Alpha-1-antitrypsin deficiency (carrier) as possible risk factor for development of colonic diverticula. A multicentre prospective case-control study: the ALADDIN study.

AIM: Connective tissue changes due to ageing or diseases leading to changes in the colonic wall are one theory for the development of diverticula. Alpha-1-antitrypsin (A1AT), a protease inhibitor that protects connective tissue, possibly plays a role in the aetiology of diverticulosis. The aim of this study was to explore associations between the development of diverticula and A1AT deficiency. METHODS: This was a multicentre prospective case-control study. A total of 221 patients aged ≥ 60 years with acute abdominal pain undergoing abdominal CT were included and analysed. Patients with diverticula were defined as the research group, patients without diverticula as controls. Genotype analysis for A1AT deficiency was performed. RESULTS: Twenty-six of 221 (11.8%) patients were diagnosed with (being a carrier of) A1AT deficiency. A non-significant difference in prevalence between patients with and without diverticula was found, 20 (13.9%) of 144 vs 6 (7.8%) of 77, respectively, with a crude OR of 1.9 (95% CI 0.7-5.0; P = 0.186) and after adjustment for confounders an adjusted OR of 1.5 (95% CI 0.5-4.0; P = 0.466). A non-significant difference in 30-day mortality rate from acute diverticulitis between A1AT deficient patients (or carriers) and those without was observed: two (22.2%) of nine patients with A1AT deficiency vs 1 (1.8%) of 55 without. CONCLUSION: We found no convincing evidence that A1AT deficiency plays a role in the aetiology of diverticulitis, although deficient patients and carriers had a higher mortality when experiencing diverticulitis. Diverticulitis is a multifactorial disease and larger numbers may be needed to explore the role of A1AT deficiency among other contributing factors.

Prevalence of alpha-1-antitrypsin deficiency carriers in a population with and without colonic diverticula. A multicentre prospective case-control study: the ALADDIN study.

PURPOSE: The underling pathophysiological mechanisms that cause the formation of colonic diverticula (diverticulosis) remain unclear. Connective tissue changes due to ageing that cause changes in collagen structure of the colonic wall is one theory. Alpha-1-antitrypsin (A1AT) is a protease inhibitor known to protect connective tissue in other organs. Associations between (carriers of) A1AT deficiency and the development of colonic diverticula will be the main focus of this study. METHODS: A multicentre prospective case-controlled study. In total, 230 patients ≥ 60 years with acute abdominal pain undergoing an abdominal computed tomography (CT) will be included. The research group consists of patients with diverticulosis and/or diverticulitis; controls are patients without diverticula (0 to ≤ 5 diverticula). Genotype analysis for A1AT deficiency will be performed. RATIONALE: Hypothetically, connective tissue changes, in particular related to (carriers of) A1AT deficiency, can contribute to the development of diverticula and diverticulitis. We expect to find a higher prevalence of A1AT carriers in patients with diverticulosis compared to patients without diverticulosis. Having diverticulosis does not affect the general health of these individuals per se, when asymptomatic. Once an association is found, present findings can be the basis for a second study to assess the risk of developing acute diverticulitis and its disease course in carriers of A1AT deficiency. Because a large cohort is needed in the latter, we shall first perform a pilot study to investigate the likelihood of the primary hypothesis. TRIAL REGISTRATION: Netherlands Trial register, NTR6251, NL55016.094.15.

Testosterone in human studies: Modest associations between plasma and salivary measurements.

Testosterone is involved in many processes like aggression and mood disorders. As it may easily diffuse from blood into saliva, salivary testosterone is thought to reflect plasma free testosterone level. If so, it would provide a welcome noninvasive and less stressful alternative to blood sampling. Past research did not reveal consensus regarding the strength of the association, but sample sizes were small. This study aimed to analyse the association in a large cohort. In total, 2,048 participants (age range 18-65 years; 696 males and 1,352 females) were included and saliva (using cotton Salivettes) and plasma were collected for testosterone measurements. Levels were determined by enzyme-linked immunosorbent assay and radioimmunoassay respectively. Free testosterone was calculated by the Vermeulen algorithm. Associations were determined using linear regression analyses. Plasma total and free testosterone showed a significant association with salivary testosterone in men (adjusted ß = .09, p = .01; and ß = .15, p < .001, respectively) and in women (adjusted ß = .08, p = .004; and crude ß = .09, p = .002 respectively). The modest associations indicate that there are many influencing factors of both technical and biological origin.

Multicenter verification of the Sysmex XN-Series.

INTRODUCTION: Verification of hemocytometry equipment deviates significantly from that of clinical chemistry equipment due to the absence of appropriate control material and the need for fresh material. In practice, verification is limited to comparison with the previously used equipment and determination of reproducibilities. Particularly in multicenter settings, harmonization of results is necessary. If the same equipment is used in several laboratory departments, calibration and uniformity are important issues. METHODS: In this study, seven Sysmex XN hematology modules distributed over three laboratories were evaluated with the same set of samples (n=160). RESULTS: Results of each Sysmex XN hematology module were compared with the results of the Sysmex XE-2100 hematology analyzer using linear regression. Although excellent correlation coefficients were obtained, in many cases the criteria for slope and/or intercept were not met. Therefore, the same data were analyzed with Bland-Altman difference plots with three times the specified CV% of the parameter as limits of agreement. At least 90% of the determinations per parameter and per module must comply with those limits of agreement. Almost all parameters on each module fulfilled these criteria, and only RBC and Ht from respectively two and four XN modules had to be recalibrated. Reproducibility of each parameter was determined 10 times in patient samples with low, normal, and high levels. Reproducibility of all parameters was within the specifications of the manufacturer and the biological variability. CONCLUSION: With this straightforward method, all seven Sysmex XN hematology modules demonstrated uniform results, which were identical to those of the previously used Sysmex XE-2100 hematology analyzer, the performance of which was well known.

Flagging performance of the Sysmex XN2000 haematology analyser.

INTRODUCTION: With the introduction of the Sysmex XN haematology analyser, the white blood cell differentiation channel (WDF) and abnormal cell detection channel (WPC) have been added with algorithms for flagging blasts and abnormal or atypical lymphocytes. METHODS: In this study, 2011 samples were evaluated on a Sysmex XN2000 analyser and microscopically reviewed using a CellaVision DM96 digital microscope. RESULTS: A reference group of apparently healthy blood donors (n = 262) demonstrated in only three samples a positive suspect flag, which could not be confirmed microscopically. Positive WBC suspect flags were demonstrated in 3% of the 2011 samples. From the 55 samples with positive WBC suspect flags, an automatic reflex test was performed within the WPC. The WPC reflex test resulted in 10× Blast?, 15× Abnormal lymph? and 15× Atypical lymph? flags, which could be confirmed microscopically in 33% of these cases. A negative flagging was demonstrated in 15 cases. Microscopic evaluation demonstrated no abnormalities in these 15 cases. However, laboratory technicians also reported the presence of abnormal lymphocytes in 158 samples without an Abnormal lymph? flag. CONCLUSION: In conclusion, the combined use of WDF and WPC resulted in a reduction of approximately 25% of the number blood smears. As a result of the various techniques for light microscopy and haemocytometry, the adequacy of the XN flagging for abnormal and atypical lymphocytes cannot be established with certainty. To improve the quality of the reported results, it is recommended that laboratory technicians incorporate the haemocytometry results and the flagging information in the microscopic slide review.

Patients with large-duct primary sclerosing cholangitis and Crohn's disease have a better outcome than those with ulcerative colitis, or without IBD.

BACKGROUND: Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD). AIM: To compare PSC/CD with other PSC patients. METHODS: Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow-up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver-related death were endpoints. RESULTS: Sixty-three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu. Small-duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small-duct PSC had a markedly better survival than large-duct PSC: no patient developed cholangiocarcinoma or liver-related death, but colorectal cancer occurred in three patients. In large-duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver-related deaths were absent compared to 7% in the other PSC groups. CONCLUSIONS: The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one-fourth has small-duct PSC. In large-duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD.

Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial.

BACKGROUND: This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT). METHODS: From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients. RESULTS: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response. CONCLUSIONS: We could not support the 'normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.

Temporal changes in hepatic antioxidant enzyme activities after ischemia and reperfusion in a rat liver ischemia model: effect of dietary fish oil.

This study investigated the hypothesis that administration of tilapia fish oil diet would attenuate warm liver ischemia/reperfusion injury (IRI) and whether fish oil modulates prooxidant/antioxidant status. Male Wistar rats were subjected to 30 min of approximately 70% hepatic ischemia followed by 1, 12, and 24 h reperfusion. Rats were randomly divided into three groups: sham-operated group (SO), control-warm hepatic ischemia (WI) group, and Oil-WI group given tilapia oil for 3 weeks followed by liver IRI. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured in the plasma. Levels of thiobarbituric acid reactive substances (TBARS) and antioxidant enzymes as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were measured in liver fractions. In the sham group, there was no enzymatic or histological change. I/R caused significant increase in serum AST, ALT, and tissue TBARS levels. As compared to the control group, animals treated with tilapia oil experienced a significant decrease (p < 0.05) in AST and ALT levels in reperfusion periods. Tissue TBARS levels in Oil-WI group were significantly (p < 0.05) reduced as compared to control group at 60 min after reperfusion. After ischemia, 1, 12, and 24 h of reperfusion, CAT, SOD, and GPx values were the lowest in the Oil-WI group and highest in the control group and were statistically significant (p < 0.05). Histological analysis also revealed that fish oil provided some protection compared with the control group. Tilapia oil exerts a protective effect during the early phase of reperfusion, and it modulates prooxidant/antioxidant status of rat liver subjected to warm IRI.

Safety and efficacy of different lanreotide doses in the treatment of polycystic liver disease: pooled analysis of individual patient data.

BACKGROUND: Long-acting lanreotide (LAN) 120 mg every 4 weeks reduces liver volume (LV) in patients with polycystic liver diseases (PCLD). Animal studies demonstrated that the inhibition of hepatic and renal cystogenesis is dose dependent. AIM: To investigate the safety and efficacy of two different LAN doses in PCLD patients. METHODS: The 6-month results of the LOCKCYST I trial, its extension study and the LOCKCYST II trial were pooled. LV at baseline and month 6 was measured by CT-scan and blindly re-analysed by two independent radiologists. RESULTS: The study population [132 treatment periods, age 49 years (IQR: 45-55), 114 women] consisted of three groups. Each received treatment every 4 weeks during 6 months: placebo (n = 26); LAN 90 mg (n = 55) or LAN 120 mg (n = 51). The inter-observer variability and agreement in the calculation of LV were excellent. Severe side effects occurred with placebo, LAN 90 mg and LAN 120 mg in respectively 0%, 7% and 16%. Change in LV's after 6 months in these three groups were respectively: increase of +36 mL [(-45)-(+138)]; decrease of -82 mL [(-285)-(+92)] and decrease of -123 mL [(-312)-(+4)] (Kruskal-Wallis One Way anova on Ranks; P = 0.002). Based on ROC analysis, a reduction of ≥120 mL in LV has a positive predictive value of 64% for improving symptoms (ROC analysis AUC: 0.729; sensitivity 73%, specificity 69%, P < 0.0001). CONCLUSIONS: Both LAN 90 mg and LAN 120 mg reduce liver volume. LAN 90 mg has less side effects. This suggests that in case of intolerance to LAN 120 mg, a dose reduction to LAN 90 mg is meaningful.

A comparative study of the immune modulating properties of antifibrinolytics in cardiac surgery.

PURPOSE: Antifibrinolytics, used in cardiac surgery to abate postoperative blood loss, share anti-inflammatory properties by suppression of pro-inflammatory D-dimer and plasmin levels. Additional drug specific immune modulating qualities are often mentioned in the discussion on which antifibrinolytic can best be used. To determine the extent and relevance of these effects, we investigated cytokine and growth factor plasma levels in cardiac surgery patients randomized to receive either tranexamic acid, aprotinin, or placebo. Corticosteroid-treated patients served to put the effects in perspective. METHODS: Using a biochip immunoassay, plasma of 36 cardiac surgery patients was quantified for 12 cytokines and growth factors, assessed preoperatively and 6, 12, 24, and 48 h after the start of cardiopulmonary bypass. Eight patients were treated with tranexamic acid, nine with aprotinin, and nine received placebo. Ten placebo-treated patients received corticosteroids. RESULTS: IL-1ß, IL-6, IL-8, IL-10, IFN-γ, TNF-α, VEGF, MCP-1, and EGF plasma concentrations significantly changed over time across all patients. Aprotinin-treated patients showed decreased pro-inflammatory TNF-α and peak MCP-1 plasma levels when compared with placebo. However, corticosteroids attenuated the inflammatory response to a much larger extent, lowering postoperative IL-6, IL-10, IFN-γ, and VEGF concentrations also. CONCLUSIONS: Aprotinin attenuates postoperative pro-inflammatory levels TNF-α and MCP-1 whereas tranexamic acid does not. The majority of plasma proteins studied, however, were not affected by the use of antifibrinolytics when compared with placebo. A clinically relevant common anti-inflammatory effect through inhibition of fibrinolysis seems therefore unlikely.

Risk factors for bleeding and clinical implications in patients undergoing liver transplantation.

INTRODUCTION: Advanced liver disease is characterized by prolonged global coagulation tests such as prothrombin time (PT). Using Model of End-stage Liver Disease (MELD) score-based allocation, many current transplant recipients show advanced end-stage liver disease with an elevated international normalized ratio (INR). The relationship between abnormalities in coagulation tests and the risk of bleeding has been recently challenged among liver disease patients. In this study we reassessed risk factors for bleeding and the clinical implications for patients who underwent orthotopic liver transplantation (OLT). METHODS: We studied OLT patients between 2005 and 2011 excluding combined transplantations, retransplantations, or cases due to acute liver failure. We collected prospectively pre-OLT, during OLT, and post-OLT clinical and biochemical data to assess the risk for bleeding using linear regression models. RESULTS: The strongest predictor of overall survival among 286 patients with a mean follow-up of 32 months was the number of blood transfusions (P = .005). The risk factor for bleeding during surgery investigated by multivariate analysis only showed the INR (P < .001) and the presence of ascites (P = .003) to independently correlate with the amount of blood transfusion. Receiver operation characteristics (ROC) analysis performed to determine the risk for massive blood transfusion (more than 6 units) revealed a cut-off value for INR ≥ 1.6. Appreciation of the operative field by the surgeon during the intervention as "wet" versus "dry", amounts of blood transfusion and fresh frozen plasma, and stay in the intensive care unit (ICU) and in the hospital were all significantly different (P < .001) for patients with INR <1.6 versus INR ≥ 1.6. CONCLUSIONS: Bleeding during OLT affects the outcome. The risk is independently influenced by the presence of ascites (probably reflecting the degree portal hypertension) and an INR ≥ 1.6. To improve survival after OLT therapeutic interventions should be further explored to reduce the need for blood transfusions.

Hypothermic machine perfusion of the liver: is it more complex than for the kidney?

BACKGROUND: Hypothermic machine perfusion (HMP) is superior to simple cold storage (SCS) for the preservation of kidney grafts. Whether HMP is superior to SCS for liver preservation is not known. Before a HMP system can be used clinically for the liver, its superiority to SCS needs to be demonstrated in an in vivo large animal transplant model. OBJECTIVE: The aim was to compare outcomes after liver transplantation (LT) following preservation by SCS or HMP using technology/perfusion conditions similar to those for kidney HMP. METHODS: Pig livers were perfused via the hepatic artery and portal vein for 4 hours with nonoxygenated 4°C University of Wisconsin machine perfusion solution. In the SCS group, flushed livers were stored in histidine-tryptophan-ketoglutarate solution. After preservation by SCS (n = 6) or HMP (n = 8) and LT, we assessed graft and recipient survivals, pH and lactate, hepatocellular damage [aspartate aminotransferase (AST)], Kupffer cell activation (ß-galactosidase), tumor necrosis factor (TNF) α production, endothelial cell function (hyaluronic acid), and expression of Krüppel-like factor (KLF) 2 and 4, which are mediators of the flow-dependent vasoprotective endothelial phenotype. RESULTS: No primary graft nonfunction was observed; livers recovered equally well from the postanhepatic metabolic acidosis in both groups. Pig survival was 5/6 (83%) in the SCS versus 2/8 (12.5%) in the HMP group (P = .04). Livers from both groups recovered equally well from the postanhepatic metabolic acidosis. AST in liver rinse-out samples obtained before LT were lower in the HMP than in the SCS group (P < .05). After reperfusion, AST and ß-galactosidase were equally increased in both groups (P = .13 and 0.962, respectively); TNF-α and hyaluronic acid levels were higher after HMP versus SCS (P = .001 and 0.043, respectively). KLF-2 and -4 expressions were equally up-regulated after reperfusion in the SCS and HMP groups. CONCLUSIONS: In this in vivo model, liver HMP with subsequent transplantation was feasible. However, we did not demonstrate an advantage of HMP, using perfusion conditions shown to be effective for the kidney, over SCS. Despite similar immediate graft function, TNF-α generation, and endothelial cell dysfunction were more pronounced after HMP.

Presumed and actual concentrations of reduced glutathione in preservation solutions.

Reduced glutathione (GSH), an important radical scavenger, has been added to various organ preservation solutions. Because GSH oxidizes into oxidized glutathione (GSSG) and only GSH has scavenging capacity, only GSH in the solution at the time of clinical use is relevant. The concentrations of GSH (GSH(conc)) and GSSG(conc) were determined in 2 static preservation solutions--University of Wisconsin (UW) and Celsior--and in 1 machine preservation solution--Kidney Preservation Solution 1 (KPS-1). We determined the half-life (T(1/2)) of freshly added GSH. The GSH(conc) in UW and KPS-1 was 0.006 ± 0.0018 mmol/L and 0.13 ± 0.30 mmol/L, respectively. The GSH(conc) in Celsior was 2.7 ± 0.17 mmol/L. The manufacturers of these solutions reported 3 mmol/L GSH. GSSG(conc) in UW, KPS-1, and Celsior was 1.58 ± 0.61 mmol/L, 1.13 ± 0.16 mmol/L, and 0.24 ± 0.01 mmol/L, respectively. T(1/2) of GSH in UW, KPS-1, and Celsior was 18 days, 86 days, and 83 days, respectively. The actual GSH(conc) in UW and KPS-1 at the time of clinical use was substantially lower than reported by the manufacturer, owing to the relatively short T(1/2) of GSH. For Celsior, the GSH(conc) was maintained. Therefore, addition of fresh GSH to UW and KPS-1 before clinical use is recommended.

Attempt to rescue discarded human liver grafts by end ischemic hypothermic oxygenated machine perfusion.

In a porcine liver transplant model, a brief period of oxygenated hypothermic machine perfusion (HMP) at the end of simple cold storage (SCS) has been shown to improve the viability of damaged liver grafts. To test the clinical validity of this strategy, we randomized SCS-discarded human liver grafts to either 4 hours of HMP (n = 13) or an additional 4 hours of SCS (n = 14). All livers were then warm reperfused to mimic ischemia-reperfusion injury ex vivo. The settings for HMP were: portal vein: 3 mm Hg, 300 mL/min and hepatic artery: 20 mm Hg, pO(2): 300 mm Hg. Perfusion used Kidney Machine Perfusion Solution at 4°C to 8°C. During warm reperfusion, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) values were higher (P < .015) among the SCS versus HMP methods at all times. The AST slope was lower in HMP versus SCS (P = .01). The LDH slope tended to be lower for HMP versus SCS (P = .07). Morphological scores were not different between HMP and SCS. At the start of warm reperfusion, MAPK was lower in HMP versus SCS (P = .02). Endothelin-1 (EDN1) and ICAM-1 tended to be lower in HMP versus SCS (P = .1 and .07, respectively). No difference was noted in MAPK, EDN1, and ICAM-1 after 60 or 120 minutes of warm reperfusion. In conclusion, HMP down-regulated MAPK and tended to reduce EDN1 and ICAM-1 mRNA in human liver grafts. During warm reperfusion, HMP versus SCS livers showed reduced AST and LDH release but no morphological difference. Further optimization of liver HMP may require different timing/duration of perfusion and/or an higher perfusion temperature.

Differential gene expression profile of porcine livers subjected to warm ischemia alone.

BACKGROUND: Livers exposed to warm ischemia (WI) are increasingly used for transplantation. The molecular mechanisms activated by WI alone (prior to procurement and transplantation) are not understood. To elucidate the pathways involved, we used microarrays to investigate the gene expression in porcine livers exposed to WI. METHODS: Porcine livers (n = 6 group) were randomly subjected to WI periods of 15, 30 or 45 minutes. mRNA was extracted and gene expression determined by microarray analysis. Using bioinformatics software, we identified differentially expressed genes and related molecular pathways. We used the corresponding human annotation of the porcine microarray for the functional analysis. RESULTS: Between 0 and 15 minutes of WI, 3530 genes were altered with a 2-log-fold change of <-0.58 or >+0.58 and P < .05. Between 0 and 30 minutes of WI, 4141 genes were differentially expressed; and between 0 and 45 minutes of WI, 2814 genes. At each time point, ∼50% of genes were up-regulated, whereas 50% were down-regulated. After pathway mapping, we found that the same pathways were induced for observed clustering of in the three WI periods: cell death, proliferation, inflammation, and metabolism pathways. Among the top genes that were up-regulated after 15 minutes of WI, the majority started to return to but did not reach baseline expression with increasing WI. A similar pattern was observed for the top suppressed genes. CONCLUSIONS: WI causes rapid changes in gene expression that affect several molecular pathways. This phenomenon seems to plateau at 15 to 30 minutes of WI. These new insights in the timing and the nature of molecular pathways induced by WI alone may help to design specific interventions to alter these changes and improve the outcome of livers from cardiac death donors.

Systematic review: the pathophysiology and management of polycystic liver disease.

BACKGROUND: Polycystic liver diseases (PCLD) represent a group of genetic disorders in which cysts occur solely in the liver, or together with renal cysts. Most of the patients with PCLD are asymptomatic, however, in some patients, expansion of liver cysts causes invalidating abdominal symptoms. AIM: To provide a systemic review on the pathophysiology and management of PCLD. METHODS: A PubMed search was undertaken to identify relevant literature using search terms including polycystic liver disease, pathophysiology, surgical and medical management. RESULTS: The most common complication in patients with PCLD is extensive hepatomegaly, which may lead to malnutrition and can be lethal. Conservative surgical approaches are only partially effective and do not change the natural course of the disease. Liver transplantation has been successfully performed in PCLD, however, in an era of organ shortage, medical management needs to be evaluated. A better understanding of the pathophysiology and the availability of animal models have already identified promising drugs. Abnormalities in cholangiocyte proliferation/apoptosis and enhanced fluid secretion are key factors in the pathophysiology. It has been demonstrated in rodents and in humans that somatostatin analogues diminish liver volume. The role of the inhibitors of the mammalian target of rapamycin (mTOR) in the management of PCLD is still under investigation. CONCLUSIONS: The exact pathophysiology of polycystic liver disease still remains unclear. In symptomatic patients, none of the currently available surgical options except liver transplantation have been shown to change the natural course of the disease. The use of somatostatin analogues has been shown to diminish liver volume.

Molecular classification of hepatocellular carcinoma anno 2011.

Hepatocellular carcinoma has an increasing incidence and high mortality. Treatment options are limited if the disease is not diagnosed in its early stage. The natural course of the disease is aggressive but not always predictable. Molecular profiling is a promising tool for classification in order to optimize prognosis prediction and treatment for an individual patient. In the last decade a large amount of studies has been conducted to better classify hepatocellular carcinomas. The focus of this review is on implications of molecular classification for prognosis and therapeutic decision making in HCC patients. Most studies used microarray technique for genome wide profiling, but other methods to detect genomic changes and microRNA are gaining interest. The whole genome profiling studies identified differences in affected signalling and tried to relate this to prognosis. Some common subgroups were identified, such as the proliferation cluster and the beta-catenin cluster. However, there is still little overlap between most studies. Better study design and bio-informatical analysis might help in this context.

Desmopressin as a pharmacological tool in vasopressinergic hypothalamus-pituitary-adrenal axis modulation: neuroendocrine, cardiovascular and coagulatory effects.

Arginine-vasopressin (AVP) is a physiological co-activator of the hypothalamus-pituitary-adrenal (HPA) axis, together with corticotrophin releasing hormone (CRH). A synthetic analogue of AVP, desmopressin (dDAVP), is often used as a pharmacological tool to assess co-activation in health and disease. The relation between dDAVP's neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic and non-specific stress effects has not been studied. A randomized, double-blind, placebo-controlled, three-way crossover study was performed in 12 healthy male and female volunteers (6 : 6). dDAVP was administered intravenously as a 10 µg bolus (over 1 min) or a 30 µg incremental infusion (over 60 min). Neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic effects and adverse events (AEs) were recorded, and autonomic nervous system (ANS) activation evaluated. The incremental infusion reached 1.8-fold higher dDAVP concentrations than the bolus. Neuroendocrine effects were similar for the 10 µg dDAVP bolus and the 30 µg incremental infusion, while cardiovascular and coagulatory effects were greater with the 30 µg dose. Osmolality and ANS activity remained uninfluenced. AEs corresponded to dDAVP's side-effect profile. In conclusion, the neuroendocrine effects of a 10 µg dDAVP bolus administered over 1 min are similar to those of a 30 µg incremental infusion administered over one hour, despite higher dDAVP concentrations after the infusion. Cardiovascular and coagulatory effects showed clear dose-related responses. A 10 µg dDAVP bolus is considered a safe vasopressinergic function test at which no confounding effects of systemic or autonomic stress were seen.

A pharmacological tool to assess vasopressinergic co-activation of the hypothalamus-pituitary-adrenal axis more integrally in healthy volunteers.

Pharmacological function tests consisting of 100 µg hCRH (corticorelin) and 10 µg dDAVP (desmopressin) mimic endogenous hypothalamus-pituitary-adrenal (HPA) axis activation. However, physiological CRH concentrations preclude informative vasopressinergic co-activation (using dDAVP) and independent quantification of both corticotrophinergic (using hCRH) and vasopressinergic (using dDAVP) activation is limited due to administration on separate occasions. This randomized, double-blind, placebo-controlled, partial five-way crossover study in healthy males and females (six : six) examined whether (1) concomitant administration of dDAVP and hCRH provides more informative vasopressinergic co-activation than dDAVP alone; and (2) whether the administration of dDAVP followed two hours later by hCRH can quantify both vasopressinergic and corticotrophinergic activation on a single test day. Combining 10 µg dDAVP with 10 µg and 30 µg hCRH caused dose-related ACTH and cortisol release which was larger than with 10 µg dDAVP alone and respectively comparable to and greater than that induced by 100 µg hCRH. Using 10 µg dDAVP alone demonstrated limited ACTH release while the effects of 100 µg hCRH two hours later were three times as large. ACTH and cortisol released by 10 µg dDAVP returned to baseline prior to 100 µg hCRH administration and dDAVP did not influence the response to subsequent hCRH administration. Dose-related vasopressinergic co-activation of the HPA axis was induced by combining 10 µg dDAVP with 10 µg and 30 µg hCRH. Combining 10 µg dDAVP with 10 µg hCRH induced the potentially most informative vasopressinergic co-activation since it is not restricted by ceiling or flooring effects. The hCRH response was not affected by prior dDAVP, allowing for a practical function test examining both HPA activation routes on the same day.