Prediction of post-operative pancreatic fistula in pancreaticoduodenectomy patients using pre-operative MRI: a pilot study

Background:

Post-operative pancreatic fistula (POPF) is one of the most fearful complications which may occur after pancreaticoduodenectomy (PD). The methods used to predict POPF pre-operatively have not been studied in great detail. We analyzed correlation between various parameters related to PD including pre-operative magnetic resonance imaging (MRI) signal intensity (SI), pathology of pancreatic fibrosis and occurrence rates of POPF, and verified that MRI SI results could be the determining values for pre-operative prediction of POPF.

Methods:

From January 2005 to August 2006, we retrospectively examined 43 cases of PDs by reviewing abdominal MRI findings, degree of fibrosis of remnant pancreatic stump, and other surgery-related parameters.

Results:

POPF encountered in PD were 11 cases (25.6%). Operation time and degree of fibrosis of remnant pancreatic cut surface were related to POPF (P= 0.030, P= 0.010). The pancreas–liver SI ratio (PLSI) between fistula group and no fistula group was −0.0009 ± 0.2 and −0.1297 ± 0.2, respectively (P= 0.0004). The pancreas–spleen SI ratio (PSSI) in each group was 0.423 ± 0.25 and 0.288 ± 0.32, respectively (P= 0.014). Using quantitative analysis, the SI ratios were 1.27 and 0.66 in each group (P= 0.013).

Conclusions:

When analyzing the results of POPF in 43 patients who underwent PD, PLSI, PSSI and qualitative analysis, fistula group differed significantly from no fistula group. Using these results, it will be helpful for us to predict the occurrence of POPF pre-operatively using MRI in PD patients.     

Aldosterone-producing adrenocortical carcinoma without hypertension

Although adrenocortical tumors are common, adrenocortical carcinomas are rare. Moreover, aldosterone-producing adrenocortical carcinomas without hypertension are exceedingly rare, with only two previously reported cases.     

Meta-analysis of cytochrome P450 2C19 polymorphism and risk of adverse clinical outcomes among coronary artery disease patients of different ethnic groups treated with clopidogrel

Loss-of-function (LOF) variants of cytochrome P450 2C19 (CYP2C19) have been hypothesized to be associated with lesser degrees of platelet inhibition and increased risk for recurrent ischemic events in patients with coronary artery disease on clopidogrel therapy; however, studies from Western countries have yielded mixed results. We aimed to assess the impact of CYP2C19 LOF variants on clinical outcomes from different ethnic groups. Sixteen prospective cohort studies including 7,035 patients carrying ≥ 1 CYP2C19 LOF allele and 13,750 patients with the wild-type genotype were included in this meta-analysis. Carriers of ≥ 1 CYP2C19 LOF allele were at significantly higher risk for adverse clinical events compared to noncarriers during clopidogrel therapy (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.13 to 1.78). The summary OR showed a significant association between CYP2C19 LOF variants and an increased risk of cardiac death (OR 2.18, 95% CI 1.37 to 3.47), myocardial infarction (OR 1.42, 95% CI 1.12 to 1.81), and stent thrombosis (OR 2.41, 95% CI 1.76 to 3.30). Stratified analysis by ethnicity of study population suggested higher odds of adverse clinical events in the Asian population with LOF variants of CYP2C19 (OR 1.89, 95% CI 1.32 to 2.72) compared to Western populations (OR 1.28, 95% CI 1.00 to 1.64). In conclusion, carrier status for LOF CYP2C19 is associated with an increased risk of adverse clinical events in patients with coronary artery disease on clopidogrel therapy despite differences in clinical significance according to ethnicity.     

Generation of lymphocytes potentiated against leukemic lymphoblasts by stimulation using leukemic cell lysate-pulsed dendritic cells in patients with acute lymphoblastic leukemia and measurement of in vitro anti-leukemic cytotoxicity

Using granulocyte-macrophage colony stimulating factor, interleukin4 and tumor necrosis factor α, we generated dendritic cells (DCs) from mononuclear cells isolated from the peripheral blood (PB) of eight patients with acute lymphoblastic leukemia (ALL), who were in complete remission (CR), and pulsed these DCs with leukemic cell lysates. Specific cytotoxicity assays were performed by incubation of effector cells (lymphocytes generated from cryopreserved mononuclear cells isolated in CR state of ALL) and targets (cryopreserved leukemic cells at diagnosis). Patients showing decreased cytotoxicity had poorer clinical courses. When we measured lymphocyte subsets, we found positive correlations between cytotoxicity levels and the proportions of T lymphocytes and CD8+ T lymphocytes, but negative correlations between cytotoxicity levels and the proportions of NK cells and regulatory T lymphocytes. In conclusion, we show here that leukemia-specific autologous DCs can be generated from the PB of ALL patients in CR, that the incubation of these DCs with leukemic cell lysates can generate lymphocytes potentiated against leukemic cells, and that relationships are evident among all of cytotoxicity, lymphocyte subsets, and patient prognosis.     

Identification and characterization of a novel efflux-related multidrug resistance phenotype in Staphylococcus aureus

Moxifloxacin is a C8-methoxy (C8-OMe) fluoroquinolone that is highly active against Staphylococcus aureus, including many strains resistant to older fluoroquinolones such as ciprofloxacin. Available data indicate that it is a poor substrate for the NorA multidrug efflux pump. We produced a mutant of S. aureus in vitro (SA-K2068) with a novel non-NorA-mediated multidrug resistance phenotype characterized by raised MICs of several fluoroquinolones, including the C8-OMe fluoroquinolones, moxifloxacin and gatifloxacin, and the organic cations ethidium and tetraphenylphosphonium. Reserpine reduced MIC increases by two- to eight-fold. SA-K2068 also demonstrated reduced accumulation of moxifloxacin, gatifloxacin and enoxacin, and increased efflux of ethidium, activities that were completely blocked by carbonyl cyanide m-chlorophenyl hydrazone (CCCP); competition experiments indicated that a single pump was responsible for the phenotype. The effect of CCCP and ionophores identified the proton motive force as the source of energy for efflux. These data, combined with previous work from our laboratory and genome sequence data, indicate that S. aureus possesses several multidrug efflux pump proteins and it is apparent that C8-OMe fluoroquinolones can be substrates for such pumps.     

Molecular remedy of complex I defects: Rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria restores the NADH oxidase activity of complex I-deficient mammalian cells

The NDI1 gene encoding rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria was cotransfected into the complex I-deficient Chinese hamster CCL16-B2 cells. Stable NDI1-transfected cells were obtained by screening with antibiotic G418. The NDI1 gene was shown to be expressed in the transfected cells. The expressed Ndi1 enzyme was recognized to be localized to mitochondria by immunoblotting and confocal immunofluorescence microscopic analyses. Using digitonin-permeabilized cells, it was shown that the transfected cells, but not nontransfected control cells, exhibited the electron transfer activities with glutamate/malate as the respiratory substrate. The activities were inhibited by flavone, antimycin A, and KCN but not by rotenone. Added NADH did not serve as the substrate, suggesting that the expressed Ndi1 enzyme was located on the matrix side of the inner mitochondrial membranes. Furthermore, although nontransfected cells could not survive in a medium low in glucose (0.6 mM), which is a substrate of glycolysis, the NDI1-transfected cells were able to grow in the absence of added glucose. When glycolysis is slow, either at low glucose concentrations or in the presence of galactose, respiration is required for cells to survive. The mutant cells do not survive at low glucose or in galactose, but they can be rescued by Ndi1. These results indicated that the S. cerevisiae Ndi1 was expressed functionally in CCL16-B2 cells and catalyzed electron transfer from NADH in the matrix to ubiquinone-10 in the inner mitochondrial membranes. It is concluded that the NDI1 gene provides a potentially useful tool for gene therapy of mitochondrial diseases caused by complex I deficiency.     

Diffusion-weighted imaging of biliopancreatic disorders: correlation with conventional magnetic resonance imaging

Diffusion-weighted magnetic resonance imaging (DWI) is a well established method for the evaluation of intracranial diseases, such as acute stroke. DWI for extracranial application is more difficult due to physiological motion artifacts and the heterogeneous composition of the organs. However, thanks to the newer technical development of DWI, DWI has become increasingly used over the past few years in extracranial organs including the abdomen and pelvis. Most previous studies of DWI have been limited to the evaluation of diffuse parenchymal abnormalities and focal lesions in abdominal organs, whereas there are few studies about DWI for the evaluation of the biliopancreatic tract. Although further studies are needed to determine its performance in evaluating bile duct, gallbladder and pancreas diseases, DWI has potential in the assessment of the functional information on the biliopancreatic tract concerning the status of tissue cellularity, because increased cellularity is associated with impeded diffusion, as indicated by a reduction in the apparent diffusion coefficient. The detection of malignant lesions and their differentiation from benign tumor-like lesions in the biliopancreatic tract could be improved using DWI in conjunction with findings obtained with conventional magnetic resonance cholagiopancreatography. Additionally, DWI can be useful for the assessment of the biliopancreatic tract in patients with renal impairment because contrast-enhanced computed tomography or magnetic resonance scans should be avoided in these patients.     

Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease

AIM: To evaluate the noninvasive parameters and hepatic fibrosis scores in obese children with nonalcoholic fatty liver disease (NAFLD).METHODS: A total of 77 children diagnosed with NAFLD via liver biopsy were included and divided into 2 subgroups according to the histopathologic staging of hepatic fibrosis: mild (stage 0-1) vs significant fibrosis (stage 2-4). Clinical and laboratory parameters were evaluated in each patient. The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST/platelet ratio index (APRI), PGA index, Forns index, FIB-4, NAFLD fibrosis score, and pediatric NAFLD fibrosis index (PNFI) were calculated.RESULTS: No clinical or biochemical parameter exhibited a significant difference between patients with mild and significant fibrosis. Among noninvasive hepatic fibrosis scores, only APRI and FIB4 revealed a significant difference between patients with mild and significant fibrosis (APRI: 0.67 ± 0.54 vs 0.78 ± 0.38, P = 0.032 and FIB4: 0.24 ± 0.12 vs 0.31 ± 0.21, P = 0.010). The area under the receiving operating characteristic curve of FIB4 was 0.81, followed by Forns index (0.73), APRI (0.70), NAFLD fibrosis score (0.58), AST/ALT ratio (0.53), PGA score (0.45), and PNFI (0.41).CONCLUSION: APRI and FIB4 might be useful noninvasive hepatic fibrosis scores for predicting hepatic fibrosis in children with NAFLD.     

The Effects of Combined Treatment with an HMG-CoA Reductase Inhibitor and PPARγ Agonist on the Activation of Rat Pancreatic Stellate Cells

Background/Aims

Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPARγ) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPARγ agonists separately inhibit pancreatic stellate cell (PaSC) activation. We studied the effects of a combination of both types of drugs on activated PaSCs via platelet-derived growth factor (PDGF), which has not previously been reported. The present study was performed to elucidate the underlying mechanisms of these effects by focusing on the impact of the signaling associated with cell-cycle progression.

Methods

Primary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantified using the BrdU method, and cell-cycle analysis was performed using a fluorescent activated cell sorter. The protein expression levels of smooth muscle actin (SMA), extracellular signal-regulated kinase (ERK), and a cell cycle machinery protein (p27Kip1) were investigated using Western blot analysis.

Results

Simvastatin reversed the effects of PDGF on cell proliferation in a dose-dependent manner. The combination of a low concentration of simvastatin (1 mM) and troglitazone (10 mM) synergistically reversed the effects of PDGF on cell proliferation but had no effect on cell viability. The expression of a-SMA was markedly attenuated by combining the two drugs, which blocked the cell cycle beyond the G0/G1 phase by reducing the levels of phosphorylated ERK and reversed the expression of p27Kip1 interrupted by PDGF.

Conclusions

Simvastatin and troglitazone synergistically inhibited cell proliferation in activated PaSCs by blocking the cell cycle beyond the G0/G1 phase. This inhibition was due to the synergistic modulation of the ERK pathway and the cell cycle machinery protein p27Kip1.