202 research outputs found

    Tissue magnetic susceptibility mapping as a marker of tau pathology in Alzheimer's disease.

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    Alzheimer's disease is connected to a number of other neurodegenerative conditions, known collectively as 'tauopathies', by the presence of aggregated tau protein in the brain. Neuroinflammation and oxidative stress in AD are associated with tau pathology and both the breakdown of axonal sheaths in white matter tracts and excess iron accumulation grey matter brain regions. Despite the identification of myelin and iron concentration as major sources of contrast in quantitative susceptibility maps of the brain, the sensitivity of this technique to tau pathology has yet to be explored. In this study, we perform Quantitative Susceptibility Mapping (QSM) and T2* mapping in the rTg4510, a mouse model of tauopathy, both in vivo and ex vivo. Significant correlations were observed between histological measures of myelin content and both mean regional magnetic susceptibility and T2* values. These results suggest that magnetic susceptibility is sensitive to tissue myelin concentrations across different regions of the brain. Differences in magnetic susceptibility were detected in the corpus callosum, striatum, hippocampus and thalamus of the rTg4510 mice relative to wild type controls. The concentration of neurofibrillary tangles was found to be low to intermediate in these brain regions indicating that QSM may be a useful biomarker for early stage detection of tau pathology in neurodegenerative diseases

    Optimal C-type Filter for Harmonics Mitigation and Resonance Damping in Industrial Distribution Systems

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    Single-tuned passive filters offer reasonable mitigation for harmonic distortion at a specific harmonic frequency with a high filtering percentage, but resonance hazards exist. Traditional damped filters offer high-pass filtering for the high-frequency range, but suffer from extra ohmic losses. C-type filters may operate in a manner similar to the tuned filters with low damping losses and marginal resonance damping capabilities. Also, they can be designed as damped filters with increased resonance damping capability. In this paper, a methodology that facilitates sizing for the C-type damped filter parameters for harmonics mitigation and resonance damping in balanced distribution system networks, is presented and discussed using the impedance-frequency index. This index evaluates the resonance damping capability provided by the damped filters analytically rather than the conventional graphical method of impedance-frequency scanning. It shows how to size shunt passive filters, while making a full use of their damping capabilities. It can disclose the parallel resonance frequencies of the equivalent system-filter impedance. A comparative study of the new approach and a conventional filter design approach, which aims to minimize total harmonic current distortion, is presented. Numerous simulation results are provided to clarify the proposed methodology, advantages, and disadvantages

    Killing Hypoxic Cell Populations in a 3D Tumor Model with EtNBS-PDT

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    An outstanding problem in cancer therapy is the battle against treatment-resistant disease. This is especially true for ovarian cancer, where the majority of patients eventually succumb to treatment-resistant metastatic carcinomatosis. Limited perfusion and diffusion, acidosis, and hypoxia play major roles in the development of resistance to the majority of front-line therapeutic regimens. To overcome these limitations and eliminate otherwise spared cancer cells, we utilized the cationic photosensitizer EtNBS to treat hypoxic regions deep inside in vitro 3D models of metastatic ovarian cancer. Unlike standard regimens that fail to penetrate beyond ∼150 µm, EtNBS was found to not only penetrate throughout the entirety of large (>200 µm) avascular nodules, but also concentrate into the nodules' acidic and hypoxic cores. Photodynamic therapy with EtNBS was observed to be highly effective against these hypoxic regions even at low therapeutic doses, and was capable of destroying both normoxic and hypoxic regions at higher treatment levels. Imaging studies utilizing multiphoton and confocal microscopies, as well as time-lapse optical coherence tomography (TL-OCT), revealed an inside-out pattern of cell death, with apoptosis being the primary mechanism of cell killing. Critically, EtNBS-based photodynamic therapy was found to be effective against the model tumor nodules even under severe hypoxia. The inherent ability of EtNBS photodynamic therapy to impart cytotoxicity across a wide range of tumoral oxygenation levels indicates its potential to eliminate treatment-resistant cell populations

    Poor nutritional status of schoolchildren in urban and peri-urban areas of Ouagadougou (Burkina Faso)

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    <p>Abstract</p> <p>Background</p> <p>Malnutrition is still highly prevalent in developing countries. Schoolchildren may also be at high nutritional risk, not only under-five children. However, their nutritional status is poorly documented, particularly in urban areas. The paucity of information hinders the development of relevant nutrition programs for schoolchildren. The aim of this study carried out in Ouagadougou was to assess the nutritional status of schoolchildren attending public and private schools.</p> <p>Methods</p> <p>The study was carried out to provide baseline data for the implementation and evaluation of the Nutrition Friendly School Initiative of WHO. Six intervention schools and six matched control schools were selected and a sample of 649 schoolchildren (48% boys) aged 7-14 years old from 8 public and 4 private schools were studied. Anthropometric and haemoglobin measurements, along with thyroid palpation, were performed. Serum retinol was measured in a random sub-sample of children (N = 173). WHO criteria were used to assess nutritional status. Chi square and independent t-test were used for proportions and mean comparisons between groups.</p> <p>Results</p> <p>Mean age of the children (48% boys) was 11.5 ± 1.2 years. Micronutrient malnutrition was highly prevalent, with 38.7% low serum retinol and 40.4% anaemia. The prevalence of stunting was 8.8% and that of thinness, 13.7%. The prevalence of anaemia (p = 0.001) and vitamin A deficiency (p < 0.001) was significantly higher in public than private schools. Goitre was not detected. Overweight/obesity was low (2.3%) and affected significantly more children in private schools (p = 0.009) and younger children (7-9 y) (p < 0.05). Thinness and stunting were significantly higher in peri-urban compared to urban schools (p < 0.05 and p = 0.004 respectively). Almost 15% of the children presented at least two nutritional deficiencies.</p> <p>Conclusion</p> <p>This study shows that malnutrition and micronutrient deficiencies are also widely prevalent in schoolchildren in cities, and it underlines the need for nutrition interventions to target them.</p

    A Case of Corticotroph Carcinoma that Caused Multiple Cranial Nerve Palsies, Destructive Petrosal Bone Invasion, and Liver Metastasis

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    A 52-year-old woman experienced sudden onset of double vision due to a right abducens nerve palsy and was diagnosed as having a pituitary macroadenoma that invaded into the right cavernous sinus. Otherwise, she was asymptomatic despite marked elevation of ACTH (293 pg/ml) and cortisol (24.6 μg/dl) levels. The patient underwent transsphenoidal surgery followed by γ-knife radiosurgery (GKR), which healed the diplopia and ameliorated the hypercortisolemia. The excised tumor was diffusely stained for ACTH with a high (15%) Ki-67 labeling index. Early tumor recurrence occurred twice thereafter, producing right lower cranial nerve palsies with petrosal bone destruction at 8 months and an ipsilateral oculomotor nerve palsy at 12 months after GKR; all palsies resolved completely with the second and third GKRs. Hypercortisolemia worsened rapidly soon after the third GKR, and the patient developed marked weight gain, hypokalemia, and hypertension. Multiple liver lesions were incidentally detected with computer tomography and identified as metastatic pituitary tumor on immunohistochemistry. An ACTH-producing adenoma should be followed carefully for early recurrence and/or metastatic spread when the tumor is an invasive macroadenoma with a high proliferation marker level. The unique aggressive behavior and high potential for malignant transformation of this case are discussed

    Design principles in housing for people with complex physical and cognitive disability: towards an integrated framework for practice

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    To develop a research-based environmental framework to guide the design and construction of suitable residential dwellings for individuals with complex disability. An environmental approach to housing design and development recognises that there are physical, psychological and social components relating to housing design, dwelling location and the neighbourhood context, and that these elements interact to affect the physical, psychological, and social wellness of individuals. Following theoretical review and synthesis, a comprehensive set of design features that are conducive to residents’ wellness and quality of life are described. It is clear that housing design and development for people with complex disability ought to consider the physical, social, natural, symbolic, and care environment in relation to housing design, dwelling location, and the neighbourhood context for improved housing outcomes. An integrated housing design and development framework is presented. It is hoped this practical matrix/evaluative tool will inform future inclusive housing design and development decisions in Australia and internationally. The application of this framework is especially relevant to political climates striving to achieve design innovation to increase housing choice for people with complex disability

    Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction

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    Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 overexpression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies

    Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study

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    Background Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation
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