845 research outputs found
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von Hippel-Lindau Disease: an Update
Funder: University of CambridgeAbstract: Purpose of Review: In this review, we discuss the key molecular and clinical developments in VHL disease that have the potential to impact on the natural history of the disease and improve patient outcomes. Recent Findings: Identifiable mutations in VHL underlie most cases of VHL and define clear genotype-phenotype correlations. Detailed clinical and molecular characterisation has allowed the implementation of lifelong screening programmes that have improved clinical outcomes. Functional characterisation of the VHL protein complex has revealed its role in oxygen sensing and the mechanisms of tumourigenesis that are now being exploited to develop novel therapies for VHL and renal cancer. Summary: The molecular and cellular landscape of VHL-associated tumours is revealing new opportunities to modify the natural history of the disease and develop therapies. Drugs are now entering clinical trials and combined with improved clinical and molecular diagnosis, and lifelong surveillance programmes, further progress towards reducing the morbidity and mortality associated with VHL disease is anticipated
Comparison of the Organic Composition of Cometary Samples with Residues Formed from the UV Irradiation of Astrophysical Ice Analogs
The NASA Stardust mission successfully collected material from Comet 81P/Wild 2 [1], including authentic cometary grains [2]. X-ray absorption near-edge structure (XANES) spectroscopy analysis of these samples indicates the presence of oxygen-rich and nitrogen-rich organic materials, which contain a broad variety of functional groups (carbonyls, C=C bonds, aliphatic chains, amines, arnides, etc.) [3]. One component of these organics appears to contain very little aromatic carbon and bears some similarity to the organic residues produced by the irradiation of ices of interstellar/cometary composition, Stardust samples were also recently shown to contain glycine, the smallest biological amino acid [4]. Organic residues produced froth the UV irradiation of astrophysical ice analogs are already known to contain a large suite of organic molecules including amino acids [5-7], amphiphilic compounds (fatty acids) [8], and other complex species. This work presents a comparison between XANES spectra measured from organic residues formed in the laboratory with similar data of cometary samples collected by the Stardust missio
Insights into the thermal performance of underground high voltage electricity transmission lines through thermo-hydraulic modelling
In this paper, a flexible numerical framework to provide thermal performance assessment for the underground buried cables, considering different geological and meteorological conditions, has been presented. Underground cables tend to retain the heat produced in the conductor, so complex coupled thermo-hydraulic response of the porous medium surrounding the cables needs to be assessed to prevent cable overheating and the associated reduction in cable capacity for carrying current. Applying a coupled thermo-hydraulic model within the developed numerical framework to conduct a health assessment on a subset of National Grid Electricity Transmission’s underground cables, this study provides novel insights into the thermal behaviour of buried circuits. The results indicate that backfill and surrounding native soil have the dominant effect on the thermal behaviour of cables, while the amount of precipitation and ambient temperature were found to have less impact on cable’s thermal behaviour. The findings strongly infer that the nature of the overloading which is undertaken in practice would have no ongoing negative impact, suggesting that more frequent or longer duration overloading regimes could be tolerated. Overall, this study demonstrates how the developed numerical framework could be harnessed to allow safe rating adjustments of buried transmission circuits
Investigation and Management of Apparently Sporadic Central Nervous System Haemangioblastoma for Evidence of Von Hippel-Lindau Disease.
Haemangioblastomas are rare, highly vascularised tumours that typically occur in the cerebellum, brain stem and spinal cord. Up to a third of individuals with a haemangioblastoma will have von Hippel-Lindau (VHL) disease. Individuals with haemangioblastoma and underlying VHL disease present, on average, at a younger age and frequently have a personal or family history of VHL disease-related tumours (e.g., retinal or central nervous system (CNS) haemangioblastomas, renal cell carcinoma, phaeochromocytoma). However, a subset present an apparently sporadic haemangioblastoma without other features of VHL disease. To detect such individuals, it has been recommended that genetic testing and clinical/radiological assessment for VHL disease should be offered to patients with a haemangioblastoma. To assess "real-world" clinical practice, we undertook a national survey of clinical genetics centres. All participating centres responded that they would offer genetic testing and a comprehensive assessment (ophthalmological examination and CNS and abdominal imaging) to a patient presenting with a CNS haemangioblastoma. However, for individuals who tested negative, there was variability in practice with regard to the need for continued follow-up. We then reviewed the results of follow-up surveillance in 91 such individuals seen at four centres. The risk of developing a potential VHL-related tumour (haemangioblastoma or RCC) was estimated at 10.8% at 10 years follow-up. The risks of developing a recurrent haemangioblastoma were higher in those who presented <40 years of age. In the light of these and previous findings, we propose an age-stratified protocol for surveillance of VHL-related tumours in individuals with apparently isolated haemangioblastoma.NIHR Cambridge Biomedical Research Centre,
VHL Alliance UK,
NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007
Development of cross-curricular key skills using a 3D immersive learning environment in schools
© Springer International Publishing AG 2017. Pedagogical opportunities offered by 3D immersive environments are not restricted to subject-based knowledge but also include non-disciplinary and cross-curricular key skills. This pilot study introduced a large 3D scene of a non-extant architectural exhibition into teaching and learning activities at three UK schools. From observation and qualitative data capture, a comparative case study identified a number of pedagogical opportunities and challenges. Despite diverse teacher and student approaches, a number of common factors were identified including constructionist teaching methods and the suitability of 3D environments for developing cross-curricular key skills and capabilities. In relation to the literature, this paper analyses how subject-aligned use of the 3D model met with differing levels of success, identifies four key skills that emerged from student use of the model across all three schools, and considers how challenges might be translated into further learning opportunities
A novel homozygous UMOD mutation reveals gene dosage effects on uromodulin processing and urinary excretion
Heterozygous mutations in encoding the urinary protein uromodulin are the most common genetic cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). We describe the exceptional case of a patient from a consanguineous family carrying a novel homozygous mutation (p.C120Y) affecting a conserved cysteine residue within the EGF-like domain III of uromodulin. Comparison of heterozygote and homozygote mutation carriers revealed a gene dosage effect with unprecedented low levels of uromodulin and aberrant uromodulin fragments in the urine of the homozygote proband. Despite an amplified biological effect of the homozygote mutation, the proband did not show a strikingly more severe clinical evolution nor was the near absence of urinary uromodulin associated with urinary tract infections or kidney stones.J.A.S. is supported by the Kidney Research Fund and the Medical Research Council (MR/M012212/1). S.A.R. is a Kidney Research UK Post-Doctoral Fellow. O.D. is supported by grants from the European Community’s Seventh Framework Programme (305608 EURenOmics), the Swiss National Centre of Competence in Research Kidney Control of Homeostasis (NCCR Kidney.CH) programme, the Swiss National Science Foundation (31003A_169850) and the Rare Disease Initiative Zu¨rich (Radiz), a clinical research priority program of the University of Zurich, Switzerland. E.O. is supported by the Fonds National de la Recherche Luxembourg (6903109) and the University Research Priority Programme ‘Integrative Human Physiology, ZIHP’ of the University of Zurich
The inter-relationship of symptom severity and quality of life in 2055 patients with primary biliary cholangitis
BackgroundAge at presentation with primary biliary cholangitis (PBC) is associated with differ-ential response to ursodeoxycholic acid (UDCA) therapy. Younger-presentingpatients are less likely to respond to treatment and more likely to need transplantor die from the disease. PBC has a complex impact on quality of life (QoL), withsystemic symptoms often having significant impact.AimTo explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it.MethodsUsing the UK-PBC cohort, symptoms were assessed using the PBC-40 and othervalidated tools. Data were available on 2055 patients.ResultsOf the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutralscores and 34% reported poor scores. Each 10-year increase in age at presentationwas associated with a 14% decrease in risk of poor perceived QoL (OR = 0.86,95% CI: 0.75–0.98, P < 0.05). All sympto m domains were similarly age-associated(P < 0.01). Social dysfunction was the symptom factor with the greatest impa ct onQoL. Median (interquartile range) PBC-40 social scores for patient s with good per-ceived QoL were 18 (14–23) compared with 34 (29–39) for those with poor QoL.ConclusionThe majo rity of patients with primary biliary cholangitis do not feel their QoL isimpaired, although impairment is reported by a sizeable minority. Age at presenta-tion is associated with impact on per ceived QoL and the symptoms impairing it,with younger patients being more affected. Social dysfunction makes the greatestcontribution to QoL impairment, and it should be targeted in trials aimed atimproving life quality
Exact results for hydrogen recombination on dust grain surfaces
The recombination of hydrogen in the interstellar medium, taking place on
surfaces of microscopic dust grains, is an essential process in the evolution
of chemical complexity in interstellar clouds. The H_2 formation process has
been studied theoretically, and in recent years also by laboratory experiments.
The experimental results were analyzed using a rate equation model. The
parameters of the surface, that are relevant to H_2 formation, were obtained
and used in order to calculate the recombination rate under interstellar
conditions. However, it turned out that due to the microscopic size of the dust
grains and the low density of H atoms, the rate equations may not always apply.
A master equation approach that provides a good description of the H_2
formation process was proposed. It takes into account both the discrete nature
of the H atoms and the fluctuations in the number of atoms on a grain. In this
paper we present a comprehensive analysis of the H_2 formation process, under
steady state conditions, using an exact solution of the master equation. This
solution provides an exact result for the hydrogen recombination rate and its
dependence on the flux, the surface temperature and the grain size. The results
are compared with those obtained from the rate equations. The relevant length
scales in the problem are identified and the parameter space is divided into
two domains. One domain, characterized by first order kinetics, exhibits high
efficiency of H_2 formation. In the other domain, characterized by second order
kinetics, the efficiency of H_2 formation is low. In each of these domains we
identify the range of parameters in which, the rate equations do not account
correctly for the recombination rate. and the master equation is needed.Comment: 23 pages + 8 figure
Numerical Relativity: A review
Computer simulations are enabling researchers to investigate systems which
are extremely difficult to handle analytically. In the particular case of
General Relativity, numerical models have proved extremely valuable for
investigations of strong field scenarios and been crucial to reveal unexpected
phenomena. Considerable efforts are being spent to simulate astrophysically
relevant simulations, understand different aspects of the theory and even
provide insights in the search for a quantum theory of gravity. In the present
article I review the present status of the field of Numerical Relativity,
describe the techniques most commonly used and discuss open problems and (some)
future prospects.Comment: 2 References added; 1 corrected. 67 pages. To appear in Classical and
Quantum Gravity. (uses iopart.cls
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Overview of the results of the organics PET Study of the cometary samples returned from comet Wild 2 by the Stardust mission
This presenation will provide an overview of the efforts and results produced by the Organics Preliminary Examination Team during their studies of the samples returned from comet Wild 2 by the Stardust spacecraft
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