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- Knock-Down of IL-1Ra in Obese Mice Decreases Liver Inflammation and Improves Insulin Sensitivity. [JOURNAL ARTICLE]
- PLoS One 2014; 9(9):e107487.
Interleukin 1 Receptor antagonist (IL-1Ra) is highly elevated in obesity and is widely recognized as an anti-inflammatory cytokine. While the anti-inflammatory role of IL-1Ra in the pancreas is well established, the role of IL-1Ra in other insulin target tissues and the contribution of systemic IL-1Ra levels to the development of insulin resistance remains to be defined. Using antisense knock down of IL-1Ra in vivo, we show that normalization of IL-1Ra improved insulin sensitivity due to decreased inflammation in the liver and improved hepatic insulin sensitivity and these effects were independent of changes in body weight. A similar effect was observed in IL1-R1 KO mice, suggesting that at high concentrations of IL-1Ra typically observed in obesity, IL-1Ra can contribute to the development of insulin resistance in a mechanism independent of IL-1Ra binding to IL-1R1. These results demonstrate that normalization of plasma IL-1Ra concentration improves insulin sensitivity in diet- induced obese mice.
- Primary Pancreatic Choriocarcinoma Revealed on FDG PET/CT. [JOURNAL ARTICLE]
- Clin Nucl Med 2014 Sep 18.
Choriocarcinoma is a cancer that usually occurs in the uterus during pregnancy. Extragonadal choriocarcinoma, although very rare, can occur. The diagnostic dilatation and curettage of the uterus in a 28-year-old woman who had vaginal bleeding and elevated human chorionic gonadotrophin level failed to identify any abnormality. FDG PET/CT revealed abnormal activity in the head of the pancreas. Pathological examination after partial pancreatectomy demonstrated primary choriocarcinoma in the pancreas.
- A Partnership Model Between High- and Low-Volume Hospitals to Improve Results in Hepatobiliary Pancreatic Surgery. [JOURNAL ARTICLE]
- Ann Surg 2014 Sep 19.
To optimize the results of low-volume (LV) centers for hepatopancreaticobiliary (HPB) surgery.High-volume (HV) centers for HPB surgery have lower mortality than LV. Strategies for collaboration between HV and LV centers are not well investigated.Postoperative outcomes of patients undergoing curative HPB resection were evaluated at an LV hospital before (2006-2008) and during the collaboration (2009-2012) and at 2 hospitals with HV for either liver or pancreatic resection (2009-2012). Itinerant tutor surgeons from the HV centers were involved in the pre-, intra- and postoperative course of HPB patients at the LV hospital.HPB cases at the LV center increased from 18 to 40 patients per year from 2006 to 2012, whereas 6-month postoperative mortality decreased from 17.8% (2006-2008) to 6% (2009-2012), P < 0.05 (liver: 10.3% vs 4.7% and pancreas: 29.4% vs 7.9%). During the collaborative study period, outcomes for hepatectomy were similar for LV and HV (85 vs 507 cases): postoperative Clavien-Dindo scores 4 and 5 were 2% and 0.2% for HV versus 2.4% and 1.2% for LV, respectively. Outcomes for pancreatic procedures (LV 63 vs HV 269 cases) showed better postoperative Clavien-Dindo scores 4 and 5 in the HV (0.7% score 4 and 1.5% score 5 for HV vs 3.2% and 6.3%, respectively, for LV) but the difference disappeared in the last 2 years (2011-2012) and matching the cases.Our partnership model helped improve postoperative outcomes at the LV center. Results at the LV hospital were comparable with the HV centers, although 2 years of partnership were required to achieve this in pancreatic surgery.
- Preoperative Pancreatic Resection (PREPARE) Score: A Prospective Multicenter-Based Morbidity Risk Score. [JOURNAL ARTICLE]
- Ann Surg 2014 Sep 19.
Development of a simple preoperative risk score to predict morbidity related to pancreatic surgery.Pancreatic surgery is standardized with little technical diversity among institutions and unchanging morbidity and mortality rates in recent years. Preoperative identification of high-risk patients is potentially one of the rare avenues for improving the clinical course of patients undergoing pancreatic surgery.Using a prospectively collected multicenter database of patients undergoing pancreatic surgery (n = 703), surgical complications were classified according to the Clavien-Dindo classification. A new scoring system for preoperative identification of high-risk patients that included only objective preoperatively assessable variables was developed using a multivariate regression model. Subsequently, this scoring system was prospectively validated from 2011 to 2013 (n = 429) in a multicenter setting.Eight independent preoperatively assessable variables were identified and included in the scoring system: systolic blood pressure, heart rate, hemoglobin level, albumin level, ASA (American Society of Anesthesiologists) score, surgical procedure, elective surgery or not, and disease of pancreatic origin or not. On the basis of 3 subgroups (low risk, intermediate risk, high risk), the proposed scoring system reached an accuracy of 75% for correctly predicting occurrence or nonoccurrence of major surgical complications in 80% of all analyzed patients within the validation cohort (c-statistic index = 0.709, P < 0.001, 95% confidence interval = 0.657-0.760).We present an easily applied scoring system with convincing accuracy for identifying low-risk and high-risk patients. In contrast to other systems, the score is exclusively based on objective preoperatively assessable characteristics and can be rapidly and easily calculated.
- Neurotrophic Factor Artemin Promotes Invasiveness and Neurotrophic Function of Pancreatic Adenocarcinoma in Vivo and in Vitro. [JOURNAL ARTICLE]
- Pancreas 2014 Sep 19.
The aim of this study was to investigate the effect of the neurotrophic factor Artemin on neuroplasticity and perineural invasion of pancreatic adenocarcinoma.Artemin expressions were detected in human pancreatic adenocarcinoma tissues by Western blot and immunohistochemistry. Artemin overexpression and RNA interference in the pancreatic cancer cell lines were performed to evaluate the effects of Artemin on cell proliferation, invasion, and neurotrophic activity in vitro and in nude orthotopic transplantation tumor models.Artemin expression in pancreatic cancer tissues was related to the incidence of lymphatic metastasis and perineural invasion as well as the mean density and total area of nerve fibers. Overexpression of Artemin in pancreatic cancer cell lines improved colony formation, cell migration, matrigel invasion, and neurotrophic activity in vitro. This overexpression also increased the volume of nude orthotopic transplantation tumors; promoted cancer cell invasion of the peripheral organs, nerves, vessels, and lymph nodes; and stimulated the proliferation of peritumoral nerve fibers. Artemin depletion by RNA interference had an inhibitory effect mentioned previously.Artemin could promote invasiveness and neurotrophic function of pancreatic adenocarcinoma in vivo and in vitro. Therefore, Artemin could be used as a new therapeutic target of pancreatic carcinoma.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
- MicroRNA Dysregulation in Liver and Pancreas of CMP-Neu5Ac Hydroxylase Null Mice Disrupts Insulin/PI3K-AKT Signaling. [JOURNAL ARTICLE]
- Biomed Res Int 2014.:236385.
CMP-Neu5Ac hydroxylase (Cmah)-null mice fed with a high-fat diet develop fasting hyperglycemia, glucose intolerance, and pancreatic β-cell dysfunction and ultimately develop characteristics of type 2 diabetes. The precise metabolic role of the Cmah gene remains poorly understood. This study was designed to investigate the molecular mechanisms through which microRNAs (miRNAs) regulate type 2 diabetes. Expression profiles of miRNAs in Cmah-null mouse livers were compared to those of control mouse livers. Liver miFinder miRNA PCR arrays (n = 6) showed that eight miRNA genes were differentially expressed between the two groups. Compared with controls, seven miRNAs were upregulated and one miRNA was downregulated in Cmah-null mice. Specifically, miR-155-5p, miR-425-5p, miR-15a-5p, miR-503-5p, miR-16-5p, miR-29a-3p, and miR-29b-3p were significantly upregulated in the liver and pancreas of Cmah-null mice. These target miRNAs are closely associated with dysregulation of insulin/PI3K-AKT signaling, suggesting that the Cmah-null mice could be a useful model for studying diabetes.
- Physical activity in solid organ transplant recipients: organizational aspects and preliminary results of the italian project. [Journal Article]
- Transplant Proc 2014 Sep; 46(7):2345-9.
Most of the difficulties when trying to realize the proposal to prescribe physical activity for transplantation patients come from patient attitudes and cultural beliefs that ignore the benefits of exercise, but there also are organizational aspects arising from the difficulties that these patients face in accessing supervised exercise facilities. To address these difficulties, the Italian study project "Transplant … and Now Sport" was developed based on a model of cooperation among transplantation specialists, sports physicians, and exercise specialists organized as a team combining their specific skills to effectively actuate the physical exercise programs. This preliminary report is based on 26 patients (16 male, 10 female; 47.8 ± 10.0 years old; 21 kidney and 5 liver transplantations; time from transplantation 2.3 ± 1.4 years) who performed prescribed and supervised exercises consisting of 3 sessions per week of aerobic and strengthening exercises for 1 year. Preliminary results show a significant decrease in body mass index (t = 1.966; P < .05) and a significant increase in peak aerobic power (t = 4.535; P < .01) and maximum workload (t = 4.665; P < .01) on the incremental cycling test. Also maximum strength of knee extensors (t = 2.933; P < .05) and elbow flexors (t = 2.450; P < .05) and countermovement jump performance (t = 2.303; P < .05) significantly increased. Creatinine and proteinuria tended to decrease, but the differences were not significant. In health-related quality of life assessed by the SF-36 questionnaire, the Bodily Pain, General Health, Vitality, Social Functioning, and Role Emotional scale scores showed a significant improvement (P < .05). Preliminary results of the study protocol "Transplant…and Now Sport" show the positive effects of the model based on cooperation among transplantation centers, sports medicine centers, and gyms in the administration of a supervised exercise prescription. These data should be considered a contribution to developing and promoting further detailed exercise protocols and to fostering improved posttransplantation health and survival, helping to ensure that physical activity becomes a safe routine medical treatment plan of patient management.
- Desensitization With Plasmapheresis and Anti-Cd20 for ABO Incompatible Kidney Transplantation From Living Donor: Experience of a Single Center in Italy. [Journal Article]
- Transplant Proc 2014 Sep; 46(7):2209-13.
Blood group incompatibility in kidney transplants from a living donor can be successfully overcome by using various desensitization protocols: intravenous immunoglobulin, plasmapheresis (PP), immunoadsorption, and double filtration PP.From July 2010 to October 2013, we performed 10 ABO incompatible kidney transplantation (KT) procedures from a living donor. The desensitization protocol was based on rituximab and PP + cytomegalovirus immune globulin. All patients received induction with basiliximab, except 1 case treated with Thymoglobuline(®) (ATG) for the simultaneous presence of donor-specific antibody. Tacrolimus and mycophenolate mofetil were initiated at the time of desensitization and continued after the transplant.After a mean follow-up of 11.6 ± 10.4 months, all patients are alive with a functioning graft. The mean serum creatinine concentration at 1 month, 3 months, 6 months, and 1 year was 1.48 ± 0.29, 1.47 ± 0.18, 1.47 ± 0.27, and 1.5 ± 0.27 mg/dl. Three episodes of acute cellular rejection occurred in 2 patients. There was only 1 case of BK virus infection, treated with reduction of immunosuppressive therapy. The protocol biopsy specimens at 1, 3, and 6 months were C4d positive in the absence of acute rejection.Desensitization with rituximab, PP, and anti-cytomegalovirus immune globulin allowed us to perform transplants from living donors to ABO incompatible recipients with excellent results and reduced costs.
- Autoantibody Profiling in a Cohort of Pediatric and Adult Patients With Autoimmune Hepatitis. [JOURNAL ARTICLE]
- J Clin Lab Anal 2014 Sep 19.
Autoimmune hepatitis (AIH) is a rare condition characterized by the presence of autoantibodies distinctive of type 1 AIH (AIH-1) and type 2 AIH (AIH-2). The aim of this study was to evaluate the autoantibody profile in a cohort of pediatric and adult AIH patients, using both indirect immunofluorescence (IIF) and a new multiplexed line-blot assay.Sera from 63 pediatric and 53 adult AIH patients were tested for antinuclear (ANA), antismooth muscle (SMA), anti-liver kidney microsome 1 (anti-LKM1), anti-liver cytosol 1 (anti-LC1) autoantibodies using IIF methods; for anti-LKM1, anti-LC1, and soluble liver antigen/liver-pancreas (anti-SLA/LP) autoantibodies using the line-blot; for anti-F-actin autoantibodies using IIF both on VSM47 cell-line and on rat intestinal epithelial cells.AIH-1 was the most common type of AIH in the adult cohort (73.6%), while AIH-2 was the most common AIH in the pediatric cohort (61.9%). Both in adult and pediatric AIH-2 anti-LKM1 were the prevalent autoantibodies. In pediatric AIH-2 anti-LC1 autoantibodies were more frequent than in adult AIH-2 (59 vs. 28.6%), and in 35.9% of cases they were present alone. In 17 patients anti-LC1 autoantibodies were detected only with the line-blot assay. The levels of anti-LKM1 and of anti-LC1 were not different between adult and pediatric AIH, and the overall agreement between the results obtained with the two IIF methods for F-actin detection was 98.8% (CI 95%: 94.4-99.7%).The line-blot assay showed a higher sensitivity than IIF for anti-LC1 detection. Anti-LKM1 and anti-LC1 autoantibody levels are not different in adults and children. An almost perfect agreement between the two IIF methods for anti-F-actin detection has been observed.
- Immunogenicity of allogeneic mesenchymal stem cells transplanted via different routes in diabetic rats. [JOURNAL ARTICLE]
- Cell Mol Immunol 2014 Sep 22.
Due to their hypoimmunogenicity and unique immunosuppressive properties, mesenchymal stem cells (MSCs) are considered one of the most promising adult stem cell types for cell therapy. Although many studies have shown that MSCs exert therapeutic effects on several acute and subacute conditions, their long-term effects are not confirmed in chronic diseases. Immunogenicity is a major limitation for cell replacement therapy, and it is not well understood in vivo. We evaluated the immunogenicity of allogeneic MSCs in vivo by transplanting MSCs into normal and diabetic rats via the tail vein or pancreas and found that MSCs exhibited low immunogenicity in normal recipients and even exerted some immunosuppressive effects in diabetic rats during the initial phase. However, during the later stage in the pancreas group, MSCs expressed insulin and MHC II, eliciting a strong immune response in the pancreas. Simultaneously, the peripheral blood mononuclear cells in the recipients in the pancreas group were activated, and alloantibodies developed in vivo. Conversely, in the tail vein group, MSCs remained immunoprivileged and displayed immunosuppressive effects in vivo. These data indicate that different transplanting routes and microenvironments can lead to divergent immunogenicity of MSCs.Cellular & Molecular Immunology advance online publication, 22 September 2014; doi:10.1038/cmi.2014.70.