Craniometaphyseal and craniodiaphyseal dysplasia, head and neck manifestations and management

Craniometaphyseal and craniodiaphyseal dysplasia are rare genetic disorders of bone due to modelling errors of long bones and skull bones. These syndromes present with multiple ENT symptomatology from an early age. The diagnostic distinction can now be made radiologically by serial skeletal survey which is important for prognosis. We review the clinical, radiological, computed tomography (CT) scan, otological, audiological and histopathological findings in two cases with craniodiaphyseal, and two cases with craniometaphyseal dysplasia, and report our experiences of medical and surgical treatment to date. In the craniodiaphyseal dysplasia, the hearing abnormality progressed from an initial conductive to a mixed loss on serial audiometric follow up. Temporal bone CT scans showed narrowing of the middle ear cavity, internal auditory meatus, and facial nerve canal at the geniculate ganglion. Benefits from choanal stenosis surgery, craniofacial remodelling and dacrocystorhinostomy were shortlived. Calcitriol therapy with a low calcium diet did not alter the clinical course of progression in our cases. The underlying defect, causing net bone formation in these phenotypically similar syndromes, appears to be different when based on the differing biochemical responses to calcitriol and bone biopsy findings. Increased numbers of osteoblasts were found in bone biopsies from both cases with craniodiaphyseal dysplasia. Early recognition is crucial in these conditions as therapy directed at the underlying bony defect has the best chance of success if initiated in infancy (Cole et al., 1988; Fanconi et al., 1988; Key et al., 1988)

Cenozoic epeirogeny of the Indian peninsula

Peninsular India is a cratonic region with asymmetric relief manifest by eastward tilting from the 1.5 km high Western Ghats escarpment toward the flood-plains of eastward-draining rivers. Oceanic residual depth measurements on either side of India show that this west-east asymmetry is broader scale, occurring over distances of >2,000 km. Admittance analysis of free-air gravity and topography shows that the elastic thickness is 10 ± 3 km, suggesting that regional uplift is not solely caused by flexural loading. To investigate how Indian physiography is generated, we have jointly inverted 530 river profiles to determine rock uplift rate as a function of space and time. Key erosional parameters are calibrated using independent geologic constraints (e.g. emergent marine deposits, elevated paleosurfaces, uplifted lignite deposits). Our results suggest that regional tilt grew at rates of up to 0.1 mm a‾¹ between 25 Ma and the present day. Neogene uplift initiated in the south and propagated northward along the western margin. This calculated history is corroborated by low-temperature ther- mochronologic observations, by sedimentary flux of clastic deposits into the Krishna- Godavari delta, and by sequence stratigraphic architecture along adjacent rifted margins. Onset of regional uplift predates intensification of the Indian monsoon at 8 Ma, suggesting that rock uplift rather than climatic change is responsible for modern-day relief. A positive correlation between residual depth measure- ments and shear wave velocities beneath the lithosphere suggests that regional uplift is generated and maintained by temperature anomalies of ±100 ⁰C within a 200 ± 25 km thick asthenospheric channel

Reassessing the Thermal Structure of Oceanic Lithosphere With Revised Global Inventories of Basement Depths and Heat Flow Measurements

Half-space cooling and plate models of varying complexity have been proposed to account for changes in basement depth and heat flow as a function of lithospheric age in the oceanic realm. Here, we revisit this well-known problem by exploiting a revised and augmented database of 2028 measurements of depth to oceanic basement, corrected for sedimentary loading and variable crustal thickness, and 3597 corrected heat flow measurements. Joint inverse modeling of both databases shows that the half-space cooling model yields a mid-oceanic axial temperature that is >100°C hotter than permitted by petrologic constraints. It also fails to produce the observed flattening at old ages. Then, we investigate a suite of increasingly complex plate models and conclude that the optimal model requires incorporation of experimentally determined temperature- and pressure-dependent conductivity, expansivity and specific heat capacity, as well as a low conductivity crustal layer. This revised model has a mantle potential temperature of 1300 ± 50°C, which honors independent geochemical constraints and has an initial ridge depth of 2.6 ± 0.3 km with a plate thickness of 135 ± 30 km. It predicts that the maximum depth of intraplate earthquakes is bounded by the 700°C isothermal contour, consistent with laboratory creep experiments on olivine aggregates. Estimates of the lithosphere-asthenosphere boundary derived from studies of azimuthal anisotropy coincide with the 1175 ± 50°C isotherm. The model can be used to isolate residual depth and gravity anomalies generated by flexural and sub-plate convective processes.Natural Environment Research Council PhD Studentshi

Public perceptions of the UK marine environment

The damaging effects of human activities on marine health suggest that a major shift is required in the way marine systems are used by individuals. Identifying how to engage society in this shift is an ongoing debate. This includes strengthening the positive connections between society and the sea. This study uses a survey (n¼1047) to investigate UK public perceptions of subtidal species and marine health to assess whether it is possible to build more positive connections between society and the sea. Respondents showed considerable interest in traditionally charismatic species (puffins, seals and seahorses) although many respondents thought these species did not live in UK seas. Gender and experience of marine environments influenced public perceptions of species. Public perceptions of marine health showed issues such as litter to be considered as the greatest indicator of poor health. Ecological concepts of habitat integrity and biodiversity were also rated as important to marine health. Social values were found to influence public perceptions of marine health. The results show that perceptions are far from uniform across the population, and such diversity of perceptions is likely impact upon methods to catalyse societal engagement with marine conservation. These findings reinforce previous research on public perceptions of UK seas, and identify opportunities for building positive connections between society and the sea. Research priorities to further the debate of engaging society with the sea are identified

Automatic extraction of actin networks in plants

This is the author accepted manuscript. The final version is available on open access from Public Library of Science via the DOI in this recordData Availability: The authors confirm that all data underlying the findings are fully available without restriction. The complete code for this paper is available on a GitHub repository at https://github.com/JordanHembrow5/DRAGoN.The actin cytoskeleton is essential in eukaryotes, not least in the plant kingdom where it plays key roles in cell expansion, cell division, environmental responses and pathogen defence. Yet, the precise structure-function relationships of properties of the actin network in plants are still to be unravelled, including details of how the network configuration depends upon cell type, tissue type and developmental stage. Part of the problem lies in the difficulty of extracting high-quality, quantitative measures of actin network features from microscopy data. To address this problem, we have developed DRAGoN, a novel image analysis algorithm that can automatically extract the actin network across a range of cell types, providing seventeen different quantitative measures that describe the network at a local level. Using this algorithm, we then studied a number of cases in Arabidopsis thaliana, including several different tissues, a variety of actin-affected mutants, and cells responding to powdery mildew. In many cases we found statistically-significant differences in actin network properties. In addition to these results, our algorithm is designed to be easily adaptable to other tissues, mutants and plants, and so will be a valuable asset for the study and future biological engineering of the actin cytoskeleton in globally-important crops.Biotechnology and Biological Sciences Research Council (BBSRC)Wellcome TrustMedical Research Council (MRC

A Candidate Sub-Parsec Supermassive Binary Black Hole System

We identify SDSS J153636.22+044127.0, a QSO discovered in the Sloan Digital Sky Survey, as a promising candidate for a binary black hole system. This QSO has two broad-line emission systems separated by 3500 km/sec. The redder system at z=0.3889 also has a typical set of narrow forbidden lines. The bluer system (z=0.3727) shows only broad Balmer lines and UV Fe II emission, making it highly unusual in its lack of narrow lines. A third system, which includes only unresolved absorption lines, is seen at a redshift, z=0.3878, intermediate between the two emission-line systems. While the observational signatures of binary nuclear black holes remain unclear, J1536+0441 is unique among all QSOs known in having two broad-line regions, indicative of two separate black holes presently accreting gas. The interpretation of this as a bound binary system of two black holes having masses of 10^8.9 and 10^7.3 solar masses, yields a separation of ~ 0.1 parsec and an orbital period of ~100 years. The separation implies that the two black holes are orbiting within a single narrow-line region, consistent with the characteristics of the spectrum. This object was identified as an extreme outlier of a Karhunen-Loeve Transform of 17,500 z < 0.7 QSO spectra from the SDSS. The probability of the spectrum resulting from a chance superposition of two QSOs with similar redshifts is estimated at 2X10^-7, leading to the expectation of 0.003 such objects in the sample studied; however, even in this case, the spectrum of the lower redshift QSO remains highly unusual.Comment: 8 pages, 2 figures, Nature in pres

Early career choices and successful career progression in surgery in the UK: prospective cohort studies

<p>Abstract</p> <p>Background</p> <p>Changes to the structure of medical training worldwide require doctors to decide on their career specialty at an increasingly early stage after graduation. We studied trends in career choices for surgery, and the eventual career destinations, of UK graduates who declared an early preference for surgery.</p> <p>Methods</p> <p>Postal questionnaires were sent, at regular time intervals after qualification, to all medical qualifiers from all UK medical schools in selected qualification years between 1974 and 2005. They were sent in the first year after qualification, at year three and five years after qualification, and at longer time intervals thereafter.</p> <p>Results</p> <p>Responses were received from 27 749 of 38 280 doctors (73%) at year one, 23 468 of 33151 (71%) at year three, and 17 689 of 24 870 (71%) at year five. Early career preferences showed that surgery has become more popular over the past two decades. Looking forward from early career choice, 60% of respondents (64% of men, 48% of women) with a first preference for a surgical specialty at year one eventually worked in surgery (p < 0.001 for the male-female comparison). Looking backward from eventual career destinations, 90% of responders working in surgery had originally specified a first choice for a surgical specialty at year one. 'Match' rates between eventual destinations and early choices were much higher for surgery than for other specialties. Considering factors that influenced early specialty choice 'a great deal', comparing aspiring surgeons and aspiring general practitioners (GPs), a significantly higher percentage who chose surgery than general practice specified enthusiasm for the specialty (73% vs. 53%), a particular teacher or department (34% vs. 12%), inclinations before medical school (20% vs. 11%), and future financial prospects (24% vs. 13%); and a lower percentage specified that hours and working conditions had influenced their choice (21% vs. 71%). Women choosing surgery were influenced less than men by their inclinations before medical school or by their future financial prospects.</p> <p>Conclusions</p> <p>Surgery is a popular specialty choice in the UK. The great majority of doctors who progressed in a surgical career made an early and definitive decision to do so.</p

Modulation of Global Low-Frequency Motions Underlies Allosteric Regulation: Demonstration in CRP/FNR Family Transcription Factors

Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dynamic fluctuations between sites are debated. We provide a foundational theory for how allostery can occur as a function of low-frequency dynamics without a change in structure. We have generated coarse-grained models that describe the protein backbone motions of the CRP/FNR family transcription factors, CAP of Escherichia coli and GlxR of Corynebacterium glutamicum. The latter we demonstrate as a new exemplar for allostery without conformation change. We observe that binding the first molecule of cAMP ligand is correlated with modulation of the global normal modes and negative cooperativity for binding the second cAMP ligand without a change in mean structure. The theory makes key experimental predictions that are tested through an analysis of variant proteins by structural biology and isothermal calorimetry. Quantifying allostery as a free energy landscape revealed a protein ‘‘design space’’ that identified the inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, through analyzing CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. This finding provides a link between the position of CRP/FNR transcription factors within the allosteric free energy landscapes and evolutionary selection pressures. Our study therefore reveals significant features of the mechanistic basis for allostery. Changes in low-frequency dynamics correlate with allosteric effects on ligand binding without the requirement for a defined spatial pathway. In addition to evolving suitable three-dimensional structures, CRP/FNR family transcription factors have been selected to occupy a dynamic space that fine-tunes biological activity and thus establishes the means to engineer allosteric mechanisms driven by low-frequency dynamics

The prevalence and determinants of polypharmacy at age 69: a British birth cohort study

BACKGROUND: To describe the development of polypharmacy and its components in a British birth cohort in its seventh decade and to investigate socioeconomic and gender differences independent of disease burden. METHODS: Data from the MRC National Survey for Health and Development were analysed to determine the prevalence and composition of polypharmacy at age 69 and changes since ages 60 to 64. Multinomial regression was used to test associations between gender, education and occupational social class and total, cardiological and non-cardiological polypharmacy controlling for disease burden. RESULTS: At age 69, 22.8% of individuals were taking more than 5 medications. There was an increase in the use of 5 to 8 medications (+ 2.3%) and over 9 medications (+ 0.8%) between ages 60–64 and 69. The greatest increases were found for cardiovascular (+ 13.4%) and gastrointestinal medications (+ 7.3%). Men experienced greater cardiological polypharmacy, women greater non-cardiological polypharmacy. Higher levels of education were associated with lower polypharmacy independent of disease burden, with strongest effects seen for over five cardiological medications (RRR 0.3, 95% CI 0.2–0.5 p < 0.001 for advanced secondary qualifications compared with no qualification); there was no additional effect of social class. CONCLUSIONS: Polypharmacy increased over the seventh decade. Those with lower levels of education had more polypharmacy (total, cardiological and non-cardiological), even allowing for disease burden. Further analysis of future outcomes resulting from polypharmacy should take into account educational and gender differences, in an effort to identify at-risk populations who could benefit from medication reviews

Increasing value and reducing waste by optimizing the development of complex interventions: Enriching the development phase of the Medical Research Council (MRC) Framework

This is the final version of the article. Available from Elsevier via the DOI in this record.Background In recent years there has been much emphasis on ‘research waste’ caused by poor question selection, insufficient attention to previous research results, and avoidable weakness in research design, conduct and analysis. Little attention has been paid to the effect of inadequate development of interventions before proceeding to a full clinical trial. Objective We therefore propose to enrich the development phase of the MRC Framework by adding crucial elements to improve the likelihood of success and enhance the fit with clinical practice Methods Based on existing intervention development guidance and synthesis, a comprehensive iterative intervention development approach is proposed. Examples from published reports are presented to illustrate the methodology that can be applied within each element to enhance the intervention design. Results A comprehensive iterative approach is presented by combining the elements of the MRC Framework development phase with essential elements from existing guidance including: problem identification, the systematic identification of evidence, identification or development of theory, determination of needs, the examination of current practice and context, modelling the process and expected outcomes leading to final element: the intervention design. All elements are drawn from existing models to provide intervention developers with a greater chance of producing an intervention that is well adopted, effective and fitted to the context. Conclusion This comprehensive approach of developing interventions will strengthen the internal and external validity, minimize research waste and add value to health care research. In complex interventions in health care research, flaws in the development process immediately impact the chances of success. Knowledge regarding the causal mechanisms and interactions within the intended clinical context is needed to develop interventions that fit daily practice and are beneficial for the end-user