Therapeutic Nano- and Microparticles for Angiogenesis Dependent Diseases

There are a number of diseases that are caused by, or depend on, irregular angiogenesis. In cancer, tumors require new vasculature in order to proliferate. In neovascular age-related macular degeneration (NVAMD), aberrant angiogenesis can result in leakage that damages the retina, causing progressive blindness in patients. Other ocular diseases, such as macular edema and proliferative diabetic retinopathy, also depend on diseased blood vessels, impairing the sight of many millions of people around the world. Therefore, blocking these pathologies has been, and continues to be, an important target of research and therapy. Peptide delivery and genetic therapy are two promising strategies for the treatment of a number of diseases. Gene therapy can be used to replace lost function both in the case of inherited and acquired diseases, such as in cancer. Here, a non-viral polymeric strategy is described for the delivery of DNA. Poly(beta-amino esters) (PBAE) are a class of cationic, hydrolytically degradable polymers that can electrostatically complex with genetic material to form gene delivery nanoparticles. The modular structure of the PBAEs allows for the creation of a library of structures with varying transfection abilities. These PBAEs are used to deliver both reporter and functional genes. Polymer structures that optimally transfect cancer cell types, such as small cell lung cancer, and endothelial cell types, such as human retinal endothelial cells, are identified. The delivery of a functional gene in vivo shows inhibition of tumor growth in a mouse model. The delivery of reporter genes allows for the identification of PBAEs that can preferentially transfect retinal endothelial cells over retinal epithelial cells in vitro. Therefore, it is shown that PBAEs can be a useful platform to deliver DNA both directly to cancer cells and to endothelial cells as a treatment for angiogenesis dependent diseases. Peptides have a number of favorable therapeutic properties, such as high specificity. Certain serpin-derived and collagen-IV derived peptides have been shown to have potent in vitro and in vivo anti-angiogenic properties. However, peptides are often difficult to translate to the clinic due to high biological clearance and poor biodistribution. Here, the use of nanoparticle and microparticle formulations are described that can counter these limitations and extend the activity of anti-angiogenic peptides by controlled release over time. A number of poly(lactide-co-glycolide) (PLGA) based nanoparticle systems are also developed for the release and passive targeting of the collagen-IV derived peptide for cancer applications. A composite polymeric microparticle system, using PBAE and PLGA, is developed for the treatment of NVAMD. This delivery system is able to release the serpin-derived peptide and inhibit neovascularization in a clinically relevant mouse model over many months. A PLGA microparticle system is also optimized for the release of the collagen-IV derived peptides, with improved long-term efficacy observed in the clinically relevant mouse model

Phase unwrapping with a rapid opensource minimum spanning tree algorithm (ROMEO)

PURPOSE: To develop a rapid and accurate MRI phase-unwrapping technique for challenging phase topographies encountered at high magnetic fields, around metal implants, or postoperative cavities, which is sufficiently fast to be applied to large-group studies including Quantitative Susceptibility Mapping and functional MRI (with phase-based distortion correction). METHODS: The proposed path-following phase-unwrapping algorithm, ROMEO, estimates the coherence of the signal both in space-using MRI magnitude and phase information-and over time, assuming approximately linear temporal phase evolution. This information is combined to form a quality map that guides the unwrapping along a 3D path through the object using a computationally efficient minimum spanning tree algorithm. ROMEO was tested against the two most commonly used exact phase-unwrapping methods, PRELUDE and BEST PATH, in simulated topographies and at several field strengths: in 3T and 7T in vivo human head images and 9.4T ex vivo rat head images. RESULTS: ROMEO was more reliable than PRELUDE and BEST PATH, yielding unwrapping results with excellent temporal stability for multi-echo or multi-time-point data. It does not require image masking and delivers results within seconds, even in large, highly wrapped multi-echo data sets (eg, 9 seconds for a 7T head data set with 31 echoes and a 208 × 208 × 96 matrix size). CONCLUSION: Overall, ROMEO was both faster and more accurate than PRELUDE and BEST PATH, delivering exact results within seconds, which is well below typical image acquisition times, enabling potential on-console application

Quantitative susceptibility mapping of carotid arterial tissue ex vivo: Assessing sensitivity to vessel microstructural composition

PURPOSE: To characterize microstructural contributions to the magnetic susceptibility of carotid arteries. METHOD: Arterial vessels were scanned using high-resolution quantitative susceptibility mapping (QSM) at 7 Tesla. Models of vessel degradation were generated using ex vivo porcine carotid arteries that were subjected to several different enzymatic digestion treatments that selectively removed microstructural components (smooth muscle cells, collagen, and elastin). Magnetic susceptibilities measured in these tissue models were compared to those in untreated (native) porcine arteries. Magnetic susceptibility measured in native porcine carotid arteries was further compared to the susceptibility of cadaveric human carotid arteries to investigate their similarity. RESULTS: The magnetic susceptibility of native porcine vessels was diamagnetic (χnative = -0.1820 ppm), with higher susceptibilities in all models of vessel degradation (χelastin-degraded = -0.0163 ppm; χcollagen-degraded = -0.1158 ppm; χdecellularized = -0.1379 ppm; χfixed native = -0.2199 ppm). Magnetic susceptibility was significantly higher in collagen-degraded compared to native porcine vessels (Tukey-Kramer, P .05). CONCLUSIONS: Magnetic susceptibility measured using QSM is sensitive to the microstructural composition of arterial vessels-most notably to collagen. The similarity of human and porcine arterial tissue susceptibility values provides a solid basis for translational studies. Because vessel microstructure becomes disrupted during the onset and progression of carotid atherosclerosis, QSM has the potential to provide a sensitive and specific marker of vessel disease

Patient-initiated second medical consultations: patient characteristics and motivating factors, impact on care and satisfaction: A systematic review

Objectives: To review the characteristics and motivations of patients seeking second opinions, and the impact of such opinions on patient management, satisfaction, and cost-effectiveness. Data sources: Embase, Medline, PsycINFO and HMIC databases. Study design: A systematic literature search was performed for terms related to second opinion and patient characteristics. Study quality was assessed using the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Data collection / Extraction methods: We included articles focused on patient-initiated second opinions, which provided quantitative data on their impact on diagnosis, treatment, prognosis or patient satisfaction, described the characteristics or motivating factors of patients who initiated a second opinion, or the cost-effectiveness of patient-initiated second opinions. Principal findings: Thirty-one articles were included in the review. 27 studies considered patient characteristics, 18 patient motivating factors, 10 patient satisfaction, and 17 clinical agreement between the first and second opinion. Seeking a second opinion was more common in women, middle age patients, more educated patients; and in people having a chronic condition, with higher income or socioeconomic status or living in central urban areas. Patients seeking a second opinion sought to gain more information or reassurance about their diagnosis or treatment. While many second opinions confirm the original diagnosis or treatment, discrepancies in opinions had a potential major impact on patient outcomes in up to 58% of cases. No studies reporting on the cost-effectiveness of patient initiated second opinions. Conclusions: Seeking a second opinion was more common in women, middle-age patients, and more educated patients, and in people having a chronic condition, with higher income or socioeconomic status or living in central urban areas. Patients seeking a second opinion sought to gain more information or reassurance about their diagnosis or treatment

Gadolinium-Enhanced Magnetic Susceptibility Contrast Is Reduced in the Corpus Callosum of a Mouse Model of Tauopathy

Alterations to white matter have been implicated in a number of neurodegenerative diseases. In this work we investigate the sensitivity of MRI magnetic susceptibility mapping to these changes using a mouse model of Tauopathy. A non-rigid registration of contrast enhanced, high resolution ex vivo mouse brain images is used to transform susceptibility maps into a common space and a voxel-wise group comparison is performed. Significant differences were observed that may indicate disruption to the tissue of the corpus callosum

Quantitative susceptibility mapping identifies hippocampal and other subcortical grey matter tissue composition changes in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is associated with widespread brain alterations. Using quantitative susceptibility mapping (QSM) alongside transverse relaxation rate ( ), we investigated regional brain susceptibility changes in 36 patients with left-sided (LTLE) or right-sided TLE (RTLE) secondary to hippocampal sclerosis, and 27 healthy controls (HC). We compared three susceptibility calculation methods to ensure image quality. Correlations of susceptibility and with age of epilepsy onset, frequency of focal-to-bilateral tonic–clonic seizures (FBTCS), and neuropsychological test scores were examined. Weak-harmonic QSM (WH-QSM) successfully reduced noise and removed residual background field artefacts. Significant susceptibility increases were identified in the left putamen in the RTLE group compared to the LTLE group, the right putamen and right thalamus in the RTLE group compared to HC, and a significant susceptibility decrease in the left hippocampus in LTLE versus HC. LTLE patients who underwent epilepsy surgery showed significantly lower left-versus-right hippocampal susceptibility. Significant changes were found between TLE and HC groups in the amygdala, putamen, thalamus, and in the hippocampus. Specifically, decreased R2* was found in the left and right hippocampus in LTLE and RTLE, respectively, compared to HC. Susceptibility and were significantly correlated with cognitive test scores in the hippocampus, globus pallidus, and thalamus. FBTCS frequency correlated positively with ipsilateral thalamic and contralateral putamen susceptibility and with in bilateral globi pallidi. Age of onset was correlated with susceptibility in the hippocampus and putamen, and with in the caudate. Susceptibility and changes observed in TLE groups suggest selective loss of low-myelinated neurons alongside iron redistribution in the hippocampi, predominantly ipsilaterally, indicating QSM's sensitivity to local pathology. Increased susceptibility and in the thalamus and putamen suggest increased iron content and reflect disease severity

High Spatial Resolution Fast-Neutron Imaging Detectors for Pulsed Fast-Neutron Transmission Spectroscopy

Two generations of a novel detector for high-resolution transmission imaging and spectrometry of fast-neutrons are presented. These devices are based on a hydrogenous fiber scintillator screen and single- or multiple-gated intensified camera systems (ICCD). This detector is designed for energy-selective neutron radiography with nanosecond-pulsed broad-energy (1 - 10 MeV) neutron beams. Utilizing the Time-of-Flight (TOF) method, such a detector is capable of simultaneously capturing several images, each at a different neutron energy (TOF). In addition, a gamma-ray image can also be simultaneously registered, allowing combined neutron/gamma inspection of objects. This permits combining the sensitivity of the fast-neutron resonance method to low-Z elements with that of gamma radiography to high-Z materials.Comment: Also published in JINST: http://www.iop.org/EJ/abstract/1748-0221/4/05/P0501

High-Level Why-Not Explanations Using Ontologies

We propose a novel foundational framework for why-not explanations, that is, explanations for why a tuple is missing from a query result. Our why-not explanations leverage concepts from an ontology to provide high-level and meaningful reasons for why a tuple is missing from the result of a query. A key algorithmic problem in our framework is that of computing a most-general explanation for a why-not question, relative to an ontology, which can either be provided by the user, or it may be automatically derived from the data and/or schema. We study the complexity of this problem and associated problems, and present concrete algorithms for computing why-not explanations. In the case where an external ontology is provided, we first show that the problem of deciding the existence of an explanation to a why-not question is NP-complete in general. However, the problem is solvable in polynomial time for queries of bounded arity, provided that the ontology is specified in a suitable language, such as a member of the DL-Lite family of description logics, which allows for efficient concept subsumption checking. Furthermore, we show that a most-general explanation can be computed in polynomial time in this case. In addition, we propose a method for deriving a suitable (virtual) ontology from a database and/or a data workspace schema, and we present an algorithm for computing a most-general explanation to a why-not question, relative to such ontologies. This algorithm runs in polynomial-time in the case when concepts are defined in a selection-free language, or if the underlying schema is fixed. Finally, we also study the problem of computing short most-general explanations, and we briefly discuss alternative definitions of what it means to be an explanation, and to be most general.Comment: in PODS 201

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

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

Changes among male and female visitors to practitioners of complementary and alternative medicine in a large adult Norwegian population from 1997 to 2008 (The HUNT studies)

Background The aim was to investigate changes in the prevalence and characteristics of male and female visitors to practitioners of complementary and alternative medicine (CAM) in a large adult population from 1997 to 2008. Methods Two cross sectional adult total population health surveys from Central Norwegian (the Nord-Trøndelag Health Studies (HUNT)). In 1997 42,277 and in 2008 50,713 respondents were included. Variables included demographics (age, education, working status), lifestyle (daily smoker, did hard physical activities), health status (self-rated health status, recent complaints, chronic complaints, psychiatric complaints, a range of diseases) and health care use (visit general practitioner, chiropractor). A test of difference between the results of multivariable logistic regression models for each year, including all variables, was used to analyse changes from 1997 to 2008. Results In 1997 9.4% (95%CI 9.1-9.6) of the population had visited a CAM practitioner in the last 12 months and this increased to 12.6% (12.3-12.9) in 2008 (p < 0.001 for difference). Prevalence of CAM use in females was almost twice as high as that in males both years. For males, the significant changes from 1997 to 2008 (p < 0.05) were an increase in odds of visiting for those under 50 years, who had a recent complaint, were widower or did hard physical activities. There was a decrease for males who had a university degree, psychiatric complaint or hay fever. For females there was an increase in the odds for those under 50 years, who had a recent complaint or chronic complaint. It was a decrease for females with reported fair global health, psychiatric complaint, hay fever or if they had visited a chiropractor. Conclusion The increase in visits was mainly among younger people of both genders with more limited complaints. A larger proportion of the more healthy part of the population is increasing their visits to CAM practitioners