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Comparison of macrophage migration inhibitory factor and neutrophil gelatinase-associated lipocalin-2 to predict acute kidney injury after liver transplantation: An observational pilot study.

Thu, 08/17/2017 - 18:48
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Comparison of macrophage migration inhibitory factor and neutrophil gelatinase-associated lipocalin-2 to predict acute kidney injury after liver transplantation: An observational pilot study.

PLoS One. 2017;12(8):e0183162

Authors: Baron-Stefaniak J, Schiefer J, Miller EJ, Berlakovich GA, Baron DM, Faybik P

Abstract
INTRODUCTION: Several biomarkers have been suggested as early predictors of acute kidney injury (AKI) after orthotopic liver transplantation (OLT). Neutrophil gelatinase-associated lipocalin-2 (NGAL) appears to be a promising predictor of AKI after OLT, but the clinical benefit remains to be proven. Recently, systemic macrophage migration inhibitory factor (MIF) has been proposed as early indicator for requirement of renal replacement therapy after OLT. The aim of this prospective, observational pilot study was to compare the predictive values of serum and urinary MIF for severe AKI after OLT to those of serum and urinary NGAL.
METHODS: Concentrations of MIF and NGAL were measured in serum and urine samples collected from patients undergoing OLT. Acute kidney injury was classified according to the KDIGO criteria, with stages 2 and 3 summarized as severe AKI. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of MIF and NGAL for the development of severe AKI.
RESULTS: Forty-five patients (mean age 55±8 years) were included. Nineteen patients (38%) developed severe AKI within 48 hours after reperfusion. At the end of OLT, serum MIF was predictive of severe AKI (AUC 0.73; 95% confidence intervals, CI 0.55-0.90; P = 0.03), whereas urinary MIF, serum NGAL, and urinary NGAL were not. On the first postoperative day, serum MIF (AUC 0.78; CI 0.62-0.93; P = 0.006), urinary MIF (AUC 0.71; CI 0.53-0.88; P = 0.03), and urinary NGAL (AUC 0.79; CI 0.64-0.93; P = 0.02) were predictive for severe AKI, while serum NGAL was not.
CONCLUSION: In the setting of OLT, MIF and NGAL had similar predictive values for the development of severe AKI.

PMID: 28813470 [PubMed - in process]

Lipophagy maintains energy homeostasis in the kidney proximal tubule during prolonged starvation.

Thu, 08/17/2017 - 18:48
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Lipophagy maintains energy homeostasis in the kidney proximal tubule during prolonged starvation.

Autophagy. 2017 Aug 16;:0

Authors: Minami S, Yamamoto T, Takabatake Y, Takahashi A, Namba T, Matsuda J, Kimura T, Kaimori JY, Matsui I, Hamano T, Takeda H, Takahashi M, Izumi Y, Bamba T, Matsusaka T, Niimura F, Isaka Y

Abstract
Macroautophagy/autophagy is a self-degradation process that combats starvation. Lipids are the main energy source in kidney proximal tubular cells (PTCs). During starvation, PTCs increase fatty acid (FA) uptake, form intracellular lipid droplets (LDs), and hydrolyze them for use. The involvement of autophagy in lipid metabolism in the kidney remains largely unknown. Here, we investigated the autophagy-mediated regulation of renal lipid metabolism during prolonged starvation using PTC-specific Atg5-deficient (atg5-TSKO) mice and an in vitro serum starvation model. Twenty-four h of starvation comparably induced LD formation in the PTCs of control and atg5-TSKO mice; however, additional 24 h of starvation reduced the number of LDs in control mice, whereas increases were observed in atg5-TSKO mice. Autophagic degradation of LDs (lipophagy) in PTCs was demonstrated by electron microscopic observation and biochemical analysis. In vitro pulse-chase assays demonstrated that lipophagy mobilizes FAs from LDs to mitochondria during starvation, whereas impaired LD degradation in autophagy-deficient PTCs led to decreased ATP production and subsequent cell death. In contrast to the in vitro assay, despite impaired LD degradation, kidney ATP content was preserved in 48-h starved atg5-TSKO mice, probably due to increased utilization of ketone bodies. This compensatory mechanism was accompanied by a higher plasma FGF21 (fibroblast growth factor 21) level and its expression in the PTCs; however, this was not essential for the production of ketone bodies in the liver during prolonged starvation. In conclusion, lipophagy combats prolonged starvation in PTCs to avoid cellular energy depletion.

PMID: 28813167 [PubMed - as supplied by publisher]

Entry Inhibitors: A Perspective for Prevention of Hepatitis C Virus Infection in Organ Transplantation.

Thu, 08/17/2017 - 18:48
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Entry Inhibitors: A Perspective for Prevention of Hepatitis C Virus Infection in Organ Transplantation.

ACS Infect Dis. 2017 Aug 16;:

Authors: Colpitts CC, Chung RT, Baumert TF

Abstract
Entry inhibitors are emerging as an attractive class of therapeutics for hepatitis C virus (HCV) infection. Entry inhibitors target either virion-associated factors or cellular factors necessary for infection. By blocking entry into cells, entry inhibitors prevent both the establishment of persistent reservoirs and the emergence of resistant variants during viral replication. Furthermore, entry inhibitors protect naïve cells from virus-induced alterations. Combining entry inhibitors with direct-acting antivirals (DAAs) may therefore improve treatment outcomes, particularly in the context of organ transplantation. The role of DAAs in transplantation, while still under clinical investigation, carries the risk of recipient infection and HCV-induced disease, since DAAs act only after infection is established. Thus, entry inhibitors provide a perspective to improve patient outcomes during organ transplantation. Applying this approach for transplant of organs from HCV-positive donors to HCV-negative recipients may also contribute to alleviate the medical burden of organ shortage.

PMID: 28812869 [PubMed - as supplied by publisher]

Increased acetaminophen related calls to Finnish PIC better reflect acetaminophen sales than serious poisonings.

Thu, 08/17/2017 - 18:48
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Increased acetaminophen related calls to Finnish PIC better reflect acetaminophen sales than serious poisonings.

Clin Toxicol (Phila). 2017 Aug 16;:1-7

Authors: Parry MJ, Isoniemi H, Koivusalo AM, Hoppu K

Abstract
OBJECTIVE: Acetaminophen (APAP) or paracetamol is a commonly encountered medicine in poisonings. We studied the changes in APAP related calls to the Finnish poison information centre (FPIC), and serious intoxications, involving hepatotoxicity or death in 2001-2014. These data were compared with paracetamol sales in Finland.
METHODS: This is a retrospective analysis of the FPIC database calls, national cause of death registry, registries of liver transplantations and molecular adsorbent recycling system (MARS)-treated patients from Helsinki University Hospital together with the National Institute of Health and Welfare registry of patients hospitalized. Data on APAP sales were obtained from the Finnish Medicines Agency.
RESULTS: Between 2001 and 2014, the number of calls/year related to human APAP exposures to the FPIC increased from 227 to 1058. No change in the age distribution of enquiries was seen. Most calls involved minors: 58% (range 52-64%) for children under 6 years old, and 9% (range 6-14%) for children of 6-15 years. In Finland, APAP related fatalities have gradually increased from an average of 7/year (range 4-10) in 2000-2005 to an average of 11/year (range 6-17) in 2010-2013, whereas the number of liver transplantations remained low, average 0.6/year (range 0-2). For patients in need of MARS-treatment, a slight decrease was seen. Total APAP sales increased from 5.6 (47% prescription, 53% OTC) to 29.7 (81% prescription, 19% OTC). DDD/1000 inhabitants/day from 2001 to 2014 is recorded. Best linear relationship (R(2) = 0.97; p < .001) was observed between total FPIC calls and total sales of APAP in 2001-2014. Fatalities show a weaker relationship with sales (R(2) = 0.317; p = .045).
CONCLUSIONS: During the study period, we see an increase in FPIC exposure calls accompanied by an increase in APAP sales. Changes in the chosen indicators for serious poisonings show only a weak association. Despite an evident trend between sales and fatalities, the correlation with fatality remains weak due to the small number of fatalities.

PMID: 28812385 [PubMed - as supplied by publisher]

Modulation of Glutathione Hemostasis by Inhibition of 12/15-Lipoxygenase Prevents ROS-Mediated Cell Death after Hepatic Ischemia and Reperfusion.

Thu, 08/17/2017 - 18:48
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Modulation of Glutathione Hemostasis by Inhibition of 12/15-Lipoxygenase Prevents ROS-Mediated Cell Death after Hepatic Ischemia and Reperfusion.

Oxid Med Cell Longev. 2017;2017:8325754

Authors: Drefs M, Thomas MN, Guba M, Angele MK, Werner J, Conrad M, Steib CJ, Holdt LM, Andrassy J, Khandoga A, Rentsch M

Abstract
BACKGROUND: Reactive oxygen species- (ROS-) mediated ischemia-reperfusion injury (IRI) detrimentally impacts liver transplantation and resection. 12/15-Lipoxygenase (12/15-LOX), an antagonistic protein of the glutathione peroxidase 4 (GPX4) signaling cascade, was proven to mediate cell death in postischemic cerebral and myocardial tissue. The aim of this study was to investigate the impact of 12/15-LOX inhibition on hepatic IRI.
METHODS: Livers of C57BL/6 mice were exposed to 60 minutes of partial warm ischemia and 90 minutes of reperfusion after previous Baicalein administration, an inhibitor of 12/15-LOX. Tissue samples were analyzed by TUNEL assay, Western blot, and spectral photometry.
RESULTS: TUNEL labeling showed a significant reduction of hepatic cell death following baicalein pretreatment. Western Blot analysis revealed a significant downregulation of Jun-amino-terminal-kinase (JNK), caspase-3, and poly-ADP-ribose-polymerase (PARP), besides considerably lowered p44/42-MAP-kinase (ERK1/2) expression after Baicalein administration. A significant elevation of glutathione oxidation was measured in Baicalein pretreated livers.
CONCLUSION: Our data show that inhibition of 12/15-lipoxygenase causes significant cell death reduction after hepatic ischemia and reperfusion by enhancing glutathione metabolism. We conclude that GPX4-dependent cell death signaling cascade might play a major role in development of hepatic IRI, in which the investigated proteins JNK, caspase-3, ERK1/2, and PARP might contribute to tissue damage.

PMID: 28811867 [PubMed - in process]

Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin, TGF-β1, IL-13 and oxidative stress.

Thu, 08/17/2017 - 18:48
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Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin, TGF-β1, IL-13 and oxidative stress.

World J Gastroenterol. 2017 Jul 28;23(28):5146-5157

Authors: de Souza VCA, Pereira TA, Teixeira VW, Carvalho H, de Castro MCAB, D'assunção CG, de Barros AF, Carvalho CL, de Lorena VMB, Costa VMA, Teixeira ÁAC, Figueiredo RCBQ, de Oliveira SA

Abstract
AIM: To evaluate the therapeutic effects of bone marrow-derived CD11b(+)CD14(+) monocytes in a murine model of chronic liver damage.
METHODS: Chronic liver damage was induced in C57BL/6 mice by administration of carbon tetrachloride and ethanol for 6 mo. Bone marrow-derived monocytes isolated by immunomagnetic separation were used for therapy. The cell transplantation effects were evaluated by morphometry, biochemical assessment, immunohistochemistry and enzyme-linked immunosorbent assay.
RESULTS: CD11b(+)CD14(+) monocyte therapy significantly reduced liver fibrosis and increased hepatic glutathione levels. Levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6 and IL-1β, in addition to pro-fibrotic factors, such as IL-13, transforming growth factor-β1 and tissue inhibitor of metalloproteinase-1 also decreased, while IL-10 and matrix metalloproteinase-9 increased in the monocyte-treated group. CD11b(+)CD14(+) monocyte transplantation caused significant changes in the hepatic expression of α-smooth muscle actin and osteopontin.
CONCLUSION: Monocyte therapy is capable of bringing about improvement of liver fibrosis by reducing oxidative stress and inflammation, as well as increasing anti-fibrogenic factors.

PMID: 28811709 [PubMed - in process]

Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

Thu, 08/17/2017 - 18:48
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Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

Transplant Rev (Orlando). 2017 Jul 26;:

Authors: Aguado JM, Silva JT, Fernández-Ruiz M, Cordero E, Fortún J, Gudiol C, Martínez-Martínez L, Vidal E, Almenar L, Almirante B, Cantón R, Carratalá J, Caston JJ, Cercenado E, Cervera C, Cisneros JM, Crespo-Leiro MG, Cuervas-Mons V, Elizalde-Fernández J, Fariñas MC, Gavaldà J, Goyanes MJ, Gutiérrez-Gutiérrez B, Hernández D, Len O, López-Andujar R, López-Medrano F, Martín-Dávila P, Montejo M, Moreno A, Oliver A, Pascual A, Pérez-Nadales E, Román-Broto A, San-Juan R, Serón D, Solé-Jover A, Valerio M, Muñoz P, Torre-Cisneros J, Spanish Society of Transplantation (SET), Group for Study of Infection in Transplantation of the Spanish Society of Infectious Diseases and Clinical Microbiology (GESITRA-SEIMC), Spanish Network for Research in Infectious Diseases (REIPI) (RD16/0016)

Abstract
Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate's phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection.

PMID: 28811074 [PubMed - as supplied by publisher]

Component separation technique for giant incisional hernia: A systematic review.

Thu, 08/17/2017 - 18:48
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Component separation technique for giant incisional hernia: A systematic review.

Am J Surg. 2017 Aug 10;:

Authors: Cornette B, De Bacquer D, Berrevoet F

Abstract
The component separation technique (CST) has gained popularity among general surgeons in the management of giant abdominal hernia. A systematic review of the MedLine and EMBASE databases was performed. 36 observational cohort studies were included for data-analysis and divided in 4 main groups: Open Anterior Approach (OAA), Transversus Abdominis Release (TAR), Laparoscopic Anterior Approach (LAA) and Perforator Preserving Approach (PPA). Surgical Site Occurrences (SSO) occurred in 21.4%, 23.7%, 20.3% and 16.0% respectively. Incidence of recurrence was 11.9% (OAA), 5.25% (TAR), 7.02% (LAA) and 6.47% (PPA) with a significant difference in the advantage of TAR over OAA (p < 0.001). Limitations in this systematic review were a lack of randomized trials, a heterogenous population and non-standardized methods for measuring outcomes, all making it difficult to postulate conclusions about CST and its modifications. Based on pooled results of 36 studies, the prevalence of SSO is comparable between the techniques with an average of one in five and the prevalence of recurrences is highest when using the Open Anterior Approach at 11.9%.

PMID: 28811004 [PubMed - as supplied by publisher]

Acute Liver Failure Due to Etodolac, a Selective Cycloxygenase- 2 (COX -2) Inhibitor Non-Steroidal Anti-Inflammatory Drug Established by RUCAM-Based Causality Assessment.

Thu, 08/17/2017 - 18:48
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Acute Liver Failure Due to Etodolac, a Selective Cycloxygenase- 2 (COX -2) Inhibitor Non-Steroidal Anti-Inflammatory Drug Established by RUCAM-Based Causality Assessment.

Ann Hepatol. 2017 Aug 08;16(5):818-821

Authors: Taneja S, Kumar P, Rathi S, Duseja A, Singh V, Dhiman RK, Chawla YK

Abstract
Drug induced liver injury is a common cause of acute liver failure (ALF). While most of these cases are due to dose dependent hepatotoxicity with acetaminophen, idiosyncratic drug-induced liver injury (DILI) is responsible for about 15% cases of ALF. Antibiotics are the most common cause of idiosyncratic DILI as well as DILI induced ALF. Etodolac is a selective cycloxygenase- 2 (COX -2) inhibitor non-steroidal anti-inflammatory drug used as an analgesic and anti-inflammatory in musculoskeletal diseases. Severe liver impairment is extremely rare. Till date, only 3 cases of ALF related to etodolac have been reported in the literature. Here we report two cases with a unique presentation of ALF occurring due to DILI caused by etodolac, as diagnosed by Roussel Uclaf Causality Assessment Method (RUCAM).

PMID: 28809737 [PubMed - in process]

Wait Time for Curative Intent Radio Frequency Ablation is Associated with Increased Mortality in Patients with Early Stage Hepatocellular Carcinoma.

Thu, 08/17/2017 - 18:48
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Wait Time for Curative Intent Radio Frequency Ablation is Associated with Increased Mortality in Patients with Early Stage Hepatocellular Carcinoma.

Ann Hepatol. 2017 Aug 08;16(5):765-771

Authors: Brahmania M, Ahmed O, Kelley M, Wong D, Kowgier M, Khalili K, Beecroft R, Renner EL, Shah H, Feld J, Janssen HLA, Sherman M

Abstract
INTRODUCTION: Radiofrequency ablation (RFA) is a recommended curative intent treatment option for patients with early stage hepatocellular carcinoma (HCC). We investigated if wait times for RFA were associated with residual tumor, tumor recurrence, need for liver transplantation, or death.
MATERIAL AND METHODS: We conducted a retrospective study of patients diagnosed with HCC between January 2010 and December 2013 presenting to University Health Network (UHN) in Toronto, Canada. All patients receiving curative intent RFA for HCC were included. Multivariable Cox regression was used to determine if wait times were associated with clinical outcomes.
RESULTS: 219 patients were included in the study. 72.6% were male and the median age was 62.7 years (IQR 55.6-71). Median tumor size at diagnosis was 21.5 mm (IQR 17-26); median MELD was 8.7 (IQR 7.2-11.4) and 57.1% were Barcelona stage 0. The cause of liver disease was viral hepatitis in 73.5% (Hepatitis B and C). The median time from HCC diagnosis to RFA treatment was 96 days (IQR 75-139). In multivariate analysis, wait time was not associated with requiring liver transplant or tumor recurrence, however, each incremental 30-day wait time was associated with an increased risk of residual tumor (HR = 1.09; 95% CI 1.01-1.19; p = 0.033) as well as death (HR = 1.23; 95% CI 1.11-1.36; p ≤ 0.001).
CONCLUSION: Incremental 30-day wait times are associated with a 9% increased risk of residual tumor and a 23% increased risk of death. We have identified system gaps where quality improvement measures can be implemented to reduce wait times and allocate resources for future RFA treatment, which may improve both quality and efficiency of HCC care.

PMID: 28809734 [PubMed - in process]

Validation of the Simplified Criteria for the Diagnosis of Autoimmune Hepatitis in Chilean-Hispanic Patients.

Thu, 08/17/2017 - 18:48
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Validation of the Simplified Criteria for the Diagnosis of Autoimmune Hepatitis in Chilean-Hispanic Patients.

Ann Hepatol. 2017 Aug 08;16(5):772-779

Authors: Candia R, Norero B, Agu Ero C, Díaz L, Ortega JP, Wolff R, Hernández-Rocha C, Duarte I, Soza A, Benítez C, Arrese M

Abstract
INTRODUCTION AND AIM: In 2008 the International autoimmune hepatitis (AIH) Group proposed the simplified diagnostic criteria for this disease. The original cohort study was performed in 11 international centers, but validation studies are scarce in Latin-America. The aim of this study is validate these criteria in Hispanic patients.
MATERIAL AND METHODS: A retrospective cohort of patients undergoing percutaneous liver biopsy and follow-up of at least 12 months was recruited from a Chilean University hospital. Patients with previous immunosuppressive therapy and liver transplant recipients were excluded. The diagnostic accuracy was analyzed using as gold standard the clinical course during long-term follow-up. Sensitivity, specificity, positive and negative predictive values (PPV and NPV) and area under the ROC curve (AUROC) were calculated.
RESULTS: Four hundred eighty one patients were evaluated, 294 were included. 218 (74.15%) were female, mean age 48.5 (± 12.3) years, mean follow-up 34 (± 18) months. 66 patients had AIH or overlap syndrome (22.45%), 96 (32.65%) non-alcoholic steatohepatitis, 40 (13.61%) primary biliary cholangitis, 31 (10.54%) hepatitis C, 8 (2.72%) hepatitis B, 53 (18.02%) other etiologies. The AUROC for AIH simplified criteria was 0.976. Using a cutoff ≥ 6 and ≥ 7 points, the sensitivity was 86.4% and 54.6%; specificity, 98.7% and 99.6%; PPV, 95% and 97.3%; and NPV, 96.2% and 88.6%, respectively.
CONCLUSION: Simplified criteria for the diagnosis of AIH have a high accuracy in our Chilean-Hispanic cohort. The female gender is strongly associated to AIH and could help in difficult cases. Further studies with a prospective design are necessary to confirm these observations.

PMID: 28809732 [PubMed - in process]

Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease.

Thu, 08/17/2017 - 18:48
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Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease.

Acta Neuropathol. 2017 Aug 14;:

Authors: Ebbert MTW, Ross CA, Pregent LJ, Lank RJ, Zhang C, Katzman RB, Jansen-West K, Song Y, da Rocha EL, Palmucci C, Desaro P, Robertson AE, Caputo AM, Dickson DW, Boylan KB, Rademakers R, Ordog T, Li H, Belzil VV

Abstract
We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive "multi-omic" analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.

PMID: 28808785 [PubMed - as supplied by publisher]

Ultrasound Guidance for Central Venous Catheterization: A Step Further to Prevent Malposition of Central Venous Catheter before Radiographic Confirmation.

Thu, 08/17/2017 - 18:48
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Ultrasound Guidance for Central Venous Catheterization: A Step Further to Prevent Malposition of Central Venous Catheter before Radiographic Confirmation.

Indian J Crit Care Med. 2017 Jul;21(7):463-465

Authors: Midha D, Chawla V, Kumar A, Mandal AK

Abstract
Ultrasound (USG) guidance has long been used for guiding central venous catheterization. USG provides direct visualization of needle puncture through the skin into the vein. Most of the time USG guidance is just limited to puncturing of the vein and seeing guidewire entering the vein while malpositioning of catheter occurs after that which is seen later on while checking chest radiograph. Repositioning of catheter after that becomes not only difficult requiring repeated chest radiograph to reconfirm position of catheter but also increases chances of infection with repeated manipulations. USG guidance can be used for tracing both guidewire and catheter during the procedure to prevent malpositioning of catheter, thus when done at the right time can prevent complication related to malpositioning and repeated manipulations. We used linear USG probe to check malposition of guidewire and microconvex probe to confirm position of central venous catheter.

PMID: 28808369 [PubMed]

Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury.

Thu, 08/17/2017 - 18:48
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Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury.

Sci Rep. 2017 Aug 14;7(1):8119

Authors: Sydor S, Manka P, Best J, Jafoui S, Sowa JP, Zoubek ME, Hernandez-Gea V, Cubero FJ, Kälsch J, Vetter D, Fiel MI, Hoshida Y, Bian CB, Nelson LJ, Moshage H, Faber KN, Paul A, Baba HA, Gerken G, Friedman SL, Canbay A, Bechmann LP

Abstract
Krüppel-like factor 6 (KLF6) is a transcription factor and tumor suppressor. We previously identified KLF6 as mediator of hepatocyte glucose and lipid homeostasis. The loss or reduction of KLF6 is linked to the progression of hepatocellular carcinoma, but its contribution to liver regeneration and repair in acute liver injury are lacking so far. Here we explore the role of KLF6 in acute liver injury models in mice, and in patients with acute liver failure (ALF). KLF6 was induced in hepatocytes in ALF, and in both acetaminophen (APAP)- and carbon tetrachloride (CCl4)-treated mice. In mice with hepatocyte-specific Klf6 knockout (DeltaKlf6), cell proliferation following partial hepatectomy (PHx) was increased compared to controls. Interestingly, key autophagic markers and mediators LC3-II, Atg7 and Beclin1 were reduced in DeltaKlf6 mice livers. Using luciferase assay and ChIP, KLF6 was established as a direct transcriptional activator of ATG7 and BECLIN1, but was dependent on the presence of p53. Here we show, that KLF6 expression is induced in ALF and in the regenerating liver, where it activates autophagy by transcriptional induction of ATG7 and BECLIN1 in a p53-dependent manner. These findings couple the activity of an important growth inhibitor in liver to the induction of autophagy in hepatocytes.

PMID: 28808340 [PubMed - in process]

Congestive Preconditioning by Portal Venous Clamping: A Novel Preventive Concept for Small Intestinal Congestive Re-Outflow Injury.

Thu, 08/17/2017 - 18:48
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Congestive Preconditioning by Portal Venous Clamping: A Novel Preventive Concept for Small Intestinal Congestive Re-Outflow Injury.

Ann Transplant. 2017 Aug 15;22:493-498

Authors: Hayashi H, Takamura H, Gabata R, Ohbatake Y, Nakanuma S, Miyashita T, Tajima H, Ninomiya I, Fushida S, Ohta T

Abstract
BACKGROUND Congestion of the small intestine, which induces mucosal damage via apoptosis, is a common pathophysiological change in hepato-biliary-pancreatic surgery, including liver transplantation. Small intestinal mucosal damage can trigger postoperative complications via various pathways. Therefore, we investigated the efficacy of intermittent portal venous clamping, which we named congestive preconditioning (CPC), for decreasing congestive re-outflow injury (CRoI) of the small intestine. MATERIAL AND METHODS Small intestinal CRoI was induced in rats by clamping the portal vein (PV) for 30 min, followed by re-outflow. The CPC group underwent 3 episodes of 5 min PV clamping and 5 min re-outflow before CRoI. The Control group underwent CRoI after 30 min simple laparotomy without any preconditioning. Survival and histological changes in the small intestine after CRoI were analyzed. The histological changes were compared CPC group to Control group using a scoring system that expressed histopathological severity. Also, small intestinal apoptosis and expression of apoptosis-related genes were analyzed by immunohistochemistry. RESULTS The survival rate of the CPC group was significantly higher than Control group. Histological scoring of small intestinal damage was significantly lower in the CPC group after 6 h of CRoI. Expression of anti-apoptotic gene, Bcl-xL was significantly increased, but pro-apoptotic gene caspase-3 and apoptotic cells did not differ significantly between the CPC group and Control group. CONCLUSIONS Induction of CPC for small intestinal CRoI was effective, which suggests that an anti-apoptotic pathway is involved in the beneficial mechanism.

PMID: 28808225 [PubMed - in process]

Rapidly progressive atherosclerosis after domino liver transplantation from a teenage donor with homozygous familial hypercholesterolemia.

Thu, 08/17/2017 - 18:48
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Rapidly progressive atherosclerosis after domino liver transplantation from a teenage donor with homozygous familial hypercholesterolemia.

J Clin Lipidol. 2017 Jul 22;:

Authors: Golbus JR, Farhat L, Fontana RJ, Rubenfire M

Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by impaired clearance of low-density lipoprotein cholesterol. Given limitations in pharmacologic therapy and the significant morbidity and mortality associated with this disease, liver transplantation may be offered to select homozygous FH patients in childhood in an effort to slow progression of atherosclerotic cardiovascular disease. In rare cases, domino liver transplantation can be performed, transplanting the livers of patients with various metabolic disorders into elderly recipients whose projected survival precludes prolonged waiting on the transplant list. Herein, we report a case of domino liver transplantation using the liver of a 14-year-old boy with homozygous FH into a 65-year-old man with primary sclerosing cholangitis and cirrhosis who developed rapidly progressive atherosclerotic cardiovascular disease involving the arteries of his proximal bilateral lower extremities, carotid arteries and superior mesenteric artery.

PMID: 28807459 [PubMed - as supplied by publisher]

TIMP3 is Regulated by Pericytes upon Shear Stress Detection Leading to a Modified Endothelial Cell Response.

Thu, 08/17/2017 - 18:48
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TIMP3 is Regulated by Pericytes upon Shear Stress Detection Leading to a Modified Endothelial Cell Response.

Eur J Vasc Endovasc Surg. 2017 Aug 11;:

Authors: Schrimpf C, Koppen T, Duffield JS, Böer U, David S, Ziegler W, Haverich A, Teebken OE, Wilhelmi M

Abstract
OBJECTIVES: Atherosclerosis is a hallmark of cardiovascular disease. Shear stress on endothelial cells has been linked to atherogenesis and to fibrous cap thinning and rupture. Pericytes reside in the sub-endothelial space of vessels and have vasoprotective effects. They are subjected to shear stress when endothelial cell integrity is disrupted. The aim was to investigate the susceptibility and response of pericytes to shear stress.
METHODS: Endothelial cells and pericytes were seeded in two dimensional monocultures and co-cultures, and in a novel three dimensional co-culture system and were subjected to no, low and high shear stress (0, 10, 30 dyne/cm(2)) for 48 h. The morphological response to flow was assessed by histology and the expression of extracellular matrix proteins was analysed using quantitative polymerase chain reaction, immunoblotting, and ELISA.
RESULTS: While endothelial cells aligned into flow direction, pericytes aligned perpendicularly (p < .001), indicating that they must be capable of sensing flow. When pericytes were embedded into a 3D matrix they showed similar alignment and pericytes built long processes towards the lumen. Under shear stress endothelial cells upregulated "a disintegrin and metalloproteinase with thrombospondin motif 1" (ADAMTS-1) (p < .01) and pericytes upregulated "tissue inhibitor of matrix metalloproteinase" (TIMP) 3 (p < .05), an inhibitor of ADAMTS-1, meanwhile differential expression of extracellular matrix (ECM) proteins could be detected in co-cultures of both cells. For TIMP3 expression direct cell-cell contact between endothelial cells and pericytes was required.
CONCLUSION: The experiments highlight that pericytes are able to sense direct flow thereby regulating ECM proteins known to be involved in vascular remodelling. Furthermore, pericytes counter-regulate endothelial ADAMTS-1 by protective TIMP3 expression to prevent matrix degradation and maintain vascular stability. For this protective effect direct cell contact was necessary. This observation might represent an adaptive, protective mechanism of pericytes to counteract endothelial damage in the onset of atherosclerosis.

PMID: 28807411 [PubMed - as supplied by publisher]

Role of hepatic trisectionectomy in advanced hepatocellular carcinoma.

Thu, 08/17/2017 - 18:48
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Role of hepatic trisectionectomy in advanced hepatocellular carcinoma.

Surg Oncol. 2017 Sep;26(3):310-317

Authors: Tsang JS, Chok KSH, Lo CM

Abstract
BACKGROUND: Advanced hepatocellular carcinoma (HCC) with underlying cirrhosis poses a major operative challenge. Patients have a dismal prognosis without curative resection. The role of hepatic trisectionectomy in these patients is not established. The aim of this study was to analyze and compare the perioperative outcome and prognosis of patients undergoing trisectionectomy with hepatic resection of a lesser extent.
METHODS: From 2000 to 2014, 48 patients underwent hepatic trisectionectomy for HCC with background cirrhosis or chronic hepatitis (Group A). Another (Group B) 520 patients underwent liver resection of a lesser extent. Patient demographics, clinicopathological data, perioperative outcome and long-term survival were compared between the 2 groups.
RESULTS: Intraoperative bloodloss, operating time and total hospital stay were significantly higher in trisectionectomy patients. Tumors were larger and more advanced in group A. The morbidity rate was 43.8% in group A compared to 27.5% in group B, p = 0.027. In-hospital mortality was 6.3% for group A. Group A had a significantly shorter time to recurrence (4.5months vs 6.2months, p = 0.036), as well as a poorer disease-free survival (DFS) than group B (6.3 months vs 15.7 months, p = 0.02). Overall survival was comparable. Tumor number, size, albumin, INR, microvascular invasions and positive resection margins were predictors of disease-free survival.
CONCLUSION: Hepatic trisectionectomy may be associated with a higher morbidity and lower DFS. However, these patients would not be suitable candidates for ablative therapy or liver transplantation. With careful patient selection and meticulous surgical technique, trisectionectomy is feasible and gives these patients the only hope of cure.

PMID: 28807252 [PubMed - in process]

Induction of autophagy reduces ischemia/reperfusion injury in steatotic rat livers.

Thu, 08/17/2017 - 18:48
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Induction of autophagy reduces ischemia/reperfusion injury in steatotic rat livers.

J Surg Res. 2017 Aug;216:207-218

Authors: Kan C, Liu A, Fang H, Dirsch O, Dahmen U, Boettcher M

Abstract
BACKGROUND: Steatotic livers are particularly vulnerable to ischemia/reperfusion injury (IRI). One of the reasons is an underlying impairment of autophagy. Autophagy is regulated by glycogen synthase kinase 3b (GSK3b) and extracellular signal-regulated kinases (ERK1/2) pathways. Both of them are target proteins of a cell-protective drug, lithium chloride. Lithium chloride treatment reduces IRI in many organs including liver. Therefore, we aimed to investigate the effect of lithium chloride treatment on autophagy induction in steatotic rat livers. We also wanted to evaluate the related cell-protective effects on the enhanced hepatic IRI.
MATERIALS AND METHODS: After inducing hepatic steatosis, rats were injected with lithium chloride or normal saline for 3 d before being subjected to 70% selective warm ischemia for 60 min. After reperfusion, rats were observed for 30 min, 6, 24, and 48 h.
RESULTS: Lithium chloride appeared to protect hepatocytes from IRI via its ability to induce autophagy by modulation of both GSK3b and ERK1/2 pathways. Hepatic damage was significantly decreased in the treatment group as indicated by a reduced inflammatory response, less apoptosis, less necrosis, and lower liver enzyme levels.
CONCLUSIONS: Simultaneous modulation of GSK3b and ERK1/2 pathways might be an interesting strategy to reduce IRI in steatotic livers with an impairment of autophagy.

PMID: 28807209 [PubMed - in process]

Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation.

Thu, 08/17/2017 - 18:48
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Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation.

Stem Cell Res Ther. 2017 Aug 14;8(1):183

Authors: Wang P, Cong M, Liu T, Xu H, Wang L, Sun G, Yang A, Zhang D, Huang J, Sun Y, Zhao W, Ma H, Jia J, You H

Abstract
BACKGROUND: Although they are expandable in vitro, hepatic progenitors are immature cells and share many immunomarkers with hepatocellular carcinoma, raising potential concerns regarding maltransformation after transplantation. This study investigated the effects of hepatic nuclear factor (HNF) 4α on the proliferation, migration, and maltransformation of hepatic progenitors and determined the feasibility of using these manipulated cells for transplantation.
METHODS: The effects of HNF4α on rat hepatic progenitors (i.e. hepatic oval cells) were analyzed by HNF4α overexpression and HNF4α shRNA. Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice injured by carbon chloride (CCl4) were then transplanted with control, HNF4α-overexpressing or HNF4α-suppressing hepatic oval cells. Finally, the engraftment of these cells in the recipient liver was analyzed.
RESULTS: Rat hepatic progenitors (i.e. hepatic oval cells) expressed HNF4α, although less than that in hepatocytes. When HNF4α was overexpressed in these cells, the proliferation and migration of hepatic oval cells were reduced; but when HNF4α was suppressed by shRNA, the proliferation and migration, and even anchorage-independent growth, of these cells were accelerated. RNA microarray and gene functional analysis revealed that suppressing HNF4α not only impaired many biosynthesis and metabolism pathways of hepatocytes but also increased pathways for cancer. When transplanted into CCl4-injured NOD/SCID mice, few HNF4α-suppressing hepatic oval cells localized into the liver, while control cells and HNF4α-overexpressing cells engrafted into the liver and differentiated into albumin-positive hepatocytes. Interestingly, the hepatocytes derived from HNF4α-overexpressing cells were less migrative and expressed less c-Myc than the cells derived from control cells.
CONCLUSION: HNF4α constrains proliferation, migration, and maltransformation of hepatic progenitors, and HNF4α-overexpressing hepatic progenitors serve as an optimal candidate for cell transplantation.

PMID: 28807057 [PubMed - in process]

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