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.

Objectives

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.

Design

Prospective, controlled, and randomized animal study.

Setting

A research institute laboratory.

Subjects

Male C57BL/6J mice (20–25g).

Interventions

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.

Conclusions

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.

Background

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.

Methods

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.

Results

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.

Conclusions

There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.

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.

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.

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.

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.

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.

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Background

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.

Conclusion

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.