Maria Carme Vila

Total paracentesis with dextran 40 vs diuretics in the treatment of ascites in cirrhosis: a randomized controlled study.

The aim of the current study was to compare total paracentesis associated with dextran-40 infusion with diuretics in the treatment of tense ascites in patients with cirrhosis. Eighty patients were randomly allocated to two groups: 40 patients were treated with paracentesis plus dextran-40 infusion (8 g per liter of ascitic fluid removed), and 40 patients with diuretics. After treatment patients were discharged with diuretics, and patients developing tense ascites during follow up (54 +/- 4 weeks) were treated according to their initial schedule. Paracentesis was more effective than diuretics in mobilizing the ascitic fluid. The incidence of complications was significantly higher (p < 0.05) in the diuretic group (38%) than in the paracentesis group (15%). This difference was mainly due to a higher incidence of hepatic encephalopathy in the former group (30% vs. 2.5%). A significantly higher incidence of hepatic encephalopathy was also observed in the diuretic group during the follow-up readmissions for ascites recurrence. There were no significant differences between the two treatment groups in the probability of survival after inclusion. Plasma renin activity and plasma aldosterone concentration measured before and 2 and 6 days after paracentesis in 20 randomly selected patients increased significantly (p < 0.05) (baseline values: 5.3 +/- 1.4 ng.ml-1.h-1 and 63 +/- 21 ng/dl; 48 h after paracentesis: 11.7 +/- 3.9 ng.ml-1.h-1 and 99 +/- 31 ng/dl; 6 days after paracentesis: 10.9 +/- 3 ng.ml-1.h-1 and 110 +/- 27 ng/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Total paracentesis in cirrhotic patients with tense ascites and dilutional hyponatremia

OBJECTIVE:The safety of large-volume paracentesis with plasma expander infusion in ascitic cirrhotic patients with advanced liver disease, hyponatremia, or renal failure has not been elucidated. Our aim was to investigate the safety of total paracentesis in cirrhotic patients with ascites and severe hyponatremia.METHODS:Forty-five cirrhotic patients with tense ascites were treated with total paracentesis and infusion of plasma expanders. At inclusion, 20 patients showed severe hyponatremia (serum sodium <130 mEq/L). In the remaining 25 patients, serum sodium was >130 mEq/L (range, 133–146 mEq/L).RESULTS:Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were significantly higher in patients with hyponatremia (PRA: 19.7 ± 5.8 ng/mL/h; PAC: 217 ± 35 ng/dL) than in those patients without hyponatremia (PRA: 4.9 ± 1.1 ng/mL/h; PAC: 95 ± 31 ng/dL), indicating a more severe systemic hemodynamic deterioration. After paracentesis, PRA and PAC increased similarly in both groups of patients. Serum sodium levels remained unchanged after paracentesis in patients with hyponatremia (127 ± 0.5 to 128 ± 1.5 mEq/L) and decreased slightly in patients without hyponatremia (137 ± 1 to 135 ± 1 mEq/L; p < 0.005). The incidence of complications during the first hospitalization, the probability of readmission for complications of cirrhosis, and the probability of survival at 1 yr were similar in both groups of patients.CONCLUSIONS:These results indicate that therapeutic paracentesis is a safe treatment for tense ascites in cirrhotic patients with severe hyponatremia.

Mechanisms of early decrease in systemic vascular resistance after total paracentesis: influence of flow rate of ascites extraction.

Background An early decrease in systemic vascular resistance (SVR) after total paracentesis has been observed in ascitic patients who developed paracentesis-induced circulatory dysfunction. Aims To investigate the mechanisms of early changes in SVR after total paracentesis and the influence of intra-abdominal pressure and the flow rate of ascites extraction on the development of an early decrease in SVR. Methods Twenty-two cirrhotic patients with tense ascites were treated by total paracentesis (7 ± 0.4 l). Measurements of intra-abdominal pressure and the volume of ascites removed were recorded every 10 min. Hormonal and haemodynamic measurements were performed at baseline and 3 h after total paracentesis. Results SVR decreased 3 h after paracentesis in 17 patients and remained stable in five patients. Patients with a decrease in SVR showed a significant increase in nitrite/nitrate serum values (4.4 ± 0.9 to 7.4 ± 1 nmol/ml; P < 0.05). A significant correlation was observed between the decrease in SVR and nitrite/nitrate serum values (r = 0.566; P < 0.05). The volume of ascites removed was similar in patients with and without a decrease in SVR. Patients with a decrease in SVR showed higher baseline intra-abdominal pressure, shorter duration of paracentesis (60 ± 4.9 vs 88 ± 0.4 min; P < 0.01) and higher flow rate of ascites extraction (1.18 ± 0.08 vs 0.81 ± 0.12 l/min; P < 0.05). Conclusions Our results confirm that an early decrease in SVR after total paracentesis is due to an increase in arterial vasodilation that may be related to an abrupt decrease in intra-abdominal pressure after fast paracentesis. Haemodynamic disturbances after total paracentesis could be prevented by reducing the flow rate of ascites extraction.

New genes emerging for colorectal cancer predisposition

Colorectal cancer (CRC) is one of the most frequent neoplasms and an important cause of mortality in the developed world. This cancer is caused by both genetic and environmental factors although 35% of the variation in CRC susceptibility involves inherited genetic differences. Mendelian syndromes account for about 5% of the total burden of CRC, with Lynch syndrome and familial adenomatous polyposis the most common forms. Excluding hereditary forms, there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause. CRC can be also considered as a complex disease taking into account the common disease-commom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect. So far, 30 common, low-penetrance susceptibility variants have been identified for CRC. Recently, new sequencing technologies including exome- and whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition. By using whole-genome sequencing, germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.

Gene expression profiling in hearts of diabetic mice uncovers a potential role of estrogen-related receptor γ in diabetic cardiomyopathy

Diabetic cardiomyopathy is characterized by an abnormal oxidative metabolism, but the underlying mechanisms remain to be defined. To uncover potential mechanisms involved in the pathophysiology of diabetic cardiomyopathy, we performed a gene expression profiling study in hearts of diabetic db/db mice. Diabetic hearts showed a gene expression pattern characterized by the up-regulation of genes involved in lipid oxidation, together with an abnormal expression of genes related to the cardiac contractile function. A screening for potential regulators of the genes differentially expressed in diabetic mice found that estrogen-related receptor γ (ERRγ) was increased in heart of db/db mice. Overexpression of ERRγ in cultured cardiomyocytes was sufficient to promote the expression of genes involved in lipid oxidation, increase palmitate oxidation and induce cardiomyocyte hypertrophy. Our findings strongly support a role for ERRγ in the metabolic alterations that underlie the development of diabetic cardiomyopathy.

Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance

Postnatal overfeeding increases the risk of chronic diseases later in life, including obesity, insulin resistance, hepatic steatosis, and type 2 diabetes. Epigenetic mechanisms might underlie the long‐lasting effects associated with early nutrition. Here we aimed to explore the molecular pathways involved in early development of insulin resistance and hepatic steatosis, and we examined the potential contribution of DNA methylation and histone modifications to long‐term programming of metabolic disease. We used a well‐characterized mouse model of neonatal overfeeding and early adiposity by litter size reduction. Neonatal overfeeding led to hepatic insulin resistance very early in life that persisted throughout adulthood despite normalizing food intake. Up‐regulation of monoacylglycerol O‐acyltransferase (Mogat)1conceivably mediates hepatic steatosis and insulin resistance through increasing intracellular diacylglycerol content. Early and sustained deregulation of Mogat1 was associated with a combination of histone modifications that might favor Mogat1expression. In sum, postnatal overfeeding causes extremely rapid derangements of hepatic insulin sensitivity that remain relatively stable until adulthood. Epigenetic mechanisms, particularly histone modifications, could contribute to such long‐lasting effects. Our data suggest that targeting hepatic monoacylglycerol acyltransferase activity during early life might provide a novel strategy to improve hepatic insulin sensitivity and prevent late‐onset insulin resistance and fatty liver disease.—Ramon‐Krauel, M., Pentinat, T., Bloks, V. W., Cebrià, J., Ribo, S., Pérez‐Wienese, R., Vilà, M., Palacios‐Marin, I., Fernández‐Pérez, A., Vallejo, M., Téllez, N., Rodríguez, M. À., Yanes, O., Lerin, C., Díaz, R., Plosch, T., Tietge, U. J. F., Jimenez‐Chillaron, J. C. Epigenetic programming at the Mogat1locus may link neonatal overnutrition with long‐term hepatic steatosis and insulin resistance. FASEB J. 32, 6025–6037 (2018).www.fasebj.org

Abstract 3031: Replication stress and DNA damage promote genomic instability in near-tetraploid colorectal cancer cells

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Aneuploidy represents a hallmark of most solid tumours, and potentially has a causal role in carcinogenesis. Also, cancer cells exhibit high rates of chromosome missegregation, which leads to chromosomal instability (CIN). However, a large amount of tumours present near-triploid karyotypes likely to go through a tetraploid transient stage. Here, by using DLD-1 isogenic diploid and tetraploid cell lines generated by single cell FACS-sorting, we aimed at exploring how polyploidization affects cellular functions and whether tetraploid per se generates CIN in a genomically stable background. First, gene expression and subsequent gene set enrichment analysis revealed that genes involved in the machinery of the DNA synthesis and replication, such as MCM2 and RRM2, and genes involved in cell cycle, were significantly upregulated in near-tetraploid cells compared to their diploid counterparts. Functionally, polyploidy cells exhibited replication stress, as indicated by higher levels of pCHK1, RPA and 53BP1 foci, which resulted in increased DNA damage in S- and M-phase. In addition, tetraploid cells displayed impaired proliferative capabilities as a consequence of a cell cycle delay confirmed by BrdU pulse and flow cytometry. Furthermore, near-tetraploid clones showed a higher amount of intracellular karyotypic heterogeneity due to the higher frequency of micronuclei formation compared to their diploid counterparts. In fact, polyploid cells displayed an increased tendency of abnormal anaphase events, including lagging chromosomes and acentric fragments. Interestingly, these heterogeneous cellular populations showed strengthen migratory capabilities and preliminary experiments suggested an increment in tumor invasiveness too. Taken together, our data suggest that near-tetraploid cells systematically undergo replication stress, which can be responsible for the increased levels of genomic instability. Citation Format: Isabel Quintanilla, Darawalee Wangsa, Markus Brown, Amaia Ercilla, Greg Klus, Maria Vila, Juan Jose Lozano, Zoltan Szallsi, Neus Agell, Antoni Castells, Thomas Ried, Jordi Camps. Replication stress and DNA damage promote genomic instability in near-tetraploid colorectal cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3031. doi:10.1158/1538-7445.AM2015-3031

Hemodynamic changes in patients developing effective hypovolemia after total paracentesis

BACKGROUND/AIMS In many centers paracentesis is considered the treatment of choice for tense ascites. However, the mechanism of effective hypovolemia after paracentesis, the main complication associated with this procedure, remains unknown. In the current study, systemic hemodynamics was sequentially studied before and after total paracentesis in 46 patients with cirrhosis and tense ascites. The aim of the study was to assess the mechanism of effective hypovolemia after paracentesis. METHODS Plasma renin activity and aldosterone, mean arterial pressure, cardiac output (ECO-Doppler) and systemic vascular resistance were measured before, and 3 h, 6 h and 6 days after total paracentesis associated with plasma volume expansion. RESULTS Effective hypovolemia after paracentesis (defined as 50% increase in plasma renin activity up to a level over 4 ng x m(-1) x h(-1) at the 6th day after paracentesis) occurred in 20 cases [plasma renin activity increased from 8+/-17 to 19+/-2.7 ng x m(-1) x h(-1)]. In the remaining 26 cases no changes in plasma renin activity [8.5+/-2.4 vs. 8.7+/-2.2 ng x m(-1) x h(-1)] were observed. The amounts of ascitic fluid volume removed were similar. Effective hypovolemia after paracentesis was associated with a significant decrease in mean arterial pressure (89+/-2 vs. 81+/-3 mmHg) and systemic vascular resistance [1263+/-67 vs. 1014+/-80 dyn x s(-1) x cm(-5)] 6 days after treatment. In contrast, no significant changes in these parameters were observed in patients not developing this complication. In the whole group of patients a significant inverse relation was observed between changes in plasma renin activity and in systemic vascular resistance (r=0.74;p< 0.001). CONCLUSIONS These results indicate that effective hypovolemia after paracentesis in cirrhosis is predominantly due to an accentuation of the arteriolar vasodilation already present in these patients.