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1.  Transabdominal Approach for Chylorrhea after Esophagectomy by Using Fluorescence Navigation with Indocyanine Green 
Case Reports in Surgery  2014;2014:464017.
A 70-year-old man who underwent two sessions of thoracoscopy-assisted ligation of the thoracic duct to treat refractory chylorrhea after radical esophagectomy for advanced esophageal cancer received conservative therapy. However, there was no improvement in chylorrhea. Then, transabdominal ligation of the lymphatic/thoracic duct at the level of the right crus of the diaphragm was performed using fluorescence navigation with indocyanine green (ICG). The procedure successfully reduced chylorrhea. This procedure provides a valid option for persistent chylothorax/chylous ascites accompanied by chylorrhea with no response to conservative treatment, transthoracic ligation, or both.
PMCID: PMC4102023  PMID: 25105050
2.  Milk Fat Globule-EGF Factor VIII Ameliorates Liver Injury after Hepatic Ischemia-Reperfusion 
The Journal of surgical research  2012;180(1):e37-e46.
Hepatic ischemia-reperfusion (I/R) injury is a serious clinical complication that may compromise liver function because of extensive hepatocyte loss. Therefore, the development of novel and effective therapies for hepatic I/R is critical for the improvement of patient outcome. It has been previously shown that administration of milk fat globule-EGF factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, exerts significant beneficial effects under acute inflammatory conditions through multiple physiological processes associated with tissue remodeling.
To determine whether administration of recombinant human (rh) MFG-E8 attenuates liver injury in an animal model of hepatic I/R. Male adult rats were subjected to 70% hepatic ischemia for 90 min, followed by reperfusion. At the beginning of reperfusion, rats were treated intravenously with normal saline (Vehicle) or rhMFG-E8 (160 μg/kg) over a period of 30 min. MFG-E8 levels and various measurements were assessed 4 h after reperfusion. In addition, survival study was conducted in MFG-E8−/− and rhMFG-E8-treated wild-type (WT) mice using a total hepatic ischemia model.
Liver and plasma MFG-E8 protein levels were significantly decreased after hepatic I/R. Administration of rhMFG-E8 significantly improved liver injury, suppressed apoptosis, attenuated inflammation and oxidative stress, and down-regulated NF-κB pathway. We also noticed that rhMFG-E8 treatment restored the down-regulated PPARγ expression after hepatic I/R. MFG-E8−/− mice showed deterioration on survival and, in contrast, rhMFG-E8-treated WT mice showed a significant improvement of survival compared with vehicle-treated WT mice.
MFG-E8-mediated multiple physiological events may represent an effective therapeutic option in tissue injury following an episode of hepatic I/R.
PMCID: PMC3401639  PMID: 22487387
MFG-E8; hepatic ischemia-reperfusion; inflammation; apoptosis; NF-κB; PPARγ
3.  Gene profiling and bioinformatics analyses reveal time course differential gene expression in surgically resected colorectal tissues 
Oncology Reports  2014;31(4):1531-1538.
It has previously been reported that gene profiles in surgically-resected colorectal cancer tissues are altered over time possibly due to the different tissue-acquisition methods and sample extraction timing that were used. However, the changes that occur are still not clearly understood. In the present study, time-dependent changes in gene expression profiling in colorectal surgical specimens were analyzed. Normal and tumor tissues at several time-points (0, 30, 60 and 120 min) were extracted, and RNA quality, microarray experiments, quantitative PCR and bioinformatics clustering were performed. Although RNA integrity was preserved 2 h after resection, inherent increased/decreased gene expression was observed from 30–120 min in approximately 10% of genes. Bioinformatics clustering could not distinguish case-by-case, probably due to gene profiling changes. Irregular changes in gene expression after surgical resection were found, which could be a crucial confounding factor for quantitative analyses.
PMCID: PMC3975991  PMID: 24573535
colorectal cancer; RNA degradation; clustering; bio- informatics; microarray
4.  Milk Fat Globule-EGF Factor 8 Attenuates Neutrophil Infiltration in Acute Lung Injury via Modulation of CXCR2 
Excessive neutrophil infiltration to the lungs is a hallmark of acute lung injury (ALI). Milk fat globule-EGF factor 8 (MFG-E8) was originally identified for phagocytosis of apoptotic cells. Subsequent studies revealed its diverse cellular functions. However, whether MFG-E8 can regulate neutrophil function to alleviate inflammation is unknown. We therefore aimed to reveal MFG-E8 roles in regulating lung neutrophil infiltration during ALI. To induce ALI, C57BL/6J wild-type (WT) and Mfge8−/− mice were intra-tracheally injected with LPS (5 mg/kg). Lung tissue damage was assessed by histology and the neutrophils were counted by a hemacytometer. Apoptotic cells in lungs were determined by TUNEL, while caspase-3 and MPO activities were assessed spectrophotometrically. CXCR2 and GRK2 expressions in neutrophils were measured by flow cytometry. Following LPS challenge, Mfge8−/− mice exhibited extensive lung damage due to exaggerated infiltration of neutrophils and production of TNF-α, MIP-2 and MPO. Increased number of apoptotic cells was trapped into the lungs ofMfge8−/− mice than WT mice, which may be due to insufficient phagocytosis of apoptotic cells or increased occurrence of apoptosis through the activation of caspase-3. In vitro studies using MIP-2 mediated chemotaxis, revealed higher migration of neutrophils of Mfge8−/− mice than WT mice via increased surface exposures to CXCR2. Administration of recombinant mouse (rm)MFG-E8 reduces neutrophil migration through up-regulation of GRK2, and down-regulation of surface CXCR2 expression. Conversely, these effects could be blocked by anti-αv-integrin antibodies. These studies clearly indicate the importance of MFG-E8 in ameliorating neutrophil infiltration and suggest MFG-E8 as a novel therapeutic potential for ALI.
PMCID: PMC3382007  PMID: 22634615
MFG-E8; Neutrophil; LPS; MIP-2; CXCR2; GRK2; αvβ3-integrin
5.  Post-treatment with the Combination of AICAR and Carnitine Improves Renal Function after Ischemia/Reperfusion Injury 
Shock (Augusta, Ga.)  2012;37(1):39-46.
Renal ischemia/reperfusion (I/R) injury is a major clinical problem where main metabolic pathways are compromised and cellular homeostasis crashes after ATP depletion. Fatty acids are major energy source in the kidneys. Carnitine palmitoyltransferase I (CPT1), a mitochondrial membrane enzyme, utilizes carnitine to transport fatty acids to mitochondria for the process of β-oxidation and ATP generation. In addition, CPT1 activity is indirectly regulated by adenosine monophosphate (AMP)-activated protein kinase, which can be activated by 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR). We hypothesized that administration of carnitine and AICAR could reestablish the energetic balance after reperfusion and ameliorate renal I/R injury. Male adult rats were subjected to renal I/R by bilateral renal pedicle clamping for 60 min, followed by administration of saline (vehicle), carnitine (250 mg/kg BW), AICAR (30 mg/kg BW), or combination of both drugs. Blood and renal tissues were collected 24 h after reperfusion for various measurements. Renal carnitine levels decreased 53% after I/R. The combined treatment significantly increased CPT1 activity and ATP levels, and lowered renal malondialdehyde and serum TNF-α levels against the vehicle group. It led to improvement in renal morphology and histological damage score associated with diminution in serum creatinine, blood urea nitrogen, and aspartate aminotransferase levels. Moreover, the combined treatment significantly improved the survival rate in comparison to the vehicle group. In contrast, administration of either drug alone did not show a significant improvement in most of the measurements. In conclusion, enhancing energy metabolism by combination of carnitine and AICAR provides a novel modality to treat renal I/R injury.
PMCID: PMC3237783  PMID: 21841537
kidney; ischemia/reperfusion; carnitine; AICAR; CPT1; energy metabolism
6.  Protective effect of milk fat globule-EGF factor VIII after renal ischemia-reperfusion injury in mice 
Critical care medicine  2011;39(9):2039-2047.
Renal ischemia-reperfusion (I/R) injury causes acute renal failure and the hallmarks of renal I/R injury are inflammation, apoptosis, necrosis, and capillary dysfunction. Milk fat globule-EGF factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, is produced by immune cells and reported to participate in multiple physiological processes associated with tissue remodeling. We have recently shown that MFG-E8 treatment attenuates organ injury, inflammatory responses, and survival after sepsis through the enhancement of phagocytosis of apoptotic cells. The purpose of this study was to determine whether administration of MFG-E8 attenuates renal I/R injury.
Prospective, controlled, and randomized animal study.
A research institute laboratory.
Male C57BL/6J mice (20–25g).
Renal I/R injury with bilateral renal pedicle clamping for 45 minutes, followed by reperfusion. A recombinant murine MFG-E8 (rmMFG-E8; 0.4 µg/20g) was given intraperitoneally at the beginning of reperfusion.
Measurements and Main Results
MFG-E8 levels, organ injury variables, inflammatory responses, histology, apoptosis, and capillary functions were assessed at 1.5 and 20 hours after reperfusion. A 60-hour survival study was conducted in MFG-E8−/− and rmMFG-E8-treated wild-type (WT) mice. After renal I/R injury, MFG-E8 mRNA and protein expressions were significantly decreased in the kidneys and spleen. Treatment with rmMFG-E8 recovered renal dysfunction, significantly suppressed inflammatory responses, apoptosis, necrosis, and improved capillary functions in the kidneys. In the survival study, MFG-E8−/− mice showed a significant deterioration and, in contrast, rmMFG-E8-treated WT mice showed a significant improvement of survival compared with vehicle-treated WT mice.
MFG-E8 can be developed as novel treatment for renal I/R injury. This protective effect appears to be mediated through the enhancement of apoptotic cell clearance and improvement of capillary functions in the kidneys.
PMCID: PMC3158289  PMID: 21666453
MFG-E8; renal ischemia-reperfusion injury; inflammation; apoptosis; necrosis; capillary function
7.  Association between insertion/deletion polymorphism in angiotensin-converting enzyme gene and acute lung injury/acute respiratory distress syndrome: a meta-analysis 
BMC Medical Genetics  2012;13:76.
A previous meta-analysis reported a positive association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the risk of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality.
We searched electronic databases through October 2011 for the terms “angiotensin-converting enzyme gene”, “acute lung injury”, and “acute respiratory distress syndrome,” and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models.
The ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects ( Pallele < 0.0001, Pdominant = 0.001, Precessive = 0.002). This finding remained significant after correction for multiple comparisons.
There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.
PMCID: PMC3459791  PMID: 22938636
Angiotensin-converting enzyme (ACE) gene; Acute lung injury (ALI); Acute respiratory distress syndrome (ARDS); Meta-analysis
8.  Surgical wound management made easier and more cost-effective 
Oncology Letters  2012;4(1):97-100.
Evidence-based guidelines for the prevention of surgical site infection (SSI) have been published by the U.S. Centers for Disease Control and Prevention (CDC). According to these guidelines, a wound should usually be covered with a sterile dressing for 24 to 48 h when a surgical incision is closed primarily. However, it is not recommended that an incision be covered by a dressing beyond 48 h. In this study, patients were stratified into two groups for analysis: patients whose surgical wound was sterilized and whose gauze was changed once daily until postoperative day 7 (7POD; group A); and patients whose surgical wound was sterilized and whose gauze was changed once daily until 2POD (group B). We evaluated the incidence of SSI, nursing hours and cost implications. The results showed that there was no significant difference in SSI occurrence between the two groups (group A, 10% vs. group B, 7.3%). By contrast, the average nursing time differed by 2.8 min (group A, 3.8 min vs. group B, 0.9 min). The material costs per patient were also reduced by $14.70 (group A, $61.80 vs. group B, $47.10). In conclusion, we applied our knowledge of the evidence-based CDC guidelines to determine whether 48-h wound management can be made easier, more uniform and more cost-effective compared to conventional wound management. The results of the present study showed that surgical wound management methods can be more convenient and inexpensive.
PMCID: PMC3398356  PMID: 22807970
surgical wound management; surgical site infection
9.  Determination of urinary trypsin inhibitor provides insight into postoperative complications in patients following esophagectomy 
The urinary trypsin inhibitor (UTI) is responsible for most of the antitryptic activity in urine and is excreted in increased amounts in urine under certain pathological conditions such as cancer and bacterial infections. Our aim in this study was to better understand the mechanisms responsible for the increase in UTI excretion on surgical stress and thus to better appreciate the information provided by inflammatory mediators. Thirty-one consecutive patients who underwent radical esophagectomy for esophageal cancer were investigated in this study. We determined serum UTI and polymorphonuclear cell elastase (PMNE), urine UTI and evaluated the effectiveness of preoperative administration of methylprednisolone on the postoperative clinical course and adverse inflammatory reactions. The results revealed that urine UTI and serum PMNE levels in the steroid group were significantly lower than those in the non-steroid group. In addition, UTI levels correlated positively with serum levels of aminotransferases. More importantly, the maximum level of urine UTI in patients without complications was lower than that in patients with complications. These results suggest that urine UTI provides useful information concerning postoperative clinical course, and that preoperative administration of methylprednisolone may contribute to decrease postoperative complications following esophagectomy.
PMCID: PMC3460310  PMID: 23060927
urinary trypsin inhibitor; steroid; esophageal cancer
10.  Pre-Treatment of Recombinant Mouse MFG-E8 Downregulates LPS-Induced TNF-α Production in Macrophages via STAT3-Mediated SOCS3 Activation 
PLoS ONE  2011;6(11):e27685.
Milk fat globule-epidermal growth factor factor 8 (MFG-E8) regulates innate immune function by modulating cellular signaling, which is less understood. Herein, we aimed to investigate the direct anti-inflammatory role of MFG-E8 in macrophages by pre-treatment with recombinant murine MFG-E8 (rmMFG-E8) followed by stimulation with LPS in RAW264.7 cells and in peritoneal macrophages, isolated from wild-type (WT) or MFG-E8−/− mice. RAW264.7 cells and mouse peritoneal macrophages treated with rmMFG-E8 significantly downregulated LPS-induced TNF-α mRNA by 25% and 24%, and protein levels by 29% and 23%, respectively (P<0.05). Conversely, peritoneal macrophages isolated from MFG-E8−/− mice produced 28% higher levels of TNF-α, as compared to WT mice when treated with LPS. In in vivo, endotoxemia induced by intraperitoneal injection of LPS (5 mg/kg BW), at 4 h after induction, serum level of TNF-α was significantly higher in MFG-E8−/− mice (837 pg/mL) than that of WT (570 pg/mL, P<0.05). To elucidate the direct anti-inflammatory effect of MFG-E8, we examined STAT3 and its target gene, SOCS3. Treatment with rmMGF-E8 significantly induced pSTAT3 and SOCS3 in macrophages. Similar results were observed in in vivo treatment of rmMFG-E8 in peritoneal cells and splenic tissues. Pre-treatment with rmMFG-E8 significantly reduced LPS-induced NF-κB p65 contents. These data clearly indicated that rmMFG-E8 upregulated SOCS3 which in turn interacted with NF-κB p65, facilitating negative regulation of TLR4 signaling for LPS-induced TNF-α production. Our findings strongly suggest that MFG-E8 is a direct anti-inflammatory molecule, and that it could be developed as a therapy in attenuating inflammation and tissue injury.
PMCID: PMC3217009  PMID: 22114683
11.  Milk Fat Globule-EGF Factor VIII in Sepsis and Ischemia-Reperfusion Injury 
Molecular Medicine  2010;17(1-2):126-133.
Sepsis and ischemia-reperfusion (I/R) injury are among the leading causes of death in critically ill patients at the surgical intensive care unit setting. Both conditions are marked by the excessive inflammatory response which leads to a lethal disease complex such as acute lung injury, systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Despite the advances in the understanding of the pathophysiology of those conditions, very little progress has been made toward therapeutic interventions. One of the key aspects of these conditions is the accumulation of apoptotic cells that have the potential to release toxic and proinflammatory contents due to secondary necrosis without appropriate clearance by phagocytes. Along with the prevention of apoptosis, that is reported to be beneficial in sepsis and I/R injury, thwarting the development of secondary necrosis through the active removal of apoptotic cells via phagocytosis may offer a novel therapy. Milk fat globule-EGF factor VIII (MFG-E8), which is mainly produced by macrophages and dendritic cells, is an opsonin for apoptotic cells and acts as a bridging protein between apoptotic cells and phagocytes. Recently, we have shown that MFG-E8 expression is decreased in experimental sepsis and I/R injury models. Exogenous administration of MFG-E8 attenuated the inflammatory response as well as tissue injury and mortality through the promotion of phagocytosis of apoptotic cells. In this review, we describe novel information available about the involvement of MFG-E8 in the pathophysiology of sepsis and I/R injury, and the therapeutic potential of exogenous MFG-E8 treatment for those conditions.
PMCID: PMC3022991  PMID: 20882259
12.  Laparoscopic Treatment for Torsion of the Gallbladder in a 7-year-old Female 
A 7-year-old girl was diagnosed with viral enteritis and was admitted to our hospital. Sudden right upper quadrant tenderness appeared 2 days after admission. Ultrasonography revealed a large thick-walled cystic gallbladder and an inflammation-induced hyperechoic cystic duct. The long axis of the gallbladder was in a horizontal rather than a vertical alignment. Computed tomography demonstrated a markedly enlarged gallbladder with a slightly thickened wall and an enhanced twisted cystic pedicle. The diagnosis of gallbladder torsion led to laparoscopic detorsion and cholecystectomy. The gallbladder was gangrenous and was rotated counterclockwise with the attachment of the mesentery to the inferior surface of the liver. Although it occurs more rarely in children than in adults, torsion of the gallbladder must be considered in the differential diagnosis of an acute abdomen. Early diagnosis and immediate laparoscopic intervention can help to achieve an excellent patient outcome.
PMCID: PMC3015957  PMID: 19793492
Torsion; Volvulus; Gallbladder
13.  Circulating IGF-binding protein 7 (IGFBP7) levels are elevated in patients with endometriosis or undergoing diabetic hemodialysis 
Insulin-like growth factor-binding protein-7 (IGFBP7) is a secretory protein with a molecular mass of approximately 30 kDa. It is abundantly expressed in the uterine endometrium during the secretory phase of the menstrual cycle. Decreased IGFBP7 expression has been observed in some cancers and leiomyomata.
To determine whether serum IGFBP7 levels reflect changes in uterine IGFBP7 expression in humans during the menstrual cycle, and to examine whether serum IGFBP7 levels are altered in patients with various disorders, we developed a novel, dual-antibody sandwich enzyme-linked immunosorbent assay (ELISA). Firstly, concentrations of IGFBP7 released into the medium were determined in cultured endometrial stromal and glandular cells. Blood samples were collected from women who had normal menstrual cycles and who had been diagnosed with endometriosis. Serum from hemodialysis patients and gastrointestinal cancers was also used to determine the IGFBP7 levels.
Using this new ELISA, we demonstrated that cultured uterine cells secrete IGFBP7 into the medium. Patients with endometriosis and those with type II diabetes mellitus undergoing hemodialysis had significantly higher serum concentrations of IGFBP7 than the relevant control subjects. There were no differences in serum IGFBP7 levels in women at different stages of the menstrual cycle. Furthermore, serum IGFBP7 levels in patients with colorectal, esophageal, or endometrial cancer were not different than normal healthy subjects.
Our observations suggest that IGFBP7 is associated with the pathophysiology of endometriosis and diabetes mellitus, and that serum IGFBP7 levels do not reflect enhanced uterine expression of IGFBP7 mRNA during the menstrual cycle.
PMCID: PMC2600820  PMID: 19019211
14.  Multiple early gastric cancer with duodenal invasion 
Early gastric cancers with duodenal invasion are rare, and no previous case of multiple early gastric cancer, one invading the duodenal bulb, has been reported.
Case presentation
A 79-year-old woman was investigated for upper abdominal discomfort. Endoscopic examination revealed an irregular nodulated lesion in the antrum area, and a reddish aggregated-type semi-circumferential nodulated lesion extending from the prepyloric area to the duodenal bulb through the normal mucosa with the antrum lesion. Biopsy revealed a tubular adenoma for the antrum lesion and a well-differentiated tubular adenocarcinoma for the prepyloric lesion. Distal gastrectomy with sufficient duodenal resection was performed. Microscopically, the antrum lesion appeared as a papillary adenocarcinoma, and the prepyloric lesion as a mainly papillary adenocarcinoma which partially invaded the submucosa without any sequential elongation for endoscopic findings. The lesion extended into the duodenal bulb, and was 12 mm in length from the oral end of Brunner's gland's area and limited within the duodenal mucosa.
Here, we present an unusual case of multiple early gastric cancer, one of which invaded the duodenum with relative wide mucosal spreading. This case illustrates that even early stage cancers located in the gastric antrum, particularly in the prepyloric area can invade the duodenum directly.
PMCID: PMC2173897  PMID: 17971200

Results 1-14 (14)