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1.  The effect of rhBMP-2 and PRP delivery by biodegradable β-tricalcium phosphate scaffolds on new bone formation in a non-through rabbit cranial defect model 
This study evaluated whether the combination of biodegradable β-tricalcium phosphate (β-TCP) scaffolds with recombinant human bone morphogenetic protein-2 (rhBMP-2) or platelet-rich plasma (PRP) could accelerate bone formation and increase bone height using a rabbit non-through cranial bone defect model. Four non-through cylindrical bone defects with a diameter of 8-mm were surgically created on the cranium of rabbits. β-TCP scaffolds in the presence and absence of impregnated rhBMP-2 or PRP were placed into the defects. At 8 and 16 weeks after implantation, samples were dissected and fixed for analysis by microcomputed tomography and histology. Only defects with rhBMP-2 impregnated β-TCP scaffolds showed significantly enhanced bone formation compared to non-impregnated β-TCP scaffolds (p<0.05). Although new bone was higher than adjacent bone at 8 weeks after implantation, vertical bone augmentation was not observed at 16 weeks after implantation, probably due to scaffold resorption occurring concurrently with new bone formation.
PMCID: PMC4012921  PMID: 23779152
rhBMP-2; PRP; calvarial defect; porous scaffolds; ceramic scaffolds; vertical augmentation
2.  A Case of Acute Cerebral Aspergillosis Complicating Influenza A/H1N1pdm 2009 
Infection & Chemotherapy  2013;45(2):225-229.
Invasive aspergillosis is a rare complication in patients with influenza infection. Several cases of invasive pulmonary aspergillosis accompanying influenza infections were reported during the influenza A/H1N1pdm 2009. We encountered a case of acute cerebral aspergillosis in a patient with influenza A/H1N1pdm 2009 infection. A 24-year-old man with uncontrolled diabetes was diagnosed with influenza A/H1N1pdm 2009 infection. Initial evaluation indicated methicillin-sensitive Staphylococcus aureus pneumonia and diabetic ketoacidosis along with influenza. During his hospital course, multiple new rim-enhancing mass lesions not evident in the initial evaluation developed in the fronto-parietal cortical and subcortical white matter and right cerebellum. Pathology and culture results confirmed the presence of Aspergillus fumigatus. Surgical drainage combined with a total of 18 weeks of antifungal therapy resulted in complete resolution of the infection. This case demonstrates that cerebral aspergillosis can present alongside influenza in patients with diabetes or those under intensive care. Clinical suspicion of invasive aspergillosis is required for a definite diagnosis and better prognosis in such cases.
PMCID: PMC3780949  PMID: 24265971
Central nervous system; Invasive aspergillosis; Influenza; Brain abscess; Diabetes mellitus
3.  Immunologic Diagnosis of Active Tuberculosis 
Infection & Chemotherapy  2013;45(1):110-112.
PMCID: PMC3780941  PMID: 24265959
4.  Correction: DNA Repair in Human Pluripotent Stem Cells Is Distinct from That in Non-Pluripotent Human Cells 
PLoS ONE  2012;7(9):10.1371/annotation/4c0baab8-74ef-47df-bb29-1506795e3350.
PMCID: PMC3935761
5.  Sintering behavior and mechanical properties of zirconia compacts fabricated by uniaxial press forming 
The purpose of this study was to compare the linear sintering behavior of presintered zirconia blocks of various densities. The mechanical properties of the resulting sintered zirconia blocks were then analyzed.
Three experimental groups of dental zirconia blocks, with a different presintering density each, were designed in the present study. Kavo Everest® ZS blanks (Kavo, Biberach, Germany) were used as a control group. The experimental group blocks were fabricated from commercial yttria-stabilized tetragonal zirconia powder (KZ-3YF (SD) Type A, KCM. Corporation, Nagoya, Japan). The biaxial flexural strengths, microhardnesses, and microstructures of the sintered blocks were then investigated. The linear sintering shrinkages of blocks were calculated and compared.
Despite their different presintered densities, the sintered blocks of the control and experimental groups showed similar mechanical properties. However, the sintered block had different linear sintering shrinkage rate depending on the density of the presintered block. As the density of the presintered block increased, the linear sintering shrinkage decreased. In the experimental blocks, the three sectioned pieces of each block showed the different linear shrinkage depending on the area. The tops of the experimental blocks showed the lowest linear sintering shrinkage, whereas the bottoms of the experimental blocks showed the highest linear sintering shrinkage.
Within the limitations of this study, the density difference of the presintered zirconia block did not affect the mechanical properties of the sintered zirconia block, but affected the linear sintering shrinkage of the zirconia block.
PMCID: PMC2994699  PMID: 21165274
Zirconia block; Mechanical properties; Sintering behavior; Linear sintering shrinkage
6.  Histologic evaluation and removal torque analysis of nano- and microtreated titanium implants in the dogs 
A number of studies about the nano-treated surfaces of implants have been conducting along with micro-treated surfaces of implants.
The purpose of this study was to get information for the clinical use of nano-treated surfaces compared with micro-treated surfaces by measuring removal torque and analyzing histological characteristics after the placement of various surface-treated implants on femurs of dogs.
Machined surface implants were used as a control group. 4 nano-treated surface implants and 3 micro-treated surface implants [resorbable blast media surface (RBM), sandblast and acid-etched surface (SAE), anodized RBM surface] were used as experimental groups. Removal torque values of implants were measured respectively and the histological analyses were conducted on both 4weeks and 8weeks after implant surgery. The surfaces of removed implants after measuring removal torque values were observed by scanning electron microscopy (SEM) at 8 weeks.
1. Removal torque values of the nano-treated groups were lower than those of micro-treated groups. 2. Removal torque values were similar in the anodized RBM surface groups. 3. On the histological views, there was much of bone formation at 8 weeks, but there was no difference between 4 and 8 weeks, and between the types of implant surfaces as well.
It is suggested that implant topography is more effective in removal torque test than surface chemistry. To get better clinical result, further studies should be fulfilled on the combined effect of surface topography and chemistry for the implant surface treatments.
PMCID: PMC2994682  PMID: 21165259
removal torque; implant; surfaces characteristics; dog; histology; SEM
7.  Cell response to a newly developed Ti-10Ta-10Nb alloy and its sputtered nanoscale coating 
The success of titanium implants is due to osseointegration or the direct contact of the implant surface and bone without a fibrous connective tissue interface.
The purpose of this study was to evaluate the osteoblast precursor response to titanium - 10 tantalum - 10 niobium (Ti-Ta-Nb) alloy and its sputtered coating.
Ti-Ta-Nb coatings were sputtered onto the Ti-Ta-Nb disks. Ti6-Al-4V alloy disks were used as controls. An osteoblast precursor cell line, were used to evaluate the cell responses to the 3 groups. Cell attachment was measured using coulter counter and the cell morphology during attachment period was observed using fluorescent microscopy. Cell culture was performed at 4, 8, 12 and 16 days.
The sputtered Ti-Ta-Nb coatings consisted of dense nanoscale grains in the range of 30 to 100 nm with alpha-Ti crystal structure. The Ti-Ta-Nb disks and its sputtered nanoscale coatings exhibited greater hydrophilicity and rougher surfaces compared to the Ti-6Al-4V disks. The sputtered nanoscale Ti-Ta-Nb coatings exhibited significantly greater cell attachment compared to Ti-6Al-4V and Ti-Ta-Nb disks. Nanoscale Ti-Ta-Nb coatings exhibited significantly greater ALP specific activity and total protein production compared to the other 2 groups.
It was concluded that nanoscale Ti-Ta-Nb coatings enhance cell adhesion. In addition, Ti-Ta-Nb alloy and its nanoscale coatings enhanced osteoblast differentiation, but did not support osteoblast precursor proliferation compared to Ti-6Al-4V. These results indicate that the new developed Ti-Ta-Nb alloy and its nanoscale Ti-Ta-Nb coatings may be useful as an implant material.
PMCID: PMC2994675  PMID: 21165256
Implant; Ti-Ta-Nb; Cell response; Sputter; Nanoscale; Osteoblast
8.  Valsartan independent of AT1 receptor inhibits tissue factor, TLR-2 and-4 expression by regulation of Egr-1 through activation of AMPK in diabetic conditions 
Patients suffering from diabetes mellitus (DM) are at a severe risk of atherothrombosis. Early growth response (Egr)-1 is well characterized as a central mediator in vascular pathophysiology. We tested whether valsartan independent of Ang II type 1 receptor (AT1R) can reduce tissue factor (TF) and toll-like receptor (TLR)-2 and-4 by regulating Egr-1 in THP-1 cells and aorta in streptozotocin-induced diabetic mice. High glucose (HG, 15 mM) increased expressions of Egr-1, TF, TLR-2 and-4 which were significantly reduced by valsartan. HG increased Egr-1 expression by activation of PKC and ERK1/2 in THP-1 cells. Valsartan increased AMPK phosphorylation in a concentration and time-dependent manner via activation of LKB1. Valsartan inhibited Egr-1 without activation of PKC or ERK1/2. The reduced expression of Egr-1 by valsartan was reversed by either silencing Egr-1, or compound C, or DN-AMPK-transfected cells. Valsartan inhibited binding of NF-κB and Egr-1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine (TNF-α, IL-6 and IL-1β) production and NF-κB activity in HG-activated THP-1 cells. Interestingly, these effects of valsartan were not affected by either silencing AT1R in THP-1 cells or CHO cells, which were devoid of AT1R. Importantly, administration of valsartan (20 mg/kg, i.p) for 8 weeks significantly reduced plasma TF activity, expression of Egr-1, TLR-2,-4 and TF in thoracic aorta and improved glucose tolerance of streptozotocin-induced diabetic mice. Taken together, we concluded that valsartan may reduce atherothrombosis in diabetic conditions through AMPK/Egr-1 regulation.
PMCID: PMC4244018  PMID: 25109475
valsartan; AMPK; Egr-1; diabetes; atherothrombosis
9.  P2Y2R activation by nucleotides released from the highly metastatic breast cancer cell contributes to pre-metastatic niche formation by mediating lysyl oxidase secretion, collagen crosslinking, and monocyte recruitment 
Oncotarget  2014;5(19):9322-9334.
Tumor microenvironmental hypoxia induces hypoxia inducible factor-1α (HIF-1α) overexpression, leading to the release of lysyl oxidase (LOX), which crosslinks collagen at distant sites to facilitate environmental changes that allow cancer cells to easily metastasize. Our previous study showed that activation of the P2Y2 receptor (P2Y2R) by ATP released from MDA-MB-231 cells increased MDA-MB-231 cell invasion through endothelial cells. Therefore, in this study, we investigated the role of P2Y2R in breast cancer cell metastasis to distant sites. ATP or UTP released from hypoxia-treated MDA-MB-231 cells induced HIF-1α expression and LOX secretion by the activation of P2Y2R, and this phenomenon was significantly reduced in P2Y2R-depleted MDA-MB-231 cells. Furthermore, P2Y2R-mediated LOX release induced collagen crosslinking in an in vitro model. Finally, nude mice injected with MDA-MB-231 cells showed high levels of LOX secretion, crosslinked collagen and CD11b+ BMDC recruitment in the lung; however, mice that were injected with P2Y2R-depleted MDA-MB-231 cells did not exhibit these changes. These results demonstrate that P2Y2R plays an important role in activation of the HIF-1α–LOX axis, the induction of collagen crosslinking and the recruitment of CD11b+ BMDCs. Furthermore, P2Y2R activation by nucleotides recruits THP-1 monocytes, resulting in primary tumor progression and pre-metastatic niche formation.
PMCID: PMC4253437  PMID: 25238333
collagen crosslinking; HIF-1α; LOX; nucleotides; premetastatic niche formation; P2Y2R
10.  Low Compliance with National Guidelines for Preventing Transmission of Group 1 Nationally Notifiable Infectious Diseases in Korea 
Yonsei Medical Journal  2014;55(2):435-441.
This study was performed to evaluate the compliance with, and adequacy of, the Korean national guidelines which had been recommended until 2011 for isolation of patients with group 1 nationally notifiable infectious diseases (NNIDs), namely cholera, typhoid fever, paratyphoid fever, shigellosis, and enterohemorrhagic Escherichia coli (EHEC) infection.
Materials and Methods
We evaluated the clinical and microbiological characteristics of confirmed cases of group 1 NNIDs and compliance with the guidelines in 20 Korean hospitals nationwide in 2000-2010. We also compared the Korean guidelines with international guidelines.
Among 528 confirmed cases (8 cases of cholera, 232 of typhoid fever, 81 of paratyphoid fever, 175 of shigellosis, and 32 EHEC infections), strict compliance with the Korean guideline was achieved in only 2.6% to 50.0%, depending on the disease. While the Korean guidelines recommend isolation of all patients with group 1 NNIDs, international guidelines recommend selective patient isolation and screening for fecal shedding, depending on the type of disease and patient status.
Compliance with the previous national guidelines for group 1 NNIDs in Korea was generally very low. Further studies are needed to evaluate whether compliance was improved after implementation of the new guideline in 2012.
PMCID: PMC3936634  PMID: 24532515
Communicable disease control; guideline adherence; patient isolation; cholera; typhoid fever; shigellosis
Nature medicine  2011;17(3):356-365.
To date, our understanding of the role of X-Box Binding Protein 1 (XBP1) in metabolic processes was limited to its ability to up-regulate ER folding capacity and thereby, to increase insulin sensitivity. Here, we demonstrate that XBP1s interacts with Forkhead box O1 (FoxO1) transcription factor and directs it to proteasome-mediated degradation. Our results provide the first evidence that, in addition to its regulatory effects on the ER system and insulin sensitivity, XBP1s can independently regulate glucose homeostasis through its interaction with FoxO1. Indeed, a DNA binding defective mutant of XBP1s, which does not have the ability to increase ER folding capacity, is still capable of reducing blood glucose levels and increasing glucose tolerance in the severely obese and diabetic ob/ob mice. XBP1-mediated degradation of FoxO1 might lead to development of new therapeutic approaches for treatment of type 2 diabetes.
PMCID: PMC3897616  PMID: 21317886
12.  High prevalence of low bone mass and associated factors in Korean HIV-positive male patients undergoing antiretroviral therapy 
Low bone mass is prevalent in HIV-positive patients. However, compared to Western countries, less is known about HIV-associated osteopenia in Asian populations.
We performed a cross-sectional survey in Seoul National University Hospital from December 2011 to May 2012. We measured bone mineral density using central dual energy X-ray absorptiometry, with consent, in male HIV-positive patients, aged 40 years and older. Diagnosis of low bone mass was made using International Society for Clinical Densitometry Z-score criteria in the 40–49 years age group and World Health Organization T-score criteria in the >50-year age group. The data were compared with those of a community-based cohort in Korea.
Eighty-four HIV-positive male patients were included in this study. Median age was 49 (interquartile range [IQR], 45–56) years, and median body mass index (BMI) was 22.6 (IQR, 20.9–24.4). Viral suppression was achieved in 75 (89.3%) patients and median duration of antiretroviral therapy was 71 (IQR, 36–120) months. The overall prevalence of low bone mass was 16.7% in the 40–49 years age group and 54.8% in the>50 years age group. Our cohort had significantly lower bone mass at the femur neck and total hip than HIV-negative Koreans in the 40–49 years age group. Low bone mass was significantly associated with low BMI, and a high level of serum carboxy-terminal collagen crosslinks, but was not associated with antiretroviral regimen or duration of antiretroviral therapy.
Low bone mass is prevalent in Korean HIV-positive males undergoing antiretroviral therapy, and may be associated with increased bone resorption.
PMCID: PMC3888902  PMID: 24433984
HIV; AIDS; osteopenia; osteoporosis
13.  Paneth cell-mediated multiorgan dysfunction after acute kidney injury 
Acute kidney injury (AKI) is frequently complicated by extra-renal multi-organ injury including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of pro-inflammatory mediators drives multi-organ injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage depleted mice decreased markedly, and intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI.
PMCID: PMC3504173  PMID: 23109723
acute renal failure; apoptosis; cytokine; inflammation; ischemia reperfusion; nephrectomy
14.  Effect of magnesium and calcium phosphate coatings on osteoblastic responses to the titanium surface 
The aim of this study was to evaluate the surface properties and in vitro bioactivity to osteoblasts of magnesium and magnesium-hydroxyapatite coated titanium.
Themagnesium (Mg) and magnesium-hydroxyapatite (Mg-HA) coatings on titanium (Ti) substrates were prepared by radio frequency (RF) and direct current (DC) magnetron sputtering.The samples were divided into non-coated smooth Ti (Ti-S group), Mg coatinggroup (Ti-Mg group), and Mg-HA coating group (Ti-MgHA group).The surface properties were evaluated using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The surface roughness was evaluated by atomic force microscopy (AFM). Cell adhesion, cell proliferation and alkaline phosphatase (ALP) activity were evaluated using MC3T3-E1 cells. Reverse transcription polymerase chain reaction (RT-PCR) analysis was performed.
Cross-sectional SEM images showed that Mg and Mg-HA depositionson titanium substrates were performed successfully. The surface roughness appeared to be similaramong the three groups. Ti-MgHA and Ti-Mg group had improved cellular responses with regard to the proliferation, alkaline phosphatase (ALP) activity, and bone-associated markers, such as bone sialoprotein (BSP) and osteocalcin (OCN) mRNA compared to those of Ti-S group. However, the differences between Ti-Mg group and Ti-MgHA group were not significant, in spite of the tendency of higher proliferation, ALP activity and BSP expression in Ti-MgHA group.
Mg and Mg-HAcoatings could stimulate the differentiation into osteoblastic MC3T3-E1 cells, potentially contributing to rapid osseointegration.
PMCID: PMC3865194  PMID: 24353877
Biocompatible materials; Surface-Coated materials; Surface properties; Alkaline phosphatase; Bone sialoprotein; Osteocalcin
15.  The Heme Oxygenase-1 Inducer THI-56 Negatively Regulates iNOS Expression and HMGB1 Release in LPS-Activated RAW 264.7 Cells and CLP-Induced Septic Mice 
PLoS ONE  2013;8(10):e76293.
The nuclear DNA binding protein high mobility group box 1 (HMGB1) has recently been suggested to act as a late mediator of septic shock. The effect of ((S)-6,7-dihydroxy-1-(4-hydroxynaphthylmethyl)-1,2,3,4-tetrahydroisoquinoline alkaloid, also known as THI-56, in an experimental model of sepsis was investigated. THI-56 exhibited potent anti-inflammatory properties in response to LPS in RAW 264.7 cells. In particular, THI-56 significantly inhibited the expression of inducible nitric oxide synthase (iNOS) and the release of HMGB1 in activated macrophages. THI-56 activated NE-F2-regulated factor 2 (Nrf-2)/heme oxygenase 1 (HO-1). The specific knockdown of the HO-1 gene by HO-1 siRNA significantly reversed the inhibitory effects of THI-56 on iNOS expression and HMGB1 release in LPS-stimulated macrophages. Importantly, THI-56 administration protected animals from death induced by either a lethal dose of LPS or cecal ligation and puncture (CLP). Furthermore, the ALT, AST, BUN, creatinine, and HMGB1 levels in the blood were significantly increased in CLP-induced septic mice, and the administration of THI-56 reduced these levels in a concentration-dependent and zinc protoporphyrin IX (ZnPPIX)-sensitive manner. In addition, the administration of THI-56 significantly ameliorated not only lung damage but also macrophage infiltration in the livers of CLP-induced septic mice, and these effects were also abrogated in the presence of ZnPPIX. Thus, we conclude that THI-56 significantly attenuates the proinflammatory response induced by LPS and reduces organ damage in a CLP-induced sepsis model through the upregulation of Nrf-2/HO-1.
PMCID: PMC3789711  PMID: 24098466
16.  Can a routine follow-up blood culture be justified in Klebsiella pneumoniae bacteremia? a retrospective case–control study 
BMC Infectious Diseases  2013;13:365.
The need for mandatory confirmation of negative conversion in Klebsiella pneumoniae bacteremia (KpB) has not been adequately addressed. We conducted a retrospective case–control study of adult patients with KpB over a 5-year period in two tertiary-care hospitals to determine the risk factors for persistent bacteremia and to reevaluate the necessity of follow-up blood culture in KpB.
Persistent KpB is defined as the finding of K. pneumoniae in more than two separate blood-culture samples for longer than a two-day period in a single episode. The case- and control-groups were patients with persistent and non-persistent KpB, respectively, and they were matched 1-to-3 according to age and gender.
Among 1068 KpB episodes analyzed after excluding polymicrobial infection and repeated KpB, follow-up blood cultures were performed in 862 cases (80.7%), 62 of which (7.2%) were persistent. Independent risk factors for persistence were intra-abdominal infection, higher Charlson’s comorbidity weighted index score, prior solid organ transplantation, and unfavorable treatment response, which was defined as positivity for at least two parameters among fever, leukocytosis, and no decrease of C-reactive protein on the second day after initial culture. A proposed scoring system using four variables, namely, intra-abdominal infection, nosocomial KpB, fever and lack of C-reactive protein decrease, the last two being assessed on the second day after the initial blood culture, showed that only 4.9% of the patients with no risk factors or with only intra-abdominal infection had persistent KpB.
Though persistent KpB is uncommon, follow-up blood culture was performed in as many as 80% of the cases in this study. A more careful clinical assessment is warranted to reduce the cost and patient inconvenience involved in follow-up blood culture.
PMCID: PMC3734211  PMID: 23914899
Klebsiella pneumoniae; Bacteremia; Risk factor; Follow-up; Blood culture
17.  Pseudomonas aeruginosa bacteremia in patients with liver cirrhosis: a comparison with bacteremia caused by Enterobacteriaceae 
BMC Infectious Diseases  2013;13:332.
This study was performed to detect risk factors for Pseudomonas aeruginosa bacteremia in patients with liver cirrhosis.
A retrospective case–control study was designed to identify risk factors for P. aeruginosa bacteremia in cirrhotic patients. The cases were cirrhotic patients with P. aeruginosa bacteremia and the controls were cirrhotic patients with Enterobacteriaceae bacteremia.
Sixty-one cases and the same number of controls were enrolled. In a multivariate analysis, younger age {adjusted odds ratio (aOR) per one year: 0.96, 95% confidence interval: 0.93 - 0.99}, nosocomial acquisition (aOR 3.87, 95% confidence interval: 1.50 - 9.94), preexisting biliary disease (aOR 4.79, 95% confidence interval: 1.92 - 10.47), and recent exposure to immunosuppressive agent (aOR 3.10, 95% confidence interval: 1.23 - 7.82) were associated with P. aeruginosa bacteremia. In the case group the frequency of appropriate initial antibiotic regimens was considerably lower than in the control group: 29.5% vs. 65.6% (P <0.01). However, thirty day mortality did not differ significantly between cases and controls (19.7% vs. 24.6%).
Nosocomial acquisition, preexisting biliary disease, and recent use of immunosuppressive agents are strong predictive factors for P. aeruginosa bacteremia in cirrhotic patients.
PMCID: PMC3720192  PMID: 23870005
Pseudomonas aeruginosa; Bacteremia; Liver cirrhosis
18.  Isoflurane activates intestinal sphingosine kinase to protect against renal ischemia-reperfusion induced liver and intestine injury 
Anesthesiology  2011;114(2):363-373.
Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury and often leads to multi-organ dysfunction and systemic inflammation. Volatile anesthetics have potent antiinflammatory effects and we aimed to determine whether the representative volatile anesthetic isoflurane protects against acute kidney injury-induced liver and intestinal injury and the mechanisms involved in this protection.
Mice were anesthetized with pentobarbital and subjected to 30 min of left renal ischemia after right nephrectomy followed by exposure to 4 h of equi-anesthetic doses of pentobarbital or isoflurane. Five hrs after renal IRI, plasma creatinine and alanine aminotransferase were measured. Liver and intestine tissues were analyzed for pro-inflammatory mRNAs, histology, sphingosine kinase-1 (SK1) immunoblotting, SK1 activity, and sphingosine-1-phosphate levels.
Renal IRI with pentobarbital led to severe renal, hepatic, and intestinal injury with focused peri-portal hepatocyte vacuolization, small intestinal apoptosis and pro-inflammatory mRNA upregulation. Isoflurane protected against renal IRI and reduced hepatic and intestinal injury via induction of small intestinal crypt SK1 mRNA, protein and enzyme activity and increase in S1P. We confirmed the importance of SK1 as mice treated with a selective SK inhibitor (SKI-II) or mice deficient in SK1 enzyme were not protected against hepatic and intestinal dysfunction with isoflurane.
Taken together, we demonstrate that isoflurane protects against multi-organ injury after renal IRI via induction of the SK1/sphingosine-1-phosphate pathway. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated hepatic and intestinal protection and lead to new therapeutic applications of volatile anesthetics during the perioperative period.
PMCID: PMC3650623  PMID: 21245730
19.  Proximal tubule sphingosine kinase-1 has a critical role in A1 adenosine receptor-mediated renal protection from ischemia 
Kidney international  2012;82(8):878-891.
Renal ischemia reperfusion injury is a major cause of acute kidney injury. We previously found that renal A1 adenosine receptor (A1AR) activation attenuated multiple cell death pathways including necrosis, apoptosis and inflammation. Here, we tested whether induction of cytoprotective sphingosine kinase (SK)-1 and sphingosine-1 phosphate (S1P) synthesis might be the mechanism of protection. A selective A1AR agonist (CCPA) increased the synthesis of S1P and selectively induced SK-1 in mouse kidney and HK-2 cells. This agonist failed to protect SK1-knockout but protected SK2-knockout mice against renal ischemia reperfusion injury indicating a critical role of SK1 in A1AR-mediated renal protection. Inhibition of SK prevented A1AR-mediated defense against necrosis and apoptosis in HK-2 cells. A selective S1P1R antagonist (W146) and global in vivo gene knockdown of S1P1Rs with small interfering RNA completely abolished the renal protection provided by CCPA. Mice selectively deficient in renal proximal tubule S1P1Rs (S1P1Rflox/flox PEPCKCre/−) were not protected against renal ischemia reperfusion injury by CCPA. Mechanistically, CCPA increased nuclear translocation of hypoxia inducible factor-1α in HK-2 cells and selective hypoxia inducible factor-1α inhibition blocked A1AR-mediated induction of SK1. Thus, proximal tubule SK-1 has a critical role in A1AR-mediated protection against renal ischemia reperfusion injury.
PMCID: PMC3443517  PMID: 22695326
apoptosis; hypoxia inducible factor-1α; inflammation; necrosis; sphingosine 1-phosphate
20.  Isoflurane postconditioning protects against intestinal ischemia-reperfusion injury and multi-organ dysfunction via transforming growth factor-beta1 generation 
Annals of Surgery  2012;255(3):492-503.
This study examined volatile anesthetic-mediated protection against intestinal ischemia-reperfusion injury (IRI).
Intestinal IRI is a devastating complication in the perioperative period leading to systemic inflammation and multi-organ dysfunction. Volatile anesthetics, including isoflurane, have anti-inflammatory effects. We aimed to determine whether isoflurane, given after intestinal ischemia, protects against intestinal IRI and the mechanisms involved in this protection.
After IACUC approval, mice were anesthetized with pentobarbital and subjected to 30 min of superior mesenteric artery ischemia, followed by 4 hrs of equianesthetic doses of pentobarbital or isoflurane. Five hrs after reperfusion, small intestine tissues were analyzed for morphological injury, apoptosis, neutrophil infiltration, pro-inflammatory mRNAs, and TGF-β1 levels. We also assessed hepatic and renal injury after intestinal IRI.
Intestinal IRI with pentobarbital led to significant small intestinal dysfunction with increased mucosal injury, TUNEL-positive cells, neutrophil infiltration, and pro-inflammatory mRNAs as well as elevated plasma alanine aminotransferase and creatinine levels. Isoflurane exposure after IRI led to significant attenuation of intestinal, hepatic, and renal injuries. Furthermore, the protective effects of isoflurane were abolished by treatment with a TGF-β1 neutralizing antibody prior to induction of IRI. Finally, isoflurane exposure led to increased TGF-β1 levels in intestinal epithelial cells and in plasma.
Our findings demonstrate that isoflurane postconditioning protects against small intestinal injury as well as hepatic and renal dysfunction after severe intestinal IRI via induction of intestinal epithelial TGF-β1. Our findings support therapeutic applications of volatile anesthetics during the intraoperative as well as postoperative periods and imply an important role of TGF-β1 signaling in modulating multi-organ injury.
PMCID: PMC3288790  PMID: 22266638
21.  Incidence and Risk Factors of Tuberculosis in Patients with Human Immunodeficiency Virus Infection 
Journal of Korean Medical Science  2013;28(3):374-377.
Korea is a low prevalence country for human immunodeficiency virus (HIV) infection and has an intermediate tuberculosis (TB) burden. We previously reported that the incidence of TB in HIV-infected patients was 9.6 cases per 100 person-years (P-Y) between 1988 and 1997. The aims of the present study were to measure any change in incidence from the previous study, and to identify risk factors for TB in HIV-infected patients. We reviewed all medical records of HIV-infected patients who were followed-up in one tertiary hospital between 1998 and 2010. Over the total observation period of 5858.33 P-Y, TB developed in 70 patients (1.19 cases per 100 P-Y; 95% confidence interval [CI], 0.91-1.47 cases per 100 P-Y). Based on Poisson regression, one risk factor associated with TB was an initial CD4+ cell count below 200 cells/µL (relative risk, 2.34; 95% CI, 1.47-3.73). Mean CD4+ cell counts of pulmonary, extrapulmonary, and both pulmonary and extrapulmonary TB were 179.8 cells/µL, 138.3 cells/µL, and 114.2 cells/µL, respectively (P = 0.55). In conclusion, the incidence of TB in HIV-infected patients has decreased since the previous study. An initial CD4+ cell count below 200 cells/µL is an independent risk factor for development of TB in HIV-infected patients.
PMCID: PMC3594599  PMID: 23486534
Tuberculosis; Incidence; Risk Factors; HIV
22.  Extracellular-regulated-kinase 5-mediated renal protection against ischemia-reperfusion injury 
ERK5, a member of the mitogen activated protein kinase, expressed in the kidneys was smaller (~80 kDa) in apparent molecular mass compared to other organs (~120 kDa). A blocking peptide experiment confirmed that the ~80 kDa detected on Western blots was a specific band detected by the anti-ERK5 antibody. Expression of the known ERK5 variants ERK5a, b, c, and T confirmed that none of the known splice variants encoded for the renal-specific ~80 kDa protein. However, RT-PCR with primers targeting the potential splice sites did not reveal a novel transcript in the kidney. The smaller molecular mass of the kidney-specific ERK5-immunoreactive protein suggested that this cyto-protective molecule may not be fully functional in the kidneys. Lentivirus-mediated in vivo overexpression of full length ERK5 in the mouse kidneys provided protection against renal IR injury. The identity of the renal-specific ~80 kDa ERK5 remains unknown but a better understanding of the ERK5 expression and post-translational processing in the kidneys may reveal a novel strategy for renal protection.
PMCID: PMC3288778  PMID: 22293190
MAPK; ERK5; Western blot; mobility shift; viral transduction; IR injury
23.  Empirical Use of Ciprofloxacin for Acute Uncomplicated Pyelonephritis Caused by Escherichia coli in Communities Where the Prevalence of Fluoroquinolone Resistance Is High 
There is little information about the effectiveness of ciprofloxacin in regions where ciprofloxacin-resistant Escherichia coli is prevalent. This study was conducted to evaluate whether ciprofloxacin is effective as the initial empirical antibiotic for treatment of uncomplicated acute pyelonephritis (APN) due to ciprofloxacin-resistant E. coli. A total of 255 women with clinical diagnoses of uncomplicated APN due to E. coli were enrolled in the emergency department between March 2005 and December 2008. All enrolled patients were initially treated with ciprofloxacin. Patients were followed up 4 to 7 days after the start of therapy and 14 to 21 days after its completion. At the first follow-up visit, ciprofloxacin was changed to the appropriate antibiotic when necessary, depending on the antibiotic susceptibility results. Not only improvement of symptoms and signs but also microbiologic eradication was assessed at each visit. Fifteen percent (39/255) of the E. coli isolates were resistant to ciprofloxacin. There was no statistically significant difference between the clinical cure rates of the ciprofloxacin-susceptible group and the ciprofloxacin-resistant group at the first follow-up (87.0% versus 76.9%, P = 0.135) or the second follow-up (98.6% versus 94.9%, P = 0.177). However, there was a lower microbiologic cure rate in the ciprofloxacin-resistant group than in the ciprofloxacin-susceptible group (92.4% versus 41.7%, P = 0.000) at the first follow-up visit. No complications occurred in the ciprofloxacin-resistant group during the follow-up period. Our findings indicate that ciprofloxacin is an appropriate choice for empirical therapy of uncomplicated APN and has no serious adverse outcomes, if it is tailored appropriately, even for women infected with ciprofloxacin-resistant E. coli.
PMCID: PMC3370741  PMID: 22391544
24.  Risk Factors for Febrile Neutropenia during Chemotherapy for HIV-Related Lymphoma 
Journal of Korean Medical Science  2012;27(12):1468-1471.
We evaluated risk factors for neutropenic fever and febrile prolonged neutropenia during vincristine-including chemotherapy to treat HIV-related lymphoma to investigate whether protease inhibitor (PI) treatment is associated with infectious complications due to drug interactions with chemotherapeutic agents. We included all HIV patients who received chemotherapy including vincristine for lymphoma at a single referral center in 1999-2010. Neutropenic fever was defined as absolute neutrophil count < 500 cells/µL with body temperature over 38℃; and prolonged neutropenia was defined if it persisted over 7 days. CODOX-M/IVAC and Stanford regimens were considered high-risk regimens for prolonged neutropenia. We analyzed 48 cycles of chemotherapy in 17 HIV patients with lymphoma. There were 22 neutropenic fever and 12 febrile prolonged neutropenia events. In multivariate analysis, neutropenic fever was associated with old age and low CD4 cell count, but not with PI use or ritonavir-boosted PI use. Low CD4 cell count and high-risk regimens were associated with febrile prolonged neutropenia. Neutropenic fever and febrile prolonged neutropenia is associated with old age, low CD4 cell count, and high-risk regimens, but not PI use, in HIV patients undergoing chemotherapy including vincristine for lymphoma.
PMCID: PMC3524424  PMID: 23255844
Human Immunodeficiency Virus; Lymphoma; Neutropenia
25.  Severity Predictors in Eschar-Positive Scrub Typhus and Role of Serum Osteopontin 
We prospectively evaluated severity predictors in terms of host, microorganism, and treatment factors in 153 eschar-positive scrub typhus patients. Severity was assessed with the Acute Physiology and Chronic Health Evaluation (APACHE) II score (< 10 versus ≥ 10) and predefined criteria of severe complications. Genotypes of Orientia tsutsugamushi were determined. Independent risk factors for severity (APACHE II score ≥ 10) were old age, diabetes mellitus, serum osteopontin > 100 ng/mL, and a group of underlying diseases (congestive heart failure, cerebrovascular disease, chronic liver disease, bronchial asthma, and chronic obstructive lung diseases). Anemia (≤ 10 g/dL) and C-reactive protein > 10 mg/dL were indicators of current severity. Neither the delay in antibiotics administration nor strain types (Boryong, Taguchi, or Kanda/Kawasaki) contributed to the severity. The risk factors for severe complications were similar. Serum osteopontin > 100 ng/mL had a negative predictive value of 96% for severe complications. This marker can be used to rule out severe disease status.
PMCID: PMC3205643  PMID: 22049051

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