Very Low Alcohol Consumption Is Associated with Lower Prevalence of Cirrhosis and Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease

The role of moderate alcohol consumption in the evolution of NAFLD is still debated. The aim of this study is to evaluate the impact of current and lifelong alcohol consumption in patients with NAFLD. From 2015 to 2020, we enrolled 276 consecutive patients fulfilling criteria of NAFLD (alcohol consumption up to 140 g/week for women and 210 g/week for men). According to their current alcohol intake per week, patients were divided in: abstainers, very low consumers (C1: <70 g/week) and moderate consumers (C2). We created a new tool, called LACU (Lifetime Alcohol Consuming Unit) to estimate the alcohol exposure across lifetime: 1 LACU was defined as 7 alcohol units per week for 1 drinking year. Patients were divided into lifelong abstainers and consumers and the latter furtherly divided into quartiles: Q1-Q4. Stratification according to alcohol intake, both current and cumulative as estimated by LACU, showed that very low consumers (C1 and Q1-Q3) displayed lower frequency of cirrhosis and hepatocellular carcinoma compared to abstainers and moderate consumers (C2 and Q4). We can speculate that up to one glass of wine daily in the context of a Mediterranean diet may be a long-term useful approach in selected NAFLD patients.     

Validation of the Italian Version of the SARC-F Questionnaire to Assess Sarcopenia in Older Adults

Background: SARC-F is a simple sarcopenia screening tool. This study aimed to examine the validity of the Italian version of SARC-F. Methods: A total of 97 elderly individuals (37/60 males/females, 65 years and older) who met the study’s selection criteria were included. SARC-F was translated into the Italian language in a culturally responsive manner. The total score was calculated by adding the scores on the five items. The participants were divided into two groups according to the total score (SARC-F < 4 vs. SARC-F ≥ 4), and their associations with various factors (handgrip test, chair stand test, and Skeletal Muscle Index assessed by DXA) have been examined by gender. In addition, the tool’s validity was analyzed by comparing it with different international working group diagnostic criteria for sarcopenia. Results: The total prevalence of sarcopenia according to the SARC-F was 14.2% and, specifically, 12.8% among men and 14.3% in women. The sensitivity of the SARC-F was (male (M): 11–50% and female (F): 22–36%) medium-low compared with the European, international, and Asian criteria of sarcopenia; however, SARC-F showed a high specificity (M: 77.3–100% and F: 79.5–100%) and a moderate Cronbach’s alpha coefficient of (0.669 (CI95%: 0.358–0.830). The participants in the SARC-F ≥ 4 group had poorer handgrip for EWGSOP2 (p < 0.001) and chair stand (p < 0.001) than the participants in the SARC-F < 4 group. Conclusions: The Italian language version of SARC-F showed high specificity, moderate reliability, and good associations with other predictive tests. The Italian version of SARC-F appears to be a useful screening tool for the diagnosis of sarcopenia in Italian elderly populations.     

HOXD8 hypermethylation as a fully sensitive and specific biomarker for biliary tract cancer detectable in tissue and bile samples

Background Biliary tract cancers (BTC) are rare but highly aggressive tumours with poor prognosis, usually detected at advanced stages. Herein, we aimed at identifying BTC-specific DNA methylation alterations.Methods Study design included statistical power and sample size estimation. A genome-wide methylation study of an explorative cohort (50 BTC and ten matched non-tumoral tissue samples) has been performed. BTC-specific altered CpG islands were validated in over 180 samples (174 BTCs and 13 non-tumoral controls). The final biomarkers, selected by a machine-learning approach, were validated in independent tissue (18 BTCs, 14 matched non-tumoral samples) and bile (24 BTCs, five non-tumoral samples) replication series, using droplet digital PCR.Results We identified and successfully validated BTC-specific DNA methylation alterations in over 200 BTC samples. The two-biomarker panel, selected by an in-house algorithm, showed an AUC > 0.97. The best-performing biomarker (chr2:176993479-176995557), associated with HOXD8, a pivotal gene in cancer-related pathways, achieved 100% sensitivity and specificity in a new series of tissue and bile samples.Conclusions We identified a novel fully efficient BTC biomarker, associated with HOXD8 gene, detectable both in tissue and bile by a standardised assay ready-to-use in clinical trials also including samples from non-invasive matrices.Subject terms: Diagnostic markers, Biliary tract cancer     

Analysis of survival after pancreatic resection for oncological pathologies

Surgical treatment of pancreatic cancer is to date the only modality that offers a chance of long-term survival. Potentially curative surgery is an option for only about 15% of patients with pancreatic adenocarcinoma. The aim of this study was to determine the survival and to assess the association of clinical, pathological, and treatment features with survival of patients who underwent resection of pancreatic cancer at the Department of Surgery of Udine University Hospital. From November 1989 to December 2005, 137 consecutive patients, who underwent surgical procedures for pancreatic cancer, were followed in our department. We performed 76 pancreatico-duodenectomy, 26 distal pancreatectomies and 35 total pancreatectomies. The surgical reconstruction after pancreatico-duodenectomy was as follows: 11 closures of the main duct with manual nonabsorbable stitches, 24 closures of the main duct with a linear stapler, 17 occlusions of the main duct with neoprene glue and 24 duct-to-mucosa anastomoses. Mean survival time was 27.7 +/- 26.93 months (mean +/- SD) and mean disease-free survival time was 25.4 +/- 23.06 months (mean +/- SD). 1, 3, 5, 7 and 9-year survival rates were 63.9, 33.7, 21.17, 12.7 and 10.2%, respectively. Significant differences in survival were recorded by the Log-rank test for age > 70 (p = 0.001), surgical procedures (p = 0.00046) and presence of metastases (p = 0.0055) The treatment of pancreatic cancer is undertaken with two different aims. The first is radical surgery for patients with early-stage disease, mainly stage I and partly stage II. In all other cases, the aim of treatment is the palliation of the several distressing symptoms related to this cancer. The standard treatment option for resectable tumours is radical pancreatic resection according to the Whipple procedure or total pancreatectomy.     

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.     

Perfusion CT compared to H<Subscript>2</Subscript><Superscript>15</Superscript>O/O<Superscript>15</Superscript>O PET in patients with chronic cervical carotid artery occlusion

INTRODUCTION: The purpose of this study was to compare the results of perfusion computed tomography (PCT) with those of (15)O(2)/H(2) (15)O positron emission tomography (PET) in a subset of Carotid Occlusion Surgery Study (COSS) patients. MATERIALS AND METHODS: Six patients enrolled in the COSS underwent a standard-of-care PCT in addition to the (15)O(2)/H(2) (15)O PET study used for selection for extracranial-intracranial bypass surgery. PCT and PET studies were coregistered and then processed separately by different radiologists. Relative measurement of cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were calculated from PET. PCT datasets were processed using different arterial input functions (AIF). Relative PCT and PET CBF values from matching regions of interest were compared using linear regression model to determine the most appropriate arterial input function for PCT. Also, PCT measurements using the most accurate AIF were evaluated for linear regression with respect to relative PET OEF values. RESULTS: The most accurate PCT relative CBF maps with respect to the gold standard PET CBF were obtained when CBF values for each arterial territory are calculated using a dedicated AIF for each territory (R (2) = 0.796, p < 0.001). PCT mean transit time (MTT) is the parameter that showed the best correlation with the count-based PET OEF ratios (R (2) = 0.590, p < 0.001). CONCLUSION: PCT relative CBF compares favorably to PET relative CBF in patients with chronic carotid occlusion when processed using a dedicated AIF for each territory. The PCT MTT parameter correlated best with PET relative OEF.     

Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans

To investigate a possible antinociceptive role of serotonin receptor subtype 3 (5-HT(3)), we evaluated the effects of a coadministration of ondansetron, a 5-HT(3) selective antagonist, and tramadol, a central analgesic dependent on enhanced serotonergic transmission. Fifty-nine patients undergoing ear, throat, and nose surgery, using tramadol for 24-h postoperative patient-controlled analgesia (bolus = 30 mg; lockout interval = 10 min) were randomly allocated either to a group receiving ondansetron continuous infusion (1 mg. mL(-1). h(-1)) for postoperative nausea and vomiting (Group O) or to a control group receiving saline (Group T). Pain and vomiting scores and tramadol consumption were evaluated at 4, 8, 12, and 24 h. Pain scores were never >4, according to a 0-10 numerical rating scale, in both groups. Group O required significantly larger doses of tramadol at 4 h (213 versus 71 mg, P < 0.001), 8 h (285 versus 128 mg, P < 0.002), and 12 h (406 versus 190 mg, P < 0.002). Vomiting scores were higher in Group O at 4 h (P < 0.05) and 8 h (P = 0.05). We conclude that ondansetron reduced the overall analgesic effect of tramadol, probably blocking spinal 5-HT(3) receptors. IMPLICATIONS: Serotonin is an important neurotransmitter of the descending pathways that down-modulate spinal nociception. In postoperative pain, ondansetron, a selective 5-HT(3) receptor antagonist, increased the analgesic dose of tramadol. We suggest that, when antagonized for antiemetic purpose, 5-HT(3) receptors foster nociception, because of their site-dependent action.