Resistance to apoptosis in complicated Crohn's disease: Relevance in ileal fibrosis.

BACKGROUND AND AIMS: The stiffening of the extracellular matrix, and changes in its cellular and molecular composition, have been reported in the pathogenesis of fibrosis. We analyze the mechanisms that perpetuate ileal fibrosis in surgical resections of complicated Crohn's disease patients. METHODS: Ileal resections were obtained from affected and non-affected tissue of stenotic or penetrating Crohn's disease behavior. Ilea from non-IBD patients were used as control tissue. All samples underwent RNA sequencing. Human small intestinal fibroblasts were treated for 48 h with IL-1ß, TFGß1, PDGFB or TNF-α. Resistance to apoptosis was analysed by RT-PCR, western blot and immunohistochemistry in ileal tissue and by RT-PCR and FACS in cultured cells. RESULTS: Growth factor-driven signaling pathways and increased RAS GTPase activity were up-regulated in affected ilea in which we found expression of both the antiapoptotic molecule MCL1 and the transcription factor ETS1 in submucosal fibroblasts, and a senescence-associated secretory phenotype. In cultured intestinal fibroblasts, PDGFB induced an ETS1-mediated resistance to apoptosis that was associated with the induction of both of TGFB1 and IL1B, a cytokine that replicated the expression of SASP detected in ileal tissue. ETS1 drove fibroblast polarization between inflammatory and fibrogenic phenotypes in IL1ß-treated cells. CONCLUSIONS: Our data show resistance to apoptosis in complicated ileal CD, and demonstrate that PDGFB induce an ETS1-mediated resistance to apoptosis associated with an inflammatory and fibrogenic pattern of expression in intestinal fibroblasts. Results point to PDGFRB, IL1R1 or MCL1 as potential targets against ileal fibrosis.

Emotional prosody recognition enhances and progressively complexifies from childhood to adolescence.

Emotional prosody results from the dynamic variation of language's acoustic non-verbal aspects that allow people to convey and recognize emotions. The goal of this paper is to understand how this recognition develops from childhood to adolescence. We also aim to investigate how the ability to perceive multiple emotions in the voice matures over time. We tested 133 children and adolescents, aged between 6 and 17 years old, exposed to 4 kinds of linguistically meaningless emotional (anger, fear, happiness, and sadness) and neutral stimuli. Participants were asked to judge the type and intensity of perceived emotion on continuous scales, without a forced choice task. As predicted, a general linear mixed model analysis revealed a significant interaction effect between age and emotion. The ability to recognize emotions significantly increased with age for both emotional and neutral vocalizations. Girls recognized anger better than boys, who instead confused fear with neutral prosody more than girls. Across all ages, only marginally significant differences were found between anger, happiness, and neutral compared to sadness, which was more difficult to recognize. Finally, as age increased, participants were significantly more likely to attribute multiple emotions to emotional prosody, showing that the representation of emotional content becomes increasingly complex. The ability to identify basic emotions in prosody from linguistically meaningless stimuli develops from childhood to adolescence. Interestingly, this maturation was not only evidenced in the accuracy of emotion detection, but also in a complexification of emotion attribution in prosody.

Applicability and accuracy improvement of transient elastography using the M and XL probes by experienced operators.

Transient elastography (TE) is the reference method to obtain liver stiffness measurements (LSM), but no results are obtained in 3.1% and unreliable in 15.8%. We assessed the applicability and diagnostic accuracy of TE re-evaluation using M and XL probes. From March 2011 to April 2012 868 LSM were performed with the M probe by trained operators (50-500 studies) (LSM1). Measurements were categorized as inadequate (no values or ratio <60% and/or IQR/LSM >30%) or adequate. Inadequate LSM1 were re-evaluated by experienced operators (>500 explorations) (LSM2) and inadequate LSM2 using XL probe (LSMXL). Inadequate LSM1 were obtained in 187 (21.5%) patients, IQR/LSM >30% in 97 (51%), ratio <60% in 24 (13%) and TE failed to obtain a measurement in 67 (36%). LSM2 achieved adequate registers in 123 (70%) of 175 registers previously considered as inadequate. Independent variables (OR, 95%CI) related to inadequate LSM1 were body mass index (1.11, 1.04-1.18), abdominal circumference (1.03, 1.01-1.06) and age (1.03, 1.01-1.04) and to inadequate LSM2 were skin-capsule distance (1.21, 1.09-1.34) and abdominal circumference (1.05, 1.01-1.10). The diagnostic accuracy (AUROC) to identify significant fibrosis improved from 0.89 (LSM1) to 0.91 (LSM2) (P = 0.046) in 334 patients with liver biopsy or clinically significant portal hypertension. A third evaluation (LSMXL) obtained adequate registers in 41 (93%) of 44 patients with inadequate LSM2. Operator experience increases the applicability and diagnostic accuracy of TE. The XL probe may be recommended for patients with inadequate values obtained by experienced operators using the M probe. http://clinicaltrials.gov (NCT01900808).

Utility of proton MR spectroscopy in the diagnosis of radiologically atypical intracranial meningiomas.

Our aim was to evaluate the usefulness of proton MR spectroscopy ((1)H MRS) in the diagnosis of radiologically atypical brain meningiomas. We studied 37 patients with intracranial meningiomas with MRI and (1)H MRS (TE 136 ms). Their spectra were quantitatively assessed and compared with those of 93 other intracranial brain neoplasms: 15 low-grade and 14 anaplastic astrocytomas, 30 glioblastomas and 34 metastases. The most characteristic features of meningiomas were the presence of alanine, high relative concentrations of choline and glutamine/glutamate and low concentrations of creatine-containing compounds, N-acetyl-containing compounds and lipids. These resonances were assembled in algorithms for two-way differentiation between meningioma and the other tumours. The performance of the algorithms was tested in the 130 patients using the leave-one-out method, with 94% success in differentiating between meningioma and other tumour. Of the 37 meningiomas, five (14%) were thought atypical on MRI, and in only one of these, found to be malignant on histology, was a diagnosis other than meningioma suggested by the algorithm. The other four were correctly classified. We suggest that (1)H MRS provides information on intracranial meningiomas which may be useful in diagnosis of radiologically atypical cases.

Pre-treatment with prednisolone does not improve the efficacy of subsequent alpha interferon therapy in chronic hepatitis C.

BACKGROUND/AIMS: Alpha interferon administration is quite disappointing as a single therapy in chronic hepatitis C. A brief course of corticosteroid therapy might increase the effectiveness of subsequent alpha interferon administration, but data on this issue are controversial. METHODS: One hundred and fifty-six consecutive patients with chronic hepatitis C were randomly assigned to be treated blind with tapering doses of oral prednisolone or placebo for 4 weeks. Two weeks after cessation of therapy, patients received alpha interferon (3 MU t.i.w.) for 48 weeks and were followed for 24 additional weeks. Response was defined by the presence of normal alanine aminotransferase (ALT) and negative HCV-RNA in serum. RESULTS: ALT activity decreased during prednisolone administration and rebounded upon withdrawal in 38% of the patients treated with this drug. Significant changes in serum bilirubin were not observed. HCV-RNA serum concentration tended to increase during prednisolone administration and to decrease upon withdrawal. ALT and HCV-RNA did not change during administration of placebo. At the end of interferon administration, 33% of patients treated with prednisolone and 25% of those treated with placebo presented biochemical and virological response. At the end of post-treatment follow-up, response was maintained in 12% and 13% of patients treated with prednisolone or placebo respectively. Response was not related to ALT or HCV-RNA changes observed during the pre-interferon phase of the study. No adverse events related to prednisolone administration were observed. CONCLUSIONS: Prednisolone administration and withdrawal induced a rebound in ALT activity and a decrease in HCV-RNA serum concentration in about one third of the patients with chronic hepatitis C. However, these changes did not enhance the effectiveness of subsequent alpha interferon therapy.

Intraventricular mass lesions of the brain.

Intraventricular tumours represent a diverse group of lesions, some of them infrequent, with a wide variety of radiological features. Determination of their precise aetiology or origin can be difficult. Nevertheless, considering patient's age, location within the ventricles, and some specific radiological features, the radiologist should be able to narrow down the differential diagnosis. This paper reviews the characteristic radiological appearances of the diverse intraventricular lesions emphasising its differential diagnosis.

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.

Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.

BACKGROUND & AIMS: Long-term primary antibiotic prophylaxis of spontaneous bacterial peritonitis has been suggested to be useful in cirrhotic patients with low ascitic fluid protein levels. However, it is unlikely that all such patients need prophylactic treatment. The aim of this study was to identify the group of cirrhotic patients with low ascitic fluid protein levels at high risk of developing a first episode of spontaneous bacterial peritonitis during outpatient follow-up. METHODS: One hundred nine cirrhotic patients with low ascitic fluid protein levels and without previous episodes of spontaneous bacterial peritonitis were followed up in an outpatient clinic. RESULTS: Twenty-eight patients developed a first spontaneous bacterial peritonitis episode. In the multivariate analysis, serum bilirubin level (>3.2 mg /dL) and platelet count (<98.000/mm(3)) independently correlated with the risk of developing the first spontaneous bacterial peritonitis (P < 0.01 and P < 0.05, respectively). According to the median relative risk coefficient, a low-risk group (relative risk <1.09) and a high-risk group (relative risk >1.09) were established. The probability of developing a first spontaneous bacterial peritonitis episode at 1-year follow-up was significantly higher in the high risk-group (low-risk group, 23.6%; high-risk group, 55%; P < 0.01) as a consequence of a higher probability of the first community-acquired episode (13.7% vs. 47.6%, respectively, P < 0.01). One-year probability of survival was significantly lower in the high-risk group (low-risk group, 57.6%; high-risk group, 38%, P < 0.05). CONCLUSIONS: Cirrhotic patients with low ascitic fluid protein levels (

S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.

BACKGROUND/AIM: The efficacy of S-adenosylmethionine (AdoMet) in the treatment of liver cell injury has been demonstrated in several experimental models. The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis. METHODS: A randomized, double-blind trial was performed in 123 patients treated with AdoMet (1200 mg/day, orally) or placebo for 2 years. All patients had alcoholic cirrhosis, and histologic confirmation of the diagnosis was available in 84% of the cases. Seventy-five patients were in Child class A, 40 in class B, and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo. RESULTS: At inclusion into the trial no significant differences were observed between the two groups with respect to sex, age, previous episodes of major complications of cirrhosis, Child classification and liver function tests. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the AdoMet group, although the difference was not statistically significant (p = 0.077). When patients in Child C class were excluded from the analysis, the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group (29% vs. 12%, p = 0.025), and differences between the two groups in the 2-year survival curves (defined as the time to death or liver transplantation) were also statistically significant (p = 0.046). CONCLUSIONS: The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease.

Intraventricular meningiomas: MR imaging and MR spectroscopic findings in two cases.

CT, MR imaging, MR spectroscopy, and angiography were performed in two men (ages 21 and 48, respectively) with intraventricular meningioma. In both cases, CT and MR imaging showed large tumors located in the trigone of the right lateral ventricle that enhanced intensely after contrast administration. MR spectroscopy was helpful in supporting a preoperative diagnosis of meningioma in both cases.

Infections caused by Escherichia coli resistant to norfloxacin in hospitalized cirrhotic patients.

Selective intestinal decontamination with norfloxacin is useful to prevent bacterial infections in several groups of cirrhotic patients at high risk of infection. However, the emergence of infections caused by Escherichia coli resistant to quinolones has recently been observed in cirrhotic patients undergoing prophylactic norfloxacin. Our aim is to determine the characteristics of the infections caused by E. coli resistant to norfloxacin in hospitalized cirrhotic patients. One hundred and six infections caused by E. coli in 99 hospitalized cirrhotic patients were analyzed and distributed into two groups: group I (n = 67), infections caused by E. coli sensitive to norfloxacin, and group II (n = 39), infections caused by E. coli resistant to norfloxacin. The clinical and analytical characteristics at diagnosis of the infection were similar in both groups. Previous prophylaxis with norfloxacin was more frequent in group II (15/67, 22.4% vs. 32/39, 82%, P <.0001), as a result of a higher number of patients submitted to continuous long-term prophylaxis in this group, whereas previous short-term prophylaxis was similar in both groups. Infections were more frequently nosocomial-acquired in group II than in group I (17/67, 25.3% vs. 20/39, 51.2%, P =.01). The type of infections was similar in both groups: urinary tract infections 38 in group I and 24 in group II, spontaneous bacterial peritonitis 8 and 2, spontaneous bacteremia 4 and 4, and bacterascites 1 and 0, respectively (pNS). Mortality during hospitalization was similar in the two groups (4/67, 5.9% vs. 5/39, 12.8%, pNS). None of the E. coli resistant to norfloxacin were also resistant to cefotaxime and only one of them was resistant to amoxicillin-clavulanic acid. Prophylaxis with norfloxacin, usually continuous long-term prophylaxis, favors the development of infections caused by norfloxacin-resistant E. coli. Long-term antibiotic prophylaxis should therefore be restricted to highly selected groups of cirrhotic patients at high-risk of infection. Infections caused by E. coli resistant to norfloxacin show a severity similar to those caused by sensitive E. coli. No significant associated resistance between norfloxacin and the antibiotics most frequently used in the treatment of bacterial infections in cirrhotic patients has been observed.

Imaging of giant pituitary adenomas.

We present five proven giant pituitary adenomas studied by CT and MRI, and review the clinical and imaging findings. Our aim was to examine the radiologic appearances and to search for criteria useful in distinguishing these tumors from other sellar and suprasellar tumours, mainly craniopharyngioma. The main differences from small adenomas were high prevalence of macrocysts, a more invasive behaviour and a clinical picture dominated by mass effect rather than endocrine disturbance. Factors supporting the diagnosis of pituitary adenoma in a giant intra- and suprasellar mass include: infrasellar extension, absence of calcification and presence of low-signal cysts on T1-weighted images.

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.

Continuous versus inpatient prophylaxis of the first episode of spontaneous bacterial peritonitis with norfloxacin.

Cirrhotic patients with ascites and low ascitic fluid total protein and/or high serum bilirubin levels are at high risk to develop the first episode of spontaneous bacterial peritonitis during long-term follow-up. The aim of the present study was to determine the efficacy of continuous long-term selective intestinal decontamination with norfloxacin in the prevention of this complication. One hundred nine cirrhotic patients with ascites and ascitic fluid total protein levels of < or = 1 g/dL or serum bilirubin levels of > 2.5 mg/dL without previous spontaneous bacterial peritonitis were prospectively randomized into two groups: group 1 (n = 56) received norfloxacin, 400 mg daily administered orally, and group 2 (n = 53) was the long-term control group, receiving norfloxacin only during hospitalization. During a mean follow-up of 43 +/- 3 weeks, there was one spontaneous bacterial peritonitis (1.8%) in group 1 and 9 (16.9%) in group 2 (P < .01). The incidence of community-acquired spontaneous bacterial peritonitis was lower in group 1 (1.8% vs. 13.2%, P < .05), whereas the incidence of nosocomial spontaneous bacterial peritonitis (0% vs. 3.7%) and the incidence of extraperitoneal infections (25% vs. 24.5%) were similar in both groups (P = NS). The actuarial probability of survival at 18 months was 75% in group 1 and 62% in group 2 (P = NS). Resistance to norfloxacin was observed in 9 of 10 (90%) Escherichia coli isolated in infections from group 1 and in 4 of 11 (36.3%) from group 2 (P < .05). The overall incidence of infections caused by norfloxacin-resistant bacteria was higher in group 1 (19.6% vs. 15%), but it did not reach statistical significance. Continuous long-term selective intestinal decontamination with norfloxacin is effective in preventing the first spontaneous bacterial peritonitis in cirrhotic patients at high risk. However, the emergence of infections caused by norfloxacin-resistant bacteria must be weighed carefully against the benefits of continuous long-term prophylaxis.

Spontaneous bacterial peritonitis in cirrhotic patients treated using paracentesis or diuretics: results of a randomized study.

Diuretic treatment in cirrhotic patients with ascites increases ascitic fluid concentration of total protein and complement components, and opsonic activity. These changes are not observed in patients treated with paracentesis. Based on these data it has been suggested that therapeutic paracentesis may be associated with an increased risk of spontaneous bacterial peritonitis (SBP) development. To assess this possibility, 80 cirrhotic patients with tense ascites were randomly allocated in two therapeutic groups: group 1 (40 patients) was treated with total paracentesis associated with plasma volume expansion and group 2 was treated with diuretics. After mobilization of ascites, patients from both groups received diuretics to avoid reaccumulation of ascites; cases that developed tense ascites during follow-up (mean follow-up period, 60 +/- 6 and 55 +/- 4 weeks, respectively) were treated according to initial randomization. Patients from both groups had similar results regarding baseline clinical and standard laboratory data, ascitic fluid concentration of total protein, complement components, and opsonic activity. Sixteen patients (7 from group 1 and 9 from group 2) developed SBP during the study period. The 4-week and 1-year probability of SBP occurrence were 2.5% and 18.6%, respectively, in group 1 patients, and 11.9% and 24%, respectively, in group 2 patients. Therefore, our study indicates that therapeutic paracentesis does not increase the early- and long-term risk of SBP development in cirrhotic patients with tense ascites.