Soo-Jin Lee

Akt/GSK3β signaling is involved in fipronil-induced apoptotic cell death of human neuroblastoma SH-SY5Y cells.

Fipronil (FPN) is a phenylpyrazole insecticide acted on insect gamma-aminobutyric acid (GABA) receptors. Although action of FPN is restricted on insect neuronal or muscular transmitter system, a few studies have assessed the effects of this neurotoxicant on neuronal cell death. To determine the mechanisms underlying FPN-induced neuronal cell death, we investigated whether reactive oxygen species (ROS) plays a role in FPN-induced apoptosis, using an in vitro model of human dopaminergic SH-SY5Y cells. FPN was cytotoxic to these cells and its cytotoxicity showed a concentration-dependent manner. Additionally, FPN treatment significantly decreased the tyrosine hydroxylase (TH) expression without change of glutamic acid decarboxylase 65 (GAD65) expression. FPN-induced dopaminergic cell death involved in increase of ROS generation since pretreatment with N-acetyl cysteine (NAC), an anti-oxidant, reduced cell death. After FPN treatment, dopamine (DA) levels decreased significantly in both cell and culture media, and oxidative effects of DA were blocked by NAC pretreatment. We showed that cell death in response to FPN was due to apoptosis since FPN increased cytochrome c release into the cytosol and activated caspase-3. It also led to nuclear accumulation of p53 and reduced the level of Bcl-2 protein in a concentration-dependent manner. Additionally, FPN altered the level of Akt/glycogen synthase kinase-3 (GSK3β) phosphorylation. FPN reduced the Akt phosphorylation on Ser473, and in parallel with the inactivation of Akt, phosphorylation of GSK3β on Ser9 which inactivates GSK3β, decreased after treatment with FPN. Furthermore, inhibition of the GSK3β signal protected the cell against FPN-induced cell death. These results suggest that regulation of GSK3β activity may control the apoptosis induced by FPN-induced oxidative stress associated with neuronal cell death.

Handle grip span for optimising finger-specific force capability as a function of hand size

Five grip spans (45 to 65 mm) were tested to evaluate the effects of handle grip span and users hand size on maximum grip strength, individual finger force and subjective ratings of comfort using a computerised digital dynamometer with independent finger force sensors. Forty-six males participated and were assigned into three hand size groups (small, medium, large) according to their hands length. In general, results showed the 55- and 50-mm grip spans were rated as the most comfortable sizes and showed the largest grip strength (433.6 N and 430.8 N, respectively), whereas the 65-mm grip span handle was rated as the least comfortable size and the least grip strength. With regard to the interaction effect of grip span and hand size, small and medium-hand participants rated the best preference for the 50- to 55-mm grip spans and the least for the 65-mm grip span, whereas large-hand participants rated the 55- to 60-mm grip spans as the most preferred and the 45-mm grip span as the least preferred. Normalised grip span (NGS) ratios (29% and 27%) are the ratios of users hand length to handle grip span. The NGS ratios were obtained and applied for suggesting handle grip spans in order to maximise subjective comfort as well as gripping force according to the users hand sizes. In the analysis of individual finger force, the middle finger force showed the highest contribution (37.5%) to the total finger force, followed by the ring (28.7%), index (20.2%) and little (13.6%) finger. In addition, each finger was observed to have a different optimal grip span for exerting the maximum force, resulting in a bow-contoured shaped handle (the grip span of the handle at the centre is larger than the handle at the end) for two-handle hand tools. Thus, the grip spans for two-handle hand tools may be designed according to the users hand/finger anthropometrics to maximise subjective ratings and performance based on this study. Results obtained in this study will provide guidelines for hand tool designers and manufacturers for designing grip spans of two-handle tools, which can maximise handle comfort and performance.

Evaluation of handle design characteristics in a maximum screwdriving torque task

The purpose of this study was to evaluate the effects of screwdriver handle shape, surface material and workpiece orientation on torque performance, finger force distribution and muscle activity in a maximum screwdriving torque task. Twelve male subjects performed maximum screw-tightening exertions using screwdriver handles with three longitudinal shapes (circular, hexagonal and triangular), four lateral shapes (cylindrical, double frustum, cone and reversed double frustum) and two surfaces (rubber and plastic). The average finger force contributions to the total hand force were 28.1%, 39.3%, 26.5% and 6.2%, in order from index to little fingers; the average phalangeal segment force contributions were 47.3%, 14.0%, 20.5% and 18.1% for distal, middle, proximal and metacarpal phalanges, respectively. The plastic surface handles were associated with 15% less torque output (4.86 Nm) than the rubber coated handles (5.73 Nm). In general, the vertical workpiece orientation was associated with higher torque output (5.9 Nm) than the horizontal orientation (4.69 Nm). Analysis of handle shapes indicates that screwdrivers designed with a circular or hexagonal cross-sectional shape result in greater torque outputs (5.49 Nm, 5.57 Nm), with less total finger force (95 N, 105 N). In terms of lateral shape, reversed double frustum handles were associated with less torque output (5.23 Nm) than the double frustum (5.44 Nm) and cone (5.37 Nm) handles. Screwdriver handles designed with combinations of circular or hexagonal cross-sectional shapes with double frustum and cone lateral shapes were optimal in this study.

Work-related injuries and fatalities among farmers in South Korea†

BACKGROUNDnAgricultural injuries are increasing in South Korea according to its workforces reduced size and increased age. Available data are insufficient to exactly understand present situation. This study evaluated the patterns and characteristics of agricultural injury and assessed the injury rates.nnnMETHODSnWe analyzed the entry and compensation data compiled in 2005 by the Safety Aid System of Farm Workers, South Koreas government insurance for agricultural injury. We examined the general characteristics, rates, and mortality of agricultural injury.nnnRESULTSnThere were 11,931 compensated events, including 219 compensated deaths. Farm injuries occurred most frequently in October, and most injuries were unintentional. The incidence and fatality rates were 16.67 per 1,000 person-years and 30.59 per 100,000 person-years, respectively. Most number of agricultural injuries occurred in October. The most common cause of deaths was accidents caused by machinery use (35.64%) for males and other transport accidents (23.53%) for females, while the most common cause of injuries for females was falls (45.39%). Incidence and mortality rate of agricultural injuries were higher in elders.nnnCONCLUSIONSnAlthough injury rates may have been underestimated owing to data limitations, we are confident that South Koreas rate is higher than those seen in other countries or occupations.

Potential autophagy enhancers protect against fipronil-induced apoptosis in SH-SY5Y cells

Oxidative stress created by environmental toxicants activates several signaling pathways. Autophagy is one of the first lines of defense against oxidative stress damage. The autophagy pathway can be induced and up-regulated in response to intracellular reactive oxygen species (ROS). Recently, we reported that fipronil (FPN)-induced mitochondria-dependent apoptosis is mediated through ROS in human neuroblastoma SH-SY5Y cells. In this study, we explored the role of autophagy to prevent FPN neurotoxicity. We investigated the modulation of FPN-induced apoptosis according to autophagy regulation. FPN activated caspase-9 and caspase-3, and induced nuclear fragmentation and condensation, all of which indicate that FPN-induced cell death was due to apoptosis. In addition, we observed FPN-induced autophagic cell death by monitoring the expression of LC3-II and Beclin-1. Exposure to FPN in SH-SY5Y cells led to the production of ROS. Treatment with N-acetyl-cysteine (NAC) effectively blocked both apoptosis and autophagy. Interestingly, pretreatment with rapamycin, an autophagy inducer, significantly enhanced the viability of FPN-exposed cells; the enhancement of cell viability was partially due to alleviation of FPN-induced apoptosis via a decrease in levels of cleaved caspase-3. However, pretreatment with 3-methyladenine (3MA) a specific inhibitor for autophagy, remarkably strengthened FPN toxicity and further induced activation of caspase-3 in these cells. Our studies suggest that FPN-induced cytotoxicity is modified by autophagy regulation and that rapamycin is neuroprotective against FPN-induced apoptosis through enhancing autophagy.

Determination of plasma topiramate concentration using LC‐MS/MS for pharmacokinetic and bioequivalence studies in healthy Korean volunteers

A rapid, simple and validated liquid chromatography coupled to tandem mass spectrometric method (LC-MS/MS) for topiramate analysis in human plasma has been applied to pharmacokinetic and bioequivalence studies in 24 healthy male Korean volunteers. The procedure involves a simple liquid extraction of topiramate and prednisone (internal standard) with acetonitrile and separation by HPLC equipped with a Capcell Pak C18 column using acetonitrile-0.1% triethylamine (80:20, v/v) as a mobile phase. Detection was carried out on an API 2000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI(-) and selectivity was achieved by MS/MS analysis, m/z 338.0 --> 77.5 and m/z 357.1 --> 327.2 for topiramate and prednisone, respectively. The method had a total run time of 2.5 min and showed good linearity over a working range of 20-5000 ng/mL in human plasma with a lower limit of quantification of 20 ng/mL. No metabolic compounds were found to interfere with the analysis. The inter-day and intra-day accuracy were in the ranges of 99.24-116.63 and 93.45-108.68%, respectively, and inter-day and intra-day precisions were below 6.24 and 5.25%, respectively. This method was successfully applied for pharmacokinetic and bioequivalence studies by analysis of blood samples taken up to 96 h after an oral administration of 100 mg of topiramate in 24 healthy Korean volunteers.

Fluazinam-induced apoptosis of SH-SY5Y cells is mediated by p53 and Bcl-2 family proteins

A number of epidemiological studies have demonstrated a strong association between the incidence of neurodegenerative disease and pesticide exposure. Fluazinam (FZN) is a preventative fungicide from the pyridinamine group that was introduced in the 1990 s and that quickly established itself as a new standard for the control of blight caused by Phytophthora infestans in potatoes. We used human neuroblastoma SH-SY5Y cells to investigate mechanisms of neuronal cell death in response to FZN and showed that FZN was cytotoxic to SH-SY5Y cells in a concentration- and time-dependent manner. Additionally, we showed that FZN treatment significantly decreased the neuron numbers including dopaminergic neurons and mitochondrial complex I activity. The cytotoxic effects of FZN were associated with an increase in reactive oxygen species (ROS) generation because pretreatment with N-acetyl cysteine, an anti-oxidant, reduced cell death. We showed that neuronal cell death in response to FZN was due to apoptosis because FZN increased cytochrome C release into the cytosol and activated caspase-3 through the accumulation of p53. FZN also reduced the levels of Bcl-2 protein but increased the levels of Bax. Our results provide insight into the molecular mechanisms of FZN-induced apoptosis in neuronal cells.

The involvement of nitric oxide on the adenosine A2 receptor-induced cardiovascular inhibitory responses in the posterior hypothalamus of rats

This study was performed to investigate the putative relationship between nitric oxide (NO) and adenosine A(2) receptors on central cardiovascular regulation in the posterior hypothalamus of rats. Posterior hypothalamic injection of drugs was performed in anesthetized, artificially ventilated male Sprague-Dawley rats. Injection of adenosine A(2) receptor agonist 5-(N-cyclopropyl)-carboxamidoadenosine (CPCA; 1, 2 and 5 nmol) produced a dose-dependent decrease of blood pressure and heart rate. Pretreatment with adenosine A(2) receptor antagonist 3,7-dimethyl-1-propargylxanthine (10 nmol) blocked the depressor and bradycardiac effects of CPCA (5 nmol). Pretreatment with soluble guanylate cyclase inhibitor LY-83,583 (5 nmol) attenuated the depressor and bradycardiac effects of CPCA (5 nmol). In addition, pretreatment with NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (40 nmol) attenuated the depressor and bradycardiac responses of CPCA (5 nmol). These results suggest that adenosine A(2) receptor in the posterior hypothalamus plays an inhibitory role in central cardiovascular regulation and that NO participates in the inhibitory response induced by adenosine A(2) receptor stimulation in the posterior hypothalamus.

Evaluation of Various Handle Grip Spans for Optimizing Finger Specific Force Based on the Users' Hand Sizes

This study evaluated the effects of handle grip span and users hand size on maximum grip strength and individual finger force using a computerized digital dynamometer with five various grip spans (45, 50, 55, 60, and 65mm). Forty-six males participated and were assigned into three hand size groups (small, middle, large) according to their hand lengths. Results showed that generally 55 and 50mm grip spans had the highest grip strength (433.6N and 430.8N, respectively), whereas 65mm grip span had the least grip strength. With respect to the interaction effect of grip span and hand size, small hand sized participants produced the highest grip forces at the 45mm grip span, followed by 50 and 55mm, middle hand size participants provided the highest grip force at the 55mm followed by 50 and 45mm, whereas large hand size participants exerted the highest grip force at the 55mm followed by 60mm. In the analysis of individual finger force, the middle finger force was the strongest and the highest contribution (37.5%) to the total finger force, followed by ring (28.7%), index (20.2%) and little (13.6%) fingers. In addition, it was noted that each finger had a different optimal grip span for exerting maximum force, resulting in a bowed contoured shaped handle (i.e., the grip span of the handle at the center is larger than that of the handle at the end) for two-handle hand tools.

Development of Nephrolithiasis in Asymptomatic Hyperuricemia: A Cohort Study

BACKGROUNDnAlthough the association between gout and nephrolithiasis is well known, the relationship between asymptomatic hyperuricemia and the development of nephrolithiasis is largely unknown.nnnSTUDY DESIGNnCohort study.nnnSETTING & PARTICIPANTSn239,331 Korean adults who underwent a health checkup examination during January 2002 to December 2014 and were followed up annually or biennially through Decemberxa02014.nnnPREDICTORnBaseline serum uric acid levels of participants.nnnOUTCOMEnThe development of nephrolithiasis during follow-up.nnnMEASUREMENTSnNephrolithiasis is determined based on ultrasonographic findings. A parametric Cox model was used to estimate the adjusted HRs of nephrolithiasis according to serum uric acid level.nnnRESULTSnDuring 1,184,653.8 person-years of follow-up, 18,777 participants developed nephrolithiasis (incidence rate, 1.6/100 person-years). Elevated uric acid level was significantly associated with increased risk for nephrolithiasis in a dose-response manner (P for trendxa0< 0.001) in men. This dose-response association was not observed in women. In male participants, multivariable-adjusted HRs for incident nephrolithiasis comparing uric acid levels of 6.0 to 6.9, 7.0 to 7.9, 8.0 to 8.9, 9.0 to 9.9, andxa0≥10.0mg/dL with uric acid levelsxa0< 6.0mg/dL were 1.06 (95% CI, 1.02-1.11), 1.11 (95% CI, 1.05-1.16), 1.21 (95% CI, 1.13-1.29), 1.31 (95% CI, 1.17-1.46), and 1.72 (95% CI, 1.44-2.06), respectively. This association was observed in all clinically relevant subgroups and persisted even after adjustment for homeostasis model assessment of insulin resistance and high-sensitivity C-reactive protein level.nnnLIMITATIONSnDietary information and computed tomographic diagnosis of nephrolithiasis were unavailable.nnnCONCLUSIONSnIn this large cohort study, increased serum uric acid level was modestly and independently associated with increased risk for the development of nephrolithiasis in a dose-response manner in apparently healthy men.