Ferran Torres

High-Efficiency Postdilution Online Hemodiafiltration Reduces All-Cause Mortality in Hemodialysis Patients

Retrospective studies suggest that online hemodiafiltration (OL-HDF) may reduce the risk of mortality compared with standard hemodialysis in patients with ESRD. We conducted a multicenter, open-label, randomized controlled trial in which we assigned 906 chronic hemodialysis patients either to continue hemodialysis (n=450) or to switch to high-efficiency postdilution OL-HDF (n=456). The primary outcome was all-cause mortality, and secondary outcomes included cardiovascular mortality, all-cause hospitalization, treatment tolerability, and laboratory data. Compared with patients who continued on hemodialysis, those assigned to OL-HDF had a 30% lower risk of all-cause mortality (hazard ratio [HR], 0.70; 95% confidence interval [95% CI], 0.53-0.92; P=0.01), a 33% lower risk of cardiovascular mortality (HR, 0.67; 95% CI, 0.44-1.02; P=0.06), and a 55% lower risk of infection-related mortality (HR, 0.45; 95% CI, 0.21-0.96; P=0.03). The estimated number needed to treat suggested that switching eight patients from hemodialysis to OL-HDF may prevent one annual death. The incidence rates of dialysis sessions complicated by hypotension and of all-cause hospitalization were lower in patients assigned to OL-HDF. In conclusion, high-efficiency postdilution OL-HDF reduces all-cause mortality compared with conventional hemodialysis.

Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer.

Notch has been linked to β-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/β-catenin (down-regulated when blocking Wnt/β-catenin) that are directly regulated by Notch (repressed by γ-secretase inhibitors and up-regulated by active Notch1 in the absence of β-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through β-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/β-catenin pathway in tumors implanted s.c. in nude mice. Crossing APCMin/+ with Jagged1+/Δ mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear β-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by β-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.

Mortality in severe sleep apnoea/hypopnoea syndrome patients: impact of treatment

The aim of this study was to determine mortality in patients with sleep apnoea/hypopnoea syndrome (SAHS) according to the treatments employed and comorbidity. An historical cohort of patients with SAHS diagnosed at a university hospital between 1982 and 1992 and followed until 1996 was studied. From a total of 475 SAHS patients, 444 (94%), with a mean±sd apnoea/hypopnoea index at diagnosis of 55±27, were located and included in the study. SAHS treatments employed were: surgery (88), weight loss (134), continuous positive airway pressure (124) and 98 patients were not treated. By the end of follow-up, 49 patients had died. According to Cox regression analysis, mortality in treated patients was lower than in those not treated, but higher in those with a history of severe chronic obstructive pulmonary disease. Mortality in nontreated patients compared with that of the general population, adjusted for age and sex, showed excessive mortality, which decreased in treated patients. Stratification by age showed a greater mortality rate ratio in patients <50 yrs. These findings were maintained when mortality from cardiovascular causes was compared. In conclusion, a rise in mortality was found in nontreated sleep apnoea/hypopnoea syndrome patients compared with the general population, whereas mortality in those treated for sleep apnoea/hypopnoea syndrome did not differ significantly from that of the general population.

Cardio- and cerebrovascular events in HIV-infected persons

Objective: Recent results from the D:A:D Study indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). The present study was performed to investigate whether this risk was similar when including other cardio- and cerebro-vascular disease events (CCVE). Design: D:A:D is an international collaboration of 11 cohorts, following 23 468 HIV-infected patients prospectively at 188 clinics in 21 countries situated in Europe, USA and Australia. Methods: The end-point was the occurrence of a first CCVE during prospective follow-up, defined as the first of: acute MI, invasive cardiovascular procedures, stroke, or death from other cardiovascular disease. Relative rates (RR) for CCVE from Poisson regression models and 95% confidence intervals (CI) are reported. All models are adjusted for other risk factors for CCVE, including age, gender, ethnicity, family history, body mass index, and smoking status as well as cohort and HIV transmission group. Results: Over 36 145 person-years of follow-up, 207 patients experienced at least one CCVE (23.7% fatal). The first event was MI in 126 patients, invasive cardiovascular procedure in 39 patients, stroke in 38 patients, and death from other cardiovascular disease in four patients. The incidence of first CCVE was 5.7 per 1000 person-years [95% confidence interval (CI) 5.0–6.5] and increased with longer exposure to CART (RR per year of exposure, 1.26; 95% CI, 1.14–1.38; P < 0.0001). Conclusion: CART increases the risk of CCVD, and this increase is comparable with how CART affects the risk of MI. This finding is consistent with the hypothesis that atherosclerosis is a side-effect of CART.

The Early Systemic Prophylaxis of Infection After Stroke Study: A Randomized Clinical Trial

Background and Purpose— Early infection after stroke is frequent but the clinical value of antibiotic prophylaxis in acute stroke has never been explored. Objective and Methods— The Early Systemic Prophylaxis of Infection After Stroke (ESPIAS) is a randomized, double-blind, placebo-controlled study of antibiotic prophylaxis in patients older than 18 years with nonseptic ischemic or hemorrhagic stroke enrolled within 24 hours from clinical onset. Interventions included intravenous levofloxacin (500 mg/100 mL/d, for 3 days) or placebo (0.9% physiological serum) in addition to optimal care. A sample size of 240 patients was calculated to identify a 15% absolute risk reduction of the primary outcome measure, which was the incidence of infection at day 7 after stroke. Secondary outcome measures were neurological outcome and mortality at day 90. Results— Based on a preplanned futility analysis, the study was interrupted prematurely when 136 patients had been included. Levofloxacin and placebo patients had a cumulative rate of infection of 6% and 6% (P=0.96) at day 1; 10% and 12% (P=0.83) at day 2; 12% and 15% (P=0.66) at day 3; 16% and 19% (P=0.82) at day 7; and 30% and 33% (P=0.70), at day 90. Using logistic regression, favorable outcome at day 90 was inversely associated with baseline National Institutes of Health Stroke Scale (OR, 0.72; 95% CI, 0.59 to 0.89; P=0.002) and allocation to levofloxacin (OR, 0.19; 95% CI, 0.04 to 0.87; P=0.03). Conclusions— Prophylactic administration of levofloxacin (500 mg/100 mL/day for 3 days) is not better than optimal care for the prevention of infections in patients with acute stroke.

Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: A prospective study with time-dependent analysis

OBJECTIVES:The aim of this study was to investigate whether hyponatremia is a risk factor of overt hepatic encephalopathy (HE) in cirrhosis.METHODS:A total of 61 patients with cirrhosis were evaluated prospectively for 1 year and all episodes of overt HE were recorded. Predictive factors of HE were analyzed using a conditional model (Prentice, Williams, and Peterson) for recurrent events to assess the relationship between HE and time-dependent covariates. The effects of hyponatremia on the brain concentration of organic osmolytes were analyzed in 25 patients using 1H-magnetic resonance spectroscopy.RESULTS:Twenty-eight of the 61 patients developed 57 episodes of overt HE during follow-up. Among a number of clinical and laboratory variables analyzed, the only independent predictive factors of overt HE were hyponatremia (serum sodium <130 mEq/l), history of overt HE, serum bilirubin, and serum creatinine. Hyponatremia was associated with low brain concentration of organic osmolytes, particularly myo-inositol (MI). Furthermore, patients with low brain MI levels had a higher probability of development of overt HE compared with that of patients with high brain MI levels.CONCLUSIONS:In patients with cirrhosis, the existence of hyponatremia is a major risk factor of the development of overt HE. Treatment of hyponatremia may be a novel therapeutic approach to preventing HE in cirrhosis.

Catecholamines, infection, and death in acute ischemic stroke

Experimental studies have recently suggested that acute ischemia may facilitate the appearance of fatal infections as part of a brain-induced immunodepression syndrome. However, the mechanisms and neurological consequences of infections complicating acute ischemic stroke have received much less attention at the bedside. The incidence of infection and death after non-septic stroke was compared in this prospective study with longitudinal changes of cytokines, leukocytes, normetanephrine (NMN) and metanephrine (MN) in 75 consecutive patients. In multivariate analysis, infection, n = 13 (17%), was associated with the upper quartile of MN (OR 3.51, 95% CI 1.30-9.51), neurological impairment (NIHSS) on admission (OR 3.99, 95% CI 1.34-11.8), monocyte count (OR 1.78, 95% CI 1.13-2.79), and increased interleukin (IL)-10 (OR 1.54, 95% CI 1.00-2.38). Mortality at 3 months, n = 16 (21%), was associated with increased levels of NMN on admission (OR 2.34 95% CI 1.15-4.76), NIHSS score (OR 2.57, 95% CI 1.29-5.11), and higher IL-6 levels (OR 1.29, 95% 1.00-1.67). These findings suggest that acute ischemic stroke is associated with an early activation of the sympathetic adrenomedullar pathway that lowers the threshold of infection and increases the risk of death. Moreover, these findings are independent of the blood borne effects of pro- and anti-inflammatory cytokines, and circulating leukocytes.

Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial.

Background and Purpose— The efficacy of the antiplatelet agent triflusal for prevention of vascular events after stroke has been reported in a pilot study. However, there is a need to confirm those results in a larger study. Methods— We performed a randomized, double-blind, multicenter study to test the efficacy of triflusal (600 mg/d) versus aspirin (325 mg/d) for prevention of vascular events in patients with stroke or transient ischemic attack (Triflusal versus Aspirin in Cerebral Infarction Prevention [TACIP]). We assessed a combined end point (incidence of nonfatal ischemic stroke, nonfatal acute myocardial infarction, or vascular death) as well as the incidence of these events separately and the incidence of major hemorrhage. Results— Of 2113 patients, 1058 received triflusal and 1055 aspirin. The mean follow-up period was 30.1 months. The incidence of combined end point (13.1% for triflusal, 12.4% for aspirin) as well the survival analysis (hazard ratio [HR] for triflusal versus aspirin, 1.09; 95% CI, 0.85 to 1.38) showed no differences between groups. The incidence of nonfatal stroke (HR, 1.09; 95% CI, 0.82 to 1.44), nonfatal acute myocardial infarction (HR, 0.95; 95% CI, 0.46 to 1.98,) and vascular death (HR, 1.22; 95% CI, 0.75 to 1.96) was also similar. A significantly higher incidence of major hemorrhages in the aspirin group was recorded (HR, 0.48; 95% CI, 0.28 to 0.82). The overall incidence of hemorrhage was significantly lower in the triflusal group (16.7% versus 25.2%) (odds ratio, 0.76; 95% CI, 0.67 to 0.86;P <0.001). Conclusions— This study failed to show significantly superior efficacy of triflusal over aspirin in the long-term prevention of vascular events after stroke, but triflusal was associated with a significantly lower rate of hemorrhagic complications.

Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation.

Significant liver fibrosis (F ≥ 2) and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mmHg) at 1 year after liver transplantation (LT) identify patients with severe hepatitis C recurrence. We evaluated whether repeated liver stiffness measurements (LSM) following LT can discriminate between slow and rapid “fibrosers” (fibrosis stage F2‐F4 at 1 year after LT). Eighty‐four patients who had undergone LT and who were infected with hepatitis C virus (HCV) and 19 LT controls who were not infected with HCV underwent LSM at 3, 6, 9, and 12 months after LT. All HCV‐infected patients underwent liver biopsy 12 months after LT (paired HVPG measurements in 74); 31 (37%) were rapid fibrosers. Median LSM (in kilopascal) at months 6, 9, and 12 were significantly higher in rapid fibrosers (9.9, 9.5, 12.1) than in slow fibrosers (6.9, 7.5, 6.6) (P < 0.01 all time points). The slope of liver stiffness progression (kPa × month) in rapid fibrosers (0.42) was significantly greater than in slow fibrosers (0.05) (P < 0.001), suggesting two different speeds of liver fibrosis progression. Figures were almost identical for patients with HVPG ≥ 6 mmHg or HVPG < 6 mmHg at 1 year after LT. Multivariate analysis identified donor age, bilirubin level, and LSM as independent predictors of fibrosis progression and portal hypertension in the estimation group (n = 50) and were validated in a second group of 34 patients. The areas under the receiver operating characteristic curve that could identify rapid fibrosers and patients with portal hypertension as early as 6 months after LT were 0.83 and 0.87, respectively, in the estimation group and 0.75 and 0.80, respectively, in the validation group. Conclusion: Early and repeated LSM following hepatitis C recurrence in combination with clinical variables discriminates between rapid and slow fibrosers after LT. (HEPATOLOGY 2009.)

Long-Term Dietary Intake and Nutritional Deficiencies following Sleeve Gastrectomy or Roux-En-Y Gastric Bypass in a Mediterranean Population

BACKGROUND Data on long-term dietary changes and nutritional deficiencies after sleeve gastrectomy (SG) in grade 3 obese patients are scarce. OBJECTIVE To prospectively compare dietary changes and nutritional deficiencies in grade 3 obese patients 5 years after SG and Roux-en-y gastric bypass (GBP). PARTICIPANTS/SETTING Three hundred and fifty-five patients who had SG (n=61) or GBP (n=294) (May 2001-December 2006) at a Spanish university hospital. DESIGN Longitudinal, prospective, observational study. PRIMARY OUTCOMES/STATISTICAL ANALYSES: Changes in energy, macronutrient, and micronutrient intake, and weight loss were analyzed using mixed models for repeated measurements. RESULTS At the 5-year follow-up visit, the percentage of excess weight loss (P=0.420) and daily energy intake (P=0.826), as well as the proportion of energy from carbohydrates (P=0.303), protein (P=0.600), and fat (P=0.541) did not differ between surgical groups. Energy intake (P=0.004), baseline weight (P<0.001), and time period (P<0.001), but not the proportion of different macronutrients or the type of surgery, independently predicted the percentage excess weight loss over time. After SG or GBP, the mean daily dietary intake of calcium, magnesium, phosphorus, and iron was less than the current recommendations. Despite universal supplementation, the prevalence of nutritional deficiencies was comparable after SG or GBP, with 25-hydroxyvitamin D being the most commonly observed deficiency (SG, 93.3% to 100%; GBP, 90.9% to 85.7%, P=not significant). In an adjusted multivariate regression model, energy intake and lipid intake independently predicted plasma 25(OH)-vitamin D levels. CONCLUSIONS Data show that SG and GBP are associated with similar long-term weight loss with no differences in terms of dietary intake. Furthermore, data demonstrate that both types of surgeries carry comparable nutritional consequences.