Pre-implantation alcohol exposure induces lasting sex-specific DNA methylation programming errors in the developing forebrain.

BACKGROUND: Prenatal alcohol exposure is recognized for altering DNA methylation profiles of brain cells during development, and to be part of the molecular basis underpinning Fetal Alcohol Spectrum Disorder (FASD) etiology. However, we have negligible information on the effects of alcohol exposure during pre-implantation, the early embryonic window marked with dynamic DNA methylation reprogramming, and on how this may rewire the brain developmental program. RESULTS: Using a pre-clinical in vivo mouse model, we show that a binge-like alcohol exposure during pre-implantation at the 8-cell stage leads to surge in morphological brain defects and adverse developmental outcomes during fetal life. Genome-wide DNA methylation analyses of fetal forebrains uncovered sex-specific alterations, including partial loss of DNA methylation maintenance at imprinting control regions, and abnormal de novo DNA methylation profiles in various biological pathways (e.g., neural/brain development). CONCLUSION: These findings support that alcohol-induced DNA methylation programming deviations during pre-implantation could contribute to the manifestation of neurodevelopmental phenotypes associated with FASD.

Developmental genome-wide DNA methylation asymmetry between mouse placenta and embryo.

In early embryos, DNA methylation is remodelled to initiate the developmental program but for mostly unknown reasons, methylation marks are acquired unequally between embryonic and placental cells. To better understand this, we generated high-resolution DNA methylation maps of mouse mid-gestation (E10.5) embryo and placenta. We uncovered specific subtypes of differentially methylated regions (DMRs) that contribute directly to the developmental asymmetry existing between mid-gestation embryonic and placental DNA methylation patterns. We show that the asymmetry occurs rapidly during the acquisition of marks in the post-implanted conceptus (E3.5-E6.5), and that these patterns are long-lasting across subtypes of DMRs throughout prenatal development and in somatic tissues. We reveal that at the peri-implantation stages, the de novo methyltransferase activity of DNMT3B is the main driver of methylation marks on asymmetric DMRs, and that DNMT3B can largely compensate for lack of DNMT3A in the epiblast and extraembryonic ectoderm, whereas DNMT3A can only partially compensate in the absence of DNMT3B. However, as development progresses and as DNMT3A becomes the principal de novo methyltransferase, the compensatory DNA methylation mechanism of DNMT3B on DMRs becomes less effective.

Timing of insulin basal rate reduction to reduce hypoglycemia during late post-prandial exercise in adults with type 1 diabetes using insulin pump therapy: A randomized crossover trial.

AIMS: To compare the efficacy of three timings to decrease basal insulin infusion rate to reduce exercise-induced hypoglycaemia in patients with type 1 diabetes (T1D) using pump therapy. METHODS: A single-blinded, randomized, 3-way crossover study in 22 adults that had T1D > 1 year and using insulin pump > 3 months (age, 40 ± 15 years; HbA1c, 56.3 ± 10.2 mmol/mol). Participants practiced three 45-min exercise sessions (ergocyle) at 60% VO2peak 3 hours after lunch comparing an 80% reduction of basal insulin applied 40 minutes before (T-40), 20 minutes before (T-20) or at exercise onset (T0). RESULTS: No significant difference was observed for percentage of time spent < 4.0 mmol/L (T-40: 16 ± 25%; T-20: 26 ± 27%; T0: 24 ± 29%) (main outcome) and time spent in target range 4.0-10.0 mmol/L (T-40: 63 ± 37%; T-20: 66 ± 25%; T0: 65 ± 31%). With T-40 strategy, although not significant, starting blood glucose (BG) was higher (T-40: 8.6 ± 3.6 mmol/L; T-20: 7.4 ± 2.5 mmol/L ; T0: 7.4 ± 2.7 mmol/L), fewer patients needed extra carbohydrates consumption prior to exercise for BG < 5.0 mmol/L (T-40: n = 3; T-20: n = 5; T0: n = 6) as well as during exercise for BG < 3.3 mmol/L [T-40: n = 6 (27%); T-20: n = 12 (55%); T0: n = 11 (50%)] while time to first hypoglycaemic episode was delayed (T-40: 28 ± 14 min; T-20: 24 ± 10 min; T0: 22 ± 11 min). CONCLUSION: Decreasing basal insulin infusion rate by 80% up to 40 minutes before exercise onset is insufficient to reduce exercise-induced hypoglycaemia.

Predictors of cardiovascular risk among patients with type 1 diabetes: A critical analysis of the metabolic syndrome and its components.

Patients with type 1 diabetes (T1D) are at increased risk for cardiovascular diseases. The metabolic syndrome (MetS), a complex disorder defined by a cluster of interconnected factors including abdominal obesity, hypertension, dyslipidaemia and insulin resistance, has been proposed to identify patients with T1D at high cardiovascular risk. The MetS has been identified in 8-45% of patients with T1D, depending on the definition and cohort studied. However, clinicians and researchers face several issues with the criteria for MetS in patients with T1D, therefore questioning its value in routine care. For example, three criteria can lead to overestimation of MetS prevalence; the impaired fasting glucose criterion is irrelevant as it is automatically fulfilled; and the widespread use of antihypertensive and lipid-lowering medications for cardiac and renal preventative purposes can contribute to overestimations of the prevalence of raised blood pressure and elevated triglycerides. In cross-sectional studies, the MetS has been associated mostly with an increased risk of microvascular complications whereas, in prospective cohorts, the predictive value of MetS for micro- and macrovascular outcomes has been inconsistent. While identifying diabetes patients at increased risk for cardiovascular complications and early mortality is crucial from a prevention standpoint, for patients with T1D, the current definition of MetS may not be the most suitable tool. The aims of the present report are to review the applicability and limitations of the MetS in patients with T1D, and to discuss alternative avenues to identify high-risk patients.

Association of aerobic fitness level with exercise-induced hypoglycaemia in Type 1 diabetes.

AIM: To determine the impact of physical fitness level on hypoglycaemia risk during exercise in people with Type 1 diabetes. METHODS: A total of 44 patients [34 adults (aged 22-70 years) and 10 adolescents (aged 12-18 years)] with Type 1 diabetes, treated with insulin pump therapy, underwent a standardized exercise session. Cardiorespiratory fitness (maximum oxygen uptake) was measured and classified, based on established norms for age and sex, into either poor (< 25th percentile) or good fitness level (> 25th percentile). Plasma glucose levels were measured every 10 min, each patient performed physical activity at 60% maximum oxygen uptake either on a treadmill for 1 h or on a bicycle for 30 min. Frequency of hypoglycaemia (plasma glucose < 4 mmol/l) and decline in plasma glucose levels during exercise were assessed. RESULTS: In all, 23 patients had a good exercise fitness level. Hypoglycaemic events occurred in 17/23 patients (74.0%) in the good fitness level group compared with 8/21 patients (38.0%) in the poor fitness level group (P = 0.02). Both groups had similar pre-exercise plasma glucose levels. The plasma glucose values during exercise in the good fitness level group compared with the poor fitness level group were: plasma glucose nadir 3.9 ± 1.6 vs 5.5 ± 2.4 mmol/l (P = 0.01) and plasma glucose change -4.6 ± 3.4 vs. -2.1 ± 3.1 mmol/l (P = 0.01). The correlation between the plasma glucose nadir and maximum oxygen uptake was r = -0.38 (P = 0.01). CONCLUSIONS: Patients with good fitness level seem to be more prone to hypoglycaemia during exercise. This could be the result of better insulin sensitivity and the fact that they tend to exercise at greater work thresholds. These results are a step toward a better understanding of the association between physical fitness and exercise-induced hypoglycaemia.

Why do families enrol in paediatric weight management? A parental perspective of reasons and facilitators.

BACKGROUND: Few children with obesity who are referred for weight management end up enroled in treatment. Factors enabling enrolment are poorly understood. Our purpose was to explore reasons for and facilitators of enrolment in paediatric weight management from the parental perspective. METHODS: Semi-structured interviews were conducted with parents of 10- to 17-year-olds who were referred to one of four Canadian weight management clinics and enroled in treatment. Interviews were audio-recorded and transcribed verbatim. Manifest/inductive content analysis was used to analyse the data, which included the frequency with which parents referred to reasons for and facilitators of enrolment. RESULTS: In total, 65 parents were interviewed. Most had a child with a BMI ≥95th percentile (n = 59; 91%), were mothers (n = 55; 85%) and had completed some post-secondary education (n = 43; 66%). Reasons for enrolment were related to concerns about the child, recommended care and expected benefits. Most common reasons included weight concern, weight loss expectation, lifestyle improvement, health concern and need for external support. Facilitators concerned the referral initiator, treatment motivation and barrier control. Most common facilitators included the absence of major barriers, parental control over the decision to enrol, referring physicians stressing the need for specialized care and parents' ability to overcome enrolment challenges. CONCLUSIONS: Healthcare providers might optimize enrolment in paediatric weight management by being proactive in referring families, discussing the advantages of the recommended care to meet treatment expectations and providing support to overcome enrolment barriers.

Efficacy of dual-hormone artificial pancreas to alleviate the carbohydrate-counting burden of type 1 diabetes: A randomized crossover trial.

AIM: Carbohydrate-counting is a complex task for many patients with type 1 diabetes. This study examined whether an artificial pancreas, delivering insulin and glucagon based on glucose sensor readings, could alleviate the burden of carbohydrate-counting without degrading glucose control. METHODS: Twelve adults were recruited into a randomized, three-way, crossover trial (ClinicalTrials.gov identifier No. NCT01930097). Participants were admitted on three occasions from 7AM to 9PM and consumed a low-carbohydrate breakfast (women: 30g; men: 50g), a medium-carbohydrate dinner (women: 50g; men: 70g) and a high-carbohydrate lunch (women: 90g; men: 120g). At each visit, glucose levels were randomly regulated by: (1) conventional pump therapy; (2) an artificial pancreas (AP) accompanied by prandial boluses, matching the meal's carbohydrate content based on insulin-to-carbohydrate ratios (AP with carbohydrate-counting); or (3) an AP accompanied by prandial boluses based on qualitative categorization (regular or large) of meal size (AP without carbohydrate-counting). RESULTS: The AP without carbohydrate-counting achieved similar incremental AUC values compared with carbohydrate-counting after the low- (P=0.54) and medium- (P=0.38) carbohydrate meals, but yielded higher post-meal excursions after the high-carbohydrate meal (P=0.004). The AP with and without carbohydrate-counting yielded similar mean glucose levels (8.2±2.1mmol/L vs. 8.4±1.7mmol/L; P=0.52), and both strategies resulted in lower mean glucose compared with conventional pump therapy (9.6±2.0mmol/L; P=0.02 and P=0.03, respectively). CONCLUSION: The AP with qualitative categorization of meal size could alleviate the burden of carbohydrate-counting without compromising glucose control, although more categories of meal sizes are probably needed to effectively control higher-carbohydrate meals.

Post-breakfast closed-loop glucose control is improved when accompanied with carbohydrate-matching bolus compared to weight-dependent bolus.

AIM: We compared post-breakfast closed-loop glucose control either matched with a carbohydrate-matching bolus or a weight-dependent bolus. METHODS: Twelve adults with type 1 diabetes consumed a 75 g CHO breakfast on two occasions. In random order, the breakfast was accompanied by a full carbohydrate-matching insulin bolus (8.30 U [7.50 U-11.50 U]) or a partial weight-dependent insulin bolus (0.047 U/kg; 3.45 U [2.95 U-3.75 U]). Postprandial glucose was regulated by sensor-responsive insulin and glucagon delivery. RESULTS: Glucose control after the weight-dependent bolus was safe and feasible (glucose values returned to pre-prandial levels after 5 h). However, 5-hr incremental area under the curve and percentage of time above 10 mmol/L were lower after the full bolus compared to the partial bolus (IAUC, 2.1 [0.8-4.2] mmol/L/hr vs 8.3 [6.5-11.4] mmol/L/hr; time in hyperglycaemia, 24% [6%-29%] vs 50% [25%-63%]; P < 0.001). CONCLUSIONS: Post-breakfast closed-loop glucose control without carbohydrate counting, but based on weight-dependent bolus is feasible but a carbohydrate-matching bolus provides better glucose control. CLINICAL TRIAL REGISTRY: NCT01519102.

Impact of elective hospital admissions on glycaemic control in adolescents with poorly controlled type 1 diabetes.

AIM: Different treatment strategies have been used to manage adolescents with poorly controlled type 1 diabetes. We investigated whether a brief elective hospital admission improves haemoglobin A(1c) (HbA(1c)) over 12 months. METHODS: We studied a retrospective cohort of adolescents with poorly controlled type 1 diabetes attending a tertiary care pediatric diabetes clinic in Montreal, Canada, between January 2005 and December 2010. Hospitalized adolescents (admitted group) were matched with controls (non-admitted group) for age and baseline HbA(1c). HbA(1c) values at baseline, 6 and 12 months were obtained from the clinic database. RESULTS: Thirty patients aged 11 to 17 years with a first elective admission for poor metabolic control were paired with 30 non-admitted patients. At baseline, HbA(1c) was 12.2±1.6% in admitted and 12.0±1.2% in non-admitted patients. There were no clinically important differences in potential confounders between groups. There was no improvement in the primary outcome as assessed by the change in HbA(1c) at 12 months in the admitted group (-1.3±2.3%) compared with the non-admitted group (-2.1±1.7%) (P=0.078). No improvement in intermediary measures of glycaemic control was observed (HbA(1c) at 6 months or change at 6 months). After 12 months, HbA(1c) values were higher in the admitted group (10.9±1.9%) versus the non-admitted group (9.9±1.4%) (P=0.016). CONCLUSION: Elective hospital admission for adolescents with poorly controlled type 1 diabetes does not seem to be an effective strategy to improve HbA(1c) over 12 months.

Annual incidence of type 1 diabetes in Québec between 1989-2000 in children.

PURPOSE: To document the number of new pediatric cases of type 1 diabetes diagnosed each year, from 1989 to 2000, in the province of Québec. To analyze secular trends and age of presentation during the same period. METHODS: Data, gathered through a government allocation program, provided the number of reported new cases. The data bank also made available the age at diagnosis, sex and geographic distribution of cases. RESULTS: A steady number of new cases, approximately 240 p.a., was diagnosed over the 12-years. The annual incidence in the pediatric population of Québec was 15 per 100,000. There was no trend towards earlier age at diagnosis. CONCLUSIONS: We found no evidence of increase in the number of children diagnosed with type 1 diabetes in Québec between 1989-2000. Also, over the same period, the data did not support a younger age at diagnosis.

A novel A10E homozygous mutation in the HSD3B2 gene causing severe salt-wasting 3beta-hydroxysteroid dehydrogenase deficiency in 46,XX and 46,XY French-Canadians: evaluation of gonadal function after puberty.

Severe 3beta-hydroxysteroid dehydrogenase (3betaHSD) deficiency is a rare form of congenital adrenal hyperplasia resulting from mutations in the HSD3B2 gene that impair steroidogenesis in both the adrenals and gonads and cause salt-wasting in both sexes and incomplete masculinization of the external genitalia in genetic males. About two thirds of the reported patients are 46,XY. We describe two French-Canadian patients from two families without a known relationship who presented with severe salt-wasting 3betaHSD deficiency in infancy. Although the diagnosis was considered clinically, plasma steroid profiles were confusing. We have thus directly sequenced DNA fragments generated by PCR amplification of the four exons, exon-intron boundaries, and the 5'-flanking regions of the HSD3B2 gene. Sequencing of exon II revealed the presence of a C to A transversion in both alleles of these two cases, thus converting codon 10 (GCA), which codes for Ala, into GAA, encoding Glu. This Ala is highly conserved in the vertebrate 3betaHSD gene family and is located in the putative NAD-binding domain of the enzyme. The mutant type II 3betaHSD enzyme carrying an A10E substitution exhibited no detectable activity in intact transfected Ad293 cells. Both homozygous patients share the same haplotype, spanning approximately 3.3 centimorgans surrounding the HSD3B2 locus, which is consistent with a founder effect for this missense mutation. The 46,XY patient presented with ambiguous genitalia at birth and underwent normal masculinization at puberty, but was azoospermic at 18.5 yr of age. The 46,XX patient presented progressive breast development, menarche, and evidence of progesterone secretion. The only previously reported cases with pubertal follow-up revealed paternity in one male and hypogonadism in one female. These findings demonstrate the complex relationships between the genotype and the gonadal phenotype in severe 3betaHSD deficiency and the difficulty in predicting fertility.

Endocrine complications of bone marrow transplantation in children.

Eighty-seven patients had a bone marrow transplantation (BMT) at our institution between 1980 and 1992. We wished to study the endocrine complications that accompany this procedure as long-term survival is now much more common. Forty-three patients were retrospectively available for review and their records were examined for evidence of thyroid, pubertal, and growth complications. Fifteen per cent of the patients showed evidence of thyroid involvement. Pubertal delay or gonadal damage was almost universal in pubertal-aged girls treated with busulfan/cyclophosphamide. Gonadal involvement was more frequent in girls than in boys (70% vs. 47%). Sixty per cent of children were shorter or grew at a slower rate. Sixty-five per cent of the children presented with one or more endocrine complications. These are the combined effects of different treatment regimens (chemotherapy, radiotherapy, combined therapy). It is essential to know the natural history of these patients in order to offer proper guidance and treatment as survival rates are increasing.

Glomerular filtration rate measurement in cirrhotic patients with renal failure.

Assessment of renal function, namely glomerular filtration rate (GFR), by the renal creatinine clearance, may be problematic and less accurate in cirrhotics; however, it is an essential element in the global evaluation of these patients. In order to better characterize misinterpretation of GFR by the renal creatinine clearance, we compared a group of cirrhotic patients with renal failure (n - 30) to a group of chronic renal failure patients (CRF) without liver disease (n - 5). Inulin and PAH clearances were measured during a 4-hour infusion of inulin and PAH; renal creatinine clearance was measured during a 24-hour urine collection and this, simultaneously with inulin and PAH clearance. We observed that in moderate to severe renal failure (renal inulin clearance 30 +/- 10 ml/min), GFR (i. e. renal inulin clearance) in cirrhotic patients was overestimated by the renal creatinine clearance, similarly to CRF patients (ratio 1.8 +/- 0.7 and 1.6 +/- 0.9 respectively); however cirrhotic patients have a lower serum creatinine (186 +/- 97 vs 133 +/- 62 micromol/l respectively). On the other hand, cirrhotic patients with mild renal dysfunction (renal inulin clearance 74 +/- 15 ml/min) had a renal creatinine clearance of 77 +/- 25 ml/min. Systemic inulin clearance overestimated renal inulin clearance, proportionally to the severity of renal dysfunction. We conclude that it is only the degree of renal failure, irrespective of etiology, that explains the overestimation of the glomerular filtration rate by the renal creatinine clearance in cirrhotic patients; hence, there is no specific alteration in the renal excretion of creatinine in cirrhotic patients.

Gene expression of natriuretic peptide receptors in rats with DOCA-salt hypertension.

In our previous studies, we found that the atrial natriuretic peptide (ANP) binding and guanylyl cyclase activity of A-type natriuretic peptide receptors (NPR-A) were upregulated in renal papillae but downregulated in vascular tissues and glomeruli of rats with deoxycorticosterone acetate (DOCA)-salt hypertension [E. Nuglozeh, G. Gauquelin, R. Garcia, J. Tremblay, and E. L. Schiffrin. Am. J. Physiol. 259 (Renal Fluid Electrolyte Physiol. 28): F130-F137, 1990]. To further understand the molecular significance of these regulations, we measured the relative abundance of the transcripts of NPR-A and NPR-B by Northern blot in the aorta, mesenteric arteries, adrenal cortex, renal papillae, and lungs in DOCA-salt hypertensive and control rats. In renal papillae we also examined the translation and transcription of NPR-A by ribosome loading and run-on assay. Compared with controls, the steady-state levels of mRNA for NPR-A were increased in the aorta and mesenteric arteries but were decreased in the adrenal cortex and renal papillae in DOCA-salt-treated rats. NPR-B mRNA was decreased in the aorta, mesenteric arteries, and adrenal cortex in hypertensive rats. In lungs the mRNA for both receptors was unchanged. Translation of NPR-A mRNA, as assessed by ribosome loading, was reduced in renal papillae. Transcriptional activity of its gene was not detectable in these tissues. Guanosine 3',5'-cyclic monophosphate levels generated by NPR-A in renal papillae and by NPR-A and NPR-B in the adrenal cortex, aorta, and mesenteric arteries of DOCA-salt-treated rats remained increased in hypertension. The higher NPR-A activity in the presence of a lower level of its mRNA in renal papillae and the higher NPR-B activity in the presence of a lower level of its mRNA in the vasculature, adrenal cortex, and lungs can alternatively be explained by receptor stabilization or increased receptor recycling.

Treatment of refractory ascites using transjugular intrahepatic portosystemic shunt (TIPS): a caution.

Ascites becomes refractory to medical treatment in nearly 10% of cirrhotic patients, who then require repeated large-volume paracentesis. In this prospective study we evaluated the use of transjugular intrahepatic portosystemic shunt (TIPS) in 30 patients with refractory ascites. TIPS was successful in all and resulted in a 54% reduction in portacaval gradient (from 22.8 +/- 0.8 to 10.4 +/- 0.6 mm Hg). Ascites became easily controlled with diuretics in 26 patients following TIPS. Ascites recurrence associated with shunt stenosis was observed during follow-up in eight patients; revision could be undertaken in five of them and resulted in good control of ascites. In responders, a marked decrease in plasma aldosterone and renin activity, a reduction in serum creatinine, and a rise in urinary sodium excretion were observed. Creatinine and inulin clearances improved significantly; PAH clearance remained unchanged. However, new-onset or worsening hepatic encephalopathy was seen in 14 patients. Severe disabling chronic encephalopathy occurred in five patients; it could be reversed successfully by balloon occlusion of the shunt in three. The cumulative survival rate was 41 and 34% at 1 and 2 years, respectively. In summary, TIPS can control refractory ascites in a majority of patients but is associated with a high rate of chronic disabling HE. In addition, the survival rate is poor. Randomized trials are needed to evaluate the exact role of TIPS in the management of refractory ascites. It is unlikely to improve survival but can ameliorate quality of life in nontransplant candidates and be useful as a bridge to transplantation, in particular, to improve denutrition associated with longstanding tense ascites.

Rat natriuretic peptide receptor genes are regulated by glucocorticoids in vitro.

The effects of glucocorticoids on NPR-A and NPR-B mRNA transcription and natriuretic peptides ANP and CNP mediated cGMP production by intact vascular smooth muscle cells (VSMC) were studied in rat. Cultured VSMC were prepared from rat mesenteric arteries of 12-week-old Sprague-Dawley rats by enzymatic digestion. Dexamethasone-induced NPR-A mRNA increase was detectable early in the incubation periods and reached a plateau after 48 hours of glucocorticoid administration. This mRNA increase was mimicked by cortisol and inhibited by the glucocorticoid receptors antagonist RU 38,486. The levels of NPR-B mRNA remained unchanged during all the periods of stimulation. However, cGMP generated by both receptors in dexamethasone treated cells was higher than in control cells and this production was mimicked by cortisol and also blocked by RU 38,486. Desoxycorticosterone acetate (DOCA) had no effect on the levels of cGMP production. The results suggest that glucocorticoids have transcriptional and posttranscriptional effects on rat mesenteric arteries cells through glucocorticoid receptors.

Changes in plasma endothelin-1 and Big endothelin-1 induced by transjugular intrahepatic portosystemic shunts in patients with cirrhosis and refractory ascites.

BACKGROUND/AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor that may be involved in the pathogenesis of splanchnic and renal hemodynamic changes associated with portal hypertension. The aim of this study was to measure the concentration of ET-1 and of its precursor Big endothelin-1 (Big ET-1) in the systemic circulation as well as in the splanchnic and renal venous beds and to evaluate changes after the relief of portal hypertension following transjugular intrahepatic portosystemic shunt placement. METHODS: Plasma concentrations of ET-1 and of Big ET-1 were measured in the vena cava, renal vein, hepatic vein and portal vein in ten patients with cirrhosis and refractory ascites before and 1-2 months after transjugular intrahepatic portosystemic shunt. The porto-caval gradient, creatinine clearance, plasma aldosterone and renin activity, as well as daily urinary sodium excretion were measured at the same time. RESULTS: The plasma concentration of ET-1 and Big ET-1, respectively, in peripheral blood of normal volunteers were 0.28 +/- 03 and 3.95 +/- 0.34 pg/ml; the concentrations of both peptides were higher in patients with cirrhosis, both in vena cava (0.61 +/- 0.14 and 10.01 +/- 1.47 pg/ml), hepatic vein (0.62 +/- 0.13 and 13.93 +/- 1.77 pg/ml), portal vein (1.21 +/- 0.12 and 17.84 +/- 1.98 pg/ml) and renal vein (0.76 +/- 0.12 and 14.21 +/- 1.55 pg/ml). Moreover ET-1 and Big ET-1 concentrations were more elevated in the portal vein than in the vena cava (+98% and +70%) and slightly higher in the renal vein as compared to the vena cava (+25% and +42%). After transjugular intrahepatic portosystemic shunt, a rise in creatinine clearance and urinary sodium excretion (+49%; and +53%) was observed together with a marked reduction in plasma aldosterone and renin activity (-59% and -49%). ET-1 and Big ET-1 concentrations remained unchanged in the vena cava whereas a significant reduction of ET-1 and Big ET-1 occurred both in the portal vein (-43% and -44%) and in the renal vein (-53% and -29%). Portal vein and renal vein concentrations of both peptides became similar to vena cava levels. CONCLUSIONS: Splanchnic and renal hemodynamic changes occurring in patients with cirrhosis and refractory ascites could be related to the production of ET-1 by splanchnic and renal vascular beds. This was abolished by transjugular intrahepatic portosystemic shunt, which could explain the exacerbation of systemic vasodilation and the improvement in renal perfusion observed after the procedure.