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Evidence supporting the Developmental Origins of Health and Disease (DOHaD) hypothesis indicates that improving early life environments can reduce non-communicable disease risks and improve health over the lifecourse. A widespread understanding of this evidence may help to reshape structures, guidelines and individual behaviors to better the developmental conditions for the next generations. Yet, few efforts have yet been made to translate the DOHaD concept beyond the research community. To understand why, and to identify priorities for DOHaD Knowledge Translation (KT) programs, we review here a portion of published descriptions of DOHaD KT efforts and critiques thereof. We focus on KT targeting people equipped to apply DOHaD knowledge to their everyday home or work lives. We identified 17 reports of direct-to-public DOHaD KT that met our inclusion criteria. Relevant KT programs have been or are being initiated in nine countries, most focusing on secondary school students or care-workers-in-training; few target parents-to-be. Early indicators suggest that such programs can empower participants. Main critiques of DOHaD KT suggest it may overburden mothers with responsibility for children’s health and health environments, minimizing the roles of other people and institutions. Simultaneously, though, many mothers-to-be seek reliable guidance on prenatal health and nutrition, and would likely benefit from engagement with DOHaD KT. We thus recommend emphasizing solidarity, and bringing together people likely to one day become parents (youth), people planning pregnancies, expecting couples, care workers and policymakers into empowering conversation about DOHaD and about the importance and complexity of early life environments.
To assess differences in cognition functions and gross brain structure in children seven years after an episode of severe acute malnutrition (SAM), compared with other Malawian children.
Prospective longitudinal cohort assessing school grade achieved and results of five computer-based (CANTAB) tests, covering three cognitive domains. A subset underwent brain MRI scans which were reviewed using a standardized checklist of gross abnormalities and compared with a reference population of Malawian children.
Children discharged from SAM treatment in 2006 and 2007 (n 320; median age 9·3 years) were compared with controls: siblings closest in age to the SAM survivors and age/sex-matched community children.
SAM survivors were significantly more likely to be in a lower grade at school than controls (adjusted OR = 0·4; 95 % CI 0·3, 0·6; P < 0·0001) and had consistently poorer scores in all CANTAB cognitive tests. Adjusting for HIV and socio-economic status diminished statistically significant differences. There were no significant differences in odds of brain abnormalities and sinusitis between SAM survivors (n 49) and reference children (OR = 1·11; 95 % CI 0·61, 2·03; P = 0·73).
Despite apparent preservation in gross brain structure, persistent impaired school achievement is likely to be detrimental to individual attainment and economic well-being. Understanding the multifactorial causes of lower school achievement is therefore needed to design interventions for SAM survivors to thrive in adulthood. The cognitive and potential economic implications of SAM need further emphasis to better advocate for SAM prevention and early treatment.
Deep Hβ narrowband and broadband images of M3 have been electronically blinked to search for cataclysmic binaries. Tests of the method on a known, faint cataclysmic enable us to set limits on the sensitivity of the technique. No bright (MB < 6) emission-line (equivalent width > 12 Å) cataclysmic binaries exist in M3 between 4 and 30 core radii from the center. Low luminosity globular X-ray sources could still be weak-lined (E.W. < 12 Å) and bright (MB ≃ +5 like some old novae) or strong-lined (E.W. ≃ 60 Å) and faint (MB > 7 like dwarf novae).
Eta Carinae is one of the most massive observable binaries. Yet determination of its orbital and physical parameters is hampered by obscuring winds. However the effects of the strong, colliding winds changes with phase due to the high orbital eccentricity. We wanted to improve measures of the orbital parameters and to determine the mechanisms that produce the relatively brief, phase-locked minimum as detected throughout the electromagnetic spectrum. We conducted intense monitoring of the He ii λ4686 line in η Carinae for 10 months in the year 2014, gathering ~300 high S/N spectra with ground- and space-based telescopes. We also used published spectra at the FOS4 SE polar region of the Homunculus, which views the minimum from a different direction. We used a model in which the He ii λ4686 emission is produced by two mechanisms: a) one linked to the intensity of the wind-wind collision which occurs along the whole orbit and is proportional to the inverse square of the separation between the companion stars; and b) the other produced by the ‘bore hole’ effect which occurs at phases across the periastron passage. The opacity (computed from 3D SPH simulations) as convolved with the emission reproduces the behavior of equivalent widths both for direct and reflected light. Our main results are: a) a demonstration that the He ii λ4686 light curve is exquisitely repeatable from cycle to cycle, contrary to previous claims for large changes; b) an accurate determination of the longitude of periastron, indicating that the secondary star is ‘behind’ the primary at periastron, a dispute extended over the past decade; c) a determination of the time of periastron passage, at ~4 days after the onset of the deep light curve minimum; and d) show that the minimum is simultaneous for observers at different lines of sight, indicating that it is not caused by an eclipse of the secondary star, but rather by the immersion of the wind-wind collision interior to the inner wind of the primary.
The objective is to determine the nature of the unseen companion of the single-lined spectroscopic binary, WR 148 (= WN7h+?). The absence of companion lines supports a compact companion (cc) scenario. The lack of hard X-rays favours a non-compact companion scenario. Is WR 148 a commonplace WR+OB binary or a rare WR+cc binary?
Eta Carinae is the most massive active binary within 10,000 light-years and is famous for the largest non-terminal stellar explosion ever recorded. Observations reveal that the supermassive (~120 M⊙) binary, consisting of an LBV and either a WR or extreme O star, undergoes dramatic changes every 5.54 years due to the stars’ very eccentric orbits (e ≈ 0.9). Many of these changes are caused by a dynamic wind-wind collision region (WWCR) between the stars, plus expanding fossil WWCRs formed one, two, and three 5.54-year cycles ago. The fossil WWCRs can be spatially and spectrally resolved by the Hubble Space Telescope/Space Telescope Imaging Spectrograph (HST/STIS). Starting in June 2009, we used the HST/STIS to spatially map Eta Carinae’s fossil WWCRs across one full orbit, following temporal changes in several forbidden emission lines (e.g. [Feiii] 4659 Å, [Feii] 4815 Å), creating detailed data cubes at multiple epochs. Multiple wind structures were imaged, revealing details about the binary’s orbital motion, photoionization properties, and recent (~5 − 15 year) mass-loss history. These observations allow us to test 3-D hydrodynamical and radiative-transfer models of the interacting winds. Our observations and models strongly suggest that the wind and photoionization properties of Eta Carinae’s binary have not changed substantially over the past several orbital cycles. They also provide a baseline for following future changes in Eta Carinae, essential for understanding the late-stage evolution of this nearby supernova progenitor. For more details, see Gull et al. (2016) and references therein.
Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolving hGBM biology in response to chemoradiotherapy will allow for the identification of cellular pathways that govern GBM therapy failure. In this study, we have developed a novel model to profile the clonal evolution of treatment naïve brain tumour initiating cell (BTIC) enriched hGBMs through chemoradiotherapy using: stem cell assays, BTIC marker expression and transcriptome analysis, immunohistochemistry, and cellular DNA barcoding technology. We report that treatment of hGBM BTICs leads to increased self-renewal capacity and higher transcript expression of stem cell genes Bmi1 and Sox2. Based on global transcriptome analysis of the in vitro treated hGBM, we also identify a hyper-aggressive form of glioma. Using our therapy-adapted hGBM-mouse xenograft model, we discover that despite tumour regression and increased mouse survival post-therapy, tumour relapse remains inevitable. The treatment-refractory cells again have increased self-renewal capacity and higher expression of Bmi1 and Sox2. Furthermore, by combining cellular DNA barcoding technology, which barcodes hGBM at single cell resolution, with our novel in vitro and in vivo therapy models, we are able to determine whether a pre-existing or a therapy driven subpopulation(s) seeds hGBM tumour relapse. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to the identification of novel therapeutic targets for the treatment of recurrent hGBM.
Glioblastoma (GBM), an aggressive primary adult brain tumor, is feared for its near uniformly fatal prognosis. Despite the use of aggressive treatment including surgical resection, radiotherapy and chemotherapy, the outcome of patients with GBM has failed to improve significantly. Numerous studies have implicated CD133+GBM subpopulation as driver of chemo- and radio-resistance. CD133 expression correlates with disease progression, recurrence, and poor overall survival of GBM patients. Here, we describe the preclinical evaluation of a recombinant CD133xCD3 bispecific T-cell engager (BiTE) antibody that redirects human polyclonal T cells to CD133+GBM cells, inducing very potent anti-tumor response. CD133-specific BiTE was constructed; with one arm recognizing the tumor antigen (CD133) while the second is specific to CD3 antigen. Using CD133high and CD133low primary GBM lines, we validated the binding of BiTEs to CD133+GBMs and CD3+T cells. In order to test the ability of BiTEs to functionally elicit CD133-specific cytotoxic responses in vitro, we performed killing assays. We observed CD133-specific BiTE mediated T cell activation and redirection to kill CD133-expressing GBM cells in a co-culture of T cells and GBM cells. The killing was more efficient in CD133high GBMs compared to CD133low GBMs, validating its specificity to target CD133+BTICs. Treatment with BiTEs yielded significant reductions in brain tumor burden in vivo. These data offers compelling evidence that BiTE-mediated cytotoxicity against treatment-resistant CD133+GBMs could provide a very potent, specific and can be a novel therapeutic strategy for GBM patients.
Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition.
• All patients with more than one of: chronic otalgia, bloody otorrhoea, bleeding, mass, facial swelling or palsy should be biopsied. (R)
• Magnetic resonance and computed tomography imaging should be performed. (R)
• Patients should undergo audiological assessment. (R)
• Carotid angiography is recommended in select patients. (G)
• The modified Pittsburg T-staging system is recommended. (G)
• The minimum operation for cancer involving the temporal bone is a lateral temporal bone resection. (R)
• Facial nerve rehabilitation should be initiated at primary surgery. (G)
• Anterolateral thigh free flap is the workhorse flap for lateral skull base defect reconstruction. (G)
• For patients undergoing surgery for squamous cell carcinoma, at least a superficial parotidectomy and selective neck dissection should be carried out. (R)
Studies of the rotation curve of our Galaxy at galactocentric radii, R, greater than the solar distance, Ro, from the center require the use of conventional optical techniques since the distances to as well as the radial velocities of Population I objects are needed.
A fourth season of work was carried out in the Spring of 1984. The centrepiece of the programme was the investigation of the well-preserved farm in the Wadi el-Amud (Lamout). The main farm buildings were excavated, faunal and botanical samples were collected systematically from within and between them, the field systems and sluices were examined in detail and investigations begun on the geomorphological and hydrological context. This report presents the basic description of the archaeological data resulting from excavation and survey; a second report will present the results of the various laboratory studies which were generated by the field work.
To determine factors affecting facial nerve outcome of vestibular schwannoma surgery.
This retrospective cohort study comprised 652 patients. The outcome measure was House–Brackmann classification at two years post-operatively. Univariate and multivariate analyses were carried out to determine the factors affecting facial nerve outcome. The incidence rates of hemifacial spasm, metallic taste and crocodile tear syndrome were recorded.
For tumours less than 1.5 cm, 95 per cent of outcomes were normal, 100 per cent were satisfactory (House–Brackmann grades I–III) and 0 per cent were unsatisfactory (grades IV–VI). For tumours 1.5–2.4 cm, 83 per cent of outcomes were normal, 99 per cent were satisfactory and 1 per cent were unsatisfactory. For tumours 2.5–3.4 cm, 68 per cent of outcomes were normal, 96 per cent were satisfactory and 4 per cent were unsatisfactory. For tumours 3.5–4.4 cm, 52 per cent of outcomes were normal, 80 per cent were satisfactory and 20 per cent were unsatisfactory. For tumours larger than 4.4 cm, 50 per cent of outcomes were normal, 72 per cent were satisfactory and 28 per cent were unsatisfactory.
Tumour size and operation year were significant predictors of facial nerve outcome. The surgical learning curve was steepest for the first 50 patients.
Wolf-Rayet (WR) stars are the evolved descendants of massive O-type stars and are considered to be progenitor candidates for Type Ib/c core-collapse supernovae (SNe). Recent results of our HST/WFC3 survey of Wolf-Rayet stars in M101 are summarised based on the detection efficiency of narrow-band optical imaging compared to broad-band methods. We show that on average 42% of WR stars, increasing to ~85% in central regions, are only detected in the narrow-band imaging. Hence, the non-detection of a WR star at the location of ~10 Type Ib/c SNe in broad-band imaging is no longer strong evidence for a non-WR progenitor channel.
Described are results showing that an oscillating flow-field can induce spatially periodic composition variations in electrodeposited NiFe films. Flow-induced NiFe composition modulated alloys (CMA's) were deposited on the disk of a rotating disk electrode by oscillating the disk rotation rate during galvanostatic plating. Deposit composition and structure were investigated using potentiostatic stripping voltammetry and scanning probe microscopy. Results illustrate a linear relationship between the composition modulation wavelength and the flow oscillation period. CMA's with wavelengths less than 10 nm can be fabricated when plating with a disk rotation rate oscillation period less than 3 seconds.
Chalcogenide semiconductors have been deposited epitaxially from aqueous solutions either chemically or electrochemically at growth rates of up to 0.7 μmhr−1. After recalling the basic principles of these deposition processes, results are presented concerning chemically deposited CdS on InP, GaP and CuInSe2 substrates, electrodeposited CdTe on InP, and CdSAnP heterostructures. Characterisation of these structures by RHEED, TEM, HRTEM, and glazing angle X ray diffraction allows to analyse the effects of substrate orientation, polarity, lattice match plus the influence of temperature on epitaxial growth. These results are discussed in terms of self organisation and a site selective growth mechanisms due to the free enegy of formation of each compound.
We have investigated transport processes on a stepped Ag(111) surface in an aqueous electrolyte by analyzing the equilibrium step fluctuations as a function of the electrode potential. No influence of the electrolyte and the potential was found in the regime of negative potentials with respect to the saturated calomel electrode. As the potential becomes positive and approaches the dissolution limit, the increasing magnitude of the step fluctuations and the change in the time dependence indicate a rapid exchange of silver atoms with the electrolyte long before the silver begins to dissolve.
We report in situ time-resolved surface x-ray scattering measurements of the underpoten-tial deposition of Cu2+ on Pt(111) in the presence of Cl− in HClO4 solution. Chronoamperometric (current vs. time) measurements indicate that after a potential step, the electrode-position current decays to 1/e of its initial value in at most 0.12 seconds. In contrast, our simultaneous time-resolved surface x-ray scattering data reveal that the overlayer requires on the order of two seconds to develop long-range periodic order. These results demonstrate that the kinetics of surface ordering can be significantly different from the kinetics of charge-transfer and illustrate the power of time-resolved surface x-ray scattering for in situ studies of electrodeposition.
Electrocrystallization of the organic superconductor bis(ethylenedithio)tetrathiafulvalene triiodide, (ET)2I3, on a highly ordered pyrolytic graphite (HOPG) substrate has been visualized using in situ atomic force microscopy (AFM). Previous studies have revealed the formation of a coincident epitaxial monolayer with a structure identical to that of a (001) layer of the superconducting beta phase of this material prior to bulk crystal growth. However, the symmetry of the HOPG substrate leads to domain boundary defects during self assembly of the separately growing domains. The number of defects is significantly reduced after an electrochemical annealing process in which the potential is cycled about the monolayer deposition potential. Annealing of these films is important if they are to be used in electronic devices as the defects may serve as barriers to electron transport in the two-dimensional layers.
In addition to (ET)2I3, monolayer growth also has been visualized during electrocrystallization of (ET)2ReO4 on HOPG. The role of coincident epitaxy with HOPG in the monolayer formation and molecular orientation will be discussed.
Structurally modified substrates have also been investigated. Studies of the electrocrystallization of (ET)2I3 on HOPG, thermally treated to produce well-defined monolayer depth pit structures, have demonstrated that (ET)2I3 monolayer growth can occur inside the pit structures. The presence of monolayer domain boundaries within large pits indicates that multiple, independent nucleation events can occur in the pits, providing an opportunity to determine critical nucleation sizes by varying the pit dimensions. Recently we have discovered that MoS2 substrates can be electrochemically etched, giving rise to monolayer deep triangular pits.
In this report, a monolayer of N-(3-aminopropyl) pyrrole is used as a template layer for the controlled growth of polypyrrole on polycrystalline and oriented films of the high temperature superconductor, YBa2Cu3O7. Large increases in the growth rate and smoothness of the polymer layer are obtained with the use of the monolayer template as compared with the bare superconductor electrodes. Observation of the electrochemical growth characteristics as well as polymer morphological properties allows for an evaluation of the local surface conductive properties of superconductor-based ceramic and thin film samples. The use of the amine substituted pyrrole self-assembled monolayer serves to drastically alter the polymer growth characteristics and the surface adhesion properties.