1,191 research outputs found

    Arteriovenous fistula: a rare complication of distal radial access for coronary angiography

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    Distal radial access is an emerging alternative approach for coronary angiography, preferred for its reduced complications and time to haemostasis, and improvement of patient and operator comfort. Arteriovenous fistula formation is a very rare complication following this approach, which requires recognition but which can be managed conservatively in certain instances

    A Versatile, Portable Intravital Microscopy Platform for Studying Beta-cell Biology In Vivo

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    The pancreatic islet is a complex micro-organ containing numerous cell types, including endocrine, immune, and endothelial cells. The communication of these systems is lost upon isolation of the islets, and therefore the pathogenesis of diabetes can only be fully understood by studying this organized, multicellular environment in vivo. We have developed several adaptable tools to create a versatile platform to interrogate β-cell function in vivo. Specifically, we developed β-cell-selective virally-encoded fluorescent protein biosensors that can be rapidly and easily introduced into any mouse. We then coupled the use of these biosensors with intravital microscopy, a powerful tool that can be used to collect cellular and subcellular data from living tissues. Together, these approaches allowed the observation of in vivo β-cell-specific ROS dynamics using the Grx1-roGFP2 biosensor and calcium signaling using the GcAMP6s biosensor. Next, we utilized abdominal imaging windows (AIW) to extend our in vivo observations beyond single-point terminal measurements to collect longitudinal physiological and biosensor data through repeated imaging of the same mice over time. This platform represents a significant advancement in our ability to study β-cell structure and signaling in vivo, and its portability for use in virtually any mouse model will enable meaningful studies of β-cell physiology in the endogenous islet niche

    Promoter keyholes enable specific and persistent multi-gene expression programs in primary T cells without genome modification

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    Non-invasive epigenome editing is a promising strategy for engineering gene expression programs, yet potency, specificity, and persistence remain challenging. Here we show that effective epigenome editing is gated at single-base precision via 'keyhole' sites in endogenous regulatory DNA. Synthetic repressors targeting promoter keyholes can ablate gene expression in up to 99% of primary cells with single-gene specificity and can seamlessly repress multiple genes in combination. Transient exposure of primary T cells to keyhole repressors confers mitotically heritable silencing that persists to the limit of primary cultures in vitro and for at least 4 weeks in vivo, enabling manufacturing of cell products with enhanced therapeutic efficacy. DNA recognition and effector domains can be encoded as separate proteins that reassemble at keyhole sites and function with the same efficiency as single chain effectors, enabling gated control and rapid screening for novel functional domains that modulate endogenous gene expression patterns. Our results provide a powerful and exponentially flexible system for programming gene expression and therapeutic cell products

    Directions for a troubled discipline:strategy research, teaching and practice introduction to the dialog

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    This Dialog responds to a growing debate about the relevance of business schools generally and the value of strategy theory and research for strategic management practice. The authors propose that academic theory and management practice can be better connected through management education. The academy researches practice, derives theory, and returns it to practice through the development of teaching materials and the teaching of current and future practitioners. The three articles in this Dialog examine how different approaches to strategy research inform strategy teaching and its application to practice. Joseph Bower explains the rise of business policy and the process research approach that informed that teaching tradition at Harvard Business School. Robert Grant responds by emphasizing the economic theory underpinnings of strategic management research and its impact on teaching. Paula Jarzabkowski and Richard Whittington conclude by proposing a strategyas-practice perspective and suggesting ways to better incorporate strategy-as-practice research into strategy teaching

    Primary health care services for the aged in the United Arab Emirates: a comparison of two models of care

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    Aim: To compare the quality of aged care provided by two different models of primary health care services in the United Arab Emirates. Methods: Cross sectional survey by chart review of 200 consecutive people aged 65 years and over attending two primary health care centers located in adjacent suburbs and serving populations with similar characteristics; a resource intensive center (RIC) and the other a resource thrifty center (RTC). Quality indicators were blood pressure levels in hypertensives and glycosylated hemoglobin (HbA1c) levels in diabetics. Results: There was no variation in age, sex or number of visits per year between the clinics. Osteoarthritis, hypertension, and diabetes were the most common diagnoses at both. The people attending the RIC had a substantially higher level of comorbidity (RIC=1.19±1.18, RTC=0.63 ± 0.68, p < 0.001), the average systolic and diastolic blood pressure for those diagnosed with hypertension was in the normal range at the RIC (138.5 ± 19.8/77.1 ± 9.9), whereas it was significantly higher and in the elevated range at the RTC (149.5 ± 17.7/85.2 ± 9.1, p < 0.001) and the HbA1c was significantly lower at the RIC (7.7 ± 1.4) than at the RTC (9.5 ± 2.0, p < 0.001). Conclusions:The quality of health outcomes for the two chronic diseases, hypertension and diabetes, appeared significantly higher at the RIC, when compared with the RTC. However, there may have been significant selection bias. Further studies are needed to determine if the RIC improves quality measures in other aspects of chronic disease care and provides a more cost effective health care service

    Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of neurofibromatosis type 1.

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    Background: Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes affected individuals to formation of benign neurofibromas, peripheral nerve tumors that can be associated with significant morbidity. Loss of the NF1 Ras-GAP protein causes increased Ras-GTP, and we previously found that inhibiting MEK signaling downstream of Ras can shrink established neurofibromas in a genetically engineered murine model. Procedures: We studied effects of MEK inhibition using 1.5 mg/kg/day PD-0325901 prior to neurofibroma onset in the Nf1 flox/flox;Dhh-Cre mouse model. We also treated mice with established tumors at 0.5 and 1.5 mg/kg/day dosees of PD-0325901. We monitored tumor volumes using MRI and volumetric measurements, and measured pharmacokinetic and pharmacodynamic endpoints. Results: Early administration significantly delayed neurofibroma development as compared to vehicle controls. When treatment was discontinued neurofibromas grew, but no rebound effect was observed and neurofibromas remained significantly smaller than controls. Low dose treatment of mice with PD-0325901 resulted in neurofibroma shrinkage equivalent to that observed at higher doses. Tumor cell proliferation decreased, although less than at higher doses with drug. Tumor blood vessels per area correlated with tumor shrinkage. Conclusions: Neurofibroma development was not prevented by MEK inhibition, beginning at 1 month of age, but tumor size was controlled by early treatment. Moreover, treatment with PD-0325901 at very low doses may shrink neurofibromas while minimizing toxicity. These studies highlight how genetically engineered mouse models can guide clinical trial design
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