Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis

Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver's metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (ABCB11); 2. the multidrug resistance protein-2 (MRP2, ABCC2) regulating the bile salts' independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ABCB1) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ABCB4). Two of the most known proteins involved in bile acids' (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs' secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the ABCB4 gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs

Low Adherence To Nutritional Recommendations In Patients With Cirrhosis: A Prospective Observational Study

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Imbalance of Neutrophils and Lymphocyte Counts Can Be Predictive of Hepatocellular Carcinoma Occurrence in Hepatitis C-related Cirrhosis Treated With Direct-acting Antivirals

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The Impact of Lifestyle Interventions in High-Risk Early Breast Cancer Patients: A Modeling Approach from a Single Institution Experience

none21noA healthy lifestyle plays a strategic role in the prevention of BC. The aim of our prospective study is to evaluate the effects of a lifestyle interventions program based on special exercise and nutrition education on weight, psycho-physical well-being, blood lipid and hormonal profile among BC patients who underwent primary surgery. From January 2014 to March 2017, a multidisciplinary group of oncologists, dieticians, physiatrists and an exercise specialist evaluated 98 adult BC female patients at baseline and at different time points. The patients had at least one of the following risk factors: BMI ≥ 25 Kg/m2, high testosterone levels, high serum insulin levels or diagnosis of MS. Statistically significant differences are shown in terms of BMI variation with the lifestyle interventions program, as well as in waist circumference and blood glucose, insulin and testosterone levels. Moreover, a statistically significant difference was reported in variations of total Hospital Anxiety and Depression Scale (HADS) score, in the anxiety HADS score and improvement in joint pain. Our results suggested that promoting a healthy lifestyle in clinical practice reduces risk factors involved in BC recurrence and ensures psycho-physical well-being.openMirco Pistelli, Valentina Natalucci, Laura Scortichini, Veronica Agostinelli, Edoardo Lenci, Sonia Crocetti, Filippo Merloni, Lucia Bastianelli, Marina Taus, Daniele Fumelli, Gloria Giulietti, Claudia Cola, Marianna Capecci, Roberta Serrani, Maria Gabriella Ceravolo, Maurizio Ricci, Albano Nicolai, Elena Barbieri, Giulia Nicolai, Zelmira Ballatore, Agnese Savini and Rossana BerardiPistelli, Mirco; Natalucci, Valentina; Scortichini, Laura; Agostinelli, Veronica; Lenci, Edoardo; Crocetti, Sonia; Merloni, Filippo; Bastianelli, Lucia; Taus, Marina; Fumelli, Daniele; Giulietti, Gloria; Cola, Claudia; Capecci, Marianna; Serrani, Roberta; Gabriella Ceravolo, Maria; Ricci, Maurizio; Nicolai, Albano; Barbieri, Elena; Nicolai, Giulia; Ballatore, Zelmira; Savini and Rossana Berardi, Agnes

Relationship of EMAST and Microsatellite Instability Among Patients with Rectal Cancer

Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in 60% of sporadic colon cancers and may be linked with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI-H) in which hypermethylation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and subsequent relaxation of MMR function with the biological consequences not known. We evaluated the prevalence of EMAST and MSI in a population-based cohort of rectal cancers, as EMAST has not been previously determined in rectal cancers. We analyzed 147 sporadic cases of rectal cancer using five tetranucleotide microsatellite markers and National-Cancer-Institute-recommended MSI (mononucleotide and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the polymerase chain reaction products and determined positive if at least two loci were found to have frame-shifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage and examined the samples for lymphocyte infiltration. Among this cohort of patients with rectal cancer (mean age 62.2 ± 10.3 years, 36% female, 24% African American), 3/147 (2%) showed MSI (three males, two African American) and 49/147 (33%) demonstrated EMAST. Rectal tumors from African Americans were more likely to show EMAST than Caucasians (18/37, 49% vs. 27/104, 26%, p = 0.014) and were associated with advanced stage (18/29, 62% EMAST vs. 18/53, 37%, non-EMAST p = 0.02). There was no association between EMAST and gender. EMAST was more prevalent in rectal tumors that showed peri-tumoral infiltration compared to those without (30/49, 60% EMAST vs. 24/98, 25% non-EMAST, p = 0.0001). EMAST in rectal cancer is common and MSI is rare. EMAST is associated with African-American race and may be more commonly seen with metastatic disease. The etiology and consequences of EMAST are under investigation, but its association with immune cell infiltration suggests that inflammation may play a role for its development

Single Cycle Structure-Based Humanization of an Anti-Nerve Growth Factor Therapeutic Antibody

Most forms of chronic pain are inadequately treated by present therapeutic options. Compelling evidence has accumulated, demonstrating that Nerve Growth Factor (NGF) is a key modulator of inflammatory and nociceptive responses, and is a promising target for the treatment of human pathologies linked to chronic and inflammatory pain. There is therefore a growing interest in the development of therapeutic molecules antagonising the NGF pathway and its nociceptor sensitization actions, among which function-blocking anti-NGF antibodies are particularly relevant candidates

Liver transplantation for transthyretin amyloidosis: experience of a single center in Italy

Liver transplantation is the only definitive treatment for transthyretin amyloidosis, with an excellent 5-year survival in endemic countries where the Met30 mutation is predominant. We report our experience of liver transplantation for transthyretin amyloidosis. We reviewed the clinical records of 17 transplanted patients (11 males, 6 females; age at liver transplant: 45.7±11.7 years). We had a wide spectrum of non-Met30 mutations (52.9%), with a predominance of Gln89 (23.5%). Five-year survival after transplantation was 43.8%; at multivariate analysis, both non-Met30 mutations (HR 17.3, 95% CI 1.03-291.7) and modified BMI (HR 0.50, 95% CI 0.29-0.87) showed significant and independent prognostic roles (P=0.048 and P=0.015, respectively). Five out of the 9 non-Met30 carriers received combined heart transplantation because of severe cardiomyopathy; they showed a trend towards a better prognosis vs. the 4 patients who did not receive combined heart transplantation (although not statistically significant; P=0.095). At follow-up, no significant improvement of transthyretin amyloidosis manifestations was observed. The results of liver transplantation for transthyretin amyloidosis in our population are poorer than those reported in the literature probably because of the high prevalence of non-Met30 mutations

Investigation on the Effects of a Pulsed Electric Field (PEF) Continuous System Implemented in an Industrial Olive Oil Plant

The aim of this study was to investigate how the treatment of olive paste of the Picholine variety with pulsed electric fields (PEF) under real operating conditions in a large-scale olive oil extraction plant affects the extractability, chemical composition and sensory profile of the oils. The application of pulsed electric fields (PEF) as a non-thermal food processing technology is interesting for many food extraction processes. The results of this study show that pulsed electric fields can be used as a pretreatment before oil separation to increase the extractability of the process and improve the content of functional components. The application of pulsed electric field (PEF) treatment (2.4 kV/cm, 4 kJ/kg, 6 µs pulse width) to olive paste through a continuous system significantly increased the extractability and total concentration of phenols (especially oleuropein derivatives) compared to the control. In addition, the volatile compounds, α-tocopherol, the fatty acid profile and the main legal quality parameters of extra virgin olive oil (EVOO), including free acidity, peroxide values, extinction indices and sensory analysis, were evaluated. The pulsed electric fields (PEF) treatment did not modify these EVOO quality parameters, neither the α-tocopherol content nor the volatile profile. The sensory properties of EVOO were not affected as well as the PEF treatment showed a similar intensity of fruity and pungent attributes without any off-flavor according to the European Union legal standards. An increase in the bitter taste attribute was observed in the PEF oils. Consequently, this study demonstrates that pulsed electric fields (PEF) processing could be implemented in olive oil processing as pretreatment for improving the efficiency of the process

A systematic review of the psychometric properties of Quebec user evaluation of satisfaction with assistive technology (QUEST)

Purpose The aim of this systematic review was to evaluate the psychometric properties of the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST). Materials and methods Searches were conducted in August 2021 on four electronic databases: MEDLINE, CINAHL, Scopus, and Web of Science. Eligible papers included cross-sectional validation studies evaluating the psychometric properties of all QUEST versions. Cronbach’s alpha, intraclass correlation coefficient, and comparison tools were reported. Study quality and risk of bias were assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. Results Nineteen studies were included in this systematic review. Results showed that the QUEST and QUEST 2.0 were available in 10 languages, and most validation studies analysed this tool in patients using mobility devices in various clinical conditions. One article analysed the child version (QUEST 2.1) in English. The most analysed psychometric property was Cronbach’s alpha for internal consistency in 14 out of 19 studies, with values ranging between 0.74 and 0.79. Overall, 17 out of 19 studies were of adequate quality, though responsiveness was never studied. Conclusion Our systematic review showed that the QUEST and its subsequent versions are reliable and valid measurement instruments to evaluate satisfaction in patients with different disabilities using various assistive technologies. This study provides useful information on the instrument’s psychometric properties in different populations and cultures. • IMPLICATION FOR REHABILITATION • This systematic review verify the appropriateness of the “Quebec User Evaluation of Satisfaction with Assistive Technology” (QUEST), as a measure of satisfaction; • This systematic review allow clinicians to keep up to date with new versions of the tool, new countries of validation and population in which it can be used. • This study supports clinicians in making informed decisions when choosing assessment tools

Liver Cirrhosis in a Patient with Sickle Cell Trait (Hb Sβ+ Thalassemia) without Other Known Causes of Hepatic Disease

Liver involvement in patients with sickle cell anemia/trait includes a wide range of alterations, from mild liver function test abnormalities to cirrhosis and acute liver failure. Approximately 15–30% of patients with sickle cell anemia present cirrhosis at autopsy. The pathogenesis of cirrhosis is usually related to chronic hepatitis B or C infection or to iron overload resulting from the many transfusions received by these patients in their lifetime. Thus, cirrhosis has been described almost exclusively in patients with sickle cell anemia, while only mild liver abnormalities have been associated with the sickle cell trait. In the present case study, we describe a young Mediterranean man carrying a sickle cell trait (Hb Sβ+ thalassemia) who developed liver cirrhosis being negative for hepatitis C and B viruses or for other causes of cirrhosis and not receiving chronic blood transfusions