Intracerebral Hemorrhage: Toward Physiological Imaging of Hemorrhage Risk in Acute and Chronic Bleeding

Despite improvements in management and prevention of intracerebral hemorrhage (ICH), there has been little improvement in mortality over the last 30 years. Hematoma expansion, primarily during the first few hours is highly predictive of neurological deterioration, poor functional outcome, and mortality. For each 10% increase in ICH size, there is a 5% increase in mortality and an additional 16% chance of poorer functional outcome. As such, both the identification and prevention of hematoma expansion are attractive therapeutic targets in ICH. Previous studies suggest that contrast extravasation seen on CT Angiography (CTA), MRI, and digital subtraction angiography correlates with hematoma growth, indicating ongoing bleeding. Contrast extravasation on the arterial phase of a CTA has been coined the CTA Spot Sign. These easily identifiable foci of contrast enhancement have been identified as independent predictors of hematoma growth, mortality, and clinical outcome in primary ICH. The Spot Sign score, developed to stratify risk of hematoma expansion, has shown high inter-observer agreement. Post-contrast leakage or delayed CTA Spot Sign, on post contrast CT following CTA or delayed CTA respectively are seen in an additional ∼8% of patients and explain apparently false negative observations on early CTA imaging in patients subsequently undergoing hematoma expansion. CT perfusion provides an opportunity to acquire dynamic imaging and has been shown to quantify rates of contrast extravasation. Intravenous recombinant factor VIIa (rFVIIa) within 4 h of ICH onset has been shown to significantly reduce hematoma growth. However, clinical efficacy has yet to be proven. There is compelling evidence that cerebral amyloid angiopathy (CAA) may precede the radiographic evidence of vascular disease and as such contribute to microbleeding. The interplay between microbleeding, CAA, CTA Spot Sign and genetic composition (ApoE genotype) may be crucial in developing a risk model for ICH

Achieving Self-Sustainability in Interactive Graphical Programming Systems

Programming is fraught with accidental complexity. Software, including tools used for programming, is inflexible and hard to adapt to one's specific problem context. Programming tools do not support Notational Freedom, so programmers must waste cognitive effort expressing ideas in suboptimal notations. They must also work around problems caused by a reliance on plain text representations instead of Explicit Structure. The idea of a Self-Sustainable programming system, open to adaptation by its users, promises a way out of these accidental complexities. However, the principles underlying such a property are poorly documented, as are methods for practically achieving it in harmony with Notational Freedom and Explicit Structure. We trace the causes of this difficulty and use them to inform our construction of a prototype self-sustainable system. By carefully reflecting on the steps involved in our specific case, we provide insight into how self-sustainability can be achieved in general, and thus how a motivated programmer can escape the aforementioned sources of accidental complexity

Buyer Power and Functional Competition for Innovation

Our analysis starts from the observation that with progressive consolidation in retailing and the spread of private labels, retailers increasingly take over functions in the vertical chain. Focusing on innovation, we isolate various reasons for why when a large retailer grows in size, this can lead to an inefficient shift of innovation activity away from manufacturers and to the large retailer. One rationale for this is the retailer's control of access to consumers, which gives rise to a rent-appropriation motive for innovation, next to a hold-up problem. With retail competition, through crowding out the manufacturer's innovative activity, a large retailer obtains a competitive advantage vis-à-vis smaller retailers. We further analyze when inefficiencies are aggravated in case a large retailer's presence threatens the manufacturer with imitation of his innovations

Technical Dimensions of Programming Systems

Programming requires much more than just writing code in a programming language. It is usually done in the context of a stateful environment, by interacting with a system through a graphical user interface. Yet, this wide space of possibilities lacks a common structure for navigation. Work on programming systems fails to form a coherent body of research, making it hard to improve on past work and advance the state of the art. In computer science, much has been said and done to allow comparison of programming languages, yet no similar theory exists for programming systems; we believe that programming systems deserve a theory too. We present a framework of technical dimensions which capture the underlying characteristics of programming systems and provide a means for conceptualizing and comparing them. We identify technical dimensions by examining past influential programming systems and reviewing their design principles, technical capabilities, and styles of user interaction. Technical dimensions capture characteristics that may be studied, compared and advanced independently. This makes it possible to talk about programming systems in a way that can be shared and constructively debated rather than relying solely on personal impressions. Our framework is derived using a qualitative analysis of past programming systems. We outline two concrete ways of using our framework. First, we show how it can analyze a recently developed novel programming system. Then, we use it to identify an interesting unexplored point in the design space of programming systems. Much research effort focuses on building programming systems that are easier to use, accessible to non-experts, moldable and/or powerful, but such efforts are disconnected. They are informal, guided by the personal vision of their authors and thus are only evaluable and comparable on the basis of individual experience using them. By providing foundations for more systematic research, we can help programming systems researchers to stand, at last, on the shoulders of giants

Buyer Power and Functional Competition for Innovation

Our analysis starts from the observation that with progressive consolidation in retailing and the spread of private labels, retailers increasingly take over functions in the vertical chain. Focusing on innovation, we isolate various reasons for why when a large retailer grows in size, this can lead to an inefficient shift of innovation activity away from manufacturers and to the large retailer. One rationale for this is the retailer's control of access to consumers, which gives rise to a rent-appropriation motive for innovation, next to a hold-up problem. With retail competition, through crowding out the manufacturer's innovative activity, a large retailer obtains a competitive advantage vis-à-vis smaller retailers. We further analyze when inefficiencies are aggravated in case a large retailer's presence threatens the manufacturer with imitation of his innovations

Molecular basis of differential target regulation by miR-96 and miR-182: the Glypican-3 as a model

Besides the fact that miR-96 and miR-182 belong to the miR-182/183 cluster, their seed region (UUGGCA, nucleotides 2–7) is identical suggesting potential common properties in mRNA target recognition and cellular functions. Here, we used the mRNA encoding Glypican-3, a heparan-sulfate proteoglycan, as a model target as its short 3′ untranslated region is predicted to contain one miR-96/182 site, and assessed whether it is post-transcriptionally regulated by these two microRNAs. We found that miR-96 downregulated GPC3 expression by targeting its mRNA 3′-untranslated region and interacting with the predicted site. This downregulatory effect was due to an increased mRNA degradation and depended on Argonaute-2. Despite its seed similarity with miR-96, miR-182 was unable to regulate GPC3. This differential regulation was confirmed on two other targets, FOXO1 and FN1. By site-directed mutagenesis, we demonstrated that the miRNA nucleotide 8, immediately downstream the UUGGCA seed, plays a critical role in target recognition by miR-96 and miR-182. Our data suggest that because of a base difference at miRNA position 8, these two microRNAs control a completely different set of genes and therefore are functionally independent

Research cardiac magnetic resonance imaging in end stage renal disease - incidence, significance and implications of unexpected incidental findings

Objectives: Left ventricular mass (LVM) at cardiac magnetic resonance imaging (CMR) is a frequent end point in clinical trials in nephrology. Trial participants with end stage renal disease (ESRD) may have a greater frequency of incidental findings (IF). We retrospectively investigated prevalence of IF in previous research CMR and reviewed their subsequent impact on participants. Methods: Between 2002 and 2006, 161 ESRD patients underwent CMR in a transplant assessment study. Images were used to assess LV mass and function. In the current study a radiologist reviewed the scans for IF. Review of patient records determined the subsequent clinical significance of IF. Results: There were 150 IF in 95 study participants. Eighty-four (56 %) were new diagnoses. One hundred and two were non-cardiac. Fifteen were suspicious of malignancy. There was a clinically significant IF for 14.9 % of the participants. In six cases earlier identification of an IF may have improved quality of life or survival. Conclusions: Without radiology support clinically important IF may be missed on CMR. Patients undergoing CMR in trials should be counselled about the frequency and implications of IF. Patients with ESRD have a higher prevalence of IF than reported in other populations. Nephrology studies require mechanisms for radiologist reporting and strategies for dealing with IF

The Potential of N-Rich Plasma-Polymerized Ethylene (PPE:N) Films for Regulating the Phenotype of the Nucleus Pulposus

We recently developed a nitrogen-rich plasma-polymerized biomaterial, designated “PPE:N” (N-doped plasma-polymerized ethylene) that is capable of suppressing cellular hypertrophy while promoting type I collagen and aggrecan expression in mesenchymal stem cells from osteoarthritis patients. We then hypothesized that these surfaces would form an ideal substrate on which the nucleus pulposus (NP) phenotype would be maintained. Recent evidence using microarrays showed that in young rats, the relative mRNA levels of glypican-3 (GPC3) and pleiotrophin binding factor (PTN) were significantly higher in nucleus pulposus (NP) compared to annulus fibrosus (AF) and articular cartilage. Furthermore, vimentin (VIM) mRNA levels were higher in NP versus articular cartilage. In contrast, the levels of expression of cartilage oligomeric matrix protein (COMP) and matrix gla protein precursor (MGP) were lower in NP compared to articular cartilage. The objective of this study was to compare the expression profiles of these genes in NP cells from fetal bovine lumbar discs when cultured on either commercial polystyrene (PS) tissue culture dishes or on PPE:N with time. We found that the expression of these genes varies with the concentration of N ([N]). More specifically, the expression of several genes of NP was sensitive to [N], with a decrease of GPC3, VIM, PTN, and MGP in function of decreasing [N]. The expression of aggrecan, collagen type I, and collagen type II was also studied: no significant differences were observed in the cells on different surfaces with different culture time. The results support the concept that PPE:N may be a suitable scaffold for the culture of NP cells. Further studies are however necessary to better understand their effects on cellular phenotypes

Diffusion and perfusion weighted magnetic resonance imaging for tumor volume definition in radiotherapy of brain tumors

Abstract Accurate target volume delineation is crucial for the radiotherapy of tumors. Diffusion and perfusion magnetic resonance imaging (MRI) can provide functional information about brain tumors, and they are able to detect tumor volume and physiological changes beyond the lesions shown on conventional MRI. This review examines recent studies that utilized diffusion and perfusion MRI for tumor volume definition in radiotherapy of brain tumors, and it presents the opportunities and challenges in the integration of multimodal functional MRI into clinical practice. The results indicate that specialized and robust post-processing algorithms and tools are needed for the precise alignment of targets on the images, and comprehensive validations with more clinical data are important for the improvement of the correlation between histopathologic results and MRI parameter images