Resveratrol protects against homocysteine-induced cell damage via cell stress response in neuroblastoma cells.

Recent findings underscore that some natural compounds are responsible for specific biochemical effects, i.e., the activation of redox-sensitive intracellular pathways and modulation of different stress proteins, such as heat shock proteins and sirtuins. Resveratrol, a natural polyphenol widely present in plants, has been shown to display various beneficial effects, including neuroprotection, in several pathological conditions. In the present study, by using differentiated SH-SY5Y neuroblastoma cells, we investigated the potential protective effects of resveratrol against homocysteine-induced neurotoxicity. We observed that homocysteine (100 µM) decreased cell viability while at the same time significantly increasing intracellular reactive oxygen species and DNA fragmentation. Cell pretreatment with resveratrol concentrations ranging from 1 to 5 µM elicited protective effects through the reduction of oxidative stress and genotoxic damage. In addition, we observed that resveratrol produced significant changes in the expression of both Hsp70 and sirtuin 1 (SIRT1). After homocysteine treatment in the presence of resveratrol, SIRT1 protein was found abundantly not only in the cytosol but also in the nucleus, as demonstrated by confocal laser scanning microscopy. The results of this study suggest that resveratrol is a potential protective agent against homocysteine-induced neurotoxicity and that beneficial effects are accompanied by changes in cell stress response. Taken together, these features contribute to our knowledge of underlying mechanisms involved in resveratrol-induced cell survival.

The Gastropack Access System as a Model to Access Gastroenterology Services for Gastroscopy Appropriateness in Patients with Upper Gastrointestinal Symptoms: A Comparison with the Open Access System.

Esophagogastroduodenoscopy (EGD) appropriateness in Open-Access System (OAS) is a relevant issue. The Gastropack Access System (GAS) is a new system to access gastroenterological services, based on the partnership between Gastroenterologists and GPs. This study aims to evaluate if GAS is superior to OAS in terms of EGDS appropriateness. Secondarily, we evaluated the diagnostic yield of EGDS according to ASGE guidelines. The GAS was developed in an area of Bologna where General Practitioners (GPs) could decide to directly prescribe EGDS through OAS or referring to GAS, where EGDS can be scheduled after contact between GPs and specialists sharing a patient's clinical information. Between 2016 and 2019, 2179 cases (M:F = 861:1318, median age 61, IQR 47.72) were referred to GAS and 1467 patients (65%) had a prescription for EGDS; conversely, 874 EGDS were prescribed through OAS (M:F = 383:491; median age 58 yrs, IQR 45.68). Indication was appropriate in 92% in GAS (1312/1424) versus 71% in OAS (618/874), p < 0.001. The rate of clinically significant endoscopic findings (CSEF) was significantly higher in GAS (49% vs. 34.8%, p < 0.001). Adherence to ASGE guidelines was not related to CSEF; however, surveillance for pre-malignant conditions was independently related to CSEF. All neoplasm were observed in appropriate EGD. GAS is an innovative method showing extremely high rates of appropriateness. ASGE guidelines confirmed their validity for cancer detection, but their performance for the detection of other conditions needs to be refined.

Transjugular intrahepatic portosystemic shunt placement for refractory ascites: a single-centre experience.

BACKGROUND: The presence of refractory ascites is a common indication for transjugular intrahepatic portosystemic shunt (TIPS). Different models have been proposed for the prediction of survival after TIPS. The aim of this study was to evaluate the predictive factors associated with patients' survival after TIPS placement for refractory ascites. METHODS: Data from all consecutive patients undergoing TIPS placement in our center for refractory ascites between February 2003 and January 2008 were prospectively recorded. RESULTS: Seventy-three patients (52M/21F; 57 ± 10 years) met the inclusion criteria; mean follow-up was 17 ± 2 months. Mean MELD value, before TIPS placement, was 15.7 ± 5.3. TIPS placement led to an effective resolution of refractory ascites in 54% of patients (n = 40) with no significant increase in severe portosystemic encephalopathy. The 1-year survival rate observed was 65.7%, while the overall mortality was 23.3% (n = 17) with a mean survival of 17 ± 14 months. MELD score (B = 0.161, p = 0.042), basal AST (B = 0.020, p = 0.090), and pre-TIPS HVPG (B = 0.016, p = 0.093) were independent predictors of overall mortality, while MELD (B = 0.419, p = 0.018) and HVPG (B = 0.223, p = 0.060) independently predicted 1-year survival. ROC curves identified MELD ≥ 19 and HVPG ≥ 25 mmHg as the best cut-off points for the prediction of 1-year mortality. CONCLUSIONS: TIPS is an effective treatment for refractory ascites in cirrhotic patients, leading to an effective ascites control in more than half patients. Improvement in patients' selection criteria could lead to better outcome and survival after this procedure. Liver function (MELD), presence of active necroinflammation (AST), and portal hypertension (HVPG) are independent predictors of patients' outcome after TIPS.

Proton pump inhibitors in cirrhosis: tradition or evidence based practice?

Proton pump inhibitors (PPI) are very effective in inhibiting acid secretion and are extensively used in many acid related diseases. They are also often used in patients with cirrhosis sometimes in the absence of a specific acid related disease, with the aim of preventing peptic complications in patients with variceal or hypertensive gastropathic bleeding receiving multidrug treatment. Contradicting reports support their use in cirrhosis and evidence of their efficacy in this condition is poor. Moreover there are convincing papers suggesting that acid secretion is reduced in patients with liver cirrhosis. With regard to Helicobacter pylori (H pylori) infection, its prevalence in patients with cirrhosis is largely variable among different studies, and it seems that H pylori eradication does not prevent gastro-duodenal ulcer formation and bleeding. With regard to the prevention and treatment of oesophageal complications after banding or sclerotherapy of oesophageal varices, there is little evidence for a protective role of PPI. Moreover, due to liver metabolism of PPI, the dose of most available PPIs should be reduced in cirrhotics. In conclusion, the use of this class of drugs seems more habit related than evidence-based eventually leading to an increase in health costs.

Systemic lupus erythematosus following virological response to peginterferon alfa-2b in a transplanted patient with chronic hepatitis C recurrence.

Autoimmune manifestations are common both in patients chronically infected by hepatitis C virus, and in patients transplanted for non-autoimmune diseases. A correlation between interferon based treatment and autoimmune diseases or the development of autoantibodies is well established in non-transplanted patients, but few data are available about transplanted patients. It is unclear whether interferon may increase the incidence of acute cellular rejection and there are few reports on the development of atypical autoimmune manifestations during post-liver transplantation interferon or pegylated interferon treatment. We describe a case of systemic lupus erythematosus following treatment with pegylated interferon alfa-2b in a transplanted patient with recurrence of chronic hepatitis C. Our experience suggest that pegylated interferon may induce autoimmune diseases in the immunosuppressed host, different from acute cellular rejection and call for a great attention to possible autoimmune disorders development during interferon based treatments in liver transplanted patients.

Appropriateness of Proton Pump Inhibitor (PPI) prescription in patients admitted to hospital: Attitudes of general practitioners and hospital physicians in Italy.

INTRODUCTION: Proton pump inhibitor (PPI) prescriptions have raised concern for both huge increase of health expenditure and possible long-term adverse effects. OBJECTIVE: To evaluate appropriateness of PPI prescription in ambulatory and hospital care. DESIGN: Observational cohort study. PATIENTS: Patients admitted to the Internal Medicine Unit of Bologna S. Orsola Hospital between 15/09/2013 and 15/12/2013. Data on clinical condition and drug therapy were collected at three time points: admission (reflecting GP's prescription), hospital stay and discharge. MAIN MEASURES: Appropriateness of PPI use was evaluated as follows: (1) agreement between PPI use/non-use and appropriate clinical condition; (2) in PPI users, assessment of Medication Appropriateness Index (MAI). Differences in appropriateness among time points were analyzed by chi-square test. Logistic regression model was used to identify possible determinants of PPI appropriateness. KEY RESULTS: Among 280 patients, 56% received PPI at least once in the three time points. Appropriateness, according to indication of use, was similar between admission and hospital stay (61% vs. 62%; p=0.82) and between hospital stay and discharge (62% vs. 59%; p=0.94). MAI score showed important, although statistically non-significant, change in appropriateness between admission and hospital stay (20% vs. 28%; p=0.16). Age≥65 was always associated with appropriate PPI use (up to OR=4.37; p<0.01), whereas cardiovascular comorbidity and conditions requiring analgesic treatment influenced appropriateness only at admission (OR=3.84; p<0.01 and OR=0.34; p<0.01, respectively). CONCLUSIONS: Hospital clinicians only rarely reconsidered GP's choice to prescribe PPI. Room for improvement in PPI appropriateness is represented by (1) assessing gastrointestinal risk in each patient under analgesics and anti-inflammatory drugs, and (2) short-term re-evaluation of PPI prescription after discharge.

Interferon plus ribavirin and interferon alone in preventing hepatocellular carcinoma: a prospective study on patients with HCV related cirrhosis.

AIM: To determine the role of interferon (IFN) with or without ribavirin in preventing or delaying hepatocellular carcinoma (HCC) development in patients with hepatitis C virus (HCV) related cirrhosis. Data on the preventive effect of IFN plus ribavirin treatment are lacking. METHODS: A total of 101 patients (62 males and 39 females, mean age 55.1+/-1.4 years) with histologically proven HCV related liver cirrhosis plus compatible biochemistry and ultrasonography were enrolled in the study. Biochemistry and ultrasonography were performed every 6 mo. Ultrasound guided liver biopsy was performed on all detected focal lesions. Follow-up lasted for 5 years. Cellular proliferation, evaluated by measuring Ag-NOR proteins in hepatocytes nuclei, was expressed as AgNOR-Proliferative index (AgNOR-PI) (cut-off = 2.5). Forty-one patients (27 males, 14 females) were only followed up after the end of an yearly treatment with IFN-alpha2b (old treatment control group = OTCG). Sixty naive patients were stratified according to sex and AgNOR-PI and then randomized in two groups: 30 were treated with IFN-alpha2b + ribavirin (treatment group = TG), the remaining were not treated (control group = CG). Nonresponders (NR) or relapsers in the TG received further IFN/ribavirin treatments after a 6 mo of withdrawal. RESULTS: AgNOR-PI was significantly lowered by IFN (P<0.001). HCC incidence was higher in patients with AgNOR-PI>2.5 (26% vs 3%, P<0.01). Two NR in the OTCG, none in the TG and 9 patients in the CG developed HCC during follow-up. The Kaplan-Mayer survival curves showed statistically significant differences both between OTCG and CG (P<0.004) and between TG and CG (P<0.003). CONCLUSION: IFN/ribavirin treatment associated with re-treatment courses of NR seems to produce the best results in terms of HCC prevention. AgNOR-PI is a useful marker of possible HCC development.

Osteoporosis and alzheimer pathology: Role of cellular stress response and hormetic redox signaling in aging and bone remodeling.

Alzheimer's disease (AD) and osteoporosis are multifactorial progressive degenerative disorders. Increasing evidence shows that osteoporosis and hip fracture are common complication observed in AD patients, although the mechanisms underlying this association remain poorly understood. Reactive oxygen species (ROS) are emerging as intracellular redox signaling molecules involved in the regulation of bone metabolism, including receptor activator of nuclear factor-κB ligand-dependent osteoclast differentiation, but they also have cytotoxic effects that include lipoperoxidation and oxidative damage to proteins and DNA. ROS generation, which is implicated in the regulation of cellular stress response mechanisms, is an integrated, highly regulated, process under control of redox sensitive genes coding for redox proteins called vitagenes. Vitagenes, encoding for proteins such as heat shock proteins (Hsps) Hsp32, Hsp70, the thioredoxin, and the sirtuin protein, represent a systems controlling a complex network of intracellular signaling pathways relevant to life span and involved in the preservation of cellular homeostasis under stress conditions. Consistently, nutritional anti-oxidants have demonstrated their neuroprotective potential through a hormetic-dependent activation of vitagenes. The biological relevance of dose-response affects those strategies pointing to the optimal dosing to patients in the treatment of numerous diseases. Thus, the heat shock response has become an important hormetic target for novel cytoprotective strategies focusing on the pharmacological development of compounds capable of modulating stress response mechanisms. Here we discuss possible signaling mechanisms involved in the activation of vitagenes which, relevant to bone remodeling and through enhancement of cellular stress resistance provide a rationale to limit the deleterious consequences associated to homeostasis disruption with consequent impact on the aging process.

Cellular stress response, redox status, and vitagenes in glaucoma: a systemic oxidant disorder linked to Alzheimer's disease.

Amyloid deposits, constituted of amyloid beta (Aß) aggregates, are a characteristic feature of several neurodegenerative diseases, such as Alzheimer's, mild cognitive impairment and Parkinson's disease. They also have been recently implicated in the pathogenesis of retinal damage, as well as age-related macular degeneration and glaucoma. Glaucoma is a progressive optic neuropathy characterized by gradual degeneration of neuronal tissue due to retinal ganglion cell loss, associated to visual field loss over time resulting in irreversible blindness. Accumulation of Aß characterizes glaucoma as a protein misfolding disease, suggesting a pathogenic role for oxidative stress in the pathogenesis of retinal degenerative damage associated to glaucoma. There is a growing body of evidence demonstrating a link between Alzheimer's disease and glaucoma. Further, several heat shock proteins (HSPs) members have been implicated both in neurodegenerative diseases and glaucomatous apoptosis. To maintain redox homeostasis vitagenes, as integrated mechanisms, operate actively to preserve cell survival under condition of stress. Vitagenes encode for sirtuin, thioredoxin and HSPs. The present study was designed to investigate cellular stress response mechanisms in the blood of patients with glaucoma, compared to control subjects. Levels of vitagenes HSP-72, heme oxygenase-1, as well as F2-isoprostanes were significantly higher in the blood of patients with glaucoma than in controls. Furthermore, in the same experimental group increased expression of Trx and sirtuin 1 were measured. Our results sustain the importance of redox homeostasis disruption in the pathogenesis of glaucoma and highlights the opportunity that new therapies that prevents neurodegeneration through non-immunomodulatory mechanisms might be synergistically associated with current glaucoma therapies, thus unraveling important targets for novel cytoprotective strategies.

Caffeine intake reduces sleep duration in adolescents.

In our study, we hypothesized that higher caffeine intake would be associated with lower sleep duration among 13-year-old adolescents. In addition, we aimed to identify food sources of caffeine intake in this sample. Eligible participants were adolescents who were born in 1990 and attended school in Porto, Portugal, in 2003/2004. Self-administered questionnaires were used, and diet was evaluated using a food frequency questionnaire. From the 2160 eligible participants, only 1522 with valid information regarding their diet were included in this study. In our sample, the median intake of caffeine was 23.1 mg/d, with soft drinks being the major source. Ice tea presented the highest median (25th-75th percentiles) contribution (33.1% [14.0-52.1]), followed by cola (21.1% [6.4-37.6]). Regarding cocoa products, chocolate bars presented a median contribution of 5.1% (1.0-14.0), and snacks containing chocolate had a contribution of 3.0% (0.5-7.2). Coffee and tea presented a negligible contribution. Adolescents who reported less sleep duration and those who spent more time watching TV during the weekend had a significantly higher caffeine intake. Overall, boys had higher intakes of caffeine from soft drinks, and private school attendees, those who had parents with more education, who reported less television viewing time and had lower body mass index presented higher intakes of caffeine from chocolate. Considering sleeping more than 9.5 hours as a reference class, for each increase of 10 mg/d in caffeine intake, we found that the odds ratio of sleeping 8.5 hours or less was 1.12 (95% confidence interval, 1.06-1.19). Our results support the hypothesis that caffeine intake was inversely associated with sleep duration in adolescents.

Adverse effects of proton pump inhibitors.

Proton pump inhibitors (PPI) are very effective drugs used largely in acid related disorders. During the last years concern have been raised regarding their overutilisation in benign condition, such as gastroesophageal reflux disease. The debate focussed also on the risk of adverse events related to long term use of PPI. Apart of the case of Helicobacter Pylori (H. Pylori) positive patients, in whose long term acid suppression lead to the development of corpus predominant atrophic gastritis, precursor of cancer; the other assumed adverse events, have never been demonstrated in prospective studies. The attention should move towards the appropriate prescription of PPI, rather than the fear adverse effects of PPI. In fact, in clinical practise, PPI are often prescribed in patients without a specific acid related disease and continued long term based on their safety profile. This review focus on the main adverse events related to long term PPI use.

G-CSF in Peg-IFN induced neutropenia in liver transplanted patients with HCV recurrence.

AIM: To evaluate the efficacy of granulocyte colony stimulating factors (G-CSF) in liver transplanted patients with hepatitis C (HCV) recurrence and Pegylated-IFN alpha-2b induced neutropenia, and to evaluate the impact of G-CSF administration on virological response. METHODS: Sixty-eight patients undergoing antiviral treatment for post-liver transplantation (OLT) HCV recurrence were enrolled. All patients developing neutropenia received G-CSF. RESULTS: Twenty three (34%) received G-CSF. Mean neutrophil count at the onset of neutropenia was 700/mmc (range 400-750/mmc); after 1 mo of G-CSF it increased to 1210/mmc (range 300-5590/mmc) (P < 0.0001). Three patients did not respond to G-CSF. Treatment duration was similar in neutropenic and non-neutropenic patients. No differences in the rate of discontinuation, infections or virological response were observed between the two groups. G-CSF was protective for the onset of de novo autoimmune hepatitis (P < 0.003). CONCLUSION: G-CSF administration is effective in the case of Peg-IFN induced neutropenia increasing neutrophil count, prolonging treatment and leading to sustained virological response (SVR) rates comparable to non-neutropenic patients. It prevents the occurrence of de novo autoimmune hepatitis.

Clinical efficacy and effectiveness of ursodeoxycholic acid in cholestatic liver diseases.

Ursodeoxycholic acid (UDCA), previously used for cholesterol gallstone dissolution, is currently considered the first choice therapy for many forms of cholestatic syndromes. Many mechanisms and sites of action have been proposed for UDCA, but definitive data are still missing regarding the key points of its efficacy and optimal dosage in order to achieve a sustained clinical effect. Among the suggested mechanisms of action of UDCA, changes in bile acid pool composition, hepatocyte membrane protection, immunomodulatory effects and bicarbonate-rich hypercholeresis have been extensively studied. However, recent evidence indicate that UDCA is a potent intracellular signalling agent that counterbalances impaired biliary secretion, inhibits hepatocyte apoptosis and protects injured cholangiocytes against toxic effects of bile acids. It is clear that the relative contribution of these mechanisms to the anticholestatic action of UDCA depends on the type and stage of the liver injury. Available clinical evidence suggest that UDCA treatment has to be initiated as early as possible and that higher doses could be more efficacious in inducing and maintaining clinical remission of cholestatic diseases. The future availability of UDCA derivatives will possibly enhance the chances to effectively treat chronic cholestatic diseases.

Hepatocellular carcinoma prevention: a worldwide emergence between the opulence of developed countries and the economic constraints of developing nations.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm, the major cause of death in patients with liver cirrhosis, and the third most common cause of cancer-related death in the world. The geographic distribution of HCC varies significantly and 80% of cases occur in developing countries (Far East and South Asia) where the prevalence of viral hepatitis is higher. The treatment of HCC is difficult because most patients are diagnosed when the tumour is in an advanced stage and is not amenable to potential curative therapy, thus prevention is the key to reducing HCC and its related morbidity and mortality. HCC is unique among cancers, occurring mostly in patients with a known risk factor. Ninety percent of HCCs develop in the context of chronic liver diseases and mainly in patients with cirrhosis. Viral hepatitis is the most common cause of HCC worldwide, followed by alcoholic liver disease (ALD) and other causes such as non-alcoholic fatty liver disease (NAFLD), genetic haemocromatosis (GH) and primary biliary cirrhosis in an advanced stage (III-V). In certain areas of the People's Republic of China, exposure to aflatoxin and HBV infection are thought to be responsible for the extraordinary high risk of HCC. Substantial progresses in the prevention of virusl-related hepatitis (screening of blood units, use of disposable sanitary tools, HBV vaccination) have been achieved in developed countries, but in the same areas, alcohol- and dysmetabolism-related HCCs are emerging problems which require specific interventions in terms of public health measures. In developing countries, economic constraints limit the development of any program for the prevention of viral hepatitis transmission (including health education campaigns, healthcare politics, primary prevention and the improvement of hygienic and sanitary conditions). When viral liver disease is established, only a minority of patients are treated worldwide and benefit a possible preventive effect of medical treatment on HCC development. Thus the real contribution of medical treatment to HCC prevention in patients with chronic viral hepatitis is small. Great efforts are needed to identify more effective medical measures for primary and secondary prevention of HCC.

Systemic fungemia and hepatic localizations of Fusarium solani in a liver transplanted patient: an emerging fungal agent.

The incidence of invasive fungal infection is increasing especially in the field of transplantation, affecting as many as 50% of bone marrow transplant (BMT) patients with neutropenia and 5-20% of solid-organ transplant (SOT) recipients. Fusarium species are soil saprophytes and plant pathogens. They may cause superficial mycoses or important opportunistic infections in patients with bone marrow suppression and neutropenia, they have been rarely described in solid organ recipients, and up to now there have been no reports of such infection in isolated liver transplanted patients. We describe a case of disseminated Fusarium solani infection with hepatic localization in a liver transplanted patient that resolved with the administration of amphotericin B. Our observation confirms that Fusarium spp. are emerging pathogens that may most frequently affect not only BMT patients and patients with hematological malignancies, but also SOT patients. They may cause both localized and disseminated infection. In conclusion, Fusarium spp. etiology should be considered in the context of infectious diseases following liver transplantation.