Tumour necrosis factor alpha upregulates platelet CD40L in patients with heart failure

AIMS: Patients with heart failure (HF) have elevated values of the pro-inflammatory protein CD40L but the underlying mechanism is unclear. This study was performed to evaluate the interplay between tumour necrosis factor alpha (TNFalpha) and CD40L in HF. METHODS AND RESULTS: In patients with HF (n=86) and healthy subjects (HS, n=43), plasma levels of soluble CD40L (sCD40L), TNFalpha, soluble receptors of TNFalpha such as soluble TNF receptors I and II (sTNFR1 and sTNFR2), and 8OH-dG, a marker of oxidative stress, were determined. Also, an in vitro study was performed by determining platelet CD40L regulation upon platelet stimulation with TNFalpha. Compared with HS, HF patients had higher plasma values of sCD40L, TNFalpha, sTNFR1 and sTNFR2, and higher platelet expression of TNFR1 and TNFR2 with a progressive increase from NYHA I to NYHA IV classification. sCD40L significantly correlated with TNFalpha, sTNFR1, and sTNFR2; plasma levels of TNFalpha significantly correlated with sCD40L. Incubation of platelets from HF patients with a TNFalpha receptor inhibitor significantly decreased platelet CD40L expression. The in vitro study demonstrated that TNFalpha significantly increased CD40L expression, an effect weakly influenced by aspirin but significantly reduced by AACOCF3, an inhibitor of PLA(2), apocynin, an inhibitor of NADPH oxidase, or staurosporine, an inhibitor of PKC. CONCLUSION: The study shows that in HF patients, platelet CD40L is upregulated by TNFalpha via a cyclooxygenase-1-independent, arachidonic acid-mediated oxidative stress mechanism.     

Topical Nifedipine With Lidocaine Ointment <Emphasis Type="Italic">vs.</Emphasis> Active Control for Treatment of Chronic Anal Fissure

PURPOSE: Chronic anal fissure may be treated by chemical or surgical sphincterotomy. The aim of this study was to test the efficacy of local application of nifedipine and lidocaine ointment in healing chronic anal fissure. METHODS: The study was performed according to a prospective, randomized, double-blind design. One hundred ten patients who gave informed consent were recruited. They received a clinical examination, a questionnaire to evaluate symptoms and pain, anorectal manometry, and anoscopy. Healing of anal fissure at Day 42 of therapy was defined as the primary efficacy variable of the study. Patients treated with nifedipine (n = 55) used topical 0.3 percent nifedipine and 1.5 percent lidocaine ointment every 12 hours for 6 weeks. The control group (n = 55) received topical 1.5 percent lidocaine and 1 percent hydrocortisone acetate ointment during therapy. Anal pressures were measured by recording resting and maximal voluntary contraction pressures at baseline and at Day 21. Long-term outcomes were determined after a median follow-up of 18 months. RESULTS: Healing of chronic anal fissure was achieved after 6 weeks of therapy in 94.5 percent of the nifedipine-treated patients (P < 0.001) as opposed to 16.4 percent of the controls. Mean anal resting pressure decreased from a mean value +/- standard deviation of 47.2 +/- 14.6 to 42 +/- 12.4 mmHg in the nifedipine group. This represents a mean reduction of 11 percent (P = 0.002). Changes of maximal voluntary contraction in nifedipine-treated patients were not significant. No changes in mean anal resting pressure and maximal voluntary contraction were observed in the control group. We did not observe any systemic side effect in patients treated with nifedipine. After the blinding was removed, recurrence of the fissure was observed in 3 of 52 patients in the nifedipine group within 1 year of treatment, and 2 of these patients healed with an additional course of topical nifedipine and lidocaine ointment. CONCLUSIONS: Our study clearly demonstrates that the therapeutic use of topical nifedipine and lidocaine ointment should be extended to the conservative treatment of chronic anal fissure.     

MARS (Molecular Adsorbent Recirculating System): experience in 34 cases of acute liver failure

As reported in the literature, the mortality rates for patients with Acute Hepatic Failure (AHF) approaches 80% in cases in which liver transplantation is not possible. Post-transplant mortality mostly depends on the severity of the neurological condition at the time of the operation (20% in I-II degree coma patients and 44% in III degree coma patients). The primary indications for liver transplantation in AHF are Fulminant Hepatitis (FH)(93%), Subfulminant Hepatitis (5%) and other indications (2%). Other causes of AHF are Primary Non-Function (PNF) and Delayed Function (DF), which occur in 7-10%. Therefore it becomes necessary to monitor the patients with a Liver Support Device to be able to improve the clinical condition of the patients before liver transplantation (LT). In our experience we used the Molecular Adsorbent Recirculating System (MARS) (MARS Monitor; Teraklin AG, Rostock Germany), which enables the selective removal of albumin-bound substances accumulating in liver failure by the use of albumin-enriched dialysate. The system is used as a bridging device to orthotopic liver transplantation (OLT) of patients with FHF. We studied 34 patients, including 16 males and 18 females: 9 were affected by Primary-Non-Function (PNF), nine by Fulminant Hepatitis (FH), six by Delayed-Non-Function (DNF), and ten by Acute on Chronic Hepatic Failure (AOCHF). The average age of the patients was 41.8 years and the average number of applications was 6.4; the median length of application was about eight hours. The parameters that we monitored, before and after each treatment, were neurological status (EEG, cerebral CT, Glasgow Coma Score), haemodynamic parameters, acid base equilibrium, and blood gas analysis. We also monitored hepatic and renal function. In addition, the clinical conditions of the patients were monitored using kidney and liver ultrasound/ultrasonography (US). Inclusion criteria were bilirubin > 15 mg/dL, ammonia > 160 micro g/dL and a Glasgow Coma Score between 6 and 11. The reduction of bilirubin and ammonia were very significant (P < 0.01), whereas the changes of International Normalized Ratio (INR) were not significant. Also the modifications of albumin, total protein, sodium, potassium and calcium were not significant. In conclusion, four out of nine patients with PNF are alive without a second transplantation and were discharged after about 48 days; four out of nine underwent OLT, while one out of nine died; five out of six patients with DF are alive without a second transplantation, and they were discharged after an average time of 55.5 days, one out of six died; six out of nine patients with fulminant hepatitis underwent OLT and four of these are alive, while two died due to sepsis; three patients are alive without OLT. Four patients with AOCHF underwent OLT and are alive, three patients are alive and on a waiting list, two died while on a waiting list and one patient who experienced reactivation of HBV infection during chemotherapy for non-Hodgkin's lymphoma is alive. In spite of the limited number of cases of our study, we believe that MARS can be applied with high tolerance for a very long period of time. In addition, its repeatability allows it to be used in patients with DNF and FH as a bridge to transplant. In patients with DNF, it is used while waiting for complete recovery of the transplanted organ.     

The Italian experience on paediatric liver transplantation: 1988-1999 report.

BACKGROUND: Liver transplantation is the treatment of choice for end-stage liver disease in both adult and paediatric patients. The Italian experience in paediatric liver transplantation during the period 1988-1999 is reported herein. PATIENTS AND METHODS: This report concerns 228 liver transplantations performed in 207 patients (100 male, 107 female, mean age 5.1+/-4.4 years) in 11 Italian centres. The mean waiting time on the transplantation list was 6.1+/-8.9 months and the main indications for the procedure were biliary atresia, inborn metabolic disorders, liver cirrhosis, liver neoplasms, Alagille syndrome, and fulminant hepatic failure. RESULTS: The cumulative survival rate was 77%, 76%, 73%, and 71% at 1, 3, 5, and 7 years. The overall prevalence of acute rejection was 54%. Survival was significantly affected by re-transplantation (p=0.0002), by United Network for Organ Sharing 4 status at transplantation (p=0.016), and, among the indications for the procedure, by fulminant hepatic failure (p=0.004). Fifty patients (24%) died during the observation period. The main causes of death were primary non-function of the graft and sepsis CONCLUSIONS: This study shows that liver transplantation in paediatric age, in Italy, is an effective procedure providing a 5-year survival rate comparable to that attained in the largest published series.     

Assessment of EtQxBox complexation in solution by steady-state and time-resolved fluorescence spectroscopy

Reliable chemical sensors with high selectivity and sensitivity toward specific target molecules require rational synthesis of receptors, in-depth characterization of their complexation abilities and highly efficient transduction of the molecular recognition event. Here we report a steady-state and time-resolved fluorescence investigation of EtQxBox, a fluorescent conformationally blocked quinoxaline-based cavitand, aimed at assessing its selectivity toward aromatic versus non-aromatic analytes in solution. Fluorescence quenching of the EtQxBox in acetone is observed at increasing concentration of both aromatic (i.e. benzonitrile) and aliphatic (i.e. acetonitrile) compounds. The combination with fluorescence lifetime measurements permits to discriminate the predominantly static quenching of the aromatic analyte, due to non-fluorescent host–guest complex formation, from the mostly dynamic quenching of the non-aromatic compound, resulting from aspecific diffusive collisions between the fluorophore and the quencher. The equilibrium association constants for both the complexes have been estimated using Stern–Volmer model.

We investigate the role of combined static and dynamic quenching in fluorescence transduction of benzonitrile and acetonitrile complexation by a rigid quinoxaline-based cavitand.     

Factors affecting long-term changes of liver stiffness in direct-acting anti-hepatitis C virus therapy: A multicentre prospective study

The long-term changes of liver stiffness (LS) in patients who achieve viral clearance after direct-acting anti-HCV therapy remain undefined. We conducted a multicentre prospective study to investigate this aspect. Patients with HCV infection treated with DAAs were enrolled from six Italian centres; they underwent clinical, biochemical, ultrasound and transient elastography evaluations before treatment (T0), 12 weeks (SVR12) and 24 months (T24) after the end of therapy. Among the 516 consecutive patients enrolled, 301 had cirrhosis. LS significantly decreased from T0 to SVR (14.3 vs 11.1 kPa, p = .002), with a progressive reduction until T24 (8.7 kPa, p < .001). However, only patients with steatosis and those who developed HCC did not experience a late improvement in LS. Multivariate analysis of baseline and follow-up variables identified steatosis as the only independent predictor of failure of LS improvement (OR 1.802, p = .013). ROC curve analysis of the association of LS with the risk of developing HCC showed that SVR12 ≥14.0 kPa had the highest accuracy (sensitivity 82%, specificity 99%; AUC: 0.774). Multivariate analysis revealed that LS was the only variable independently associated with an increased risk of developing HCC (OR 6.470, p = .035). Achieving an SVR was associated with a progressive, long-term decline of LS, suggesting a late improvement in liver fibrosis, besides the resolution of inflammation. Fatty liver and the development of HCC interfered with late reduction of LS. Patients with an LS ≥14 kPa at 12 weeks after the end of treatment were at higher risk for developing HCC.     

Atrial fibrillation ablation: is common practice far from guidelines’ world? The Italian experience from a national survey

Journal of Interventional Cardiac Electrophysiology - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, occurring in 1–2% of the general population. Catheter ablation...