Hye Young Lee

Enhanced TGF-β1 is involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced oxidative stress in C57BL/6 mouse testis

2,3,7,8-Tedtrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic endocrine disruptors and has been reported to induce oxidative stress in the reproductive organs. However, the mechanism by which TCDD induces oxidative stress is unclear. The aim of this study is to examine the role of the general cytokine, TGF-beta1, in TCDD-induced oxidative stress in the male reproductive system. To examine the effect of TCDD on antioxidant enzyme activity, we administered TCDD orally to C57BL/6 mice at 1 microgkg/day for 4 days. Using Smad2-siRNA, we examined the involvement of Smad and non-Smad pathways in TCDD-induced oxidative stress. We also measured the mRNA levels of typical antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and analyzed the activation of TGF-beta1, and the downstream signals, Smad2, Smad4, transcription factors (c-Jun, ATF3), and three major MAPKs (JNK, ERK, p38). After TCDD treatment, the mRNA levels of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were significantly decreased. In addition, TGF-beta1 activity increased and the receptor-activated protein, Smad2, was activated while Smad4 was not. The levels of major transcription factors, c-Jun and ATF3, and the regulator of these transcription factors, MAPK, were also increased by TCDD administration. The mRNA levels of the 3 antioxidant enzymes in the Smad2-siRNA and TCDD co-treated group were higher than that of the TCDD-only treated group but still decreased when compared to control. C-Jun and ATF3 levels were also increased in Smad2-siRNA and TCDD co-treated testes compared to control. However, the levels of c-Jun and ATF3 were lower than those in the group treated with TCDD only. Of the three MAPKs which showed increase in expression after TCDD treatment, p38 was the only one that showed a decrease with Smad2 inhibition, while both ERK and JNK expression were unaffected. In conclusion, we found that the activated TGF-beta1-Smad pathway is involved in TCDD-induced oxidative stress. Furthermore, the effects of TCDD on the testes are caused by the coordinated action of both Smad and non-Smad pathways.

Toxic effects of lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on development of male reproductive system: involvement of antioxidants, oxidants, and p53 protein.

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD) is a potent endocrine disruptor compound and induces multiple organ dysfunctions. The effect of TCDD exposure both in adults and in utero has been well established. However, little is known about the effects of TCDD acquired through mothers milk on the development of the male reproductive system. The aim of this study was to investigate the effects and mechanisms of TCDD from lactational exposure. TCDD (1 μg/kg) was administered to C57BL/6 mouse mothers for 4 days from the day of delivery. On postnatal day 30 (PND 30) and postnatal day 60 (PND 60), body weight, body length, and anogenital distance (AGD) of male offspring were measured. The weights of the testes and epididymides were also measured. Epididymides were used for sperm counts, and testes were used to measure the activity of antioxidant enzymes (SOD, CAT, GPX, GR), the parameters of oxidative stress (hydrogen peroxide, MDA), and testosterone. In addition, expression of p53 and the proapoptotic protein, Bax, were analyzed by Western blot. TCDD exposure decreased body weight, body length, and AGD in both PND 30 and PND 60 groups compared with the control group. The activity of all antioxidant enzymes at PND 60 was decreased after TCDD treatment. TCDD treatment decreased testicular testosterone levels in both the PND 30 and PND 60 groups. The expression of p53 and Bax were also upregulated by TCDD and did not return to normal levels by PND 60. These data suggest that TCDD affects development of male offspring when the mother is exposed to TCDD during lactation. In addition, oxidative stress is a major mediator of TCDD‐induced adverse effects, and p53 may play an important role in this mechanism.

Decreased Interstitial Cells of Cajal-like Cells, Possible Cause of Congenital Refluxing Megaureters: Histopathologic Differences in Refluxing and Obstructive Megaureters

OBJECTIVESnTo evaluate the location of interstitial cells of Cajal-like cells and the ureteral aspect using histopathologic studies of obstructive and refluxing megaureters to reveal the different pathogenesis of megaureters in the human urinary tract. The underlying pathophysiology of obstructive megaureter and refluxing megaureter is poorly understood.nnnMETHODSnThe data from 14 patients with obstructive megaureter (7 boys and 7 girls), with a mean age of 12 months (range 2-84), and 9 patients with refluxing megaureter (7 boys and 2 girls), with a mean age of 11 months (range 4-24), were compared. We investigated the difference in the histopathologic aspects using Massons trichrome, terminal uridine deoxynucleotidyl transferase dUTP nick end labeling (for apoptosis), and human c-kit antibody (CD117 for interstitial cells of Cajal-like cells) between the obstructive and refluxing megaureters.nnnRESULTSnThe proportion of smooth muscle was significantly lower in segments of refluxing megaureter (32.04% +/- 4.96%) than in the segments of obstructive megaureter (52.48% +/- 3.46%; P < .01). The number of apoptotic cells was significantly increased in the obstructive megaureter (mean 1661 +/- 135.1 cells) compared with the refluxing megaureter (mean 375.2 +/- 65.14 cells; P < .0001). The number of c-kit positive cells was significantly lower in the refluxing megaureter (mean 83.60 +/- 48.84 cells) than in the obstructive megaureter (mean 463.6 +/- 100.4 cells; P < .05).nnnCONCLUSIONSnThe differences in the histopathologic aspects can provide information on the possible pathophysiology of obstructive and refluxing megaureters. Ureteral peristalsis can be affected by the increased myocyte apoptosis in the obstructive megaureter and by the decreased number of interstitial cells of Cajal-like cells and smooth muscle content in refluxing megaureters. Additional research is warranted to elucidate the exact pathophysiology.

Regular exercise training reduces coronary restenosis after percutaneous coronary intervention in patients with acute myocardial infarction.

BACKGROUNDnIt is well known that cardiac rehabilitation (CR) including regular exercise training (ET) is cardioprotective with respect to clinical events in patients with acute myocardial infarction (AMI). However, it is not known whether the regular ET may affect coronary restenosis after percutaneous coronary intervention (PCI) with stenting in AMI. The aim of this study was to evaluate the effect of regular ET on a stented coronary segment and its association with inflammatory markers in AMI.nnnMETHODSnConsecutively 74 AMI patients who underwent PCI with implantation of a drug-eluting stent and 9 month follow-up angiography were included. Thirty seven patients who received CR with ET were assigned to the ET group. Another 37 patients who did not participate in ET, of similar age to those of participants, were assigned to the control group. At 9 months, angiographic restenosis measured as in-segment late luminal loss of the stented coronary artery was analyzed via quantitative coronary angiography using CAAS 5.9.nnnRESULTSnThere were no significant differences in baseline characteristics including age, sex, body mass index, smoking, DM, hypertension, lipid profile, use of statin, and complete blood cell between two groups. On 9 month follow-up angiography, late luminal loss per stent was significantly smaller in the ET group compared to the control group (0.14 ± 0.57 vs. 0.54 ± 0.88 mm, p=0.02). Maximal oxygen consumption (VO2max) significantly improved in the ET group after 9months (27.9 ± 6.4 vs. 30.8 ± 5.2 mL/kg/min, p<0.001). Increment in high density lipoprotein-cholesterol (HDL-C) was significantly larger in the ET group at 9 months (0.15 ± 0.12 vs. 0.04 ± 0.24 mg/dL, p=0.03).nnnCONCLUSIONnRegular ET contributes to a significant reduction in late luminal loss in the stented coronary segment in AMI patients. This effect was associated with increased exercise capacity and increased HDL-C.

Function of the Cold Receptor (TRPM8) Associated with Voiding Dysfunction in Bladder Outlet Obstruction in Rats

Purpose Bladder outlet obstruction (BOO) causes storage and voiding dysfunction in the lower urinary tract. We investigated the expression of transient receptor potential cation channel subfamily M member 8 (TRPM8) to evaluate the relationship between TRPM8 expression and overactive bladder (OAB) in a rat model of BOO. Methods Fifty female Sprague-Dawley rats were divided into 4 groups; normal (n=10), normal-menthol (n=10), BOO (n=15), BOO-menthol (n=15). After 3 weeks, cystometry was performed by infusing physiological saline and menthol (3 mM) into the bladder at a slow infusion rate. The histological changes and expression of TRPM8 in the bladder were investigated by Massons trichrome staining, immunofluorescence and reverse transcription-polymerase chain reaction. Results Cystometry showed that the intercontraction interval (ICI; 428.2±23.4 vs. 880.4±51.2, P<0.001), micturition pressure (MP; 25.7±1.01 vs. 71.80±3.01, P<0.001), and threshold pressure (2.9±0.25 vs. 9.2±1.58, P<0.01) were significantly increased in BOO rats. The bladder wall was significantly dilated compared with the control. Detrusor muscle hypertrophy and a thick mucosa layer were observed in BOO bladder. After menthol treatment, ICIs were decreased and MPs were increased in the menthol treatment groups. TRPM8-positive cells and mRNA were predominantly increased in the bladder and dorsal root ganglia of all groups compared with the normal group. Conclusions Increased bladder wall thickness and proportion of collagen probably affect voiding dysfunction. Furthermore, an increase of TRPM8 expression in BOO may induce entry of Ca2+ from the extracellular space or stores. The increase of Ca2+ probably causes contraction of smooth muscle in BOO. However, OAB symptoms were not observed after menthol treatment although the expression of TRPM8 was abundant in the bladder epithelium after menthol treatment. Although OAB in BOO models may be caused by complex pathways, regulation of TRPM8 presents possibilities for OAB treatment.

Extracorporeal pelvic floor magnetic stimulation in children with voiding dysfunction.

To determine the effect of extracorporeal pelvic floor magnetic stimulation in children with an overactive bladder, as although such stimulation is an effective treatment for voiding dysfunction such as urge incontinence (UI) and urgency‐frequency syndrome, experience in children is scarce.

Diagnostic Value of Anteroposterior Diameter of Fetal Renal Pelvis During Second and Third Trimesters in Predicting Postnatal Surgery Among Korean Population: Useful Information for Antenatal Counseling

OBJECTIVEnTo establish prognostic data regarding fetal hydronephrosis using the anteroposterior diameter (APD) and the need for interventional surgery in the Korean population.nnnMETHODSnA total of 187 children with an APD of ≥ 4 mm on obstetric ultrasound scans at any gestational age were retrospectively reviewed. The affected renal units were divided into 2 groups: surgical and nonsurgical. The ultrasound findings were compared at 3 gestational ages: second trimester (15-26 weeks gestation), early third trimester (27-33 weeks gestation), and late third trimester (34-40 weeks gestation).nnnRESULTSnThe area under the receiver operating characteristic curve was 0.770, 0.828, and 0.812 at the second, early third, and late third trimesters, respectively. A 100% sensitivity for predicting postnatal surgery could be achieved at a cutoff APD of 5 mm during the second trimester, 8 mm during the early third trimester, and 10 mm during the late third trimester if scheduled antenatal ultrasound scans were performed. A cutoff APD of 11 mm during the second trimester was of diagnostic value in selecting children at risk of postnatal surgery with an odds ratio of 5.13 (95% confidence interval 1.62-16.25), with relatively high sensitivity and specificity. With a cutoff of 15 mm during the early third and late third trimesters, the odds ratio was 11.51 (95% confidence interval 5.05-26.23) and 6.94 (95% confidence interval 3.30-14.57), respectively.nnnCONCLUSIONnCompared with an APD of 10 mm, the most commonly used standard cutoff value in predicting postnatal hydronephrosis and its outcome, an APD cutoff of 5, 8, and 10 mm during the second, early third, and late third trimesters, respectively, is more specific in predicting the need for postnatal surgical intervention in the Korean population.

Testosterone alters testis function through regulation of piRNA expression in rats.

Piwi-interacting RNAs (piRNAs) play a role in gene silencing of retrotransposons, maintenance of spermatogenesis and maturation in germlines. The piRNA and PIWI protein are essential for fertility. To reveal piRNA function associated with testosterone, we investigated the expression of piRNA and piwi protein in normal male rats and testosterone-treated rats. Normal Sprague–Dawley (SD) rats were randomly selected and sacrificed at neonatal to late adolescence stage stages (2, 9, 16, 20, 24, 28, 35, and 42xa0days, nxa0=xa06 each). Additional SD rats were divided into four groups: group 1 received weekly injections of testosterone enanthate (8xa0mg/100xa0g) during 1–3xa0weeks; group 2 during 3–5xa0weeks; group 3 during 1–5xa0weeks; and group 4 was the control (nxa0=xa020 each). These animals were sacrificed at an age of 60xa0days. We investigated piRNA, PIWI, and Ago3 protein levels using real-time PCR, Western blot, and immunohistochemistry in each group. In normal rats, PIWI protein and piRNA were expressed at P24. The expression of PIWI and piRNA gradually increased from adolescence to adulthood on Western blot, real-time PCR and immunohistochemistry. In testosterone-treated rats, the expression of PIWI protein was analyzed by Western blot and shown to be significantly increased in group 1 (neonatal to juvenile injection). In real-time PCR, the expression of piRNA after testosterone treatment was increased in all groups (G1 166.8xa0±xa02.7; G2 113.3xa0±xa04.6; G3 70.2xa0±xa01.5 vs. control, 32.87xa0±xa02.0, all pxa0<xa00.001). The expression of testosterone in adolescence induces the development of male genitourinary organs and spermatogenesis. At the same time, the sexual hormones may activate the piRNA and PIWI protein. Our data demonstrate that patterns of piRNA and PIWI expression are similar to the secretion pattern of testosterone, and that piRNA expression was increased after testosterone treatment. Therefore, testosterone may affect testis function through the regulation of piRNA expression in rats.

Atrial fibrillation and the risk of myocardial infarction: a nation-wide propensity-matched study

In addition to being an established complicating factor for myocardial infarction (MI), recent studies have revealed that atrial fibrillation (AF) increased risk of MI. This study is to evaluate the risk of MI associated with AF in a nationwide population based cohort. We examine the association between AF and incident MI in 497,366 adults from the Korean National Health Insurance Service database, who were free of AF and MI at baseline. AF group (nu2009=u20093,295) was compared with propensity matched no-AF group (nu2009=u200913,159). Over 4.2 years of follow up, 137 MI events occurred. AF was associated with 3-fold increased risk of MI (HR, 3.1; 95% CI, 2.22–4.37) in both men (HR, 2.91; 95% CI 1.91–4.45) and women (HR, 3.52; 95% CI 2.01–6.17). The risk of AF-associated MI was higher in patients free of hypertension, diabetes, ischemic stroke, and dyslipidemia at baseline. The cumulative incidence of AF-associated MI was lower in patients on anticoagulant and statin therapies. Our finding suggests that AF complications beyond stoke should extend to total mortality to include MI.

Clinical course of vesicoureteral reflux in patients with hypospadias

Objectives:u2003 The prevalence of vesicoureteral reflux (VUR) in hypospadic patients is reportedly higher than in healthy children. We investigated the prevalence and the clinical course of VUR in hypospadic patients.