Ischemic colitis represents the most common form of gastrointestinal ischemia. The presumed etiologies are numerous; however, it typically develops "spontaneously," in the absence of major vasculature occlusion, and in the presence of viable intestine elsewhere. It is most usefully classified into gangrenous and nongangrenous forms, the latter of which may be subdivided into transient and chronic types. Ischemic colitis may develop in people who are otherwise healthy, although a variety of clinical settings, such as shock, predispose to its occurrence. It usually presents as an acute abdominal illness with bloody diarrhea. Diagnosis is confirmed by colonoscopy. Therapy and outcome are dependent on the severity of disease. Nongangrenous colonic ischemia usually requires only medical management and is associated with a good prognosis. The chronic subtype may lead to the sequelae of persistent segmental colitis or colonic strictures, occasionally requiring surgery. Urgent operative intervention and a high morbidity and mortality are the hallmarks of gangrenous colonic ischemia. Special considerations must be given to those patients in whom ischemic colitis develops in the context of colon carcinoma or obstructing colon lesions, after abdominal aortic surgery, and following cardiopulmonary bypass. This review will discuss the clinical spectrum of ischemic colitis.

Most children undergoing congenital heart surgery can be extubated in the operating room. Most neonates, including many undergoing complex procedures, can be extubated within the first 24 hours after surgery. Early extubation was associated with low morbidity rates and short lengths of intensive care unit and hospital stays.

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T he type 2 ryanodine receptor (RYR2) is an integral membrane protein of the cardiomyocyte sarcoplasmic reticulum (SR) that functions as a Ca 2+ -activated Ca 2+ ion channel. Each receptor is a homotetramer, measuring roughly 29×29×12 nm, which can be readily identified in electron micrographs based on its location within the dyadic cleft and on its size and shape. 1,2 Rotary shadowing studies of type 1 ryanodine receptors (RYR1) in skeletal muscle triads 3 and numerous transmission electron micrographs of cardiac muscle 4 left the impression that the tetramers filled the dyadic cleft, forming a defect-free crystalline array, often referred to as a checkerboard. The array's formation is thought to be an intrinsic property of the protein reflecting the homotetramer's 4-fold symmetry whereby adjacent tetramers were noncovalently connected through their adjacent clamp domains.5 This is also thought to provide the structural basis for interprotein allosteric interactions. 6,7 Electron tomography and super-resolution fluorescence microscopy later revealed that the dyad contained subarrays that did not completely fill the cleft, and although neither technique had the resolution to determine the position and orientation of individual tetramers, the super resolution study assumed a regular checkerboard array when fitting their data. 8,9 A single-tilt tomogram with higher resolution indicated that the subarrays were unlikely to be fitted with a simple checkerboard. 10 RYR1 tetramers, purified from skeletal muscle and inserted in artificial bilayers, spontaneously formed 2 different types of array that depended on the free Mg 2+ concentration. Using a nominally Mg 2+ -free buffer, the tetramers formed a checkerboard, but with the addition of 4 mmol/L Mg 2+ , the tetramers were more densely packed in a side-by-side orientation although there was no physical contact between them. 11,12 The organization of the tetramers at the expected intracellular free Mg 2+ concentration of ≈1 mmol/L was not investigated. Whether RYR2 behaves similarly, and if such changes can occur in vivo, is unknown.In this study, we examined dual-tilt tomograms to visualize the position directly of individual RYR2 tetramers in adult rat ventricular myocytes. When fixed in situ, where the Mg Rationale: Single-tilt tomograms of the dyads in rat ventricular myocytes indicated that type 2 ryanodine receptors (RYR2s) were not positioned in a well-ordered array. Furthermore, the orientation and packing strategy of purified type 1 ryanodine receptors in lipid bilayers is determined by the free Mg 2+ concentration. These observations led us to test the hypothesis that RYR2s within the mammalian dyad have multiple and complex arrangements. Objectives:To determine the arrangement of RYR2 tetramers in the dyads of mammalian cardiomyocytes and the effects of physiologically and pathologically relevant factors on this arrangement. Methods and Results:We used dual-tilt electron tomography to produce en-face views of dyads, enabling a direct examination of RYR2 dis...

The PI3K/Akt/mTOR (phosphatidylinositol 3 kinase/ Akt/mammalian target of rapamycin) signalling pathway is an established driver of oncogenic activity in human malignancies. Therapeutic targeting of this pathway holds significant promise as a treatment strategy. Everolimus, an mtor inhibitor, is the first of this class of agents approved for the treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. Everolimus has been associated with significant improvements in progression-free survival; however, it is also associated with increased toxicity related to its specific mechanism of action. Methods: A comprehensive review of the literature conducted using a focused medline search was combined with a search of current trials at http://ClinicalTrials.gov/. Summary tables of the toxicities of the various classes of PI3K/Akt/mTOR inhibitors were created. A broad group of Canadian health care professionals was assembled to review the data and to produce expert opinion and summary recommendations for possible best practices in managing the adverse events associated with these pathway inhibitors. Results: Differing toxicities are associated with the various classes of PI3K/Akt/mTOR pathway inhibitors. The most common unique adverse events observed in everolimus clinical trials in breast cancer include stomatitis (all grades: approximately 60%), noninfectious pneumonitis (15%), rash (40%), hyperglycemia (15%), and immunosuppression (40%). To minimize grades 3 and 4 toxicities and to attempt to attain optimal outcomes, effective management of those adverse events is critical. Management should be interdisciplinary and should use approaches that include education, early recognition, active intervention, and potentially prophylactic strategies. Discussion: Everolimus likely represents the first of many complex oral targeted therapies for the treatment of breast cancer. Using this agent as a template, it is essential to establish best practices involving and integrating multiple disciplines for the management of future PI3K/Akt/mTOR signalling pathway inhibitors.