Transgenic overexpression of mitofilin attenuates diabetes mellitus-associated cardiac and mitochondria dysfunction.

Mitofilin, also known as heart muscle protein, is an inner mitochondrial membrane structural protein that plays a central role in maintaining cristae morphology and structure. It is a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex which is important for mitochondrial architecture and cristae morphology. Our laboratory has previously reported alterations in mitochondrial morphology and proteomic make-up during type 1 diabetes mellitus, with mitofilin being significantly down-regulated in interfibrillar mitochondria (IFM). The goal of this study was to investigate whether overexpression of mitofilin can limit mitochondrial disruption associated with the diabetic heart through restoration of mitochondrial morphology and function. A transgenic mouse line overexpressing mitofilin was generated and mice injected intraperitoneally with streptozotocin using a multi low-dose approach. Five weeks following diabetes mellitus onset, cardiac contractile function was assessed. Restoration of ejection fraction and fractional shortening was observed in mitofilin diabetic mice as compared to wild-type controls (P<0.05 for both). Decrements observed in electron transport chain (ETC) complex I, III, IV and V activities, state 3 respiration, lipid peroxidation as well as mitochondria membrane potential in type 1 diabetic IFM were restored in mitofilin diabetic mice (P<0.05 for all). Qualitative analyses of electron micrographs revealed restoration of mitochondrial cristae structure in mitofilin diabetic mice as compared to wild-type controls. Furthermore, measurement of mitochondrial internal complexity using flow cytometry displayed significant reduction in internal complexity in diabetic IFM which was restored in mitofilin diabetic IFM (P<0.05). Taken together these results suggest that transgenic overexpression of mitofilin preserves mitochondrial structure, leading to restoration of mitochondrial function and attenuation of cardiac contractile dysfunction in the diabetic heart.

Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart.

The mitochondrion has been implicated in the development of diabetic cardiomyopathy. Examination of cardiac mitochondria is complicated by the existence of spatially distinct subpopulations including subsarcolemmal (SSM) and interfibrillar (IFM). Dysfunction to cardiac SSM has been reported in murine models of type 2 diabetes mellitus; however, subpopulation-based mitochondrial analyses have not been explored in type 2 diabetic human heart. The goal of this study was to determine the impact of type 2 diabetes mellitus on cardiac mitochondrial function in the human patient. Mitochondrial subpopulations from atrial appendages of patients with and without type 2 diabetes were examined. Complex I- and fatty acid-mediated mitochondrial respiration rates were decreased in diabetic SSM compared with nondiabetic (P ≤ 0.05 for both), with no change in IFM. Electron transport chain (ETC) complexes I and IV activities were decreased in diabetic SSM compared with nondiabetic (P ≤ 0.05 for both), with a concomitant decline in their levels (P ≤ 0.05 for both). Regression analyses comparing comorbidities determined that diabetes mellitus was the primary factor accounting for mitochondrial dysfunction. Linear spline models examining correlative risk for mitochondrial dysfunction indicated that patients with diabetes display the same degree of state 3 and electron transport chain complex I dysfunction in SSM regardless of the extent of glycated hemoglobin (HbA1c) and hyperglycemia. Overall, the results suggest that independent of other pathologies, mitochondrial dysfunction is present in cardiac SSM of patients with type 2 diabetes and the degree of dysfunction is consistent regardless of the extent of elevated HbA1c or blood glucose levels.

Multi-vessel giant coronary artery aneurysm in an elderly female.

Coronary artery aneurysm (CAA) is a rare anomaly. The right coronary artery is the most commonly affected, followed by the left circumflex (LCX), or the left anterior descending artery (LAD). Three-vessel disease or left main (LM) involvement is extremely rare. A giant coronary artery aneurysm (GCAA) has an extremely low incidence and refers to an aneurysm that is 20 mm or greater in size. Most CAAs occur as a consequence of atherosclerosis. Most patients with CAA are males, have three-vessel disease, and a history of myocardial infarction (MI). Thrombosis within the aneurysm can lead to distal embolization and MI. Depending on the severity of coronary stenosis, management of patients with LM CAAs is either surgical or medical.

Impact of Positive Nodal Metastases in Patients with Thymic Carcinoma and Thymic Neuroendocrine Tumors.

INTRODUCTION: Thymic carcinomas and thymic neuroendocrine tumors are rare diseases often treated with surgical resection. Currently, there are no guidelines regarding nodal dissection at the time of tumor resection. Moreover, the prognostic significance of nodal metastases is unclear. The goal of this study was to define the incidence and prognostic relevance of nodal metastases in patients with thymic carcinoma and thymic neuroendocrine tumors. METHODS: The Surveillance, Epidemiology and End Results database was queried for patients who underwent surgical resection of thymic carcinoma or a thymic neuroendocrine tumor with documented pathological examination of lymph nodes. The incidence of nodal metastases and the impact on survival were examined. RESULTS: We identified 176 patients with thymic carcinoma and 53 with thymic neuroendocrine tumors. A median of three lymph nodes was sampled per patient. Positive metastasis to at least one lymph node was identified in 92 patients (40.2%). Nodal metastasis was more common in patients with thymic neuroendocrine tumors than in patients with thymic carcinoma (62.3% versus 33.5%). In multivariate analysis, nodal metastasis was more likely in patients with thymic neuroendocrine tumors and with more advanced tumors. The presence of nodal metastases had significant, independent, adverse impact on survival (hazard ratio, 2.933, 95% confidence interval, 1.903-4.521, p = 0.001). Median survival was 47 months in patients with nodal metastasis and 124 months in patients without nodal metastases (p < 0.001). CONCLUSIONS: Nodal status seems to be an important prognostic factor in patients with thymic carcinoma and thymic neuroendocrine tumors. Nodal sampling should be performed during resection of these thymic malignancies.

Applications of pyroelectric materials in array-based detectors.

The development of low-cost, uncooled (room temperature operation) thermal detector arrays has been accelerating in recent years and now commercial products are becoming widely available. As costs come down and volumes rise, these devices are entering the consumer marketplace, providing everything from sophisticated security and people-monitoring devices to hand-held thermal imagers for preventative maintenance and building inspection. Two technologies have established significant market shares in uncooled thermal detector array products. These are resistive microbolometers and pyroelectric ceramics. To address the true mass market, the pyroelectric arrays offer significant cost advantage. In this paper, recent developments in a variety of products based on pyroelectric ceramic arrays are described and their performance and applicability are compared and contrasted with competing technologies. This includes the use of low-element-count arrays for applications in people counting and queue measurement, and the drive for cost-effective imaging arrays for mass-market thermal imaging. The technical challenges in materials production, device development, and low-cost manufacture are reviewed and future opportunities and challenges are outlined.