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1.  Struvite Crystallization of Anaerobic Digestive Fluid of Swine Manure Containing Highly Concentrated Nitrogen 
In this study, the optimal operation factors for struvite crystallization for removing and recovering nitrogen and phosphorus from anaerobic digestive fluid of swine manure containing highly concentrated nitrogen was determined. Every experiment for the struvite crystallization reaction was conducted by placing 1,000 mL of digestion fluid in a 2,000 mL Erlenmeyer flask at various temperatures, pH, and mixing speed. Except for special circumstances, the digestion fluid was centrifuged (10,000 rpm, 10 min) and then the supernatant was used for the experiment at room temperature and 100 rpm. The optimal mole ratio of PO43−:Mg2+ was 1:1.5, and the pH effect ranging from 9 to 11 was similar, when mixed for 1 hour. Under this condition, the removal efficiency of NH4+-N and PO43−-P was 40% and 88.6%, respectively. X-shaped crystal was observed by light and scanning electron microscopy. In addition, struvite crystal structure was confirmed through X-ray diffraction analysis.
PMCID: PMC4478498  PMID: 26104412
Struvite; Anaerobic Digestive Fluid; Swine Manure
2.  Phenotype Difference between Familial and Sporadic Ankylosing Spondylitis in Korean Patients 
Journal of Korean Medical Science  2014;29(6):782-787.
Clustered occurrences of ankylosing spondylitis (AS) in family have been noticed. We evaluated patients with AS confirmed by the modified New York criteria for familial history of AS (one or more first to third degree relatives). The clinical characteristics and the recurrence risks (number of AS patients/number of familial members) of the familial AS compared to sporadic AS were investigated. Out of a total of 204 AS patients, 38 patients (18.6%) reported that they had a familial history of AS. The recurrence risks in the familial AS patients for first, second and third degree family members were 14.5%, 5.2%, and 4.4% respectively. Erythrocyte sedimentation rate (ESR) (22.6±22.2 vs 35.4±34.4, P=0.029) and C-reactive protein (CRP) (1.24±1.7 vs 2.43±3.3, P=0.003) at diagnosis, body mass index (21.9±2.7 vs 23.7±3.3, P=0.002) and frequency of oligoarthritis (13.2% vs 33.7%, P=0.021) were significantly lower in the familial form. The presence of HLA-B27 (97.4% vs 83.1%, P=0.044) was significantly higher in familial AS. In conclusion, Korean familial AS patients show a lower frequency of oligoarthritis, lower BMI, lower ESR and CRP at diagnosis and higher presence of HLA-B27.
Graphical Abstract
PMCID: PMC4055810  PMID: 24932078
Spondylitis, Ankylosing; Familial; Sporadic; Phenotype; Recurrence Risk
3.  Comparison of Two Creatinine-Based Equations for Predicting Decline in Renal Function in Type 2 Diabetic Patients with Nephropathy in a Korean Population 
Aim. To compare two creatinine-based estimated glomerular filtration rate (eGFR) equations, the chronic kidney disease epidemiology collaboration (CKD-EPI) and the modification of diet in renal disease (MDRD), for predicting the risk of CKD progression in type 2 diabetic patients with nephropathy. Methods. A total of 707 type 2 diabetic patients with 24 hr urinary albumin excretion of more than 30 mg/day were retrospectively recruited and traced until doubling of baseline serum creatinine (SCr) levels was noted. Results. During the follow-up period (median, 2.4 years), the CKD-EPI equation reclassified 10.9% of all MDRD-estimated subjects: 9.1% to an earlier stage of CKD and 1.8% to a later stage of CKD. Overall, the prevalence of CKD (eGFR < 60 mL/min/1.73 m2) was lowered from 54% to 51.6% by applying the CKD-EPI equation. On Cox-regression analysis, both equations exhibited significant associations with an increased risk for doubling of SCr. However, only the CKD-EPI equation maintained a significant hazard ratio for doubling of SCr in earlier-stage CKD (eGFR ≥ 45 mL/min/1.73 m2), when compared to stage 1 CKD (eGFR ≥ 90 mL/min/1.73 m2). Conclusion. In regard to CKD progression, these results suggest that the CKD-EPI equation might more accurately stratify earlier-stage CKD among type 2 diabetic patients with nephropathy than the MDRD study equation.
PMCID: PMC3884626  PMID: 24454370
4.  Behçet’s disease presenting with Budd–Chiari syndrome and intracardial thrombus: a case report 
Budd–Chiari syndrome has been described as a late complication of Behçet’s disease. Although the mortality rate associated with Behçet’s disease is low, it can escalate in the presence of Budd–Chiari syndrome and may be further complicated by intracardial thrombus formation. It is therefore important to detect and initiate management early in the disease course. The imaging modalities of choice should be minimally invasive as certain procedures may aggravate Behçet’s disease by initiating a thrombosis or aggravating an existing one. In Behçet’s disease-induced Budd–Chiari syndrome, cardiac investigation is crucial in the work-up in order to identify any cardiac involvement and determine the etiology of intracardial thrombus. Furthermore, the treatment should ultimately focus on controlling the activity of Behçet’s disease. We report an unusual case of Behçet’s disease presenting with Budd–Chiari syndrome complicated by intracardial thrombus in a young Korean man.
PMCID: PMC3658241  PMID: 23754909
Behçet’s disease; Budd-Chiari syndrome; intracardial thrombus
5.  Visual working memory deficits in patients with Parkinson's disease are due to both reduced storage capacity and impaired ability to filter out irrelevant information 
Brain  2010;133(9):2677-2689.
Given that Parkinson's disease broadly affects frontostriatal circuitry, it is not surprising that the disorder is associated with a reduction of working memory. We tested whether this reduction is due to diminished storage capacity or impaired ability to exclude task-irrelevant items. Twenty-one medication-withdrawn patients and 28 age-matched control subjects performed a visuospatial memory task while their electroencephalograms were recorded. The task required them to remember the orientations of red rectangles within the half of the screen that was cued while ignoring all green rectangles. Behavioural and electroencephalogram measures indicated that patients with Parkinson's disease were impaired at filtering out distracters, and that they were able to hold fewer items in memory than control subjects. The results support recent suggestions that the basal ganglia help control access to working memory.
PMCID: PMC2929336  PMID: 20688815
Parkinson's disease; visual working memory; event-related potentials; selective attention; dopamine
6.  Comparison of Patients Starting Hemodialysis with Those Underwent Hemodialysis 15 Years Ago at the Same Dialysis Center in Korea 
Maintenance dialysis is made decreased the death rate of patients with end-stage renal disease; however, mortality is still high. The aim of this study was to identify the association between clinical parameters at the start of hemodialysis with survival and compare these findings with data from patients who underwent hemodialysis about 15 years ago at the same dialysis center.
We reviewed 117 patients who started hemodialysis between 2000 and 2004. We analyzed medical histories, laboratory findings, and clinical outcomes, and compared them with patients who started hemodialysis 15 years ago at the same center.
The proportion of elderly patients and those with diabetes increased from 17% and 18% in the previous study to 33% and 49% in this study, respectively. Elderly and patients with diabetes had much higher mortalities than their counterparts. Nevertheless, the overall survival rate (66% vs. 71% at 5 years) and survival of patients with diabetes improved (55% vs. 75% at 1.5 years). Common causes of death were infection and cardiovascular disease in the present study; however, inadequate dialysis accounted for 25% of deaths in the previous study.
The overall survival rate of patients undergoing hemodialysis has improved over the 15-year interval, even with an increased proportion of elderly patients and patients with diabetes. Adequate dialysis and further medical improvements could ameliorate mortality in patients undergoing dialysis.
PMCID: PMC2880693  PMID: 20526393
Renal dialysis; Mortality; Survival analysis
7.  The Effect of Dialysis Membrane Flux on Amino Acid Loss in Hemodialysis Patients 
Journal of Korean Medical Science  2007;22(4):598-603.
We examined whether high flux membranes (HF) may induce a greater loss of amino acids compared to low flux membranes (LF). Ten hemodialysis patients participated in this study. Pre- and post-hemodialysis plasma amino acid profiles were measured by reverse-phase high pressure liquid chromatography for both HF and LF. We measured the dialysate amino acid losses during hemodialysis. The reduction difference for plasma total amino acid (TAA), essential amino acid (EAA), and branch chained amino acid (BCAA) was not significantly different in comparisons between the two membranes. (HF vs. LF; TAA 66.85±30.56 vs. 53.78±41.28, p=0.12; EAA 14.79±17.16 vs. 17.97±28.69, p=0.12; BCAA 2.21±6.08 vs. 4.16±10.98 mg/L, p=0.13). For the HF, the reduction in plasma amino acid levels for TAA and EAA were statistically significant. Although it was not statistically significant, the dialysate losses of BCAA were greater than the reduction in plasma (plasma reduction vs. dialysate loss; HF 2.21±6.08 vs. 6.58±4.32, LF 4.16±10.98 vs. 7.96±3.25 mg/L). HF with large pores and a sieving coefficient do not influence dialysate amino acid losses. Hemodialysis itself may influence the dialysate amino acid losses and may have an effect on protein metabolism.
PMCID: PMC2693805  PMID: 17728495
Amino Acid; High Flux Membrane; Low Flux Membrane
8.  Relationship between Pulmonary Surfactant Protein and Lipid Peroxidation in Lung Injury due to Paraquat Intoxication in Rats 
Pulmonary damage resulting from lipid peroxidation is a principal effect of paraquat intoxication. The host-defense functions of surfactant are known to be mediated by the surfactant proteins A and D (SP-A and SP-D, respectively). The primary objective of this study was to evaluate the variations over time in levels of surfactant protein and lipid peroxidation (LPO) in lung tissue following free-radical-induced injury.
42 adult, male, Sprague-Dawley rats were administered intraperitoneal injections of paraquat (35 mg/kg body weight). SP-A and SP-D levels were determined via Western blot. LPO in the left lung homogenate was measured via analyses of the levels of thiobarbituric acid-reactive substances.
LPO levels peaked at 6 hours, with no associated histological changes. SP-D levels increased until hour 12 and declined until hour 48; SP-D levels subsequently began to increase again, peaking at hour 72. SP-A levels peaked at hour 6, declining thereafter.
We suggest that in the early phase of paraquat injury, SP-D levels reflect alveolar damage and that de novo synthesis of SP-D takes 72 hours. Levels of SP-A, on the other hand, reflect abnormalities in the surfactant system in the late stage of paraquat intoxication. Surfactant proteins may play a role in protecting the lungs from reactive oxygen injury. A time-dependent variation has been observed in the levels of surfactant proteins A and D following paraquat injury, and it has been suggested that these proteins play a role in the protection of lung tissue against ROS-induced injuries.
PMCID: PMC2687609  PMID: 17616020
Paraquat; Lipid peroxidation; Surfactant protein A; Surfactant protein D
9.  Pharmacokinetics of Glutathione and Its Metabolites in Normal Subjects 
Journal of Korean Medical Science  2005;20(5):721-726.
To determine the loading and maintenance dosage of glutathione (GSH) for patients suffering from reactive oxygen species (ROS) injury such as acute paraquat intoxication, a kinetic study of reduced GSH was performed in synchrony with that of cysteine (Cys), cystine (Cys2), and methionine (Met). Human subject's porticipitation was voluntary. The effective dose of Cys, Cys2, and Met against ROS in fibroblast cells generated by paraquat was assessed using laser scanning confocal microscopy. Both Cys and Met suppressed ROS in a dose-dependent manner at concentrations of 1-1,000 µM; the concentration required to suppress ROS by 50% was 10 µM for Cys and 50 µM for Met. Using metabolite kinetics with the assumption that Cys and Met are the metabolites of GSH, expected concentrations of Cys and Met of above 20 and 50 µM were estimated when GSH was administered at 50 mg/kg body weights every 205.4 min for Cys and 427.4 min for Met.
PMCID: PMC2779265  PMID: 16224142
Cysteine; Cystine; Glutathione; Methionine; Paraquat; Reactive Oxygen Species; Pharmacokinetics
10.  Various autogenous fresh demineralized tooth forms for alveolar socket preservation in anterior tooth extraction sites: a series of 4 cases 
The aim of this study was to evaluate the clinical relevance of autogenous fresh demineralized tooth (Auto-FDT) prepared at chairside immediately after extraction for socket preservation. Teeth were processed to graft materials in block, chip, or powder types immediately after extraction. Extraction sockets were filled with these materials and dental implants were installed immediately or after a delay. A panoramic radiograph and a conebeam CT were taken. In two cases, tissue samples were taken for histologic examination.
Vertical and horizontal maintenance of alveolar sockets showed some variance depending on the Auto-FDT and barrier membrane types used. Radiographs showed good bony healing. Histologic sections showed that it guided good new bone formation and resorption pattern of the Auto-FDT.
This case series shows that Auto-FDT prepared at chairside could be a good material for the preservation of extraction sockets. This study will suggest the possibility of recycling autogenous tooth after immediate extraction.
PMCID: PMC4559089  PMID: 26366388
Alveolar socket preservation; Bone regeneration; Biocompatible; Bone substitute; Autogenous demineralized tooth
11.  Time points for obtaining representative values of 24-hour blood pressure in chronic kidney disease 
Ambulatory blood pressure (BP) monitoring has been widely recommended for evaluating the status of BP, but is lacking in practicality. Determination of the specific time points for BP measurement that are representative of 24-hour mean BP could be useful and convenient in hypertensive patients with chronic kidney disease (CKD).
A total of 1,317 patients for whom 24-hour ambulatory BP monitoring was performed were enrolled in a multicenter study on hypertensive CKD. We analyzed the time points at which systolic blood pressure (SBP) values exhibited the smallest differences from 24-hour mean SBP (mSBP). We included office mSBP and analyzed the relationships between SBPs at the office and the time points with the smallest differences from 24-hour mSBP using several methods.
The time points with the smallest differences from 24-hour mSBP were 7:00 AM, 2:00 PM, and 9:30 PM. In regression analysis, SBPs at 7:00 AM and 9:30 PM were better correlated with 24-hour mSBP than SBPs at 2:00 PM and the office. The proportions of patients with SBPs within 30% of 24-hour mSBP were higher at 7:00 AM and 9:30 PM. The best consistency between the uncontrolled hypertensive groups, defined as ≥ 135 mmHg of 24-hour mSBP and higher values of SBPs corresponding to 135 mmHg of 24-hour mSBP, were observed at the 7:00 AM and 9:30 PM time points.
The specific time points for SBPs that correlated well with 24-hour mSBP in hypertensive CKD patients were 7:00 AM and 9:30 PM.
PMCID: PMC4578022  PMID: 26354061
Ambulatory blood pressure measurement; Blood pressure measurement; Chronic kidney disease; Hypertension; Timing for representative blood pressure
12.  Olfactory-related cortical atrophy is associated with olfactory dysfunction in Parkinson’s disease 
Olfactory dysfunction is often associated with Parkinson’s disease (PD) and can precede characteristic motor symptoms by several years. Olfactory-related cortical atrophy has been reported in PD, although the extent and association between cortical atrophy and olfactory dysfunction have been controversial. The present study examined whether olfactory dysfunction is associated with gray matter (GM) volume in brain regions subserving primary and secondary olfactory processing.
High-resolution T1-weighted brain magnetic resonance images were acquired from 40 PD without dementia and 40 matched Controls along with smell identification scores. Brain volumes were compared using voxel-based morphometry (VBM).
Compared to Controls, PD patients sustained greater GM loss localized to bilateral piriform cortex (PC) and orbitofrontal cortex (OFC). Reduced olfactory performance in PD was significantly associated with lower GM volumes in PC and OFC.
Both primary and secondary olfactory cortical atrophy occurred in PD and were associated with olfactory dysfunction.
PMCID: PMC4116478  PMID: 24482154
Parkinson's disease; olfaction; MRI; Voxel-based morphometry; olfactory cortex
13.  Effects of Hormone Therapy on Serum Lipid Levels in Postmenopausal Korean Women 
Journal of Menopausal Medicine  2015;21(2):104-111.
This study was conducted to examine the effects of hormone therapy on serum lipid levels in postmenopausal Korean women.
This retrospective cohort study included 154 healthy postmenopausal Korean women. Seventy-nine women took oral estrogen (conjugated equine estrogen 0.625 mg/day or equivalent), and 75 applied estrogen transdermally using 0.1% 17β-estradiol gel. Micronized progesterone (MP) was added to 40 women of oral group and 49 women in transdermal group. Serum levels of triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and lipoprotein (a) were measured before, 3 and 6 month after hormone therapy.
At baseline, mean body mass index (BMI) were lower (22.76 vs. 23.74 kg/m2) and proportion of family history of cardiovascular disease (CVD) (61 vs. 39%) were higher in oral group. In oral group, LDL-C and lipoprotein(a) levels decreased, and triglyceride and HDL-C levels increased significantly after 3 and 6 months. There was no significant change in lipoprotein levels compared to the baseline in transdermal group. There were also no differences with additional MP. Changing pattern of HDL-C during 6 months was significantly different by the route of estrogen administration.
Oral estrogen therapy might be more beneficial than transdermal estrogen in terms of lipid in postmenopausal Korean women. The estrogen effects are not influenced by adding MP.
PMCID: PMC4561737  PMID: 26357648
Hormone replacement therapy; Lipids; Progesterone; Drug administration route
14.  History of smoking and olfaction in Parkinson’s disease 
Olfactory dysfunction is the most common pre-motor symptom in Parkinson’s disease, and smoking is known to be associated with lower risk of PD. This study tested the hypothesis that smoking is associated with better olfaction in PD.
Smoking history was obtained from 76 PD subjects [22 with a history of smoking (smokers), 54 who never smoked (non-smokers)], and 70 Controls (17 smokers, 53 non-smokers). Olfaction was assessed using the 40-item University of Pennsylvania Smell Identification Test (UPSIT). The olfactory scores between groups and subgroups were compared using analysis of covariance with adjustment for age, gender, and MAO-B inhibitor usage.
Overall the olfactory score was lower in PD compared to Controls (olfactory scores: 21.54 vs. 33.45, p<0.0001). Among Controls, there was no significant difference in olfaction between smokers and non-smokers (olfactory scores: 33.2 vs. 34.2, p=0.95). Among PD subjects, however, smokers scored significantly better regarding olfaction compared to non-smokers (olfactory scores: 24.4 vs. 19.9, p=0.02).
These data suggest that history of smoking is associated with better olfaction among PD patients. The finding may be related to why smoking may be protective against PD. Further studies are needed to confirm this finding and investigate the underlying mechanism(s).
PMCID: PMC4107167  PMID: 24833119
Smoking; Parkinson’s disease; Olfactory; Cigarette
15.  Profiling and Characterization of Influenza Virus N1 Strains Potentially Resistant to Multiple Neuraminidase Inhibitors 
Journal of Virology  2014;89(1):287-299.
Neuraminidase inhibitors (NAIs) have been widely used to control influenza virus infection, but their increased use could promote the global emergence of resistant variants. Although various mutations associated with NAI resistance have been identified, the amino acid substitutions that confer multidrug resistance with undiminished viral fitness remain poorly understood. We therefore screened a known mutation(s) that could confer multidrug resistance to the currently approved NAIs oseltamivir, zanamivir, and peramivir by assessing recombinant viruses with mutant NA-encoding genes (catalytic residues R152K and R292K, framework residues E119A/D/G, D198N, H274Y, and N294S) in the backbones of the 2009 pandemic H1N1 (pH1N1) and highly pathogenic avian influenza (HPAI) H5N1 viruses. Of the 14 single and double mutant viruses recovered in the backbone of pH1N1, four variants (E119D, E119A/D/G-H274Y) exhibited reduced inhibition by all of the NAIs and two variants (E119D and E119D-H274Y) retained the overall properties of gene stability, replicative efficiency, pathogenicity, and transmissibility in vitro and in vivo. Of the nine recombinant H5N1 viruses, four variants (E119D, E119A/D/G-H274Y) also showed reduced inhibition by all of the NAIs, though their overall viral fitness was impaired in vitro and/or in vivo. Thus, single mutations or certain combination of the established mutations could confer potential multidrug resistance on pH1N1 or HPAI H5N1 viruses. Our findings emphasize the urgency of developing alternative drugs against influenza virus infection.
IMPORTANCE There has been a widespread emergence of influenza virus strains with reduced susceptibility to neuraminidase inhibitors (NAIs). We screened multidrug-resistant viruses by studying the viral fitness of neuraminidase mutants in vitro and in vivo. We found that recombinant E119D and E119A/D/G/-H274Y mutant viruses demonstrated reduced inhibition by all of the NAIs tested in both the backbone of the 2009 H1N1 pandemic (pH1N1) and highly pathogenic avian influenza H5N1 viruses. Furthermore, E119D and E119D-H274Y mutants in the pH1N1 background maintained overall fitness properties in vitro and in vivo. Our study highlights the importance of vigilance and continued surveillance of potential NAI multidrug-resistant influenza virus variants, as well as the development of alternative therapeutics.
PMCID: PMC4301112  PMID: 25320319
16.  Different Functional and Structural Characteristics between ApoA-I and ApoA-4 in Lipid-Free and Reconstituted HDL State: ApoA-4 Showed Less Anti-Atherogenic Activity 
Molecules and Cells  2015;38(6):573-579.
Apolipoprotein A-I and A-IV are protein constituents of high-density lipoproteins although their functional difference in lipoprotein metabolism is still unclear. To compare anti-atherogenic properties between apoA-I and apoA-4, we characterized both proteins in lipid-free and lipid-bound state. In lipid-free state, apoA4 showed two distinct bands, around 78 and 67 Å on native gel electrophoresis, while apoA-I showed scattered band pattern less than 71 Å. In reconstituted HDL (rHDL) state, apoA-4 showed three major bands around 101 Å and 113 Å, while apoA-I-rHDL showed almost single band around 98 Å size. Lipid-free apoA-I showed 2.9-fold higher phospholipid binding ability than apoA-4. In lipid-free state, BS3-crosslinking revealed that apoA-4 showed less multimerization tendency upto dimer, while apoA-I showed pentamerization. In rHDL state (95:1), apoA-4 was existed as dimer as like as apoA-I. With higher phospholipid content (255:1), five apoA-I and three apoA-4 were required to the bigger rHDL formation. Regardless of particle size, apoA-I-rHDL showed superior LCAT activation ability than apoA-4-rHDL. Uptake of acetylated LDL was inhibited by apoA-I in both lipid-free and lipid-bound state, while apoA-4 inhibited it only lipid-free state. ApoA-4 showed less anti-atherogenic activity with more sensitivity to glycation. In conclusion, apoA-4 showed inferior physiological functions in lipid-bound state, compared with those of apoA-I, to induce more pro-atherosclerotic properties.
PMCID: PMC4469915  PMID: 25997739
apolipoprotein A-I; apolipoprotein A-4; fructosylation; recombinant high-density lipoprotein
17.  Glycated albumin and the risk of micro- and macrovascular complications in subjects with Type 1 Diabetes 
We investigated the relationship between the glycemic indices glycated albumin (GA) and glycated hemoglobin (HbA1c) and the progression of diabetic vascular complications [diabetic nephropathy (DN) and carotid artery atherosclerosis (CAA)] in subjects with type 1 diabetes (T1D).
A total of 154 participants with a median follow-up of 2.8 years were enrolled in this retrospective longitudinal study. We recruited T1D subjects who had regularly measured urine albumin-creatinine ratios and estimated glomerular filtration rates, as well as tested HbA1c and GA levels consecutively every 3 or 6 months. A subgroup of 54 subjects was measured repeated carotid intima-media thickness (IMT).
We classified subjects into the DN progression (Group I; n = 30) with either deteriorated stages of chronic kidney disease (n = 18) or albuminuria progression (n = 17), and the non-progression (Group II; n = 124). In multiple logistic regression analyses, baseline albuminuria (odds ratio [OR] = 2.64, 95 % confidence interval [CI] = 1.03–6.74), mean GA levels (OR = 2.03, 95 % CI = 1.27–3.26) were significantly associated with progression of DN. However, there was no association with mean HbA1c (OR = 0.98, 95 % CI = 0.62–1.54). In a subgroup analysis for follow-up measurements of carotid IMT, age was independently associated with the presence of plaque and the mean IMT. However glycemic indices were not significantly associated with CAA.
Mean GA levels were more closely associated with DN progression than mean HbA1c in subjects with T1D. However, they were not associated with the CAA.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0219-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4438622  PMID: 25975731
Type 1 diabetes; Glycated albumin; Diabetic nephropathy; Carotid artery atherosclerosis
18.  Low Baseline Interleukin-17A Levels Are Associated with Better Treatment Response at 12 Weeks to Tocilizumab Therapy in Rheumatoid Arthritis Patients 
Journal of Immunology Research  2015;2015:487230.
T helper 17-related cytokines have been implicated in rheumatoid arthritis (RA) pathogenesis. The study aimed to identify cytokines associated with the treatment response of RA patients to tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin- (IL-) 6 receptor. As an independent substudy of the 24-week, randomized, double-blinded CWP-TCZ301 trial of TCZ in RA patients with an inadequate response to disease-modifying antirheumatic drugs, serum levels of cytokines including tumor necrosis factor-alpha, IL-17A, IL-21, IL-23, IL-6, and soluble IL-6 receptor were measured. Baseline IL-17A levels were significantly lower in RA patients who achieved disease activity score 28 (DAS28) remission at 12 weeks of TCZ treatment, compared to patients not in remission. Patients were stratified into IL-17A low group and IL-17A high group. Significantly more patients in the IL-17A low group achieved remission as compared to the IL-17A high group (47.6 versus 17.4%, P = 0.032). DAS28 improvement was significantly better in the IL-17A low group than in the IL-17A high group at 12 weeks (P = 0.045) and 24 weeks (P = 0.046) after adjustment. Other baseline cytokines were not associated with treatment response to TCZ. The data demonstrate that low baseline IL-17A levels are associated with better clinical response to TCZ treatment in RA patients.
PMCID: PMC4398953  PMID: 25922848
19.  An alternative treatment option for a bony defect from large odontoma using recycled demineralization at chairside 
Odontoma is the most common odontogenic benign tumor, and the treatment of choice is generally surgical removal. After excision, bone grafts may be necessary depending on the need for further treatment, or the size and location of the odontoma. Although the osteogenic capacity of a demineralized tooth was verified as early as 1967 by Urist and many other investigators, the cumbersome procedure, including a long demineralization time, may be less than comfortable for clinicians. A modified ultrasonic technology, with periodic negative pressure and temperature control, facilitated rapid and aseptic preparation of demineralized teeth for bone grafts. This approach reduces the demineralization time dramatically (≤80 minutes), so that the graft material can be prepared chairside on the same day as the extraction. The purpose of this article is to describe two cases of large compound odonotomas used as graft material prepared chairside for enucleation-induced bony defects. These two clinical cases showed favorable wound healing without complications, and good bony support for future dental implants or orthodontic treatment. Finally, this report will suggest the possibility of recycling the benign pathologic hard tissue as an alternative treatment option for conventional bone grafts in clinics.
PMCID: PMC4411726  PMID: 25922824
Odontoma; Recycled demineralization
20.  C-C Chemokine Receptor 2 Inhibitor Ameliorates Hepatic Steatosis by Improving ER Stress and Inflammation in a Type 2 Diabetic Mouse Model 
PLoS ONE  2015;10(3):e0120711.
Hepatic steatosis is the accumulation of excess fat in the liver. Recently, hepatic steatosis has become more important because it occurs in the patients with obesity, type 2 diabetes, and hyperlipidemia and is associated with endoplasmic reticulum (ER) stress and insulin resistance. C-C chemokine receptor 2 (CCR2) inhibitor has been reported to improve inflammation and glucose intolerance in diabetes, but its mechanisms remained unknown in hepatic steatosis. We examined whether CCR2 inhibitor improves ER stress-induced hepatic steatosis in type 2 diabetic mice. In this study, db/db and db/m (n = 9) mice were fed CCR2 inhibitor (2 mg/kg/day) for 9 weeks. In diabetic mice, CCR2 inhibitor decreased plasma and hepatic triglycerides levels and improved insulin sensitivity. Moreover, CCR2 inhibitor treatment decreased ER stress markers (e.g., BiP, ATF4, CHOP, and XBP-1) and inflammatory cytokines (e.g., TNFα, IL-6, and MCP-1) while increasing markers of mitochondrial biogenesis (e.g., PGC-1α, Tfam, and COX1) in the liver. We suggest that CCR2 inhibitor may ameliorate hepatic steatosis by reducing ER stress and inflammation in type 2 diabetes mellitus.
PMCID: PMC4376739  PMID: 25816097
21.  Distinct action of the α-glucosidase inhibitor miglitol on SGLT3, enteroendocrine cells, and GLP1 secretion 
The Journal of Endocrinology  2015;224(3):205-214.
Oral ingestion of carbohydrate triggers glucagon-like peptide 1 (GLP1) secretion, but the molecular mechanism remains elusive. By measuring GLP1 concentrations in murine portal vein, we found that the ATP-sensitive K+ (KATP) channel is not essential for glucose-induced GLP1 secretion from enteroendocrine L cells, while the sodium-glucose co-transporter 1 (SGLT1) is required, at least in the early phase (5 min) of secretion. By contrast, co-administration of the α-glucosidase inhibitor (α-GI) miglitol plus maltose evoked late-phase secretion in a glucose transporter 2-dependent manner. We found that GLP1 secretion induced by miglitol plus maltose was significantly higher than that by another α-GI, acarbose, plus maltose, despite the fact that acarbose inhibits maltase more potently than miglitol. As miglitol activates SGLT3, we compared the effects of miglitol on GLP1 secretion with those of acarbose, which failed to depolarize the Xenopus laevis oocytes expressing human SGLT3. Oral administration of miglitol activated duodenal enterochromaffin (EC) cells as assessed by immunostaining of phosphorylated calcium–calmodulin kinase 2 (phospho-CaMK2). In contrast, acarbose activated much fewer enteroendocrine cells, having only modest phospho-CaMK2 immunoreactivity. Single administration of miglitol triggered no GLP1 secretion, and GLP1 secretion by miglitol plus maltose was significantly attenuated by atropine pretreatment, suggesting regulation via vagal nerve. Thus, while α-GIs generally delay carbohydrate absorption and potentiate GLP1 secretion, miglitol also activates duodenal EC cells, possibly via SGLT3, and potentiates GLP1 secretion through the parasympathetic nervous system.
PMCID: PMC4324305  PMID: 25486965
miglitol; SGLT3; GLP1 secretion; L cell
22.  Dioscorea batatas Extract Attenuates High-Fat Diet-Induced Obesity in Mice by Decreasing Expression of Inflammatory Cytokines 
The objective of the present study was to determine whether Dioscorea batatas (DB) extract reduces visceral fat accumulation and obesity-related biomarkers in mice fed a high-fat diet (HFD) and whether genes associated with adipogenesis and inflammation could be modulated by a diet containing DB extract.
Male C57BL/6J mice were divided into 4 groups (n=10 per group): normal diet (ND), HFD, 100 mg/kg DB extract-gavage with HFD, and 200 mg/kg DB extract-gavage with HFD. The mice were fed the experimental diets for 14 weeks. At 12 weeks, micro-computed X-ray tomography (micro-CT) was performed.
Supplementation of the diet with DB extract for 14 weeks significantly prevented HFD-induced increases in body weight, visceral adipose tissue, plasma lipid levels, and leptins. The area of visceral fat was reduced by DB extract supplementation when examined by micro-CT. Supplementation with DB extract resulted in the downregulation of the adipogenic transcription factor (C/ERBα) and its target gene (CD36) in epididymal adipose tissue, compared to HFD alone. DB extract decreased the expression of proinflammatory cytokines (TNF-α, MCP-1, and IL-6) in epididymal adipose tissue.
Our results suggest that DB extract may prevent HFD-induced obesity by downregulating the expression of genes related to adipogenesis and inflammation in visceral adipose tissue.
PMCID: PMC4335589  PMID: 25681821
Adipogenesis; Diet, High-Fat; Dioscorea; Obesity
23.  Effects of Tumor Necrosis Factor-α on Podocyte Expression of Monocyte Chemoattractant Protein-1 and in Diabetic Nephropathy 
Nephron Extra  2015;5(1):1-18.
Tumor necrosis factor (TNF)-α is believed to play a role in diabetic kidney disease. This study explores the specific effects of TNF-α with regard to nephropathy-relevant parameters in the podocyte.
Cultured mouse podocytes were treated with recombinant TNF-α and assayed for production of monocyte chemoattractant protein-1 (MCP-1) by enzyme-linked immunosorbent assay (ELISA). TNF-α signaling of MCP-1 was elucidated by antibodies against TNF receptor (TNFR) 1 or TNFR2 or inhibitors of nuclear factor-kappaB (NF-κB), phosphatidylinositol 3-kinase (PI3K) or Akt. In vivo studies were done on male db/m and type 2 diabetic db/db mice. Levels of TNF-α and MCP-1 were measured by RT-qPCR and ELISA in the urine, kidney and plasma of the two cohorts and correlated with albuminuria.
Podocytes treated with TNF-α showed a robust increase (∼900%) in the secretion of MCP-1, induced in a dose- and time-dependent manner. Signaling of MCP-1 expression occurred through TNFR2, which was inducible by TNF-α ligand, but did not depend on TNFR1. TNF-α then proceeded via the NF-κB and the PI3K/Akt systems, based on the effectiveness of the inhibitors of those pathways. For in vivo relevance to diabetic kidney disease, TNF-α and MCP-1 levels were found to be elevated in the urine of db/db mice but not in the plasma.
TNF-α potently stimulates podocytes to produce MCP-1, utilizing the TNFR2 receptor and the NF-κB and PI3K/Akt pathways. Both TNF-α and MCP-1 levels were increased in the urine of diabetic db/db mice, correlating with the severity of diabetic albuminuria.
PMCID: PMC4369122  PMID: 25852733
TNF receptor 2; Nuclear factor-kappaB; Phosphatidylinositol 3-kinase; Akt or protein kinase B; Albuminuria; Diabetic rodent model
24.  Comparative study of the shear bond strength of various veneering materials on grade II commercially pure titanium 
To compare the shear bond strength of various veneering materials to grade II commercially pure titanium (CP-Ti).
Thirty specimens of CP-Ti disc with 9 mm diameter and 10 mm height were divided into three experimental groups. Each group was bonded to heat-polymerized acrylic resin (Lucitone 199), porcelain (Triceram), and indirect composite (Sinfony) with 7 mm diameter and 2 mm height. For the control group (n=10), Lucitone 199 were applied on type IV gold alloy castings. All samples were thermocycled for 5000 cycles in 5-55℃ water. The maximum shear bond strength (MPa) was measured with a Universal Testing Machine. After the shear bond strength test, the failure mode was assessed with an optic microscope and a scanning electron microscope. Statistical analysis was carried out with a Kruskal-Wallis Test and Mann-Whitney Test.
The mean shear bond strength and standard deviations for experimental groups were as follows: Ti-Lucitone 199 (12.11 ± 4.44 MPa); Ti-Triceram (11.09 ± 1.66 MPa); Ti-Sinfony (4.32 ± 0.64 MPa). All of these experimental groups showed lower shear bond strength than the control group (16.14 ± 1.89 MPa). However, there was no statistically significant difference between the Ti-Lucitone 199 group and the control group, and the Ti-Lucitone 199 group and the Ti-Triceram group. Most of the failure patterns in all experimental groups were adhesive failures.
The shear bond strength of veneering materials such as heat-polymerized acrylic resin, porcelain, and indirect composite to CP-Ti was compatible to that of heatpolymerized acrylic resin to cast gold alloy.
PMCID: PMC4341190  PMID: 25722841
Titanium; Bond strength; Veneering material; Heat-polymerized acrylic resin; Porcelain; Indirect composite
Parkinsonism & related disorders  2013;19(12):10.1016/j.parkreldis.2013.07.018.
Whereas the motor dysfunction in Parkinson’s disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss.
High-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right-handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences.
PD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients.
Non-demented PD subjects demonstrate cortical structural changes in frontal and parieto-occipital regions compared to controls. The association between typically recognized “frontal lobe” function and occipital lobe volume suggested a compensatory role of occipital lobe to primary fronto-striatal pathology in PD. Further longitudinal study of these changing structure-function relationships is needed to understand the neural bases of symptom progression in PD.
PMCID: PMC3858507  PMID: 23932064
Parkinson’s disease; Cognition; MRI; Voxel-based morphometry; Gray Matter Volume

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