Dendritic Cells Transduced to Express Interleukin 4 Reduce Diabetes Onset in Both Normoglycemic and Prediabetic Nonobese Diabetic Mice

Background: We and others have previously demonstrated that treatment with bone marrow derived DC genetically modified to express IL-4 reduce disease pathology in mouse models of collagen-induced arthritis and delayed-type hypersensitivity. Moreover, treatment of normoglycemic NOD mice with bone marrow derived DC, genetically modified to express interleukin 4 (IL-4), reduces the onset of hyperglycemia in a significant number of animals. However, the mechanism(s) through which DC expressing IL-4 function to prevent autoimmune diabetes and whether this treatment can reverse disease in pre-diabetic NOD mice are unknown. Methodology/Principal Findings: DC were generated from the bone marrow of NOD mice and transduced with adenoviral vectors encoding soluble murine IL-4 (DC/sIL-4), a membrane-bound IL-4 construct, or empty vector control. Female NOD mice were segregated into normoglycemic (<150mg/dL) and prediabetic groups (between 150 and 250 mg/dL) on the basis of blood glucose measurements, and randomized for adoptive transfer of 106 DC via a single i.v. injection. A single injection of DC/sIL-4, when administered to normoglycemic 12-week old NOD mice, significantly reduced the number of mice that developed diabetes. Furthermore, DC/sIL-4, but not control DC, decreased the number of mice progressing to diabetes when given to prediabetic NOD mice 12-16 weeks of age. DC/sIL-4 treatment also significantly reduced islet mononuclear infiltration and increased the expression of FoxP3 in the pancreatic lymph nodes of a subset of treated animals. Furthermore, DC/sIL-4 treatment altered the antigen-specific Th2:Th1 cytokine profiles as determined by ELISPOT of splenocytes in treated animals. Conclusions: Adoptive transfer of DC transduced to express IL-4 into both normoglycemic and prediabetic NOD mice is an effective treatment for T1D. © 2010 Ruffner, Robbins

Exploring the effects of replicating shape, weight and recoil effects on VR shooting controllers

Commercial Virtual Reality (VR) controllers with realistic force feedback are becoming available, to increase the realism and immersion of first-person shooting (FPS) games in VR. These controllers attempt to mimic not only the shape and weight of real guns but also their recoil effects (linear force feedback parallel to the barrel, when the gun is shot). As these controllers become more popular and affordable, this paper investigates the actual effects that these properties (shape, weight, and especially directional force feedback) have on performance for general VR users (e.g. users with no marksmanship experience), drawing conclusions for both consumers and device manufacturers. We created a prototype replicating the properties exploited by commercial VR controllers (i.e. shape, weight and adjustable force feedback) and used it to assess the effect of these parameters in user performance, across a series of user studies. We first analysed the benefits on user performance of adding weight and shape vs a conventional controller (e.g. Vive controller). We then explore the implications of adding linear force feedback (LFF), as well as replicating the shape and weight. Our studies show negligible effects on the immediate shooting performance with some improvements in subjective appreciation, which are already present with low levels of LFF. While higher levels of LFF do not increase subjective appreciations any further, they lead users to reach their maximum distance skillset more quickly. This indicates that while adding low levels of LFF can be enough to influence user’s immersion/engagement for gaming contexts, controllers with higher levels of LFF might be better suited for training environments and/or when dealing with particularly demanding aiming tasks

Proliferative activity in human breast cancer: Ki-67 automated evaluation and the influence of different Ki-67 equivalent antibodies

<p>Abstract</p> <p>Background</p> <p>Ki67 labeling index (Ki67 LI), the percentage Ki67 immunoreactive cells, is a measure of tumor proliferation, with important clinical relevance in breast cancer, and it is extremely important to standardize its evaluation.</p> <p>Aim</p> <p>To test the efficacy of computer assisted image analysis (CAIA) applied to completely digitized slides and to assess its feasibility in routine practice and compare the results obtained using two different Ki67 monoclonal antibodies.</p> <p>Materials and methods</p> <p>315 consecutive breast cancer routinely immunostained for Ki-67 (223 with SP6 and 92 with MM1 antibodies previously examined by an experienced pathologist, have been re-evaluated using Aperio Scanscope Xs.</p> <p>Results</p> <p>Mean human Ki67 LI values were 36%± 14.% and 28% ± 18% respectively for SP6 and MM1 antibodies; mean CAM Ki67 LI values were 31%± 19% and 22% ± 18% respectively for SP6 and MM1. Human and CAIA evaluation are statistically highly correlated (Pearson: 0.859, p<0.0001), although human LI are systematically higher. An interobserver variation study on CAIA performed on 84 cases showed that the correlation between the two evaluations was linear to an excellent degree.</p> <p>Discussion</p> <p>Our study shows that a) CAIA can be easily adopted in routine practice, b) human and CAIA Ki67 LI are highly correlated, although human LI are systematically higher, c) Ki67 LI using different evaluation methods and different antibodies shows important differences in cut-off values.</p

Misperceptions About β-Blockers and Diuretics

Based on a series of clinical trials showing no difference in the effectiveness or tolerability of most major classes of antihypertensive medications, the Joint National Commission on High Blood Pressure Treatment recommends that physicians prescribe β-blockers or diuretics as initial hypertensive therapy unless there are compelling indications for another type of medication. Nevertheless, many physicians continue to favor more expensive medications like angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers as first line agents. The persistent use of these agents raises questions as to whether physicians perceive ACE inhibitors and calcium channel blockers to be better than β-blockers and diuretics. METHODS:  We surveyed 1,200 primary care physicians in 1997, and another 500 primary care physicians in 2000, and asked them to estimate the relative effectiveness and side effects of 4 classes of medication in treating a hypothetical patient with uncomplicated hypertension: ACE inhibitors, β-blockers, calcium channel blockers, and diuretics. In addition, we asked them to indicate whether they ever provided free samples of hypertension medications to their patients. RESULTS:  Perceptions of the relative effectiveness and side effects of the 4 classes of hypertension medications did not significantly change over the 3 years, nor did prescription recommendations. Physicians perceive that diuretics are less effective at lowering blood pressure than the other 3 classes ( P  < .001). They also perceive that β-blockers are less tolerated than the other 3 classes ( P  < .001). In a multivariate model, perceptions of effectiveness and tolerability displayed significant associations with prescription preference independent of background variables. The only other variable to contribute significantly to the model was provision of free medication samples to patients. CONCLUSIONS:  Despite numerous clinical trials showing no difference in the effectiveness or side-effect profiles of these 4 classes of drugs, most physicians believed that diuretics were less effective and β-blockers were less tolerated than other medications. Moreover, their prescription practices were associated with their provision of free samples provided by pharmaceutical representatives, even after adjusting for other demographic characteristics. Efforts to increase physicians’ prescribing of β-blockers and diuretics may need to be directed at overcoming misunderstandings about the effectiveness and tolerability of these medicines. J GEN INTERN MED 2003;18:977–983.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75385/1/j.1525-1497.2003.20414.x.pd

Genomic variation landscape of the human gut microbiome

While large-scale efforts have rapidly advanced the understanding and practical impact of human genomic variation, the latter is largely unexplored in the human microbiome. We therefore developed a framework for metagenomic variation analysis and applied it to 252 fecal metagenomes of 207 individuals from Europe and North America. Using 7.4 billion reads aligned to 101 reference species, we detected 10.3 million single nucleotide polymorphisms (SNPs), 107,991 short indels, and 1,051 structural variants. The average ratio of non-synonymous to synonymous polymorphism rates of 0.11 was more variable between gut microbial species than across human hosts. Subjects sampled at varying time intervals exhibited individuality and temporal stability of SNP variation patterns, despite considerable composition changes of their gut microbiota. This implies that individual-specific strains are not easily replaced and that an individual might have a unique metagenomic genotype, which may be exploitable for personalized diet or drug intake

Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.: Apoptosis and regulatory T cells

International audienceApoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover

Urban Biodiversity and Landscape Ecology: Patterns, Processes and Planning

Effective planning for biodiversity in cities and towns is increasingly important as urban areas and their human populations grow, both to achieve conservation goals and because ecological communities support services on which humans depend. Landscape ecology provides important frameworks for understanding and conserving urban biodiversity both within cities and considering whole cities in their regional context, and has played an important role in the development of a substantial and expanding body of knowledge about urban landscapes and communities. Characteristics of the whole city including size, overall amount of green space, age and regional context are important considerations for understanding and planning for biotic assemblages at the scale of entire cities, but have received relatively little research attention. Studies of biodiversity within cities are more abundant and show that longstanding principles regarding how patch size, configuration and composition influence biodiversity apply to urban areas as they do in other habitats. However, the fine spatial scales at which urban areas are fragmented and the altered temporal dynamics compared to non-urban areas indicate a need to apply hierarchical multi-scalar landscape ecology models to urban environments. Transferring results from landscape-scale urban biodiversity research into planning remains challenging, not least because of the requirements for urban green space to provide multiple functions. An increasing array of tools is available to meet this challenge and increasingly requires ecologists to work with planners to address biodiversity challenges. Biodiversity conservation and enhancement is just one strand in urban planning, but is increasingly important in a rapidly urbanising world

Understanding acute ankle ligamentous sprain injury in sports

This paper summarizes the current understanding on acute ankle sprain injury, which is the most common acute sport trauma, accounting for about 14% of all sport-related injuries. Among, 80% are ligamentous sprains caused by explosive inversion or supination. The injury motion often happens at the subtalar joint and tears the anterior talofibular ligament (ATFL) which possesses the lowest ultimate load among the lateral ligaments at the ankle. For extrinsic risk factors to ankle sprain injury, prescribing orthosis decreases the risk while increased exercise intensity in soccer raises the risk. For intrinsic factors, a foot size with increased width, an increased ankle eversion to inversion strength, plantarflexion strength and ratio between dorsiflexion and plantarflexion strength, and limb dominance could increase the ankle sprain injury risk. Players with a previous sprain history, players wearing shoes with air cells, players who do not stretch before exercising, players with inferior single leg balance, and overweight players are 4.9, 4.3, 2.6, 2.4 and 3.9 times more likely to sustain an ankle sprain injury. The aetiology of most ankle sprain injuries is incorrect foot positioning at landing – a medially-deviated vertical ground reaction force causes an explosive supination or inversion moment at the subtalar joint in a short time (about 50 ms). Another aetiology is the delayed reaction time of the peroneal muscles at the lateral aspect of the ankle (60–90 ms). The failure supination or inversion torque is about 41–45 Nm to cause ligamentous rupture in simulated spraining tests on cadaver. A previous case report revealed that the ankle joint reached 48 degrees inversion and 10 degrees internal rotation during an accidental grade I ankle ligamentous sprain injury during a dynamic cutting trial in laboratory. Diagnosis techniques and grading systems vary, but the management of ankle ligamentous sprain injury is mainly conservative. Immobilization should not be used as it results in joint stiffness, muscle atrophy and loss of proprioception. Traditional Chinese medicine such as herbs, massage and acupuncture were well applied in China in managing sports injuries, and was reported to be effective in relieving pain, reducing swelling and edema, and restoring normal ankle function. Finally, the best practice of sports medicine would be to prevent the injury. Different previous approaches, including designing prophylactice devices, introducing functional interventions, as well as change of games rules were highlighted. This paper allows the readers to catch up with the previous researches on ankle sprain injury, and facilitate the future research idea on sport-related ankle sprain injury