Methylglyoxal induces cell death through endoplasmic reticulum stress‐associated ROS production and mitochondrial dysfunction

Diabetic retinopathy (DR) and age‐related macular degeneration (AMD) are two important leading causes of acquired blindness in developed countries. As accumulation of advanced glycation end products (AGEs) in retinal pigment epithelial (RPE) cells plays an important role in both DR and AMD, and the methylglyoxal (MGO) within the AGEs exerts irreversible effects on protein structure and function, it is crucial to understand the underlying mechanism of MGO‐induced RPE cell death. Using ARPE‐19 as the cell model, this study revealed that MGO induces RPE cell death through a caspase‐independent manner, which relying on reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) loss, intracellular calcium elevation and endoplasmic reticulum (ER) stress response. Suppression of ROS generation can reverse the MGO‐induced ROS production, MMP loss, intracellular calcium increase and cell death. Moreover, store‐operated calcium channel inhibitors MRS1845 and YM‐58483, but not the inositol 1,4,5‐trisphosphate (IP3) receptor inhibitor xestospongin C, can block MGO‐induced ROS production, MMP loss and sustained intracellular calcium increase in ARPE‐19 cells. Lastly, inhibition of ER stress by salubrinal and 4‐PBA can reduce the MGO‐induced intracellular events and cell death. Therefore, our data indicate that MGO can decrease RPE cell viability, resulting from the ER stress‐dependent intracellular ROS production, MMP loss and increased intracellular calcium increase. As MGO is one of the components of drusen in AMD and is the AGEs adduct in DR, this study could provide a valuable insight into the molecular pathogenesis and therapeutic intervention of AMD and DR.     

Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium

By means of a combination of genome-wide and follow-up studies, recent large-scale association studies of populations of European descent have now identified over 46 loci associated with coronary artery disease (CAD). As part of the TAICHI Consortium, we have collected and genotyped 8556 subjects from Taiwan, comprising 5423 controls and 3133 cases with coronary artery disease, for 9087 CAD SNPs using the CardioMetaboChip. We applied penalized logistic regression to ascertain the top SNPs that contribute together to CAD susceptibility in Taiwan. We observed that the 9p21 locus contributes to CAD at the level of genome-wide significance (rs1537372, with the presence of C, the major allele, the effect estimate is -0.216, standard error 0.033, p value 5.8x10^-10). In contrast to a previous report, we propose that the 9p21 locus is a single genetic contribution to CAD in Taiwan because: 1) the penalized logistic regression and the follow-up conditional analysis suggested that rs1537372 accounts for all of the CAD association in 9p21, and 2) the high linkage disequilibrium observed for all associated SNPs in 9p21. We also observed evidence for the following loci at a false discovery rate >5%: SH2B3, ADAMTS7, PHACTR1, GGCX, HTRA1, COL4A1, and LARP6-LRRC49. We also took advantage of the fact that penalized methods are an efficient approach to search for gene-by-gene interactions, and observed that two-way interactions between the PHACTR1 and ADAMTS7 loci and between the SH2B3 and COL4A1 loci contribute to CAD risk. Both the similarities and differences between the significance of these loci when compared with significance of loci in studies of populations of European descent underscore the fact that further genetic association of studies in additional populations will provide clues to identify the genetic architecture of CAD across all populations worldwide.     

Association of Urinary Cadmium with Mortality in Patients at a Coronary Care Unit

Background

Determine the effect of the day 1 urinary excretion of cadmium (D1-UE-Cd) on mortality of patients admitted to a coronary care unit (CCU).

Methods

A total of 323 patients were enrolled in this 6-month study. Urine and blood samples were taken within 24 h after CCU admission. Demographic data, clinical diagnoses, and hospital mortality were recorded. The scores of established systems for prediction of mortality in critically ill patients were calculated.

Results

Compared with survivors (n = 289), non-survivors (n = 34) had higher levels of D1-UE-Cd. Stepwise multiple linear regression analysis indicated that D1-UE-Cd was positively associated with pulse rate and level of aspartate aminotransferase, but negatively associated with serum albumin level. Multivariate Cox analysis, with adjustment for other significant variables and measurements from mortality scoring systems, indicated that respiratory rate and D1-UE-Cd were independent and significant predictors of mortality. For each 1 μg/day increase of D1-UE-Cd, the hazard ratio for CCU mortality was 3.160 (95% confidence interval: 1.944–5.136, p < 0.001). The chi-square value of Hosmer-Lemeshow goodness-of-fit test for D1-UE-Cd was 10.869 (p = 0.213). The area under the receiver operating characteristic curve for D1-UE-Cd was 0.87 (95% confidence interval: 0.81–0.93).

Conclusions

The D1-UE-Cd, an objective variable with no inter-observer variability, accurately predicted hospital mortality of CCU patients and outperformed other established scoring systems. Further studies are needed to determine the physiological mechanism of the effect of cadmium on mortality in CCU patients.     

Investigation of the Differential Contributions of Superficial and Deep Muscles on Cervical Spinal Loads with Changing Head Postures

Cervical spinal loads are predominately influenced by activities of cervical muscles. However, the coordination between deep and superficial muscles and their influence on the spinal loads is not well understood. This study aims to document the changes of cervical spinal loads and the differential contributions of superficial and deep muscles with varying head postures. Electromyography (EMG) of cervical muscles from seventeen healthy adults were measured during maximal isometric exertions for lateral flexion (at 10°, 20° and terminal position) as well as flexion/extension (at 10°, 20°, 30°, and terminal position) neck postures. An EMG-assisted optimization approach was used to estimate the muscle forces and subsequent spinal loads. The results showed that compressive and anterior-posterior shear loads increased significantly with neck flexion. In particular, deep muscle forces increased significantly with increasing flexion. It was also determined that in all different static head postures, the deep muscle forces were greater than those of the superficial muscle forces, however, such pattern was reversed during peak efforts where greater superficial muscle forces were identified with increasing angle of inclination. In summary, the identification of significantly increased spinal loads associated with increased deep muscle activation during flexion postures, implies higher risks in predisposing the neck to occupationally related disorders. The results also explicitly supported that deep muscles play a greater role in maintaining stable head postures where superficial muscles are responsible for peak exertions and reinforcing the spinal stability at terminal head postures. This study provided quantitative data of normal cervical spinal loads and revealed motor control strategies in coordinating the superficial and deep muscles during physical tasks.     

Cortical Bone Morphological and Trabecular Bone Microarchitectural Changes in the Mandible and Femoral Neck of Ovariectomized Rats

ObjectiveThis study used microcomputed tomography (micro-CT) to evaluate the effects of ovariectomy on the trabecular bone microarchitecture and cortical bone morphology in the femoral neck and mandible of female rats.ResultsRegarding the trabecular bone microarchitectural parameters, the BV/TV of the trabecular bone microarchitecture in the femoral necks of the control group (61.199±11.288%, median ± interquartile range) was significantly greater than that of the ovariectomized group (40.329±5.153%). Similarly, the BV/TV of the trabecular bone microarchitecture in the mandibles of the control group (51.704±6.253%) was significantly greater than that of the ovariectomized group (38.486±9.111%). Furthermore, the TbSp of the femoral necks in the ovariectomized group (0.185±0.066 mm) was significantly greater than that in the control group (0.130±0.026mm). Similarly, the TbSp of the mandibles in the ovariectomized group (0.322±0.047mm) was significantly greater than that in the control group (0.285±0.041mm). However, the TbTh and TbN trends for the mandibles and femoral necks were inconsistent between the control and ovariectomized groups. Regarding the cortical bone morphology parameters, the TtAr of the femoral necks in the ovariectomized group was significantly smaller than that in the control group. There was no significant difference in the TtAr, CtAr, or CtTh of the femoral necks between the control and ovariectomized groups, and no significant difference in the CtTh of the mandibles between the control and ovariectomized groups. Moreover, the BV/TV and TbSp of the mandibles were highly correlated with those of the femurs (r_s = 0.874 and r_s = 0.755 for BV/TV and TbSp, respectively). Nevertheless, the TbTh, TbN, and CtTh of the mandibles were not correlated with those of the femoral necks.ConclusionAfter the rats were ovariectomized, osteoporosis of the trabecular bone microarchitecture occurred in their femurs and mandibles; however, ovariectomy did not influence the cortical bone morphology. In addition, the parametric values of the trabecular bone microarchitecture in the femoral necks were highly correlated with those of the trabecular bone microarchitecture in the mandibles.     

Assessment of Median Nerve Mobility by Ultrasound Dynamic Imaging for Diagnosing Carpal Tunnel Syndrome

Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy and is characterized by median nerve entrapment at the wrist and the resulting median nerve dysfunction. CTS is diagnosed clinically as the gold standard and confirmed with nerve conduction studies (NCS). Complementing NCS, ultrasound imaging could provide additional anatomical information on pathological and motion changes of the median nerve. The purpose of this study was to estimate the transverse sliding patterns of the median nerve during finger movements by analyzing ultrasound dynamic images to distinguish between normal subjects and CTS patients. Transverse ultrasound images were acquired, and a speckle-tracking algorithm was used to determine the lateral displacements of the median nerve in radial-ulnar plane in B-mode images utilizing the multilevel block-sum pyramid algorithm and averaging. All of the averaged lateral displacements at separate acquisition times within a single flexion–extension cycle were accumulated to obtain the cumulative lateral displacements, which were curve-fitted with a second-order polynomial function. The fitted curve was regarded as the transverse sliding pattern of the median nerve. The R² value, curvature, and amplitude of the fitted curves were computed to evaluate the goodness, variation and maximum value of the fit, respectively. Box plots, the receiver operating characteristic (ROC) curve, and a fuzzy c-means clustering algorithm were utilized for statistical analysis. The transverse sliding of the median nerve during finger movements was greater and had a steeper fitted curve in the normal subjects than in the patients with mild or severe CTS. The temporal changes in transverse sliding of the median nerve within the carpal tunnel were found to be correlated with the presence of CTS and its severity. The representative transverse sliding patterns of the median nerve during finger movements were demonstrated to be useful for quantitatively estimating median nerve dysfunction in CTS patients.     

Differentiation of Malignant and Benign Incidental Breast Lesions Detected by Chest Multidetector-Row Computed Tomography: Added Value of Quantitative Enhancement Analysis

To retrospectively determine the association between breast lesion morphology and malignancy and to determine the optimal value of lesion enhancement (HU, Hounsfield units) to improve the diagnostic accuracy of breast cancer in patients with incidental breast lesions (IBLs). A total of 97 patients with 102 IBLs detected from July 2009 to December 2012 were enrolled in this study. Two radiologists analyzed CT images for the presence of malignancy based on the morphology of the lesions alone and in combination with an enhancement value (HU) analysis. There were 36 malignant and 66 benign IBLs. When the morphology and enhancement values were combined, the sensitivity, specificity, and accuracy were 92%, 97%, and 95%, respectively, for reader 1 and 89%, 94%, and 92%, respectively, for reader 2. The addition of HU values led to correct changes in the diagnosis; specifically, the accuracy of the diagnosis of reader 1 and reader 2 improved by 6.9% and 11.8%, respectively. The addition of the enhancement value (HU) to the CT morphology improved the diagnostic accuracy in the differentiation of malignant from benign IBLs by using the region of interest (ROI) to measure the HU within the most suspicious part of the lesion.