Gender disparities in the association between epicardial adipose tissue volume and coronary atherosclerosis: A 3-dimensional cardiac computed tomography imaging study in Japanese subjects

ABSTRACT: BACKGROUND: Growing evidence suggests that epicardial adipose tissue (EAT) may contribute to the development of coronary artery disease (CAD). In this study, we explored gender disparities in EAT volume (EATV) and its impact on coronary atherosclerosis. METHODS: The study population consisted of 90 consecutive subjects (age: 63 +/- 12 years; men: 47, women: 43) who underwent 256-slice multi-detector computed tomography (MDCT) coronary angiography. EATV was measured as the sum of cross-sectional epicardial fat area on CT images, from the lower surface of the left pulmonary artery origin to the apex. Subjects were segregated into the CAD group (coronary luminal narrowing > 50%) and non-CAD group. RESULTS: EATV/body surface area (BSA) was higher among men in the CAD group than in the non-CAD group (62 +/- 13 vs. 33 +/- 10 cm3/m2, p < 0.0001), but did not differ significantly among women in the 2 groups (49 +/- 18 vs. 42 +/- 9 cm3/m2, not significant). Multivariate logistic analysis showed that EATV/BSA was the single predictor for >50% coronary luminal narrowing in men (p < 0.0001). Predictors excluded were age, body mass index, hypertension, diabetes mellitus, and hyperlipidemia. CONCLUSIONS: Increased EATV is strongly associated with coronary atherosclerosis in men.     

Mechanism of A23187-induced apoptosis in HL-60 cells: dependency on mitochondrial permeability transition but not on NADPH oxidase

Calcium ions (Ca(2+)) are involved in a number of physiological cellular functions including apoptosis. An elevation in intracellular levels of Ca(2+) in A23187-treated HL-60 cells was associated with the generation of both intracellular and extracellular reactive oxygen species (ROS) and induction of apoptotic cell death. A23187-induced apoptosis was prevented by cyclosporin A, a potent inhibitor of mitochondrial permeability transition (MPT). The generation of extracellular ROS was suppressed by the NADPH oxidase inhibitor diphenylene iodonium, and by superoxide dismutase, but these agents had no effect on A23187-induced apoptosis. In contrast, the blocking of intracellular ROS by a cell-permeant antioxidant diminished completely the induction of MPT and apoptosis. In isolated mitochondria, the addition of Ca(2+) induced a typical MPT concomitant with the generation of ROS, which leads to augmentation of intracellular ROS levels. These results indicate that intracellular not extracellular ROS generated by A23187 is associated with the opening of MPT pores that leads to apoptotic cell death.     

Knock down of gamma-glutamylcysteine synthetase in rat causes acetaminophen-induced hepatotoxicity

Drug-induced hepatotoxicity is mainly caused by hepatic glutathione (GSH) depletion. In general, the activity of rodent glutathione S-transferase is 10 to 20 times higher than that of humans, which could make the prediction of drug-induced hepatotoxicity in human more difficult. Gamma-glutamylcysteine synthetase (gamma-GCS) mainly regulates de novo synthesis of GSH in mammalian cells and plays a central role in the antioxidant capacity of cells. In this study, we constructed a GSH-depletion experimental rat model for the prediction of human hepatotoxicity. An adenovirus vector with short hairpin RNA against rat gamma-GCS heavy chain subunit (GCSh) (AdGCSh-shRNA) was constructed and used to knock down the GCSh. In in vitro study in H4IIE cells, a rat hepatoma cell line, GCSh mRNA and protein were significantly decreased by 80% and GSH was significantly decreased by 50% 3 days after AdGCSh-shRNA infection. In the in vivo study in rat, the hepatic GSH level was decreased by 80% 14 days after a single dose of AdGCSh-shRNA (2 x 10(11) pfu/ml/body), and this depletion continued for at least 2 weeks. Using this GSH knockdown rat model, acetaminophen-induced hepatotoxicity was shown to be significantly potentiated compared with normal rats. This is the first report of a GSH knockdown rat model, which could be useful for highly sensitive tests of acute and subacute toxicity for drug candidates in preclinical drug development.     

Molecular properties of the glucosaminidase AcmA from Lactococcus lactis MG1363: Mutational and biochemical analyses

The major autolysin AcmA of Lactococcus lactis ssp. cremoris MG1363 is a modular protein consisting of an N-terminal signal sequence, a central enzymatic region (glu_acma as a glucosaminidase), and a C-terminal cell-recognition domain (LysM123). glu_acma (about 160 amino acids) belongs to the glycoside hydrolase (GH) 73 family, and the two acidic residues E128 and D153 have been thought to be catalytically important. In this study, amino-acid substitution analysis of AcmA was first carried out in the Escherichia coli system. Point mutations E94A, E94Q, E128A, D153A, and Y191A markedly reduced cell-lytic activity (3.8%, 1.1%, 4.2%, 4.8%, and 2.4%, respectively), whereas E128Q and D153N retained significant residual activities (32.1% and 44.0%, respectively). On the other hand, Y191F and Y191W mutations retained high activities (66.2% and 46.0%, respectively). These results showed that E94 (rather than E128 and D153) and the aromatic residue Y191 probably play important roles in catalysis of AcmA. Together with mutational analysis of another GH73 glucoaminidase Glu_atlwm from the Staphylococcus warneri M autolysin Atl_WM, these results suggested that the GH73 members cleave a glycosidic bond via a substrate-assisted mechanism, as postulated in the GH20 members. AcmA and Glu_atlwm were purified from E. coli recombinant cells, and their enzymatic properties were studied.     

Estimation of handgrip force using frequency-band technique during fatiguing muscle contraction

In this paper, we propose a force estimation model to compute the handgrip force from SEMG signal during fatiguing muscle contraction tasks. The appropriate frequency range was analyzed using various combinations of a wavelet scale, and the highest accuracy was achieved at a range from 242 to 365 Hz. After that, eight healthy individuals performed a series of static (70%, 50%, 30%, and 20% MVC) and dynamic (0–50% MVC) muscle contraction tasks to evaluate the performance of this technique in comparison with that of former method using the Root Mean Square of the SEMG signal. Both methods had comparable results at the beginning of the experiments, before the onset of muscle fatigue. However, differences were clearly observed as the degree of muscle fatigue began to increase toward the endurance time. Under this condition, the estimated handgrip force using the proposed method improved from 17% to 134% for static contraction tasks and 40% for dynamic contraction tasks. This study overcomes the limitation of the former method during fatiguing muscle contraction tasks and, therefore, unlocks the potential of utilizing the SEMG signal as an indirect force estimation method for various applications.     

Lacrimal Hypofunction as a New Mechanism of Dry Eye in Visual Display Terminal Users

Background

Dry eye has shown a marked increase due to visual display terminal (VDT) use. It remains unclear whether reduced blinking while focusing can have a direct deleterious impact on the lacrimal gland function. To address this issue that potentially affects the life quality, we conducted a large-scale epidemiological study of VDT users and an animal study.

Methodology/Principal Findings

Cross sectional survey carried out in Japan. A total of 1025 office workers who use VDT were enrolled. The association between VDT work duration and changes in tear film status, precorneal tear stability, lipid layer status and tear secretion were analyzed. For the animal model study, the rat VDT user model, placing rats onto a balance swing in combination with exposure to an evaporative environment was used to analyze lacrimal gland function. There was no positive relationship between VDT working duration and change in tear film stability and lipid layer status. The odds ratio for decrease in Schirmer score, index of tear secretion, were significantly increased with VDT working year (P = 0.012) and time (P = 0.005). The rat VDT user model, showed chronic reduction of tear secretion and was accompanied by an impairment of the lacrimal gland function and morphology. This dysfunction was recovered when rats were moved to resting conditions without the swing.

Conclusions/Significance

These data suggest that lacrimal gland hypofunction is associated with VDT use and may be a critical mechanism for VDT-associated dry eye. We believe this to be the first mechanistic link to the pathogenesis of dry eye in office workers.     

Joint gap kinematics in posterior-stabilized total knee arthroplasty measured by a new tensor with the navigation system

BACKGROUND: The management of soft tissue balance during surgery is essential for the success of total knee arthroplasty (TKA) but remains difficult, leaving it much to the surgeon's feel. Previous assessments for soft tissue balance have been performed under unphysiological joint conditions, with patellar eversion and without the prosthesis only at extension and 90 deg of flexion. We therefore developed a new tensor for TKA procedures, enabling soft tissue balance assessment throughout the range of motion while reproducing postoperative joint alignment with the patellofemoral (PF) joint reduced and the tibiofemoral joint aligned. Our purpose in the present study was to clarify joint gap kinematics using the tensor with the CT-free computer assisted navigation system. METHOD OF APPROACH: Joint gap kinematics, defined as joint gap change during knee motion, was evaluated during 30 consecutive, primary posterior-stabilized (PS) TKA with the navigation system in 30 osteoarthritic patients. Measurements were performed using a newly developed tensor, which enabled the measurement of the joint gap throughout the range of motion, including the joint conditions relevant after TKA with PF joint reduced and trial femoral component in place. Joint gap was assessed by the tensor at full extension, 5 deg, 10 deg, 15 deg, 30 deg, 45 deg, 60 deg, 90 deg, and 135 deg of flexion with the patella both everted and reduced. The navigation system was used to obtain the accuracy of implantations and to measure an accurate flexion angle of the knee during the intraoperative joint gap measurement. RESULTS: Results showed that the joint gap varied depending on the knee flexion angle. Joint gap showed an accelerated decrease during full knee extension. With the PF joint everted, the joint gap increased throughout knee flexion. In contrast, the joint gap with the PF joint reduced increased with knee flexion but decreased after 60 deg of flexion. CONCLUSIONS: We clarified the characteristics of joint gap kinematics in PS TKA under physiological and reproducible joint conditions. Our findings can provide useful information for prosthetic design and selection and allow evaluation of surgical technique throughout the range of knee motion that may lead to consistent clinical outcomes after TKA.