survival even more effectively than FSP vaccination alone. CONCLUSION: Our pre-clinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention

Multimessenger science opportunities with mHz gravitational waves

Large scale structure and cosmolog

Two levels of the inspired oxygen fraction in propofol-anesthetized dogs with high intracranial pressure: cardiopulmonary function

In the initial stage of traumatic brain injury, the use of 1.0 inspired oxygen fraction (FiO2) is indicated. However, high FiO2 has been correlated with atelectasis. Thus, the effects of FiO2 = 1.0 and FiO2 = 0.6 on the cardiopulmonary function in propofol-anesthetized dogs with high intracranial pressure (ICP) were evaluated. Eight dogs were anesthetized on two occasions, receiving, during controlled ventilation, an FiO2 = 1 (G100) or an FiO2 = 0.6 (G60). Propofol was used for induction (10mg.kg-1) followed by a continuous rate infusion (0.6mg.kg-1.minute-1). An increase in the ICP was induced by temporary obliteration of the right jugular vein (OJv) 50 minutes after induction of anesthesia. The measurement was taken twenty minutes after OJv (T0) and then at 15-minute intervals (T15 to T60). Alveolar oxygen partial pressure in G60 was lower than in G100 during the whole procedure. Alveolar-arterial oxygen gradient in G100 was greater than in G60 at T0 and at T60. No differences were observed for arterial oxygen partial pressure/inspired oxygen fraction ratio, arterial-to-alveolar oxygen pressure ratio, respiratory index, venous admixture, oxygen delivery, oxygen consumption, oxygen extraction, heart rate, mean pulmonary arterial pressure, pulmonary arterial occlusion pressure, cardiac index, stroke index and systemic vascular resistance index. In G100, mean arterial pressure at T0 was higher than at T45. In dogs with high ICP, the cardiopulmonary function was not influenced by the different FiO2 used.No estágio inicial do trauma encefálico, o emprego de fração inspirada de oxigênio (FiO2) de 1,0 é indicado. Todavia, altas FiO2 têm sido correlacionadas com atelectasia. Assim, avaliaram-se os efeitos das FiO2 = 1.0 e FiO2 = 0.6 sobre a função cardiopulmonar em cães com pressão intracraniana (PIC) elevada e anestesiados com propofol. Oito animais foram anestesiados em duas ocasiões e receberam, durante a ventilação controlada, FiO2 = 1(G100) ou FiO2 = 0,6 (G60). Propofol foi usado para indução (10mg.kg-1) e seguido por infusão contínua (0,6mg.kg-1minuto-1). O aumento da PIC foi induzido pela obliteração temporária da veia jugular (OJv). As mensurações foram realizadas 20 minutos após OJv (T0) e em intervalos de 15 minutos (de T15 a T60). A pressão parcial de oxigênio alveolar no G60 foi menor do que no G100 durante todo o procedimento. O gradiente alveolar-arterial no G100 foi maior do que no G60, em T0 e T60. Não foram observadas diferenças para: relação pressão parcial de oxigênio/fração inspirada de oxigênio, relação arterioalveolar, índice respiratório, mistura arteriovenosa, oferta de oxigênio, consumo de oxigênio, taxa de extração de oxigênio, frequência cardíaca, pressão da artéria pulmonar média, pressão de oclusão da artéria pulmonar, índice cardíaco, índice sistólico e índice de resistência vascular sistêmica. No G100, a pressão arterial média em T0 foi maior do que em T45. Em cães com alta PIC, a função cardiopulmonar não foi influenciada pelas diferentes FiO2 empregadas.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Unesp Faculdade de Ciências Agrárias e VeterináriasUnesp Faculdade de Ciências Agrárias e Veterinária

A Pre-Landing Assessment of Regolith Properties at the InSight Landing Site

This article discusses relevant physical properties of the regolith at the Mars InSight landing site as understood prior to landing of the spacecraft. InSight will land in the northern lowland plains of Mars, close to the equator, where the regolith is estimated to be ≥3--5 m thick. These investigations of physical properties have relied on data collected from Mars orbital measurements, previously collected lander and rover data, results of studies of data and samples from Apollo lunar missions, laboratory measurements on regolith simulants, and theoretical studies. The investigations include changes in properties with depth and temperature. Mechanical properties investigated include density, grain-size distribution, cohesion, and angle of internal friction. Thermophysical properties include thermal inertia, surface emissivity and albedo, thermal conductivity and diffusivity, and specific heat. Regolith elastic properties not only include parameters that control seismic wave velocities in the immediate vicinity of the Insight lander but also coupling of the lander and other potential noise sources to the InSight broadband seismometer. The related properties include Poisson’s ratio, P- and S-wave velocities, Young’s modulus, and seismic attenuation. Finally, mass diffusivity was investigated to estimate gas movements in the regolith driven by atmospheric pressure changes. Physical properties presented here are all to some degree speculative. However, they form a basis for interpretation of the early data to be returned from the InSight mission.Additional co-authors: Nick Teanby and Sharon Keda