Hyperglycemic Myocardial Damage Is Mediated by Proinflammatory Cytokine: Macrophage Migration Inhibitory Factor

Diabetes has been regarded as an inflammatory condition which is associated with left ventricular diastolic dysfunction (LVDD). The purpose of this study was to examine the expression levels of macrophage migration inhibitory factor (MIF) and G protein-coupled receptor kinase 2 (GRK2) in patients with early diabetic cardiomyopathy, and to investigate the mechanisms involved in MIF expression and GRK2 activation.83 patients in the age range of 30-64 years with type 2 diabetes and 30 matched healthy men were recruited. Left ventricular diastolic function was evaluated by cardiac Doppler echocardiography. Plasma MIF levels were determined by ELISA. To confirm the clinical observation, we also studied MIF expression in prediabetic rats with impaired glucose tolerance (IGT) and relationship between MIF and GRK2 expression in H9C2 cardiomyoblasts exposed to high glucose.Compared with healthy subjects, patients with diabetes have significantly increased levels of plasma MIF which was further increased in diabetic patients with Left ventricular diastolic dysfunction (LVDD). The increased plasma MIF levels in diabetic patients correlated with plasma glucose, glycosylated hemoglobin and urine albumin levels. We observed a significant number of TUNEL-positive cells in the myocardium of IGT-rats but not in the control rats. Moreover, we found higher MIF expression in the heart of IGT with cardiac dysfunction compared to that of the controls. In H9C2 cardiomyoblast cells, MIF and GRK2 expression was significantly increased in a glucose concentration-dependant manner. Furthermore, GRK2 expression was abolished by siRNA knockdown of MIF and by the inhibition of CXCR4 in H9C2 cells.Our findings indicate that hyperglycemia is a causal factor for increased levels of pro-inflammatory cytokine MIF which plays a role in the development of cardiomyopathy occurring in patients with type 2 diabetes. The elevated levels of MIF are associated with cardiac dysfunction in diabetic patients, and the MIF effects are mediated by GRK2

Further Evidence on the Effect of Regulation on the Exit of Small Auditors from the Audit Market and Resulting Audit Quality

SUMMARY Following the introduction of SOX in 2002 and the introduction of PCAOB inspections starting from 2003, DeFond and Lennox (2011) found that a large number of small auditors exited the SEC client audit market during the 2002–2004 period and that these exiting auditors were of lower quality relative to non-exiting auditors. This paper seeks to verify whether SOX and the introduction of PCAOB inspections improved audit quality through incentivizing small auditors providing lower audit quality to exit the market. Using client discretionary accruals and the likelihood of the clients restating financial statements as proxies for audit quality, we do not find that the small auditors that exited the market for SEC client audits were of lower quality than successor small audit firms that did not exit the market. JEL Classifications: G18; L51. Data Availability: Data are available from the public sources cited in the text.</jats:p

Establishing combination PAC-1 and TRAIL regimens for treating ovarian cancer based on patient-specific pharmacokinetic profiles using <i>in silico</i> clinical trials

AbstractOvarian cancer is commonly diagnosed in its late stages, and new treatment modalities are needed to improve patient outcomes and survival. We have recently established the synergistic effects of combination tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and procaspase activating compound (PAC-1) therapies in granulosa cell tumours (GCT) of the ovary, a rare form of ovarian cancer, using a mathematical model of the effects of both drugs in a GCT cell line. Here, to understand the mechanisms of combined TRAIL and PAC-1 therapy, study the viability of this treatment strategy, and accelerate preclinical translation, we leveraged our mathematical model in combination with population pharmacokinetics (PopPK) models of both TRAIL and PAC-1 to expand a realistic heterogeneous cohort of virtual patients and optimize treatment schedules. Using this approach, we investigated treatment responses in this virtual cohort and determined optimal therapeutic schedules based on patient-specific pharmacokinetic characteristics. Our results showed that schedules with high initial doses of PAC-1 were required for therapeutic efficacy. Further analysis of individualized regimens revealed two distinct groups of virtual patients within our cohort: one with high PAC-1 elimination, and one with normal PAC-1 elimination. In the high elimination group, high weekly doses of both PAC-1 and TRAIL were necessary for therapeutic efficacy, however virtual patients in this group were predicted to have a worse prognosis when compared to those in the normal elimination group. Thus, PAC-1 pharmacokinetic characteristics, particularly clearance, can be used to identify patients most likely to respond to combined PAC-1 and TRAIL therapy. This work underlines the importance of quantitative approaches in preclinical oncology.</jats:p

EPI-743 for Friedreichs Ataxia Patients with Point Mutations

Objective: To assess the effects of EPI-743 in patients with Friedreich’s Ataxia (FA) point mutations on neurologic function as measured by the Friedreich’s Ataxia Rating Scale (FARS). Background: FA is an autosomal recessive degenerative disorder characterized by ataxia, dysarthria, sensory loss, diabetes, and cardiomyopathy. FA patients with a point mutation (FA-PM) carry an expanded GAA repeat on one allele and a point mutation/deletion on the other allele; this is a rare variant. The natural history of FA includes progressively deteriorating neurologic function with FARS worsening 3.55 points in 12 months and 6.16 points in 24 months. EPI-743 is a therapeutic being developed for treatment of patients with mitochondrial diseases and disorders of oxidative stress. Methods: Three patients with genetically confirmed FA-PM (G130V) were administered EPI-743 400mg PO TID for 18 months in an open-label study. Assessments were completed quarterly. Relative mean changes in FARS total and subscale scores from baseline to 6 and 18 months of treatment were calculated as change([percnt]) = ((meanX - mean0) / mean0 × 100) where X represents the time point. Results: After 6 months of treatment, total FARS score improved an average of 9[percnt] (baseline mean total FARS=64, 6m mean total FARS=58). While all subscales improved, bulbar and upper limb coordination sub-scales were most improved (bulbar mean improvement of 80[percnt] [from 0.83 to 0.17] and upper limb coordination 53[percnt] [from 3.17 to 1.5]). Mean improvements persisted at 18 months from baseline (FARS total: 6[percnt], bulbar subscale: 20[percnt], upper limb coordination: 37[percnt]), although they attenuated. No serious adverse events, including hematologic or cardiac, were observed. Conclusions: EPI-743 was associated with clinically significant improvement in neurological function in patients with FA-PM over 18 months. These findings support further study of EPI-743 in patients with FA due to point mutations

Simulating the impact of climate change on the growth of Chinese fir plantations in Fujian province, China

Background: Climate change represents a considerable source of uncertainty with respect to the long-term health and productivity of Chinese fir (Cunninghamia lanceolata (Lamb.) Hook.) plantations in southeastern China. Methods: We employed the process-based, stand-level model FORECAST Climate to investigate the potential impact of four alternative climate-change scenarios on the long-term growth and development of Chinese fir plantations in Fujian province, China. The capability of the model to project seasonal patterns of productivity related to variation in temperature and moisture availability was evaluated using 11 years of 8-day composite MODIS remote sensing data. Results: Simulation results suggest climate change will lead to a modest increase in long-term stemwood biomass production (6.1 to 12.1% after 30 to 60 years). The positive impact of climate change was largely attributable to both a lengthening of the growing season and an increase in nutrient-cycling rates. The increase in atmospheric CO2 concentrations associated with the different emission scenarios led to an increase in water-use efficiency and a small increase in productivity. While the model predicted an overall increase in dry-season moisture stress, it did not predict increased levels of drought-related mortality. Conclusions: Climate change is expected have positive impact on the growth of Chinese fir in the Fujian region of China. However, the projected increase in plantation productivity associated with climate change may not be realised if the latter also results in enhanced activity of biotic and abiotic disturbance agents.Forestry, Faculty ofNon UBCReviewedFacult

Longitudinal Study of Gait Dysfunction in Friedreich\u27s Ataxia Using the GAITRite Walkway System

Objective: To quantify longitudinal changes in gait in Friedreich’s Ataxia (FA) patients compared to controls during a 24-month period using the GAITRite Walkway System. Background: FA is a devastating neurodegenerative disease. Measures to accurately quantify small changes in neurological function in FA patients are needed to facilitate therapeutic clinical trials. Design/Methods: This was a prospective, longitudinal study that assessed ambulatory FA patients compared to age- and gender-matched controls. FA patients were examined at baseline and at 6, 12, and 24 months, using the GAITRite Walkway system, a portable instrument used to assess gait parameters, and the Friedreich’s Ataxia Rating Scale (FARS). Controls were evaluated at baseline and 12 months. Changes in various gait parameters over time were estimated and compared using descriptive statistics and multilevel modeling. Results: Eight FA patients (aged 29.4 ± 9.0) and 8 controls (aged 29.6 ± 9.1) were included in this analysis. In FA patients, the mean FARS score increased 21.0[percnt] over two years (baseline: 40.6; 12 months: 45.4; 24 months: 49.1). Using longitudinal multilevel modeling, the FARS score was estimated to increase 0.13 points per month in FA patients, reflecting an increase in neurological dysfunction. Comfortable gait velocity declined 15[percnt] after 12 months and 30.5[percnt] after 24 months in the FA group, and showed high validity for measuring neurological dysfunction. Comfortable gait velocity correlated strongly with the FARS total score (r=-0.536;p Conclusions: Comfortable gait velocity as measured by the GAITRite system showed better sensitivity to changing gait that did the FARS, and had excellent reproducibility in controls whose gait was not expected to change. Comfortable gait velocity is easily performed, and may be an important and clinically relevant endpoint for future clinical trials

Correlation of GAITRite Walkway System and Biodex Balance System Measures to the FARS Score in Friedreich\u27s Ataxia Patients: A Validation Study

Objective: To test the validity of the GAITRite Walkway System and Biodex Balance System for measuring parameters of neurological dysfunction in Friedreich’s Ataxia (FA) patients against the standard of the Friedreich’s Ataxia Rating Scale (FARS). Background: FA is a neurodegenerative disease causing ataxia and cardiomyopathy. Precise measures are needed to test disease progression in FA in clinical trials. The GAITRite Walkway System and the Biodex Balance System are quantitative measures that evaluate gait and balance dysfunction using computerized technology. Design/Methods: In this prospective, longitudinal study, ambulatory FA patients were examined at baseline, and at 6, 12, and 24 months using the GAITRite and Biodex Systems and the FARS. Healthy, matched controls were tested at baseline and 12 months. All analyses were carried out using SAS 9.4. Results:Eight FA patients and 8 controls were included in this analysis. The following GAITRite parameters correlated significantly with the total FARS score in FA patients; comfortable walking velocity (r=-0.536; p Conclusions: In this study, multiple GAITRite and Biodex measures correlated significantly with the FARS scores, suggesting a high degree of clinical significance and providing evidence for validation of these measures in FA patients

EPI-743 (Alpha-Tocotrienol Quinone) Demonstrates Long-Term Improvement in Neurological Function and Disease Progression in Friedreich’s Ataxia

Objective: To evaluate the long-term safety and clinical effects of EPI-743 in Friedreich’s Ataxia (FRDA). Background: FRDA is an inherited ataxia caused by impairment of mitochondrial iron-sulfur-cluster protein assembly. EPI-743 is a compound that targets oxidoreductase enzymes essential for redox control of metabolism. Design/Methods: We conducted a multicenter trial that included a 6-month multiple dose placebo controlled phase, followed by an 18-month phase in which all subjects received treatment with EPI-743. The primary study objective was low contrast visual acuity as assessed by Early Treatment Diabetic Retinopathy Study (ETDRS). The key secondary study endpoint was neurological function as assessed by the Friedreich’s Ataxia Rating Scale (FARS)-NEURO. Results: A total of 63 subjects were enrolled in the trial; 61 completed the initial phase. EPI-743 was found to be safe and well tolerated, and demonstrated consistent pharmacology. During the placebo-controlled phase, there were no significant improvements in the primary or secondary endpoints using raw scores. However, significantly more patients taking low-dose EPI-743 had a 3-point or greater improvement (equivalent to one year of symptom progression in natural history cohorts) in the FARS NEURO than patients taking placebo (p = 0.047). Longitudinal modeling at 24 months revealed significantly improved disease progression in all drug groups when compared to natural history data. Using FA Clinical Outcome Measure data, the mean FARS increase (worsening) in untreated patients over 24 months is 4.8 points, compared to a mean decrease (improvement) in all patients taking EPI-743 of 1.8 points (2 tailed t-test with equal variance p = 0.00001). Conclusions: EPI-743 was safe and well tolerated, and although it did not reach the primary endpoint following six months, long-term treatment resulted in significantly improved neurological outcome after 24 months compared to natural history data