[Clinical research: from bench to bedside].
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Biomedical Research↗
Biomedical subjects
Juan Rodés
Publications and source records attributed to Juan Rodés.
[Deaths by a medical resident. Could they have been avoided?].
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Clinical Competence↗
[Non-alcoholic steatohepatitis].
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Clinical Trials as Topic↗
Role of a research ethics committee in follow-up and publication of results.
Follow-up of clinical trials is a commitment rarely fulfilled by research ethics committees (RECs). We assessed the output of clinical trials submitted in 1997 to our REC, and talked to principal investigators, sponsors, contract research organisations, or a combination of these. During 1997, our REC reviewed 166 clinical trials, and approved 158. The recruitment rate was lower than expected in 45% (64/143) of all initiated clinical trials; 64% (92/143) were finished in accordance with protocol. 3 years after, the results of only 21% (26/123) of finished clinical trials were published in peer-reviewed journals, rising to 31% (38/123) if in-press articles were included. RECs should devote more effort and resources to assess public dissemination of results of clinical trials.
Clinical Trials as Topic↗
[A secure job for ever].
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Health Care Reform↗
Characterization and evolution of NS5A quasispecies of hepatitis C virus genotype 1b in patients with different stages of liver disease.
The quasispecies nature of hepatitis C virus (HCV) is thought to play a central role in modulating viral functions. Recent work has linked NS5A protein with viral replication, resistance to interferon (IFN), and control of cellular growth, probably through the interaction of its protein kinase R (double stranded RNA-activated protein kinase, PKR) binding domain (PKR-bd) with cellular PKR, but knowledge of how PKR-bd viral population evolves during disease progression is limited. Since we have previously described an association between amino acid composition of the PKR-bd and the presence of HCC, in this report we further investigated the dynamic behavior of viral population parameters by sequencing an average of 20 clones per sample in 27 samples from 19 untreated patients with different degrees of liver disease, 8 of whom were followed over time. Viral population parameters varied widely from patient to patient, but no differences were observed in the complexity, diversity, types of nucleotide changes, or evolutionary pattern of the quasispecies according to the stage of liver disease. In five samples, we detected "quasispecies-tails"; that is, clones whose minimum genetic distance to the remaining clones of their own quasispecies were higher than the maximum genetic distance found between any other two clones of the same sample. In summary, independent of the degree of liver disease, or the mutations detected within the consensus sequence of the PKR-bd, the NS5A of HCV presents a flexible and variable quasispecies structure that remains largely stable during the natural course of an HCV infection, highlighting the central role of NS5A protein in viral life cycle.
Amino Acid Sequence↗
Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis.
Vascular remodeling is an active process that consists in important modifications in the vessel wall. Endothelium-derived nitric oxide (NO) plays a major role in this phenomenon. We assessed wall thickness (WT), total wall area (TWA), lumen diameter, and total nuclei number/cross-section (TN) in cirrhotic rats with ascites and in control rats. A second group of cirrhotic rats received the NO synthesis inhibitor, L-NAME, or vehicle daily for 11 weeks and systemic hemodynamics, arterial compliance, aortic NO synthase 3 (NOS3) protein expression, and vascular morphology were analyzed. Cirrhotic vessels showed a significant reduction in WT, TWA, and TN as compared to control vessels. Long-term inhibition of NOS activity in cirrhotic rats resulted in a significant increase in WT, TWA, and TN as compared to cirrhotic rats receiving vehicle. NOS3 protein abundance was higher in aortic vessels of nontreated cirrhotic animals than in controls. This difference was abolished by chronic treatment with L-NAME. NOS inhibition in cirrhotic rats resulted in higher arterial pressure and peripheral resistance and lower arterial compliance than cirrhotic rats receiving vehicle. Therefore, vascular remodeling in cirrhosis with ascites is a generalized process with significant functional consequences that can be negatively modulated by long-term inhibition of NOS activity.
Animals↗
Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II.
BACKGROUND & AIMS: The renin-angiotensin system plays an important role in hepatic fibrogenesis. In other organs, myofibroblasts accumulated in damaged tissues generate angiotensin II, which promotes inflammation and extracellular matrix synthesis. It is unknown whether myofibroblastic hepatic stellate cells, the main hepatic fibrogenic cell type, express the renin-angiotensin system and synthesize angiotensin II. The aim of this study was to investigate whether quiescent and activated human hepatic stellate cells contain the components of the renin-angiotensin system and synthesize angiotensin II. METHODS: Hepatic stellate cells were freshly isolated from normal human livers (quiescent hepatic stellate cells) and from human cirrhotic livers (in vivo activated hepatic stellate cells). Culture-activated hepatic stellate cells were used after a second passage of quiescent hepatic stellate cells. Angiotensinogen, renin, and angiotensin-converting enzyme were assessed by quantitative polymerase chain reaction. Angiotensin II production was assessed by enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Quiescent hepatic stellate cells barely express the renin-angiotensin system components--angiotensinogen, renin, and angiotensin-converting enzyme--and do not secrete angiotensin II. In contrast, both in vivo activated hepatic stellate cells and culture-activated hepatic stellate cells highly express active renin and angiotensin-converting enzyme and secrete angiotensin II to the culture media. Mature angiotensin II protein is also detected in the cytoplasm of in vivo activated and culture-activated hepatic stellate cells. Growth factors (platelet-derived growth factor and epidermal growth factor) and vasoconstrictor substances (endothelin-1 and thrombin) stimulate angiotensin II synthesis, whereas transforming growth factor-beta and proinflammatory cytokines have no effect. Vasodilator substances markedly attenuate the effect of endothelin-1. CONCLUSIONS: After activation, human hepatic stellate cells express the components of the renin-angiotensin system and synthesize angiotensin II. These results suggest that locally generated angiotensin II could participate in tissue remodeling in the human liver.
Angiotensin II↗
Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats.
BACKGROUND & AIMS: Portal hypertension in cirrhosis is secondary to an increase in hepatic resistance that occurs mainly through collagen deposition. However, recent evidence points to a major contribution by other factors, such as an intrahepatic reduction in nitric oxide production. Akt is a major activator of the endothelial nitric oxide synthase (eNOS) enzyme, but its potential role in intrahepatic resistance in cirrhosis is unknown. For this reason the aims of the present study were to determine whether there is an impaired Akt activation in cirrhotic livers and how this phenomenon relates to the decrease in NO production associated with portal hypertension. METHODS: Cirrhosis was induced in rats by carbon tetrachloride inhalation. Protein abundance and phosphorylation status of Akt and eNOS were examined by Western blotting. The role of Akt in the liver of cirrhotic rats was investigated through infection with adenoviruses encoding either beta-galactosidase (beta-gal) or constitutively active Akt (myr-Akt). RESULTS: The liver of cirrhotic animals showed a significant reduction in Akt and eNOS phosphorylation. Adenoviral delivery of myr-Akt restored eNOS phosphorylation and increased the intrahepatic concentration of guanosine 3',5'-cyclic monophosphate. These events were associated with normalization in portal pressure and a significant increase in mean arterial pressure after 3 days of adenoviral infection. In contrast, transduction of livers with beta-gal did not produce any change in these hemodynamic parameters. CONCLUSIONS: myr-Akt gene therapy restored Akt activation and NO production in the cirrhotic liver, suggesting that this therapy may be useful for the treatment of portal hypertension.
Adenoviridae↗
Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial.
BACKGROUND/AIMS: The efficacy and safety of rifaximin in comparison with lactitol in the treatment of acute hepatic encephalopathy was assessed in a prospective randomized, double-blind, double-dummy, controlled trial. METHODS: A total of 103 patients with grade I-III acute hepatic encephalopathy were randomized to receive rifaximin (50 patients, 1200 mg/day) or lactitol (53 patients, 60 g/day) for 5-10 days. Changes in the portal-systemic encephalopathy (PSE) index on entry and at the end of the study were used to evaluate the efficacy of the two therapies. RESULTS: Both groups were comparable before treatment with regard to demographic data and characteristics of the hepatic encephalopathy episode. The global efficacy of both therapies was similar: 81.6% in the rifaximin group and 80.4% in the lactitol group showed improvement or total regression of the episode. A significantly better evolution of the PSE index was observed in the rifaximin group, due to a greater effect of rifaximin in two components of the index: EEG abnormalities and ammonia levels. No serious adverse events related to either treatment were found during the study. CONCLUSIONS: Rifaximin may be considered a useful and safe alternative therapy to lactitol in the treatment of acute hepatic encephalopathy in cirrhosis.
Acute Disease↗
p27(Kip1) is an independent predictor of recurrence after surgical resection in patients with small hepatocellular carcinoma.
BACKGROUND/AIMS: Alterations in p27(Kip1) (p27) and cyclin E (cycE) expression are found in tumors and are related to poor prognosis. This study assesses the role of these cell cycle regulators in the development of recurrence after surgical resection in 46 cirrhotic patients (age: 61.3+/-7 years, 30 males, 44 Child-Pugh's A, 30 HCV-positive) with small hepatocellular carcinoma (HCC, size: 3.1+/-1.5cm, 40 solitary at pathological examination). METHODS: p27 and cycE expression in tumoral and non-tumoral liver were analyzed by Western blot (WB). p27 was also assessed by immunohistochemistry (IHC). RESULTS: Tumor p27 underexpression (50% decreased vs. non-tumoral liver) occurred in 12 cases. Throughout follow-up, 26 patients developed recurrence, which was significantly higher in patients with p27 underexpression than in those without (3-year recurrence: 80 vs. 44%, respectively, P=0.026). IHC showed concordant inverse findings: 13 tumors showed high p27 staining that was related to lower recurrence rate (P=0.019). Multivariate analysis identified p27 measured by WB as an improved predictor of recurrence (OR: 3.09, 95% CI: 1.26-7.08, P=0.016). By contrast, cycE, increased in 66% of the tumors, had no impact on recurrence but was associated to poor differentiation (P=0.015) and microvascular invasion (P=0.016). CONCLUSIONS: p27 underexpression is frequent in relatively early stages of HCC and constitutes an independent predictor of recurrence after surgical resection.
Aged↗
Effect of the V1a/V2-AVP receptor antagonist, Conivaptan, on renal water metabolism and systemic hemodynamics in rats with cirrhosis and ascites.
BACKGROUND: Selective V(2)-AVP receptor antagonists are effective in inducing aquaresis in humans and rats with cirrhosis, hyponatremia and water retention. However, it is unknown whether dual V(1a)/V(2)-AVP antagonists are also efficacious as aquaretic agents under these conditions. This is important, particularly considering that blockade of V(1a)-AVP receptors could aggravate cardiocirculatory function in decompensated cirrhosis. AIMS: To evaluate the renal, hormonal and hemodynamic effects induced by the chronic oral administration of the V(1a)/V(2)-AVP antagonist, Conivaptan, in rats with CCl(4)-induced cirrhosis, ascites and severe water retention. METHODS: We assessed the aquaretic efficacy of 10-day chronic oral administration of Conivaptan (0.5mg/kg body weight (bw)) in cirrhotic rats with hyponatremia and water retention. Urine volume (UV), osmolality (UOsm), and sodium excretion (U(Na)V) were measured daily. At the end of the study arterial pressure was also measured. RESULTS: Conivaptan produced an acute increase in UV, a reduction in UOsm and, at the end of the investigation, cirrhotic rats receiving the V(1a)/V(2)-AVP receptor antagonist did not show hyponatremia or hypoosmolality. Conivaptan also normalized U(Na)V without affecting creatinine clearance and arterial pressure. CONCLUSIONS: Dual V(1a)/V(2)-receptor antagonists may be therapeutically useful for the treatment of water retention and dilutional hyponatremia in human cirrhosis.
Administration, Oral↗
Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation.
BACKGROUND/AIMS: After liver transplantation (LT) infection of the graft with the hepatitis C virus (HCV) is almost universal and chronic hepatitis and cirrhosis develop in a significant proportion of patients. One of the possible strategies to prevent HCV infection recurrence is to eradicate HCV before LT. METHODS: We evaluated the efficacy and safety of antiviral therapy to prevent HCV recurrence in 30 HCV-cirrhotic patients awaiting LT. At the time of inclusion 15 patients were Child-Pugh A and 15 Child-Pugh B/C. The infecting genotype was 1b in 25 patients. Treatment with interferon alpha-2b 3 MU/day and ribavirin 800 mg/day was initiated when the expected time for LT was less than 4 months and continued until LT. The median duration of treatment was 12 weeks. RESULTS: Nine patients (30%) achieved a virological response and 21 did not respond to therapy. In nine (43%) of the 21 non-responders viral load decreased > or =2 log10 during treatment. A viral load decrease > or = 2 log10 at week 4 of treatment was the strongest predictor of virological response. All nine virological responders have already undergone LT; six patients remain free of infection after a median follow-up of 46 weeks and HCV infection recurred in three patients after LT. In one of these patients HCV-RNA was still detectable in the explanted liver. Side effects were frequent and dose reduction was necessary in 19 (63%) of the 30 patients; no patient died while on therapy. CONCLUSIONS: Our data support the utilization of antiviral therapy in HCV-infected patients awaiting LT as one of the strategies to prevent hepatitis C recurrence after transplantation.
Adult↗
Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers.
BACKGROUND/AIMS: Cirrhotic livers exhibit endothelial dysfunction that contributes to the increased hepatic vascular resistance. The present study evaluates the role of cyclooxygenase (COX)-derived prostanoids, implicated in the pathogenesis of endothelial dysfunction in other settings, in the pathogenesis of endothelial dysfunction in cirrhotic livers. METHODS: Endothelial dysfunction was evaluated by performing concentration-effect curves to acetylcholine after precontracting the liver with methoxamine in groups of control and CCl(4)-cirrhotic rat livers preincubated either with vehicle, indomethacin, the COX-1 selective inhibitor, SC-560, the COX-2 selective inhibitor, SC-236, the thromboxane A(2) receptor antagonist, SQ 29,548 or the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine. Thromboxane A(2) (TXA(2)) production was determined in samples of the perfusate. RESULTS: Cirrhotic livers exhibited endothelial dysfunction, as shown by the significantly lower relaxation to acetylcholine than control livers, that was totally corrected by indomethacin. COX-1 inhibition and TXA(2) blockade, but not COX-2 inhibition, also corrected endothelial dysfunction. Acetylcholine significantly increased TXA(2) production in cirrhotic but not in control livers. Indomethacin and COX-1 inhibition, but not COX-2 or NO inhibition, prevented the increased production of TXA(2). CONCLUSIONS: An increased production of TXA(2) is involved in the pathogenesis of endothelial dysfunction in cirrhotic rat livers. This is mainly mediated by COX-1, but not by COX-2.
Animals↗
Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers.
In cirrhotic livers, increased resistance to portal flow, in part due to an exaggerated response to vasoconstrictors, is the primary factor in the pathophysiology of portal hypertension. Our aim was to evaluate the response of the intrahepatic circulation of cirrhotic rat livers to the alpha(1)-adrenergic vasoconstrictor methoxamine and the mechanisms involved in its regulation. A portal perfusion pressure dose-response curve to methoxamine was performed in control and cirrhotic rat livers preincubated with vehicle, the nitric oxide synthase blocker N(G)-nitro-L-arginine (L-NNA), indomethacin cyclooxygenase (COX) inhibitor, L-NNA + indomethacin, or the thromboxane (TX) A(2) receptor blocker SQ 29,548. TXA(2) production, COX-1 and COX-2 mRNA expression, and immunostaining for TXA(2) synthase were evaluated. Cirrhotic livers exhibited a hyperresponse to methoxamine associated with overexpression of COX-2 and TXA(2) synthase as well as with increased production of TXA(2). The hyperresponse to methoxamine of cirrhotic livers disappeared by COX inhibition with indomethacin but not after NO inhibition. SQ 29,548 also corrected the hyperresponse of cirrhotic livers to methoxamine. In conclusion, COX-derived prostanoids, mainly TXA(2), play a major role in regulating the response of cirrhotic livers to methoxamine.
6-Ketoprostaglandin F1 alpha↗
Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis.
Postprandial hyperemia is associated with a significant increase in portal pressure in cirrhosis, which may contribute to progressive dilation and rupture of gastroesophageal varices. In cirrhosis, an insufficient hepatic production of nitric oxide (NO) may impair the expected hepatic vasodilatory response to increased blood flow, further exaggerating the postprandial increase in portal pressure. This study was aimed at investigating whether low doses of an oral NO donor might counteract the postprandial peak in portal pressure. Twenty-three portal hypertensive cirrhotics, 8 of them under propranolol therapy, were randomized to receive orally 5-isosorbide mononitrate (ISMN; 10 mg; n = 11) or placebo (n = 12) and a standard liquid meal 15 minutes later. Hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and hepatic blood flow (HBF) were measured at baseline and 15, 30, and 45 minutes after a meal. ISMN significantly attenuated the postprandial increase in portal pressure as compared with placebo (peak HVPG increase: 2.4 +/- 1.4 mm Hg vs. 5.2 +/- 2.1 mm Hg, P =.002). Percentual increases in HBF were similar in both groups. MAP decreased slightly in ISMN group (-7.5% +/-.5%; P <.01 vs. baseline). These effects were also observed in patients on chronic propranolol therapy. In conclusion, hepatic NO supplementation by low doses of ISMN effectively reduces the postprandial increase of portal pressure in cirrhosis, with only a mild effect on arterial pressure. The same was observed in patients receiving propranolol. Our results suggest that therapeutic strategies based on selective hepatic NO delivery may improve the treatment of portal hypertension.
Aged↗
Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.
In cirrhotic patients under pharmacologic treatment for portal hypertension, a reduction in hepatic venous pressure gradient (HVPG) of >or=20% of baseline or to or=20% of baseline or to or=20% or to <or=12 mm Hg is associated with a marked reduction in the long-term risk of developing complications of portal hypertension and with improved survival.
Antihypertensive Agents↗
Increased carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis.
Carbon monoxide, a product of the heme-oxygenase (HO) pathway, is an important endogenous vasoactive substance. Production of CO has not been assessed in human cirrhosis. The aim of this study was to assess production of CO in patients with cirrhosis with and without spontaneous bacterial peritonitis (SBP). CO concentration in the exhaled air and blood carboxyhemoglobin (COHb) levels, as estimates of total HO activity, were determined in 16 healthy subjects, 32 noninfected cirrhotic patients (20 with ascites), and 19 patients with SBP, all nonsmokers. Noninfected cirrhotic patients had a CO concentration in the exhaled air and COHb levels significantly higher compared with values of healthy subjects (2.3 +/- 0.2 ppm vs. 0.7 +/- 0.1 ppm and 1.0% +/- 0.1% vs. 0.6% +/- 0.1%, respectively; P <.05 for both). Patients with ascites had the highest values. Both CO concentration in the exhaled air and COHb levels were very high in patients with SBP (5.6 +/- 0.6 ppm and 1.9% +/- 0.2%; P <.01 vs. the other 2 groups) and decreased slowly after resolution of the infection, reaching values similar to those of noninfected patients 1 month after SBP. In patients with SBP, there was a significantly direct correlation between CO and plasma renin activity (PRA) (r = 0.71, P <.001). In conclusion, these results support the existence of increased CO production in human cirrhosis, which further increases in the setting of SBP. Increased CO production may participate in the disturbance of circulatory function that occurs during severe bacterial infections in cirrhosis.
Bacterial Infections↗